Global Aesthetics Consensus: Hyaluronic Acid Fillers and Botulinum Toxin Type ARecommendations for Combined Treatment and Optimizing Outcomes in Diverse Patient Populations



## Consensus objectives and methodology
From January 17 through 19, 2014, a multidisciplinary group of key opinion leaders in the core aesthetic specialties from Asia, Australia, Europe, and North and South America convened the Global Aesthetics Consensus Group to formulate updated guidelines for aesthetic use of hyaluronic acid fillers and botulinum toxin type A. This publication provides recommendations for combined treatments. It also presents concepts for treatment planning and implementation in diverse patient populations. The Global Aesthetics Consensus Group is well suited for these objectives by virtue of its own geographic and ethnic diversity. The methodology used for determining consensus is summarized in [fig_ref] Table 1: Methodology for Global Aesthetics Consensus Group Panel Consensus [/fig_ref].

## Evolving concepts in facial aging
Facial aging occurs at all levels. The epidermis, dermis, subcutis, and bone undergo remodeling throughout life; degradation of existing tissue is balanced with generation of new tissue. With age, regenerative properties decline and the balance of remodeling becomes disrupted, such that there is a net loss of tissue that is recognized as resorption. From a quantitative perspective, volume loss is significant from the deeper tissue layers, with deflation and descent of depleted subcutaneous fat compartments and loss of bone [fig_ref] Figure 1: Age-related bony changes are mainly in the periorbital and midcheek zones, including... [/fig_ref]. [bib_ref] Changes in the facial skeleton with aging: Implications and clinical applications in..., Mendelson [/bib_ref] [bib_ref] Aging of the mandible and its aesthetic implications, Shaw [/bib_ref] [bib_ref] Models of facial aging and implications for treatment, Lambros [/bib_ref] [bib_ref] Observations on periorbital and midface aging, Lambros [/bib_ref] [bib_ref] Concertina effect and facial aging: Nonlinear aspects of youthfulness and skeletal remodeling,..., Pessa [/bib_ref] [bib_ref] A review of the literature on the aging adult skull and face:..., Albert [/bib_ref] [bib_ref] Home of Younger Skin" (HOYS) program: Defining the change in apparent skin..., Goodman [/bib_ref] Total collagen content of the skin also decreases. There is qualitative degeneration of tissue components, including dermal collagen and elastin. [bib_ref] Topically applied physiologically balanced growth factors: A new paradigm of skin rejuvenation, Sundaram [/bib_ref] 

## Plastic and reconstructive surgery - may 2016
These processes result in three-dimensional alterations in facial shape and contour; skin laxity, folds, and rhytides; and surface changes, including skin roughness and xerosis. The primary extrinsic causes of skin aging have been characterized as the "three S's"-sun (ultraviolet radiation), smoking, and stress. They increase oxidative stress by means of reactive oxygen species overload and concomitant antioxidant depletion. Multiple biochemical pathways are triggered. They promote collagen loss by inducing suppression of transforming growth factor- receptor II; overexpression of matrix metalloproteinases, which are collagenases; and increased inflammation through the nuclear factor kappa B pathway. Ultraviolet radiation also directly damages the skin's structural proteins. Intrinsic skin aging is related to a progressive agerelated decline in antioxidant capacity, coupled with increased reactive oxygen species production from oxidative metabolism in skin cells. This contributes to oxidative stress. Chromosomal analysis of aging cells reveals progressive telomere shortening, associated with tissue damage. The rates of extrinsic and intrinsic aging vary considerably, based on individual exposure to the causative factors and hereditary predisposition. [bib_ref] Topically applied physiologically balanced growth factors: A new paradigm of skin rejuvenation, Sundaram [/bib_ref] [bib_ref] Collagen alterations in chronically sun-damaged human skin, Schwartz [/bib_ref] The multifactorial cause of facial aging provides the rationale for combined treatments. The balance of fillers with toxin depends on individualized patient assessment and functional understanding of what the observations mean. In previous guidelines, toxin has been considered the foundation of treatment to the upper face, with fillers playing a larger role in the middle and lower face. [bib_ref] Advances in facial rejuvenation: Botulinum toxin type a, hyaluronic acid dermal fillers,..., Carruthers [/bib_ref] Increasingly, however, fillers are seen as improving the effects of toxin-and are particularly indicated as patient age increases. The consensus panel acknowledged that combined treatment has value throughout the face.

## Optimizing treatment outcomes in diverse patient populations
The objective of aesthetic treatment is often described as facial rejuvenation. A broader perspective, encompassing patient age, ethnicity, and sex, yields the more accurate objective of facial harmonization-through correction of acquired (usually age-related) disharmonies, together with modification of congenital characteristics. In recognition of growing patient diversity in clinical practice, the panel recommended enrollment of more heterogeneous subject populations in injectables studies.

## Age
Surveys report that the typical age at which patients seek cosmetic procedures is between 30 and 50 years.When clinically indicated, fillers and toxin are of demonstrable benefit to older and younger patients. A retrospective review from 2008 to 2013 of a database endorsed by the American Society of Plastic Surgeons showed that patients older than 65 years had significantly more cosmetic facial procedures performed than did younger patients (62.9 percent versus 12 percent). There was no statistically significant difference in complication rates following all procedures in older patients (mean age, 69.1 years; 1.94 percent) versus younger patients (mean age, 39.2 years; 1.84 percent). This was despite the greater presence of health risks in the older group, including higher body mass index and higher incidence of diabetes mellitus. [bib_ref] Safety of cosmetic procedures in elderly and octogenarian patients, Yezhelyev [/bib_ref] The variable time course and manifestations of aging underscore the importance of both chronologic and physiologic age when planning treatment. Individualized analysis includes assessment of tissue quality, extent and pattern of volume loss from soft and hard tissues, extent and pattern of muscular contraction, and surface skin changes. Selection of appropriate injectables to achieve the best results has been compared metaphorically to an artist's choices from a palette of paints to create a beautiful picture. As an extension of this metaphor, the face may be considered the "canvas" for aesthetic interventions.
Respect for the aging facial canvas is an evolving and fundamental principle of treatment. A paradigm shift is advocated from the youthful face as the "gold standard," toward age-appropriate facial harmonization. For example, it is inadvisable to try to restore the midface convexity (ogee curve) of a 50-year-old with depleted facial skeletal support to a level appropriate for a 25-year-old. Attempts to do so by filler injection may produce passable results in repose. But there may be undesirable effects in animation, such as impingement of the midface on the lid-cheek junction when smiling, or a discernible ledge between the submalar region and the lower face. Overvolumization is best avoided by viewing patients before, during, and after injection-not only at rest, but also in animation. A conservative approach is preferable, particularly with newer, longer lasting hyaluronic acid fillers, for which the panel agreed that "less is often more." Although these principles may seem obvious and even superfluous to state explicitly, they can become obscured if adherence to rigid algorithms and cutaneous landmarks (which shift with age) supersedes a patient-tailored approach.
There is no upper limit for age beyond which patients cease to benefit from volume restoration. Declining tissue quality and consequent skin laxity are indications for combining fillers with lasers, energy-based devices, [bib_ref] Nonsurgical rejuvenation of the upper eyelid and brow, Sundaram [/bib_ref] or surgery when appropriate. In older patients, fewer injection sites and smaller toxin doses at each site may be indicated if muscle mass or function is reduced.
In younger patients, age-related disharmonies are not yet prominent. Emphasis is typically on modification of congenital characteristics or of acquired disharmonies that are age-independent, such as from injuries. Treatment of younger patients is commonly described as proactive or "preventive" (e.g., when glabellar or frontal lines that were present since childhood or incipient in early adulthood are injected with toxin).

## Gender
Male and female faces are governed by different treatment principles. There are considerable differences in anatomy and in what is aesthetically appealing. Harmonization of the female face entails restoring prominence to the upper and middle thirds with a lower facial taper, to achieve a heart or inverted triangle shape. In contrast, the male face is perceived as harmonious when somewhat longer, with more equal prominence of facial thirds and a well-defined jawline. The average male skull is significantly larger than that of a female skull. The frontal, maxillary, zygomatic, and mandibular bones tend to be broader, squarer, and flatter, and the supraorbital rim is more prominent. Men have greater average muscle mass and a higher density of blood vessels. [bib_ref] Botulinum toxin in men: Review of relevant anatomy and clinical trial data, Keaney [/bib_ref] Gender-related differences in epidermal and dermal thickness and fat distribution are considered to be modulated by sex steroids. [bib_ref] Gender differences in skin: A review of the literature, Dao [/bib_ref] [bib_ref] Gender-linked differences in human skin, Giacomoni [/bib_ref] Study of composite facial images indicates that greater facial symmetry confers a more gender-typical appearance for men and women. [bib_ref] Symmetry is related to sexual dimorphism in faces: Data across culture and..., Little [/bib_ref] Many caveats that apply to treatment of men with injectables pertain to avoidance of facial feminization. The panel cautioned that overvolumization of the male midface produces a feminizing convexity. It is also important not to overfill the temple, as temporal hollowing is aesthetically appealing in many men. Injection of fillers into the lips may be appropriate for some men (e.g., to improve vermilion border definition), but care must be taken to avoid a feminine shape or fullness. Inappropriate elevation of the eyebrows (especially the lateral tails) with toxin will tend to feminize a male face.

## Ethnicity
Clinical data with Evidence Levels I and II support the safety and efficacy of botulinum toxin Plastic and Reconstructive Surgery - May 2016 type A and hyaluronic acid fillers in persons of color [bib_ref] Juvederm vs. Zyplast Nasolabial Fold Study Group. Comparison of smooth-gel hyaluronic acid..., Baumann [/bib_ref] [bib_ref] A four-month randomized, doubleblind evaluation of the efficacy of botulinum toxin type..., Grimes [/bib_ref] [bib_ref] Safety and effectiveness of hyaluronic acid fillers in skin of color, Grimes [/bib_ref] [bib_ref] A multicenter study of the safety and effectiveness of hyaluronic acid with..., Downie [/bib_ref] [fig_ref] Figure 2: Efficacy of nasolabial fold correction with crosslinked hyaluronic acid filler in patients... [/fig_ref]. Guidelines based on patient ethnicity should not obscure the basic tenet that ideals of beauty are largely preserved across time and cultures. Although some quantifiable congenital characteristics are commonly associated with specific ethnicities, 31-35 the general principles of individualized analysis and correction apply to every patient. Geographic variations in treatment approaches have evolved as worldwide use of injectables has expanded. This is a manifestation of ethnicity and prevalent facial morphotypes, cultural preferences, and global migration patterns.
Additional considerations pertain to immigrant patients (e.g., the cultural overlays when Asian patients consult with European or American surgeons). Asian, Latin American, African, and other patients are sometimes perceived mistakenly as uniform populations. However, there are significant physical and cultural variations within these continents. Ethnic mixing, because of intermarriage, adds to the multiplicity of facial morphotypes. These considerations inform qualitative and quantitative differences in treatment. Compared with whites, Asians are more likely to display central face retrusion; flattening of the anteromedial midface; recessed piriform fossae; flatter, broader foreheads; retrognathia; and microgenia. [bib_ref] Comparison of the aesthetic facial proportions of southern Chinese and white women, Sim [/bib_ref] [bib_ref] Proportionality in Asian and North American Caucasian faces using neoclassical facial canons..., Le [/bib_ref] These congenital characteristics account for the prevalence of filler injection to the medial midface, nose, chin, and forehead of younger Asian patients. In older patients, volumization of these regions remains a priority, in conjunction with correction of age-related disharmonies. Skeletal structure affects resting tone and contraction of the overlying musculature. A recent classification of Asian facial morphotypes proposes division into three basic categories to guide treatment strategies with botulinum toxin and fillers. [bib_ref] Aesthetic applications of botulinum toxin type A in Asians: An international, multidisciplinary..., Sundaram [/bib_ref] Validation of this classification and the associated treatment strategies is now in process.
Variations in incidence and presentation of photoaging among ethnic groups are attributable in part to physical differences, such as variations in fibroblast size and structure, [bib_ref] Skin of color: Biology, structure, function, and implications for dermatologic disease, Taylor [/bib_ref] [bib_ref] Ethnic skin types: Are there differences in skin structure and function?, Rawlings [/bib_ref] and in part to differences in lifestyle. Although all ethnic groups eventually manifest signs of photoaging, whites typically have an earlier onset and display more rhytides at a younger age. The old adage that skin of color ages more by folding than wrinkling underscores a key point-that volume loss is ubiquitous to all ethnicities. It therefore follows that restoration of volume and correction of related sequelae, including effects on associated musculature, are fundamental strategies for every patient.

## Longitudinal treatment planning
Ongoing treatment with hyaluronic acid fillers and botulinum toxin yields cumulative improvements. The greatest benefits are obtained if patients return for treatment when the previous results start to diminish rather than after they disappear completely. Ultimately, treatment may be required less frequently, and doses can often be reduced. A retrospective medical chart review of 194 patients who received a total of 4402 onabotulinum-toxinA treatments to glabellar lines over a mean of 9.1 years demonstrated sustained patient and physician satisfaction. [bib_ref] Patient satisfaction and safety with aesthetic onabotulinumtoxinA after at least 5 years:..., Trindade De Almeida [/bib_ref] Greater perceived benefits were reported in patients treated for longer periods.
The long-term restorative potential of diluted (reconstituted) Hylacross hyaluronic acid filler (Juvederm Ultra; Allergan, Inc., Irvine, Calif.) is indicated by a retrospective evaluation of more than 350 patients whose clinical improvement after superficial injection of facial fine lines persisted beyond the time frame that could be accounted for by space-filling effects alone. [bib_ref] Reconstituted injectable hyaluronic acid: Expanded applications in facial aesthetics and additional thoughts..., Fagien [/bib_ref] The scientific rationale is provided by a rat study, in which enzyme-linked immunosorbent assay and reverse-transcriptase polymerase chain reaction showed up-regulation of types I and III collagen and elastin expression after intracutaneous injection of Hylacross filler, but not after control injection of saline. [bib_ref] Skin extracellular matrix (ECM) stimulation following injection of a hyaluronic acid-based dermal..., Paliwal [/bib_ref] A recent prospective study of onabotulinum-toxinA raised the possibility of biomechanical restoration, demonstrating increased skin pliability and elastic recoil after injection of the lateral orbital, forehead, and glabellar regions of 40 women. [bib_ref] Skin biomechanical changes after injection of onabotulinum toxin A: Prospective assessment of..., Bonaparte [/bib_ref] Because botulinum toxin spreads in a three-dimensional manner after injection, the mechanism of action could be intramuscular or related to the overlying skin. Previous anecdotal reports of improvement in skin texture and turgor after intradermal toxin injection [bib_ref] The wrinkles soothing effect on the middle and lower face by intradermal..., Chang [/bib_ref] [bib_ref] Use of intradermal botulinum toxin to reduce sebum production and facial pore..., Shah [/bib_ref] [bib_ref] Safety and efficacy of intradermal injection of botulinum toxin for the treatment..., Rose [/bib_ref] have been attributed to intracutaneous fluid retention, by means of effects on acetylcholine receptors, which exist on keratinocytes, melanocytes, and cells of the sebaceous glands. [bib_ref] Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors, Kurzen [/bib_ref] Several Global Aesthetics Consensus Group recommendations describe lower toxin doses than in previous guidelines. This is to modulate rather than obliterate muscular activity, with developing understanding that combining toxin with fillers is more appropriate for some indications in which toxin alone was advocated in the past. Some panelists expressed concern that overtreatment with toxin, especially with short retreatment intervals, could produce muscular atrophy that would exacerbate volume loss. Blinded, placebo-controlled studies of botulinum toxin type A for moderate to severe crow's feet show little clinical difference between the two most efficacious doses, although higher doses tended to provide greater patient satisfaction. [bib_ref] Botox Facial Aesthetics Study Team. Double-blind, randomized, placebo-controlled, dose-response study of the..., Lowe [/bib_ref] Longevity is used in studies as an endpoint of efficacy. In clinical practice, a more qualitative focus on functional and aesthetic appropriateness of the results may serve patients better. With counseling, the philosophy of more frequent visits to achieve and maintain consistently good, rather than overdone, results is readily understood by patients by extrapolation from other health and beauty arenas.

## Response to repeated treatments with botulinum toxin type a
The response rate to botulinum toxin type A for aesthetic applications is very high. In cases of apparent nonresponse or partial response to any toxin formulation, practitioners should first consider causes such as inappropriate patient selection, dosing, or placement of injection sites. If volume loss is a significant contributor to rhytides, they will respond better to combined fillers and toxin than to toxin alone. It is obvious that underdosing or incorrect placement of toxin in target muscles can impair treatment response. Overdosing with resultant recruitment of adjacent muscles can give the illusion of nonresponse, as can injection into muscles that are not the primary cause of what needs to be addressed.
From an evidence-based perspective, it is challenging to evaluate reports of secondary treatment failure with toxin, because they are typically anecdotal and retrospective. Pertinent details are likely to be missing if the practitioner who is consulted for nonresponse did not perform the treatment. Although a number of case reports describe secondary treatment failure in the presence of neutralizing antibodies, there is no highlevel evidence to implicate antibodies as the actual cause. [bib_ref] Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medicine: Five case..., Torres [/bib_ref] summarizes challenges in interpreting current data. [bib_ref] Clinical relevance of botulinum toxin immunogenicity, Benecke [/bib_ref] [bib_ref] Individualized management of cervical dystonia with different serotypes of botulinum toxin: Recent..., Kamm [/bib_ref] [bib_ref] Meta-analysis of neutralizing antibody conversion with onabotulinum-toxinA (Botox) across multiple indications, Naumann [/bib_ref] [bib_ref] Comparison of efficacy and immunogenicity of original versus current botulinum toxin in..., Jankovic [/bib_ref] [bib_ref] Formation of neutralizing antibodies in patients receiving botulinum toxin type A for..., Yablon [/bib_ref] [bib_ref] Botox (botulinum toxin type A) purified neurotoxin complex prepared from the new..., Aoki [/bib_ref] Ongoing monitoring of the increasing number of patients who receive repeated treatments will allow conclusions that are evidence-based, rather than circumstantial.

## Application of science to optimize clinical efficacy and safety
New and emerging hyaluronic acid fillers are arranged in families that are designed for layered tissue implantation. Examples include cohesive polydensified matrix (Belotero; Merz, Frankfurt am Main, Germany), Optimal Balance Technology (Emervel; Galderma, Lausanne, Switzerland), Resilient Hyaluronic Acid (Teosyal; Teoxane, Geneva, Switzerland), and Vycross (Allergan). [fig_ref] Table 3: Typical Products in a Hyaluronic Acid Filler Family Designed for Layered Implantation,... [/fig_ref] The intended clinical applications of each product are informed by its rheologic (flow-related) properties, which depend on its manufacturing process. [bib_ref] Comparative physical properties of hyaluronic acid dermal fillers, Kablik [/bib_ref] [bib_ref] Comparison of the rheological properties of viscosity and elasticity in two categories..., Sundaram [/bib_ref] Deep volumizers typically have higher elasticity (G), to confer firmness and resistance to applied force; and higher viscosity, to confer resistance to spread. For example, deep volumizer Vycross (Voluma) has higher elasticity than midlevel Vycross (Volift), which has higher elasticity than the superficial volumizer (Volbella). 59-61 Elasticity is higher in Vycross than in Hylacross products. [bib_ref] Comparison of the rheological properties of viscosity and elasticity in two categories..., Sundaram [/bib_ref] [bib_ref] Biophysical characteristics of hyaluronic acid soft-tissue fillers and their relevance to aesthetic..., Sundaram [/bib_ref] Complex viscosity (*), which accurately measures whole gel behavior, is higher in deep volumizer Vycross than in Hylacross. [bib_ref] Biophysical characteristics of hyaluronic acid soft-tissue fillers and their relevance to aesthetic..., Sundaram [/bib_ref] Science-based selection of filler products and injection techniques allows a more evidence-based approach toward safety and efficacy. Treatment outcomes can be predicted by a product's scientific design, in the context of its target tissue and the techniques that are used to implant it. [bib_ref] Igniting discovery, dialogue, and global innovation through international collaboration, Sundaram [/bib_ref] Two controlled, split-face studies of Evidence Level II fulfill the rheologic prediction that optimal nasolabial fold correction requires a significantly smaller volume of a higher than a lower elasticity filler. [bib_ref] A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for..., Moers-Carpi [/bib_ref] [bib_ref] Novel hyaluronic acid dermal filler: Dermal gel extra physical properties and clinical..., Monheit [/bib_ref] Histopathologic and ultrasonographic studies directly correlate a filler's viscosity and cohesivity to its pattern of spread and tissue integration after in vivo, intradermal implantation. [bib_ref] Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers, Flynn [/bib_ref] [bib_ref] Superficial dermal injection of hyaluronic acid soft tissue fillers: Comparative ultrasound study, Micheels [/bib_ref] [bib_ref] Ultrasonographic and histological comparative study of 3 hyaluronic acid gels, Micheels [/bib_ref] The initial focus was on elasticity as a primary determinant of tissue "lift" when fillers were implanted deeply as boluses. It was subsequently proposed that the "lift capacity" of a hyaluronic acid filler is determined not only by elasticity but also by cohesivity. [bib_ref] Lift capabilities of hyaluronic acid fillers, Borrell [/bib_ref] A certain level of cohesivity (i.e., the tendency of the filler not to dissociate because of affinity of its molecules for each other) can be considered a prerequisite to maintain filler integrity during and after implantation. A standardized, five-point visual scale for hyaluronic acid filler cohesivity was recently developed and validated. [bib_ref] Cohesivity of hyaluronic acid fillers: Development and clinical implications of a novel..., Sundaram [/bib_ref] Convergence of these data with seminal studies of facial fat compartments and bony 

## . secondary treatment failure with botulinum toxin type a for aesthetic indications: evidence-based and experiential analysis
Presence of neutralizing antibodies is not a predictor of nonresponse to toxin; recent publications describe both responders and nonresponders as having neutralizing antibodies. No controlled, long-term studies have compared the immunogenicity of different botulinum toxin products. The true clinical impact of neutralizing antibodies is difficult to determine because of limitations in antibody measurement techniques, and interclinic variability in defining secondary nonresponsiveness.*  The incidence of neutralizing antibodies is low; meta-analysis indicates a prevalence of <0.25% for the formation of neutralizing antibodies against onabotulinumtoxinA, when injected for glabellar lines.  Potential risk of antibody formation is considered to have been mitigated by product reformulation to reduce protein load per dose,  and the trend toward lower dosing for aesthetic applications.*  Consensus panelists with experience of using onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA did not note any connection between a specific product and nonresponse to treatment, or the alleviation of nonresponse. Frequent re-treatment has been suggested as a risk factor for secondary treatment failure; however, panelists with experience performing secondary "touch-up" treatments 2-4 wk after primary toxin treatment in many patients over several years reported no emergence of nonresponders. anatomy [bib_ref] Changes in the facial skeleton with aging: Implications and clinical applications in..., Mendelson [/bib_ref] [bib_ref] Aging of the mandible and its aesthetic implications, Shaw [/bib_ref] [bib_ref] Models of facial aging and implications for treatment, Lambros [/bib_ref] [bib_ref] Observations on periorbital and midface aging, Lambros [/bib_ref] [bib_ref] Concertina effect and facial aging: Nonlinear aspects of youthfulness and skeletal remodeling,..., Pessa [/bib_ref] [bib_ref] Discussion: Aging of the facial skeleton: Aesthetic implications and rejuvenation strategies, Rohrich [/bib_ref] [bib_ref] The youthful cheek and the deep medial fat compartment, Rohrich [/bib_ref] [bib_ref] The anatomy of suborbicularis fat: Implications for periorbital rejuvenation, Rohrich [/bib_ref] [bib_ref] The fat compartments of the face: Anatomy and clinical implications for cosmetic..., Rohrich [/bib_ref] [bib_ref] The anatomy and clinical implications of perioral submuscular fat, Rohrich [/bib_ref] elucidates the primary objective of volume replacement as inflation of age-deflated soft tissues, and thus restoration of three-dimensional tissue support. A filler's elasticity, cohesivity, and water binding all contribute to this multilevel process. It is a composite of layered tissue expansion, with vertical and horizontal vectors; and tissue projection, with more vertical, bolus-type vectoring predominantly from deep tissues. [bib_ref] Nonsurgical rejuvenation of the upper eyelid and brow, Sundaram [/bib_ref] [bib_ref] Biophysical characteristics of hyaluronic acid soft-tissue fillers and their relevance to aesthetic..., Sundaram [/bib_ref] The scientific balance of each hyaluronic acid product parallels its clinical characteristics. Higher elasticity increases tissue projection by providing firmness and resistance to muscular and gravitational forces. Cohesivity confers more three-dimensional tissue expansion. As an example of how scientific balance influences clinical behavior, it is instructive to compare Vycross and Hylacross fillers. The lower cohesivity of Vycross has been described as providing more malleability. [bib_ref] Basics of dermal filler rheology, Pierre [/bib_ref] The lower water uptake of Vycross, as measured by in vitro gel swelling assay, is attributed to tighter hyaluronic acid cross-linking. [bib_ref] Basics of dermal filler rheology, Pierre [/bib_ref] Additional factors contribute to tissue swelling after in vivo implantation of hyaluronic acid fillers. Dilutionreconstitution of Hylacross 41 decreases tissue swelling, presumably because of preinjection saturation of some water-binding sites.
In vitro resistance of Hylacross filler to degradation by ovine testicular hyaluronidase has been attributed to its cross-linking, cohesivity, and total hyaluronic acid concentration. [bib_ref] In vitro resistance to degradation of hyaluronic acid dermal fillers by ovine..., Jones [/bib_ref] The longevity of Vycross filler is attributed to cross-linking, independent of concentration. [bib_ref] Basics of dermal filler rheology, Pierre [/bib_ref] From a safety perspective, it is noteworthy that these fillers are degraded transarterially after implantation into cadaveric arteries-by exogenous hyaluronidase injected into surrounding soft tissue, or by immersion of closed arterial segments in hyaluronidase at therapeutic doses. [bib_ref] Transarterial degradation of hyaluronic acid filler by hyaluronidase, Delorenzi [/bib_ref] [See Video, Supplemental Digital Content 1, which demonstrates transarterial degradation of Vycross and Hylacross fillers, by injection of exogenous hyaluronidase into the surrounding soft tissues, in a fresh, frozen cadaver model in real time. In section 1 of this video, dyed Hylacross filler (Juvederm Ultra) is injected into the facial artery lateral to the oral commissure, and product flows to the mid cheek. Digital pressure on the lower part of the vessel demonstrates that the filler gel distends and completely occludes the vessel. Ovine hyaluronidase at a concentration of 150 IU/ml (Hyalase; Sanofi-Aventis, Gentilly, France) is infiltrated around, but not directly into, the vessel containing Hylacross filler. Digital pressure and simulated tissue massage are applied. The Hylacross filler within the artery is depolymerized because of transarterial enzymatic action of the hyaluronidase. Both the vascular distention and obstruction are removed as the filler product is broken down and disperses. In section 2 of this video, dyed Vycross filler (Juvederm Volift) is injected into the superficial temporal artery, and readily flows along the vessel to escape from the cut end of the vessel. Ovine hyaluronidase (150 IU/ml) infiltrated around, but not directly into, the artery breaks down and disperses the Vycross filler within it. In a more graphic demonstration of enzymatic depolymerization, droplets of hyaluronidase that are applied directly to extruded Vycross filler rapidly break it down and disperse it. In section 3 of this video, dyed Vycross filler (Juvederm Volbella) is injected into the facial artery at the lower nasolabial fold, and extrudes from the cut end of a downstream arterial branch in the alar fold danger zone. This video demonstrates how injection of hyaluronic acid filler into a vessel of significant diameter can result in its spread to distant locations along the vascular tree of that vessel. The action of hyaluronidase is rapid and profound, despite infiltration into the surrounding soft tissue, rather than direct intravascular infiltration. This is demonstrated by dispersal of the filler within the vessel after a short period. Hyaluronidase also has a

## Table 4. key points from premeeting panel survey and consensus proceedings regarding the upper face, midface, and lower face

## Upper face (glabella, forehead, and lateral periocular regions)
Botulinum toxin type A alone was the most common approach to treating the upper face. Combination therapy was used for 18-21% of patients [fig_ref] Figure 3: Video [/fig_ref]. Glabellar lines or forehead: The panel considered same-session or sequential treatments as equally viable options, with choice dependent on patient evaluation, and other considerations such as the patient's ability to return for sequential treatment. Lateral periocular region: Sequential treatment was preferred in almost two-thirds of cases. Sequential treatment of the upper face: Most panelists preferred initial toxin, followed by filler. Same-session treatment: Panelists recommended injection of filler first, followed by toxin, to avoid unnecessary tissue manipulation following toxin injection. Also, filler can be more accurately implanted at the desired level if the tissue is not distended beforehand by injected toxin.

## Midface (lower eyelid, nose, and cheek)
Combined treatment of the midface was used less frequently than botulinum toxin or filler alone. The panel preferred filler alone in 92% of treatments to the cheek. Same-session and sequential treatments were viable options when treating the lower eyelid or nose with filler and toxin. Some panelists cautioned against same-session treatment of the infraorbital region because of increased risk of swelling. Most panelists considered the use of toxin for nasal tip elevation to be ancillary to that of fillers, based on understanding the primary need to correct volume loss and restore support to the nasal tip. Combined treatment of the cheek was not a common strategy but was considered appropriate in limited situations, such as hyperdynamic "accordion" cheek lines. Lower face (oral commissure, lip, masseter, and jawline/neck regions)
Frequency of combined treatments was 42% to the oral commissure, 27% to the lips, 19% to the jawline and neck, and 8% to the masseter. Oral commissure and marionette lines: Same-session treatment with filler followed by botulinum toxin was preferred over sequential sessions in approximately two-thirds of cases. Same-session and sequential treatment were both considered viable options for the lips and perioral region, jawline, and neck. The Consensus panel noted that same-session treatment with filler and then toxin was appropriate for patients with chin retrusion and consequent overactivity of mentalis; including Asians, in whom this congenital characteristic is quite common. For the masseter, clinicians were advised to: (1) distinguish muscular hypertrophy from parotid gland hypertrophy or muscular prominence caused by volume loss and (2) [fig_ref] Figure 3: Video [/fig_ref] presents results of the premeeting panel surveys. lists key points for the upper, mid, and lower face. Tables 5 through 7 provide consensus toxin dosages and representative filler product selections for combined treatment. The panel did not recommend specific changes in dosing or product selections compared to solo treatment, which is discussed in other Global Aesthetics Consensus Group publications. [bib_ref] Global Aesthetics Consensus Group: Botulinum toxin type A. Evidence-based review, emerging concepts,..., Sundaram [/bib_ref] [bib_ref] Global Aesthetics Consensus Group: Hyaluronic acid soft-tissue fillers: Evidence-and opinion-based review and..., Liew [/bib_ref] They noted that the frequency of re-treatment may decrease when fillers and toxin are combined. summarizes consensus recommendations and position statements. 78

## Consensus recommendations for combined treatment

# Conclusions
Combined treatment was originally advocated to address aspects of facial aging that were regarded as distinct. Volume restoration with fillers ameliorated facial folds and contours. Weakening of overcontracting muscles with botulinum toxin improved hyperdynamic rhytides. The lower face was viewed as most appropriate for combined treatments. The potential for 

## . global aesthetics consensus group recommendations and position statements for combined treatment with hyaluronic acid fillers and botulinum toxin type a in diverse patient populations

## Recommendation or position statement
Tables 5 through 7 present consensus recommendations for botulinum toxin type A dosage and hyaluronic acid product selection, in combined treatment of the upper, mid, and lower face and the neck. R Combined treatment with hyaluronic acid fillers and botulinum toxin is a standard of care, for which it is appropriate to consider and evaluate every patient. R Recommended dosing of botulinum toxin in combined treatment is the same as for botulinum toxin alone. R Recommendations for hyaluronic acid filler product selection are the same for combined treatment as for these fillers alone. R The aim of treatment with fillers and botulinum toxin may be best understood as age-appropriate harmonization of facial proportions and contours. R There is no upper age limit for treatment with fillers or botulinum toxin. Patient selection at all ages is based on the same safety and efficacy criteria. R Preventive or early treatment with botulinum toxin is a treatment option in appropriately selected younger patients. R Treatment of patients younger than 18 yr with fillers or botulinum toxin should be considered carefully from an ethical perspective. The appropriate objective is correction of congenital or acquired disharmonies, rather than facial enhancement. R Ethnically appropriate treatment with fillers and botulinum toxin entails integration of a patient-tailored approach, including analysis of facial morphotype, with individual and cultural expectations. R Gender-appropriate treatment with fillers and botulinum toxin requires different strategies in men than in women. In particular, feminization of the male face should be avoided. R A total of no more than 4 ml per treatment session is recommended for deep volumizer Vycross filler.
For volume efficiency, it is best implanted by means of needle microboluses or cannula dispersion. Significant improvement in facial contours is achievable with as little as 2 ml. Reevaluation of patients after treatment can determine the necessity for injecting further product. R Reevaluation of patients 2-4 wk after treatment with fillers or botulinum toxin is beneficial to optimize outcomes and patient satisfaction. R The response rate to botulinum toxin type A is very high. Partial or complete nonresponse occurs rarely. In cases of apparent nonresponse, practitioners should first consider the possibility of inappropriate patient selection, inadequate dosing, or incorrect placement of injection sites. The Consensus panel has not noted any relationship between a specific botulinum toxin product and either nonresponse to treatment or alleviation of nonresponse. R Any procedures that deepithelialize the skin, or cause tissue edema, such as laser resurfacing, should be avoided on the same day as filler or botulinum toxin procedures. PS Diversity of ethnicity, skin type, and gender is desirable for subjects enrolled in studies to evaluate the safety and efficacy of solo and combined treatment with fillers and botulinum toxin. PS R, recommendation; PS, position statement. synergy and importance of individualized treatment planning were recognized. The Global Aesthetics Consensus Group's recommendations reflect growing use of combined treatment for the lower face, and also for the upper face and certain areas of the midface. The principle of individualization has been extended to a fully patient-tailored philosophy. This integrates considerations of physiologic and chronologic age, sex, ethnicity and its associated facial morphotypes, and cultural overlays. Lower dosing of botulinum toxin modulates the activity of excessively contracting muscles rather than paralyzing them. The contribution of volume deficits in the soft and hard tissues to muscular activity is increasingly recognized. Research continues to deepen our understanding of how scientific balances in hyaluronic acid fillers influence their indications and clinical performance. The current rationale for combining fillers and toxin is that they address intimately related processes. When viewed from this new perspective, the identification of various patterns of muscular activity (e.g., in the formation of glabellar [bib_ref] Glabellar contraction patterns: A tool to optimize botulinum toxin treatment, De Almeida [/bib_ref] or nasal oblique lines 80 ) has significant implications. Rather than serving as a mandate to target all overcontracting muscles with toxin, it provides the imperative to seek and carefully identify the primary cause of muscular recruitment. A focus on aesthetic units, rather than isolated stigmata of aging such as rhytides, is necessary to optimize results from both fillers and toxin. The evolving concepts discussed in this publication direct the clinician toward the creation of panfacial harmony and balance.
[fig] Figure 1: Age-related bony changes are mainly in the periorbital and midcheek zones, including the superomedial and inferolateral aspects of the orbit, the medial suborbital and piriform areas of the maxilla, and the prejowl area of the mandible. Arrows indicate the areas of the facial skeleton susceptible to resorption with aging. The size of the arrow correlates with the amount of resorption. (From Mendelson B, Wong CH. Changes in the facial skeleton with aging: Implications and clinical applications in facial rejuvenation. Aesthetic Plast Surg. 2012;36:753-760. Reprinted with permission from Springer International Publishing AG.  EFE.) [/fig]
[fig] Figure 2: Efficacy of nasolabial fold correction with crosslinked hyaluronic acid filler in patients with Fitzpatrick skin phototype VI. Nasolabial folds are shown before injection and 2 and 24 weeks after injection with Hylacross hyaluronic acid filler. (Above) Before and after injection of Juvederm Ultra. (Below) Before and after injection of Juvederm Ultra Plus. (From Grimes PE, Thomas JA, Murphy DK. Safety and effectiveness of hyaluronic acid fillers in skin of color. J Cosmet Dermatol. 2009;8:162-168. Reprinted with permission from John Wiley & Sons.) [/fig]
[fig] *: Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs 2012;26:e1-e9. Kamm C, Benecke R. Individualized management of cervical dystonia with different serotypes of botulinum toxin: Recent therapeutic advances and risk development of neutralizing antibodies. Eur Neurol J. 2010;2:49-54. Naumann M, Carruthers A, Carruthers J, et al. Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX) across multiple indications. Mov Disord. 2010;25:2211-2218. Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology 2003;60:1186-1188. Yablon SA, Brashear A, Gordon MF, et al. Formation of neutralizing antibodies in patients receiving botulinum toxin type A for treatment of poststroke spasticity: A pooled-data analysis of three clinical trials. Clin Ther. 2007;29:683-690. Aoki KR, Merlino G, Spanoyannis A, Wheeler L. Botox (botulinum toxin type A) purified neurotoxin complex prepared from the new bulk toxin retains the same preclinical efficacy as the original but with reduced immunogenicity. Poster presented at: 51st Annual Meeting of the American Academy of Neurology; April 17-24, 1999; Toronto, Ontario, Canada. Poster 06.109. [/fig]
[fig] Figure 3: Video. Supplemental Digital Content 1 demonstrates transarterial degradation of Vycross and Hylacross fillers, by injection of exogenous hyaluronidase into the surrounding soft tissues, in a fresh, frozen cadaver model in real time. Courtesy of Dr. Mark Magnusson, Dr. Tim Papadopoulos, and the Australasian Society of Aesthetic Plastic Surgery. This content was developed for the Society's Anatomical and Live Injecting Workshop, in association with the Australasian Society of Aesthetic Plastic Surgery Annual Non-Surgical Symposium.  2014 Australasian Society of Aesthetic Plastic Surgery, available in the "Related Videos" section of the full-text article on PRSJournal.com or, for Ovid users, available at, http://links.lww.com/PRS/B683. Consensus panel's practice patterns in the (left) upper face, (center) midface, and (right) lower face, based on premeeting surveys. Percentage use of botulinum toxin alone, filler alone, and botulinum toxin plus filler are shown for each facial zone. Because percentages are rounded to the nearest whole number, they may not add up to 100 percent. PO, perioral; OC, oral commissure; ML, marionette lines. [/fig]
[table] ,20: Disclosure: Andre Vieira Braz, M.D. states that he is a consultant and speaker with Allergan, Galderma, and Palomar. Jean D. A. Carruthers, M.D. states that she is a consultant and researcher with Allergan, Merz and Kythera. Koenraad L. De Boulle, M.D. states that he is a consultant, member of the speaker's board, and recipient of honoraria and grants for studies and lectures for Allergan; a consultant for Kythera and Genevrier; and a consultant and member of the speaker's bureau for Johnson & Johnson. Steven Fagien, M.D. states that he is a consultant/investigator for Allergan, Galderma, Merz, Kythera and Aquavit. Greg J. Goodman, M.D. states that he has no financial interests that would conflict with the manuscript; he serves on advisory boards and speaker panels for Allergan, Galderma, and Merz that may be seen to have an interest in the outcome of a consensus document. Soo-Keun Lee, M.D. states that he is a consultant for Allergan. Steven Liew, F.R.A.C.S. states that he serves on advisory boards for Allergan, Galderma, and Kythera and has received honoraria from Allergan and Galderma for delivering local and international workshops and lectures and trials. Gary Monheit, M.D. states that he is a consultant and clinical investigator for Allergan Corporation (Juvederm), Ipsen/Medicis (Dysport), MELA Sciences, Inc. (MelaFind), Revance, Kythera, Galderma, Mentor, and Merz; a consultant for Myoscience and Qmed; and a clinical investigator for Dermik Laboratories (Sculptra) and Contura (Aquamid). Herve Raspaldo, M.D. states that he is a consultant for Allergan and Galderma. Rod Rohrich, M.D. states that he receives instrument royalties from Eriem Surgical, Inc and book royalties from CRC Press and Taylor and Francis Publishing. Gerhard Sattler, M.D. states that he is a clinical investigator for Allergan, Galderma, Merz, Regeneron and Novartis; a participant in advisory board meetings for Allergan, Galderma and Merz; and a speaker for Allergan, Galderma and Merz. Massimo Signorini, M.D. states that he is a medical expert for and takes part in advisory boards and workshops for Allergan, Inc. Hema Sundaram, M.D. states that she serves as a clinical investigator and/or consultant for Allergan, Cosmo-France, Evolus/Strathspey Crown, Galderma, HaoHai Healthcare, IBSA, Kythera, Merz, and Teoxane. Arthur Swift, M.D. states that he is a speaker, clinical researcher and advisor to Allergan, Galderma and Merz. Ada R. Trindade de Almeida, M.D. states that she is an advisor for Allergan, Merz, Galderma, Roc and Mantecorp and has participated in clinical trials for Allergan. Dr. Trindade is also a speaker for Allergan and Theraskin. Yan Wu, M.D. states that she serves as a clinical investigator for Allergan, GlaxoSmithKline, Lanzhou Biological Products Institute and Freda Biopharm (Shandong hyaluronic acid filler). [/table]
[table] Table 1: Methodology for Global Aesthetics Consensus Group Panel Consensus: Grading of Statements and Opinions Developed during the Conference*  [/table]
[table] Table 3: Typical Products in a Hyaluronic Acid Filler Family Designed for Layered Implantation, and TheirUsual Implantation Depths* [/table]
[table] Table 5: Consensus Recommendations and Expert Panel Opinion Regarding Combination Treatment of the Upper Face* [/table]
[table] Table 6: Consensus Recommendations and Expert Panel Opinion Regarding Combination Treatment of theMiddle Face* Botulinum toxin dosage recommendations may be extrapolated with care, and appropriate dosages, to other toxin formulations. The paradigm of layered hyaluronic acid filler implantation is illustrated by representative product selections for deep volumizer, midlevel, and superficial Vycross, and for Hylacross. Selections may be extrapolated as appropriate to other hyaluronic acid filler families. [/table]
[table] Table 7: Consensus Recommendations and Expert Panel Opinion Regarding Combination Treatment of the Lower Face* DAO, depressor anguli oris. *Botulinum toxin dosage recommendations may be extrapolated with care, and appropriate dosages, to other toxin formulations. The paradigm of layered hyaluronic acid filler implantation is illustrated by representative product selections for deep volumizer, midlevel, and superficial Vycross, and for Hylacross. Selections may be extrapolated as appropriate to other hyaluronic acid filler families. and Reconstructive Surgery  May 2016 rapid effect when applied directly to hyaluronic acid filler lying free within the soft tissue. Courtesy of Dr. Mark Magnusson, Dr. Tim Papadopoulos, and the Australasian Society of Aesthetic Plastic Surgery. This content was developed for the Society's Anatomical and Live Injecting Workshop, in association with the Australasian Society of Aesthetic Plastic Surgery Annual Non-Surgical Symposium.  2014 Australasian Society of Aesthetic Plastic Surgery, available in the "Related Videos" section of the full-text article on PRSJournal.com or, for Ovid users, available at, http://links.lww. com/PRS/B683.] [/table]