Introduction

Botulinum toxin has been employed for clinical cosmetic use for over twenty years. Currently it is the most commonly performed non-surgical facial cosmetic procedure and is also widely used for non-cosmetic purposes. Botulinum toxin type A (BoNT-A) is produced from Clostridium botulinum and acts on presynaptic neurons to block acetylcholine release by cleavage of the SNAP-25 protein. There are three formulations of BoNT-A that are currently approved cosmetically by the Food and Drug Administration (FDA) for the treatment of moderate to severe glabellar rhytides: (Botox^® – Allergan, US), (Dysport^® – Medicis / Ipsen, Arizona, US and France), (Xeomin^® – Germany). Following cosmetic botulinum toxin A injections, the effects begin to be noticeable within 1 to 3 days and will typically last for 3 to 4 months.

Although these botulinum toxin A formulations are FDA approved only for treating glabellar rhytides, they are also commonly used cosmetically in other areas on the face and neck. The frontalis is a large forehead muscle responsible for the development of horizontal forehead lines (HFLs) due to contraction – which raises the eyebrows and upper eyelids, and over time results in these contraction lines etching into the forehead. The forehead is thus a major target area for botulinum toxin treatment owing to the vertical movement of the underlying frontalis muscle to lift the eyebrows during animation. The inferior frontalis fibers insert into periocular muscles including: the procerus, corrugator supercilii, orbicularis oculi, and depressor supercilii. Superiorly, the fibers course horizontally and insert into the galea of the scalp, often with no fibers in the midline between the hairline and the middle of the forehead.

Side effects

Potential side effects from botulinum toxin use in the forehead include injection site pain, swelling, and bruising, as well as headache, eyebrow ptosis, eyelid ptosis, diplopia, and the development of new rhytides. New rhytides may appear as a result of overcompensation of untreated adjacent muscles. A case series by Kang et al (2011) of four patients receiving BoNT-A for HFLs reported the development of lower frontalis and glabellar protrusions as well as new unilateral forehead rhytides above the eyebrow. In all patients, most of the new rhytides were almost completely resolved within 4 weeks without further treatment. Indeed, the majority of side effects resulting from cosmetic use of botulinum toxin in the forehead as well as in other aesthetic regions resolve spontaneously without treatment.

Other possible side effects from botulinum toxin treatment of HFLs include eyebrow and eyelid ptosis and periorbital edema, which are also self-limited. BoNT-A agents have been shown to spread up to 3 cm from the site of injection, but this may depend on the actual agent used and the method of dilution. Certain predisposing factors for eyebrow ptosis include age greater than 50 years and patients with mild eyebrow ptosis at baseline. Patients with pre-existing low eyelid platforms (i.e. the upper eyelid itself hangs down to or near the level of eyelashes) and dermatochalasis (Fig. 14.1; redundant skin at the eyebrow that hangs down toward the eyelid) should also be carefully evaluated to decide whether or not to proceed with treatment of the HFLs. Techniques that may help to prevent eyebrow ptosis include simultaneous treatment of brow depressors (especially the superior–lateral aspect of the orbicularis oculi) and to avoid eyelid ptosis by choosing injection points sufficiently superior to the orbital rim.

Figure 14.1 Dermatochalasis: redundant skin at the eyebrow that hangs down toward the eyelid, with eyes (A) closed and (B) open.

Pearl 2

Evaluate forehead and brow position prior to treatment by studying the frontalis at rest and with animation, and document each of these appearances with a photograph prior to treatment (Fig. 14.2).

Figure 14.2 Clinical photograph of horizontal forehead lines at rest and with brows raised: (A, B) before and (C, D) after treatment with botulinum toxin type A.

Injection techniques

Numerous different injection points and total units have been suggested for treating the forehead rhytides. The difficulty associated with treating this region is related to individual differences in frontalis muscle and forehead structure, as well as how the muscle is used functionally for facial expression. Individualized injection techniques are typically required, especially for patients with tall (wide) and short (narrow) foreheads, in order to achieve effective results and prevent complications such as eyebrow depression. For example, some physicians will perform two or more horizontal lines of injection for patients with tall foreheads while administering only one horizontal line of injection for those with short foreheads. However, these lines are not usually absolutely straight and typically we employ a higher injection point above the mid-brow in women, to avoid flattening an arched feminine brow.

In a study reported by Ozsoy et al in 2005, 90 patients with short and tall foreheads were treated with BoNT-A using different injection techniques. In the study, a glabella–frontal hairline distance greater than 70 mm was considered to be a tall forehead, while a distance less than 60 mm was classified as a short forehead. For tall foreheads, three vertical lines of injections were performed; for short foreheads, three horizontal lines of injections were given. The authors reported effective results in all patients without any instances of ptosis or brow asymmetry. In this study, the average age of male and female participants ranged from 41.5 to 42.3 years. In an older population, brow repositioning may develop and become problematic, especially for those with dermatochalasis who depend on the lower lateral frontalis muscle to hoist up the affected brow.

In addition to the physical variability of each patient, there are also differences in the properties of the botulinum toxin products currently available on the market. The different formulations of BoNT-A are made from different bacterial strains and processing methods. The commonly used formulations in the United States include onabotulinumtoxinA (Botox Cosmetic^®; Allergan Inc., Irvine, CA, USA) and abobotulinumtoxinA (Dysport^®; Ipsen Ltd, Slough, UK). Both products are commonly used cosmetically for treating the head and neck region and they have been compared for the treatment of HFLs. Xeomin^® (incobotulinumtoxinA; Merz Pharmaceuticals GmbH, Frankfurt, Germany) has been recently approved, but has not been widely used in the United States. A randomized, double-blinded, split-face study of 24 patients compared onabotulinumtoxinA and abobotulinumtoxinA for the treatment of forehead rhytides and their effects on electromyographic (EMG) activity of the frontalis muscle. A 3 : 1 conversion ratio was used and patients were observed for 20 weeks following injection. AbobotulinumtoxinA was found to have longer-lasting effects than onabotulinumtoxinA at a 3 : 1 conversion ratio. Based on these findings, the authors concluded that the conversion ratio of 3 : 1 may still be too high for bioequivalence.

Similar results for these two products have also been reported with the use of other dose ratios, for example by Nestor & Ablon (2011). A randomized, double-blinded, split-face study of 20 patients compared abobotulinumtoxinA and onabotulinumtoxinA at a 2.5 : 1 dose ratio, for the treatment of horizontal forehead lines. AbobotulinumtoxinA was shown to have a significantly longer duration of effect when compared with onabotulinumtoxinA. The median duration of full efficacy for abobotulinumtoxinA was 103 days and for onabotulinumtoxinA it was 87 days. Indeed, the optimal conversion ratio for complete bioequivalence has not yet been elucidated and it may be possible that 2.5 : 1 is too high as well, and that these products should be considered as completely independent products.

In 2004, consensus recommendations for the use of Botox Cosmetic^® were published by Carruthers et al. With regards to the treatment of HFLs, there was a wide range in the number of injection points suggested by the panel, ranging from two to 12 sites, with most falling between four and six. Regardless of the number of injection sites, the panel of experts recommended them to be at least 1–2 centimeters above the orbital rim to decrease the likelihood of brow ptosis. Furthermore, it was suggested treatment avoids the first horizontal forehead rhytid above the eyebrows and instead utilizes injectable fillers in the lower forehead lines. Regarding total doses for treating the forehead, a range of 10–20 units was recommended for women and 20–30 units for men. Lastly, clinical reassessment of eyebrow position 2 weeks after injection was recommended to determine the need for further treatment. However, in the Carruthers et al 2008 Consensus (published in 2011), the actual recommended dosage in the forehead was essentially reduced by half after other consensus reviews began to advocate a ‘natural relaxed look’.

The optimal total number of BoNT-A units for treating forehead lines has been evaluated and the results have varied. In a study involving 59 female patients with moderate to severe horizontal forehead rhytides, three doses of BoNT-A (Botox^®, Botox Cosmetic^®; Allergan Inc., Irvine, CA, USA) were compared for their safety and efficacy by Carruthers et al in 2003. The total amounts utilized were 16, 32, and 48 units, administered over eight injection sites of the brow elevators and brow depressors. Efficacy was evaluated by monitoring the response rate and duration using the facial wrinkle scale (FWS) for a total of 48 weeks. The authors found greater efficacy and longer duration of effect with the higher doses. Side effects encountered in the study were mild to moderate and included but were not limited to injection site pain, swelling, bruising, and headache. There was no significant increase in adverse effects in patients treated with higher overall doses.

In contrast, a 2006 prospective study by Levy et al of BoNT-A (of Vistabel^®, which is the name for Botox^® in European markets; Allergan Inc., Irvine, CA, USA) compared two lower doses (5 and 10 units) for the treatment of forehead rhytides in 24 patients. These total units were given over five injection sites. There was an 8-month follow-up period during which the investigators evaluated the patients clinically via standardized photography and objectively through 3D in vivo skin profilometry with computer-assisted evaluation. No differences were observed between the two groups, as both doses demonstrated significant improvement with the same level of effectiveness and duration. In this study, the authors recommended using lower doses for treatment of the frontalis muscle given the similar clinical improvement when compared with higher doses.

Pearl 5

Start with minimal injection dosages regardless of the toxin utilized and encourage follow-up at 2 weeks to re-evaluate (Fig. 14.3).

Figure 14.3 Clinical photograph of horizontal forehead lines: (A) before and (B) after treatment with botulinum toxin type A.

Consensus recommendations by Ascher et al 2010 for the use of Dysport^® (Ipsen Ltd, Slough, UK) and Azzalure^® (Galderma SA, Lausanne, Switzerland), which is the name for Dysport^® in European markets, have also been published by leaders in the field. Together, both products are quantified in units derived from the company that first developed the product (Speywood Biopharm Ltd, Maidenhead, Berkshire, UK), in Speywood Units (s.U). With regards to treatment of HFLs, it was recommended to use four to six injection points given in a V-shaped pattern, which should be slightly curved in women and straight in men. Lateral injection points should be made on the external orbital rim lines. For physicians who are less experienced with BoNT-A injections, these injections should be at least 4–5 above the orbital rim or on the upper two-thirds of the forehead. The injections should be made perpendicularly and superficially into the frontalis muscle. The total doses for HFLs suggested by the panel were 20–60 s.U, with 5–10 s.U per injection point. Importantly, the consensus panel also recommended starting at low doses, as did the consensus guidelines for Botox Cosmetic^®, since the frontalis is very responsive to treatment. It is important to note, however, that in many patients the V-pattern of injection can look quite unnatural, especially upon animation, and appear as the so-called ‘mephisto look’. Therefore again, the pattern of injection must be individualized depending on frontalis prominence, positioning, and eyebrow shape, as well as degree of dermatochalasis.

Treatment of scars

In addition to the management of rhytides, botulinum toxin has been an effective adjuvant treatment for minimizing scars (Fig. 14.4). This beneficial effect on scars is believed to be related to a decreased amount of tension and movement around an incision or wound site from toxin-mediated immobilization. The decrease in tension is believed to shorten the duration of the inflammatory phase of wound healing. Areas subject to greater tension and movement such as the chest, shoulders, and scapula are prone to hypertrophic scarring and keloid formation. A randomized-controlled trial reported by Gassner et al in 2000 involved six primates treated with BoNT-A versus placebo after undergoing symmetric pairs of standard excisions on either side of the forehead. The sides treated with BoNT-A were found to heal with a significantly better appearance than placebo-treated sides. The authors also noted that immobilization allows the surgeon to use finer sutures for closure, further contributing to a superior cosmetic outcome.

Figure 14.4 Botulinum toxin type A injection: (A) immediately after closure of surgical defect and (B) clinical appearance at 4 months’ postop.

Similar studies of BoNT-A in wound healing involving human subjects have also been performed. In a study by Wilson in 2006, 40 patients with traumatic and surgical scars of the forehead and cheek underwent scar revision procedures followed immediately by BoNT-A injections. The majority of patients had significant improvement of the final scar appearance, by subjective and objective assessment scales, over a 12–16-month follow-up period. One limitation of the study was the lack of a control group undergoing scar revision without BoNT-A treatment. In 2006, another randomized controlled trial (by Gassner et al) evaluated and treated 31 patients at the Mayo Clinic with either forehead lacerations or excision of forehead masses. The patients received either BoNT-A or placebo injections to the wound site within 24 hours of surgery. During a 6-month follow-up, the areas treated by BoNT-A were found to have significantly better results than placebo, measured by a visual analog scale.

A study by Kadunc et al (2007) on the use of botulinum toxin A prior to resurfacing of the upper lip for upper perioral vertical rhytides demonstrated better results on the BoNT-A pretreated side. The authors suggested that this improvement may be not only related to less mechanical movement and stress across the healing wound, but also possibly to a decrease in metabolic activity in the area. Therefore, the effect of BoNT-A in helping to decrease scarring in sutured closures may be related to both phenomena.

More recently, a retrospective study by Flynn (2009) described the findings of patients receiving intraoperative botulinum toxin type A or B following reconstructive surgery after Mohs micrographic surgery for non-melanoma skin cancers and one case of melanoma in situ. Of the eighteen patients, the most commonly treated area was the forehead and the remaining areas included the nose, chin, glabella, scalp, and zygoma. Botulinum toxin was placed in a 1–2 cm radius around the suture lines. All patients exhibited good to excellent results with good apposition of wound edges. Again, a limitation of the study was the lack of a control group undergoing Mohs micrographic surgery and reconstruction without botulinum toxin injection. The authors noted that botulinum toxin type B (BoNT-B) has been reported to be faster-acting and of shorter duration – therefore type B may be better suited for use following surgical reconstruction. However, in this study, no differences were seen between sites treated with botulinum toxin type A and those treated with type B.

With reference to onset and spread between sub-types A and B of botulinum toxin, a small prospective split-face study involving eight patients, reported in 2003 by Flynn & Clark, examined the rate of onset and area of diffusion of botulinum toxin types A and B for moderate to severe forehead rhytides. Utilizing computer analysis and time-lapse motion pictures, botulinum toxin type B was found to have a slightly faster onset and larger radius of diffusion than BoNT-A. However, whether this difference is significant enough to produce a clinically visible difference in surgical scar healing remains to be seen.

Conclusion

Botulinum toxin continues to be the most commonly performed non-surgical facial cosmetic procedure today. It remains an effective treatment modality for HFLs and its use in this region requires careful individualized planning to achieve optimal results and minimize the risk of complications. Due to the significant variability of this anatomical region, many techniques and guidelines have been published to help refine the approach of treating physicians. The use of BoNT-A is also gaining attention as an adjuvant treatment to help minimize the ultimate cosmesis of surgical and traumatic wounds. Future studies will help to determine the most effective treatment parameters for this relatively new indication.