Filling agents	Indications for combination therapy	Outcomes
Hyaluronic acid	– Deep resting glabellar rhytides – Horizontal forehead rhytides and brow lift – Nasojugal folds / hypertrophic orbicularis – Melomental folds / mouth frown – Facial contouring – Neck

– Reduced dynamic component of rhytide

– More accurate estimation of filler volume (preventing overcorrection)

– Increased longevity of implant

– Superior aesthetic result

Calcium hydroxylapatite –Radiesse^® Collagen –Evolence^® Poly-l-lactic acid –Sculptra^®

A number of studies have shown superior efficacy and patient satisfaction associated with combination therapy compared to fillers alone, particularly in individuals with deep resting rhytides. In 2003, Carruthers and colleagues compared the efficacy of BoNT alone or in combination with hyaluronic acid (HA) in 16 patients with moderate-to-severe resting glabellar rhytides via retrospective analysis. Response to the filling agent plus chemodenervation was compared clinically and photographically to the response to BoNT alone. In 94% of patients receiving combination therapy, severity of rhytides decreased from moderate or severe to mild. By contrast, patients receiving BoNT alone experienced only moderate success. To further examine the relationship between chemodenervation and filling agents, Carruthers and Carruthers conducted a randomized trial of 38 patients with moderate-to-severe glabellar rhytides receiving HA alone or in combination with BoNT; the latter group showed a better response both at rest and on maximum frown (Fig. 22.2). The addition of BoNT also extended the duration of the filling agent, from 18 weeks for HA alone, to 32 weeks for combination therapy. Patel and colleagues found improved clinical effects of longer duration and greater patient satisfaction in 65 subjects who received BoNT and collagen for the treatment of glabellar rhytides compared to patients who received either modality alone. In 2010, Carruthers and colleagues demonstrated similar results in a multicenter, randomized trial of 90 women treated with BoNT, HA, or in combination for rejuvenation of the perioral area and lower face. Combination therapy was superior to either modality used alone (Fig. 22.3).

Figure 22.2 Response to combination of HA with BoNT: (A) pre-treatment, and (B) post-treatment.

Figure 22.3 Perioral rejuvenation with BoNT alone (A, D), Juvéderm (B, E), or in combination (C,F). (A–C): Baseline; (D–F): after 24 weeks.

Although initially considered treatment for only deeper folds and rhytides, combination treatment with toxins and fillers is considered the standard regimen for facial rejuvenation in many cosmetic offices, with a greater emphasis on augmentation. This shift comes, in part, from a greater understanding of the three-dimensional nature of aging, particularly loss of volume from and bone remodeling in the malar and zygomatic regions, brow, and infraorbital hollow. Moreover, clinicians take a more holistic approach, considering not only the treatment of targeted rhytides and folds, but also their interaction with adjacent regions and the influence of augmentation on the appearance of the face as a whole. Volumizing the glabella and medial forehead, for example, can lift the brow, soften forehead lines, elevate the root of the nose, and lessen horizontal procerus rhytides (Fig. 22.4). The authors (JC and AC) use fillers increasingly to layer in a smooth, thin sheet of filler throughout entire regions (i.e. the forehead, upper lip, sides of the chin and anterior cheeks), lessening the need for other modalities.

Figure 22.4 (A, B) Soft tissue augmentation of the glabella and medial forehead enhances aesthetic appearance of the brow without other modalities.

Pearl 3

In the upper face, filler added to neurotoxin gives a softer and more natural result, especially with filler reflation of the entire forehead and temples.

Pearl 4

In the lower face, neurotoxin added to filler gives a smoother jawline and elevation of the mouth corners and support for the vertical perioral rhytides (‘lipstick lines’).

Pearl 5

In both upper and lower face, the filler lasts much longer when the subject also receives neurotoxin to relax the musculature.

Pearl 6

In lower face and neck, the combination is also effective, with the relaxation of the platysma improving the cervicomental angle and the filler along the mandibular margin elevating the skin of the neck and smoothing the contour of the jawline.

Lasers and light-based therapies

Lasers – including broadband light and radiofrequency devices – have become an indispensable part of the cosmetic surgeon’s armamentarium in combating photoaging (Table 22.2). Concomitant use of BoNT and these devices leads to optimal improvement of dynamic rhytides, superior and longer-lasting outcomes, better healing of newly remodeled skin, and a more permanent eradication of wrinkles.

Table 22.2 Lasers and light-based therapies with adjuvant BoNT

Lasers / light-based therapies	Indications for combination therapy	Outcomes
Ablative	– Lower eyelid – Lateral canthus – Perioral region

– Reduced appearance of rhytides

– Healing of newly remodeled skin

– Superior and longer-lasting outcomes

– Prevention of underlying musculature from molding into new folds or rhytides

– Carbon dioxide

– Erbium : yttrium aluminum garnet

Non-ablative

– Intense pulsed light

– Thermage

Ablative lasers

Ablative laser resurfacing with either carbon dioxide (CO₂) or erbium : yttrium aluminum garnet (Er : YAG) lasers has shown dramatic facial rejuvenation. Without concurrent BoNT, dynamic rhytides commonly recur or may even appear more pronounced after resurfacing in the lower eyelid, lateral canthus, and perioral regions within 6–12 months because of continued animation. Not only does pre-treatment with BoNT allow for undisturbed healing and remodeling and better aesthetic results, but regular postoperative injections (every 6–12 months), in addition to an ongoing appropriate skin care program (sunscreen, alpha-hydroxy acid, tretinoin) can prolong the effects of resurfacing and provide a better long-term result. In a prospective, clinical study, Carruthers & Carruthers first reported better aesthetic result when combining BoNT and resurfacing to the periocular area, later corroborated by West & Alster, who showed enhanced and more prolonged correction of forehead, glabellar, and lateral canthal rhytides over a 9-month period when combining CO₂ laser therapy with BoNT. Additional studies by Worcester and Zimbler and colleagues confirmed that chemodenervation prior to laser resurfacing for the treatment of hyperdynamic facial rhytides yielded superior results compared to resurfacing alone, particularly in areas of greater mobility.

Combination therapy may be used in a number of therapeutic areas. Injections in the perioral region must be approached with caution to avoid interference with the function of the lips and mouth. When softening vertical perioral rhytides and marionette lines, concomitant use of BoNT weakens an overactive depressor anguli oris muscle contributing to the depressive pull on the lip corners and formation of deep creases. BoNT administered to the orbicularis oris can diminish vertical lines caused by the lip sphincter. Chemodenervation may also be applied prior to the use of full-face resurfacing to enhance the softening of the forehead and periocular rhytides and nasolabial folds by injections into the frontalis, glabella, orbicularis oculi, and sometimes the zygomaticus complex.

Non-ablative light sources

Photodynamic therapy, such as intense pulsed light (IPL), and non-ablative radiofrequency energy (Thermage) are popular, non-invasive technologies used to reverse photoaging with less recovery time or risk associated with ablative laser resurfacing.

IPL – a non-ablative broadband light source – is one of the most successful treatment options for the treatment of photodamaged skin, reducing both lentigines and vascular lesions, such as telangiectasias, port-wine stains, and poikiloderma. Studies have shown that IPL improves skin texture, pore size, and fine wrinkles, though the jury is out on the treatment of all rhytides with IPL alone. Combination therapy with BoNT, however, increases the overall aesthetic benefit, with an improvement in texture and telangiectasis, along with a decrease in the appearance of rhytides.

Carruthers & Carruthers compared IPL alone or in combination with BoNT for the treatment of the periorbital area. Patients who received both modalities experienced a 15% improvement in overall aesthetic benefit at the 6-month evaluation (Fig. 22.5). Remarkably, the overall improvement in wrinkling, texture, and blemishes in the combined treatment group exceeded those of the IPL-only group more than 6 months after BoNT, far longer than the expected duration of its direct effect. The noted improvements in telangiectasias underscore the ability of BoNT to regulate blood vessel constriction and treat persistent facial flushing. Although the complete mechanism of action is not fully understood, this enhancement may be partially due to the denervating effect of BoNT, which prevents the active muscular disturbance of newly deposited dermal collagen. Similarly, Khoury and colleagues evaluated small wrinkles and fine lines, erythema, hyperpigmentation, pore size, skin texture, and overall appearance for 8 weeks in a randomized, split-face study in which patients were treated with BoNT or saline plus IPL. Adjunctive BoNT achieved a greater degree of improvement in small wrinkles and fine lines and erythema.

Figure 22.5 The synergy of IPL and BoNT: greater improvement in overall aesthetic appearance 6 months after combination therapy (Botox^® plus intense pulsed light).

Data from Carruthers J. Carruthers A 2004 The effect of full-face broad band light treatments alone and in combination with bilateral crow’s feet BTX-A chemodenervation. Dermatologic Surgery vol 30, issue 3, March:355–366

A monopolar radiofrequency (RF) device that delivers a controlled thermal injury to the deep dermis, the Thermage CPT system (Solta Medical, Hayward, California) was introduced in 2002 and became a popular option to impart mild tightening of the skin, particularly in the brow, periorbital region, and mid- and lower face. Research suggested that Thermage was a safe and effective treatment for rejuvenation that compared favorably to other non-ablative devices with modest improvements in facial rhytides. However, Thermage is not without risks: poor patient selection can result in disappointing outcomes and satisfaction, and results are often unpredictable. Although no controlled studies are available, BoNT can be used in combination with Thermage to immobilize musculature, prolonging duration of effect and enhancing elevation when used as part of non-surgical browlift procedures. As in the case of non-ablative lasers, BoNT serves to inhibit the underlying muscles from molding the newly formed collagen into additional wrinkles.

Aesthetic surgery

As a result of the increasing demand for non-invasive, injection-based facial rejuvenation, the number of surgical procedures in cosmetic dermatology has declined. However, some patients – such as those with excessive lower eyelid fat, for example – cannot be treated adequately with BoNT, fillers, or resurfacing alone and require surgical intervention. In many surgical approaches in the head and neck, underlying muscular action can reverse the intended surgical outcome, and therefore results may be short-lived. Chemodenervation is a strong partner and key adjunct to many aesthetic surgeries (Table 22.3). Pre- and post-treatment injections aid in stabilizing musculature while procedures heal (reducing repetitive muscular actions and thus the rate of dehiscence), improving outcomes and longevity of the procedure and circumventing complications, particularly for brow lift, blepharoplasty, and facelift.

Table 22.3 BoNT before surgery

Surgical procedures	Outcomes
Brow lift Blepharoplasty Lateral canthal suspension Facelift Neck procedures

– Stabilization of musculature during healing

– Reduced rate of dehiscence

– Fewer post-surgical complications

– Improved aesthetic outcome and longevity

Endoscopic brow lift

Endoscopic brow lift has gained wide recognition as a novel technique to correct brow ptosis in a minimally invasive manner with fewer complications than the classic coronal brow lift method. However, unpredictable results and postsurgical complications – alopecia, hairline changes, brow asymmetry, paresthesia, frontal branch nerve paralysis, and scalp dysesthesia – have led to a decline in popularity, particularly with the discovery of the less-invasive chemical brow lift produced by BoNT that approaches endoscopic lift in magnitude.

Chemical brow lift through BoNT was discovered serendipitously from treatment of glabellar frown lines, when it became apparent that treatment resulted in central and medial brow elevation as well due to partial inactivation and increased resting tone of the frontalis. Although injections of BoNT alone can effectively treat mild brow ptosis, moderate-to-severe ptosis requires endoscopic brow lifting to restore the brow to its normal position. Brow lifts may have unpredictable outcome depending on the postsurgical healing. Stabilization of the brow musculature is essential since periosteal refixation requires approximately 6–12 weeks. During this healing period, BoNT provides the perfect tool to chemically maintain the brows in elevated positions to prevent a quick descent. Pre-treatment of the brow depressors 2 weeks prior to operative lifting can not only promote periosteal fixation to the desired position (with less resistance to surgical brow repositioning) but also may prevent uneven regrowth of the muscles, a possible complication of surgical excision of the depressor fibers. In the postoperative setting, injections of BoNT can extend the life of the elevations provided by endoscopic brow lifts, which are often compromised within 6 months, and can be used to correct any resultant eyebrow asymmetry.

Blepharoplasty

Many patients requiring upper lid blepharoplasty have one brow slightly lower than the other. In order to prevent complications, pre-treatment with BoNT in the manner of a chemical brow lift creates brows of equal height and allows the surgeon to more accurately estimate the amount of skin to be resected and hold the incision line within the confines of the orbital margin, leading to a superior aesthetic surgical result.

For lower eyelid blepharoplasty, BoNT enhances wound healing (see below) and is often used as reinforcement during lateral canthal suspension procedures, such as the lateral tarsal strip or lateral retinacular suspension, to prevent dehiscence and protect the security of the reconstruction. The results of the surgery are often compromised by the repetitive muscular actions that distort the outcome. Lateral tarsal strip procedures often end in dehiscence of the temporal repair; pre-treatment with 5 U BoNT into the lateral fibers of the orbicularis will minimize the pull on the medial side of the surgical incision through repeated muscular contraction, treating the lateral canthal rhytides at the same time. Eyelid malposition sometimes results from prior surgical procedures; the clinician can use BoNT in the postoperative setting to correct any remaining or resultant asymmetries.

Facelift

Facelift, necklift, and platysma repair surgeries involve the imbrication of the superficial musculoaponeurotic system and the plication of the platysma muscle, leading to eventual platysmal banding and a noted contrast between the rejuvenated face and the untreated neck. Moreover, in necklift and platysma repair surgeries, the activity of the platysma pulls the skin downward and can reverse the effect of the procedures over time. Treatment of these recurrent bands with BoNT can avoid further surgery and improve aesthetic appearance; injection of the platysma before and after the procedures may enhance the longevity of the outcome. In addition, post-facelift synkinesis – in which the buccal branch of the VII nerve has been peripherally damaged and activates the levator labii superioris or zygomaticus when the patient blinks – can be alleviated by small doses (1–2 U) of BoNT into the affected muscle. Similarly, injury to the marginal mandibular nerve controlling the depressors of the lower lip is a complication of neck liposuction that often accompanies facelifts and repairs to the platysma. It is usually short-lived and BoNT administered to the contralateral side may re-establish symmetry while the nerve damage recovers.

Wound healing and scars

Injection of BoNT prior to surgical procedures or into the muscles underlying or surrounding a sutured wound has shown to improve cosmesis and aid in the healing process (Table 22.4). Because the major factor influencing the final appearance of a scar is the tension exerted on the edges of the wound in the healing stage, wound immobilization is a basic therapeutic principle in plastic surgery. Surgical techniques for immobilization can only reduce – not eliminate – such tension. As a result, continuous muscle activity surrounding a wound leads to a prolonged inflammatory response and hypertrophic and hyperpigmented scars. Pre-treatment of the underlying muscles in surgical procedures allows surgeons to use finer sutures and achieve better cosmesis. Animal and human studies have shown that immobilization with BoNT in the muscles surrounding or underlying a sutured wound can improve the cosmetic appearance of cutaneous scars by eliminating tension produced by muscular forces surrounding the scar in the face and elsewhere. Gassner and colleagues first demonstrated a statistically significant improvement in the appearance of forehead lacerations immobilized by BoNT compared to control wounds in primates in 2000; a subsequent randomized, placebo-controlled study of 31 human subjects presenting with traumatic forehead lacerations or undergoing elective excisions of forehead masses showed that patients who received BoNT in the musculature adjacent to the wound within 24 hours experienced enhanced healing and cosmesis (Fig. 22.6). Choi and colleagues showed that postoperative treatment with BoNT prevented complications in a series of 11 patients at high risk of impaired wound healing after complex eyelid reconstruction, and Flynn found that intraoperative BoNT aided wound healing in patients undergoing surgical reconstruction after Mohs micrographic surgery for the treatment of skin cancer.

Table 22.4 Adjunctive BoNT to promote wound healing and improve the appearance of scars

Indications for adjuvant therapy	Outcomes
Anywhere; particularly useful in areas of greater mobility, such as the periorbital or perioral regions	– Immobilization of wound – Use of finer sutures – Eliminated muscular activity – Decreased tension on wound edges – Improved aesthetic outcome and longevity