COMMENTARY
Asian Consensus Recommendations on the Aesthetic Usage of Botulinum Toxin Type A MICHAEL A.C. KANE, MD*
The author is a consultant to Allergan, Valeant, Merz, Galderma and Prevalence
A
sian Consensus Recommendations on the Aesthetic Usage of Botulinum Toxin Type A is an ambitious and thoughtful addition to the scientific literature.1 It is not easy to produce such a paper. Whether as a member2–4 or chairman5 of such an endeavor, it is a difficult undertaking for many reasons. It is always difficult to get a group of experts to agree on anything, let alone something as challenging, personal, and artistic as injection of botulinum toxin type A (BoNT-A). As the authors indicate, although there are several consensus papers with guidelines for Caucasian patients, these guidelines are not directly applicable to Asian patients. There are several reasons given for this nontransferability, but the one that I think is most important is the artistic “notions of beauty” that the authors discuss. Although I believe that there is an increasing convergence of beauty ideals globally, there are still real differences in how people from different parts of the globe see each other. Anatomic differences aside, Asian beauty is not the same as Caucasian beauty. One anatomic difference I would like to add to the authors’ list of skin differences and muscular anatomy differences is the difference in fat anatomy. As Pessa6 has pointed out, during the aging process, discrete fat pads below the skin behave differently. With the difference in amount and distribution of facial fat being so different between Asian and Caucasian people, there is no reason to believe that the aging of their fat would be identical.
As with any consensus paper, there are some assertions that are clearly true, some that are controversial, and some that an individual reviewer finds somewhat shocking. This paper starts out with a whopper: that with the exception of Dysport, all of the other botulinum toxin type A formulations (Botulax, BTXA, Neuronox, and Xeomin) are equivalent to the accepted standard of the authors – Botox (Allergan, Irvine, CA). This would assume that the potencies of all of these formulations, as well as their dose– response curves are identical. Two consensus or review papers7,8 and an animal study9 (all 4 years or older) are given as the basis for this bold assertion. By contrast, more than a dozen papers in the scientific literature have compared the potency of Botox with that of Xeomin. Perhaps the most quoted is the Sattler paper10 comparing Botox with Xeomin at 24 U to the glabella in 381 patients, which showed extremely similar responder rates at weeks 4 and 12. There are also focal dystonia papers wherein investigators treat blepharospasm (in 256 patients)11 and cervical dystonia (in 463 patients)12 prospectively with equal but varying doses of Botox and Xeomin with similar efficacy at their primary endpoints, but there is also a basic science paper13 and a clinical experience paper14 that propose that Botox is more potent than Xeomin, but neither paper contains a clinical, prospective, randomized, equidose trial. Of interest is the fact that the authors assign Dysport a dose ratio of 2 to 4:1 when compared to all of the other BoNT-As. I am
*Plastic Surgery, Manhattan Eye, Ear & Throat Hospital, New York City, New York © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:1861–1867 DOI: 10.1111/dsu.12369 1861
AESTHETIC USAGE OF BOTULINUM TOXIN TYPE A
unsure whether the authors could not quite come to a consensus, which brought about the wide range, or if they all (or mostly all) agreed that there is a true range. If it is the latter, then I absolutely support this rather wide dose ratio range. All drugs have a dose–response curve. Every time I have seen comparable dose– response curves for Botox and Dysport, I have noted that they were not parallel. Unless the curves are parallel, there cannot be a single coefficient to compare the potency of the drugs but rather a sliding scale. I differ with the authors, however, on the statement that Dysport has different strains of origin than the other formulations. Dysport, Botox, and Xeomin are all derived from the Hall strain.15,16 There are different subtypes and the potential for sequence variation,17 but they are from the same family tree of the Hall strain. For the purpose of this review, I will accept the authors’ assertion of equipotency and note that the toxins primarily used were Neuronox and Botox. Where I discuss my dosing of patients, I will use the authors’ standard of Botox units. The authors and the consensus panel, The Korean Academy of Corrective Dermatology, are Korean. The majority of the patients they treat are Korean. Care must be taken when assuming that treatment of Korean patients can be extrapolated across all of Asia. The Caucasian consensus papers come from the United States,2–5 which has a heterogeneous Caucasian population, or European authors from several different countries.18,19 The Europeans might have had different recommendations based on skin thickness, facial shape, and notions of beauty if all of the experts and most of the patients were only from Spain or Ireland or Eastern Europe or Scandinavia. The authors also recommend reconstituting a 100-U vial with 2.0 mL of saline. Why? No rationale is given. Care is taken to report the results of a questionnaire given to 500 Korean doctors by a pharmaceutical company. The results of this questionnaire reveal that the most common reconstitution volume is 2.5 mL, and only 21% of respondents used 2.0 mL, yet the dogmatically recommended reconstitution volume is 2.0 mL, with no explanation
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given. I have never understood reconstitution recommendations. I know expert injectors who reconstitute with 1.0 mL and experts who use 6.0 mL. I have used 4.0 mL per 100-U vial since 1991. All that matters is how many units one delivers to which neuromuscular junctions. How they get there is up to the judgment, planning, and skill of the injector. The first anatomic area that the authors discuss is the forehead and frontalis. I agree with the authors’ discussion that Asians tend to have less contractility and wrinkles in the forehead than Caucasians. The dose range recommended (6–13.5 U) may seem a bit high at first glance owing to the relative lack of motion of Asian foreheads. My median frontalis dose is 4 U for Caucasians, but the authors note that Korean foreheads are wider, and they recommend intradermal injections for Asians versus intramuscular injections for Caucasians. This explains some of the higher-than-expected dosage because many more units will not find their way to neuromuscular junctions from the thick forehead skin, and there is more surface area to cover. The intradermal recommendation is not explained. One thing I disagree with is the regimented approach to the forehead with five equidistant injection points exactly 2 cm above the brows and another four points 1 to 1.5 cm above the first line. Another concept I strongly disagree with is the frequently espoused idea not to inject the lower frontalis. All patients are individuals and need to be approached as such. Not treating the lower frontalis while diffusely weakening the upper frontalis often leads to an unnatural appearance to my eye and can contribute to suprabrow rhytides. Admittedly, suprabrow rhytides are less commonly a problem in Asian patients, but they still occur. The authors state that the glabella is the most treated area in Asians. This is also my most frequently treated area in Caucasian patients, but in my Asian patients, I think the glabella is tied with the crow’s feet area for most common injection site. The forehead is a distant third in my practice when considering the three upper face areas. There is a geometric description of injection points based partially on the brow (do
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Asians not pluck and shape their brows as often as Caucasians? This can make for quite a mobile landmark), which I reject based on its regimented nature. Happily, there is some wiggle room, with a recommendation of three or five injection points, but I agree wholeheartedly that Asian corrugators are shorter and require significantly fewer units than Caucasian corrugators.20 Their recommendation of 8 U for the glabellar complex is also my median dose for Asian patients. My median dose for Caucasian patients with their longer corrugators is 15 U. The next treatment area to be discussed is that for brow lifting. Personally, I reject this as an area. I have fought this in consensus conferences that I have been a part of. Lifting of the brows is a complex interplay between the lateral brow depressors, the medial brow depressors, and a differentially weakened brow elevator. It is not a simple treatment but a delicate balance between the three most commonly treated areas of the upper face. I believe that the height and shape of the brows illustrates one of the greatest discrepancies between Asian and Caucasian ideals of beauty. Caucasian patients frequently or nearly always request or desire some degree of brow elevation. My Asian patients only rarely do so, but an even greater difference exists in desired brow shape, as the authors point out. Asian patients do not like the “ideal brow,” with a sharp lateral peak. Good for them. I never appreciated the concept of the ideal brow myself but rather a brow that matches one’s face. My Asian patients frequently remind me that they do not want… and then they manually lift their lateral brows. They are not showing me a Mephisto or Spock brow. Rather, they fear what their Caucasian contemporaries actually desire – a lateral peak. A mild elevation is considered all right as long as the peak, if present, is soft and more medial. The authors get this exactly right. Maybe this was a loquacious way to say they that they hit the nail on the head with their first nine words of this section “brow lifting is not a popular procedure in Asia.” The next section addresses the treatment of crow’s feet, a common treatment for Asian patients. I have
found that this is usually the first area for which my younger Asian patients seek treatment. The injection pattern described is a familiar three-point pattern well lateral to the lateral canthus commonly described for Caucasian patients. I prefer to inject patients based on their functional anatomy, with more units placed in the dominant neuromotor units21 rather than a standard pattern. The authors say that “the degree of periorbital wrinkling is higher in Caucasians than Asians,” and I fully agree, but I would add that Asians are much less tolerant of these wrinkles than their same-aged Caucasian patients. I agree with the authors’ assumption that muscle fiber size is probably smaller in Asians and their skin is thicker, which is why their lateral canthal lines are less severe. Because they are less severe, and the contractions of the orbicularis oculi are less forceful, recommended doses are less, but because these smaller lines conflict more with Asian standards of beauty, they are injected in a greater percentage of my patients. The authors note that injections in Asians should be intradermal as opposed to intramuscular like in Caucasians, but the consensus papers cited22 are older papers. Newer recommendations and most physicians inject intradermally or just above the muscle when treating Caucasian patients. Infraorbital wrinkles are discussed next. The authors state that these wrinkles are commonly treated in Asian patients, and I agree. I tend to inject the area a bit more cephalad than their recommended 1 cm below the lash line, but this is a variable point for me – I inject directly into the neuromotor units that are primarily causing the rhytides, and this is highly variable. The authors’ analysis of the “jelly roll” versus the “charming roll” and the different way that Caucasian and Asian patients see this fullness is excellent, but I would like to add a third group to the discussion at this point in the commentary: younger, fully assimilated women who see themselves more as American than Asian. Over the years, many of my Asian patients have seemed pleasantly surprised when it became apparent that I understood the attractiveness of this roll to Asian eyes and preserved
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it and sometimes even augmented it with a little hyaluronic acid filler. In the last 6 months, I have had two young (late 20s/early 30s) patients request that I remove the “bags” under their eyes, which were not infraorbital fat but pretarsal muscle. When I explained to them that this bulge was a sign of beauty of Asian eyelids, especially to Asians, they looked at me as though I were from another planet or, more likely, another century. Maybe they had a point. Here I was, a Caucasian man, telling Asian women that their Asian eyes looked better to other Asians with the roll intact because Asian people had a different cultural ideal of beauty when it came to Asian eyelids. It does seem rather ridiculous when written. I rarely inject the full roll in Caucasians because, except for young patients with a fairly taut lower lid, I find the small retraction of the lower lid outweighs the benefits of fewer rhytides. A bowed lower lid is a senile change. Asian patients, with their higher lower lid position can withstand a drop of a millimeter or so (as long as the roll stays intact) better than their Caucasian contemporaries. Asian patients may also benefit from the appearance of larger eyes. Caucasian patients rarely look better with bigger eyes if the apparent size increase is due to a lower and hence more senile lower eyelid margin. The authors address bunny lines next and state that these injections are “not uncommon in Asia” and need more units than Caucasian bunny lines. I agree on both points. I think this is the wrinkling area with the largest discrepancy in incidence between Caucasian and Asian patients. In my Caucasian neuromodulator population, I estimate that approximately 15% of the patients walking through my door receive nasalis injections. About half of my Asian patients have this area treated. It is also the only area (besides the masseter) where I routinely require more units for Asian patients, with a median of 5 U for Asians and 2.5 U for Caucasians. Nasal shaping is next on the list, and I agree with the authors that nasal flare is a common indication in Asian patients and in my experience much less common in Caucasian patients. The exception to this is
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in Caucasian patients with postrhinoplasty deformity, who often lack tip support and are poor operative candidates or understandably do not want another operation. The lack of tip support causes further alar spread, which can be ameliorated slightly with neuromodulator injections to the ala. Because of scar tissue in these patients, I usually inject at two to three points per ala rather than the one point described. These patients often also receive concomitant hyaluronic acid filler injections along the dorsum, tip, and columella. With their lack of dorsal height, small amount of alar cartilage remaining, poor tip support, and wide nasal ala, the overresected Caucasian patient is somewhat analogous to the Asian (or perhaps more accurately, non-Japanese Asian) primary nasal patient, and the injection planning for fillers and toxins is similar. Injection of a tip-raising neuromodulator is a different question altogether. The first time I presented nasal tip elevation with toxins at a national meeting was 1996,23 and it became a part of my presentations for a few years. It is one of those things that I used to teach that I now regret. I agree that it may seem as though some patients get a little tip elevation from injection of the depressor septi muscle as described, but I think it is mostly illusory. In 1998, I wanted to give a presentation solely devoted to tip elevation with toxins instead of the usual one or two cases I was showing. So I sorted through boxes of old Kodachrome slides and was rather embarrassed with what I found. In beforeand-after slides matched for positioning, posture, and smile effort, I found almost no change in true nasal tip height but rather a drop in the lip columellar junction. Some patients had a slight elevation to the tip, but the tip to the untrained eye appeared to be significantly elevated. Although I could take an acute lip columellar angle and make it more obtuse, the tip itself was rarely actually raised a significant amount. Perhaps I am arguing semantics here because this change frequently fools the patient, their injectors, and (formerly) this author into thinking the tip is elevated, I prefer to be more anatomically precise in what I am describing. If you want to say that toxin predictably opens the lip columellar angle, which gives the appearance of an elevated nasal tip, I am with you all the way. This is analogous to adding a bit of filler along the anterior
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mandibular jawline to decrease the appearance of the jowls. When I do this, I do not claim to be raising the jowl, just making it appear less obvious. Perioral wrinkles are addressed next, and the authors are correct when they state that this is less frequently performed in Asians than Caucasians. Because the authors do not state an opinion as to why they think this happens, I will do so here. Such is the advantage of writing a free-form commentary over a rigorous consensus paper. I think the thickness of Asian skin retards the development of rhytides, and the large size of Asian lips makes even larger size after orbicularis oris injection not so beneficial. The authors describe a four-point technique that I abandoned also in 1998. When I examined my old Kodachromes carefully, it became apparent that I was not getting even spread of neuromodulator throughout the lip and was having areas of hypomotility abutting areas with more normal motion. So I began to dilute my toxin a bit more and inject it in a horizontal spreading manner.24 I have never had speech impairment but nearly always will be told that drinking through a straw is difficult. I do not consider the latter (or the appearance of larger lips) to be a complication but rather a treatment guide to appropriate dosing. The gummy smile, one of my favorite indications, is discussed next. The authors do not comment on incidence, but I believe a gummy smile is slightly more common in Asian patients in my general neuromodulator population. In 1999, I presented a paper on the gummy smile that was published a few years later.25 This may have skewed the incidence in my patient population for a few years because these patients were frequently referred to me. The authors’ injection placement is lateral and inferior to mine as they seek to weaken the levator labii superioris alaeque nasi, levator labii superioris, and zygomaticus minor. I only want to weaken the levator labii superioris alaeque nasi because this more precisely affects the central upper lip, whereas injecting all three muscles tends to drop the entire lip. With a patient with a typical gummy smile, I do not want to drop the entire lip. Part
of the deformity (besides seeing a lot of gingiva) is the unfavorable canine smile pattern,26 which results from too much central upper lip elevation. So, in most patients with a gummy smile, I see two problems; the upper lip is too high, and its shape is unpleasant because it is too high centrally relative to laterally. Dropping only the central upper lip 2 to 3 mm is my goal, with the higher, more medial injection point at the nasal bone and maxilla groove. The authors state that drooping of the mouth corners is a risk of their technique. This can be reduced by leaving the lateral upper lip elevators alone. The authors state that “use of BTA alone in treating marionette lines is regarded as difficult and risky,” and so it is not commonly done. I agree strongly that marionette lines are rarely injected in Asian patients but not because it is risky. I rarely do it because it is rarely indicated. I think this is one example of the way that most Asian faces animate differently than Caucasian faces. Conversely, it is my most commonly injected lower face area in Caucasian patients. I inject much lower doses than the 6 to 10 U recommended.27 These 6 to 10 U of the authors are injected into the depressor anguli oris (DAO) alone. This is risky. I sometimes inject both the DAO and depressor labii inferioris depending on the functional anatomy of the patients’ smile. My median total dose in Asian patients is 3.75 U. The dimpled chin and mentalis is next. This is an area where I differ strongly with the authors over injection technique. The superficial surface of the mentalis muscle is covered with fascia that has strong fibrous septae running to the dermis above. These septae transmit the surface topography of the muscle to the skin. Therefore, smoothing the superficial mentalis is critical for success. Just as important is keeping as much deep muscle active as possible. The mentalis supports all of the soft tissues of the chin medial to the mandibular ligament to the pogonion. It is essential for lower face support and oral competence. Keeping as much of the deep muscle functional while keeping the superficial muscle quiet is the key to reducing complications and ptosis of the lower face. Therefore,
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I disagree with the deep, perpendicular injections described and instead place several threads parallel to the skin surface along the superficial muscle fibers, aiming for the muscle–septae interface. The masseter is commonly injected in Asian patients. Of my Asian patients, I inject the masseter most commonly in patients of Korean descent. The authors recommend a common three-point pattern based on facial geometry. As you might suspect, I do not inject the masseter in a set pattern but in an individualized manner based on patients’ functional anatomy.28 I have the patients relax and clench repeatedly and inject the bulk of my neuromodulator where the muscle is most hypertrophic – it is really very simple. The three-point technique described is a good and safe basic technique that minimizes complications but will sometimes have you injecting into areas that are not very dynamic. Perhaps this is why the authors’ recommended dose range for Asian patients of 50 to 60 U is a bit higher than mine at 30 to 40 U. My dose range for most Caucasian patients is 15 to 20 U. Here is another area where different ideals of beauty come into play. Asian patients in general prefer a heartshaped face with a soft lateral jawline. Caucasian patients often prefer the appearance of a strong mandibular angle. For this reason, in Caucasian patients, I often inject a large masseter or a masseter in a teeth grinder with neuromodulator and at the same time add definition along the mandibular angle with a calcium-based or hyaluronic acid filler. I agree with everything the authors write about the treatment of platysmal bands.29 I would further postulate that the reason Asian patients seek this treatment less often is because they ahve thicker skin and what appears to me to be a favorable retention of more evenly distributed subcutaneous fat over time. I believe that the anterior layers of fat and skin are the key to success with botulinum in this area.30 Calf injections for hypertrophy are rarely done in the west, even among my Asian patients. Perhaps this is another difference between patients of Asian descent in America and Asian patients.
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This is an excellent paper with safe and carefully considered consensus recommendations for the treatment of Asian patients with botulinum. I feel this adds significantly to the scientific literature. Consensus papers are compromise papers that attempt to distill an efficacious technique in as safe a way as possible. In both of these aspects, the authors were successful. I hope I did not appear to be too critical of certain aspects of this paper. In my own consensus papers, I have signed off on things I did not totally agree with – this is what consensus means. In summary, if I had to distill the largest differences in ideals of beauty between my Asian and Caucasian patients, Asian patients are bothered much more by their crow’s feet, do not care as much about brow elevation, do not like the “ideal brow” peak, and are bothered a great deal by gummy smiles and wide jaws. In general, Asian patients do not move their foreheads as much, scrunch their noses more often, have gummy smiles a bit more frequently, do not work their DAOs as strongly, have big masseters, and have favorable skin and fat characteristics in the perioral and neck areas. What cannot be emphasized strongly enough is that we are talking about large groups with billions of members here. Each large group (Asians and Caucasians) is composed of large subgroups (e.g., Chinese, Korean, Japanese, Scandinavian, Northern European, Mediterranean descent) that likewise tend to have distinguishing characteristics when it comes to facial anatomy and ideals of beauty as well. Finally, one gets to the individual. Although we may assign certain anatomic and psychosocial attributes to large groups, they cannot be assigned to individuals. Each individual patient is deserving of your respect and a thorough examination and discussion that avoids plopping them into a convenient stereotype. This is one reason I am so against geometric injection points, standardization of injections, routine dosing, and diagrams of faces with injection points drawn upon them, although these things are helpful for the neophyte injector. I hope, after injecting and following up a few patients, the good injector will get rid of his or her diagrams and tables and individualize a treatment plan for each and every patient.
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References 1. Ahn BK, Kim YS, Kim HJ, Rho NK, et al. Asian consensus recommendations on the aesthetic usage of botulinum toxin type A. Dermatol Surg 2013. 2. Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics. Plast Reconstr Surg 2004; 114:1–22S. 3. Carruthers A, Kane MA, Flynn TC, Huang P, et al. The convergence of medicine and neurotoxins: a focus on botulinum toxin type A and its application in aesthetic medicine – a global, evidence-based botulinum toxin consensus education initiative: part I: botulinum toxin in clinical and cosmetic practice. Dermatol Surg 2013;39(3):493–509. 4. Maas C, Kane MA, Bucay VW, Allen S, et al. Current aesthetic use of abobotulinumtoxinA in clinical practice: an evidence-based consensus review. Aesthet Surg J 2012;32(1):8–29S. 5. Kane M, Donofrio L, Ascher B, Hexsel D, et al. Expanding the use of neurotoxins in facial aesthetics: a consensus panel’s assessment and recommendations. J Drugs Dermatol 2010;9:s7–22. 6. Rohrich R, Pessa JE. The fat compartments of the face: anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg 2007;119(7):2219–27.
16. Frevert J. Content of botulinum neurotoxin in botox/vistabel, dysport/azzalure, and xeomin/bocouture. J Drugs Dermatol 2010;10(2):67–73. 17. Smith TJ, Lou J, Geren IN, Forsyth CM, et al. Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization. Infect Immun 2005;73(9):5450–7. 18. Ascher B, Talarico S, Cassuto D, Escobar S, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood unit) – Part I: upper facial wrinkles. J Eur Acad Dermatol Venereol 2010;24:1278–84. 19. Ascher B, Talarico S, Cassuto D, Escobar S, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood unit)-Part II: wrinkles on the middle and lower face, neck and chest. J Eur Acad Dermatol Venereol 2010;24:1285–95. 20. Kane MA. Commentary: a double-blind, randomized, placebocontrolled, two-dose comparative study of botulinum toxin type A for treating glabellar lines in Japanese subjects. Aesthetic Plast Surg 2008;32(6):933–5. 21. Kane M. Classification of crow’s feet patterns in Caucasian women: the key to individualizing treatment. Plast Reconstr Surg 2003;112(5):33–9S.
7. Carruthers A, Carruthers J. Botulinum toxin products overview. Skin Therapy Lett 2008;13:1–4.
22. Carruthers JD, Glogau RG, Blitzer A; Facial Aesthetics Consensus Group Faculty. Advances in facial rejuvenation: botulinum toxin type A, hyaluronic acid dermal fillers, and combination therapies – consensus recommendations. Plast Reconstr Surg 2008;121:5–30S.
8. Karsai S, Raulin C. Current evidence on the unit equivalence of different botulinum neurotoxin A formulations and recommendations for clinical practice in dermatology. Dermatol Surg 2009;35:1–8.
23. Kane M. Botox treatment for facial wrinkles. Advances in Aesthetic Plastic Surgery: The Cutting Edge Symposium, sponsored by Manhattan Eye, Ear & Throat Hospital 1996 Oct 4; New York, NY: Manhattan Eye, Ear & Throat Hospital; 1996.
9. Stone AV, Ma J, Whitlock PW, Koman LA, et al. Effects of Botox and Neuronox on muscle force generation in mice. J Orthop Res 2007;25:1658–64.
24. Kane MA. The functional anatomy of the lower face as it applies to rejuvenation via chemodenervation. Facial Plast Surg 2005;21 (1):55–64.
10. Sattler G, Callander MJ, Grablowitz D, Walker T, et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines. Dermatol Surg 2010;36(Suppl 4):2146–54.
25. Kane MA. The effect of botulinum toxin injections on the nasolabial fold. Plast Reconstr Surg 2003;112(5):66–72S.
11. Roggenk€ amper P, Jost WH, Bihari K, Comes G, et al. Efficacy and safety of a new botulinum toxin A free of complexing proteins in the treatment of blepharospasm. J Neural Transm 2006;113(3):303–12.
27. Kane MA. Refinements in injection technique for the depressor anguli oris muscle: functional anatomic considerations. Plast Surg Pulse 2010;2(3):14–6.
12. Benecke R, Jost WH, Kanovsky P, Ruzicka E, et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005;64(11):1949–51. 13. Hunt T, Clarke K. Potency evaluation of a formulated drug product containing 150-kd botulinum neurotoxin type A. Clin Neuropharmacol 2009;32(1):28–31. 14. Banegas RA, Farache F, Rancati A, Chain M, et al. The South American Glabellar Experience Study (SAGE): a multicenter retrospective analysis of real-world treatment patterns following the introduction of incobotulinumtoxinA in Argentina. Aesthet Surg J 2013;33(7):1039–45. 15. Wortzman MS, Pickett A. The science and manufacturing behind botulinum neurotoxin type A-ABO in clinical use. Aesthet Surg J 2009;29(65):S34–42.
26. Rubin LR. The anatomy of a smile: its importance in the treatment of facial paralysis. Plast Reconstr Surg 1974;53(4):384–7.
28. Kane MA. Commentary: botulinum toxin A for lower facial contouring: a prospective study. Aesthetic Plast Surg 2007;31:452–3. 29. Kane MA. Nonsurgical treatment of platysmal bands with injection of botulinum toxin A. Plast Reconstr Surg 1999;103 (2):656–63. 30. Kane MA. Nonsurgical treatment of platysma bands with injection of botulinum toxin A revisited. Plast Reconstr Surg 2003;112(5):125–6S.
Address correspondence and reprint requests to: Michael Kane, MD, Plastic Surgery, Manhattan Eye, Ear & Throat Hospital, 115 East 67 St, New York, New York 10065, or e-mail: [email protected]
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Asian Consensus Recommendations on the Aesthetic Usage of Botulinum Toxin Type A MICHAEL A.C. KANE, MD*
The author is a consultant to Allergan, Valeant, Merz, Galderma and Prevalence
A
sian Consensus Recommendations on the Aesthetic Usage of Botulinum Toxin Type A is an ambitious and thoughtful addition to the scientific literature.1 It is not easy to produce such a paper. Whether as a member2–4 or chairman5 of such an endeavor, it is a difficult undertaking for many reasons. It is always difficult to get a group of experts to agree on anything, let alone something as challenging, personal, and artistic as injection of botulinum toxin type A (BoNT-A). As the authors indicate, although there are several consensus papers with guidelines for Caucasian patients, these guidelines are not directly applicable to Asian patients. There are several reasons given for this nontransferability, but the one that I think is most important is the artistic “notions of beauty” that the authors discuss. Although I believe that there is an increasing convergence of beauty ideals globally, there are still real differences in how people from different parts of the globe see each other. Anatomic differences aside, Asian beauty is not the same as Caucasian beauty. One anatomic difference I would like to add to the authors’ list of skin differences and muscular anatomy differences is the difference in fat anatomy. As Pessa6 has pointed out, during the aging process, discrete fat pads below the skin behave differently. With the difference in amount and distribution of facial fat being so different between Asian and Caucasian people, there is no reason to believe that the aging of their fat would be identical.
As with any consensus paper, there are some assertions that are clearly true, some that are controversial, and some that an individual reviewer finds somewhat shocking. This paper starts out with a whopper: that with the exception of Dysport, all of the other botulinum toxin type A formulations (Botulax, BTXA, Neuronox, and Xeomin) are equivalent to the accepted standard of the authors – Botox (Allergan, Irvine, CA). This would assume that the potencies of all of these formulations, as well as their dose– response curves are identical. Two consensus or review papers7,8 and an animal study9 (all 4 years or older) are given as the basis for this bold assertion. By contrast, more than a dozen papers in the scientific literature have compared the potency of Botox with that of Xeomin. Perhaps the most quoted is the Sattler paper10 comparing Botox with Xeomin at 24 U to the glabella in 381 patients, which showed extremely similar responder rates at weeks 4 and 12. There are also focal dystonia papers wherein investigators treat blepharospasm (in 256 patients)11 and cervical dystonia (in 463 patients)12 prospectively with equal but varying doses of Botox and Xeomin with similar efficacy at their primary endpoints, but there is also a basic science paper13 and a clinical experience paper14 that propose that Botox is more potent than Xeomin, but neither paper contains a clinical, prospective, randomized, equidose trial. Of interest is the fact that the authors assign Dysport a dose ratio of 2 to 4:1 when compared to all of the other BoNT-As. I am
*Plastic Surgery, Manhattan Eye, Ear & Throat Hospital, New York City, New York © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:1861–1867 DOI: 10.1111/dsu.12369 1861
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unsure whether the authors could not quite come to a consensus, which brought about the wide range, or if they all (or mostly all) agreed that there is a true range. If it is the latter, then I absolutely support this rather wide dose ratio range. All drugs have a dose–response curve. Every time I have seen comparable dose– response curves for Botox and Dysport, I have noted that they were not parallel. Unless the curves are parallel, there cannot be a single coefficient to compare the potency of the drugs but rather a sliding scale. I differ with the authors, however, on the statement that Dysport has different strains of origin than the other formulations. Dysport, Botox, and Xeomin are all derived from the Hall strain.15,16 There are different subtypes and the potential for sequence variation,17 but they are from the same family tree of the Hall strain. For the purpose of this review, I will accept the authors’ assertion of equipotency and note that the toxins primarily used were Neuronox and Botox. Where I discuss my dosing of patients, I will use the authors’ standard of Botox units. The authors and the consensus panel, The Korean Academy of Corrective Dermatology, are Korean. The majority of the patients they treat are Korean. Care must be taken when assuming that treatment of Korean patients can be extrapolated across all of Asia. The Caucasian consensus papers come from the United States,2–5 which has a heterogeneous Caucasian population, or European authors from several different countries.18,19 The Europeans might have had different recommendations based on skin thickness, facial shape, and notions of beauty if all of the experts and most of the patients were only from Spain or Ireland or Eastern Europe or Scandinavia. The authors also recommend reconstituting a 100-U vial with 2.0 mL of saline. Why? No rationale is given. Care is taken to report the results of a questionnaire given to 500 Korean doctors by a pharmaceutical company. The results of this questionnaire reveal that the most common reconstitution volume is 2.5 mL, and only 21% of respondents used 2.0 mL, yet the dogmatically recommended reconstitution volume is 2.0 mL, with no explanation
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given. I have never understood reconstitution recommendations. I know expert injectors who reconstitute with 1.0 mL and experts who use 6.0 mL. I have used 4.0 mL per 100-U vial since 1991. All that matters is how many units one delivers to which neuromuscular junctions. How they get there is up to the judgment, planning, and skill of the injector. The first anatomic area that the authors discuss is the forehead and frontalis. I agree with the authors’ discussion that Asians tend to have less contractility and wrinkles in the forehead than Caucasians. The dose range recommended (6–13.5 U) may seem a bit high at first glance owing to the relative lack of motion of Asian foreheads. My median frontalis dose is 4 U for Caucasians, but the authors note that Korean foreheads are wider, and they recommend intradermal injections for Asians versus intramuscular injections for Caucasians. This explains some of the higher-than-expected dosage because many more units will not find their way to neuromuscular junctions from the thick forehead skin, and there is more surface area to cover. The intradermal recommendation is not explained. One thing I disagree with is the regimented approach to the forehead with five equidistant injection points exactly 2 cm above the brows and another four points 1 to 1.5 cm above the first line. Another concept I strongly disagree with is the frequently espoused idea not to inject the lower frontalis. All patients are individuals and need to be approached as such. Not treating the lower frontalis while diffusely weakening the upper frontalis often leads to an unnatural appearance to my eye and can contribute to suprabrow rhytides. Admittedly, suprabrow rhytides are less commonly a problem in Asian patients, but they still occur. The authors state that the glabella is the most treated area in Asians. This is also my most frequently treated area in Caucasian patients, but in my Asian patients, I think the glabella is tied with the crow’s feet area for most common injection site. The forehead is a distant third in my practice when considering the three upper face areas. There is a geometric description of injection points based partially on the brow (do
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Asians not pluck and shape their brows as often as Caucasians? This can make for quite a mobile landmark), which I reject based on its regimented nature. Happily, there is some wiggle room, with a recommendation of three or five injection points, but I agree wholeheartedly that Asian corrugators are shorter and require significantly fewer units than Caucasian corrugators.20 Their recommendation of 8 U for the glabellar complex is also my median dose for Asian patients. My median dose for Caucasian patients with their longer corrugators is 15 U. The next treatment area to be discussed is that for brow lifting. Personally, I reject this as an area. I have fought this in consensus conferences that I have been a part of. Lifting of the brows is a complex interplay between the lateral brow depressors, the medial brow depressors, and a differentially weakened brow elevator. It is not a simple treatment but a delicate balance between the three most commonly treated areas of the upper face. I believe that the height and shape of the brows illustrates one of the greatest discrepancies between Asian and Caucasian ideals of beauty. Caucasian patients frequently or nearly always request or desire some degree of brow elevation. My Asian patients only rarely do so, but an even greater difference exists in desired brow shape, as the authors point out. Asian patients do not like the “ideal brow,” with a sharp lateral peak. Good for them. I never appreciated the concept of the ideal brow myself but rather a brow that matches one’s face. My Asian patients frequently remind me that they do not want… and then they manually lift their lateral brows. They are not showing me a Mephisto or Spock brow. Rather, they fear what their Caucasian contemporaries actually desire – a lateral peak. A mild elevation is considered all right as long as the peak, if present, is soft and more medial. The authors get this exactly right. Maybe this was a loquacious way to say they that they hit the nail on the head with their first nine words of this section “brow lifting is not a popular procedure in Asia.” The next section addresses the treatment of crow’s feet, a common treatment for Asian patients. I have
found that this is usually the first area for which my younger Asian patients seek treatment. The injection pattern described is a familiar three-point pattern well lateral to the lateral canthus commonly described for Caucasian patients. I prefer to inject patients based on their functional anatomy, with more units placed in the dominant neuromotor units21 rather than a standard pattern. The authors say that “the degree of periorbital wrinkling is higher in Caucasians than Asians,” and I fully agree, but I would add that Asians are much less tolerant of these wrinkles than their same-aged Caucasian patients. I agree with the authors’ assumption that muscle fiber size is probably smaller in Asians and their skin is thicker, which is why their lateral canthal lines are less severe. Because they are less severe, and the contractions of the orbicularis oculi are less forceful, recommended doses are less, but because these smaller lines conflict more with Asian standards of beauty, they are injected in a greater percentage of my patients. The authors note that injections in Asians should be intradermal as opposed to intramuscular like in Caucasians, but the consensus papers cited22 are older papers. Newer recommendations and most physicians inject intradermally or just above the muscle when treating Caucasian patients. Infraorbital wrinkles are discussed next. The authors state that these wrinkles are commonly treated in Asian patients, and I agree. I tend to inject the area a bit more cephalad than their recommended 1 cm below the lash line, but this is a variable point for me – I inject directly into the neuromotor units that are primarily causing the rhytides, and this is highly variable. The authors’ analysis of the “jelly roll” versus the “charming roll” and the different way that Caucasian and Asian patients see this fullness is excellent, but I would like to add a third group to the discussion at this point in the commentary: younger, fully assimilated women who see themselves more as American than Asian. Over the years, many of my Asian patients have seemed pleasantly surprised when it became apparent that I understood the attractiveness of this roll to Asian eyes and preserved
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it and sometimes even augmented it with a little hyaluronic acid filler. In the last 6 months, I have had two young (late 20s/early 30s) patients request that I remove the “bags” under their eyes, which were not infraorbital fat but pretarsal muscle. When I explained to them that this bulge was a sign of beauty of Asian eyelids, especially to Asians, they looked at me as though I were from another planet or, more likely, another century. Maybe they had a point. Here I was, a Caucasian man, telling Asian women that their Asian eyes looked better to other Asians with the roll intact because Asian people had a different cultural ideal of beauty when it came to Asian eyelids. It does seem rather ridiculous when written. I rarely inject the full roll in Caucasians because, except for young patients with a fairly taut lower lid, I find the small retraction of the lower lid outweighs the benefits of fewer rhytides. A bowed lower lid is a senile change. Asian patients, with their higher lower lid position can withstand a drop of a millimeter or so (as long as the roll stays intact) better than their Caucasian contemporaries. Asian patients may also benefit from the appearance of larger eyes. Caucasian patients rarely look better with bigger eyes if the apparent size increase is due to a lower and hence more senile lower eyelid margin. The authors address bunny lines next and state that these injections are “not uncommon in Asia” and need more units than Caucasian bunny lines. I agree on both points. I think this is the wrinkling area with the largest discrepancy in incidence between Caucasian and Asian patients. In my Caucasian neuromodulator population, I estimate that approximately 15% of the patients walking through my door receive nasalis injections. About half of my Asian patients have this area treated. It is also the only area (besides the masseter) where I routinely require more units for Asian patients, with a median of 5 U for Asians and 2.5 U for Caucasians. Nasal shaping is next on the list, and I agree with the authors that nasal flare is a common indication in Asian patients and in my experience much less common in Caucasian patients. The exception to this is
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in Caucasian patients with postrhinoplasty deformity, who often lack tip support and are poor operative candidates or understandably do not want another operation. The lack of tip support causes further alar spread, which can be ameliorated slightly with neuromodulator injections to the ala. Because of scar tissue in these patients, I usually inject at two to three points per ala rather than the one point described. These patients often also receive concomitant hyaluronic acid filler injections along the dorsum, tip, and columella. With their lack of dorsal height, small amount of alar cartilage remaining, poor tip support, and wide nasal ala, the overresected Caucasian patient is somewhat analogous to the Asian (or perhaps more accurately, non-Japanese Asian) primary nasal patient, and the injection planning for fillers and toxins is similar. Injection of a tip-raising neuromodulator is a different question altogether. The first time I presented nasal tip elevation with toxins at a national meeting was 1996,23 and it became a part of my presentations for a few years. It is one of those things that I used to teach that I now regret. I agree that it may seem as though some patients get a little tip elevation from injection of the depressor septi muscle as described, but I think it is mostly illusory. In 1998, I wanted to give a presentation solely devoted to tip elevation with toxins instead of the usual one or two cases I was showing. So I sorted through boxes of old Kodachrome slides and was rather embarrassed with what I found. In beforeand-after slides matched for positioning, posture, and smile effort, I found almost no change in true nasal tip height but rather a drop in the lip columellar junction. Some patients had a slight elevation to the tip, but the tip to the untrained eye appeared to be significantly elevated. Although I could take an acute lip columellar angle and make it more obtuse, the tip itself was rarely actually raised a significant amount. Perhaps I am arguing semantics here because this change frequently fools the patient, their injectors, and (formerly) this author into thinking the tip is elevated, I prefer to be more anatomically precise in what I am describing. If you want to say that toxin predictably opens the lip columellar angle, which gives the appearance of an elevated nasal tip, I am with you all the way. This is analogous to adding a bit of filler along the anterior
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mandibular jawline to decrease the appearance of the jowls. When I do this, I do not claim to be raising the jowl, just making it appear less obvious. Perioral wrinkles are addressed next, and the authors are correct when they state that this is less frequently performed in Asians than Caucasians. Because the authors do not state an opinion as to why they think this happens, I will do so here. Such is the advantage of writing a free-form commentary over a rigorous consensus paper. I think the thickness of Asian skin retards the development of rhytides, and the large size of Asian lips makes even larger size after orbicularis oris injection not so beneficial. The authors describe a four-point technique that I abandoned also in 1998. When I examined my old Kodachromes carefully, it became apparent that I was not getting even spread of neuromodulator throughout the lip and was having areas of hypomotility abutting areas with more normal motion. So I began to dilute my toxin a bit more and inject it in a horizontal spreading manner.24 I have never had speech impairment but nearly always will be told that drinking through a straw is difficult. I do not consider the latter (or the appearance of larger lips) to be a complication but rather a treatment guide to appropriate dosing. The gummy smile, one of my favorite indications, is discussed next. The authors do not comment on incidence, but I believe a gummy smile is slightly more common in Asian patients in my general neuromodulator population. In 1999, I presented a paper on the gummy smile that was published a few years later.25 This may have skewed the incidence in my patient population for a few years because these patients were frequently referred to me. The authors’ injection placement is lateral and inferior to mine as they seek to weaken the levator labii superioris alaeque nasi, levator labii superioris, and zygomaticus minor. I only want to weaken the levator labii superioris alaeque nasi because this more precisely affects the central upper lip, whereas injecting all three muscles tends to drop the entire lip. With a patient with a typical gummy smile, I do not want to drop the entire lip. Part
of the deformity (besides seeing a lot of gingiva) is the unfavorable canine smile pattern,26 which results from too much central upper lip elevation. So, in most patients with a gummy smile, I see two problems; the upper lip is too high, and its shape is unpleasant because it is too high centrally relative to laterally. Dropping only the central upper lip 2 to 3 mm is my goal, with the higher, more medial injection point at the nasal bone and maxilla groove. The authors state that drooping of the mouth corners is a risk of their technique. This can be reduced by leaving the lateral upper lip elevators alone. The authors state that “use of BTA alone in treating marionette lines is regarded as difficult and risky,” and so it is not commonly done. I agree strongly that marionette lines are rarely injected in Asian patients but not because it is risky. I rarely do it because it is rarely indicated. I think this is one example of the way that most Asian faces animate differently than Caucasian faces. Conversely, it is my most commonly injected lower face area in Caucasian patients. I inject much lower doses than the 6 to 10 U recommended.27 These 6 to 10 U of the authors are injected into the depressor anguli oris (DAO) alone. This is risky. I sometimes inject both the DAO and depressor labii inferioris depending on the functional anatomy of the patients’ smile. My median total dose in Asian patients is 3.75 U. The dimpled chin and mentalis is next. This is an area where I differ strongly with the authors over injection technique. The superficial surface of the mentalis muscle is covered with fascia that has strong fibrous septae running to the dermis above. These septae transmit the surface topography of the muscle to the skin. Therefore, smoothing the superficial mentalis is critical for success. Just as important is keeping as much deep muscle active as possible. The mentalis supports all of the soft tissues of the chin medial to the mandibular ligament to the pogonion. It is essential for lower face support and oral competence. Keeping as much of the deep muscle functional while keeping the superficial muscle quiet is the key to reducing complications and ptosis of the lower face. Therefore,
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I disagree with the deep, perpendicular injections described and instead place several threads parallel to the skin surface along the superficial muscle fibers, aiming for the muscle–septae interface. The masseter is commonly injected in Asian patients. Of my Asian patients, I inject the masseter most commonly in patients of Korean descent. The authors recommend a common three-point pattern based on facial geometry. As you might suspect, I do not inject the masseter in a set pattern but in an individualized manner based on patients’ functional anatomy.28 I have the patients relax and clench repeatedly and inject the bulk of my neuromodulator where the muscle is most hypertrophic – it is really very simple. The three-point technique described is a good and safe basic technique that minimizes complications but will sometimes have you injecting into areas that are not very dynamic. Perhaps this is why the authors’ recommended dose range for Asian patients of 50 to 60 U is a bit higher than mine at 30 to 40 U. My dose range for most Caucasian patients is 15 to 20 U. Here is another area where different ideals of beauty come into play. Asian patients in general prefer a heartshaped face with a soft lateral jawline. Caucasian patients often prefer the appearance of a strong mandibular angle. For this reason, in Caucasian patients, I often inject a large masseter or a masseter in a teeth grinder with neuromodulator and at the same time add definition along the mandibular angle with a calcium-based or hyaluronic acid filler. I agree with everything the authors write about the treatment of platysmal bands.29 I would further postulate that the reason Asian patients seek this treatment less often is because they ahve thicker skin and what appears to me to be a favorable retention of more evenly distributed subcutaneous fat over time. I believe that the anterior layers of fat and skin are the key to success with botulinum in this area.30 Calf injections for hypertrophy are rarely done in the west, even among my Asian patients. Perhaps this is another difference between patients of Asian descent in America and Asian patients.
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This is an excellent paper with safe and carefully considered consensus recommendations for the treatment of Asian patients with botulinum. I feel this adds significantly to the scientific literature. Consensus papers are compromise papers that attempt to distill an efficacious technique in as safe a way as possible. In both of these aspects, the authors were successful. I hope I did not appear to be too critical of certain aspects of this paper. In my own consensus papers, I have signed off on things I did not totally agree with – this is what consensus means. In summary, if I had to distill the largest differences in ideals of beauty between my Asian and Caucasian patients, Asian patients are bothered much more by their crow’s feet, do not care as much about brow elevation, do not like the “ideal brow” peak, and are bothered a great deal by gummy smiles and wide jaws. In general, Asian patients do not move their foreheads as much, scrunch their noses more often, have gummy smiles a bit more frequently, do not work their DAOs as strongly, have big masseters, and have favorable skin and fat characteristics in the perioral and neck areas. What cannot be emphasized strongly enough is that we are talking about large groups with billions of members here. Each large group (Asians and Caucasians) is composed of large subgroups (e.g., Chinese, Korean, Japanese, Scandinavian, Northern European, Mediterranean descent) that likewise tend to have distinguishing characteristics when it comes to facial anatomy and ideals of beauty as well. Finally, one gets to the individual. Although we may assign certain anatomic and psychosocial attributes to large groups, they cannot be assigned to individuals. Each individual patient is deserving of your respect and a thorough examination and discussion that avoids plopping them into a convenient stereotype. This is one reason I am so against geometric injection points, standardization of injections, routine dosing, and diagrams of faces with injection points drawn upon them, although these things are helpful for the neophyte injector. I hope, after injecting and following up a few patients, the good injector will get rid of his or her diagrams and tables and individualize a treatment plan for each and every patient.
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References 1. Ahn BK, Kim YS, Kim HJ, Rho NK, et al. Asian consensus recommendations on the aesthetic usage of botulinum toxin type A. Dermatol Surg 2013. 2. Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics. Plast Reconstr Surg 2004; 114:1–22S. 3. Carruthers A, Kane MA, Flynn TC, Huang P, et al. The convergence of medicine and neurotoxins: a focus on botulinum toxin type A and its application in aesthetic medicine – a global, evidence-based botulinum toxin consensus education initiative: part I: botulinum toxin in clinical and cosmetic practice. Dermatol Surg 2013;39(3):493–509. 4. Maas C, Kane MA, Bucay VW, Allen S, et al. Current aesthetic use of abobotulinumtoxinA in clinical practice: an evidence-based consensus review. Aesthet Surg J 2012;32(1):8–29S. 5. Kane M, Donofrio L, Ascher B, Hexsel D, et al. Expanding the use of neurotoxins in facial aesthetics: a consensus panel’s assessment and recommendations. J Drugs Dermatol 2010;9:s7–22. 6. Rohrich R, Pessa JE. The fat compartments of the face: anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg 2007;119(7):2219–27.
16. Frevert J. Content of botulinum neurotoxin in botox/vistabel, dysport/azzalure, and xeomin/bocouture. J Drugs Dermatol 2010;10(2):67–73. 17. Smith TJ, Lou J, Geren IN, Forsyth CM, et al. Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization. Infect Immun 2005;73(9):5450–7. 18. Ascher B, Talarico S, Cassuto D, Escobar S, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood unit) – Part I: upper facial wrinkles. J Eur Acad Dermatol Venereol 2010;24:1278–84. 19. Ascher B, Talarico S, Cassuto D, Escobar S, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood unit)-Part II: wrinkles on the middle and lower face, neck and chest. J Eur Acad Dermatol Venereol 2010;24:1285–95. 20. Kane MA. Commentary: a double-blind, randomized, placebocontrolled, two-dose comparative study of botulinum toxin type A for treating glabellar lines in Japanese subjects. Aesthetic Plast Surg 2008;32(6):933–5. 21. Kane M. Classification of crow’s feet patterns in Caucasian women: the key to individualizing treatment. Plast Reconstr Surg 2003;112(5):33–9S.
7. Carruthers A, Carruthers J. Botulinum toxin products overview. Skin Therapy Lett 2008;13:1–4.
22. Carruthers JD, Glogau RG, Blitzer A; Facial Aesthetics Consensus Group Faculty. Advances in facial rejuvenation: botulinum toxin type A, hyaluronic acid dermal fillers, and combination therapies – consensus recommendations. Plast Reconstr Surg 2008;121:5–30S.
8. Karsai S, Raulin C. Current evidence on the unit equivalence of different botulinum neurotoxin A formulations and recommendations for clinical practice in dermatology. Dermatol Surg 2009;35:1–8.
23. Kane M. Botox treatment for facial wrinkles. Advances in Aesthetic Plastic Surgery: The Cutting Edge Symposium, sponsored by Manhattan Eye, Ear & Throat Hospital 1996 Oct 4; New York, NY: Manhattan Eye, Ear & Throat Hospital; 1996.
9. Stone AV, Ma J, Whitlock PW, Koman LA, et al. Effects of Botox and Neuronox on muscle force generation in mice. J Orthop Res 2007;25:1658–64.
24. Kane MA. The functional anatomy of the lower face as it applies to rejuvenation via chemodenervation. Facial Plast Surg 2005;21 (1):55–64.
10. Sattler G, Callander MJ, Grablowitz D, Walker T, et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines. Dermatol Surg 2010;36(Suppl 4):2146–54.
25. Kane MA. The effect of botulinum toxin injections on the nasolabial fold. Plast Reconstr Surg 2003;112(5):66–72S.
11. Roggenk€ amper P, Jost WH, Bihari K, Comes G, et al. Efficacy and safety of a new botulinum toxin A free of complexing proteins in the treatment of blepharospasm. J Neural Transm 2006;113(3):303–12.
27. Kane MA. Refinements in injection technique for the depressor anguli oris muscle: functional anatomic considerations. Plast Surg Pulse 2010;2(3):14–6.
12. Benecke R, Jost WH, Kanovsky P, Ruzicka E, et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005;64(11):1949–51. 13. Hunt T, Clarke K. Potency evaluation of a formulated drug product containing 150-kd botulinum neurotoxin type A. Clin Neuropharmacol 2009;32(1):28–31. 14. Banegas RA, Farache F, Rancati A, Chain M, et al. The South American Glabellar Experience Study (SAGE): a multicenter retrospective analysis of real-world treatment patterns following the introduction of incobotulinumtoxinA in Argentina. Aesthet Surg J 2013;33(7):1039–45. 15. Wortzman MS, Pickett A. The science and manufacturing behind botulinum neurotoxin type A-ABO in clinical use. Aesthet Surg J 2009;29(65):S34–42.
26. Rubin LR. The anatomy of a smile: its importance in the treatment of facial paralysis. Plast Reconstr Surg 1974;53(4):384–7.
28. Kane MA. Commentary: botulinum toxin A for lower facial contouring: a prospective study. Aesthetic Plast Surg 2007;31:452–3. 29. Kane MA. Nonsurgical treatment of platysmal bands with injection of botulinum toxin A. Plast Reconstr Surg 1999;103 (2):656–63. 30. Kane MA. Nonsurgical treatment of platysma bands with injection of botulinum toxin A revisited. Plast Reconstr Surg 2003;112(5):125–6S.
Address correspondence and reprint requests to: Michael Kane, MD, Plastic Surgery, Manhattan Eye, Ear & Throat Hospital, 115 East 67 St, New York, New York 10065, or e-mail: [email protected]
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