Real-world Implications of Botulinum Neurotoxin A Immunoresistance for Consumers and Aesthetic Practitioners: Insights from ASCEND Multidisciplinary Panel.

Background: As long-term, regular aesthetic botulinum neurotoxin A (BoNT-A) use becomes more commonplace, it is vital to understand real-world risk factors and impact of BoNT-A immunoresistance. The first Aesthetic Council on Ethical Use of Neurotoxin Delivery panel discussed issues relating to BoNT-A immunoresistance from the health care professionals' (HCPs') perspective. Understanding the implications of BoNT-A immunoresistance from the aesthetic patient's viewpoint allows HCPs to better support patients throughout their aesthetic treatment journey. Methods: A real-world consumer study surveyed 363 experienced aesthetic BoNT-A recipients across six Asia-Pacific territories. The survey mapped participants' BoNT-A aesthetic treatment journey and characterized awareness and attitudes relating to BoNT-A immunoresistance and treatment implications. At the second Aesthetic Council on Ethical use of Neurotoxin Delivery meeting, panelists discussed survey findings and developed consensus statements relating to the impact of BoNT-A immunoresistance on the aesthetic treatment journey. Results: Aesthetic BoNT-A patients' depth of knowledge about BoNT-A immunoresistance remains low, and risk/benefit communications need to be more lay-friendly. The initial consultation is the most important touchpoint for HCPs to raise awareness of BoNT-A immunoresistance as a potential side effect considering increased risk with repeated high-dose treatments. HCPs should be cognizant of differences across BoNT-A formulations due to the presence of certain excipients and pharmacologically unnecessary components that can increase immunogenicity. Standardized screening for clinical signs of secondary nonresponse and a framework for diagnosing and managing immunoresistance-related secondary nonresponse were proposed. Conclusion: These insights can help patients and HCPs make informed treatment decisions to achieve desired aesthetic outcomes while preserving future treatment options with BoNT-A.

The Use of Hyaluronidase in Aesthetic Practice: A Comparative Study of Practitioner Usage in Elective and Emergency Situations.

BACKGROUND: Hyaluronic acids (HAs) continue to be the fillers of choice worldwide and their popularity is growing. Adverse events (AEs) are able to be resolved through the use of hyaluronidase (HYAL). However, routine HYAL use has been at issue due to perceived safety issues. OBJECTIVES: There are currently no guidelines on the use of HYAL in aesthetic practice, leading to variability in storage, preparation, skin testing, and beliefs concerning AEs. This manuscript interrogated the use of this agent in daily practice. METHODS: A 39-question survey concerning HYAL practice was completed by 264 healthcare practitioners: 244 from interrogated databases and 20 from the consensus panel. Answers from those in the database were compared to those of the consensus panel. RESULTS: Compared to the database group, the consensus group was more confident in the preparation of HYAL, kept reconstituted HYAL for longer, and was less likely to skin test for HYAL sensitivity and more likely to treat with HYAL in an emergency, even in those with a wasp or bee sting anaphylactic history. Ninety-two percent of all respondents had never observed an acute reaction to HYAL. Just over 1% of respondents had ever observed anaphylaxis. Five percent of practitioners reported longer-term adverse effects, including 3 respondents who reported loss of deep tissues. Consent before injecting HA for the possible requirement of HYAL was always obtained by 74% of practitioners. CONCLUSIONS: Hyaluronidase would appear to be an essential agent for anyone injecting hyaluronic acid filler. However, there is an absence of evidence-based recommendations with respect to the concentration, dosing, and treatment intervals of HYAL, and these should ideally be available.

Biostimulating fillers and induction of inflammatory pathways: A preclinical investigation of macrophage response to calcium hydroxylapatite and poly-L lactic acid.

INTRODUCTION: Initial macrophage response to biostimulatory substances is key in determining the subsequent behavior of fibroblasts and the organization of newly synthesized collagen. Though histological studies suggest that calcium hydroxylapatite (CaHA) filler initiates a regenerative healing response with collagen and elastin deposition similar to natural, healthy tissue rather than an inflammatory response with fibrosis, the relative activity of macrophages stimulated by CaHA, as well as how this activity compares to that induced by other biostimulatory fillers, has not been explored. The aim of the study is to characterize the in vitro macrophage response to two biostimulory fillers, CaHA and PLLA (poly-L lactic acid), and to evaluate their inflammatory potential. METHODS: Primary human macrophages were incubated with two dilutions (1:50 and 1:100) of commercially available CaHA or PLLA. After 24 h incubation, an inflammation array was used to screen for the expression of 40 cytokines, released by macrophages. ELISA was used to confirm array results. RESULTS: Four cytokines were significantly upregulated in M1 macrophages incubated with PLLA compared to both unstimulated controls and CaHA: CCL1 (p < 0.001), TNFRII (p < 0.01), MIP-1α (p < 0.05), and IL-8 (p < 0.001). In M2 macrophages, MIP-1α (p < 0.01) and MIP-1ß (p < 0.01) were significantly upregulated by PLLA compared to CaHA and unstimulated controls. CONCLUSION: Together, these findings indicate that the CaHA mode of action is a non-inflammatory response while PLLA initiates expression of several cytokines known to play a role in inflammation. Our study supports the concept that these two "biostimulatory" fillers follow distinct pathways and should be considered individually with regard to mechanism of action.

Surgical or Nonsurgical Facial Rejuvenation: The Patients' Choice.

Background: Patients seeking a pan-facial rejuvenation may not receive appropriate medical advice on surgical versus nonsurgical treatments, resulting in those who are best-suited for surgery receiving nonsurgical options, and vice versa. Patients who requested total-face, nonsurgical revitalization were surveyed to understand the factors influencing this decision-making. Methods: Patients consulting for total facial rejuvenation were surveyed on their reasons for seeking nonsurgical versus surgical interventions by an investigator with 30 years of plastic surgery experience, practicing in a nonsurgical clinic alongside a dermatologist and aesthetic physician. Results: Of the 92 patients surveyed, 78% completed the survey, 47% of whom had considered facelift surgery, and 14% of whom proceeded to inquiries or consultations with a plastic surgeon about facelift surgery. All respondents were women, and age was not an exclusion factor. Forty-four percent would still consider facelifts in later life. Among the most common reasons for choosing nonsurgical approaches were a desire for natural and subtle results, cost, having flexibility in treatment choice, concerns about surgical and anesthesia risks, downtime, the ability to distribute treatments over time, and scarring. Conclusions: Many patients book nonsurgical treatments without prior professional advice, and consider these as a temporary solution, but may desire surgery later in life. Before conducting nonsurgical treatments, doctors should identify this group and avoid interventions that may interfere with optimal surgical outcomes later. Also, some patients desire surgical outcomes when surgery is not a feasible option, and thus seek nonsurgical alternatives. For this group, realistic goals must be set before treatment to avoid disappointment.

Hi5 Protocol for the Use of Microfocused Ultrasound with Visualization.

Background: Microfocused ultrasound with visualization (MFU-V) is used for lifting and tightening of facial tissues. Standard protocols are completed in a single session. Despite excellent outcomes, we identified several barriers of entry for a significant number of patients. Therefore, we devised an individualized pan-facial protocol that is delivered as a series of short, intense treatments to address these issues. Methods: We enrolled 12 participants with mild-to-moderate skin and fibromuscular laxity to receive one superficial and one deep pass per visit (average 280 lines). Qualitative improvements were rated by both patients and physicians at 6 or 10 months due to COVID-19 delays. Changes in the submentum and eyebrow heights were quantified. Results: Ten patients (age range: 31-61 years) underwent an average of four MFU-V treatments. Two patients were excluded after massive weight gain. Skin and fibromuscular ptosis and overall soft tissue laxity improved in all patients. Mean brow height increased by 1.7 mm, whereas the mean submental lift was 78.7 mm2. All patients and treating physicians rated an improvement in appearance, whereas independent physicians rated improvements in 87% of cases. Four patients self-rated as "markedly improved." Pain was rated at up to 6.2 (out of 10). Although mask-wearing was mandatory, loss of elasticity, wrinkles, and skin roughness all improved. Superficial welts (n = 5), erythema (n = 3), tenderness (n = 3), and mild bruising (n = 2) occurred, but all resolved within a few days and no severe or permanent adverse events occurred. Conclusion: The Hi5 protocol was noninferior to standard single-session protocols and improved brow heights and submental lifting.

Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections.

BACKGROUND: The pathogenesis of delayed-onset tissue nodules (DTNs) due to hyaluronic acid (HA) injections is uncertain. OBJECTIVES: To formulate a rational theory for DTN development and their avoidance and treatment. METHODS: A multidisciplinary and multicountry DTN consensus panel was established, with 20 questions posed and consensus sought. Consensus was set at 75% agreement. RESULTS: Consensus was reached in 16 of 20 questions regarding the pathogenesis of DTNs, forming the basis for a classification and treatment guide. CONCLUSIONS: The group believes that filler, pathogens, and inflammation are all involved in DTNs and that DTNs most likely are infection initiated with a variable immune response. Injected filler may incorporate surface bacteria, either a commensal or a true pathogen, if the skin barrier is altered. The initially high molecular weight HA filler is degraded to low molecular weight HA (LMWHA) at the edge of the filler. Commensals positioned within the filler bolus may be well tolerated until the filler is degraded and the commensal becomes visible to the immune system. LMWHA is particularly inflammatory in the presence of any local bacteria. Commensals may still be tolerated unless the immune system is generally heightened by viremia or vaccination. Systemic pathogenic bacteremia may also interact with the filler peripheral LMWHA, activating Toll-like receptors that induce DTN formation. Given this scenario, attention to practitioner and patient hygiene and early systemic infection treatment deserve attention. Classification and treatment systems were devised by considering each of the 3 factors-filler, inflammation, and infection-separately.

Sensory Symptoms Associated with Aesthetic Botulinum Toxin A Treatments.

A retrospective review of patients who switched from onabotulinumtoxinA (onaA) and/or abobotulinumtoxinA (aboA) to incobotulinumtoxinA (incoA) found anecdotal reports of differences in "feel," including a "lighter" feel or treatment-associated tightness. We surveyed the frequency of these sensations as an initial proof of concept of toxin proprioception among our patients who switched toxins. Methods: Seventy-nine patients who had past facial aesthetic treatments with more than one botulinum toxin A (BoNT/A) formulation completed a questionnaire on their experience of treatment-associated sensations, including stiffness or a frozen feeling. Results: Treatment-associated sensations of tightness (47.3%), headache (41.8%), heaviness (38.2%), feeling frozen (29.1%), stiffness (20.0%), and weakness (20.0%) were reported by 55 of 79 patients. Furthermore, 78.2% of 55 patients noted an interformulation sensory difference. Of 79 patients surveyed, 68.4% of onaA-treated patients associated sensations with onaA, 39.1% of aboA-treated patients associated sensations with aboA, and 12.2% of incoA-treated patients associated sensations with incoA. Conclusions: Some patients reported a different feel between toxins, and the difference in frequency of treatment-associated sensation varies between the different formulations used. Given the fine coordination of facial expressive muscles, we suspect that associated proprioceptive afferents are involved. Our findings confirm that post-toxin treatment-associated sensations can be detected by some patients, and this is likely due to the variations between the formulations. Failing to advise patients of this before switching formulations may cause a misperception that the treatment is not working well or that its effect has worn off prematurely, and some patients may consider switching formulations to reduce these conscious proprioceptive sensations.

Creating Lift in the Lower Face With Botulinum Toxin A Treatment: An Anatomical Overview With Videos and Case Studies Illustrating Patient Evaluation and Treatment.

Background: Relaxation of depressor muscles in the lower face with botulinum toxin A (BoNT-A) can create a lifting effect and dramatically improve jawline contour and resting facial expression. Even with the recent increase in interest in lower face rejuvenation, BoNT-A is a relatively under-recognized tool for treatment of this area. When treating the lower face, an understanding of anatomy and the relationship between the facial muscles is especially important, as injection patterns must be customized for consistently positive outcomes. Objectives: This study was aimed to provide basic knowledge of the activities of the muscles in the lower face and neck and to describe the basis for injecting BoNT-A to create lift in this area. Expert guidance for injection is also provided. Methods: As part of a continuing medical education course on differentiating botulinum toxin products, a panel of 4 expert physician injectors participated in a live webinar to discuss the implications of increasing toxin use. Results: The practical guidance in this manuscript is based on the most frequently requested information by audience members and the information considered critical for success by the authors. The authors outline the functional anatomy of the lower face most relevant for BoNT-A treatment and case studies as well as methods for patient evaluation and injection technique are also provided. Videos showing treatment planning and injection technique for the lower face and neck are included. Conclusions: BoNT-A is an important nonsurgical tool for creating lift in the lower face.

Emerging Trends in Botulinum Neurotoxin A Resistance: An International Multidisciplinary Review and Consensus.

Botulinum neurotoxin A (BoNT-A) injection is the most widely performed aesthetic procedure and a first-line therapeutic option for various medical conditions. The potential for BoNT-A immunoresistance and secondary nonresponse related to neutralizing antibody (NAb) formation warrants attention as the range of BoNT-A aesthetic applications continues to expand. Methods: An international multidisciplinary panel reviewed published evidence on BoNT-A immunoresistance in aesthetic and therapeutic applications and discussed best practices integrating clinical, ethical, and aesthetic considerations. Consensus statements relating to awareness, assessment, and management of the risk of NAb-related secondary nonresponse in aesthetic practice were developed. Results: There was a consensus that, as doses used in aesthetic practice become like those in therapeutics, rates of NAb formation may be expected to increase. However, the true extent of NAb formation in aesthetics is likely underestimated due to limitations of published evidence and variability in treatment patterns of aesthetic patients. Since BoNT-A therapy is often lifelong, practitioners need to recognize immunogenicity as a potential complication that might affect future therapeutic use and strive to minimize modifiable risk factors. The selection and use of a BoNT-A product with the least immunogenic potential from the beginning may thus be advantageous, especially when treatment with high doses is planned. Conclusions: In view of current trends in BoNT-A aesthetic use, it is essential for practitioners to conduct thorough clinical assessments, inform patients of treatment risks, and develop BoNT-A treatment plans to minimize immunogenicity. This can help preserve the option of continued or future BoNT-A treatment with satisfactory outcomes.

Immunogenicity Associated with Aesthetic Botulinumtoxin A: A Survey of Asia-Pacific Physicians' Experiences and Recommendations.

Background: Most botulinum toxin A (BoNT/A) products contain unnecessary bacterial components that increase the risk of developing neutralizing antibodies (nAbs). Reports of secondary nonresponse and treatment failures (STF) due to nAbs have accompanied a surge in new BoNT/A products. Methods: To formulate recommendations on managing toxin resistance, we reviewed the evidence on BoNT/A-associated immunogenicity and evaluated Asian physicians' current BoNT/A practices, knowledge, and real-world experiences, as provided by survey outcomes conducted with 128 Asian experts (regular botulinum toxin injectors). Results: Most doctors believe STF occurs, some patients exhibit partial symptoms, and impurities (eg, complexing proteins) in BoNT/A preparations risk STF. Bioassays that distinguish non-nAbs from nAbs that hinder toxin function remain unavailable to most doctors, though most would perform testing if given the option. Doctors in the Asia-Pacific region have differing strategies for managing STF, depending on the availability of alternatives or tests. They recommended switching to a highly-purified formulation free of complexing proteins and other impurities to lower the risk of immunogenicity, or offering treatment holidays of 2 -2.5 years. They suggested restarting treatment with the same highly purified formulation, especially for repeated treatments, large-dose injections, and younger patients who will accumulate higher lifetime doses, so as to minimize immunogenic risks and preserve long-term treatment outcomes. Importantly, doctors should always initiate patients on pure formulations rather than switching to these only after resistance develops. Conclusion: Choosing highly purified BoNT/A products at treatment initiation enhances long-term efficacy and patient satisfaction while minimizing the risk of immune activation and nAb formation.

Movement of the Syringe During Filler Aspiration: An Ultrasound Study.

BACKGROUND: Aspiration prior to hyaluronic acid filler injection is often taught as a safety maneuver to minimize the risk of intravascular injection; however, the validity of this technique in aesthetic practice is being increasingly challenged. One key assumption underpinning the validity of the aspiration test is that the needle tip does not move during the aspiration and subsequent injection of filler. OBJECTIVES: The aim of this study was to visualize and measure needle tip movement in real time during aspiration and injection of filler. Secondary objectives were to assess the impact of injector experience and double-handed versus single-handed aspiration technique in maintaining stability of the syringe. METHODS: Under real-time ultrasound visualization, 3 injectors with different levels of experience injected hyaluronic acid filler into pork belly tissue utilizing both double-handed and single-handed aspiration techniques. Needle tip movements were recorded and measured by means of ultrasound and video. RESULTS: The aspiration maneuver is in all cases associated with retrograde movement of the needle tip, ranging from 1.1 to 5.3 mm (mean, 2.9 mm), whereas injection leads to anterograde movement ranging from 0.6 to 4.1 mm (mean, 1.9 mm). Double-handed aspiration is associated with less needle tip movement than single-handed aspiration (P = 0.037). Greater experience is also associated less movement of the needle tip (P < 0.0001). CONCLUSIONS: In all cases, the aspiration and injecting maneuver is associated with micromovements of the needle tip, of a magnitude consistently significant relative to the typical size of facial vessels. Although needle tip movement is only a single factor limiting the usefulness of the aspiration test, the results of this study suggest that it is not advisable to rely only on aspiration as a method to prevent intravascular injection.

Aspiration Before Tissue Filler-An Exercise in Futility and Unsafe Practice.

BACKGROUND: Aesthetic physicians rely on certain anecdotal beliefs regarding the safe practice of filler injections. These include a presumed safety advantage of bolus injection after a negative aspiration. OBJECTIVES: The authors sought to review and summarize the published literature on inadvertent intravascular injection of hyaluronic acid and to investigate whether the technique of aspiration confers any safety to the practitioner and the patient. METHODS: Pertinent literature was analyzed and the current understanding of the safety of negative and positive aspiration outlined. RESULTS: The available studies demonstrate that aspiration cannot be relied on and should not be employed as a safety measure. It is safer to adopt injection techniques that avoid injecting an intravascular volume with embolic potential than utilize an unreliable test to permit a risky injection. CONCLUSIONS: To prevent intravascular injection, understanding "injection anatomy" and injection plane and techniques such as slow, low-pressure injection are important safety measures. Assurance of safety when delivering a bolus after negative aspiration does not appear to be borne out by the available literature. If there is any doubt about the sensitivity or reliability of a negative aspiration, there is no role for its utilization. Achieving a positive aspiration would just defer the risk to the next injection location where a negative aspiration would then be relied on.

Neuromodulating the SMAS for Natural Dynamic Results.

Physicians using neuromodulators need to develop an in-depth and holistic understanding of the facial musculature as a single, large, functional structure that does not work in isolation. In this Special Topic, I review the anatomy of the continuous fibromuscular layer of the face, discuss how certain age-related indications develop as a consequence of imbalances to this unified structure, and propose considerations for neuromodulator-based interventions of the upper, mid, and lower face. I provide evidence-supported recommendations on the most optimal applications of neuromodulators to help rebalance the musculoaponeurotic layer for more natural outcomes. Through outcomes of my patients, I show how the facial mimetic muscles can be modulated with careful placement of botulinum toxin, without causing unnatural facial expressions, to achieve an expressive, well-balanced face that reflects health, vitality and happiness.

An Alternative Periorbital Treatment Option Using Calcium Hydroxyapatite for Hyperpigmentation Associated with the Tear Trough Deformity.

BACKGROUND: The nasojugal groove or tear trough (TT) area deformity produces visible, pigmented, difficult-to-treat hollows. Hyaluronic acid (HA) filler-based correction yields variable results and complications. We developed an alternative, minimally invasive treatment for this area. METHODS: Patients with significant, visible TT area pigmentation, and/or those requiring corrections for TT filler removal, were given lignocaine-diluted calcium hydroxyapatite (CaHA) fillers. CaHA boluses were placed deep on the bone, under the origin of the orbicularis retaining ligament, and under the sub-orbicularis oculi fat. Diluted CaHA was used as a subcutaneous biostimulatory wash. Efficacy and complications were assessed using the Global Aesthetic Improvement Scale and a modified Tear Trough Rating Scale, at 4 and 18 months. RESULTS: Twelve patients, between 25 and 52 years of age, were treated and showed immediate improvements in hyperpigmentation due to light reflection and some visibility of the filler through skin. Lower eyelid swelling and redness occurred a few days postinjection but resolved spontaneously. Over 4 to 6 months, hyperpigmentation and skin tone, thickness, and color improved noticeably. Global Aesthetic Improvement Scale and modified Tear Trough Rating Scale scores indicated that all patients experienced satisfactory improvements. Three prior HA patients required a second CaHA treatment at 4-6 months for a satisfactory correction, one of whom required a third CaHA "wash" at 10 months. Some mild redness was observed for up to 12 weeks in a few patients; however, no differences in the degree of redness were observed between those treated for dark circles or post-HA correction. One patient experienced a persistent, dull erythema for 8 months; another had overt erythema and swelling following a chest infection which resolved with antibiotics and hydrocortisone cream. No nodules developed in any patient. CONCLUSIONS: We developed an alternative TT deformity treatment that leverages CaHA unique rheology and neocollagenesis-stimulating ability, which lifted and supported the prolapsing orbicularis retaining ligament, improved skin quality, and rejuvenated the periocular area without direct injections into the TT.