Neuromodulators for Skin.

Neurotoxins are the most popular nonsurgical aesthetic procedure for men and women of all ages. Five botulinum toxin A (BoNTA) products represent the current palette of available BoNTA for cosmetic use. Off-label uses of BoNTA continue to expand and are now used for skin rejuvenation, to treat various skin disorders, and in facial nerve paralysis. Dermal and subdermal injections of dilute BoNTA has grown in popularity and been shown to improve skin texture and quality. Common targets for chemodenervation in facial nerve synkinesis are ipsilateral orbicularis oculi, mentalis, depressor anguli oris, buccinator, corrugator muscles, and the ipsilateral and/or contralateral frontalis.

Safety, Pharmacodynamic Response, and Treatment Satisfaction With OnabotulinumtoxinA 40 U, 60 U, and 80 U in Subjects With Moderate to Severe Dynamic Glabellar Lines.

BACKGROUND: OnabotulinumtoxinA 20 U reduces glabellar line (GL) severity at maximum frown for approximately 3 to 4 months. Small studies have suggested that >20-U doses may increase the efficacy and duration of response for GLs. OBJECTIVES: The aim of this study was to evaluate safety, pharmacodynamic response, and treatment satisfaction with onabotulinumtoxinA doses ≥20 U for GLs. METHODS: This 48-week, double-blind study compared 40, 60, and 80 U onabotulinumtoxinA vs 20 U and placebo in women with moderate or severe dynamic GLs on the Allergan Facial Wrinkle Scale. The following parameters were evaluated: the percentage of subjects with investigator-assessed ≥1-grade Facial Wrinkle Scale improvement from baseline at maximum frown (responders) at Week 24; the estimated median duration of response; the proportion of mostly/very satisfied responders on the Facial Line Satisfaction Questionnaire follow-up Items 1 to 5; and treatment-emergent adverse events. RESULTS: The modified intent-to-treat population (N = 226) had a mean age of 48.0 years, with similar baseline GL severity between treatment groups. Week 24 responder rates were 0% for placebo and 16.0%, 32.0%, 30.6%, and 38.5% for onabotulinumtoxinA 20, 40, 60, and 80 U, with significant (P < 0.05) differences for 40 and 80 U vs 20 U. Median duration of response was longer with all higher doses vs 20 U (≥24.0 vs 19.7 weeks; P < 0.05 vs 20 U at Week 24). Facial Line Satisfaction Questionnaire results indicated high subject satisfaction. The incidence and severity of treatment-emergent adverse events did not exhibit a dose-response effect. CONCLUSIONS: GL treatment with onabotulinumtoxinA doses >20 U demonstrated longer duration of response and higher patient-reported satisfaction vs the on-label 20-U dose with no apparent impact on safety variables.

The First of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the safety of prabotulinumtoxinA for treatment of glabellar lines. METHODS: This was a multicenter, open-label, repeat-dose, 1-year phase II safety study. Adults with moderate to severe glabellar lines at maximum frown, as assessed by the investigator on the validated 4-point photonumeric Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), were enrolled. On day 0, patients received an initial treatment of 20 U prabotulinumtoxinA (4 U/0.1 mL freeze-dried formulation injected into 5 target glabellar sites). On and after day 90, patients received a repeat treatment (RT) if their Glabellar Line Scale score was ≥2 at maximum frown by investigator assessment. Safety was evaluated throughout the study. RESULTS: The 352 study patients received a median total dose of 60 U, that is, 3 treatments per year. Fifty-one patients (14.5%) experienced adverse events (AEs) assessed as possibly study drug related; 11.1% experienced study drug-related AEs after the initial treatment. With each RT, progressively lower percentages of patients experienced study drug-related AEs. Six patients (1.7%) experienced study drug-related AEs of special interest: 3 eyelid ptosis (0.9%), 2 speech disorder (0.6%), and 1 blepharospasm (0.3%). Seven patients (2.0%) experienced serious AEs; none were study drug related. Of the 2393 samples tested, 2 patients (0.6%) tested positive for antibotulinum toxin antibodies at a single postbaseline visit. CONCLUSIONS: The safety of RTs of 20 U of prabotulinumtoxinA for moderate to severe glabellar lines was first established in this early phase II study based on a broad range of outcomes.

A Randomized, Blinded, Prospective Clinical Study Comparing Small-Particle Versus Cohesive Polydensified Matrix Hyaluronic Acid Fillers for the Treatment of Perioral Rhytids.

BACKGROUND: Perioral rhytids are a bothersome sign of aging for many patients. Although multiple treatments exist, choosing an optimal modality may be difficult considering that rhytids in this region are fine and the anatomy dynamic. OBJECTIVES: The authors sought to compare the efficacy and safety as well as patient satisfaction of a small-particle hyaluronic acid filler with 0.3% lidocaine (SP-HAL, Restylane Silk) and cohesive polydensified matrix hyaluronic acid filler (CPM-HA, Belotero Balance) in reducing superficial perioral rhytids. METHODS: The study was double-blinded, and 48 patients with moderate to severe superficial perioral rhytids were enrolled. Patients were randomized to receive either CPM-HA in the left perioral region and SPHAL in the right or vice versa. Rhytid severity was measured by patients utilizing a linear analog scale, and by investigators utilizing a validated 5-point scale, for 180 days following treatment. RESULTS: Both SP-HAL and CPM-HA achieved a reduction in rhytid severity, and neither treatment group returned to baseline after 180 days. Investigator-reported scores for rhytid severity were significantly better for SP-HAL than CPM-HA and remained so at 180 days (P < .05). SP-HAL also proved significantly better for reducing rhytids according to patient scores, although this difference occurred between 120 and 180 days only. Adverse events included rash and mild acne for CPM-HA, and SP-HAL was associated with 1 postinflammatory nodule and 2 occurrences of Tyndall effect. CONCLUSIONS: Although both SP-HAL and CPM-HA are effective at reducing perioral rhytid severity and have similar safety profiles, SP-HAL possesses a longer duration of effect.

A Double-Blind, Randomized Clinical Trial to Determine Effects of Increasing Doses and Dose-Response Relationship of IncobotulinumtoxinA in the Treatment of Glabellar Rhytids.

BACKGROUND: IncobotulinumtoxinA is an effective neuromodulator for treating glabellar rhytids. The relationship between dose and reduction in rhytid severity is well established. However, the effects of escalating doses on the treatment duration response are less understood. OBJECTIVES: The aim of this study was to assess the effects of increasing doses of incobotulinumtoxinA on the treatment duration for glabellar rhytids. METHODS: A randomized, double-blind, Phase IV study was conducted at a fully accredited, outpatient surgical facility. Subjects (31 female, 7 male) with moderate to severe glabellar rhytids were randomized to 1 of 3 incobotulinumtoxinA dose groups: 20, 60, or 100 U. Effect duration was determined by calculating the time to return to baseline for dynamic glabellar lines during maximal contraction. Follow-up was completed through 1 year, and adverse events were monitored. RESULTS: The median duration of effect was 120 days (95% confidence interval [CI] [90, 180 days]), 180 days (95% CI [180, 210 days]), and 270 days (95% CI [240, 330 days]) for the 20-, 60-, and 100-U groups, respectively. A Wald chi-square test from the Cox regression on the primary efficacy variable indicated a statistically significant effect of dose group on time to baseline (chi square = 54.63; df = 2; P < 0.001). Hazard ratios were HR = 0.21 (95% CI [0.10; 0.43] for the 60-U vs the 20-U group, and HR = 0.06 (95% CI [0.10; 0.43]) for the 100-U vs the 20-U group, indicating a statistically longer return to baseline for both the 60- and 100-U cohorts. CONCLUSIONS: There is a dose-dependent relationship between incobotulinumtoxinA and duration of effect in the glabella.

A Multicenter Study to Evaluate Subject Satisfaction With Two Treatments of AbobotulinumtoxinA a Year in the Glabellar Lines.

BACKGROUND: Real-world re-treatment intervals for botulinum toxins vary, but most subjects receive treatment less frequently than the manufacturer-recommended minimum intervals. In subjects receiving treatment with AbobotulinumtoxinA (ABO) less frequently, high levels of satisfaction and psychosocial improvements in well-being, self-confidence, and quality of life are observed. OBJECTIVE: To evaluate subject satisfaction with a twice yearly re-treatment schedule. METHODS AND MATERIALS: This open-label, multicenter, interventional study evaluated subject satisfaction following injections of ABO 50 U in the glabellar lines at baseline and 6 months. The primary end point was subject satisfaction at 12 months. Secondary endpoints included subject satisfaction, FACE-Q scales, and glabellar line severity scale (GLSS). RESULTS: Ninety-five percent of the 120 subjects were "highly satisfied" or "satisfied" with their treatment outcomes at 12 months. FACE-Q total scores suggested that subjects were less bothered by glabellar lines and felt better about their facial appearance with each treatment versus baseline. Approximately half of subjects had ≥1-grade improvement from baseline in GLSS at 12 months. Median onset of effect was 2 days. CONCLUSION: The majority of subjects (95%) were satisfied with ABO treatment every 6 months; results were supported by high subject satisfaction, long duration, rapid onset, natural-looking results, and overall psychological wellness and safety.

Nerve Blocks Prior to Microfocused Ultrasound Treatment are Safe and Reduce Patient Discomfort.

BACKGROUND: Microfocused ultrasound with visualization has become one of the more popular nonsurgical facial rejuvenation therapies available. Although the treatment has gained wide acceptance, providing adequate pain relief during the procedure can be challenging. OBJECTIVES: The aim of this study was to test our hypothesis that nerve blocks prior to treatment would be well tolerated and significantly reduce patient discomfort. METHODS: Subjects undergoing microfocused ultrasound were offered the choice of participating in a split face nerve block, bilateral block, or a control group. Nerves targeted included infraorbital, supratrochlear, supraorbital, zygomaticofrontal, mental, great auricular, and cervical plexus. Pain assessment was based on a 10-point Wong-Backer FACES Pain score. RESULTS: A total of 65 patients were included in the study: 28 in the split face group, 19 in the bilateral block group, and 18 without a block. The mean [standard deviation] pain score of the bilateral block cohort was 3.9 [1.2], and that of the control group was 5.1 [1.7] (P = 0.001). Patients in the split face cohort reported a higher pain score on the unblocked side of the face (7.5 [1.3]) than on the blocked side (2.9 [1.0]) (P < 0.001). The mean pain score for local anesthetic injection was 2.7 and 1.4 for the split face and the bilateral groups, respectively. There were no adverse events. CONCLUSIONS: Nerve blocks are well tolerated and significantly improve patient comfort during microfocused ultrasound treatment without compromising outcomes or increasing adverse events.

Safety and Effectiveness of VYC-17.5L for Long-Term Correction of Nasolabial Folds.

BACKGROUND: Juvéderm Vollure XC (VYC-17.5L; Allergan plc, Dublin, Ireland) belongs to a family of hyaluronic acid gels based on the Vycross technology platform. OBJECTIVES: The authors sought to evaluate the safety and effectiveness of Vollure for correction of moderate to severe nasolabial folds (NLFs) over 18 months and after repeat treatment. METHODS: In this prospective, randomized study, patients (N = 123) received initial/touch-up treatment with Vollure in 1 NLF and control filler in the contralateral NLF. Patients received optional repeat treatment with Vollure after month 12, 15, or 18. Assessments included investigator-rated NLF Severity Scale responder rates (≥1-point improvement vs baseline), patient-assessed Appraisal of Nasolabial Folds scale of the FACE-Q questionnaire, and patient satisfaction (11-point scale). RESULTS: Median volume of Vollure injected was 1.7 mL for initial/touch-up treatment combined and 0.6 mL for repeat treatment. The NLF Severity Scale responder rates were 93%, 85%, and 59% at months 6, 9, and 18 after initial/touch-up treatment and increased to 94% at 1 month after repeat treatment. Mean patient-reported FACE-Q scores significantly improved from baseline at all timepoints. Most patients were very satisfied with treatment at all timepoints from day 3 (75%) through month 18 (68%) and at 1 month after repeat treatment (94%). Common injection site responses after initial/touch-up and repeat treatment were firmness, swelling, and tenderness to touch; most were mild/moderate. CONCLUSIONS: Vollure was safe and effective for correction of moderate to severe NLFs, with results lasting 18 months in 59% of NLFs. Repeat treatment required one-third of the injection volume to achieve similar improvement in NLF severity as initial/touch-up treatment.

Efficacy, Safety, and Subject Satisfaction After AbobotulinumtoxinA Treatment for Moderate to Severe Glabellar Lines.

BACKGROUND: The aesthetic use of botulinum toxins is widely accepted in routine treatment of glabellar lines. OBJECTIVE: To strengthen existing efficacy and safety data, and examine subject satisfaction concerning abobotulinumtoxinA (ABO) treatment for moderate to severe glabellar lines. MATERIALS AND METHODS: A 150-day prospective, single-dose, multicenter, randomized, parallel-group, placebo-controlled, double-blind study of 300 subjects treated with ABO (50 Units [U]). Response was defined as having no or mild glabellar lines after treatment (primary objective was Day 30 response). Glabellar line severity, onset and duration of effect, satisfaction, treatment emergent adverse events (TEAEs), and treatment-related adverse events (TRAEs) were assessed. RESULTS: Median time to onset of effect was 2 days. Day 30, ABO treatment response was 89% and 85% for investigator and subject assessments, respectively (p < .001 vs placebo). At Day 120, 60% of subjects demonstrated ≥1 grade improvement and 45% at Day 150. Subject satisfaction concerning glabellar line appearance was high (93%) at Day 14 and maintained by 35% through Day 150 with ABO treatment. No serious AEs were related to study treatment. CONCLUSION: Most ABO-treated subjects sustained ≥1 grade glabellar line improvements over 120 days, and satisfaction was maintained by >30% of subjects throughout 150 days. ABO was well tolerated.

Autologous Fat Harvest and Preparation for Optimal Predictable Outcomes.

Best practices in fat transfer to the face focus on tissue harvest and processing techniques. This article discusses the role of adipose-derived mesenchymal stem cells (MSCs) in mitigating tissue loss in grafting. Discrepancies among common practice and recent study results have propagated uncertainty with long-term results. Fortunately, recent increases in the understanding of these MSCs are leading providers to identify statistically more favorable tissue donor sites, harvest technique, and preparation methods to increase their concentration in transferred tissue. Future studies are needed to support or confound the long-term effects of MSC transfer on facial fat grafting.

Injectable fillers: review of material and properties.

With an increasing understanding of the aging process and the rapidly growing interest in minimally invasive treatments, injectable facial fillers have changed the perspective for the treatment and rejuvenation of the aging face. Other than autologous fat and certain preformed implants, the collagen family products were the only Food and Drug Administration approved soft tissue fillers. But the overwhelming interest in soft tissue fillers had led to the increase in research and development of other products including bioengineered nonpermanent implants and permanent alloplastic implants. As multiple injectable soft tissue fillers and biostimulators are continuously becoming available, it is important to understand the biophysical properties inherent in each, as these constitute the clinical characteristics of the product. This article will review the materials and properties of the currently available soft tissue fillers: hyaluronic acid, calcium hydroxylapatite, poly-l-lactic acid, polymethylmethacrylate, and autologous fat (and aspirated tissue including stem cells).

Efficacy and safety of and patient satisfaction with injectable hyaluronic acid with 0.3% lidocaine hydrochloride for the treatment of superficial perioral lines or superficial lateral canthal lines.

BACKGROUND: It is commonly requested that perioral and lateral canthal rhytides, which result from extrinsic and intrinsic factors, be rejuvenated. OBJECTIVE: To valuate the safety and efficacy of and patient satisfaction with injectable hyaluronic acid (HA) with 0.3% lidocaine hydrochloride in reducing superficial, vertical perioral wrinkles and superficial, horizontal, lateral canthal rhytides. MATERIALS AND METHODS: This was a two-center, evaluator-masked, 180-day study in which 40 patients with moderate to severe superficial, vertical perioral lines or superficial, horizontal, lateral canthal lines were treated at their baseline visit with up to three 0.9-mL syringes of HA (5.5 mg/mL) with 0.3% lidocaine hydrochloride. The investigator and a blinded evaluator assessed patients 7 days after treatment and then every 30 days after the initial treatment session for 180 days. RESULTS: Subjects experienced statistically significant improvement in their superficial, vertical perioral lines and superficial, horizontal, lateral canthal lines and maintained those results for 180 and 120 days, respectively. Three patients experienced delayed-onset periocular nodule formation associated with swelling and erythema at sites of injection, which were histologically consistent with a granulomatous reaction to the product. CONCLUSION: Injectable HA with a particle size of 350 µm was efficacious and resulted in high patient improvement scores in improving moderate to severe superficial, vertical perioral lines and superficial, horizontal, lateral canthal lines. Three of the 40 enrolled patients demonstrated granuloma formation.

Juvederm ultra for lip enhancement: an open-label, multicenter study.

BACKGROUND: Juvéderm Ultra injectable gel (Allergan, Inc, Irvine, California) is approved in the United States to treat moderate to severe wrinkles and folds, such as nasolabial folds. It is also used to enhance the appearance of the lips. OBJECTIVES: The authors evaluated the safety and effectiveness of Juvéderm Ultra injectable gel for lip enhancement and assessed the utility of 3 new lip-specific effectiveness scales. METHODS: In this multicenter study, 50 subjects received lip enhancement with Juvéderm Ultra injectable gel. The subjects were observed closely by the treating investigator and results were evaluated by a blinded independent rater and by subject self-assessment for up to 48 weeks to determine the durability of the effects. A validated lip fullness scale (LFS) was used for analysis. Treatment satisfaction was assessed by investigators and subjects using an 11-point scale. RESULTS: At week 12, 71% of subjects had achieved their goals for lip fullness and had maintained improvement of at least 1 grade on the LFS, which greatly exceeded the a priori criterion of 40% for success. At week 24, improvement in lip fullness was still present for 56% of subjects. Satisfaction and goal achievement exceeded 90% for subjects as well as investigators. Common side effects were predominantly mild or moderate in intensity and resolved within 1 week in the majority of subjects. CONCLUSIONS: Juvéderm Ultra injectable gel is safe and effective for lip enhancement. Scales for assessing lip fullness provide an objective method to determine the effectiveness of treatment.

Current aesthetic use of abobotulinumtoxinA in clinical practice: an evidence-based consensus review.

The amount and complexity of scientific and clinical evidence for aesthetic use of botulinum neurotoxin type A (BoNT-A) has expanded rapidly in recent years, especially for abobotulinumtoxinA, necessitating reassessment of current knowledge about aesthetic use of abobotulinumtoxinA and other BoNT-A preparations. A committee of 13 plastic surgeons, facial plastic surgeons, and dermatologists engaged in a live discussion of information from a systematic literature review and an Internet-based survey of their beliefs and practices. The committee achieved consensus on most issues. It was concluded that doses of different BoNT-A preparations cannot be interconverted with a fixed ratio. The size of the "field of effect" is difficult to measure, and comparisons between preparations have yielded equivocal results. Nonresponse due to neutralizing antibodies appears exceedingly rare with currently available BoNT-A preparations and of little concern clinically. BoNT-A dose, injection depth, and injection technique should be adjusted according to the anatomic area being treated and each patient's individual characteristics and goals. Aesthetic use of BoNT-A has a good safety profile. Most adverse events are minor and related to the trauma of injection, although special care is needed in certain anatomic areas. Detailed recommendations for treatment of different anatomic areas are presented. BoNT-A products are often used in conjunction with other treatment modalities (eg, fillers and resurfacing), but little agreement was reached on best practices. The findings reported in this consensus document may serve as a practical guide for aesthetic practitioners as they apply the latest knowledge about BoNT-A in providing their patients with optimal care.

Facial filler and neurotoxin complications.

Botulinum neuromodulators and injectable dermal fillers have become part of the armamentarium in the treatment of facial aging. Their successful use requires a fundamental knowledge of anatomy and physiology and a sound understanding of their risks and complications. Although neuromodulators and fillers continue to demonstrate a strong record of safety, several notable risks exist.

Split-face double-blind study comparing the onset of action of onabotulinumtoxinA and abobotulinumtoxinA.

OBJECTIVE: To report and discuss the outcome of a prospective, internally controlled, randomized, double-blind, split-face study comparing the onset of action of 2 commercially available botulinum neuromodulators. METHODS: Ninety individuals with moderate-to-severe lateral orbital rhytids were treated with onabotulinumtoxinA, 10 U, and abobotulinumtoxinA, 30 U, for the treatment of lateral orbital rhytids. Participants were assessed live with a validated 5-point photographic scale before treatment and on days 2, 4, and 6 after treatment. Photographs were taken at each encounter. Statistical analysis was applied to evaluate for any significant difference in onset of action between the 2 products. RESULTS: AbobotulinumtoxinA and onabotulinumtoxinA demonstrated statistically significant change from baseline at day 2 in the treatment of lateral orbital rhytids at maximal contraction and rest when evaluated independently by investigator and participant (P.001). Also at day 2, the improvement with abobotulinumtoxinA was better than that with onabotulinumtoxinA for the primary end point of maximal contraction graded by the investigator, although this did not reach statistical significance (P=.21); by day 4, the greater improvement achieved with abobotulinumtoxinA reached statistical significance (P=.02) and remained superior at day 6 (P=.02). The primary findings were strengthened by similar results in the secondary end points of patient self-grade at maximal contraction and at rest and of investigator grade at rest. CONCLUSIONS: In conclusion, both abobotulinumtoxinA and onabotulinumtoxinA achieved statistically significant onset of action at day 2. This improvement was seen in all end points, with abobotulinumtoxinA demonstrating a trend toward greater improvement than onabotulinumtoxinA at day 2 and a statistically significant greater improvement at days 4 and 6 when looking at maximal contraction.

Neuromodulators: available agents, physiology, and anatomy.

Neuromodulators have risen to the forefront of aesthetic medicine. By reversibly relaxing target muscles, neuromodulators exhibit their effect by softening hyperfunctional lines. An understanding of their physiology, relevant facial anatomy, and current agents is imperative for a successful aesthetic practice.

An internally controlled, double-blind comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA.

OBJECTIVE: To compare 2 commercially available botulinum neuromodulators in a randomized, double-blind, split-face study. METHODS: Ninety patients were treated with 10 U of onabotulinumtoxinA and 30 U of abobotulinumtoxinA for the treatment of lateral orbital rhytids. Patients were assessed live with a validated 5-point photographic scale prior to treatment and at 30 days. Patients were also photographed at each visit. RESULTS: AbobotulinumtoxinA demonstrated a statistically significant advantage compared with onabotulinumtoxinA in the treatment of lateral orbital rhytids at maximal contraction, as evaluated independently by the investigator (P = .01) and patient (P = .03). AbobotulinumtoxinA was also favored by the patient over onabotulinumtoxinA 67% of the time. While abobotulinumtoxinA seemed to treat lateral orbital rhytids better at rest, as evidenced by the data and photographs, this difference was not statistically significant (P = .42). CONCLUSIONS: AbobotulinumtoxinA offers superior efficacy in the treatment of lateral orbital rhytids compared with onabotulinumtoxinA. Further studies are needed to compare the 2 products in different muscle groups and for other indications.