Botulinum Toxins in Clinical Aesthetic Practice

SERIES IN COSMETIC AND LASER THERAPY

Series Editors

David J. Goldberg, Nicholas J. Lowe, and Gary P. LaskPublished in association with the Journal of Cosmetic and Laser Therapy

David J. Goldberg, Fillers in Cosmetic Dermatology, ISBN 9781841845098

Philippe Deprez, Textbook of Chemical Peels, ISBN 9781841842954

C. William Hanke, Gerhard Sattler, Boris Sommer, Textbook of Liposuction, ISBN 9781841845326

Paul J. Carniol, Neil S. Sadick, Clinical Procedures in Laser Skin Rejuvenation, ISBN 9780415414135

David J. Goldberg, Laser Hair Removal, Second Edition, ISBN 9780415414128

Benjamin Ascher, Marina Landau, Bernard Rossi, Injection Treatments in Cosmetic Surgery, ISBN 9780415386517

Avi Shai, Robert Baran, Howard I. Maibach, Handbook of Cosmetic Skin Care, Second Edition, ISBN 9780415467186

Jenny Kim, Gary Lask, Comprehensive Aesthetic Rejuvenation: A Regional Approach, ISBN 9780415458948

Neil Sadick, Paul Carniol, Deborshi Roy, Luitgard Wiest, Illustrated Manual of Injectable Fillers, ISBN 9780415476447

Paul Carniol, Gary Monheit, Aesthetic Rejuvenation Challenges and Solutions: A Global Perspective, ISBN 9780415475600

Neil Sadick, Diane Berson, Mary P. Lupo, Zoe Diana Draelos, Cosmeceutical Science in Clinical Practice, ISBN 9780415471145

Anthony Benedetto, Botulinum Toxins in Clinical Aesthetic Practice, Second Edition, ISBN 9780415476362

Robert Baran, Howard I. Maibach, Textbook of Cosmetic Dermatology, Fourth Edition, ISBN 9781841847009

David J. Goldberg, Alexander L. Berlin, Disorders of Fat and Cellulite, ISBN 9780415477000

Kenneth Beer, Mary P. Lupo, Vic A. Narurkar, Cosmetic Bootcamp Primer: Comprehensive Aesthetic Management, ISBN 9781841846989

Walter P. Unger, Ronald Shapiro, Robin Unger, Mark Unger, Hair Transplantation, Fifth Edition, ISBN: 9781616310066

Botulinum Toxins in Clinical Aesthetic Practice

Second Edition

Edited by

Anthony V. Benedetto DO FACPClinical Associate Professor of Dermatology

Department of Dermatology University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, USAand

Dermatologic SurgiCenterPhiladelphia, Pennsylvania, USA

First published in 2006 by Taylor & FrancisThis edition published in 2011 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK.Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th Floor, New York, NY 10017, USA.

© 2011 Informa UK Ltd, except as otherwise indicated.

No claim to original U.S. Government works.

Reprinted material is quoted with permission. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention.

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Dedication

This book is dedicated to those physicians who are committed to providing patients with the best medical care using state-of-the-art techniques; and to the coauthors who have contributed valuable time and expertise in the creation of this book. Lastly, to Dianne, whose encouragement and loving support permitted me to accomplish that which at times has appeared insurmountable.

vii

Contents

List of contributors viii

Foreword ixAlastair Carruthers

Preface xAnthony V. Benedetto

Prologue The search for beauty: historical, cultural, and psychodynamic trends xiCaroline S. Koblenzer

1 Pharmacology, immunology, and current developments 1K. Roger Aoki

2 Facial anatomy and the use of botulinum toxin 15James M. Spencer

3 Cosmetic uses of Botulinum toxin A in the upper face 24Anthony V. Benedetto

4 Cosmetic uses of Botulinum toxin A in the mid face 101Anthony V. Benedetto

5 Cosmetic uses of Botulinum toxin A in the lower face, neck, and upper chest 140Anthony V. Benedetto

6 Skin resurfacing with Microbotox and the treatment of keloids 190Woffles T. L. Wu

7 Facial and lower limb contouring 206Woffles T. L. Wu

8 Botulinum toxin type A treatment for Raynaud’s phenomenon and other novel dermatologic therapeutic applications 223Irèn Kossintseva, Benjamin Barankin, and Kevin C. Smith

9 Botulinum toxins-A other than BOTOX® 234Gary D. Monheit

10 Botulinum toxin B 240Neil S. Sadick and Yekaterina Kupava

11 Botulinum toxin in the management of focal hyperhidrosis 248Dee Anna Glaser

12 Medicolegal considerations of cosmetic treatment with botulinum toxin injections 263David J. Goldberg

Appendix 1 Muscles of facial expression 267

Appendix 2 The preparation, handling, storage, and mode of injection of onabotulinumtoxinA 272

Appendix 3 Patient treatment record 274

Appendix 4 Informed consent for the treatment of facial and body wrinkles with BoNTA 275

Appendix 5 Side-effects and contraindications to BoNTA injections 276

Index 279

viii

List of contributors

K. Roger Aoki PhD Vice President, Neurotoxins Research Program, Department of Biological Sciences, Allergan, Inc., Irvine, California, USA

Anthony V. Benedetto DO FACP Clinical Associate Professor of Dermatology, Department of Dermatology, University of Pennsylvania School of Medicine, and Medical Director, Dermatologic SurgiCenter, Philadelphia, Pennsylvania, USA

Benjamin Barankin MD FRCP Dermatologist, The Dermatology Centre, Toronto, Ontario, Canada

Dee Anna Glaser MD Professor & Vice Chairman, Director Cosmetic & Laser Surgery, Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA

David J. Goldberg MD JD Director, Skin Laser & Surgery Specialists of NY/NJ, New Jersey, Clinical Professor of Dermatology and Director of Laser Research, Mount Sinai School of Medicine, New York, and Adjunct Professor of Law, Fordham University School of Law, New York, New York, USA

Caroline S. Koblenzer MD Clinical Professor of Dermatology, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Irèn Kossintseva MD University of British Columbia, Vancouver, British Columbia, Canada

Yekaterina KupavaSadick Research Group, New York, New York, USA

Gary D. Monheit MD Monheit Dermatology Associates, South Birmingham, Total Skin & Beauty Dermatology Center, and Clinical Associate Professor, Department of Dermatology, Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, USA

Neil S. Sadick MD Sadick Dermatology & Aesthetic Surgery, New York, New York, USA

Kevin C. Smith MD FACP FRCPC (Dermatology) Dermatologist, Niagara Falls Dermatology and Skin Care Centre, Niagara Falls, Ontario, Canada

James M. Spencer MD MS Clinical Professor of Dermatology, Department of Dermatology, Mount Sinai School of Medicine, New York, New York, and Medical Director, Spencer Dermatology & Skin Surgery Center, Saint Petersburg, Florida, USA

Woffl es T. L. Wu MD Woffl es Wu Aesthetic Surgery & Laser Centre, Camden Medical Centre, Singapore

ix

Foreword

Dr. Benedetto is a well-known expert in both dermatology and aesthetic medicine. His especial area of expertise is the surgical or pro-cedural side of dermatology and he has spent many years perfecting skin cancer treatment techniques and treating many thousands of skin cancer patients successfully. However, he has also achieved a deserved reputation in the cosmetic world, especially in the use of botulinum toxin. For many years he has been interested in the application of botu-linum toxin, not just to the upper face but also to the lower face and especially in individuals with facial asymmetry.

This elegant book is appropriate for all who are interested in this field of knowledge. It will be appreciated not only by health care workers who administer the toxin but also by those who enjoy its beneficial effects. The former will improve their skill in the use of the material and the latter will learn more about how botulinum toxin can be used for good. I encourage all of you who are interested in this topic to read this excellent book.

Alastair CarruthersVancouver, Canada

September 2010

It is an honor and a pleasure to write a Foreword for the new edition of Dr. Benedetto’s book Botulinum Toxins in Clinical Aesthetic Practice. The first edition of this book, under the title Botulinum Toxin in Clini-cal Dermatology was very well received and much admired. However, time has moved on and it is time to update the information which was available in the earlier book. The amount of information about the botulinum neurotoxins and especially about their cosmetic use has increased dramatically in the last few years with new papers being pub-lished daily. It is important to have a synthesis of this new information and its integration into the previously available knowledge. In addi-tion, the range of individuals who are administering the toxin has increased significantly. Hence the new edition of this book.

I have particularly appreciated Dr. Benedetto’s selection of his co-authors; each is an acknowledged expert in the area in which they are writing. Dr. Benedetto has written many of the “core” chapters himself but has called on the assistance of other experts in important topics such as cosmetic indications which are less used in North America. Readers will be delighted by the clear anatomic diagrams and apprecia-tive of the clear advice on the handling and dilution of the currently available toxins—subjects which have caused much confusion.

x

Preface

Just a few short years ago the compilation of different injection techniques for the cosmetic use of the then-available botulinum neurotoxins (BoNTs), namely BOTOX® Cosmetic and Myobloc™/Neurobloc™, appeared to be a daunting undertaking. Because of the exponential developments in the clinical use of botulinum toxin A (BoNTA), this second edition quickly became a foregone conclusion. Maintaining the original mission of an instructional manual, this updated edition attempts to record the improvements that naturally have evolved from earlier injection techniques. It also introduces newer and innovative ways to utilize the different BoNTs that are presently available worldwide.

In the United States, the glabella remains the only area of the face that is approved by the FDA for the cosmetic use of BOTOX® Cosmetic, now identified by its nonproprietary name of onabotulinumtoxinA. Consequently, except for the glabella, all the cosmetic injection tech-niques described in this edition, as in the previous one, apply to nonap-proved, off-label indications, which makes this book unlike most other textbooks in medicine.

It is sobering to realize that throughout human existence men as well as women have always sought ways to improve their appearance. Dr. Caroline Koblenzer takes us through a historical interpretation of beauty and the beautiful and how the use of BoNT can supplement our patients’ incessant attempts to maintain the appearance of youthful-ness. Faced with an overwhelming amount of new scientific and tech-nical information, Dr. Roger Aoki updates us with some of the latest developments in the pharmacology and immunology of BoNTs.

Understanding functional anatomy cannot be over emphasized and Dr. James Spencer has made a concerted effort to apply his knowledge of anatomy in a meaningful and practical way as it relates to the use of BoNTs. The nuclear chapters on treating the face, neck, and chest with injections of BoNTA have been reorganized and expanded, assimilat-ing a number of improved injection techniques with the plethora of recently published clinical articles.

Dr. Woffles Wu, one of the early initiators of the intradermal use of BoNTA, has complemented this edition with his innovative techniques of muscle contouring and skin redraping. Reducing muscle bulk and girth of various parts of the body are techniques that are frequently

practiced in the East and are quickly becoming popular in the West. Dr. Kevin Smith continues to impress us with avant-garde uses of BoNTA for treating Raynaud’s phenomenon and other painful conditions and scars as well as describing potential techniques for lifting the female breasts with injections of BoNTA. He also presents some tips on the management of an acute overdose of BoNTA.

OnabotulinumtoxinA (BOTOX® Cosmetic) is no longer the only BoNTA approved in the United States. As anticipated in the first edi-tion, DYSPORTTM (abobotulinumtoxinA) finally made its debut in the U.S. market about a year ago. Dr. Gary Monheit, who headed the U.S. clinical trials for onabotulinumtoxinA, has updated the injection tech-niques for its clinical use. He also previews the pharmacology of the noncomplexed (naked) BoNTAs and introduces incobotulinumtox-inA, a “naked” BoNTA currently used in Europe, Mexico, and South America and soon to be introduced into the U.S. market. He also gives us a peek into the future with as much information currently permis-sible about a topical BoNTA presently undergoing phase II and III clinical investigation. The chapter on BoNTB (rimabotulinumtoxinB), the only nontype A neurotoxin approved by the FDA, has been updated by Dr. Neil Sadick. Dr. Dee Anna Glaser, current President and Found-ing Member of the International Hyperhidrosis Society, has revised and updated the chapter on hyperhidrosis.

Another enhancement to this edition is Dr. David Goldberg’s expert rendition of medicolegal considerations for those physicians who treat patients for cosmetic purposes. This important aspect of medical prac-tice rarely is addressed, but there are pertinent issues of which we should be aware.

Particular recognition and a special expression of gratitude is due to Lisa Van Horn for her organizational skills and secretarial expertise that facilitated the completion of this book. Finally, we are all indebted to those physicians who have treated and continue to care for patients with BoNTs for therapeutic and cosmetic purposes. Their commitment to the improvement of their patients through the advancement of sound and effective medical care should be lauded and emulated.

Anthony V. Benedetto DO FACPSeptember 2010

xi

prologue The search for beauty: historical, cultural, and psychodynamic trends

Caroline S. Koblenzer

INTRODUCTION Why, one may ask, in a social climate where poverty is rife and the delivery of basic health care, if not absent, certainly unevenly distri-buted, why is the search for what is perceived as physical beauty still so much a part of the lives of so many? This question has generated con-siderable sociologic research ( 1–4 ), and that it is indeed the case, is demonstrated by the nearly $12 billion that was spent on cosmetic pro-cedures in 2008 alone ( 5 ). In order for us to appreciate the reasons for this vast expenditure, it is important for us to understand that inher-ently there is, at any given time, a “consensual view,” a stereotype, of what constitutes beauty ( 1–4 ), and how, if one is to be successful in life, it is important that one do one’s best to conform to that stereotype for a number of very important and indeed realistic reasons.

In what follows, we will consider the ways in which the consensual view of beauty in Western civilizations, and most particularly in North America, has changed over the centuries. This in contrast to the Orient where traditional esthetics remained firmly in place until Western influences were introduced. How the view has changed for both men and women, and some of the forces that have led to those changes will also be considered, while in order to understand better the ongoing need to try to conform to the prevailing stereotype, the psychological development of the body image, and how the way one feels about one-self and about that image impact one’s performance in every sphere of life, will also be described. Finally, aspects of the current stereotype and what forces are at work to determine its form will be discussed, as will the impact on the psychosocial well-being of the individual, when attempts are made to achieve the stereotype.

THE CONSENSUAL VIEW OF BEAUTY As noted, there is generally held to be a consensual agreement within a given culture as to what features are deemed beautiful, though clearly there is great variability between cultures as to what particular charac-teristics are desired ( 4 ). One certainly might wonder how such a con-sensual decision could be arrived at, and indeed studies are under way to determine which parts of the brain are activated, and what affective stimuli are involved, when the level of beauty of a given face is under consideration ( 6 , 7 ). Western literature is replete with discussion as to whether or not physical beauty equates to moral goodness and whether it necessarily parallels physical health ( 1 , 8 ). To some, it is merely a “new indicator of social worth” ( 8 ), and, indeed, historically it appears that there has been a “trickle-down” effect, as concepts of beauty espoused by the rich have passed down through the socioeconomic levels to become more widely held ( 9 ).

An anthropologic view is that we are—unconsciously, one would presume—intent only on procreation and thus we find attractive those features that would point to procreation as a possibility ( 3 , 6 , 10–12 ).These features have been characterized as symmetry of face and body, full lips, smooth clear skin, clear eyes, lustrous hair, good muscle tone, animated facial expression, and a high energy level—features that one would intuitively associate with good health, certainly, although studies suggest that these features are not necessarily associated with fertility ( 10–14 ).

But one need only look at art through the ages to see that this par-ticular stereotype has not always been sought, and that the consensual

view of beauty has changed back and forth over time, as has been well-summarized in the literature ( 3 , 10 , 14 ). In the Middle Ages, for example, Western feminine beauty was portrayed as fragile and ethereal—a reflection, perhaps, of the veneration of women that was characterized in tales of chivalry—while later, in the sixteenth and sev-enteenth centuries, beautiful women were portrayed as much more robust. By the eighteenth century, fragility had returned, and in the early part of the nineteenth century, the frail, pale willowy woman was once again regarded as the beauty ideal, an ideal that it is suggested was consonant with the puritanical prudishness of the time. Later, in the latter part of the century, a much more robust, heavier-set woman emerged as a beauty, reflecting the fact that times had become eco-nomically easier, and the middle classes were more financially secure. This more heavy-set, robust style of femininity was in turn superseded by a muscular, athletic-looking woman, as sports began to be intro-duced on college campuses, and women started to take a more active part in the working world ( 3 , 10 ).

Just as in women, the consensual view of beauty in men has also changed over the years. In the mid-1800s the male ideal was pale and thin, “dyspeptic men, the puny forms, and the bloodless cheeks” due perhaps to lack of exercise and the “prevailing air of serious business.” It was stated at the time that “a straight back and a well-carried chest” meant that a man was either a “soldier or a foreigner” ( 15 ). Lord Byron’s look was that most admired, with “chiseled features, great fine-ness and silkiness of the hair, and tapering extremities,” and indeed, Byron reputedly was wont to subject himself to diet regimens to main-tain that look, perhaps an early—and indeed male—example of body dysmorphic issues and anorexia, problems that, particularly in young women, are very much with us today. Prince Albert, the Prince Con-sort, was slender and with fine features, and of course Napoleon, another admired character, was short ( 16 ).

In the latter part of the nineteenth century, this somewhat esthetic concept of beauty was reversed completely as European immigrants to America brought with them traditions of physical exercise and dedica-tion to outdoor sports. Andrew Jackson, the frontiersman, assumed the presidency, and the “trickle-down effect” on taste was clear, as men, eager to display their financial prosperity, showed off their rubicund faces and protruberant abdomens ( 19 ). By the early 1900s, this again had changed, and the new image of youthful masculinity and beauty was a tall and athletic figure, with fine features ( 16–18 ).

Though cosmetics had been associated initially with royalty and the aristocracy, and later with prostitution and the theater, even two hun-dred years ago many ordinary women lightened their complexions by ingesting or applying arsenic in addition to guarding their skin from sunlight. By then cosmetic manufacturers were advertising more exten-sively, and the more widespread use of their products was justified by such terms as “elegant,” “stunning,” and “chic” ( 19 ).

THE CURRENT CONSENSUAL VIEW More than any prior generation, our current consensual beauty ideal of both face and body, male and female, is generated to a large extent by our exposure to omnipresent advertising by the cosmetic, fashion and media industries, and most recently by some of our colleagues. This advertising may be in print, on-line, or on the air, but it constantly

xii BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

reminds us that we may be falling short, in one way or another ( 8 , 20–27 ). Today’s ideal for women is young, very slender and clad in the fashions sported by the models and media idols whom we see, whether or not we choose, several times each day. Her complexion is smooth and beautifully enhanced by the clever application of cosmet-ics ( 28 ), her hair glistening, and her muscles toned. Yet, interestingly in one study, when questioned, young women found those faces that most approximated the mean, rather than the ideal, to be the most attractive ( 22 ). For men, though still young and slim, the ideal handsome male has defined clean-cut masculine features, and most importantly, slen-der bodies with well-defined muscles ( 1 ). In both sexes, as the indi-vidual progresses through the different phases of life, from childhood to old age, these concepts of beauty and how that person perceives himself or herself in relation to the prevailing concepts remain crucial, and the goal for the emotionally healthy is still to strive to meet them. In both, symmetry is important and in both, youth is of the essence ( 1 , 3 , 12 , 28–30 ).

In either case, as Hilhorst notes, beauty can be achieved by “cultural means” and thus it expresses both our present culture, and our per-sonal choices ( 2 , 3 ). These choices, in turn, are determined by the way in which we perceive ourselves, how we feel about that perception, and how we compare it with others. In other words, despite the fact that our choices are strongly influenced by the prevailing ideal, choices about the way we display ourselves are made fundamentally on the basis of our body-image and our self-esteem—two aspects of the self that are integral to the personality at every phase of life ( 2 , 31–35 ).

Body Image and Self-esteem What we understand by “body-image” is complex and multidimen-sional. It is not only “the picture of our own body that we form in our own mind” ( 32 ), but also the way that we feel about ourselves. Having both physical and psychologic components, body-image is intimately associated with self-esteem. Clearly this complex is of some impor-tance, since the way in which we see ourselves, whether it pleases us or whether we see deficiencies, affects every aspect of our lives—our thoughts, our emotions, and our relationships ( 31 ).

Development of Body Image and Self-esteem One may wonder why it is that for one person even a minor flaw in appearance is devastating, while for another that flaw, or even greater disfigurements, may be of no consequence whatsoever. Infant observa-tion studies have shown that these very different feelings about oneself have their beginnings during one’s very early life experience, and evolve in the context of one’s earliest relationships ( 35 ).

The emotional environment for the infant is contained within the relationship between the infant and the primary caretaker. In the recip-rocal interaction that takes place between the two, if tactile stimulation is congruent with the infant’s needs, and the environment accepting, the infant will begin to incorporate and make a part of himself or her-self both a capacity to modulate anxiety, and an understanding of the boundaries between the self and the other, with an appreciation of his or her own size, shape, and physical configuration. The quality and the amount of empathic touching that takes place within this fundamental relationship will help to determine the integrity of the body image, how close it is to reality, and whether the feelings about the self that are generated, are positive or negative. When the caretaker is in tune with the infant’s feelings, expressing love and admiration in smile and touch, the body-image will be stable, the boundaries firm, the self-esteem positive, and the individual confident and secure ( 33 , 34 ). The inner feelings aroused in this early stage of development are reinforced by parental attitudes as the child grows. Parental values and expectations with regard to looks and behaviors—what is perceived as beautiful or good—are transmitted verbally and nonverbally to the child, and

whether these parental attitudes are overtly met with cooperation or with opposition, at some level most children wish to grow up to be like the parents, and to please them and make them proud. However, the reverse is also true—when demanding, perfectionistic, and rigid par-ents have expectations that are unrealistic, the inevitable parental dis-appointment or dissatisfaction is, in like fashion, internalized by the child, becoming a part of the self, and impacting the body-image and the quality of self-esteem ( 34 ). Feelings of guilt arise, and dissatisfac-tion with different aspects of the self may later lead to anxiety or depression, and to disquieting issues about lack of goodness or beauty, with feelings of ugliness associated with a poor personal presentation.

Progressing into adolescence, the child must separate emotionally from the parents in order to develop an individual identity. Aspects of the parents that the child admires will be incorporated and integrated into the personality, but as the child separates, it is peers, father-figures or sports idols who become the ones to emulate in looks, dress, and the ideals of masculinity for boys. Indeed the boy may try out many styles, perhaps carried to extremes—for example body piercing, tattoos, etc.—before arriving at his own comfortable identity. For the girl the task is more difficult, as she is still under great pressure to please the mother and to incorporate admired maternal traits. She too must struggle to separate, and at the same time emulate in attitude and style, the peers, models and media idols that she so admires. For both boys and girls acceptance by the peer group, and the “sameness” as peers, are of paramount importance for emotional well-being ( 31 , 32 ).

As the adolescent matures, the body-image and self-esteem become established as psychological entities, and come to settle at some point along the broad spectrum of affects, from positive to negative. In adult life, social interaction and appearance-related feedback serve to rein-force, or exaggerate the individual’s feelings about the internalized per-sona, whether those feelings be positive or negative ( 37 ). It is important to note that the powerful impact of the media on those feelings, cannot be overestimated ( 3 , 20–25 ).

WHY AIM TO EMULATE THE IDEAL? And so what are the advantages of emulating the current cultural ideal of beauty, in so far as one is able? Those who most closely approximate the ideal, although they may serve as objects of comparison for the less well-favored, generating envy, nevertheless have enormous personal, social, and professional advantages, as many studies have shown. A small sampling will serve to illustrate this point.

In terms of subjective experience, physically attractive people report-edly receive more social reinforcement, have closer relationships, and experience greater intimacy and greater satisfaction in their sexual interactions than do those less favored ( 38 , 39 ). Objectively, examples of the benefits of conforming to the current consensual ideal of beauty can be found in essentially every aspect of life. Pretty children, for example, get better grades than those perceived as plain; plain children attract greater antipathy from their fathers ( 40 ); pretty waitresses get better tips ( 41 ); physically attractive men and women are more readily hired, receive earlier promotions, and make more money than do those who less clearly approximate the current consensual ideal ( 2 , 42 ); while women tend to marry those of equivalent good looks, so that the beau-tiful woman is more likely to get the handsome husband ( 43 ). It may also be that those who are physically and attractively well-endowed bring out good qualities in others; for example in one study, when a man believed himself to be speaking to a beautiful woman by tele-phone, he was found to make conversation that was significantly more interesting than in the obverse ( 44 ).

It is important for us to remember that the media images that we cannot avoid, and that reflect our current consensus of what is beauti-ful, are not wholly realistic, as they have been touched-up, air-brushed, and enhanced in a number of ways ( 42 ). But it is plain that ours is a

xiiiPROLOGUE: THE SEARCH FOR BEAUTY: HISTORICAL, CULTURAL, AND PSYCHODYNAMIC TRENDS

culture of youth, and as the population ages, and as economic condi-tions deteriorate, men and women are tending to work longer, and to retire at a greater age, thus increasing competition in the workplace. In order to remain competitive, men like women are struggling to look younger, healthier, more physically active, and more consonant with the current ideal of masculine good looks. Thus both men and women are seeking cosmetic improvement in greater numbers than ever before ( 3 , 5 , 8 , 21 , 26 , 42 , 45–47 ).

Clearly we are not dealing in absolutes, and as noted earlier, there is a broad spectrum that encompasses the different levels of emotional health that we encounter in practice ( 31 , 35 , 46–48 ) At one end of the spectrum is the successful individual who has a generally positive self-esteem, but who may have physical features that for one reason or another, he/she may want to change a little, or make more youthful. Such an individual will have goals that are realistic, and is likely to be satisfied by the results of any procedure that is undertaken.

The narcissistic individual may have an entirely realistic view of his or her appearance, but yet may find it imperfect for one or another reason, and seeking perfection, may demand procedures that will not satisfy, because, of course, that individual’s view of perfection may not be attainable ( 49 ).

At the other end of the spectrum is the unfortunate person for whom early life experience has led to a negative and insecure body-image with boundaries that are not firm, poor self-esteem, and a depressive affect ( 33 , 34 ). This person makes constant negative comparison with others, both anticipating and attracting negative social feedback in a way that generates a destructive emotional downward spiral. For this person, social situations become progressively more uncomfortable, intimacy is to be avoided, and survival in the workplace may be threatened. Such a person, in defense against these depressive feelings of hopelessness, may deride those who seek ways to improve themselves. Alternatively, such a person may seek ever more radical interventions—surgical or nonsurgical—to improve the real or less-real perceived deficits in face or body configuration that have come to dominate that person’s life ( 48 ).

Body dysmorphic disorder is the name given to the condition in which there is no abnormality, or a very minor abnormality, that is perceived by the individual in a negative way, which is out of propor-tion to the reality. The perception of abnormality may be relatively mild or of frankly delusional proportions and may lead the individual to engage in behaviors that are self-destructive ( 42 , 47 , 48 ). These are the patients who may have anorexia or bulimia, or who may demand ever more radical surgical interventions from the cosmetic surgeon. It is of critical importance to recognize this syndrome, since nothing that the surgeon undertakes will satisfy, and both suicide of the patient and murder of the surgeon are reported ( 49–51 ).

And so, though beauty may indeed be “in the eye of the beholder” ( 52 ), should that beholder be the self, looking into the mirror, the search for beauty may become a very important part of that behold-er’s life, in ways that will depend on the psychological make-up of that same beholder. Clearly, in some this may be healthier than in others.

In the earlier histories of man, age and the acquired wisdom of the years was respected. Aging Greek philosophers such as Plato and Aristotle, though not young, were valued for their wisdom—indeed there was once the concept that age was beautiful ( 53 ). Sadly, during our current generation this view does not hold sway. Youth, and all that youth implies, is the most valuable attribute, and the search for youth—at least as far as looks are concerned—seems to be insatiable. Hence, the rush for botulinum toxin.

Botulinum toxin injections, by eliminating wrinkles, can not only temporarily erase the ravages of time, and create a younger look, but they may also be employed to generate symmetry of face and body ( 54 ).

Thus, although there are increasing numbers of medical conditions for which botulinum toxin has been found effective ( 55–58 ), if we look back anthropologically, by engendering this symmetry, together with a smooth, clear skin, botulinum toxin can help to create the physical features historically believed to signify fertility—perhaps another of the unconscious motivators in the current botulinum toxin craze ( 3 , 6 , 10–12 ).

The “trickle-down” wish by the less socially privileged to enjoy the same physical features that characterize those of greater privilege ( 9 ) may play a part here also. In our media-driven age, the “privileged”—those of the “rich and famous” media idols, sports figures, and models that we see in so many venues each day—are either very young, or, by dint of hard work, and often at considerable expense, have erased wrin-kles, unwanted body weight, and others of the possible signs of aging. Thus it is often the goal of those of us of perhaps lesser “privilege” to emulate that same look in so far as we can, providing yet another force that contributes to the botulinum toxin craze.

Finally, as noted, while medical advances are prolonging healthy life, economic forces are making it necessary for many to work past the usual retirement age. As younger people enter the workforce, their energy and youthful good looks are both psychologically and realisti-cally threatening to those of more advanced age.

And so it is clear that, at this time at least, there are not only deeply entrenched psychological reasons for us to do our best to conform to the current cultural ideal of beauty. Given the realities of our world, and given that our current cultural ideal is one of youth, there are also many very realistic reasons for us to try to emulate that ideal. One way that we can do so—a way that is currently popular for reasons that this book will explain—is by jumping onto the botulinum toxin bandwagon.

REFERENCES 1. Leist A. What makes bodies beautiful. J Med Philos 2003; 28(2):

187–219. 2. Hilhorst MT. Physical beauty: only skin deep? Med Health Care

Philos 2002; 5: 11–21. 3. Sarwer DB, Grossbart TA, Didie ER. Beauty and society. Semin

Cutan Med Surg 2003; 22(2); 79–92. 4. Jackson L. Physical attractiveness. A sociocultural perspective. In:

Pruzinski T, Cash TF, eds. Body Images. New York: The Guilford Press, 2002: 13–21.

5. American Society for Aesthetic Plastic Surgery. Cosmetic Surgery National Data Bank Statistics 2008. Available at www.surgery.org/sites/default/files/2008stats.pdf (accessed November 4, 2010).

6. Nadal M, Munar E, Capo MA, Rossello J, Cela-Conde CJ. Towards a framework for the study of the neural correlates of aesthetic pref-erence. Spat Vis 2008; 21(3–5): 379–96.

7. Santos IM, Young AW. The effects on inversion and negation on societal inferences from faces. Perception 2008; 37(7): 1001–78.

8. Honigman R, Castle DJ. Aging and cosmetic enhancement. Clin Intervent Aging 2006; 1(2): 115–9.

9. Banner LW. American Beauty. New York: Alfred W. Knopf, 1983: 3–8. 10. Pawlowski B, Boothroyd LG, Perrett DI, Kluska S. Is female attrac-

tiveness related to final reproductive success? Coll Antropol 2008; 32(2): 457–60.

11. Swami V, Furnham A. Joshi K. The influence of skin tone, hair length, and hair color on ratings of women’s physical attractive-ness, health and fertility. Scand J Psychol 2008; 49(5): 429–37.

12. Rhodes G. The evolutionary psychology of facial beauty. Annu Rev Psychol 2006; 57: 199–226.

13. Fink B, Neave N. The biology of facial beauty. Int J Cosmet Sci 2005; 27(6): 317–25.

14. Banner LW. American Beauty. New York: Alfred Knopf, 1983: 45–65.

xiv BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

15. Parker-Willis N. Rag-Bag: A Collection of Ephemera. New York: Charles Scribner, 1855: 22.

16. Stuart- Wortley E. Travels in the United States in 1849–1850, Vol 1. New York: Harper Bros, 1851: 54–5.

17. Sala GA. America Revisited. London: . Vizzatelli, 1882: 65. 18. Beard G. Physical future of the American people. Atlantic Monthly.

1879; 43: 7325. 19. Brenner LW. American Beauty. New York:. Alfred Knopf, 1983:

28–44. 20. Yamamiya Y, Cash TF, Melnyk SE, Posavac HD, Posavac SS. Wom-

en’s exposure to thin-and-beautiful media images: Body-image effect on media-ideal internalization and impact-reduction inter-ventions. Body-Image 2004; 2(1): 74–8.

21. Crocket, RJ, Pruzinsky T, Persing JA. The Influence of plastic sur-gery “reality-TV” on cosmetic surgery patient-expectations and decision-making. Plasst Reconstr Surg 2007; 120(1): 316–24.

22. Aherne AL, Bennett KM, Hetherington MM. Internalization of the ultra-thin ideal: Positive associations with underweight fashion models are associated with drive for thinness in young women. Eat Disord 2008; 16(4): 294–307.

23. Hargreaves D. Tiggemann M. The effect of television commercials on mood and body dissatisfaction. The role of appearance schema activation. J Soc Clin Psychol 2002; 21: 328–49.

24. Potter T, Corneille O. Locating attractiveness in the face space: Faces are more attractive when closer to their group prototype. Psychon Bull Rev 2008; 15(3): 615–22.

25. Tiggemann M. Media influence on body image development. In: Cash TF, Pruzinky T, eds. Body Image: A Handbook of Theory, Research and Clinical Practice. New York: The Guilford Press, 2002: 91–8.

26. Schlessinger J. Skin care for men and its marketing. Dermatol Ther 2007; 20(6): 452–6.

27. Hermann B. Ideals of beauty and the medical manipulation of the body between the free choice and coercion. Ethic Med 2006; 18(1): 71–80.

28. Mulherne R, Fieldman G, Hussey T, Leveque JL, Pineau P. Do cos-metics enhance female Caucasian facial attractiveness? Int J Cos-met Sci 2003; 25(4): 199–205.

29. Koblenzer CS, The psychologic effects of aging and the skin. Clin Dermatol 1996; 14: 171–7.

30. Grosslink CK, Cox CL, McClure SJ, DeJong ML. Ravishing or rav-aged: Women’s relationships with women in the context of western beauty culture. Int J Aging Hum Dev 2008; 66(4): 307–27.

31. Kreuger DW. Psychodynamic perspectives on body image. In: Cash TF, Puzinski T, eds. Body Image. New York: The Guilford Press, 2002: 30–46.

32. Kreuger DW. Developmental and psychodynamic perspectives in body image. In:Cash TF, Pruzinski T, eds. Body Images. New York: The Guilford Press, 1990: 255–71.

33. Weiss SJ. Parental touching: Correlates of a child’s body concept. In: Barnard KE, Brazelton TB, eds. Touch, the Foundation of Experi-ence. Madison, CT: International Universities Press, 1990: 425–50.

34. McDevitt JB, Mahler MS. Object constancy, individuality and internalization. In: Greenspan SI, Pollock GH, eds. The Course of Life, Vol. 11: Early Childhood. Madison CT: International Univer-sities Press, 1989: 37–57.

35. Beiser HR. Ages 11–14. In: Greenspan SI, Pollcock GH. eds. The Course of Life, Vol 1V: Adolescence. Madison, CT: International Universities Press, 1991: 106–15.

36. Staples HD, Smarr ER. The Bridge to adulthood. In: Greenspan SI, Pollcock GH. eds. The Course of Life, Vol 1V: Adolescence, 1991: 407–25.

37. Cash TF, Fleming EC. Body image and social relationships. In: Cash TF, Pruzinsky T, eds. Body Image. New York: The Guilford Press, 2002: 277–86.

38. Cash TF. The psychology of physical appearance. In: Cash TF, Pru-zinski T, eds. Body Images. New York: International Universities Press, 1990: 51–7.

39. Koblenzer CS. Psychosocial aspects of beauty: How and why to look good. Clin Dermatol 2003; 21: 473–5.

40. Elder GH Jr, Nguyen TG, Caspi A. Linking family hardship to chil-dren’s lives. Child Devel 1985; 56: 361–75.

41. Lynn M. Determination and consequences of female attractiveness and sexiness: Realistic tests with restaurant waitresses. Arch Sex Behav 2009; 38(5): 737–45.

42. Grossbart TA, Sarwer DB. Cosmetic surgery: surgical tools— Psychosocial goals. Semin Cutan Med Surg. 1999; 18(2): 101–11.

43. Lee L, Loewenstein G, Hong J, Young J. If I’m not hot, are you hot or not? Physical attractiveness evaluations and dating preferences as a function of one’s own attractiveness. Psychol Sci 2008; 19(7): 669–77.

44. Wack ER, Tantieff-Dunn S. Cyber sexy: Electronic game-play and perceptions of attractiveness among college-aged men. Body Image 2008; 5(4): 365–74.

45. The American Society for Aesthetic Plastic Surgery. Cosmetic Sur-gery Quick Facts: 2005 ASAPS Statistics. http://www.surgery.org/press/procedurefacts.

46. Grossbart TA, Sarwer DB. Psychosocial issues and their relevance to the cosmetic surgery patient. Semin Cutan Med Surg 2003; 22(2): 136–47.

47. Castle DJ, Honigman RJ, Phillips KA. Does cosmetic surgery improve psychosocial wellbeing? Med J Austral 2002; 176(12): 601–4.

48. Malick F, Howard J, Koo J. Understanding the psychology of cos-metic patients. Dermatol Ther 2008; 21(2): 151.

49. Castle DJ, Phillps KA, Dufresne RG Jr. Body dysmorphic disorder and cosmetic dermatology: more than skin deep. J Cosmet Derma-tol 2004; 3(2): 99–103.

50. Ritvo EC, Melnick I Marcus GR, Glick ID. Psychiatric conditions in cosmetic surgery patients. Facial Plastic Surg 2006; 22: 194–7.

51. Cotterill JA, Cunliffe WJ. Suicide in dermatology patients. Br J Dermatol 1997; 137: 246–50.

52. Hungerford MW. 1878. “Molly Brown.” Quoted in Bartlett J. Familiar Quotations, 14th edn. Boston, MA: Little, Brown and Company, 1968: 831b.

53. Goldsmith O. She Stoops to Conquer. Act 1. 1775. 54. Tantaro G, Ranso R, Santagata M, Santillo V. Itro A. Lower facial

contouring with botulinum toxin. Type A. J Craniofac Surg 2008; 19(6): 1613–7.

55. Bertoni M, Castagna A, Baracich A, Berti G, Lazzaretti S, Morandi C. Administration of botulinum toxin after total hip replacement. Eur J Phys Rehab Med 2006; 44(6): 461–5.

56. Sahai A, Dawson C, Khan MS, Dasgupta P; GKT Botulinum Study Group. Urology 2010; 75(3): 552–7.

57. Spears RC. Efficacy of botulinum toxin type A in new persistent daily headache. Headache Pain 2008; 9(6): 405–6.

58. Yoon. H, Chung WS, Shim BS. Bottulinum toxin A for the manage-ment of vulvodynia. Int J Impot Res 2007; 19(1): 86–7.

1

The minute quantities of botulinum toxin type A injected directly into its site of action (in this case, extraocular muscles) prevented systemic absorption of clinically significant amounts.

Following this initial success, Schantz, now working at the University of Wisconsin, began developing botulinum toxin type A for testing in humans for Dr. Scott, focusing on purification, high potency, and pres-ervation. Because no protein drugs of this type had ever been devel-oped, the methods and requirements were novel. Schantz selected the Hall strain of Clostridium botulinum for type A toxin for production because it yielded a good quantity of high-quality toxin, which was necessary for further purification and regulatory requirements. Scott went on to successfully use the botulinum toxin type A that Schantz had produced for the treatment of strabismus and blepharospasm in humans ( 2 ). The batch of botulinum toxin type A developed by Schantz was eventually approved for human use by the U.S. Food and Drug Administration (FDA) in 1989 ( Fig. 1.1 ) under the name Oculinum. This preparation was later acquired by Allergan Inc. and, under the name BOTOX®, has been the primary treatment for focal dystonias since the late 1980s, and, over the past decade, has become an impor-tant adjunctive treatment worldwide for adult spasticity and juvenile cerebral palsy. The FDA approved the use of BOTOX® Cosmetic in 2002 for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle acidity in patients 18 to 65 years of age.

SYNTHESIS, STRUCTURE, AND PRODUCTS Botulinum neurotoxins are produced by bacteria as multimeric pro-tein complexes consisting of the neurotoxin and associated hemag-glutinin and nonhemagglutinin proteins. These neurotoxin-associated proteins stabilize and protect the ∼ 150 kDa type A botulinum neuro-toxin from degradation in the gastrointestinal tract, as well as enhance its enzymatic activity ( 3 , 4 ). Different bacterial strains synthesize com-plexes that vary in size and protein composition, as well as neurotoxin serotype ( 5 ).

Seven different botulinum neurotoxin serotypes (A, B, C1, D, E, F, and G) and three different sizes of protein complexes have been repor-ted in the literature. The serotype and protein complex size app ear to covary, such that each serotype is associated with a specific set of com-plex sizes ( Table 1.1 ) ( 5 ). All of the serotypes form the 300 kDa com-plex; serotypes A, B, C1, and D (hemagglutinin positive) form the 500 to 700 kDa complex and only type A forms the 900 kDa complex ( 6 , 7 ).

When botulinum neurotoxin products are manufactured for clini-cal use, the neurotoxin complexes are isolated and purified using procedures that are specific to the manufacturer. These processes determine which, if any, of the neurotoxin-associated proteins are retained in the final product. For example, during the purification process used to manufacture the Allergan botulinum toxin type A product (henceforth identified as onabotulinumtoxinA), only the ∼ 900 kDa complex is retained ( 8 , 9 ), whereas in the purification pro-cess used to manufacture the Ipsen type A product (henceforth iden-tified as abobotulinumtoxinA), an unknown mixture of complexes are retained ( 10 ). All of the neurotoxin-associated proteins are removed in the purification and manufacture of a botulinum neuro-toxin type A product Xeomin® (U.S. nonproprietary name assigned as inco botulinumtoxinA) from Merz. This product is currently awaiting FDA approval (as of April 2010) but is available in several

1 Pharmacology, immunology, and current developments K. Roger Aoki

INTRODUCTION Botulinum neurotoxins are proteins synthesized by clostridial bacteria. For clinical use, these proteins are isolated, purified, and formulated into specific products in a complex series of steps that are strictly reg-ulated by governmental agencies in most countries where the prod-ucts are approved. Because botulinum neurotoxins are derived from living organisms, they are regulated as biological products as opposed to conventional, synthetic drugs. For biological products, the method of manufacture determines not only the purity of the final product but also the reproducibility of unit activity—the dosage measurement for botulinum neurotoxins. The final formulation of the product is also critical, as this can affect product stability, efficacy, safety, and immunogenicity.

This chapter discusses the history, synthesis, and structure of botuli-num neurotoxins, as well as their basic and clinical pharmacology. We also review the immunology of these proteins, our understanding of which has deepened in recent years with the identification of specific epitopes against which neutralizing antibodies are formed. Finally, we introduce several current developments in botulinum neurotoxin therapy that have broadened our view of the pharmacology of these proteins, as well as opened new avenues for clinical therapy.

HISTORY Botulinum toxin type A stands alongside digitalis, atropine, and pac-litaxel as natural compounds that, although first noted for their toxic properties, are now routinely used as medicines. The recorded history of botulinum neurotoxins dates back to human encounters with improperly stored food, which caused the sickness known as botu-lism when ingested ( Fig. 1.1 ). In the early 1800s, the German physi-cian Kerner provided one of the earliest descriptions of food poisoning caused by botulism that followed ingestion of smoked sausages ( 1 ). In the late 1800s, Professor van Ermengem, a Belgian microbiologist, iden-tified botulinum neurotoxin as the cause of botulism in a group of Belgian musicians who had eaten inappropriately prepared sausages.

The events of the Second World War stimulated research and study into the activity of botulinum neurotoxins. Much of this research was conducted by Drs. Lamanna, Schantz, and colleagues at Fort Detrick, Maryland, where botulinum neurotoxin type A (BoNTA) was purified, obtained in crystalline form, and synthesized in sufficient quantities for research ( Fig. 1.1 ) ( 1 ). A number of other investigators, including Burgen and Brooks, made much progress throughout the late 1940s and 1950s in understanding the mechanism of action of botulinum neurotoxins. By the late 1960s, the inhibitory effects of botulinum toxin type A on acetylcholine release at the neuromuscular junction had been well characterized in experimental animals ( 1 ).

Working at the Smith-Kettlewell Eye Research Institute in San Francisco in the 1970s, ophthalmologist Alan Scott was investigating alternatives to surgery for his patients with strabismus, a condition of ocular misalignment. Dr. Scott believed that a substance that could chemically weaken the extraocular muscles pulling the eyes out of alignment might prove a useful alternative to surgical excision of the muscles. On the advice of a colleague, Dr. Scott contacted Professor Edward Schantz ( Fig. 1.1 ) to ask whether he had a substance that might be used to produce such chemical denervation. Schantz sug-gested botulinum toxin type A and Scott soon reported that this protein was able to correct strabismus in an experimental model ( 1 ).

2 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

European Union countries ( 11 ). The BoNTB-based product, Myobloc®/ Neurobloc® is a ∼ 700 kDa complex. It has been assigned the chemical name rima botulinumtoxinB. All approved botulinum toxin-based products are assigned a unit of activity, which are specific for each product and are not interchangeable nor convertible between products.

The active botulinum neurotoxin protein in all serotypes is synthesized as a single chain of approximately 150 kDa that must be nicked or cleaved by proteases in order to be active ( Fig. 1.3 ) ( 12 ). Cleavage results in a di-chain molecule consisting of an approximately 100-kDa heavy chain and an approximately 50-kDa light chain, linked by a disulfide bond ( 5 ).

The crystal structure of botulinum neurotoxin type A was first reported by Professor Raymond Stevens and colleagues ( 13 ), which confirmed many of the predictions made based on studies of physiol-ogy and pharmacology. The protein structure is flat and comprises three modules: the endopeptidase (light chain), the translocation domain (N-terminal half of the heavy chain), and the binding domain (C-terminal half of the heavy chain). The crystal structure of botulinum neurotoxin type B (BoNTB) is similar to that of BoNTA ( 14 ). Reports on the crystal structures of the light chains of

botulinum neurotoxin serotypes D (BoNTD) and G (BoNTG) have provided insights into the structural details of protease substrate recognition, as described in the next section ( 15 , 16 ).

PHARMACOLOGY Mechanism of Action Botulinum neurotoxins exert their activity through a multistep pro-cess that includes binding to nerve terminals, internalization, and inhibition of calcium-dependent neurotransmitter release ( 17 ). All neuro transmitters are calcium-dependent. This chapter focuses on recent developments in the mechanism of action of botulinum neuro-toxins, and the reader is referred to several comprehensive reviews for additional information on the basic mechanisms ( 18 , 19 ).

Binding The heavy chain ( ∼ 100 kDa) subunit of the botulinum neurotoxin molecule binds to receptors on nerve terminal membranes, located primarily but not exclusively on cholinergic neurons ( 20 , 21 ). The binding of botulinum neurotoxins to nerve cell membranes has been explained via a double receptor model, in which the coreceptor

Table 1.1 Neurotoxin Protein Complex Sizes Associated with Each Serotype

Serotype

Neurotoxin protein complex size

~300 kDa (formerly M)

~500 – 700a kDa (formerly L)

~900 kDa (formerly LL)

A X X XB X XC

1X X

D (HA+) X XD (HA-) XE XF X

Abbreviation: HA, hemagglutinin.aHA positive.

Figure 1.1 History of botulinum neurotoxin development.

Neurologic effects first noted from sausage ingestion

1822 1940s

BTX-A isolated,purified

1989

Strabismus,blepharo-spasm

First FDA approval

FDA approval for glabellarlines

2002

1960s

Studies of BTX-A in

animalmuscle

2004

FDA approval forprimary axillaryhyperhidrosis

Bacteriaidentified ascause of botulism

1895

FDA approval for cervical dystonia

20001980s and 1990s

Studied for treatment of dystonias, spasticity, selected other conditions

1970s

First tested in strabismuspatients

Figure 1.2 Professor Ed Schantz in his laboratory.

PHARMACOLOGY, IMMUNOLOGY, AND CURRENT DEVELOPMENTS 3

comprises a ganglioside and protein component. Botulinum neurotox-ins have long been known to interact with gangliosides ( 22 ), with the exception being BoNTD, which appears to bind to a phospholipid but not to gangliosides ( 23 ). The crystal structure of BoNTA in complex with the ganglioside cell surface coreceptor GT1b (G = ganglioside; T = trisialo-ganglioside; 1b = carbohydrate’s sequence) has recently been reported ( 24 , 25 ). Based on these observations, the authors sug-gested that GT1b may mediate the initial contact between the botuli-num toxin and the neuronal membrane, which would serve to greatly increase the local toxin concentration at the membrane surface, permi-tting the toxin to diffuse in the plane of the membrane and bind to its protein receptor ( Fig. 1.4 ) ( 24 ).

The protein component of the receptor for botulinum toxin type A has been identified as secretory vesicle protein synaptic vesicle protein 2 (SV2) ( 26 , 27 ). During exocytosis, intravesicular portions of SV2 proteins are exposed to the cytoplasm, providing an exposed surface to which BoNTA can bind ( Fig. 1.5 ) ( 26 , 27 ). Additional research in neuroblastoma cells suggests that FGFR3 (fibroblast growth factor receptor-3) may also be a possible protein receptor for botulinum toxin type A ( 28 ). Synaptotagmins I and II have been identified as the protein receptors for BoNTB and BoNTG ( 29 , 30 ). Synaptotagmins are localized to synaptic vesicle membranes and binding of BoNTB and BoNTG to these proteins leads to their inter-nalization into neurons ( 30 , 31 ). The crystal structure of BoNTB in complex with synaptotagmin II has been reported ( 30 , 32 ). The authors observed that synaptotagmin II formed a short helix that bound to a hydrophobic groove in BoNTB and BoNTG; this bind-ing groove varied in other serotypes, supporting the serotype differ-ences in protein co-receptors ( 30 ).

Translocation Following binding, botulinum neurotoxins are translocated into the neuronal cytosol via receptor-mediated endocytosis ( 33 ). There appear to be two distinct internalization processes: a rapid uptake, which may utilize the vesicle recycling system, and a slower uptake requiring hours, which may be a less specific endocytotic process. This internalization

process is energy-dependent and is critical for the activity of botulinum neurotoxins ( 34 ). Upon acidification of the endosome, it is hypothe-sized that a pH-dependent change in the translocation domain of the heavy chain facilitates the translocation of the light chain into the cyto-plasmic compartment. The exact mechanism of this translocation process is not known, but it has been speculated that the heavy chain can form a pore through which the light chain can pass ( 33 ). Recent data indicates that acidification does not trigger substantial structural changes to the botulinum toxin protein as previously thought, but instead may eliminate repulsive electrostatic interactions between the translocation domain and the membrane, leading to the protein’s translocation ( 35 ).

Figure 1.3 Structure of botulinum neurotoxin unnicked, inactive single-chain pro-tein (150 kDa; left ) and nicked, activated di-chain protein (100-kDa and 50-kDa chains; right ).

COOH

Heavychain

Lightchain

SS

COOH

NH2

SS

S-S

NH2

COOH

NH2

S-S

Figure 1.4 Potential binding model for botulinum toxin type A. BoNTA displayed as rainbow colored ribbon, GT1b as CPK spheres and Synt-II as a gray ribbon. ( A ) Free BoNTA above the cell surface displaying GT1b. ( B ) BoNTA bound to GT1b on the cell surface. ( C ) BoNTA bound to GT1b and Synt-II on the neuron surface. ( D ) BoNTA entering the cell through endocytosis. ( E ) Side view of the BoNTA along the axis of possible rotation. ( F ) The N-terminal domain of the translocation domain (loops 600 and 760) of the 100 Å long helixes from the translocation domain swing-ing into contact with the membrane inside the acidified endosome; it is also possible that the other end of the translocation domain make the initial contact with the membrane. Source : From Ref. 24 .

(A) (B)

(C)

(D)

(E)

(F)

4 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Enzymatic Activity Once inside the cytosol, the light chain cleaves one or more of the SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor) proteins necessary for vesicle docking and fusion, thereby reducing exocytotic neurotransmitter release ( Fig. 1.6 ). Each serotype cleaves a specific peptide bond on one or more of the SNARE proteins ( 33 ). The enzymatic activity of the light chain requires the presence of the intramolecular zinc.

In response to reduced neurotransmitter release, neuronal sprouts appear at motor-nerve terminals and nodes of Ranvier, which have been noted within 2 days after injection of BoNTA into mammalian soleus muscles ( 36 ). These sprouts persist and become more complex (increased branching and length) for at least 50 days following intra-muscular injection of BoNTA. Sprouts may establish functional synap-tic contacts ( 36 ). However, recent evidence at the rat neuromuscular junction indicates that neurotransmitter release can be detected from

Figure 1.5 Molecular model of an average SV. The model is based on space-filling models of all macromolecules at near atomic resolution. (A) Outside view of a vesicle. (B) View of a vesicle sectioned in the middle (the dark-colored membrane components represent cholesterol). (C) Model containing only synaptobrevin to show the surface density of the most abundant vesicle component. The following proteins were included (copy number in parentheses): VAMP4 (2), SNAP-29 (1), vti1a (2) Syntaxin 6 (2), other syntaxins (4), other synaptotagmins (5), other Rab proteins (15), Munc-18 (2), other transporters (2), chloride channels (2), and trimeric GTPases (2). Source : From Ref. 110 .

(A)

(B)

TrimericGTPase

Othertransporter

Rab

Munc18

Synapsin

VAMP4

SNAP29

Synaptophysin

CIC3

SynaptotagminSynaptobrevin

Vti1aSNAP25

V-ATPase

CSP

SV2

SCAMP

Syntaxin

VGLUT

(C)

PHARMACOLOGY, IMMUNOLOGY, AND CURRENT DEVELOPMENTS 5

original terminals about the time that new sprouts have established a functional synapse, and accounts for more than 80% of total acetylcho-line release ( 37 ). Eventually, exocytosis is restored, the original termi-nals recover, and the sprouts regress ( 38 ). After re-innervation is complete, the target tissue is fully functional ( 36 ) and there is no clinical indication that postbotulinum re-innervation produces func-tionally substandard synapses. However, in rats, acetylcholine release has been found to recover more slowly after multiple injections than

single injections ( 37 ). If this finding were also true in humans, it may suggest a tendency for increased duration of clinical response fol-lowing multiple injections; however, this has been reported in only one study out of 44 studies of repeated injections with BoNTA ( 39 ). The dosage did not change in 22 of 44 studies, increased in 4 studies, and were not reported over time in 17 studies ( 39 ). The relevance of the preclinical observation to the clinical results remains to be determined.

Figure 1.6 Mechanism of action of botulinum neurotoxins. Source : from Ref. 111 .

Neuromuscular junctionMotor nerveterminus

Synaptic vesicle SNARE proteinsform complex

Normal neurotransmitter release

Vesicle and terminalmembranes fuse

Synapticfusioncomplex

NeurotransmitterreleasedAcetylcholine

Acetylcholinereceptor

Muscle fiber contracts

Muscle cell

Synaptobrevin

SNAP-25

Syntaxin

SNAREproteins

Nerve terminus

Synapticcleft

Muscle cell

Botulinum toxinendocytosed

Light chain cleavesspecific SNARE proteins

Light chain

Heavy chain

Botulinumtoxin

Type C

Types A,C,E

Types B,D,F,G

SNARE complexdoes not form

Membranesdo not fuse

Neurotransmitternot released

Muscle fiber paralyzed

Muscle cell

(A)

(B)

Exposure to botulinum toxin

6 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Lack of Retrograde Transport Unlike tetanus toxin, the active portion of the botulinum toxin protein does not undergo retrograde transport and transcytosis across neurons to exert effects in distant regions ( 40 ). However, Antonucci and col-leagues recently published a paper that appears to contradict this well-known distinction between botulinum and tetanus toxins ( 41–43 ). These authors reported retrograde transport and transcytosis of botu-linum toxin into rat brain following administration into the muscles that control whisker movements—a report that was rapidly taken up by the popular press ( 44 ) and even the Journal of the American Medical Association ( 45 ).

However, the results of this study are complicated by a number of important issues ( 46 ). First, the authors used a high dose of a labora-tory preparation of BoNTA that was injected into a single site of the rat whisker pad ( 41 ). The dose used was 135 pg or approximately 450 pg/kg. By way of comparison, patients treated with onabotulinumtoxinA for cosmetic glabellar treatments typically receive approximately 20 units or 3 pg/kg administered into multiple muscles, which is ∼ 150-fold lower than the dose used by Antonucci and colleagues. Administration of this high dose may have triggered nonspecific uptake and could have overloaded the protein transport system of the neuron. The use of such high doses of a different type (i.e., laboratory preparation BoNTA) into a single site negates the relevance of these results in a clinical setting with humans. Over 20 years of treatment with BoNTA (onabotulinum-toxin A), of the facial area has not observed any deleterious central effects and that physicians can safely use BoNTA for therapy ( 47 ).

A second issue with this study is that the authors used an incom-pletely characterized antibody to differentiate between cleaved and uncleaved SNAP-25, the key substrate for BoNTA ( 41 ). The appearance of cleaved SNAP-25 in central neurons was taken to indicate retrograde transport of the active BoNTA enzyme. That is, the authors did not attempt to directly determine the presence of BoNTA in the central neurons but rather detected a fragment of the protein known to be cleaved by the BoNTA enzyme as a measure of toxin activity in the brain. They detected this protein fragment using Western blot or immunohistochemistry. However, the inference that a positive signal in these assays indicates the presence of cleaved SNAP-25 depends on the specificity of the antibody used. Because the antibody was not well characterized, it cannot be concluded with certainty that the protein binding to it was cleaved SNAP-25. A study that attempted to directly detect botulinum toxin type A in various tissues following intramuscu-lar injection using radiolabeled neurotoxin did not find evidence of distribution into the central nervous system ( 48 ).

These points represent major objections to the findings from the Antonucci et al. study. The conclusions of the study do not appear to be entirely justified and, in particular, their relevance to clinical use of botulinum neurotoxins is questionable.

Nonmotor Anticholinergic Effects Botulinum neurotoxins act not only on efferent motor pathways but also on efferent autonomic efferent pathways, which also utilize acetyl-choline as a neurotransmitter. The inhibitory effects of BoNTA on autonomic nerve terminals have led to its successful use in conditions of autonomic hyperactivity such as hyperhidrosis and gustatory sweat-ing ( 49 ). Although the effects on autonomic and motor nerve terminals are thought to occur by a similar mechanism (i.e., binding, internaliza-tion, and inhibition of neurotransmitter release), the clinical effects are of longer duration in some autonomic conditions than in neuro-muscular conditions. The reason for this difference is unknown.

Direct evidence from preclinical studies and indirect evidence from clinical studies indicate that BoNTA affects afferent pathways via inhibition of neural input to intrafusal fibers ( 49 , 50 ). Intrafusal fibers are encapsulated fibers that make up muscle spindles ( Fig. 1.7 ), or the

proprioceptive organs located among skeletal muscle fibers (extrafusal fibers). Extrafusal fibers are innervated by alpha motor neurons, whereas intrafusal fibers are innervated by gamma motor neurons and Ia sensory afferents. The inhibition of gamma motor neurons decreases activation of muscle spindles, which effectively changes the sensory afferent system by reducing the Ia traffic. Filippi and colleagues con-firmed this hypothesis by establishing that local injections of BoNTA directly reduce afferent Ia fiber traffic in rats, thereby modulating sen-sory feedback ( 50 ). Histologic support for the direct effect of BoNTA on the rat muscle spindles supported the electrophysiologic results ( 51 ).

Berardelli and colleagues have examined potential clinical correlates of BoNTA’s effects on intrafusal fibers. These investigators evaluated electrophysiological variables in muscles injected for the treatment of writer’s cramp ( 52 ). In these patients, BoNTA reduced the tonic vibra-tion reflex to an even greater extent than the maximal M-wave and maximal voluntary contraction. Additionally, the tonic vibration reflex but not the other variables remained reduced in several patients whose clinical benefit persisted for 7 months. The authors speculated that suppression of the tonic vibration reflex may result from effects of the neurotoxin on intrafusal muscle fibers, causing reduced spindle inflow to the central nervous system during vibration ( 52 ). Similar effects were noted in individuals with spasticity who retained some degree of motor function ( 53 ). Combined with the preclinical findings, these results suggest that the overall effect of BoNTA therapy, at medically relevant doses, may be a combination of a direct effect on the primary nerve-end organ communication coupled with an indirect effect on the overall system. These reports utilized onobotulinumtoxinA and should not be applied to other products, as summarized below.

Research documenting the effects of botulinum neurotoxins on neu-rotransmitters other than acetylcholine is accumulating, particularly as it relates to pain and urinary tract dysfunction. The current develop-ments in this area are discussed in the last section of this chapter.

CLINICAL PHARMACOLOGY Differences Between Botulinum Neurotoxin Products Because botulinum neurotoxins are biological products, their clinical pharmacology depends on a variety of factors, including the bacterial strain used in production, methods of isolation and purification, sero-type, formulation, and procedures used to determine biological activ-ity ( Table 1.2 ). These factors vary for each commercially available botulinum neurotoxin product. Each product’s distinct formulation results in a unique interaction with biologic systems following injec-tion. The system is exposed to different ingredients and different num-bers of molecules that likely influence local osmotic gradients and diffusion. Additionally, isolation and purification methods can influ-ence the antigenicity of biological products ( 54 ). Even minor changes to the formulation of biological products can influence clinical pro-file, as demonstrated with a human erythropoietin analog epoetin alfa ( 54 ). In Europe, the switch from albumin to polysorbate 80 in the formulation of one of these products [Eprex (J&J), in EU, Australia,

Figure 1.7 Muscle spindle structure showing intrafusal and extrafusal fibers.

Muscle spindle

Extrafusalfibers

Intrafusalfibers

PHARMACOLOGY, IMMUNOLOGY, AND CURRENT DEVELOPMENTS 7

Singapore, and Canada] led to an unpredicted increase in cases of pure red cell aplasia—a severe form of potentially lethal anemia ( 54–57 ). Additional changes to the product have since reduced cases of this nor-mally rare immunogenic response to low levels ( 55 ), but this example illustrates the complexity of biological products and the unpredictable effects of even small changes in manufacturing process or formulation.

Of paramount importance with botulinum neurotoxin products is the difference in units of biological activity. Units of different botuli-num neurotoxin products are not equivalent and cannot be inter-changed using a single ratio ( 58 , 59 ). Not only do botulinum neurotoxin products exhibit pharmacologic differences ( 60 , 61 ), but they are also used clinically at different doses depending on the indication and individual presentation ( 62 ).

Approved Products Even products that are labeled as containing the same number of units per vial do not necessarily exhibit the same biological activity. This was demonstrated in a recent comparison of two BoNTA products, both labelled at 100 units ( 63 ). One of the products botulinum neurotoxin A (incobotulinumtoxinA, Merz) was found to contain substantially fewer units per vial when compared against onabotulinumtoxinA reference standard ( 63 ). Additionally, units of the incobotulinum toxinA product were substantially lower when tested one year later, which was still prior to the product’s expiration date. These results suggest product degradation over time and emphasize that attempts to interchange BoNTA products fail to take into consideration potentially critical effects of formulation on biological product performance.

Many attempts have been made to compare the units of several established BONTA products (onabotulinumtoxinA and abobotuli-numtoxinA) ( 58 , 64 , 65 ). Although in the past it was reported by some investigators that these two products were clinically comparable

when used at dose ratios of approximately 1:3 to 1:5, a growing body of evidence suggests that the products exhibit different clinical characteristics regardless of the dose ratio ( 58 , 66 , 67 ). In particular, abobotulinum toxinA seems to exhibit a somewhat different side effect profile than onabotulinumtoxinA ( 66 , 68–70 ). This conclusion is also supported by preclinical comparisons, which are more highly contro-lled and can employ a broader range of doses than is possible in human studies ( 60 , 61 ). Despite these results, some authors report dose ratios as low as 1:1 ( 71 ). It should be noted that the bulk of the literature does not support this dose ratio, and it does not represent clinical practice ( 62 ). Clinical use of this dose ratio could have serious consequences for patients; for instance, use of onabotulinumtoxinA at the higher doses needed for abobotulinumtoxinA could lead to inadvertent side effects, whereas use of abobotulinumtoxinA at doses used for ona-botulinumtoxinA could lead to inadequate efficacy and duration of action. Clearly, to maximize patient safety and clinical benefit, it is critical that clinicians use each BoNTA product at doses that have been established for that specific product in the specific indication.

The botulinum toxin type B (rimabotulinutoxinB, BoNTB) from Elan/Solstice also cannot be compared to other products based on a dose ratio. Doses of this product are often up to several orders of magnitude higher than onabotulinumtoxinA depending on the indication and individual patient presentation, and adverse event profiles differ ( 72 ).

Unlicensed Products The case against dose conversion of botulinum neurotoxins has become even more prominent with the unscrupulous use of counter-feit and unlicensed products. One case of nonequivalent units was demonstrated with a botulinum toxin type A product CNBTX-A (Nanfeng) that was previously available in China but was not appro-ved there or in any other country ( 73 ). The label on each vial indica-ted 55 units, but the product was not accompanied by a package insert or dosing recommendations. Testing against an onabotulinumtoxinA reference standard showed that a vial of CNBTX-A contained 243 units of biological activity ( 73 ). Serious consequences could have resulted if clinicians had obtained this nonapproved product and applied it to patients based on doses of an approved product. This alarming varia-tion in biological activity strongly indicates that clinicians must not rely on dosing of one neurotoxin product to ascertain dosing of another. This finding also indicates the dangers of nonapproved neurotoxins—the lack of literature to guide dosing of this product and the lack of an approved manufacturing process could lead to serious, unintended consequences for patients.

These risks were validated by the unscrupulous use of a highly con-centrated laboratory preparation of BoNTA (that occurred in 2006). This neurotoxin product, which was clearly labeled for laboratory use only, was illegally administered to several individuals in a Florida clinic for cosmetic purposes ( 74 ). All of the individuals exposed to this highly concentrated laboratory preparation of BoNTA experienced progressive muscle weakness and neuropathies, and were eventually hospita lized for up to 14 weeks ( 74 ).

The dangers of using unlicensed botulinum neurotoxin prepara-tions are unambiguous: clinicians risk patient safety. It is critical that clinicians verify the botulinum neurotoxin product they are using and use it at doses recommended by the manufacturer and/or docu-mented in the published clinical literature. The data documenting the nonequivalence of botulinum neurotoxin units is summarized in Figure 1.8 .

Neuromuscular Injection In the clinic, BoNTA is most often injected into overactive muscles that vary depending on the condition to be treated and the patient’s individual presentation. Onset of action following intramuscular

Table 1.2 Characteristics and Packaging of Different Botulinum Neurotoxin Products (11,59,108,109)

Botulinum neurotoxin product (year, country of first approval)

Biological units per

vial FormulationMethod of

stabilization

BOTOX® (Allergan)

Onabotulinumtoxin A

(1989, USA)

100 U

50 U

Botulinum toxin

type A 900-kDa

protein

500,000 ng serum

albumin

900,000 ng sodium

chloride

Vacuum dried

Dysport® (Ipsen)

Abobotulinumtoxin A

(1991, UK)

500 U

300 U

(USA)

Botulinum toxin

type A 500- and

900-kDa protein

125,000 ng serum

albumin

2,500,000 ng lactose

Lyophilized

Xeomin® (Merz)

Botulinum neurotoxin A

(2005, Germany)

100 U Botulinum toxin

type A 150-kDa

protein

1 mg serum albumin

4.7 mg sucrose

Lyophilized

Myobloc®/Neurobloc®

(Elan/Solstice)

Rimabotulinumtoxin B

(2000, USA)

2500 U,

5000 U,

or

10,000 U

Botulinum toxin

type B 500–700-kDa

protein

0.05% serum

albumin

0.1 M sodium

chloride

0.01 M sodium

succinate

Liquid

formulation,

pH 5.6

8 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

injection is approximately 3 to 7 days ( 75 ). The beneficial effects of each treatment with BoNTA last approximately 3 to 5 months in neu-romuscular conditions ( 75 , 76 ). The duration of BoNTB is somewhat shorter than that of BoNTA and has been reported as 6 to 8 weeks with 1000 units and 10 to 12 weeks with 2000 units in the management of brow or glabellar lines ( 75 ).

Due to the chronic nature of most of the neuromuscular condi-tions that botulinum neurotoxins are used to treat, repeated injec-tions are typically required over the course of many years. The results of numerous studies indicate that most patients respond to BoNTA for many years without decrements in safety, responsiveness, or qual-ity of life, and without increased doses ( 77 , 78 ). Some studies have reported enhanced benefits with BoNTA following repeated injec-tions, showing increased duration, decreased adverse events, or greater functional improvements (e.g., gait in children with cerebral palsy) with successive injections ( 39 ). In the case of improved gait, this may be due to adaptation of the patient to reduced tone. How-ever, the increased duration and other benefits may also be due to altered sensory feedback from the periphery to the central nervous system ( 79 ).

Intradermal Injection In the treatment of focal hyperhidrosis, BoNTA is injected intrader-mally instead of intramuscularly. The onset of action of BoNTA in various forms of hyperhidrosis is within 1 week, and benefits last approximately 7 months ( 80 , 81 ). Benefits are maintained following repeated injections for at least 16 months ( 80 ).

Several studies have examined the use of BoNTB (rimabotulinum-toxinB) for axillary hyperhidrosis. These studies have found that type B significantly reduces sweating, but with distal autonomic side effects that are not observed with type A such as visual accommodation diffi-culties and dry mouth ( 82 ).

IMMUNOLOGY Like most foreign proteins introduced into the body, botulinum neuro-toxins can be antigenic and, under the certain circumstances (e.g. dose and frequency), elicit immune responses designed to inactivate the protein. Only antibodies directed against the 150-kDa neurotoxin neutralize its activity ( 83 ). Antibodies may occasionally be formed

against the nontoxin proteins in the botulinum neurotoxin complex, but these do not affect clinical responsiveness ( 83 ).

Within the BoNTA molecule, antibodies directed against certain peptides within amino acid residues 449 to 1296 of the heavy chain are neutralizing ( 83 ). Nearly all of the regions overlap or coincide with the regions on the protein that bind to synaptosomes ( 84 ), providing a physical basis for their neutralizing effect (i.e., blocking the binding of BoNTA to the nerve terminal). Similar results have been found for BoNTB (rimabotulinumtoxinB) ( 85 ). Research has further shown that the pattern of antibody recognition varies among patients with neu-tralizing antibodies, such that not all patients develop antibodies to the same portion of the BoNTA molecule ( 84 ). These findings under-score the role of individual genetic factors in neutralizing antibody development.

In addition to individual genetic factors, manufacturing methods and formulation are known to affect the immunogenicity of biological products ( 54 , 86 ), and thus, it cannot be assumed that the rate of neu-tralizing antibody formation will be the same with all botulinum neuro-toxin products. Both short-term and long-term (e.g. 2-year) studies are needed with each individual product to adequately determine its anti-genicity in a given clinical population at relevant doses.

Few studies have been published on the antigenicity of botulinum neurotoxin preparations in cosmetic use, partly because the relatively low doses utilized minimize the potential for neutralizing antibody formation. In a short-term spasticity study and a long-term cervical dystonia study, the rate of neutralizing antibody formation with ona-botulinumtoxinA (Allergan) has been documented at approximately 1% ( 87 , 88 ). In these studies, the sera of all available patients were ana-lyzed using the mouse protection assay, which is the gold standard test due to its specificity, despite its relative lack of sensitivity. Abobotu-linumtoxinA (Ipsen) did not elicit any antibody formation in a short-term spasticity study ( 89 ); however, in a longer-term study of 93 dystonia patients who received a mean of 4 treatments (range 1–13), the overall rate of neutralizing antibody formation was 3% (4% among cervical dystonia patients) ( 90 ). The neutralizing antibody formation rate with incobotulinumtoxinA (Merz) has not been reported. The neutralizing antibody formation rate with rimabotulinumtoxintyptB (Solstice) has been reported as 10% after 1 year or 18% after 18 months of treatment for cervical dystonia ( 91 ).

Figure 1.8 Units of different botulinum neurotoxin preparations are not equivalent (see text for references).

Unapproved, unlicensed preparations

Approved, licensed preparations

BOTOX® Reference product in nearly all unit activity comparison studies

Dysport® No single ratio adequate to convert from BOTOX® doses; adverse event profile somewhat different from BOTOX®

Myobloc® Botulinum toxin type B; clinical doses much higher than for the type A preparations

Xeomin® Different unit activity from BOTOX® in preclinical tests

CNBTX-A Vial labeled 55 units; actual bioactivity in Allergan unit assay 243 units

Laboratory preparations

Can be exceedingly potent; not for human use; patients hospitalized following injection for cosmetic purposes

Patient safety is at risk if clinicians use unlicensed preparations

Each approved product should be used at doses recommended by the manufacturer or documented in the clinical literature

PHARMACOLOGY, IMMUNOLOGY, AND CURRENT DEVELOPMENTS 9

Primary or secondary clinical nonresponsiveness has been reported in the absence of neutralizing antibodies, suggesting that there may be other reasons for lack of response to botulinum neurotoxins. These reasons include patient perception (e.g., subsequent injections may appear to have a less dramatic effect than the first) ( 92 ), either because patients continue to experience some benefit from the previ-ous injection or perhaps due to lack of memory about the severity of their condition prior to injection. The injections may not be directed into the optimal muscles or the muscles involved may have changed from the previous visit either due to progression of the disorder or neural adaptation ( 93 ). These changes may require a modification of injection sites, dose, or both in order to maintain optimal treatment benefit.

CURRENT DEVELOPMENTS Several interesting developments are currently taking place in botuli-num neurotoxin therapy. The first concerns the activity of these pro-teins in the treatment of pain and the second is the novel information on mechanism of action and clinical benefit derived from the appli-cation of these proteins on urinary tract disorders such as overactive bladder and benign prostatic hypertrophy.

Pain Beneficial effects of BoNTA on pain were stimulated by the finding that injections into patients with cervical dystonia relieved not only the aberrant muscle activity, but also the associated neck and shoulder pain ( 94 ). The benefits reported for BoNTA in chronic migraine ( 95 ) and the lack of direct concordance between its effects on muscle relax-ation and improvement in pain in neuromuscular conditions ( 96 ) suggest that pain relief may not be strictly secondary to the reduction of muscle contractions. This has led to an increase in research direc-ted at identifying possible mechanisms by which BoNTA may act to reduce pain.

Pain is transmitted to the central nervous system by two types of afferent nerves or primary nociceptive afferents: A-delta fibers that mediate sharp, pricking pain and C fibers that mediate slow, burning pain. The cell bodies of these neurons are located in the dorsal root ganglia, where they send out a single process that branches to innervate the periphery as free nerve endings (nociceptors—pain sensory organs) and the other to innervate the central nervous system, synapsing on neurons in the dorsal horn of the spinal cord. Pain sensations detected in the face and head are transmitted by trigeminal neurons (A delta and

C fibers) whose cell bodies are located in the trigeminal ganglion and whose axons synapse in the brain stem. Type C fibers release sub-stance P, somatostatin, and other neuropeptides from both central and peripheral terminals. These peptides mediate pain and inflam-matory reactions.

BoNTA has been found to inhibit substance P release from cultured dorsal root ganglion neurons ( 97 ). Substance P is a peptide neurotrans-mitter released by primary nociceptive afferents (C fibers). Addition-ally, botulinum toxin type A has been found to reduce the stimulated but not basal release of calcitonin gene-related peptide (CGRP) from cultured trigeminal ganglia neurons ( 98 ). CGRP is an inflammatory neuropeptide that is contained within dorsal root ganglia neurons and colocalized with substance P in most trigeminal and other sensory ganglia neurons. BoNTA inhibits the release of acetylcholine from both alpha and gamma motor neurons, thus eliciting muscle relax-ation. Additionally, BoNTA has antinociceptive effects in several ani-mal models ( 99 , 100 ). A possible mechanism by which BoNTA may act in reducing pain through inhibition of pain neuropeptides, direct reduction of peripheral sensitization of the pain nerve, and therefore indirect reduction of central sensitization associated with chronic pain ( Fig. 1.9 ).

Beneficial effects of BoNTA on pain associated with postherpetic neuralgia was reported in several case studies in 2002 ( 101 ). A recent randomized, controlled study has confirmed these effects in patients with neuropathic pain due to postherpetic neuralgia or focal nerve injury accompanied by spontaneous pain and mechanical allodynia ( Fig. 1.10 ) ( 102 ). Results of this study indicated that BoNTA was more effective than placebo at reducing spontaneous pain intensity, which correlated with the preservation of thermal sensation at baseline ( 102 ). BoNTA also improved allodynia and decreased cold pain threshold, without affecting perception thresholds. Neuropathic symptoms and general activity also significantly improved in these patients, and injec-tions were well tolerated. The authors concluded that BoNTA may induce direct analgesic effects in patients with chronic neuropathic pain independent of its effects on muscle tone. These findings suggest that BoNTA may be a useful treatment for certain types of neuropathic pain that include a neurogenic inflammatory mechanism. Some chronic pain conditions include postherpetic neuralgia, painful dia-betic neuropathy, complex regional pain syndrome, chronic mig raine, overactive bladder (see below), arthritis, etc. Studies examining the effects of these proteins in other conditions characterized by a promi-nent pain component are ongoing.

Figure 1.9 Possible mechanism of botulinum neurotoxin inhibition of pain. Botulinum toxin type A may directly inhibit primary sensory fibers, leading to a reduction of peripheral sensitization, and an indirect reduction in central sensitization, receptor field expansion, and allodynia. Abbreviations: CNS, central nervous system; CGRP, calcitonin gene related peptide; TRPV1, transient receptor potential cation channel, subfamily V, member 1 (i.e. capsaicin receptor); c-Fos, a protein produced by the proto-oncogene of the immediate early gene family of transcription factors.

Peripheralstimulation

Prevents:• Release of glutamate, CGRP, SP• Peripheral sensitization• Formalin P-II pain• (TRPV1 expression)

Antidromic activation

CNS

Botulinumtoxin/A

Indirectly prevents:• Central sensitization• Inhibits c-Fos• Receptor field expansion• Allodynia

Additional activation

Clinical relevance of these preclinical results remain to be established

X

Release of glutamateand peptides in CNS

10 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Lower Urinary Tract Disorders BoNTA is an effective therapy for the treatment of overactive bladder, as demonstrated by a recent European consensus report that concluded that “the use of botulinum neurotoxin type A (BoNTA) is recom-mended in the treatment of intractable symptoms of neurogenic

detrusor overactivity (NDO) or idiopathic detrusor overactivity (IDO) in adults (grade A)” ( 103 ).

When injected into the bladder, BoNTA reduces acetylcholine release from parasympathetic cholinergic fibers that innervate the detrusor muscle, leading to muscle relaxation. In addition to these motor effects,

Figure 1.11 Proposed mechanism of action of botulinum toxin type A (BoNTA) injected into the overactive bladder wall. It has been proposed that a complex system of inter-actions exists between the release of neurotransmitters and actions on respective receptors located on the urothelium and suburothelium, corresponding to pathways of bladder mechanosensation. All connections identified by arrows are thought to be upregulated in detrusor overactivity. BoNTA may exert a multimodal effect on those pathways via multiple inhibition of the vesicular release of neurotransmitters and neuropeptides by the urothelium and suburothelial nerves and reduction of the axonal expression of SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor)-complex-dependent proteins that are thought to be involved in bladder mechanosensation. bl, basal lamina of urothelium; mf, myofibroblast layer; det, detrusor muscle; TRPV1, transient receptor potential vanilloid 1; P2X3, ionotropic purinergic receptor type 3; P2Y, metabotropic purinergic receptors; M2/M3, muscarinic acetylcholine receptors types 2 and 3; NK1, neurokinin receptor type 1 (SP receptor); SP, substance P; NGF, nerve growth factor; ACh, acetylcholine; ATP, adenosine triphosphate. Source: From Ref. 103.

Urine(pH changes, temperature changes, mechanical stretch)

TRPV1 TRPV1TRPV1

TRPV1

TRPV1

SP

M3M3M2

M2

M2 M2

M2

M2

bl

mf

det

P2X3

P2X3

Ach

ACh

Ach

P2X3

P2X3

ATP

NGFNGFATP

P2Y

P2Y

P2X3

NK-1NK-1

TRPV1

M3

M3

SPTRPV1

ATP

SP

ATP/ACh

Figure 1.10 Mean improvement in pain intensity (visual analog scale) in patients with neuropathic pain. Results from a randomized, double-blind, placebo-controlled trial of 29 patients (n = 15 botulinum toxin type A [BoNTA], n = 14 placebo) (102).

0

10

20

30

40

50

60

70

80

Baseline Week 4 Week 12 Week 24

Mea

n pa

in s

core

(vi

sual

ana

log

scal

e) BoNTA

Placebo

**

*

PHARMACOLOGY, IMMUNOLOGY, AND CURRENT DEVELOPMENTS 11

BoNTA may affect sensory nerves in the bladder. In a preclinical model of bladder pain, BoNTA has been found to reduce the release of CGRP from afferent nerves ( 104 ). Additionally, BoNTA has been found to affect the vanilloid receptor transient receptor potential vanilloid receptor-1 (TRPV1) and the purinergic receptor P2X3 ( 105 ). TRPV1 is expressed on peripheral nociceptors, where increased levels are involved in maintaining inflammatory hyperalgesia. P2X3 (purinergic receptor P2X, ligand-gated ion channel, 3), a receptor for adenosine triphosphate (ATP), is expressed on primary afferent fibers and func-tions in pain transmission. In individuals with neurogenic or idio-pathic detrusor overactivity, levels of TRPV1 and P2X3 receptors were significantly decreased following BoNTA administration, which corre-lated with improvements in clinical and urodynamic parameters ( 105 ). These findings suggest that BoNTA may produce its clinical benefit, in part, by decreasing the levels of these sensory receptors ( Fig. 1.11 ).

BoNTA also reduces the level of nerve growth factor in the bladder of individuals with detrusor overactivity ( 106 ). Recent evidence has confirmed that patients with detrusor overactivity exhibit increased levels of nerve growth factor in the bladder, and the reduction of these levels is associated with clinical response to BoNTA ( 107 ).

SUMMARY AND CONCLUSIONS Basic and clinical research on botulinum neurotoxins continues to progress rapidly. The past few years have seen major advances in our understanding of botulinum neurotoxin binding, with the identifica-tion of protein coreceptors for serotypes A and B. Our understanding of the immunology of botulinum neurotoxins is also proceeding, as demonstrated by the identification of the epitope regions on the pro-tein’s heavy chain. In addition to the traditional anticholinergic action of botulinum neurotoxins, novel pharmacological actions of these proteins have been identified that may contribute to their mecha-nism of action in various conditions. These novel mechanisms largely involve sensory afferent neurons and may play a role in botulinum neurotoxin’s effects in primary pain conditions and lower urinary tract disorders.

With the development of additional clinical indications for botuli-num neurotoxins, more clinical products based on these proteins are entering the marketplace. Because botulinum neurotoxins are bio-logical products, different preparations manufactured using different methods, and having different formulations possess unique clinical performance profiles. Particularly important to clinicians are the dosing differences among these products. Dose confusion could compromise clinical efficacy or patient safety or both.

As research and development of botulinum neurotoxins advances, it seems likely that additional applications will be identified for these important therapeutic proteins. As in the case of chronic pain and lower urinary tract diseases, investigations into the mechanism of action of botulinum neurotoxins may even expand our knowledge of the disease mechanisms themselves. In such ways, the clinical and basic sciences of botulinum neurotoxins are intertwined.

REFERENCES 1. Schantz EJ, Johnson, EA. Botulinum toxin: the story of its devel-

opment for the treatment of human disease. Perspect Biol Med 1997; 40(3): 317–27.

2. Scott, AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980; 87(10): 1044–9.

3. Sharma SK, Singh BR. Hemagglutinin binding mediated protec-tion of botulinum neurotoxin from proteolysis. J Nat Toxins 1998; 7: 239–53.

4. Sharma SK, Singh BR. Enhancement of the endopeptidase activ-ity of purified botulinum neurotoxins A and E by an isolated

component of the native neurotoxin associated proteins. Biochemistry 2004; 43: 4791–8.

5. Sakaguchi G, Kozaki S, I. O. Structure and function of botulinum toxins. In: AIouf JE, ed. Bacterial Protein Toxins. London: Academic Press, 1984: 435–43.

6. Sakaguchi G, Ohishi I, Kozai S. Purification and oral toxicities of Clostridium botulinum progenitor toxins. In: Lewis GEJ, ed. Biomedical Aspects of Botulism. New York: Academic Press, 1981: 21–34.

7. Inoue K, Fujinaga Y, Watanabe T, et al. Molecular composition of Clostridium botulinum type A progenitor toxins. Infect Immun 1996; 64: 1589–94.

8. Zhang L, Lin WJ, Li S, et al. Complete DNA sequences of the bot-ulinum neurotoxin complex of Clostridium botulinum type A-Hall (Allergan) strain. Gene 2003; 315: 21–32.

9. Lietzow MA, Gielow ET, Le D, et al. Subunit stoichiometry of the Clostridium botulinum type A neurotoxin complex deter-mined using denaturing capillary electrophoresis. Protein J 2008; DOI: 10.1007/s10930-008-9151-2.

10. Hambleton P, Capel B, Bailey N, et al. Production, purification and toxoiding of Clostridium botulinum type A toxin. In: Lewis GEJ, ed. Biomedical Aspects of Botulism. New York: Academic Press, Inc., 1981: 247–60.

11. Benecke R, Jost WH, Kanovsky P, et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005; 64: 1949–51.

12. DasGupta BR. Activation of Clostridium botulinum type B toxin by an endogenous enzyme. J Bacteriol 1971; 108: 1051–7.

13. Lacy DB, Tepp W, Cohen AC, et al. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol 1998; 5: 898–902.

14. Swaminathan S, Eswaramoorthy S. Structural analysis of the cat-alytic and binding sites of Clostridium botulinum neurotoxin B. Nat Struct Biol 2000; 7: 693–9.

15. Arndt JW, Chai Q, Christian T, et al. Structure of botulinum neurotoxin type D light chain at 1.65 Å resolution: repercus-sions for VAMP-2 substrate specificity. Biochemistry 2006; 45: 3255–62.

16. Arndt JW, Yu W, Bi F, et al. Crystal structure of botulinum neuro-toxin type G light chain: serotype divergence in substrate recogni-tion. Biochemistry 2005; 44: 9574–80.

17. Simpson LL. The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol Rev 1981; 33: 155–88.

18. Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins. Eur J Neurol 2006; 13 Suppl 4: 1–9.

19. Montecucco C, Schiavo G, Rossetto O. The mechanism of action of tetanus and botulinum neurotoxins. Arch Toxicol Suppl 1996; 18: 342–54.

20. Black JD, Dolly JO. Interaction of 125I-labeled botulinum neuro-toxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell Biol 1986; 103: 521–34.

21. Black JD, Dolly JO. Selective location of acceptors for botulinum neurotoxin A in the central and peripheral nervous systems. Neuroscience 1987; 23: 767–79.

22. Eidels L, Proia RL, Hart DA. Membrane receptors for bacterial toxins. Microbiol Rev 1983; 47: 596–620.

23. Tsukamoto K, Kohda T, Mukamoto M, et al. Binding of Clostrid-ium botulinum type C and D neurotoxins to ganglioside and phospholipid. Novel insights into the receptor for clostridial neu-rotoxins. J Biol Chem 2005; 280: 35164–71.

24. Stenmark P, Dupuy J, Imamura A, et al. Crystal structure of botulinum neurotoxin type A in complex with the cell surface

12 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

co-receptor GT1b-insight into the toxin-neuron interaction. PLoS Pathog 2008; 4: e1000129.

25. Gangliodises. [Available from: http://www.cyberlipid.org/glycolip/glyl0036.htm]

26. Mahrhold S, Rummel A, Bigalke H, et al. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 2006; 580: 2011–14.

27. Dong M, Yeh F, Tepp WH, et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006; 312: 592–6.

28. Fernandez-Salas E, Garay PE, Iverson C, Malik SZ, Steward LE, Aoki KR. Identification of FGFR3 as a putative receptor for botulinum neurotoxin type A uptake in neuronal cells. Pre-sented at the 5th International Conference on Basic and Thera-peutic Aspects of Botulinum and Tetanus Toxins. Denver, CO, June 22–25, 2005.

29. Dong M, Tepp WH, Liu H, et al. Mechanism of botulinum neuro-toxin B and G entry into hippocampal neurons. J Cell Biol 2007; 179: 1511–22.

30. Jin R, Rummel A, Binz T, et al. Botulinum neurotoxin B recog-nizes its protein receptor with high affinity and specificity. Nature 2006; 444: 1092–5.

31. Dong M, Richards DA, Goodnough MC, et al. Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J Cell Biol 2003; 162: 1293–303.

32. Chai Q, Arndt JW, Dong M, et al. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 2006; 444: 1096–100.

33. Pellizzari R, Rossetto O, Schiavo G, et al. Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses. Philos Trans R Soc Lond B Biol Sci 1999; 354: 259–68.

34. Black JD, Dolly JO. Interaction of 125I-labeled botulinum neuro-toxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol 1986; 103: 535–44.

35. Galloux M, Vitrac H, Montagner C, et al. Membrane interaction of botulinum neurotoxin A translocation (T) domain. The belt region is a regulatory loop for membrane interaction. J Biol Chem 2008; 283: 27668–76.

36. Meunier FA, Herreros J, Schiavo F. Molecular mechanism of action of botulinal neurotoxins and the synaptic remodeling they induce in vivo at the skeletal neuromuscular junction. In: Massar EJ, ed. Neurotoxicology Handbook, Vol. 1. Totwa, NJ: Humana Press, 2001: 307–49.

37. Rogozhin AA, Pang KK, Bukharaeva E, et al. Recovery of mouse neuromuscular junctions from single and repeated injections of botulinum neurotoxin A. J Physiol 2008; 586: 3163–82.

38. de Paiva A, Meunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A 1999; 96: 3200–5.

39. Gordon MF, Barron R. Effectiveness of repeated treatment with botulinum toxin type A across different conditions. South Med J 2006; 99: 853–61.

40. Deinhardt K, Schiavo G. Endocytosis and retrograde axonal traf-fic in motor neurons. Biochem Soc Symp 2005; 139–50.

41. Antonucci F, Rossi C, Gianfranceschi L, et al. Long-distance retro-grade effects of botulinum neurotoxin A. J Neurosci 2008; 28: 3689–96.

42. Lalli G, Bohnert S, Deinhardt K, et al. The journey of tetanus and botulinum neurotoxins in neurons. Trends Microbiol 2003; 11: 431–7.

43. Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol 2004; 44: 167–93.

44. Begley S. A new reason to frown. Does Botox get into the brain? Troubling research contradicts earlier findings about the treat-ment. Newsweek 2008; 151: 45.

45. Kuehn BM. Studies, reports say botulinum toxins may have effects beyond injection site. JAMA 2008; 299: 2261–3.

46. Aoki KR, Brin MF, Whitcup SM. Is botulinum toxin really mov-ing into the CNS like tetanus toxin? J Neurosci 2008; Available at: http://www.jneurosci.org/cgi/eletters/28/14/3689.

47. Curra, A and Berardelli, A. Do the unintended actions of botuli-num toxin at distant sites have clinical implications? Neurology 2009; 72: 1095–9.

48. Tang-Liu DD, Aoki KR, Dolly JO, et al. Intramuscular injection of 125I-botulinum neurotoxin-complex versus 125I-botulinum-free neurotoxin: time course of tissue distribution. Toxicon 2003; 42: 461–9.

49. Naumann M, So Y, Argoff CE, et al. Assessment: Botulinum neu-rotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technol-ogy Assessment Subcommittee of the American Academy of Neu-rology. Neurology 2008; 70: 1707–14.

50. Filippi GM, Errico P, Santarelli R, et al. Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol 1993; 113: 400–4.

51. Rosales RL, Arimura K, Takenaga S, et al. Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle Nerve 1996; 19: 488–96.

52. Trompetto C, Curra A, Buccolieri A, et al. Botulinum toxin changes intrafusal feedback in dystonia: a study with the tonic vibration reflex. Mov Disord 2006; 21: 777–82.

53. Trompetto C, Bove M, Avanzino L, et al. Intrafusal effects of botu-linum toxin in post-stroke upper limb spasticity. Eur J Neurol 2008; 15: 367–70.

54. Roger SD, Mikhail A. Biosimilars: opportunity or cause for con-cern? J Pharm Pharm Sci 2007; 10: 405–10.

55. Boven K, Knight J, Bader F, et al. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mys-tery. Nephrol Dial Transplant 2005; 20 Suppl 3: iii33–40.

56. McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion 2008; 48: 1754–62.

57. Boven K, Knight J, Bader F, et al. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mys-tery. Nephrol Dial Transplant 2005; 20(Suppl 3): iii33–40.

58. Sampaio C, Costa J, Ferreira JJ. Clinical comparability of mar-keted formulations of botulinum toxin. Mov Disord 2004; 19 Suppl 8: S129–36.

59. BOTOX(R) (Botulinum toxin type A) Prescribing Information. Allergan, Inc. Irvine, CA, October, 2006.

60. Aoki KR. A comparison of the safety margins of botulinum neu-rotoxin serotypes A, B, and F in mice. Toxicon 2001; 39: 1815–20.

61. Aoki KR. Botulinum neurotoxin serotypes A and B prepara-tions have different safety margins in preclinical models of muscle weakening efficacy and systemic safety. Toxicon 2002; 40: 923–8.

62. Marchetti A, Magar R, Findley L, et al. Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord 2005; 20: 937–44.

63. 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.

64. Sampaio C, Ferreira JJ, Simoes F, et al. DYSBOT: a single-blind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations

PHARMACOLOGY, IMMUNOLOGY, AND CURRENT DEVELOPMENTS 13

of botulinum toxin type A—Dysport and Botox—assuming a ratio of 4:1. Mov Disord 1997; 12: 1013–8.

65. Nussgens Z, Roggenkamper P. Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol 1997; 235: 197–9.

66. Ranoux D, Gury C, Fondarai J, et al. Respective potencies of Botox and Dysport: a double blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry 2002; 72: 459–62.

67. Bihari K. Safety, effectiveness, and duration of effect of BOTOX after switching from Dysport for blepharospasm, cervical dysto-nia, and hemifacial spasm dystonia, and hemifacial spasm. Curr Med Res Opin 2005; 21: 433–8.

68. Naumann M, Yakovleff A, Durif F. A randomized, double-masked, crossover comparison of the efficacy and safety of botulinum toxin type A produced from the original bulk toxin source and current bulk toxin source for the treatment of cervical dystonia. J Neurol 2002; 249: 57–63.

69. Truong D, Comella C, Fernandez HH, et al. Efficacy and safety of purified botulinum toxin type A (Dysport((R))) for the treat-ment of benign essential blepharospasm: A randomized, placebo-controlled, phase II trial. Parkinsonism Relat Disord 2008; 14: 407–14.

70. Truong D, Duane DD, Jankovic J, et al. Efficacy and safety of bot-ulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, double-blind, placebo-controlled study. Mov Disord 2005; 20: 783–91.

71. Wohlfarth K, Kampe K, Bigalke H. Pharmacokinetic properties of different formulations of botulinum neurotoxin type A. Mov Disord 2004; 19 Suppl 8: S65–7.

72. Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology 2005; 65: 1423–9.

73. Hunt T, Clarke K. Potency of the botulinum toxin product CNBTX-A significantly exceeds labeled units in standard potency test. J Am Acad Dermatol 2008; 58: 517–8.

74. Chertow DS, Tan ET, Maslanka SE, et al. Botulism in 4 adults following cosmetic injections with an unlicensed, highly concen-trated botulinum preparation. JAMA 2006; 296: 2476–9.

75. Lowe NJ, Yamauchi PS, Lask GP, et al. Botulinum toxins types A and B for brow furrows: preliminary experiences with type B toxin dosing. J Cosmet Laser Ther 2002; 4: 15–18.

76. Brashear A, Watts MW, Marchetti A, et al. Duration of effect of botulinum toxin type A in adult patients with cervical dystonia: a retrospective chart review. Clin Ther 2000; 22: 1516–24.

77. Hsiung GY, Das SK, Ranawaya R, et al. Long-term efficacy of bot-ulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord 2002; 17: 1288–93.

78. Defazio G, Abbruzzese G, Girlanda P, et al. Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study. Arch Neurol 2002; 59: 418–20.

79. Giladi N. The mechanism of action of botulinum toxin type A in focal dystonia is most probably through its dual effect on efferent (motor) and afferent pathways at the injected site. J Neurol Sci 1997; 152: 132–5.

80. Naumann M, Lowe NJ, Kumar CR, et al. Botulinum toxin type a is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. Arch Dermatol 2003; 139: 731–6.

81. Lowe NJ, Yamauchi PS, Lask GP, et al. Efficacy and safety of botu-linum toxin type a in the treatment of palmar hyperhidrosis: a double-blind, randomized, placebo-controlled study. Dermatol Surg 2002; 28: 822–7.

82. Dressler D, Benecke R. Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperhidrosis. Eur Neurol 2003; 49: 34–8.

83. Goschel H, Wohlfarth K, Frevert J, et al. Botulinum A toxin ther-apy: neutralizing and nonneutralizing antibodies—therapeutic consequences. Exp Neurol 1997; 147: 96–102.

84. Dolimbek BZ, Aoki KR, Steward LE, et al. Mapping of the regions on the heavy chain of botulinum neurotoxin A (BoNT/A) recog-nized by antibodies of cervical dystonia patients with immuno-resistance to BoNT/A. Mol Immunol 2007; 44: 1029–41.

85. Dolimbek BZ, Steward LE, Aoki KR, et al. Immune recognition of botulinum neurotoxin B: antibody-binding regions on the heavy chain of the toxin. Mol Immunol 2008; 45: 910–24.

86. Schellekens H. Follow-on biologics: challenges of the “next gen-eration”. Nephrol Dial Transplant 2005; 20 Suppl 4: iv31–6.

87. Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immuno-genicity by mouse protection assay. Mov Disord 2008; 23: 1353–60.

88. Yablon SA, Brashear A, Gordon MF, et al. Formation of neutral-izing antibodies in patients receiving botulinum toxin type A for treatment of poststroke spasticity: a pooled-data analysis of three clinical trials. Clin Ther 2007; 29: 683–90.

89. Bakheit AM, Fedorova NV, Skoromets AA, et al. The beneficial antispasticity effect of botulinum toxin type A is maintained after repeated treatment cycles. J Neurol Neurosurg Psychiatry 2004; 75: 1558–61.

90. Zuber M, Sebald M, Bathien N, et al. Botulinum antibodies in dystonic patients treated with type A botulinum toxin: frequency and significance. Neurology 1993; 43: 1715–8.

91. Myobloc(R) Prescribing Information. Solstice Neurosciences, Inc. South San Francisco, CA, 2004.

92. Brashear A, Bergan K, Wojcieszek J, et al. Patients’ perception of stopping or continuing treatment of cervical dystonia with botu-linum toxin type A. Mov Disord 2000; 15: 150–3.

93. Gelb DJ, Yoshimura DM, Olney RK, et al. Change in pattern of muscle activity following botulinum toxin injections for torticol-lis. Ann Neurol 1991; 29: 370–6.

94. Tsui JK, Eisen A, Stoessl AJ, et al. Double-blind study of botuli-num toxin in spasmodic torticollis. Lancet 1986; 2: 245–7.

95. Dodick DW, Mauskop A, Elkind AH, et al. Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analy-sis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study. Headache 2005; 45: 315–24.

96. Brin MF, Fahn S, Moskowitz C, et al. Localized injections of botu-linum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987; 2: 237–54.

97. Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neuro-toxins. Toxicon 2000; 38: 245–58.

98. Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botuli-num toxin type A: implications for migraine therapy. Headache 2004; 44: 35–42; discussion 3.

99. Cui M, Khanijou S, Rubino J, et al. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004; 107: 125–33.

100. Chuang YC, Yoshimura N, Huang CC, et al. Intraprostatic botuli-num toxin a injection inhibits cyclooxygenase-2 expression and suppresses prostatic pain on capsaicin induced prostatitis model in rat. J Urol 2008; 180: 742–8.

101. Kagan A. Case study of botulinum toxin type A for postherpetic neuralgia [letter]. Am J Pain Mgmt 2002; 12: 43–4.

14 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

102. Ranoux D, Attal N, Morain F, et al. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 2008; 64: 274–83.

103. Apostolidis A, Dasgupta P, Denys P, et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol 2009; 55(1): 100–19.

104. Chuang YC, Yoshimura N, Huang CC, et al. Intravesical botuli-num toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 2004; 172: 1529–32.

105. Apostolidis A, Popat R, Yiangou Y, et al. Decreased sensory recep-tors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 2005; 174: 977–82; discussion 82–3.

106. Giannantoni A, Di Stasi SM, Nardicchi V, et al. Botulinum-A toxin injections into the detrusor muscle decrease nerve growth

factor bladder tissue levels in patients with neurogenic detrusor overactivity. J Urol 2006; 175: 2341–4.

107. Liu HT, Chancellor MB, Kuo HC. Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur Urol 2009; 56(4): 700–7.

108. Ipsen, Ltd. Dysport Summary of Product Characteristics. United Kingdom. Available at: http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=870. June, 2007.

109. Setler P. The biochemistry of botulinum toxin type B. Neurology 2000; 55(suppl 5): S22–8.

110. Takamori S, Holt M, Stenius K, et al. Molecular anatomy of a trafficking organelle. Cell 2006; 127(4): 831–46.

111. Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001; 285(8): 1059–70.

15

muscle is hyperfunctional. The result will be permanent creases in the skin perpendicular to the long axis of the muscle. For example, habitual overuse of the corrugator muscles to pull the eyebrows down and in will result in vertical or oblique creases in the overlying skin. Normally, the muscles of facial expression communicate emotional states. How-ever, a permanent crease sends an inappropriate message. A permanent glabellar crease communicates anger or worry when the person feels neither. Botulinum toxin can be used to temporarily weaken hyper-functional muscles, and thus improve or eliminate the overlying skin crease.

In addition to animating the skin, the position of some important facial structures is partly determined by underlying muscle tension. At rest, our muscles are not completely flaccid, but rather maintain a rest-ing tension that enables our body to maintain position. For example, contracture of the frontalis pulls the eyebrows up, but at rest normal muscle tension holds the eyebrows up at a normal position. If the func-tion of the frontalis is completely lost, such as is seen with severing of the temporal branch of the seventh cranial nerve, the eyebrow will droop downward (eyebrow ptosis) ( Fig. 2.2 ). Often, normal position results from the dynamic exchange of opposing muscle groups. Careful use of BoNTA to alter such relationships can be used to alter the posi-tion of structures such as the eyebrows and corners of the mouth.

UPPER FACE The largest muscle of the upper face is the frontalis, and is a frequent site of BoNTA therapy ( Fig. 2.1 ). The frontalis begins superiorly at the frontal scalp where the fibers originate from the galea aponeurotica, a fascial plane of the scalp that lies beneath the fat. The fibers of the fron-talis extend vertically downward where they mesh with the skin and muscles at the eyebrow and glabella. The muscle actually has two halves; each separately innervated by the right and left temporal branches of the seventh cranial nerve. Thus, in the superior aspect of the midline forehead there is no muscle, but rather a fascial band or aponeurosis separating the two halves of the frontalis ( 3 ).

The frontalis has one function: to raise the eyebrows. At rest, normal resting tension of the frontalis holds the eyebrows in a normal position. Evidence of the importance of unconscious normal resting tension is seen when the motor nerve supplying this muscle, the temporal branch of the seventh cranial nerve, is severed. Cutting this nerve produces not only complete hemiparalysis of the forehead, but with time ptosis of the eyebrow on the affected side ( Fig. 2.2 ). The resting position of the eyebrow is determined by the resting tension of the frontalis muscle pulling the eyebrow up, and the resting tension of the medial and lat-eral portions of the orbicularis oculi, which pull it down. By judicious use of this balance the eyebrow can be elevated: by weakening the downward pulling muscles, one now has unopposed upward tension and the eyebrow will rise. This effect can be enhanced by selective use of BoNTA within a single muscle. If the central portion of the frontalis is paralyzed while the lateral portions are not, the resting tension in the still functional lateral portions will increase, and thus the lateral aspect of the eyebrows will rise. This can be very helpful for patients with a lateral droop of their eyebrows.

With conscious effort, the vertically oriented frontalis will pull up the eyebrows. This is an important aspect of nonverbal emotional com-munication, but with repeated overuse, horizontal rhytides will develop. By weakening the middle and upper portions of the frontalis, these

2 Facial anatomy and the use of botulinum toxin James M. Spencer

INTRODUCTION Botulinum toxin has the ability to block cholinergic nerve transmission to skeletal muscle and thus produce a temporary flaccid paralysis. This has enabled physicians to treat a number of medical problems characterized by hyperfunctional muscle. This has also enabled cos-metic physicians to soften or eliminate rhytides caused by hyperfunc-tional muscles. A thorough understanding of the muscular anatomy of the face is necessary for the judicious use of botulinum toxin (Appendix 4).

All cholinergic nerves have receptors for botulinum toxin, and thus are a potential target for the action of this protein. Normally, an action potential travels down the neuronal axon and reaches the distal portion at the neuromuscular junction. Within the distal end of the axon are preformed vesicles containing the neurotransmitter, acetylcholine. In response to the action potential, the preformed vesicles dock and fuse with the terminal axonal membrane and release their contents out of the axon and into the synaptic cleft. In turn, the acetylcholine activates muscle contraction. A group of proteins known as the SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor) com-plex is responsible for fusing, docking, and releasing acetylcholine from their vesicles. Botulinum toxin A (BoNTA) works by inactivating the SNARE complex. With time, new sprouts from the axon re-establish functional contact with the muscle. However, ultimately the original motor endplate regains function, and the sprouts regress. Thus, the effects of BoNTA are temporary.

For cosmetic use, the target of BoNTA has principally been the mus-cles of facial expression. The muscles of the face can be divided into two groups: the muscles of facial expression and the muscles of masti-cation ( 1 ). The muscles of facial expression are somewhat unique in their arrangement and function. On the body, muscles typically have bony attachments via ligaments at either end and are responsible for movement of the body. Most of the muscles of facial expression are not attached to bone: rather they have soft tissue attachments. They tend not to move the body, but rather to move the skin and related struc-tures to facilitate communication. Emotional states are communicated and understood by muscular action of the face. Raising or lowering the eyebrows can communicate surprise, anger, sadness, or tiredness. The muscles of facial expression are connected to the overlying skin through a series of fibrous septae and an intervening fascial layer known as the superficial muscular aponeurotic system (SMAS). Thus when the underlying muscle contracts, the overlying skin moves with it. The muscles of mastication, such as the masseter and temporalis, have bony attachments and function to move the jaw in a way similar to muscles elsewhere on the body ( 2 ).

With age, the muscles of the face tend to atrophy, resulting in sagging of the face. This sagging is addressed through surgical lifting proce-dures. However, with repeated contraction of the muscles, areas of the skin overlying the muscle can develop creases from repeated mecha-nical folding and pleating. As the muscle shortens during contraction, the overlying skin will be folded. This folding occurs perpendicular to the axis of muscle contraction. For example, the major muscle of the forehead is the frontalis ( Fig. 2.1 ). The fibers of the frontalis are verti-cally oriented, and thus contraction of this muscle shortens the fore-head and pulls up the eyebrows. With repeated action over many years, the forehead can develop horizontal creases or rhytides. Many people in the course of normal activity overutilize a certain muscle: thus the

16 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

rhytides can be softened or eliminated. However, caution must be used not to weaken the frontalis too close to the eyebrows. If the portion of the frontalis immediately above the eyebrows is paralyzed, a brow pto-sis may result. As a general principle, injections should always be at least 1 cm above the eyebrow, so those muscle fibers of the frontalis will remain functional and hold the eyebrows up.

The glabellar complex is composed of the paired corrugator supercilii and the single procerus ( Fig. 2.3 ). The corrugators roughly define a V, with the base at the nasal root. At their base, each belly of the corrugator attach to the frontal bone. As the muscle travels up and laterally, it fans out and attaches to the skin. These muscles pull the eyebrows down and in. The procerus arises in the midline at the upper aspect of the nasal bone and travels vertically up between the corrugators and attaches to the skin in the midline of the lower forehead. This muscle pulls the forehead down in this location. The fibers of the corrugators, procerus, and adjacent medial portion of the orbicularis oculi are often intertwined and fused in nature, and clean dissection of these structures is more a mental construct than a physical reality.

The orbicularis oculi is a circular muscle that functions to close the eyelids. It functions as a sphincter, encircling the globe, and upon con-tracture closes the eyelids ( Fig. 2.4 ). Around each eye, the orbicularis oculi arises from the medial canthal ligament, located just medial to the globe. The muscle fans out from the ligamentous attachment superi-orly to about the level of the eyebrow where it inserts into the skin and frontalis, and inferiorly to the level of the lower orbital rim, to encircle the globe 360°. It is customarily divided into two portions: the palpre-bral portion, which overlies the eyelids and the orbital portion, which is outside the margins of the eyelids and over the bony orbital margin. It is the orbital portion that is a potential target for the use of BoNTA. If the muscle were completely paralyzed, the patient would be unable to blink or close the eyelids. However, selective weakening of different portions of this muscle can produce cosmetic enhancement. Laterally, the fibers of this circular muscle travel vertically, and with contracture produce perpendicularly (horizontally) oriented “crow’s feet” rhytides. The application of BoNTA to the lateral portion of the orbicularis oculi muscle will diminish crow’s feet.

Figure 2.1 Frontalis. This is the largest muscle of the upper face and a frequent site of botulinum toxin therapy.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Figure 2.2 Brow ptosis resulting from cutting the temporal branch of the seventh cranial nerve during surgery for skin cancer.

FACIAL ANATOMY AND THE USE OF BOTULINUM TOXIN 17

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Figure 2.3 Glabellar complex; paired corrugator supercilii and the midline procerus.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi–orbitalportion

preseptalpretarsal

Orbicularis oculipalpebral portion

Figure 2.4 Orbicularis oculi. This muscle encircles the eye and functions as a sphincter. Note the fibers of this muscle are vertically oriented at the medial and lateral most aspects where they function as depressors of the eyebrow.

18 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Treatment must be given outside the orbital rim (injection approxi-mately 1 cm lateral to the orbital rim) to avoid unwanted weakening of the muscles of ocular motion, which are inside the orbital rim. These same vertical fibers of the lateral orbicularis oculi also pull the lateral portion of the eyebrow down, and thus treatment in this area can be used to raise the lateral eyebrows. Similarly, the medial most portion of this muscle is also vertically oriented, and serves to pull the medial eye-brow down. Since these medial vertical fibers are so closely associated with the corrugator supercilii, treatment of the corrugators most likely provides some weakening effect of these medial fibers as well. Some authors have identified a separate vertically oriented depressor in this area just adjacent to the corrugators termed the depressor supercilii ( 4 , 5 ). As mentioned previously, in reality the fibers of the corrugators, procerus, and medial orbicularis oculi are fused and intertwined, mak-ing clean and separate dissection of these muscles difficult at best. It may be that in some patients, the medial vertically oriented portion of the orbicularis oculi is well developed and gives the impression of a separate muscle.

In the center of the orbicularis oculi, the fibers are horizontally ori-ented and are vital for closing the eyelids. However, selectively weakening the horizontal fibers of the lower portion of the orbicularis oculi helps to soften the creases seen with smiling at the outer half of the lower lid. Such creases can become quite prominent when the lateral vertical portion (crow’s feet area) of the orbicularis oculi is paralyzed with BoNTA. Furthermore, weakening the mid section of the lower lid palprebral portion of the orbicularis oculi has been shown to slightly relax the lower eyelid and thus “opens” the eye, giving a larger, rounder eye ( 6 ).

The location of the orbicularis oculi in relationship to other struc-tures is unique in the periocular region, and requires an adjustment of injection technique. In most areas of the body, the layers from outside to inside are: epidermis, dermis, fat, fascia, muscle, periosteum, and bone. Thus, in most sites, one needs to pass the injection needle through skin, fat, and fascia to reach the muscle. However, the orbicularis oculi has a unique anatomy. The arrangement from outside to inside is: epidermis, dermis, muscle (orbicularis oculi), fascia (septum), and fat. Thus the target muscle in the periocular area is just under the skin, and a very thin skin at that. Therefore, injections into the orbicularis oculi should be very superficial. Figure 2.5 shows the anterior view of the skull, showing muscle attachments and Figure 2.6 shows the lateral view of the skull, showing muscle attachments.

MID FACE The mid face contains few muscles amenable to therapy with BoNTA, but some important muscles to avoid. The nose contains three main muscles: the procerus, which has already been discussed with the glabellar complex, the nasalis muscle, and the depressor septi nasi ( Fig. 2.7 ). The nasalis is shaped roughly like an upside-down horse-shoe, with the upper part traveling transversely across the nasal dorsum (also known as the compressor naris), and two lower arms traveling vertically down the sides of the nose (also known as the dilator naris). Application of small amounts of BoNTA to the lateral upper part of the nose may help soften “bunny lines,” which are oblique rhytides of the upper lateral nose seen in some patients with expression. The third nasal muscle, the depressor septi nasi, travels vertically up the colu-mella from the upper lip, where it can pull the nasal tip down with smiling. BoNTA injections into this location can elevate the nasal tip in the proper patient.

There are multiple levators of the upper lip, which generally ori-ginate from bony attachments in the mid face and travel down to insert into the lip ( Fig. 2.6 ). In the midline is the depressor septi nasi, which originates in the midline upper lip and runs up and attaches on to the columella of the nose. Extending laterally on both sides are a series of paired muscles required for the complex functions, such as speaking,

eating, and facial expression of the upper lip. Just lateral to the midline of the upper lip is the paired levator labii superioris alaque nasi, which inserts bilaterally into the medial portion of the upper lip and runs superiorly up along the side of the nose to originate from the skull at the level of the inner canthus. Moving laterally, the next muscle to insert in the upper lip is the levator labii superioris, which extends upward and originates on bone at the level of the lower orbital rim in the mid pupillary line. Lateral to this is the zygomaticus minor and then the zygomaticus major. These muscles extend upward at an oblique angle from the upper lip and attach just below the lateral portion of the orbital rim. Paralysis of the upper poles of these muscles can be an unintended consequence of injecting too low in the lateral canthal area when treating crow’s feet. The patient may note difficulty raising the lip to smile. Inserting into the lateral aspect of the upper lip

Figure 2.5 Anterior view of the skull showing muscle attachments. 1, Corrugator supercilli; 2, Orbicularis oculi: 2a, Upper orbital part; 2b, Palpebral part; 3, Medial palpebral ligament; 4, Procerus; 5, Levator labii superioris alaeque nasi; 6, Levator labii superioris; 7, Zygomaticus minor; 8, Zygomaticus major; 9, Levator anguli oris; 10, Nasalis, transverse; 11, Nasalis, alar; 12, Depressor septi; 13, Buccinator; 14, Depressor labii inferioris; 15, Depressor anguli oris; 16, Platysma; 17, Mentalis; 18, Masseter; 19, Temporalis; 20, Incisivus labii superioris; 21, Incisivus labii inferi-oris; 22, Sternocleidomastoid; 23, Levator palpebrae superioris; 24, Inferior oblique; 25, Inferior rectus; 26, Lateral rectus; 27, Superior oblique; 28, Medial rectus; 29, Superior oblique. Source: Ref. 7.

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FACIAL ANATOMY AND THE USE OF BOTULINUM TOXIN 19

is the levator anguli oris, which originates superiorly at the canine fossa. Lastly, the risorus also inserts at the lateral portion of the upper lip and travels obliquely upward toward the ear. Several muscles come together to insert at the lateral commissure of the lips. This area is known as the modiolus, and can be thought of as a dense, fibromuscu-lar interface that acts as a scaffold for the various muscles to pull on including the zygomaticus major, levator anguli oris, depressor anguli oris, platysmal pars modiolaris, buccinator, and orbicularis oris. The number of muscles in this area shows the complex functions performed by the mouth: eating, speaking, and expression of emotions. Patients who raise the upper lip too high on smiling (gummy smile) can be treated with BoNTA by weakening the levator labii superioris alaque nasi at the level of the nasal ala. Figure 2.5 shows the anterior view of the skull, showing muscle attachments and Figure 2.6 shows the lateral view of the skull, showing muscle attachments.

LOWER FACE The muscles of the lower face are increasingly becoming targets for BoNTA therapy. The major muscle of facial expression of the lower face is the orbicularis oris, a circular muscle that encircles the mouth and functions as a sphincter. The various levators and depressors of the lips insert into this muscle and the lip itself, and originate from bony attach-ments above and below respectively. Contracture of the superficial, horizontally oriented fibers that travel along the upper and lower lips is responsible for the vertical rhytides seen above the upper and below the lower lips. However, complete paralysis of this portion of the orbicularis

oris would interfere with eating and speaking and is to be avoided. How-ever, very slight weakening of this upper portion, while still preserving overall function, can be used to soften upper lip vertical rhytides.

There are two depressors of the lips, the depressor anguli oris, and the depressor labii inferioris ( Fig. 2.8 ). These muscles insert superiorly into the lateral and medial orbicularis oris respectively, and originate inferiorly at the border of the mandible. The depressor anguli oris inserts at the corners of the mouth and travels down and slightly laterally to a bony origin at the border of the mandible. It is responsible for pulling down the corners of the mouth. If this muscle is weakened by injection at its lower mandibular head (so as not to affect the orbicularis oris), there is now an unopposed levator of the corner of the mouth. In this way, a subtle but noticeable elevation of the corners of the mouth can be achieved. It is important to avoid paralysis of the muscle just medial to this, the depressor labii inferioris. Lastly, the mentalis inserts medially into the lower lip under the depressor labii inferioris and travels straight down to originate at the midline of the chin. It is responsible for protrusion of the lower lip. It is also respon-sible in some patients for creation of the mental crease, a horizontal furrow under the lip on the upper portion of the chin. Injection of the mentalis can soften the mental crease.

NECK Botulinum toxin is used therapeutically in the neck for a variety of medical problems, but only one muscle in the neck is of cosmetic concern, the platysma ( Fig. 2.8 ). The platysma is a broad, thin muscle

Figure 2.6 Lateral view of the skull showing muscle attachments. 1, Corrugator supercilli; 2, Orbicularis oculi (orbital and palpebral parts), 3, Orbicularis oculi (lacrimal parts); 4, Medial palpebral ligament; 5, Procerus; 6, Levator labii superioris alaeque nasi; 7, Levator labii superioris; 8, Nasalis, transverse; 9, Nasalis, alar; 10, Depressor septi; 11, Levator anguli oris; 12, Buccinator; 13, Mentalis; 14, Depressor labii inferioris; 15, Depressor anguli oris; 16, Platysma; 17, Masseter; 18, Temporalis; 19, Zygomaticus major; 20, Zygomaticus minor; 21, Sternocleidomastoid; 22, Occipital belly of occipitafrontalis; 23, Incisivus labii inferioris; 24, Incisivus labii superioris. Source: Ref. 7.

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20 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 2.8 Depressors of the lip.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Figure 2.7 Muscles of the mid face.

FACIAL ANATOMY AND THE USE OF BOTULINUM TOXIN 21

Temporal branch

Zygomatic branches

Buccal branches

Marginal mandibularbranch

Parotid gland

Cervical branches

Figure 2.10 Branches of the seventh cranial nerve. Reprinted with permission from Ref. 8.

originating below the clavicle and extending upward to cover the entire anterior neck. Superiorly, at the level of the mandible it meshes with the depressors of the lower face and the superficial fascia of the face, the SMAS. It is the most superficial muscle of the neck, and is thought to be responsible both for horizontal neck rhytides from repeated con-tracture, as well as vertically oriented platysmal bands, seen as the sheet-like muscle separates into cords with time. The downward pull of a hyperkinetic platysmal also can blunt the distinctly defined cervico-mandibular angle. Multiple superficial injections of BoNTA into this muscle can soften all of these cosmetic problems. Figure 2.5 shows the anterior view of the skull, showing muscle attachments and Figure 2.6 shows the lateral view of the skull, showing muscle attachments.

NERVES OF THE FACE Use of BoNTA is guided by a functional understanding of the muscles to be treated rather than the nerves that supply them. However, an understanding of the innervation of the face is important for a complete anatomic picture.

Innervation of the face is principally supplied by two nerves, the fifth cranial nerve and the seventh cranial nerve, which provide sensation and motor function respectively. The fifth cranial nerve is the trigemi-nal nerve and splits into three branches to provide cutaneous sensation of the face. The branches are termed V1, V2, and V3 and are arranged vertically, with V1 being superior, V2 in the middle, and V3 inferiorly ( Fig. 2.9 ). The first branch is the ophthalmic division, and innervates the upper one-third of the face. It originates in the semilunar ganglion and enters the orbit where it divides into the lacrimal branch to the upper lateral eyelid, a nasociliary branch to the glabella and nasal dorsum, and the larger frontal branch, which supplies the forehead and periocular area. The frontal branch in turn gives rise to the supraorbital and supratrochlear branches. The supratrochlear branch exits at the level of the skull in the area of the corrugators while the supraorbital branch exits at the midline along the superior orbital rim, and thus

Figure 2.9 Branches of the fifth cranial nerve. 1, Supra-orbital nerve – V1; 2, Supra-

trochlear nerve – V1; 3, Lacrimal nerve – V

1; 4, Infratrochlear nerve – V

1; 5, External

nasal nerve – V1; 6, Infra-orbital nerve – V

2; 7, Zygomaticofacial and zygomaticotem-

poral nerves – V2; 8, Auriculotemporal – V

3; 9, Buccal nerve – V

3; 10, Mental nerve – V

3.

Reprinted with permission from Ref. 7.

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both are a potential target for direct trauma from the needle used for BoNTA injection. In the area of the glabellar complex where such trauma could theoretically occur, the supratrochlear nerve is deep to the muscle at the level of bone. Injection of BoNTA in the middle of the

22 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

superior orbital rim is not recommended, so damage to the supraorbital nerve can be avoided.

The maxillary division (V2) supplies sensation to the skin of the mid face. This nerve also originates in the semilunar ganglia. This nerve gives rise to multiple branches that supply the sensation to the cheek and side of the face, the conjunctivae and the skin of the lower eyelid, the side of the nose and the nasal vestibule, and the mucosa and skin of the upper lip. The trunks and foramina of these nerves are not in loca-tions where direct trauma from needle injection is likely.

The mandibular branch (V3) provides both a sensory and a motor function. The motor portion of the mandibular nerve provides func-tion for the four muscles of mastication. Its main sensory branches supply the skin of the lower lip, chin, skin of the lateral cheek, lower mandibular region, lower gingival, and around the ear and temporal regions. Of note for injections of BoNTA, the mental branch, which provides sensation to the lower lip and chin, exits the skull at the men-tal foramen, which is on the lower lateral aspect of the chin, and theo-retically could be traumatized if the injection needle entered the foramen during injection of the depressor anguli oris.

Figure 2.11 ( A ) Internal carotid system. Adapted with permission from Ref. 8. (Continued)

Frontal branch

Lacrimal artery

Anterior ethmoidalartery

Posterior ethmoidalarteryZygomatico-orbitalartery

Superficial temporalartery

Internal carotid artery

Ophthalmic artery

Maxillary artery

Posterior auricularartery

External carotid artery

Common carotid artery

Orbital branch ofsuperficial temporalartery

Supraorbitalartery

Supratrochlearartery

Dorsal (external) nasalartery

Angular artery

Zygomaticofacial

Infraorbital artery

Transverse facial artery

Facial artery

Superior labial artery

Inferior labial artery

Mental artery

(A)

Motor function of the face is provided by the seventh cranial nerve, the facial nerve ( Fig. 2.10 ). Although the action of BoNTA is to block transmission from branches of this nerve to the muscles of facial expression, injection points are determined by the muscles themselves and not the course of the nerve. The facial nerve exits the skull at the stylomastoid foramen, which is located just below and medial to the auditory canal, under the parotid gland. The trunk typically divides into five branches, but there is significant anatomic variation. The tem-poral branch travels superiorly to innervate the orbicularis oculi, the frontalis, and the corrugator supercilii, all targets of BoNTA therapy. The zygomatic branch travels upward toward the lateral canthus to fur-ther supply the orbicularis oculi. The buccal branch travels more medially to innervate the muscles of the mid face, and there may be significant anastomosis between the zygomatic and buccal branches. The mandibular branch travels down below the mandible, travels medially, and eventually crosses back up across the mandible (highly variable from person to person) to supply the orbicularis oris, the depressor anguli oris, and the mentalis. The cervical branch travels to the neck to supply the platysma.

FACIAL ANATOMY AND THE USE OF BOTULINUM TOXIN 23

VASCULAR SUPPLY The consequence of intravascular injection of BoNTA is ecchymosis or even a hematoma, but there is no systemic risk to the patient from intravascular injection with the amount used for cosmetic purposes. From primate data, it is estimated that the lethal dose of intravascular injection of BoNTA would be in the range of 2800 units, or 28 vials of BoNTA ( 9 ). However, hitting a vessel may produce an unsightly ecchy-mosis, and the BoNTA may not be delivered to the intended muscle and thus cannot do its job. Therefore, some knowledge of the location and course of the major vessels of the face is helpful.

The face receives arterial blood from various branches of the inter-nal and external carotids. The majority of the skin and subcutaneous tissue of the face is supplied by branches of the external carotid artery, with the internal carotid supplying only the eyes, the upper two-thirds of the nose, and the central forehead via the ophthalmic branch ( Fig. 2.11A,B ).

The internal carotid enters the skull at the carotid canal, travels ante-riomedially toward the cavernous sinus and ultimately toward the cir-cle of Willis. From inside the skull it gives off the ophthalmic arteries, which in turn give rise to branches relevant to a discussion of BoNTA. The ophthalmic artery travels anteriorly through the optic canal to enter the bony orbit. From here, they divide into several branches including the supraorbital and supratrochlear branches that exit the orbit through the foramen along the superior orbital rim. The supra-trochlear branch emerges in the area of the corrugators deep to the muscle with the supratrochlear branch of the fifth cranial nerve and travels superiorly with frequent branching as it goes. In the area of the corrugator complex, this artery is vulnerable to needle puncture and bleeding from BoNTA injection. The supraorbital branch exits the orbit in the midline of the superior orbital rim with the supraorbital

branch of the fifth cranial nerve and travels superiorly deep to the fron-talis. Midline injections at the orbital rim with BoNTA are ill-advised, and thus the trunk of this branch and its accompanying nerve are not likely to be directly traumatized during injection.

The external carotid artery has multiple divisions that travel both superficially and deep to supply the head ( Fig. 2.11A,B ). However, there are a few points that merit special attention when injecting BoNTA. As it travels up the lateral aspect of the neck, the external carotid gives off the facial artery. This branch travels medially and superiorly to cross the mandible and course across the cheek at approx-imately a 60° angle toward the nasal ala. At the level of the oral commis-sure, it gives off two labial arteries that encircle the lips. The facial artery continues superiorly to the base of the nasal ala, where it anasto-moses with the angular artery traveling down the junction of the cheek and lateral nose.

The external carotid itself continues up the lateral aspect of the neck to terminate into two branches below the dermis anteroinferior to the tragus of the ear. One of these is the superficial temporal artery that runs superiorly in front of the ear and up the lateral aspect of the tem-ple and forehead. It runs superficially under the subcutaneous fat and fascia, above muscle, and thus is subject to trauma during cutaneous surgery or injections. The second branch of the terminus of the exter-nal carotid is the internal maxillary artery, which travels deep and is not relevant to BoNTA injections.

Venous drainage of the face generally follows the arterial pattern ( Fig. 2.11A,B ). The veins of the face follow the pattern of arterial vessels, with flow in the opposite direction. The veins of the central forehead and glabellar region merit special mention. The supraorbital and supra-trochlear veins run with the corresponding arteries and nerves, and drain into the bony orbits to terminate in the orbital veins. These in turn drain into the cavernous sinus, thus creating the potential portal for the spread of disease to intracranial structures. Despite this theoretical risk, infection has not been a reported problem with BoNTA injections.

Botulinum toxin has rapidly become the most, popular noninvasive cosmetic treatments currently available ( 10 ). Its cosmetic benefit derives from its ability to selectively relax localized areas of facial mus-cle. A complete understanding of these muscles allows the physician to successfully utilize this medication.

REFERENCES 1. Larrabee WF Jr, Makielski KH. Surgical Anatomy of the Face.

New York: Raven Press, 1993. 2. Williams P. Gray’s Anatomy, 38th edn. New York: Churchill-

Livingstone-Elsevier. 3. Bentsianov B, Blitzer A. Facial anatomy. Clin Dermatol 2004; 22(1):

3–13. 4. Daniel RK, Landon B. Endoscopic forehead lift: anatomic basis.

Aesthet Surg Jour 1997; 17: 97–104. 5. Cook Jr. BE, Lucarelli MJ, Lemke BN. Depressor supercilii muscle:

anatomy, histology, and cosmetic implications. Opthalmic Plast Reconstr Surg 2001; 17: 404–11.

6. Flynn TC, Carruthers J, Carruthers A. Botulinum A toxin treat-ment of the lower eyelids improves infraorbital rhytides and widens the eye. Dermatol Surg 2001; 27: 703–8.

7. Berkowitz BKB, Moxham BJ. Head and Neck Anatomy: A Clinical Reference. London and New York: Informa Healthcare, 2002.

8. Leatherbarrow B. Oculoplastic Surgery. London and New York: Informa Healthcare, 2011.

9. BoNTA cosmetic (package insert). Irvine, CA: Allergan Inc., 2002. 10. ASAPS statistics on Cosmetic Surgery. [Available from http://www.

surgery.org/download/2008stats.pdf]

Figure 2.11 (Continued) ( B ) Sources of arterial supply of the face. 1, External carotid artery; 2, Posterior auricular artery; 3, Superficial temporal artery; 4, Supra-orbital artery; 5, Zygomatico-orbital artery; 6, Supratrochlear artery; 7, Lacrimal artery; 8, Dorsal (external) nasal artery; 9, Transverse facial artery; 10, Infra-orbital artery; 11, Maxillary artery; 12, Superior and inferior labial arteries; 13, Mental artery; 14, Facial artery. Adapted with permission from Ref. 7.

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off-label, unapproved manner, higher or lower dilutions of onabotu-linumtoxinA prove to be clinically more appropriate, depending on the muscles being treated. Precise dosing and accurate injections of ona-botulinumtoxinA will modify muscle movements of the face and body in a safe and reproducible way. This in turn can be used to improve a particular aesthetic problem reliably and for extended periods of time. Also, emphasis is placed on what to do and what not to do when inject-ing onabotulinumtoxinA. Outcomes and results of different injection techniques specifically only for onabotulinumtoxinA are discussed so as to avoid adverse sequelae and complications.

Some may criticize the “cookbook” approach of these chapters. However, this systematic detailing of where, why, and how much ona-botulinumtoxinA to inject is necessary to understand when treating a certain problem in a particular area of the body, and, therefore, this detailing was done intentionally. It is important to note, however, that the face is the only area of the body where the muscles attach directly underneath the skin. Consequently, when these muscles contract, they move the skin of the face (hence the designation “mimetic facial mus-cles”), producing folds and wrinkles always in a perpendicular orienta-tion to the direction of muscle contraction. Nowhere else in the body are there similar mimetic muscles that contract voluntarily or involun-tarily whereby nonverbal communication intentionally or uninten-tionally is expressed. The reader must never lose sight of the fact that every single individual patient is different and should never be treated in an identical way without justification. These next three chapters strive to provide both the neophyte and experienced physician the rationale for why and how a patient should be treated with a particular amount of onabotulinumtoxinA in one area or another for a distinct, reproducible outcome. By explicitly presenting certain techniques and the reasons for their use, the reader also needs to understand that this is only the author’s perception and interpretation of a given aesthetic problem and his approach to managing the problem, for that patient, who may or may not present again in the future in exactly the same way (see chap. 1). Consequently, when a physician is preparing to treat a patient with onabotulinumtoxinA, it does not matter if the patient is new or one who has been treated before, the physician should approach that patient as if he or she were receiving onabotulinumtoxinA for the first time. The physician must comprehensively evaluate the patient’s current aesthetic problem prior to commencing with the injections of onabotulinumtoxinA and not necessarily rely totally on past treatment dosing. The physician should be flexible and treat the patient’s con-cerns and specific offending changes that are present at the time. Treat the patient, not the picture.

Clinical examples and solutions presented in these next three chap-ters are only paradigms of reasonably acceptable clinical outcomes. The reader therefore should be able to extrapolate for himself or herself a preferred approach and injection technique when treating patients with similar clinical problems, provided there is sound justification for such a manner of treatment.

In 1989, onabotulinumtoxinA, known at that time as Oculinum, was first approved by the FDA in the United States for the treatment of stra-bismus and blepharospasm. By 2000, onabotulinumtoxinA now called BOTOX ® was approved by the FDA for the treatment of cervical dysto-nia. In 2002, the FDA approved BOTOX ® for the cosmetic purpose of treating glabellar frown lines. This resulted in the manufacturer’s desig-nation of the brand name BOTOX ® Cosmetic. In 2009 both BOTOX ®

3 Cosmetic uses of Botulinum toxin A in the upper face Anthony V. Benedetto

INTRODUCTION Botulinum neurotoxin (BoNT) has taken the practice of medicine by surprise and with a furor. Rarely can one find such an ordinary protein that in its natural form is so deadly, but by purification and extraction techniques can be utilized for therapeutic and cosmetic purposes by both physicians and surgeons. The utilization of BoNTs in neuromus-cular disorders has provided fortuitous relief for many tormented with incurable diseases, affording them an encouraging respite from their devastating afflictions. The countless possibilities for the use of BoNT in clinical medicine are continuously being discovered. For a wide range of medical and surgical specialists, including neurologists, physiatrists, ophthalmologists, otolaryngologists, gastroenterologists, urologists, and now even dermatologists, cosmetic and aesthetic physi-cians and surgeons, BoNT has proven to be a powerful adjunctive modality for a multitude of disorders.

Although this text is not the first one concerned with the use of BoNT, it is one of the few texts to address the use of BoNT solely for dermatological, cosmetic, and aesthetic purposes. In the United States injecting BoNT for cosmetic and aesthetic purposes for any reason other than to diminish glabellar frown lines is considered off-label use and not Food and Drug Administration (FDA) approved. Whether or not the FDA and other governmental regulatory agencies in other countries will ever approve every single indication for which the BoNTs have proven to be efficacious, the fact remains that BoNTs are extremely reliable, nontoxic, and safe. BoNTs, provide reproducible results when administered as prescribed. Consequently, BoNTs are quickly becom-ing a part of the armamentarium of many physicians and surgeons worldwide.

In these subsequent three chapters on the cosmetic use of BoNT in the face and body in order to avoid ambiguity and confusion with the injection of appropriate and effective doses of BoNT, any reference to Botulinum neurotoxin serotype A (BoNTA), will denote explicitly and specifically BOTOX ® Cosmetic (onabotulinumtoxinA). The treatment of patients with onabotulinumtoxinA for dermatological, cosmetic, and aesthetic purposes is presented in a systematic fashion, first by identifying the anatomical basis of different unaesthetic changes acquired by men and women as they “age” and “wrinkle.” Next, normal functional anatomy is discussed to elucidate the reasons for these dis-pleasing changes so that a suitable plan of correction with onabotu-linumtoxinA can be initiated. The anatomical drawings used to illustrate normal anatomy of facial muscles (see chaps. 2–5) will depict superfi-cial musculature on the left side of the figure and deeper musculature on the right. Functional anatomy is emphasized because the only way to utilize any type of BoNT properly is to have an in-depth understand-ing of how to modify the normal movements of facial mimetic muscles and other muscles elsewhere on the body. When injections of onabotu-linumtoxinA are appropriately performed, desirable and reproducible results without adverse sequelae are created. In this and the next two chapters, suggestions will be made on how much to reconstitute a vial of onabotulinumtoxinA to arrive at various preferred dilutions for dif-ferent anatomical sites. The FDA-approved manufacturer’s recommen-dation for product reconstitution is to use 2.5 ml of nonpreserved normal saline. The approved and recommended dilution is for glabel-lar frown lines only, since this is the only FDA- approved indication for the cosmetic use of onabotulinumtoxinA. However, when treating other areas of the face and body for cosmetic purposes, albeit in an

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 25

and BOTOX® Cosmetic were assigned the nonproprietary name of ona-botulinumtoxinA by the FDA. In the not too distant future, new and different formulations of BoNTA other than onabotulinumtoxinA will be approved for use in the United States for both therapeutic and cos-metic uses. The first of these is Dysport ® (abobotulinumtoxinA), which was recently (May 2009) approved by the FDA and is discussed in-depth in chapter 9 along with other formulations of BoNTA not yet available in the United States. In order to distinguish the current and future dif-ferent formulations of BoNTA from one another without mentioning their tradenames or brand names, the FDA has assigned nonproprietary names, a type of “generic” name, to the different formulations of the BoNTs. OnabotulinumtoxinA was assigned to BOTOX ® and BOTOX ® Cosmetic; and abobotulinumtoxinA was assigned to Dysport ® . Botuli-num neurotoxin type B (BoNTB) known as Myobloc TM in the United States and Neurobloc TM in Europe was assigned the name rimabotu-linumtoxinB; FDA-approved and available in the United States, rimabotulinumtoxinB is discussed in chapter 10.

The different formulations and brand names of BoNTA that are cur-rently in use in other parts of the world outside of the United States are still being measured and defined for equivalency with onabotulinum-toxinA. It is extremely important to understand that the specific units and dosages of the BoNTA discussed in chapters 3 to 5, are only for onabotulinumtoxinA (i.e., BOTOX ® Cosmetic) unless explicitly stated otherwise. The same number of units specifically identified and detailed here for onabotulinumtoxinA (BOTOX ® Cosmetic) absolutely cannot be used with the identical unit dose to treat patients with BoNTA of another source or manufacturer, even if a ratio of equiva-lency is provided as being 1:1. Injectors of onabotulinumtoxinA (BOTOX ® Cosmetic) have quickly learned from their frustrating experiences in the past when using rimabotulinumtoxinB (Myobloc/Neurobloc) that comparative equivalencies are not easily extrapolated. Not only was it difficult to establish a conversion dosage for equating rimabotulinumtoxinB with onabotulinumtoxinA, it also was found that a muscle in a particular area of the face or body did not respond equivalently with a fixed dose conversion ratio of rimabotulinum-toxinB with onabotulinumtoxinA (see chap. 1) ( 1 ). The dose conver-sion ratio was even found to be different when similar or adjacent muscles in the same patient were treated. For example, if the average equivalency unit dose was found to be 150:1 (i.e., units of rimabotu-linumtoxinB to units of onabotulinumtoxinA) when treating the fron-talis with rimabotulinumtoxinB, then one naturally assumed the same equivalency ratio would be applicable for treating any of the other mimetic muscles of the face. However, when rimabotulinumtoxinB was used for another facial muscle, for example, the orbicularis oculi or corrugator supercilii, the equivalency of rimabotulinumtoxinB to

onabotulinumtoxinA was not the same, but namely 125:1, or there-about. Diffusion characteristics and rates also seem to influence the inability to establish any type of fixed conversion ratio between rimabotulinumtoxinB with onabotulinumtoxinA. Therefore the equivalent dose ratio for rimabotulinumtoxinB could not be fixed, at least in the author’s personal experience. This confounding of dose equivalencies using onabotulinumtoxinA (i.e., BOTOX ® Cosmetic) as the standard to which all other serotypes of BoNT are measured will only become compounded when different formulations of BoNTA or other BoNT serotypes are administered, and the reasons for this are briefly touched upon in chapters 1, 9, and 10. Therefore, when using any other type of BoNT other than onabotulinumtoxinA (i.e., BOTOX® Cosmetic), it is imperative that one learns how to administer that par-ticular type of BoNT independently of any conversion ratios, because individual muscles may respond in a distinctly different manner with certain formulations and specific serotypes of BoNT ( 2 ).

The understanding of the pharmacokinetics and pharmacodynam-ics of BoNT is still only in its early stages, and the possibilities for future developments are boundless. It is intriguing to understand that the cosmetic use of onabotulinumtoxinA was initiated by the insight and convictions of two astute and courageous physicians, an ophthalmolo-gist wife and her dermatologist husband. If it were not for the persistence of Jean and Alastair Carruthers in promoting their seren-dipitous observations, many other perceptive and insightful physicians would not have had the opportunity or confidence to learn more about BoNT and its use in clinical aesthetic medicine. The challenge now being passed onto the reader is that with some basic knowledge of how to inject a few drops of BoNT appropriately and safely; while treating patients with compassion and professionalism, additional innovative and ingenious uses of BoNT can be uncovered, be they for cosmetic or therapeutic purposes ( Fig. 3.1 ).

CENTRAL BROW (GLABELLAR) FROWN LINES Introduction: Problem Assessment and Patient Selection The area most frequently treated with BoNT is the central brow or gla-bella and its frown lines ( 3–13 ). The glabella is the smooth, flat, trian-gular elevation of the frontal bone superior to the nasal radix positioned between the two superciliary ridges or arches. On the skin surface, the glabella is the space between the eyebrows. The muscles of the “glabel-lar complex” were the first and currently the only muscles of the face or body into which onabotulinumtoxinA can be injected for cosmetic purposes that have been approved in the United States by the FDA. Treatment of all other muscles in any other part of the face or body with injections of onabotulinumtoxinA for cosmetic reasons is done solely and expressly in an off-label, nonapproved manner.

(A) (B)

Figure 3.1 ( A ) This 53-year-old patient with unintentional frowning during intense concentration is shown before an onabotulinumtoxinA treatment. ( B ) Same patient 3 weeks after onabotulinumtoxinA injections in the forehead and glabellar area seen here with and without frowning.

26 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

There are four depressor muscles of the brow that cause the horizon-tal and vertical creases of the glabella. These muscles allow one to squint to protect the eyes from projectiles, gusts of air, and the elements (i.e., glaring light, wind, dust, sand, etc.) by lowering the eyebrows and adducting them medially. However, hyperkinetic depressor muscles can cause persistent, unintentional adduction and lowering of the medial aspect of the eyebrows, causing wrinkling between the eyes. For example, this central brow frowning during moments of intense con-centration can be misinterpreted by others as a veritable frown, which usually expresses negative feelings of concern, tiredness, disappoint-ment, frustration, anger, pain, suffering, etc. ( Fig. 3.1A ). Weakening the four depressors of the glabella with injections of onabotulinumtoxinA can raise the eyebrows and virtually eliminate the frown lines of the glabella. This allows a person to appear more relaxed, conveying a posi-tive sentiment when one ordinarily might be frowning and expressing a negative demeanor ( Fig. 3.1B ). An elevated brow generally expresses a positive attitude, whereas a depressed brow expresses a negative one. In addition, low-set eyebrows may promote the formation of upper eyelid and lateral canthal hooding ( Fig. 3.2 ). Arched or peaked eye-brows usually are more attractive in women whereas men in general prefer more horizontal eyebrows. However, beware of women who pluck or have had permanent tattooing of their eyebrows, because the natural position of their brows may be deceptively displaced ( 14 , 15 ).

The overall contour and shape of the eyebrows depend on many fac-tors, including age, sex, culture, ethnicity, and current fashion trends ( 16 ). The size, shape, and position of the eyebrows can vary widely, depending on the shape of the face (i.e., oval, round, square, or long/narrow) ( Fig. 3.3A,B ) ( 17 ). In the literature and in clinical practice, there really is no rigid definition or description of the “ideal eyebrow” that can be applied to all faces universally. Eyebrows that appear aes-thetically pleasing on one face may look abnormal and unattractive on another face. Therefore, a detailed pretreatment assessment of how an individual’s eyebrow position and shape conforms to the “ideal brow” contour for that particular individual is vital to producing acceptable results with injections of onabotulinumtoxinA.

The brow has both static and dynamic qualities of beauty and expres-siveness that change with advancing age ( 18 ). This is seen as brow ptosis in varying degrees, which can modify the shape and position of the brows, thereby compromising the youthful appearance and aesthetic attractiveness of a person. The ideal contour of the female eyebrow as outlined by Westmore ( 16 , 18 ) is typical of an oval face. The medial brow should begin on the same vertical plane as the lateral extent of the ala and the inner canthus ( Fig. 3.4A,B ). The eyebrow should end later-ally ( Fig. 3.4C ) where it meets an oblique line drawn from the most lateral point of the ala ( Fig. 3.4A ) through the lateral canthus. The medial and lateral ends of the eyebrow ( Fig. 3.4B,C ) lie on approxi-mately the same horizontal plane. The apex of the arc of the eyebrow lies on a vertical line ( Fig. 3.4D,E ) directly above the lateral limbus of the iris of the eye ( 19 ). The tail (lateral aspect) of the eyebrow can lie 1 to 2 mm above the lowest point of its head (medial aspect) on the hori-zontal plane ( Fig. 3.4B,C ). In addition, according to Angres, one also should take into account the patient’s intercanthal distance when assess-ing a patient’s eyebrow position ( 15 ). If the intercanthal distance is nor-mal, the brow should start at a vertical line that bisects the medial canthus ( Fig. 3.4A,B ). However, if the intercanthal distance is increased, the eyebrow should begin medial to the medial canthus. On the other hand, a narrower intercanthal distance requires the eyebrow to start lateral to the vertical line, that is, the medial canthus ( Fig. 3.4A,B ).

Finally, when the face is not oval, additional modifications to West-more’s “ideal brow” may be necessary ( Fig. 3.3B ). For example, a square face favors soft curves with the apex of the arch lateral to the lateral limbus and the tail of the eyebrow directed at the center of the ear. A long/thin face may look more attractive with a straighter, less-arched

eyebrow, with the tail pointing closer to the top of the ear. This visually will avoid elongating an already long face. A round face is enhanced with a high arch that also points to the top of the ear to enhance the angularity of the ear. Lastly, the overall silhouette of a female eyebrow should be that of the wing of a gull ( Fig. 3.5 ).

The male eyebrow normally has less of an arc than the female eye-brow and is usually flatter or nearly horizontal ( Fig. 3.6 ). It typically should be positioned lower on the superciliary arch just above the superior bony orbital margin. Also, the lateral aspect of the male eye-brow is usually more prominent. The pretreatment position and sym-metry of the eyebrows and eyelids will dictate the technique that will be needed to treat the glabellar frown lines. In women whose eyebrows are barely arched, strategically placed injections of onabotulinumtoxinA into the brow depressors, can elevate the eyebrows by allowing the lower fibers of the frontalis to raise the eyebrows unopposed by the decussating fibers of the corrugator supercilii, procerus and orbicularis oculi ( Fig. 3.7A,B ) ( 14 ).

Trindade de Almeida has classified glabellar frown lines into five dis-tinct patterns ( 20 ). Although the muscular anatomy is by and large alike in most patients, individual skeletal morphology and idiosyn-cratic muscular movements can produce unique variations in the pat-tern of wrinkles in the glabellar area as well as anywhere else on the face during intentional animation and spontaneous expression. These dif-ferences in glabellar wrinkle patterns indicate that the strength of each glabellar muscle is not identical and uniform in every patient and one set of muscles may be stronger or weaker than its codepressor set of muscles. Their response to neurostimulation also is uniquely different in every individual. Therefore, the pattern of glabellar frowning is dependent upon which muscles are stronger or weaker, and the injected dose of onabotulinumtoxinA must vary accordingly. Some glabellar wrinkle patterns are observed more frequently than others according to Trindade de Almeida ( Fig. 3.8A–E ) ( 20 ).

Functional Anatomy (see Appendix 1) Contracting any of the mimetic muscles of the face will cause wrin-kling of the skin perpendicular to the orientation of those muscle fibers and the direction of their movement. Therefore, the muscles that pro-duce the vertical lines of the glabella because their fibers are oriented more or less horizontally are the medial brow depressors, that is, cor-rugator supercilii, and the medial fibers of the orbital orbicularis oculi.

The corrugator supercilii is a small, narrow, deeply situated paired muscle that arises just inferior to the medial aspect of the superciliary

Figure 3.2 Low set eyebrows promote upper eyelid and lateral canthal hooding in this 59-year-old patient.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 27

arch approximately 4 mm lateral to the nasion ( Fig. 3.9 ). The nasion is the point of juncture of the nasofrontal with the internasal bony sutures ( 21 ). Clinically it can be palpated as the center of the concavity at the nasal radix (or root). The corrugator supercilii extends laterally and upwardly through the palpebral and orbital fibers of the orbicu-laris oculi, inserting into the soft tissue and skin above the middle of the eyebrow in the vicinity of the midpupillary line and the supraor-bital notch. The bulk of the corrugator supercilii can be found overlying

the inferior aspect of the superciliary arch ( Fig. 3.10 ) ( 21 , 22 ). It lies directly against the bone and just beneath the interdigitating muscle fibers of the orbicularis oculi, procerus, depressor supercilii, and fron-talis medially and beneath interdigitating fibers of the frontalis and orbicularis oculi laterally ( Fig. 3.9 ). Anatomic studies have demon-strated that the thickest portion of the belly of the corrugator is at or just above a horizontal plane drawn through the middle of the eyebrow and approximately 2.0 cm from the nasion ( Fig. 3.10A,B ) ( 19 , 21 , 23 ).

Figure 3.3 (A) Different shapes of eyebrows and how they affect the overall appearance and shape of the face. (B) Different shapes of eyebrows look more appropriate on certain shapes of faces.

SHAPE DIAGRAM PHOTO EFFECT

Round angled Makes a face appearrounder. Softens facesand emphasizes theheart in a heart shapedface.

Angled Will make the faceappear more youthful.

Soft angled Similar to above, but itspeak is softer, moresubtle and feminine.This is often referred toas the ideal brow.

Curved Defaults to a thoughtfulexpression. Gives amore professional look.

Flat Horizontal line makes theface appear shorter andmore oval. Great forlonger face. Natural look.

(A)

Long Oval Heart Square Round Diamond

(B)

28 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.5 The ideal eyebrow of a woman outlines the wing of a gull.

Figure 3.4 The peak of the arch of a female brow should be just above the lateral limbus. The tail of the brow should be on a horizontal plane 1–2 mm above the lowest point of its head.

A

B

D

E

C

The outermost fibers of the orbicularis oculi are called the orbital portion of the orbicularis oculi. The orbital orbicularis oculi arises from the bony structures of the lateral nose and medial orbit, including the medial canthal ligament. Its fibers then run superiorly and inferiorly, forming a wide sphincteric ring around the bony orbit that extends beyond the edges of the bony orbital rim and into the eyelids ( Fig. 3.11 ). The medial aspect of the orbital orbicularis oculi occasionally is referred to as the depressor supercilii by some

Figure 3.6 The ideal eyebrow of a man is less arched and lower set than a woman’s.

authors. Contraction of the orbital orbicularis oculi approximates the upper with the lower eyelids, either deliberately or involuntarily. The inner portion of the orbicularis oculi overlies the eyelid and is identified as the palpebral portion of the muscle. The palpebral orbicularis oculi is subdivided into the preseptal and pretarsal portions ( Fig. 3.11 ).

The horizontal lines of the glabella and nasal root are produced by the contraction of the vertically oriented fibers of the procerus, depres-sor supercilii, and the medial fibers of the orbital orbicularis oculi. These three muscles also are referred to as the medial brow depressors. The procerus is a thin, pyramidal muscle centrally located in the midline between the two eyebrows. It lies 1 to 4 mm beneath the sur-face of the skin ( Fig. 3.12 ). The procerus arises from the fascia covering the nasal bridge and lower part of the nasal bone and the upper part of the upper lateral nasal cartilage. It inserts superiorly into the skin and subcutaneous tissue at the nasal radix and lower part of the forehead between the two eyebrows. Contraction of the procerus pulls the medial aspect of the eyebrows downward, creating the horizontal frown lines across the root of the nose. Anatomic studies have demon-strated that the procerus can be longer in women than in men and, at times, bifid similar to the frontalis ( 23 , 24 ).

The depressor supercilii is considered by many a component part of the medial fibers of the orbital orbicularis oculi ( Fig. 3.13 ) ( 19 ). Yet others consider it a separate and distinct muscle from the orbicu-laris oculi and corrugator supercilii ( 25 ). The depressor supercilii is a small muscle that has been found to originate directly from bone as one or two distinct muscle heads from the nasal process of the frontal bone and the frontal process of the maxilla, approximately 10 mm above the medial canthal tendon ( 25 ). In cadaver dissections where the depressor supercilii originated as two separate heads, the angular vessels passed in between the two bundles of muscles ( 25 ). In cadav-ers where there was only one head originating at the medial canthus, the angular vessels were found coursing anteriorly to the muscle. The depressor supercilii then passed vertically upward to insert into the undersurface of the skin at the medial aspect of the eyebrow, approxi-mately 13 to 14 mm superior to the medial canthal tendon. It appeared superior in orientation to the medial aspect of the orbital orbicularis oculi ( 25 ). Not only does it help move the eyebrow down-ward and close the eyelid, but the depressor supercilii also partici-pates in the functioning of the physiological lacrimal pump by compressing the lacrimal sac.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 29

Figure 3.7 (A) This 28-year-old patient with relatively flat arches before treatment. (B) After treatment, the eyebrows are elevated and arched with strategically placed onabotu-linumtoxinA. Note the right eyebrow also is slightly lifted.

(A) (B)

Figure 3.8 Glabella: patterns of contraction. Five subtypes: (A) “U” pattern, (B) “V” pattern, (C) “Omega” pattern, (D) “opposing lines” pattern, and (E) “inverted Omega” pattern; three patterns with depression of medial brow (A, B, and E); one with elevation of medial brow (C); one with predominantly horizontal movement (D). Source : Courtesy of

Trindade de Almeida.

(A) (B)

(C) (D) (E)

Opening and closing the eyes is partially accomplished by the con-traction of the accessory muscles of the upper eyelid: one being the levator palpebrae superioris, a striated muscle, the other a nonstriated, smooth muscle called the superior tarsal or Müller’s muscle. The leva-tor palpebrae superioris is the main retractor of the upper eyelid. It is a thin, flat, triangular sheet of striated muscle originating at the apex of the orbit at the common tendinous ring or annulus of Zinn on the lesser wing of the sphenoid behind the globe and just above the origin of the superior rectus muscle (Fig. 3.14) ( 1 , 26 ). The levator palpebrae superioris is positioned superior to the superior rectus as they both

pass over the superior aspect of the eyeball within the bony orbit. Approximately at the level of Whitnall’s transverse suspensory liga-ments, the superior rectus attaches to the superior aspect of the globe at the level of the superior-conjunctival fornix, while the levator palpe-brae superioris continues anteriorly as a wide aponeurosis. As the apo-neurosis continues forward, some of its tendinous fibers attach to the anterior surface of the tarsus, and the rest pass in between the muscle fibers of the pretarsal orbicularis oculi and attach to the undersurface of the eyelid skin. Its tendinous attachments in the upper eyelid are responsible for the formation of the superior eyelid crease ( Fig. 3.15 ).

30 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.10 The corrugator supercilii lies directly against the bone. (A) Skull with view of the corrugator supercilii superimposed with letters. The thickest part of the belly of the muscle is approximately 2.0 cm from the nasion. (B) A patient with representation of corrugator supercilii drawn in red with superimposed lettering. Abbreviations : X, nasion; O, origin; B, belly; I, insertion of corrugator supercilii.

XO

BI

X

O

B

I

(A) (B)

Dilution (see Appendix 2)

Different clinicians have their favorite patterns of injecting the glabella with varying doses of different concentrations of onabotulinumtoxinA

(11). The manufacturer’s package insert recommends reconstituting the 100 U vial of onabotulinumtoxinA with 2.5 ml of unpreserved normal

saline. Thus yielding 4 U of onabotulinumtoxinA per 0.1 ml of solution (27). However, since the brow depressors decussate with each other

and are in close proximity in a very small and confi ned area, it is extremely important to inject accurately precise amounts of onabotulinum-

toxinA in this area. Therefore, many seasoned injectors still reconstitute the 100 U vial of onabotulinumtoxinA with only 1 ml of normal

saline. This provides 1 U of onabotulinumtoxinA in every 0.01 ml of solution, which is easily injected using a 0.3 ml Becton-Dickinson insulin

U-100 syringe with a 31-gauge needle directly attached (Becton, Dickinson and Company, Franklin Lakes, NJ, USA). The advantage of using

an insulin syringe is that the needle is directly swaged onto the hub of the syringe, so there is little or no additional wastage of product in the

hub of the needle or in the neck of the syringe (Fig. 3.16). In addition, each unit line marked on the syringe barrel corresponds to 0.01 ml or

1 U of onabotulinumtoxinA when a 100 U vial of onabotulinumtoxinA is reconstituted with 1 ml of saline. In this way, only minimal volumes

of onabotulinumtoxinA will be needed to produce the desired results. In addition, most practitioners have now switched to using preserved

saline with 0.9% benzyl alcohol (28).

Figure 3.9 The corrugator supercilii lies on the bone and beneath the other glabellar muscles.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 31

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) The pretreatment evaluation should include examining the patient at rest and in full motion. Lightly palpate the muscles of the glabellar area with the palmar surface of the finger tips as the person squints

and frowns. This will help determine the location, size, and strength of the individual muscles of the glabella. A frequently used and standard-ized technique for treating the glabella is to inject onabotulinum-toxinA into five different sites with doses that range anywhere from 4 to 10 U or more at each site ( Fig. 3.17 ) ( 7–13 , 27 ). Electromyographic

Figure 3.11 The orbicularis oculi has different subdivisions and interdigitates with the other depressors and elevator of the glabella.

Figure 3.12 The procerus is the midline, deep muscle of the glabella.

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Corrugator supercilii

Procerus

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Frontalis

Procerus

Depressor superciliiOrbicularis oculi – orbital

portion

Orbicularis oculi –palpebral portion

preseptalpretarsal Corrugator supercilii

32 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.13 The depressor supercilii is the diminutive muscle of the glabella.

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Corrugator supercilii

Frontalis

Procerus

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Depressorsupercilii

Levator palpebrae superioris

Superior rectus

Inferior rectusInferior oblique

Inferior check ligament

Inferior conjunctival fornix

Superior conjunctival fornix

Orbicularis oculi

Inferior conjunctival sac

Eyeball

Cornea

Palpebral fissure

Superior tarsal plate

Superior tarsal muscle of Müller (smooth)

Sclera

Bulbar and palpebral conjunctiva

Orbital septum

Intraconal fat

Dural sheath

Fascial sheath of eyeball

Extraconal fat

Subarachnoid space

Episcleral space

Figure 3.14 The levator palpebrae superioris is the main retractor of the upper eyelid. It is a striated muscle. Müller’s superior tarsal muscle is not striated; it is a smooth muscle.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 33

guidance in this area has not particularly improved treatment out-comes because these facial muscles are superficial and easily localized by palpation and topographical landmarks ( 12 , 21 , 23 , 29–33 ).

Patients who possess thinner, less sebaceous skin with finer wrinkles and shallower skin furrows and folds that can be spread apart and

reduced with the fingers (“glabellar spread test”) seem to have better, longer-lasting results ( 13 ). There are, however, some patients who are more difficult to treat because they are less responsive to the effects of onabotulinumtoxinA. In this group of patients who are more difficult to treat, there is one type of patient who possesses thick sebaceous skin with deep, intractable wrinkles whose furrows are difficult to pull apart with the fingers. Usually these turn out to be men and sometimes women who spend a lot of time outdoors. The other type are those who possess the inelastic, redundant skin seen with dermatochalasis and whose furrows are also deep but very easy to pull apart. These patients characteristically are older and unfortunately are not ideal candidates for glabellar chemodenervation, because frequently their final outcomes are less than ideal. Typically, in these patients, after having onabotulinumtoxinA injected with impeccable technique, the resultant relaxation of the glabellar muscles causes in folding of the lax and redundant glabellar skin. Consequently, there remains some evi-dence of frown lines and wrinkles even if higher doses of onabotu-linumtoxinA are subsequently injected.

Generally, glabellar frown lines in women can be satisfactorily treated with a total dose of about 20 to 30 U or more of onabotulinum-toxinA injected into the standard five injection sites ( Fig. 3.18 ) ( 4 , 11 , 29 , 39–45 ). Men, on the other hand, usually require a significantly higher dose of onabotulinumtoxinA (40–80 U) injected at seven sites across the glabella and medial brow to produce a reasonable effect that lasts at least 3 to 4 months ( Fig. 3.19 ) ( 3 , 33–36 ). When glabellar lines

Figure 3.16 A 3/10 ml Becton-Dickinson insulin U-100 syringe with a 31-gauge needle swaged directly onto the syringe. Note the absence of any dead space between the hub of the needle and the neck of the syringe. Each unit notch on the barrel cor-responds to 0.01 ml or 1 U.

Figure 3.15 (A) Close-up view of the upper eyelid anatomy and muscle attachments. (B) Anterior view of the orbit, its neurovascular structures, and the attachments of the levator aponeurosis and orbital septum.

(A)

Frontal bone

Orbital septum

Orbital septum

Zygomatic bone

Superior tarsus

Inferior tarsus

Insertion of levator palpebraesuperioris muscleand aponeurosis

Lateral palpebral ligamentand overlying raphe

Supraorbital artery and nerve

Supratrochlear artery and nerve

Dorsal nasal arteryand infratrochlear nerveLacrimal sac

Medial palpebral ligament

Maxilla (frontal process)

Infraorbital artery and nerve

(B)

Levator palpebraesuperioris

Superior tarsalmuscle of Müller(smooth)

Superior tarsus

Tarsal gland

Palpebral conjunctiva

Ciliary glands

Cilia

Skin

Orbicularis oculi(palpebral part)

34 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.17 Standard five injection points for treating glabellar frown lines.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Figure 3.18 Standard five injection points for treating glabellar lines in a female frowning (A) before and (B) 3 weeks after an onabotulinumtoxinA treatment.

XXX

XX

(A) (B)

XXX

XXXX

(A) (B)

Figure 3.19 Standard seven injection points for treating stronger glabellar muscles causing deeper furrows and frown lines in a 51-year-old male (A) before and (B) 1 month after an onabotulinumtoxinA treatment.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 35

are deeper, longer, or thicker on one side of the midline, that set of medial depressors muscles (e.g., corrugator supercilii, depressor supercilii, and medial aspect of the orbital orbicularis oculi) should receive a slightly higher dose of onabotulinumtoxinA than the medial depressors on the contralateral side. The two injection points in addition to the standard five are those given over the midpupillary line, bilaterally, which usually are needed when treating men, so that the mid brow does not elevate and become more arched than is generally the case naturally ( Fig. 3.20A–D ) ( 37 ). Remember to remain at least 1 to 2 cm above the orbital rim at the midpupillary line to avoid blepharoptosis.

Some injectors have felt that the glabella should be treated separately and in one session first, before the frontalis is treated in a subsequent session, especially with first-time patients ( 3 , 34 ). They feel that some of the frontalis will be influenced by the diffusion of onabotulinumtoxinA when the glabella is treated first ( 14 ). This consequently can reduce the amount of wrinkling remaining on the forehead. This in turn low-ers dosage requirements and may change the injection pattern neces-sary to treat the frontalis. Ultimately this may produce a better final result. Recently, however opinions have reversed and more and more injectors currently are treating the forehead and the glabella during the same session, and results seem to be comparable and just as effec-tive ( Figs. 3.20A and 3.21A,B ) ( 34 , 38 ).

Treating glabellar lines with onabotulinumtoxinA and producing opti-mal results is not a simple task. There have been many injection patterns reported in the literature over the years, and they all produce optimal

results when the ideal patient is treated properly with a given injection pat-tern. This leads one to believe that any injection pattern will work and so injecting onabotulinumtoxinA is easy. However, this is not quite the case.

What is most important is the evaluation of the patient, and the treating physician’s understanding of why certain wrinkles are formed and which muscle(s) are creating them. Once a sound assessment is made and a justifiable treatment approach is designed, then it does not matter which of the injection patterns one uses. Patients should be treated individually according to their idiosyncratic pattern of muscle movement. A three, five, seven, or even more injection point pattern can be used if it is appropriate for that particular patient ( 4 , 20 , 39 ). Treat the patient, not the picture. However, the novice injector needs a point of reference; a standard of injection patterns to guide one during the early treatment sessions. As the neophyte injector acquires a better understanding of the functional anatomy and its responses to different patterns of injections with onabotulinumtoxinA, then a more directed and individualized approach to onabotulinumtoxinA injections will automatically develop (see Trindade de Almeida patterns below) ( 40 ). Do not forget to identify, photograph, and indicate to the patient prior to all onabotulinumtoxinA injections any variation in the anatomy that might be present and cause the patient’s eyebrows to be asymmetric. It appears that as much as 45% to 65% of the general female popula-tion has some form of brow asymmetry prior to ever being treated with a BoNT (author’s personal observation). Written documentation of the conversation about a patient’s idiosyncrasies and asymmetries is

Figure 3.20 (A) Typical injection points and amount of units for a man who works outdoors and has strong depressors and levators of the brow and forehead causing very deep lines. Before treatment with onabotulinumtoxinA injections. (B) Same patient 2 weeks after the initial onabotulinumtoxinA treatment and before an additional 6 U of onabotu-linumtoxinA. Note elevated lateral eyebrows and where additional 3 U of onabotulinumtoxinA were injected on each side to lower the lateral tail of the eyebrows in this man who usually has straight eyebrows. (C) Same patient having a touch-up injection of 3 U of onabotulinumtoxinA 2 weeks after his initial onabotulinumtoxinA treatment. (D) Same patient 5 weeks after the initial onabotulinumtoxinA treatment and 3 weeks after a touch-up treatment (note the flatter less arched lateral brows).

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36 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

absolutely necessary and must be completed along with a written record of the patient’s acknowledgement and response before ever ini-tiating treatment with onabotulinumtoxinA.

In order to treat the glabellar frown lines and produce optimal, reproducible results with the least amount of complications, it is rec-ommended that precise injections of relatively concentrated doses and low volumes be used on both sides of the midline whether or not the doses are equal. With the patient sitting up or in the semireclined posi-tion gently palpate the medial aspect of the eyebrows as the patient squints and frowns. After locating the belly of the corrugator supercilii with the pads of the second and third fingertips of the nondominant hand, ask the patient to raise the eyebrows as high as possible, keeping the tip of the index finger positioned over the thickest part of the belly of the corrugator supercilii. Prior to inserting the needle, the index fin-ger of the nondominant hand should be advanced slightly cephalad and above the point of maximal muscle thickness. This usually is just above the eyebrow. The thumb now is placed at the margin of the supraorbital bony rim. The needle then is guided over the upper edge of the thumb, between it and the index finger, and inserted into the skin at a 60° to 90° angle until penetration into the corrugator superci-lii can be felt ( 21 , 33 ). Entry into the corrugator is usually discerned

when, after passing through the dermis and subcutaneous tissue, an abrupt release of resistance is felt as the needle penetrates fascia and muscle fibers of the corrugator. At this point, the needle may or may not impinge onto the bone. If it does, the patient will sense sharp pain. The needle should then be withdrawn gently enough to move away from the bone, but not enough to exit the belly of the corrugator. The bore of the needle tip should be pointed upward and away from the globe, as it is slowly advanced into the belly of the corrugator supercilii in an oblique direction, slightly upward and lateral. Always remain deep within the muscle and medial to the supraorbital notch and approximately 1.5 to 2.0 cm superior to the supraorbital bony margin ( Fig. 3.22 ). Refrain from striking the frontal bone with the needle tip, so as not to inflict any additional pain upon the patient, which occurs when periosteum is pierced. However, this may not be avoidable when first learning how to find the deeply seated corrugators and effectively inject them at the proper depth. Placing the nondominant index finger and thumb on the brow just above and below the eyebrow prior to injecting onabotulinumtoxinA serves many purposes. It prevents injecting onabotulinumtoxinA too low and close to the orbital rim. By applying direct pressure with the thumb inferior to the border of the supraorbital bony rim, Binder et al. felt that they were able to reduce

Figure 3.22 Technique of injecting the corrugator supercilii (note the position of the thumb and index finger of the nondominant hand).

Figure 3.23 Technique of injecting the medial aspect of the orbicularis oculi and depressor supercilii (note the position of the index finger and the thumb of the non-dominant hand).

Figure 3.21 This 37-year-old patient had both the glabellar and forehead frown lines treated at the same session. (A) Before onabotulinumtoxinA treatment. (B) Same patient two weeks after treatment.

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COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 37

Figure 3.24 (A) Note the parallel corrugations along the brow of this 44-year-old man frowning. (B) Note the parallel corrugations along the brow of this 61-year-old woman frowning. (C) Note the relaxation of the parallel corrugations of the brow of this same 61-year-old woman frowning.

(A)

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migration of onabotulinumtoxinA behind the orbital septum ( 21 , 33 ). This maneuver also assists in identifying the location and direction of the corrugator supercilii, because it can be felt by light palpation. It also is important to inject slowly to avoid dispersing the onabotulinum-toxinA to surrounding, nontargeted muscles. Now inject 4 to 10 U of onabotulinumtoxinA into the strongest portion of the muscle, which is located approximately 2 cm superior and 2 cm lateral to the nasion or the center of the concavity at the nasal root ( Figs. 3.9 and 3.10A,B ) ( 21 ). Next withdraw the needle out of the skin and redirect the tip of the needle medially in the direction of the nasion. Insert the needle at or adjacent to the most medial aspect of the superciliary arch approxi-mately 2 cm directly superior to the ocular caruncle at the inner can-thus ( Fig. 3.23 ). Injecting another 2 to 6 U of onabotulinumtoxinA at this point of maximum muscle contraction will treat the medial verti-cal muscle fibers of the orbital orbicularis oculi and the depressor supercilii. Because the fibers of the orbicularis oculi are closely adher-ent to the overlying skin, injections can be given either intradermally or in the superficial subcutaneous plane at this site. Superficial injections here also should affect the depressor supercilii and avoid puncturing the supratrochlear vessels and nerve. A pleasing vertically upward lift to the medial brow can be accomplished by this technique, if fibers of the frontalis are not inadvertently affected ( 41 , 42 ). Gentle massage in an upward and lateral direction for a few seconds immediately after the injection helps relieve the acute pain the patient might have experienced,

and can disperse the toxin into the areas intended for treatment. Heavy-handed massage will definitely disperse the onabotulinumtox-inA beyond the area and into muscle fibers not intended for treatment, that is, into the fibers of the lower frontalis, which can produce brow ptosis.

Next, watch as the patient frowns again, and notice to what extent the mid brow adducts toward the glabella. Stronger corrugators will visibly pull the skin just above the eyebrows medially. In some patients, additional corrugations vertically along the brow that are parallel to the central vertical glabellar lines also will be formed ( Fig. 3.24A ). These corrugations can be reduced by injecting 4 to 10 U of onabotulinumtoxinA deeply into the belly of the corrugator super-cilii (i.e., at the medial aspect of the eyebrow) and 4 to 10 U intra-dermally near where the corrugators insert into the mid brow, which is just medial to the supraorbital notch or midpupillary line ( Fig. 3.24B,C ). The medial brow injections are given deeply directly into the belly of the corrugator, while the more lateral injections over the mid brow should be applied superficially since the fibers of the corrugators in this location are superficial and insert into the under surface of the skin ( Fig. 3.25 ). These injections should reduce the adduction of the brow and eliminate corrugations.

Next, an injection of approximately 4 to 10 U of onabotulinum-toxinA is given between the eyebrows at the nasal root into the belly of the procerus and into the interdigitating fibers of the depressor

38 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

supercilii and medial fibers of the orbital orbicularis oculi ( Fig. 3.26 ). The dose needed for this injection of onabotulinumtoxinA will depend upon the overall muscle strength and depth of the horizontal glabellar wrinkles that are present ( 23 ). The strength of the procerus can be determined by gently palpating the glabellar area with the pads of the second and third fingertips of the nondominant hand, while the patient repeatedly squints and frowns. Glabellar wrinkles tend to be deeply fixed in the skin, especially the horizontal ones. Those that are more resistant to treatment with onabotulinum-toxinA commonly are found in men and women who spend a lot of time outdoors, because their glabellar muscles are significantly hypertrophied from frequent squinting. Intramuscular instead of subcutaneous injections of onabotulinumtoxinA into the procerus can be accomplished by gently grasping the soft tissue of the root of the nose between the thumb and the index finger of the nondominant hand. Then elevate the skin and muscle before placing the needle between the two fingers and injecting onabotulinumtoxinA into one or two sites in the center of the nasal radix ( Fig. 3.26 ). The site of injection should be anywhere from 1 to 3 mm above or below the center of the nasion. The weaker muscle fibers of the procerus are injected with at least 4 U of onabotulinumtoxinA, while the stronger ones usually can be injected with up to 10 U and possibly even more in one, two, or more injection points. The depressor supercilii already will have been partially treated by the injections given at the medial aspect of the superciliary arch and eyebrows when the medial orbital orbicularis oculi is treated. Likewise, when the procerus is injected some diffusion of the onabotulinumtoxinA into the interdigitating fibers of the depressor supercilii and medial orbital orbicularis oculi will occur, particularly when gentle massage upward and laterally is performed to the right and left immediately after injection.

Some patterns of glabellar frowning are seen more frequently than others ( 20 ). The most common pattern forms observed by Trindade de Almeida were those produced by the simultaneous adduction and depression of the glabella (64%). This occurs when the corrugators con-tract and parallel vertical lines are formed in the center of the glabella as the skin of the brow moves toward the midline. At the same time, the procerus pulls the skin of the brow inferiorly, forming horizontal lines at the root of the nose. There are two distinct patterns when this happens. The less frequently observed pattern (27%) is what Trindade de Almeida calls the “U” pattern ( Fig. 3.27A,B ) ( 20 ). In these patients, the 5-point injection technique is corrective with 4 to 10 U of onabotulinumtoxinA given at each injection point ( Fig. 3.27C ) ( 20 ).

Stronger, more hyperkinectic corrugators and procerus produce similar glabellar frown lines but they are deeper and more acute, resulting in a pattern that better resembles a “V.” This was seen in 37% of the patients studied ( Fig. 3.28A,B ). Higher doses of onabotulinumtoxinA in the 7-point injection pattern are usually necessary to diminish these lines ( Fig. 3.28A–D ) ( 20 ).

Another, less frequently observed (10%) pattern of patients was one where, when they frown, the eyebrows initially adduct centrally and the glabella drops inferiorly. Then with continued frowning the upper part of the glabella will slide superiorly toward the frontal hairline and the mid-to-lateral end of the brow will move inferiorly to create an overall pattern that outlines the Greek letter omega ( Fig. 3.29A,B ) ( 20 ). In these individuals the corrugators and fibers of the medial brow depres-sors seem to contract in unison with the muscle fibers of the lower-to-mid-central frontalis. Inject 4 to 8 U or more of onabotulinumtoxinA at multiple sites into the corrugators and medial brow depressors, 0 to 4 U of onabotulinumtoxinA into the procerus and 4 to 6 U into the lower medial frontalis ( Fig. 3.29A–D ) ( 20 ).

There are those individuals whose predominant movement when frowning causes the center of the glabella to travel inferiorly along with the eyebrows. There are deep horizontal wrinkle lines across the nasal radix but minimal to no vertical glabellar lines ( Fig. 3.30A,B ) ( 20 ). In such individuals, treat the procerus with 6 to 10 U of onabotulinum-toxinA and the depressor supercilii and medial orbital orbicularis oculi with 4 to 6 U of onabotulinumtoxinA and the corrugators with 4 to 6 U of onabotulinumtoxinA. This “inverted omega” pattern was the least encountered (6%) and was attributed to individuals with a flat nasal radix and in Asians ( Fig. 3.30A–D ) ( 20 ).

Another less commonly seen glabellar frown pattern is the one where there is just adduction of the mid-to-lateral brow centrally with mini-mal production of horizontal glabellar lines or vertical movement of the glabella either inferiorly or superiorly. There seems to be a neutralizing balance of movements between the procerus and the frontalis that pro-duces minimal or no horizontal glabellar frown lines in this “converging arrows” (or “parallel lines” author) pattern (20%) ( Fig. 3.31A,B ) ( 20 ). In these individuals mid-to-lateral brow corrugations can be seen more frequently depending on the person’s age and amount of skin laxity present (Fig. 3.24B). Inject 4 to 8 U or more of onabotulinumtoxinA into the belly of the corrugator supercilii ( Fig. 3.31A,C ). The medial horizontal fibers of the upper orbital orbicularis oculi may play a roll in the brow corrugations, which would require one or more intradermal injections of 4 to 6 U of onabotulinumtoxinA approximately 1 to 2 cm

Figure 3.26 Technique of injecting the procerus (note the position of the index finger and the thumb of the non-dominant hand).

Figure 3.25 Superficial injection of the lateral insertion point of the corrugator supercilii.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 39

Figure 3.27 (A) Mild to moderate approximation and depression of the medial brow forming typical and most commonly seen glabellar frown lines (the “U” pattern). (B) Commonly seen “U” type of glabellar contraction and resulting pattern of frown lines. Muscles involved: predominantly the corrugators and procerus. Source : Courtesy of Trindade de Almeida. (C) Five point pattern of injection for this most commonly encountered glabellar “U” pattern. Source : Courtesy of Trindade de Almeida. (D) Same patient frowning two weeks after an onabotulinumtoxinA treatment.

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Figure 3.28 (A) Moderate to severe approximation and depression of the medial brow forming very deep glabellar frown lines (the “V” pattern) in this 62-year-old woman. (B) Vigorous glabellar contraction and resulting “V” pattern of frown lines. Muscles involved: strong corrugators, procerus, and medial aspect of the orbicularis oculi. Source : Courtesy of Trindade de Almeida. (C) Seven point pattern of injection for this exaggerated glabellar “V” pattern. Higher doses of onabotulinumtoxinA usually are needed for treatment. Source : Courtesy of Trindade de Almeida. (D) Same patient frowning and at rest two weeks after an onabotulinumtoxinA treatment.

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40 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

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Figure 3.29 (A) Adduction and elevation of the medial brows and depression of the mid and lateral brow forms the “omega” pattern of glabellar frowning. (B) This type of glabellar contraction results in the “omega” pattern of frown lines. Muscles involved: corrugators and lower central frontalis. Source : Courtesy of Trindade de Almeida. (C) This eight point pattern of injection is used for glabellar “omega” pattern. Higher doses of onabotulinumtoxinA are needed for the corrugators and lower central frontalis and usually none for the procerus. Source : Courtesy of Trindade de Almeida. ● Author’s modification when indicated. (D) Same patient frowning 2 weeks after an onabotulinumtoxinA treatment.

Figure 3.30 (A) More depression than adduction of the medial brow with this “inverted omega” pattern of glabellar frowning. Note the deep horizontal line at the root of the nose. (B) Less frequently seen type of glabellar adduction producing an “inverted omega” pattern of frown lines. Muscles involved: mostly the procerus and depressor supercilii. Source : Courtesy of Trindade de Almeida. (C) A different seven point pattern of injection for this uncommon glabellar “inverted omega” pattern. Higher doses of onabotuli-numtoxinA are needed for the procerus. Source : Courtesy of Trindade de Almeida. (D) Same patient frowning 2 weeks after onabotulinumtoxinA treatment.

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COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 41

Figure 3.31 (A) Adduction and approximation mainly of the eyebrows form this “parallel lines” pattern of glabellar frowning. There is little to no depression or elevation of the medial brow. (B) This is an uncommon type of glabellar contraction resulting in a “parallel lines” pattern of frown lines. Muscles involved: mainly the corrugators and the medial orbital orbicularis oculi. Source : Courtesy of Trindade de Almeida. (C) This six point pattern of onabotulinumtoxinA injections targets mainly the corrugators and the mid section of the upper orbital orbicularis oculi. Source: Courtesy of Trindade de Almeida. ● Author’s modification when indicated. (D) Same patient frowning 3 weeks after an onabotulinumtoxinA treatment.

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above the supraorbital bony rim at the midpupillary line and medially along the superciliary arch ( Fig. 3.31A–D ). The procerus also can be treated with 4 to 6 U of onabotulinumtoxinA when indicated (author’s modification) (Fig. 3.24A).

Outcomes (Results) (see Appendix 3) When proper injection techniques are followed, results are predictable and reproducible. The vertical lines between the eyebrows and the hor-izontal rhytides across the root of the nose will diminish and usually disappear. Glabellar and midbrow corrugations if treated appropriately also will be reduced and temporarily eliminated.

There can be a noticeably high arching of the eyebrows of approxi-mately 2 to 3 mm, caused by the levator action of the frontalis in those patients whose glabellar depressors have been substantially weakened, but the interdigitating muscle fibers of the frontalis immediately above the brow have not ( Fig. 3.32 ) ( 41–43 ). There also can be an increase in the distance between the eyebrows and an elevation of the medial aspect of the eyebrows when glabellar frown lines are treated with ona-botulinumtoxinA because of the dynamic relationship between the brow depressors (corrugator, orbicularis oculi, procerus, depressor supercilii) and their brow levator (frontalis) ( 32 , 41–43 ). Accentuated high arching eyebrows may be attractive in most women, but usually

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Figure 3.32 Arching of the eyebrows before and after onabotulinumtoxinA treatment in this 62-year-old woman.

42 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

are not in men. In order to avoid a high arching brow in men, an addi-tional 4 to 6 U of onabotulinumtoxinA can be injected intradermally 1.5 to 2.0 cm above the supraorbital margin at the midpupillary line ( Figs. 3.19 and 3.20A–D ) ( 6 , 44 ).

Usually, one can expect the effect of an onabotulinumtoxinA treat-ment of glabellar frown lines to last at least 3 to 4 months. Patients who are treated for the very first time with onabotulinumtoxinA may expe-rience some asymmetry and therefore should return for an evaluation and possible touch-up injections within 2 to 3 weeks after a treatment. Frequently, the effects of onabotulinumtoxinA may last longer with each subsequent treatment session. Therefore, after the first 2 to 3 years of treatment sessions regularly scheduled every 3 to 5 months, some patients may prefer to return for their next retreatment on an as-needed basis (see Appendix 2).

Complications (Adverse Sequelae) (see Appendix 5) Ptosis of the upper eyelid is the most significant complication seen when injecting onabotulinumtoxinA in and around the glabella ( Fig. 3.33 ) ( 9 , 10 ). It is felt by some that blepharoptosis is caused by the migration of injected onabotulinumtoxinA through the orbital septum, weakening the levator palpebrae superioris ( Fig. 3.34A,B ).

This is found to occur more frequently when large volumes of highly diluted onabotulinumtoxinA are injected deeply and low, close to the bony supraorbital margin at the midpupillary line. Occasionally at this location some actual muscle fibers of the levator palpebrae superioris extend anteriorly into the levator aponeurosis, allowing for easy access of the onabotulinumtoxinA that has diffused through the barrier of the orbital septum to weaken some of the muscle fibers of the upper eyelid levator, and produce ptosis of the upper eyelid ( Fig. 3.15 ).

Blepharoptosis, when it occurs, is seen as a 1 to 2 mm or more drop in the upper eyelid, obscuring the upper border of the iris ( Fig. 3.33 ). Ptosis can appear up to 7 to 10 days after an onabotulinumtoxinA injection and usually can last 2 to 4 weeks or even longer ( 4 , 6 , 9 , 10 ). An antidote for blepharoptosis is apraclonidine 0.5% eye drops (Iopidine ® , Alcon Laboratories, Inc., Fort Worth, TX, USA). The ocular instillation of apraclonidine, an alpha-2-adrenergic agonist with mild alpha-1 activity, causes Mueller’s muscle (a nonstriated, smooth, sympathomi-metic levator muscle of the upper eyelid) to contract, temporarily rais-ing the upper eyelid approximately 1 to 2 mm ( Figs. 3.15 and 3.34A,B). One or two drops should be instilled into the affected eye. If ptosis persists after 15 to 20 minutes, intraocular instillation of an additional one or two drops may be required before the affected eyelid will elevate. This procedure can be repeated three to four times a day. It is advisable to use apraclonidine eye drops only when absolutely necessary, because approximately 20% of patients can develop a contact conjunctivitis with frequent use. The mydriatic and vasoconstrictor phenyl-ephrine (Neo-Synephrine ® HCl, 2.5% ophthalmic solution, Sanofi Pharmaceuticals, Inc., New York, USA or Myfrin 2.5%, Alcon Laboratories, Inc., Fort Worth, TX, USA) is an alpha-1 agonist that also can be used when apraclonidine is not available ( 34 ). However, there are more potential side effects associated with the use of phenylephrine than with apraclonidine. Specifically, even when only the 2.5% oph-thalmic solution is used, phenylephrine can acutely exacerbate narrow angle glaucoma, cardiac arrhythmias, and hypertension. Because it also is a mydriatic, even one drop of phenylephrine will prevent the patient from accommodating as usual and visual acuity can be compromised. Naphazoline (Naphcon-A ® , Alcon Laboratories, Inc., Fort Worth, TX, USA or Vasocon-A ® , Novartis Ophthalmics, East Hanover, NJ, USA) is another ophthalmic decongestant containing adrenergic properties that can be used to stimulate Mueller’s muscle to contract, temporarily lifting a ptotic upper eyelid ( 45 ). The different brands of Naphazoline also contain different antihistaminic additives, so they should be used infrequently, with caution and strictly on an as-needed basis when uti-lizing them just to reverse blepharoptosis.

Figure 3.33 Eyelid ptosis in this 49-year-old patient. Note a drop of 1–2 mm of the left upper eyelid that occurred approximately 10 days after an onabotulinumtoxinA treatment.

(A) (B)

Figure 3.34 (A) Eyelid ptosis in this 67-year-old patient. Note a drop of 1–2 mm of the right upper eyelid that occurred approximately 7 days after onabotulinumtoxinA was used to treat forehead and glabellar wrinkles. Patient is actively blinking. (B) Same patient 30 minutes after the instillation of 2 drops of apraclonidine into the right eye.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 43

Blepharoptosis also can be induced secondarily when the lower fibers of the frontalis are weakened, producing a drop in the height of the brow. The weight of the ptotic brow then impinges upon the upper eyelid and causes it to droop, narrowing the vertical palpebral aperture. This seems to occur more frequently in older patients who possess der-matochalasis of the skin of the eyelids and brow. In order to compen-sate for a heavy, lax brow, some individuals, regardless of age, involuntarily use the lower fibers of their frontalis to lift the soft tissue of the brow, which also maintains their upper eyelids in a raised posi-tion ( 21 ). When this compensatory action of the frontalis is weakened by onabotulinumtoxinA, a secondary blepharoptosis is created ( 45 ).

In younger patients with taut skin and no compensatory brow lift-ing, brow ptosis often can occur medially when there is an overzealous injection of onabotulinumtoxinA in the center of the forehead. Medial brow ptosis is exhibited by the medial head of the eyebrows appearing excessively lower than the lateral tail of the eyebrows. A bulge of skin in the center of the glabella also can accompany the “medial dip” of the eyebrows. This occurs because the lower central fibers of the frontalis are overly weakened and there is some activity of the fibers of the medial depressors, that is, the procerus, depressor supercilii, and medial orbital orbicularis oculi, pulling down on the center of the fore-head and glabella ( Fig. 3.35A,B ).

Lagophthalmos or incomplete eyelid closure is another potential complication that can occur particularly when overzealous injections of

onabotulinumtoxinA are given in the periorbital area. Lagophthalmos results when there is a loss of the normal sphincteric function of the orbicularis oculi, and the upper eyelid does not close and approximate firmly against the lower eyelid. Loss of the sphincteric function of the orbicularis oculi either with involuntary blinking or with deliberate forced eye closure can occur when onabotulinumtoxinA diffuses into the palpebral portion of the orbicularis oculi, causing undue eyelid weakness. Lagophthalmos has been seen more frequently in patients treated for strabismus when extraocular muscles are treated with higher doses of onabotulinumtoxinA than when patients are treated for cosmetic reasons in the periocular area with the usual lower doses of onabotulinumtoxinA ( 46 ). On the other hand, patients who have an attenuated orbital septum because of age or other reasons may be more prone to this adverse sequela. If incomplete eyelid approximation is present for extended periods of time, exposure of the cornea can result in symptomatic dry eyes or exposure keratitis. There is no antidote for lagophthalmos, which can persist as long as the effects of the onabotu-linumtoxinA are present. So protecting the patient from developing sec-ondary dry eyes is extremely important, because excessive corneal exposure will lead to desiccation of the cornea and superficial punctate keratitis. Immediate consultation with an ophthalmologist at the first sign of lagophthalmos will prevent any additional eye injury.

Asymmetry is a minor adverse sequelae that sometimes is unavoid-able, particularly when a patient is treated for the first time with

Figure 3.35 (A) The “medial brow dip” of the central glabella and eyebrows of this 40-year-old occurred after onabotulinumtoxinA injections because the lower central fronta-lis was overly treated. Patient is frowning before and after onabotulinumtoxinA. Note the fullness of the medial brow skin after treatment. (B) The “medial brow dip” of the central glabella of this 45-year-old patient was avoided after onabotulinumtoxinA injections because the central frontalis was not treated.

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44 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

onabotulinumtoxinA ( Fig. 3.36 ). There are three types of asymmetry that can be corrected with injections of onabotulinumtoxinA; iatro-genic; idiosyncratic; and incidental or acquired. An example of inci-dental or acquired asymmetry is Bell’s or facial (7th cranial) nerve palsy, or when one side of the face acquires a weakness because of an illness (e.g., cerebral vascular accident), or an accidental or traumatic injury. Idiosyncratic asymmetry occurs when a person is born with the inability to control or move a facial muscle to its fullest extent, while its

counterpart muscle on the contralateral side of the face is unaffected. This can result, for example, in one eyebrow or one eyelid being higher than the other ( Figs. 3.36 and 3.37 ) or in a crooked, asymmetric smile (see chap. 5, pp. 154–160).

Many of those individuals who possess, unbeknownst to them, an idiosyncratic lower lying asymmetric brow on one side, commonly will also possess a lower lying upper eyelid on the same side (i.e., a second-ary blepharoptosis) ( Fig. 3.38A–C ). With age, compensatory brow

Figure 3.36 Note the left eyebrow is higher than the right before and after treatment with onabotulinumtoxinA. Note the medial brow dip after treatment.

Figure 3.37 Patient is seen before and 2 weeks after onabotulinumtoxinA treatment. Note the slightly higher elevation of the right eyebrow, which is seen as the patient raises her eyebrows before and after treatment. Note also the medial brow dip after treatment.

Figure 3.38 (A) This 53-year-old woman at rest did not know she had a naturally occurring brow ptosis on the right with an accompanying secondary blepharoptosis of the right eyelid. (B) Same patient with an asymmetrical left brow elevation found with forced raising of eyebrows before a treatment of onabotulinumtoxinA. (C) Same patient 8 weeks after an onabotulinumtoxinA treatment at rest gazing forward.

(A) (B) (C)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 45

lifting will raise the brows to maintain unobstructed vision ( Fig. 3.39A ). When the frontalis of these patients is treated with injections of onabotulinumtoxinA, the patient’s compensatory brow lifting can be interrupted. This diminution of compensatory brow lifting can occur even when only the upper fibers of the frontalis are weakened. The lower fibers of the frontalis do not necessarily have to be treated directly with injections of onabotulinumtoxinA to drop the brow a few milli-meters. With a drop in brow height comes a concomitant drop in upper

eyelid height, and those patients who already have an asymmetrically lower upper eyelid on one side now appear to have developed blepha-roptosis from the onabotulinumtoxinA injections ( Fig. 3.39A–C ). But in reality they more accurately have pseudoblepharoptosis, which is simply an unmasking of the ptosis they already possessed, probably because of an age related attenuation of the strength of the upper lid levator of that eye ( Fig. 3.40A,B ). When the patient first realizes that one upper eyelid is lower than the other, blame on the injector and the

Figure 3.39 This 70-year-old with compensatory brow lifting and an undetected left eyelid ptosis at rest (A) and frowning (B) before onabotulinumtoxinA treatment. Blepha-roptosis (C) is seen at rest 1 month after onabotulinumtoxinA. The patient and treating physician assumed the blepharoptosis was caused by onabotulinumtoxinA until the before and after treatment pictures were compared, which then prompted the diagnosis of “pseudoblepharoptosis.”

(A) (B)

(C)

Figure 3.40 (A) This 57-year-old patient with compensatory left brow lifting before treatment with onabotulinumtoxinA injections. (B) Same patient 2 weeks after onabotuli-numtoxinA demonstrates a slight pseudoblepharoptosis on the left.

(A) (B)

46 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

onabotulinumtoxinA is a foregone conclusion ( 47 ). However, the astute physician will evaluate the patient carefully prior to any treat-ment and document the clinical findings with pretreatment photo-graphs. This will enable the physician to discuss the actual problem with the patient and graphically demonstrate the presence of the com-pensatory brow lifting before embarking on a perilous course to treat-ment failure ( Figs. 3.39A–C and 3.40A,B ). So instead of the physician being led to believe that the patient developed blepharoptosis because

of a poor injection technique, the physician will be able to identify that the patient always had an idiosyncratic subclinical upper eyelid asym-metry that can be unmasked and even exaggerated with injections of onabotulinumtoxinA ( Fig. 3.41A–C ). This manifestation of pseudo-blepharoptosis frequently occurs in patients over the age of 60 years who are treated for forehead wrinkles and glabellar frown lines with injections of onabotulinumtoxinA. Correction of pseudoblepharopto-sis is not always totally successful but can be attempted by injecting

Figure 3.42 (A) This 42-year-old patient is seen at rest with a higher right eyebrow 2 weeks after onabotulinumtoxinA injections of the glabella and forehead and just before an additional 2 U of onabotulinumtoxinA were given. (B) Same patient at rest 3 weeks after the additional 2 U of onabotulinumtoxinA were given and 5 weeks after her initial treatment with onabotulinumtoxinA. Notice the relative symmetry of both eyebrows.

2

(A) (B)

(A) (B)

(C)

Figure 3.41 (A) Compensatory brow lifting raises the right eyebrow in this 60-year-old patient to lift a ptotic right eyelid. (B) Same patient. Brows are fairly symmetrical with frowning, but the right upper lid is still ptotic before injections of onabotulinumtoxinA. (C) Same patient 1 week post onabotulinumtoxinA. The left brow was lifted with ona-botulinumtoxinA and both eyebrows appeared fairly symmetrical. This paradoxically makes the right upper eyelid appear ptotic even though the right brow was not treated with onabotulinumtoxinA.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 47

intradermally the lateral and medial pretarsal orbicularis oculi of the upper eyelid on the affected side with low doses of onabotulinumtox-inA ( 45 , 48 ).

The best way to avoid additional difficulties with patient rapport and confidence is to keep carefully documented written and photographic clinical notes (see Appendix 3). Discuss the physical findings with the patient and point out existing idiosyncratic asymmetries, anatomical differences, and potential adverse outcomes prior to treatment. Inform-ing the patient of such findings before any treatment commences always is considered by the patient an accurate diagnosis of a unique situation. Explaining the circumstances and reasons for a particularly poor outcome after treatment always is considered by the patient an excuse for an improperly executed therapeutic procedure.

Iatrogenic asymmetry arises when an injection of onabotulinum-toxinA causes one side of the face to become weaker than the other ( Fig. 3.42A ). There are many reasons for this. The primary reason for one side of the face to become weaker than the other after an injection of onabotu-linumtoxinA is when the stronger side is not injected with the equivalent dose of onabotulinumtoxinA as the contralateral side. This could be the

result of the onabotulinumtoxinA not diffusing as equally and completely through all the fibers of a muscle or group of muscles. Another reason could be that some of the fibers might have been physically resistant to the onabotulinumtoxinA, because those particular fibers were idiosyncrati-cally thicker or stronger than the rest of the area and may have required a higher dose of onabotulinumtoxinA. Another possibility is that the injec-tion was not given precisely symmetrically or in the thickest and strongest part of the muscle, causing a particular section of muscle to retain most or some of its strength. Iatrogenic asymmetry is probably the easiest to rec-tify. Generally with a few additional units of onabotulinumtoxinA injected into the appropriate area, iatrogenic asymmetry can be easily and expedi-tiously ameliorated ( Fig. 3.42B ).

Other untoward sequelae of more limited significance and duration can occur. These are the same adverse sequelae as those experienced with any type of subcutaneous or intramuscular injection. They include ecchymoses, edema, and erythema at the injection sites ( Fig. 3.43 ), headache, and flu-like malaise. Rarely, if ever, do any of these side effects last beyond the day of the treatment, except for ecchymoses, which can last up to 10 days or more.

For some patients, a dull and transient headache with or without general body malaise occurs after injections of onabotulinumtoxinA that can last beyond 24 to 72 hours ( 49 ). The occurrence of headache immediately after an onabotulinumtoxinA injection seems paradoxical since onabotulinumtoxinA injections also are used to treat tension and migraine headaches by neurologists and other medical specialists. Headaches seem to occur more frequently in first time patients after their initial and subsequent treatment sessions. They stop occurring with repeat treatments, usually after the third, fourth, or fifth treat-ment session. Also, for the first-time recipient of a periorbital treatment of onabotulinumtoxinA, the presence of periorbital edema lasting a few hours to days may occur. This could be attributed to lymph stasis, possibly produced by a nondetectable attenuation of the sphincteric pumping action of the orbicularis oculi, reducing the efficiency of lymph fluid clearance from the surrounding soft tissue.

For some women, habitual scowling is the result of spending a lot of time outdoors, or suffering from constant and persistent headaches, or being plagued with poor vision and refusing to wear corrective eye-glasses, among many other things. Incessant contraction of the corrugator supercilii, manifested by habitual scowling, causes the medial end of the eyebrows to approach the midline. Many of these women will pluck and shorten the transverse length of their eyebrows by removing

Figure 3.43 Note the erythema and edema in the pattern of the injections 10 minutes after a treatment of onabotulinumtoxinA of the forehead and glabella.

Figure 3.44 Note the widening of the glabellar interbrow space and the shortening of the transverse length of the brow at rest and frowning due to excessive plucking of the eyebrows.

48 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.46 (A,B) This 66-year-old patient at rest before and 4 weeks after onabotulinumtoxinA treatment of the glabellar frown and forehead lines. (C,D) This 66-year-old frowning before and 4 weeks after onabotulinumtoxinA treatment of the glabellar frown and forehead lines.

6 66

66

2 2 222 2

6 66

66

2 2 222 2

(A) (B)

(C) (D)

Figure 3.47 This 43-year-old patient at rest before and 2 weeks after an onabotulinumtoxinA treatment of the glabellar frown lines.

5

55

55

(A) (B)

Figure 3.45 This 56-year-old patient at rest before and one month after onabotulinumtoxinA treatment of the glabellar frown lines. Note the different dosages for areas of stronger muscle contraction.

6

6

5

4

4

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 49

Figure 3.48 This 57-year-old before and frowning 2 weeks after an onabotulinumtoxinA treatment of the glabellar frown and forehead lines.

6

66

66

2

2

2 2 222 22

Figure 3.49 This 52-year-old patient before and 3 weeks after an onabotulinumtoxinA treatment of glabellar frown lines.

6

66

66

Figure 3.50 This 43-year-old patient frowning before and 2 weeks after onabotulinumtoxinA treatment of glabellar frown lines.

4

5 5

6 6

Before After

50 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.51 This 59-year-old frowning before and 2 weeks after an onabotulinumtoxinA treatment of glabellar frown lines.

5

5 6

6 6

Before After

Figure 3.52 This 71-year-old patient frowning before and 2 weeks after an onabotulinumtoxinA treatment of glabellar frown and forehead lines.

6

443

6

22 222

2

(A) (B)

Figure 3.53 This 49-year-old patient frowning before and 2 weeks after an onabotulinumtoxinA treatment of glabellar frown lines.

5

6 75 5

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 51

eyebrow hair from the medial end of their brow. This will widen the glabellar interbrow space, so they do not look like they are habitually scowling, when they actually are ( Fig. 3.44 ). After injections of onabotu-linumtoxinA are given to reduce the number and extent of glabellar frown lines, the corrugators are no longer constantly contracting and adducting the eyebrows toward each other, narrowing the interbrow glabellar space. In fact, the transverse width of the glabella returns to its normal position because the corrugators are more relaxed at rest. How-ever, those women who have plucked the medial portion of their eye-brows to visually widen a scowling brow before onabotulinumtoxinA, now complain after onabotulinumtoxinA that they look practically hyperteloric because their eyebrows are now widely separated. However, it is only because the medial aspects of their eyebrows have been exces-sively plucked that causes them to appear this way and not the injections of onabotulinumtoxinA. Such an adverse sequelae is difficult to predict, but warning prospective patients, who pluck their eyebrows, of such a side effect will prevent further disappointment on the part of the patient and additional frustration on the part of the physician. Also, beware of the patients who color in the shape of their eyebrows, because the shape that is chosen on the day of an onabotulinumtoxinA treatment may not necessarily correspond to the natural anatomical position of that per-son’s brow. Injections of onabotulinumtoxinA may return the area to its natural anatomic position, which paradoxically may appear to be dis-torting the glabellar area, when in reality it is not. Patients with perma-nent eyebrow tattooing may present with similar challenges and after treatment disappointments.

Serious reactions, particularly those of immediate hypersensitivity such as anaphylaxis, urticaria, soft tissue edema, and dyspnea have been extremely rare. When they occur, appropriate medical treatment must be instituted immediately (see Appendix 5).

Figures 3.45 to 3.53 are some examples of different patients treated with onabotulinumtoxinA for glabellar frown lines. Some also had treat-ment of their forehead frown lines during the same treatment session.

Treatment Implications When Injecting the Glabella

1. Accurate amounts of precisely placed injections of minimal

volume onabotulinumtoxinA reduce the incidence of brow and

eyelid ptosis.

2. Men may need higher doses of onabotulinumtoxinA than

women for comparable results.

3. Women prefer arched eyebrows; men prefer straight, non-arched

eyebrows.

4. When injecting the corrugator supercilii with onabotulinum-

toxinA, remain medial to the midpupillary line and 1.5 to 2.0 cm

above the supraorbital bony margin, and deep within the belly

of the muscle.

5. Blepharoptosis can be transiently reversed with alpha- adrenergic

agonist eye drops, but brow ptosis cannot be reduced and remits

only when the effects of onabotulinumtoxinA diminish.

6. Preexisting asymmetry of the brow and eyelids should be

identifi ed and discussed with the patient before treatment, and

might be corrected by accurately injecting appropriate doses of

onabotulinumtoxinA on both the affected and non-affected side.

7. Patients with inelastic, redundant skin of the brow who have

compensatory brow lifting because of a preexisting blepharop-

tosis can easily develop pseudoblepharoptosis when injections

of onabotulinumtoxinA decompensate their brow lifting on the

affected side.

HORIZONTAL FOREHEAD LINES Introduction: Problem Assessment and Patient Selection The easiest area of the face to treat with injections of onabotulinum-toxinA is the forehead ( 37 ). Many individuals contract their frontalis constantly for various and sundry reasons, and, in so doing, the skin buckles, creating parallel grooves and elevations across their foreheads. On the other hand, the presence of horizontal forehead lines seems to be directly proportional to one’s age or time spent in the sun. Older indi-viduals generally have a number of forehead lines that become deeper with time. As one ages, the skin of the face, along with that of the rest of the body, typically becomes more inelastic and redundant. When this occurs in the upper face, a characteristic hooding of the brow over the upper eyelids also can result, which commonly is observed in the sixth or seventh decade in those individuals so predisposed. For these indi-viduals a properly functioning frontalis is essential in maintaining a normal field of vision, because it is this muscle that will keep the brow from drooping and producing a hood of skin that drapes over the upper eyelids, interfering with their forward and upward gaze.

Younger patients who have horizontal forehead lines commonly attempt to conceal their obtrusiveness by wearing their frontal hair with a fringe or in bangs ( Fig. 3.54A,B ).

Generally, the presence of horizontal forehead lines causes one to appear stressed, worried, tired, or old. Abruptly raising the eyebrows by acutely contracting the frontalis also can express an emotion of sur-prise or even fear: emotions that one usually may not want to express too readily in certain situations ( Fig. 3.55 ). When done properly, injec-tions of onabotulinumtoxinA can diminish forehead wrinkling and replace one’s negative expressions with those that are more positive.

All too often it is the female rather than the male patient who is more concerned over the presence of forehead lines. Many of these women fre-quently are determined to eliminate any vestige of the appearance of a fore-head wrinkle. A cautious and empathetic cosmetic physician will remind such patients that the absolute absence of forehead wrinkles, especially at full contracture or while expressing an emotion, may not be particularly appropriate for any reason. It portrays an individual as too artificial and stone-like in appearance, and thus should not be desirable. Because of the levator function of the frontalis, its interaction with the depressor muscles of the glabella and periorbital area, and the potential risk of overtreatment causing brow ptosis, there are many who believe treating the frontalis with onabotulinumtoxinA is not really as easy as one would expect ( 34 ).

Functional Anatomy (see Appendix 1) The horizontal forehead lines are produced by the contraction of the muscle fibers of the frontalis, the only levator muscle of the upper third of the face ( Fig. 3.56 ; see Fig. 2.2a,b). The function of the frontalis is to elevate the eyebrows, and the skin of the brow and forehead, and to oppose the depressor action of the muscles of the glabella and brow. It also retracts the scalp as a function of its participation in the occipito-frontalis galea aponeurotic complex.

The frontalis is a pair of quadrilaterally shaped, distinct muscles whose fibers are oriented vertically, producing the horizontal wrinkles of the forehead, which are perpendicular to the direction of muscle contraction. The frontalis lies beneath a thick layer of sebaceous skin and subcutaneous tissue and has no attachment to bone. The frontalis is indirectly connected to the occipitalis by the epicranial, membranous galea aponeurotica, which attaches to both muscles on either side of the scalp vertex, the occipitalis posteriorly and the frontalis anteriorly. The frontalis originates from the membranous galea aponeurotica superiorly and inserts into the subcutaneous tissue and skin of the brow at the level of the superciliary ridge (or arch) of the frontal bone. The fibers of the frontalis also interdigitate with muscle fibers of the brow depressors, that is, the procerus, corrugator supercilii, depressor supercilii, and orbicularis oculi. In some patients there can be a

52 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.55 Contracting the frontalis expresses surprise or even fear.

downward extension of the membranous galea aponeurotica in the midline composed of little or no muscle fibers ( Fig. 3.56 ) ( 22 ). When present, injections of onabotulinumtoxinA into this area are unneces-sary. However, in some men and even women, there are well-developed muscle fibers in the center of the forehead ( Fig. 3.57A,B ). They can be detected by light palpation over the area while the patient actively raises and lowers the eyebrows. When functional muscle fibers of the frontalis can be detected in the center of the forehead, injections of onabotulinumtoxinA in the midline of the forehead are needed to pro-duce the desired effect ( Fig. 3.57C ).

Dilution (see Appendix 2)

Controlled, widespread diffusion can be a desired effect when inject-

ing onabotulinumtoxinA into the forehead. To avoid brow ptosis,

the muscle fi bers of the frontalis must remain fully functional 1.5 to

2.5 cm above the eyebrow (i.e., 2.0–3.5 cm above the actual bony or-

bital margin). Then higher dilutions and larger volumes of onabotu-

linumtoxinA can be injected into the upper forehead. Consequently,

injectors will use anywhere from 1 to 4 ml of non-preserved saline

to reconstitute a 100U vial of onabotulinumtoxinA when treating

the forehead (48). The dilution recommended by the manufacturer

and approved by the FDA and specifi ed in the onabotulinumtoxinA

product’s package insert is 2.5 ml of nonpreserved saline or 4 U of

onabotulinumtoxinA per 0.1 ml of solution.

Figure 3.54 (A) Two patients before an onabotulinumtoxinA treatment with deep forehead lines. Note the fringe of hair concealing their forehead wrinkles. (B) A patient before and after a treatment with onabotulinumtoxinA. The bangs were pushed aside to see the forehead rhytides.

(A)

(B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 53

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) A typical dose for injecting the forehead in women is approximately 8 to 18 U of onabotulinumtoxinA. This can be injected either subcutane-ously or intramuscularly at four to six sites across the forehead with 2 to 4 U of onabotulinumtoxinA placed in each site at intervals of 1.5 to 2 cm apart on either side of a deep crease ( Fig. 3.58A ) ( 51 , 52 ). For men, the typical dose is approximately 16 to 30 U of onabotulinumtoxinA and occasionally higher ( 51 , 53 ). This can be injected at 4 to 12 or even more sites either subcutaneously or intramuscularly depending on the height and width of the forehead, with up to 4 to 5 U of onabotulinum-toxinA placed in each site, depending on the strength of the frontalis ( Fig. 3.58B ) ( 3 , 53 , 54 ). Some patients, either men or women, can have many rows of fine forehead wrinkles, whereas others can have one or two rows of deeply set folds and furrows. The number and dosage of the onabotulinumtoxinA injections will depend on many factors, including the number and depth of the wrinkles, the size, shape, and strength of the muscle and the height, width, and shape of the forehead ( Fig. 3.59 ) ( 34 , 37 , 55 ). More often than expected, and unbeknownst to the individual, a patient will present with asymmetrical eyebrows prior to their first treatment with onabotulinumtoxinA. Patients must be made aware of their idiosyncratic differences and their anatomic par-ticulars must be documented both in the patient’s clinical chart and in their photographic record. Sometimes the eyebrows can be made symmetrically level with each other with carefully placed injections of onabotulinumtoxinA ( Fig. 3.60A,B ) and sometimes they cannot ( Fig. 3.61A,B ).

The patient usually is injected in an upright sitting or semire-clined position. The pattern of injection across the forehead can vary. One can randomly inject 2 to 4 U of onabotulinumtoxinA sub-cutaneously or intramuscularly at any point on the forehead that is at least 2 to 2.5 finger breadths (i.e., 2–3.5 cm) above the superior

margin of the bony orbit ( Fig. 3.62 ). One also can inject as much as 24 U of onabotulinumtoxinA or more subcutaneously across the forehead in a horizontal plane parallel to the wrinkles present ( Figs. 3.63 and 3.64 ) ( 22 ). Another pattern that can be used is to inject 2 to 4 U of onabotulinumtoxinA subcutaneously in a wavy M configura-tion, whose arms diverge upward toward the lateral frontal hairline recession and then downward laterally ( Figs. 3.62, 3.63, and 3.65A,B ). This is accomplished by starting at a point in the midline approxi-mately 2 to 4 cm above the medial aspect of the eyebrows, and inject-ing at three or four points moving upwardly and laterally in a diagonal pattern following the upward and downward arc of the eye-brows themselves. A distance of 2 to 3 cm should be maintained from the injection points and the upper border of the eyebrows, fin-ishing inferior to the frontal hairline recession and 3 to 4 cm above the lateral aspect of the eyebrows, depending on the height of the forehead ( Fig. 3.66A,B ) ( 34 ). Injections in a pattern that is too high above the lateral tail of the eyebrows may result in unaffected fibers of the frontalis elevating the lateral eyebrow in the so-called “Mephisto” or “Mr. Spok” pattern ( Fig. 3.67A–D ). Otherwise, the simplest approach to treating the forehead is to inject onabotu-linumtoxinA in a linear fashion across the forehead, maintaining the same distance above (approximately 2–3cm) and parallel to the eye-brows across the forehead with the highest point of injection being at the apex of an arched eyebrow ( Fig. 3.68A,B ). This pattern is best for women who have a relatively short rise to the height of their fore-head ( Figs. 3.63 and 3.66 ). This pattern will keep the onabotulinum-toxinA high enough above the eyebrows so they can form a peaked arch. Another technique is to inject subcutaneously approximately 2 to 4 U of onabotulinumtoxinA at sites approximately 2 cm apart and across the entire forehead horizontally at a point midway between the brow and the hairline also maintaining a constant distance above the eyebrows ( Figs. 3.62 , 3.63 , and 3.66 ). This is advisable if the

Figure 3.56 Frontalis, the only levator of the forehead.

Procerus

Depressor supercilii

Corrugator supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Frontalis

54 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.57 (A) Men with deep forehead lines. The 58-year-old on the right works outdoors. (B) Some women can have a well developed frontalis in the middle of their fore-head. Neither of these women works outdoors. (C) This 63-year-old man who spends a lot of time outdoors has a well developed frontalis, seen here raising his eyebrows before and 2 weeks after an onabotulinumtoxinA treatment. Note the non-tanned skin in the base of the forehead lines after treatment on the left.

(A)

(B)

(C)

Figure 3.58 (A) Typical injection sites in a woman with an average sized forehead. (B) Typical injections sites in a man with an average size forehead.

545

44

22

66 6

66

3

333

33

3333

33

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 55

Figure 3.59 Random pattern injections into a forehead that is high and wide with multiple parallel wrinkles. This patient had 2 U of onabotulinumtoxinA injected at each site.

X

X

X XX

X XXX

XXX

Figure 3.60 (A,B) This 68-year-old patient with an average size forehead, and low-set eyebrows, was unaware that her right eyebrow was higher than her left. After onabotuli-numtoxinA treatment they were symmetrical. Note the higher dosing on the right versus the left.

2 2222

2 2 2 2

(A) (B)

Figure 3.61 (A,B) This 50-year-old patient has a high and narrow forehead and multiple rows of forehead wrinkles. Note the left eyebrow is higher than the right one before and after treatment with onabotulinumtoxinA.

22

2

22

(A) (B)

hairline is set low and if there are only one or two rows of horizontal wrinkles across the forehead ( Fig. 3.63 ).

If the width of the forehead is narrow, that is, less than 12 cm between the anterior temporal lines, then four or five injections sub-cutaneously of 2 to 4 U of onabotulinumtoxinA at each injection site across the forehead are sufficient ( Fig. 3.61A,B ). One can feel the ante-rior temporal line by first identifying the zygomatic process of the frontal bone, which is the superior portion of the upper lateral wall of the bony orbit ( Fig. 3.69 ). Its posterior edge continues upward, as a palpable protruding ridge along the lateral edge of the frontal bone, and arches upward and backward, delineating the anterior and supe-rior boundary of the temporal fossa. If an individual has a wider brow, that is, more than 12 cm between the right and left anterior temporal lines, then five, six, or possibly more injection sites across the forehead are probably necessary, with 2 to 4 U of onabotulinumtoxinA injected at each site subcutaneously ( Figs. 3.59 , 3.64–3.66 ). The stronger the frontalis, the more units of onabotulinumtoxinA will be required to produce a desired effect.

Gentle massage upward and laterally at the injection sites for a few seconds helps to relieve the acute and transient pain of an injection and

56 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.62 This 40-year-old patient with a low and wide forehead with the right eyebrow higher than the left before treatment with onabotulinumtoxinA. Note the position of the injection points: lower on the right lateral brow and higher over the left brow. Note the position of the right eyebrow 1 week after treatment with onabotulinumtoxinA.

22

22

22

2

Figure 3.63 This 36-year-old patient has an average low and narrow forehead with the right eyebrow higher than the left.

5

4544

22

Figure 3.64 This 38-year-old patient has a high and wide forehead and an asymmetrically lower right eyebrow.

2 2 22

2 2 22 2

XXX XX

XX

(A) (B)

Figure 3.65 (A) Typical injection sites in a woman with an average size forehead. (B) Same patient 2 weeks after onabotulinumtoxinA injection.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 57

Figure 3.66 (A,B) This 45-year-old patient raising her eyebrows before and 3 weeks after onabotulinumtoxinA treatment of only the forehead.

222 2

2

22

(A) (B)

Figure 3.67 (A) A 54-year-old patient with forehead wrinkles directly over the left eyebrow (arrow) observed with forced brow elevation before treatment. (B) Same patient 2 weeks after initial treatment with onabotulinumtoxinA. Note left brow is now higher than right brow with forced eyebrow elevation. An additional 2 U of onabotulinumtoxinA was injected during this follow-up visit. (C) Same patient 5 weeks after the initial treatment with onabotulinumtoxinA and 3 weeks after a touch-up of 2 U of onabotulinum-toxinA. The left eyebrow remains slightly elevated laterally at rest with eyes wide open (D) but not with eyes closed.

222 22

222

(A) (B)

(C) (D)

Figure 3.68 (A,B) This 40-year-old at rest before and 2 weeks after an onabotulinumtoxinA treatment of only the forehead.

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2

22

22

(A) (B)

58 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

X

Figure 3.69 Photo of skull illustrating the location and extent of anterior and supe-rior temporal line. X, zygomatic process of the frontal bone; blue arrow, anterior temporal line; red arrow, superior temporal line.

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(C)

Figure 3.70 (A) A 62-year-old patient with compensatory brow elevation. The arrow points to the horizontal forehead line and hyperkinetic frontalis immediately above the left lateral brow. (B) Same patient after onabotulinumtoxinA. Note the hyperkinetic lower lateral frontalis on the left. Two weeks after the initial treatment, 2 U of onabotulinum-toxinA were injected 2–2.5 cm above the lateral left brow at a point of maximum contraction of the frontalis. (C) Same patient 5 weeks after initial treatment and three weeks after touch-up over the left eyebrow.

can help disperse the toxin locally. Prolonged or heavy-handed massage can disperse the liquid onabotulinumtoxinA beyond the intended area of injection, weakening adjacent muscles fibers and producing unwanted results, for example, brow ptosis.

Outcomes (Results) (see Appendix 4) An adequate result when treating the frontalis is to completely elimi-nate the horizontal lines of the forehead when the patient is at rest, but to provide the ability for some movement and minimal wrinkling when the patient is animated or actively expressing an emotion. Ideally, weakening of the frontalis should last at least 3 full months when a suf-ficient dose of onabotulinumtoxinA is injected. Frequently, after repeat treatments and occasionally after the first treatment session in some patients, the effects of onabotulinumtoxinA weakening can last as long as 4 to 6 months after onabotulinumtoxinA is injected ( 34 ). Overgen-erous intramuscular injections of the frontalis with high doses of ona-botulinumtoxinA will eliminate totally all movement of the muscle, even with forced contraction, creating a flat mask-like and motionless forehead and some degree of brow ptosis especially in patients (young or old) with inelastic skin. There usually is never a good aesthetic rea-son for such total denervation of the frontalis or any other muscle of facial expression even if it is only a temporary effect. In addition, the overall duration of results usually is not extended in any area when

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 59

Figure 3.71 (A) This 52-year-old patient with mild forehead wrinkling at rest before and 3 weeks after an onabotulinumtoxinA treatment of only the forehead. (B) Same patient raising her eyebrows, before and 3 weeks after an onabotulinumtoxinA treatment of only the forehead. Note persistent wrinkles just above both lateral eyebrows.

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(B)

onabotulinumtoxinA is injected at a higher dose than that which is normally adequate for the individual’s problem.

Occasionally and especially with the initial treatment of forehead wrinkles, the effect of onabotulinumtoxinA weakening may not occur symmetrically, and there may be wrinkling on one side of the forehead and not on the other, even at rest. It is imperative that the physician warn the patient of this before treatment and require the patient to return 2 to 3 weeks after a treatment session so that any minor asym-metries can be corrected. This is accomplished by injecting 1 to 2 U of onabotulinumtoxinA in the vicinity of the persistent asymmetric wrinkling and muscle hyperactivity ( Fig. 3.67 ). Remember, this should always be done at least 2 to 3 cm above the eyebrow, so as not to pro-duce brow ptosis inadvertently. This is particularly important for those patients who have multiple rows of low-lying horizontal fore-head lines ( Fig. 3.70A ). By allowing the lower fibers of the frontalis to remain active, there typically may be a wrinkle or two immediately above the eyebrow and asymmetric brow elevation that might persist, because they cannot be reduced without causing brow ptosis ( Fig. 3.70B,C ). Most of the time, these narrow horizontal lines immediately adjacent to, if not within, the upper border of the eyebrow can be identified during the pretreatment physical examination and manage-ment planning ( Figs. 3.67 , 3.71A,B , and 3.72A–D ). When low-lying horizontal forehead wrinkles occur, the patient should be made aware of their presence and given the option of other cosmetic procedures (e.g., fillers or resurfacing), before commencing with the injections of onabotulinumtoxinA. These minor horizontal forehead lines usually are the manifestation of excessively lax skin and a hyperactive frontalis being recruited to elevate a weighty brow to prevent brow hooding and visual field obstruction. One runs the risk of causing brow ptosis if total reduction of these lower forehead lines is attempted. Consequently, the patient is better off totally ignoring these lines. If they remain after treatment with onabotulinumtoxinA and still are extremely bothersome to the patient, they can be treated with a soft

tissue filler within 2 to 4 weeks or after the injections of onabotu-linumtoxinA have completely taken effect.

Complications (Adverse Sequelae) (see Appendix 5) When treating the frontalis with onabotulinumtoxinA, appropriate injection patterns and meticulous injection technique are extremely important in avoiding brow ptosis ( 44 , 56 ). This is best accomplished by remaining at least 2 to 3.5 cm above the supraorbital bony margin or 1.5 to 2.5 cm above the eyebrow depending on the idiosyncratic anatomy of the individual patient being treated. This will enable the muscle fibers of the frontalis to remain functional with adequate resting tone in the area directly above the brow so that the eyebrows will not droop and produce hooding over the upper eyelids ( Figs. 3.67A–D and 3.73A,B ).

In most patients, horizontal forehead lines are present in conjunction with glabellar frown lines. In these patients, it is imperative that the gla-bellar area is treated before or contemporaneously with the forehead; otherwise, because of the depressor action of the glabellar muscles, brow ptosis may be difficult to avoid. Maintaining an adequate resting tone of the lower fibers of the frontalis just over the brow (approxi-mately 2–3cm) will help prevent brow ptosis by elevating the brow when the glabellar depressors are treated, because the resting tone of the glabellar depressors is slightly stronger than the resting tone of the brow levator, that is, frontalis ( Fig. 3.74A,B ). There is no antidote for brow ptosis, which can last as long as the onabotulinumtoxinA injection is effective. Injections of low-dose, low-volume onabotulinumtoxinA pre-cisely placed in the superficial fibers of the lateral, upper, orbital orbicu-laris oculi may help to reduce the extent of brow ptosis (see below).

Clinical experience has indicated that when a more concentrated dose of onabotulinumtoxinA is used (i.e., dilutions of 1 ml per 100 U vial of ona-botulinumtoxinA) there is minimal volume injected and migration of the onabotulinumtoxinA is negligible. The results also seem to last longer ( 56 ). On the other hand, to prevent total paralysis of muscle movement, espe-cially with forced contraction of the frontalis, a different approach can be

60 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.72 (A) This 40-year-old patient at rest before and 3 weeks after an onabotulinumtoxinA treatment of only the forehead. (B) Same patient raising his eyebrows before and 3 weeks after an onabotulinumtoxinA treatment of only his forehead. (C) Same patient at rest before and 1 week after his 4th onabotulinumtoxinA treatment of only his forehead. (D) Same patient raising eyebrows before and 1 week after his 4th onabotulinumtoxinA treatment of only his forehead.

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utilized when attempting to aesthetically reduce horizontal forehead lines. Since there does not seem to be any agreement in the literature on which dilutions should be used when reconstituting a 100 U vial of onabotu-linumtoxinA, or which dosage regimens are most effective, one then can inject the forehead with the same number of units of onabotulinumtox-inA, but with a more dilute solution ( 4 , 50 , 57 ). Namely, a 100 U vial of onabotulinumtoxinA can be reconstituted with 2 to 4 ml of saline when used solely for injecting the frontalis. This requires a greater volume to be injected. The toxin then can disperse over a wider area of the forehead, providing an effect that is less intensely paralyzing ( 48 ). However, injecting

large volumes of diluted onabotulinumtoxinA possibly might limit the duration of its effectiveness ( 6 , 57 ). As long as non-targeted muscle fibers (i.e., those of the lower frontalis) are not directly in the wake of the intended toxin diffusion, this may be a more forgiving alternative injection tech-nique, especially for the neophyte injector.

Other more common adverse sequelae that occur with an injection of onabotulinumtoxinA are related more to the actual physical injec-tion rather than to the material injected. All of these adverse events are transient and generally do not last longer than 24 to 36 hours. They include ecchymoses, local edema, erythema, and pain at the injection

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 61

Figure 3.74 This 53-year-old patient (A) before and (B) 2 weeks after an onabotulinumtoxinA treatment of only the forehead. Note the slight bilateral brow ptosis after treatment when the glabella is not adequately treated.

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Figure 3.73 (A) This 32-year-old woman is shown raising her eyebrows before and 1 month after treatment of only the forehead. (B) Same patient is shown at rest before and 1 month after treatment of only the forehead. Note the gentle arching of the brows after treatment with onabotulinumtoxinA.

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(B)

and adjacent sites ( Fig. 3.43 ). For some patients, a dull and transient headache with or without general body malaise occurs after injections of onabotulinumtoxinA that can last beyond 24 to 72 hours ( 49 ). The occurrence of headache immediately after an onabotulinumtoxinA injection seems paradoxical since onabotulinumtoxinA injections are also used to treat tension and migraine headaches by neurologists and

other specialists. Serious reactions, particularly of the immediate hypersensitivity type such as anaphylaxis, urticaria, soft tissue edema, and dyspnea have been extremely rare. When they occur, appropriate medical treatment must be instituted immediately.

Figures 3.75 to 3.83 are additional examples of different patients treated with onabotulinumtoxinA for horizontal forehead lines.

62 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.76 This 56-year-old patient frowning before and 2 weeks after an onabotulinumtoxinA treatment for forehead and frown lines.

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Figure 3.77 This 64-year-old patient raising eyebrows before and 3 weeks after an onabotulinumtoxinA treatment for forehead and frown lines. Note the “medial dip” of the glabella.

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Figure 3.75 This 48-year-old patient frowning (A) before and (B) 3 weeks after an onabotulinumtoxinA treatment of forehead and glabellar frown lines.

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Treatment Implications When Injecting the Frontalis

1. Identify and document brow or forehead asymmetries prior to treatment with onabotulinumtoxinA.

2. Injections of onabotulinumtoxinA in the forehead can be placed subcutaneously or intramuscularly.

3. Weaken the frontalis; do not paralyze it.

4. The lower horizontal forehead lines may not be treatable if brow ptosis is to be avoided, especially in older patients.

5. Posttreatment forehead asymmetry can be corrected with a few units of onabotulinumtoxinA given into the hyperactive fi bers of the fronta-

lis, 2 to 4 weeks after a treatment session.

6. Counteract brow ptosis and elevate the eyebrows with low volume, intradermal injections of 2 to 4 U of onabotulinumtoxinA into the lateral

brow and the upper lateral fi bers of the orbital orbicularis oculi (see following section). Otherwise, brow ptosis will remain as long as the

current onabotulinumtoxinA treatment is effective.

7. The frontalis is best treated after or in conjunction with an onabotulinumtoxinA treatment of the glabellar frown lines.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 63

Figure 3.78 This 59-year-old patient raising eyebrows before and 3 weeks after an onabotulinumtoxinA treatment for forehead and frown lines. An additional 2U were given over the left brow.

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Figure 3.80 This 52-year-old patient raising eyebrows before and 2 weeks after an onabotulinumtoxinA treatment for forehead and frown lines. Note the “medial dip” of the glabella.

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Figure 3.81 This 45-year-old patient raising eyebrows before and 2 months after an onabotulinumtoxinA treatment for forehead and frown lines.

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Figure 3.79 This 42-year-old patient raising eyebrows before and 2 weeks after an onabotulinumtoxinA treatment for forehead and frown lines.

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64 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

PERIORBITAL AREA: LATERAL CANTHAL LINES Introduction: Problem Assessment and Patient Selection One of the first signs of aging is the wrinkles that radiate away from the lateral canthus outwardly and laterally, which are sometimes referred to as “crow’s feet” ( Fig. 3.84 ). Depending on a person’s skin type, his-tory of sun exposure, and muscle strength, crow’s feet can appear in someone as young as 20 years of age. The natural thinness and abun-dance of the skin in the lateral periorbital area make this site prone to wrinkling. These lateral canthal lines initially appear only during animation, they soon accentuate while smiling, laughing, or squinting and become increasingly noticeable with time. Their presence causes one to appear perpetually tired and fatigued and even older than one’s current age. For a woman, crow’s feet are the bane of her appearance, especially when make-up accumulates in the depths of the creases. For men, crow’s feet are a sign of hard work and fun in the sun.

When lateral canthal wrinkles are caused by the contraction of the lat-eral aspect of the orbital orbicularis oculi, they are referred to as dynamic wrinkles. They are the result of infolding and pleating of the overlying skin as the muscle contracts and they radiate away from the lateral can-thus ( Figs. 3.84 and 3.85 ). These wrinkles are perpendicular to the direc-tion of the lateral muscle fibers of the orbital orbicularis oculi, which run mostly in a vertical direction around the lateral canthus ( Fig. 3.85 ). These types of wrinkles can be diminished by injections of onabotulinum-toxinA ( 58–60 ). In some patients, however, age and photodamage are the

major contributing factors that produce lateral canthal wrinkles. These types of wrinkles are always present whether or not a person is actively animating and therefore are referred to as static wrinkles. When the bulk of crow’s feet are the result of static wrinkles, injections of onabotulinum-toxinA will be less effective. Only a resurfacing procedure or a soft tissue filler might help efface static wrinkling of the lateral canthus. When the bulk of crow’s feet are produced by the hyperactivity of the lateral orbital orbicularis oculi, then injections of onabotulinumtoxinA can play a significant role in diminishing the wrinkling ( Fig. 3.86A,B ).

Functional Anatomy (see Appendix 1) The orbicularis oculi is a broad, flat, elliptical muscle. It encircles the globe and the periphery of the bony orbit. It is divided into three parts, the orbital, palpebral, and lacrimal parts (Fig. 3.87). The orbital part is the outermost portion of the muscle that forms a complete ellipse around the bony orbit. The orbital orbicularis oculi originates from the nasal component of the frontal bone, the frontal process of the maxilla, and the medial palpebral ligament. Its fibers form complete ellipses, without interruption even in its lateral aspect, where there is no bony attachment. In its superior aspect the orbital portion of the orbicularis oculi interdigitates with the muscle fibers of the frontalis, corrugator supercilii, depressor supercilii, and the procerus. It inserts into the soft tissue of the brow, anterior temple (superficial temporalis fascia), cheeks (interdigitating with fibers of the levator labii superioris

Figure 3.83 This 66-year-old patient raising eyebrows before and 1 month after an onabotulinumtoxinA treatment for forehead and frown lines.

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Figure 3.82 The 61-year-old patient raising eyebrows before and 2 weeks after an onabotulinumtoxinA treatment for forehead and frown lines. Note the higher left eyebrow before treatment and the additional 1 U at the follow-up visit.

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COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 65

Figure 3.84 (A) Crow’s feet accentuated by squinting in a person who is 31-years old. (B) Same condition in a person who is 68-years old.

(A) (B)

alaeque nasi, levator labii superioris, and zygomaticus minor), and medial and lateral canthal tendons. Contraction of the orbital orbicu-laris oculi approximates the upper with the lower eyelids, as with forced, volitional eyelid closure, and depresses the medial and lateral aspects of the eyebrows. Certain medial fibers of the orbital orbicularis

oculi have been referred to by some as the depressor supercilii. However, the depressor supercilii in recent anatomic studies has been identified as a distinct and separate pair of muscles, which insert into the under-surface of the skin at the medial aspect of the eyebrows. They pull the eyebrows downward when they contract (see Fig. 3.87 ) ( 36 , 37 ).

Figure 3.85 Lateral side of the orbital portion of the orbicularis oculi.

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

66 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.87 The orbicularis oculi is a sphincteric type muscle and is divided into three parts: the orbital, palpebral, and lacrimal parts.

Depressor superciliiOrbicularis oculi-

orbital part

Orbicularis oculi-lacrimal part

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Orbicularis oculi-palpebral "part" bifid

The fibers of the palpebral part of the orbicularis oculi arise from the medial palpebral ligament and from the bone on either side of the ligament. Its fibers are subdivided into pretarsal and preseptal portions ( Fig. 3.88 ). The pretarsal portion courses over the eyelids and the preseptal portion lies superficial to the orbital septum at the junction between the bony orbit and eyelid. The preseptal fibers arise from the bifurcation of the medial palpebral ligament, while the upper and lower pretarsal fibers traverse laterally to join and form the lateral palpebral raphe.

Contraction of the palpebral orbicularis oculi provides the sphincteric action of the eyelids and gently closes them involuntarily, as occurs with blinking or sleep. The palpebral orbicularis oculi should not be treated with onabotulinumtoxinA for cosmetic purposes except in certain

Figure 3.86 (A) Squinting produces a myriad of lateral orbital wrinkles in this 64-year-old woman before a treatment of onabotulinumtoxinA into her crow’s feet. (B) Same patient squinting 3 weeks after onabotulinumtoxinA injections.

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situations and only by the most experienced injector because it can cause loss of the intentional and involuntary function of eyelid closure.

The lacrimal part of the orbicularis oculi is located posterior to the medial palpebral ligament and lacrimal sac ( Fig. 3.89 ). Its fibers arise from the upper part of the lacrimal crest and travel posteriorly to the lacrimal sac and insert onto the upper and lower tarsal plates medial to the lacrimal puncta. Contraction of the lacrimal orbicularis oculi draws the eyelids and lacrimal papillae posteriorly against the globe, thereby placing the lacrimal puncta in direct contact with the lacrimal lake. Compression on the lacrimal sac dilates it, facilitating the lacrimal pump by creating negative back pressure within the canalicular system, and allowing tears to flow into the nasolacrimal duct.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 67

Figure 3.88 The palpebral part of the orbicularis oculi is subdivided into the preseptal and pretarsal portions.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Frontalis

Procerus

Depressor superciliiPalpebral orbicularis oculi-

preseptal portion

pretarsal portion

Figure 3.89 The lacrimal part of the orbicularis oculi lies posterior to the medial canthal ligament.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Orbicularis oculi-lacrimal partLevator labii

superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Because crow’s feet are enhanced during smiling or laughing, the contraction of the risorius and zygomaticus major et minor also contribute to the formation of these lateral canthal rhytides. The zygomaticus major originates anterior to the zygomaticotemporal

suture line deep to the orbicularis oculi and travels diagonally toward the corner of the mouth ( Fig. 3.90 ). It decussates with the modiolus and inserts into the skin and mucosa of the corners of the mouth. The zygomaticus major moves the angle of the mouth

68 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

superiorly, laterally, and posteriorly when a person laughs, smiles, or chews.

The zygomaticus minor originates from the zygomatic bone posterior to the zygomaticomaxillary suture line, just anterior to the origin of the

Figure 3.91 Risorius is the muscle of laughter and moves the commissure laterally and slightly upward.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

zygomaticus major, travels downward and forward and inserts into the mediolateral aspect of the upper lip ( Fig. 3.90 ). The zygomaticus minor helps to create and elevate the nasolabial fold and to elevate the upper lateral aspect of the upper lip, producing the expression of disdain.

Figure 3.90 Zygomaticus major assists in lifting the lateral upper lip and oral commissure. Zygomatic minor elevates the upper lip more centrally.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 69

Figure 3.92 Crow’s feet accentuated by squinting or smiling in a person who is 64 years old.

The risorius is band like, usually poorly developed, and lies at the upper border of the facial platysma ( Fig. 3.91 ). It does not originate from bone, but from the connective tissue and fascia overlying the parotid gland, platysma, masseter, and mastoid process. The risorius travels horizontally across the face, superficially to the platysma, decus-sates with the modiolus, and inserts into the skin of the oral commis-sure. The risorius at times can be indistinguishable from the platysma. The risorius can stretch the lower lip and displace the skin of the cheek posteriorly when laughing, grinning, or smiling—producing dimples in some individuals. Along with the platysma, the risorius can move the oral commissures in numerous facial movements in downward, upward, and lateral directions. Consequently, when a person laughs, smiles, or grins they contract the risorius and zygomaticus major et minor, which also can accentuate the lower aspect of their crow’s feet ( Fig. 3.92 ).

Dilution (see Appendix 2)

When injecting onabotulinumtoxinA in the periorbital area, it is

imperative that minimal volumes be precisely placed. This will neces-

sitate reconstituting a 100 U vial of onabotulinumtoxinA with only

1 ml of normal saline. The recommended and approved method of

reconstituting a 100 U vial of onabotulinumtoxinA with 2.5 ml of

normal saline may not be the best dilution for accurate dosing when

injecting precise amounts of onabotulinumtoxinA in areas of the face

other than the glabella.

Dosing: How to Correct the Problem (see Appendix 3) (What to Do and What Not to Do) When one performs injections of onabotulinumtoxinA or any other pharmaceutical in the periorbital area, both the patient and the physician should remain unencumbered, comfortable, and without

distractions. The patient should be in a sitting or semireclined position, approachable from both the left and right sides. When injecting ona-botulinumtoxinA in the lateral canthal area, one should stand on the opposite side of the area to be treated with the patient facing toward the injector. This will allow the physician to approach the lateral can-thus with the tip of the needle pointed lateral to and away from the patient’s eye. Stretching the skin over the target area with the nondom-inant hand under ample lighting enables the physician to visualize most of the blood vessels that lie just beneath the surface of the skin in this area ( Fig. 3.93A ).

Since the skin of the periorbital area is thin, the tip of the needle should be inserted no more deeply than 2 to 3 mm below the skin sur-face ( 14 ). Raising a wheal at each injection point will guarantee the injections were given at the proper depth ( Fig. 3.93B,C ). This will allow the onabotulinumtoxinA to diffuse slowly and evenly into the underly-ing muscle fibers of the lateral periorbita. While injecting onabotu-linumtoxinA into the lateral canthus, it is important to remain at least 1 to 1.5 cm lateral to the lateral bony orbital rim. Approximately 2 to 4 U of onabotulinumtoxinA can be injected into each of two to four sites subcutaneously at the lateral orbital area 1.0 to 1.5 cm apart from each other for a total of 4 to 16 U of onabotulinumtoxinA on each side ( Fig. 3.94A,B ). Men may need slightly higher dosing, approximately 10 to 20 U per side for comparable results ( Fig. 3.95A,B ) ( 4 ).

Because there can be variable patterns of the lateral canthal lines from one person to the next, onabotulinumtoxinA treatments should be individualized for each patient. Generally, the lateral canthal lines can be identified as upper eyelid creases, lateral canthal creases, or lower eyelid or malar creases ( Fig. 3.96 ). Characteristically, a patient can possess any one or multiple patterns of creases that can even be different in shape and severity from the left-to-right side of the face ( Fig. 3.97 ) ( 62 ). Even though Kane identified four different patterns of crow’s feet, he concluded that the actual patterns manifested by patients were of no true anatomic significance. What mattered mostly was the recognition that there is a diversity in the motion of an individual’s orbicularis oculi creating different crow’s feet patterns and conse-quently they should be treated with varying doses of onabotulinum-toxinA accordingly. In addition, a person may have a certain percentage of either static or dynamic wrinkles, but only the dynamic ones are reducible by injections of onabotulinumtoxinA. The number of injec-tion sites and the amount of onabotulinumtoxinA injected will depend on the pattern, depth, and severity of the lateral canthal wrinkling as well as the thickness of the skin and the presence or absence of blood vessels ( Fig. 3.97 ) ( 53 , 59–66 ). Men, generally, will be satisfied with less of a reduction in wrinkling of the lateral canthi, especially with active movements such as smiling and laughing.

In order to avoid puncturing any one of the many superficial vessels found in and around the lateral canthus, the total dose of onabotu-linumtoxinA can be injected intradermally or subcutaneously as a sin-gle bolus at one or two sites, producing one or two wheals on the surface of the skin ( Fig. 3.98 ) ( 10 ). The wheals of onabotulinumtoxinA are then gently massaged laterally and away from the orbital fossa in an upward and downward direction. By carefully kneading a bolus of onabotulinumtoxinA around the lateral canthus, the injected onabotu-linumtoxinA is dispersed subcutaneously and over the muscle fibers of the lateral orbital orbicularis oculi. This maneuver can prevent postinjection ecchymoses if none of the periorbital vessels are punctured. The bolus of onabotulinumtoxinA is always injected 1 to 1.5 cm lateral to the lateral bony orbital margin.

When treating crow’s feet, especially at the level of the lower eyelid and lateral malar prominence, it is extremely important to inject ona-botulinumtoxinA in the intradermal or superficial subcutaneous plane, where the superficial muscle fibers of the orbital orbicularis oculi insert ( 14 ).

70 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

3

33

(A) (B)

Figure 3.94 This 59-year-old woman at rest (A) before and (B) 6 weeks after treatment with onabotulinumtoxinA.

(A) (B)

(C)

Figure 3.93 (A) Technique of injecting the crow’s feet or lateral orbital orbicularis oculi. Note the injector stands on the opposite side, pointing and inserting the needle away from the lateral canthus and globe. Stretching the skin with the nondominant hand assists in visualizing superficial periocular vasculature. (B) Raising a wheal at each injection point will guarantee the injection was given at the proper depth in the crow’s feet. (C) Note the wheals of injected onabotulinumtoxinA.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 71

3

3

(A) (B)

Figure 3.95 This 56-year-old man squinting (A) before and (B) 2 weeks after a treatment with onabotulinumtoxinA.

Figure 3.97 Different patterns of crow’s feet: a—upper; b—lateral; and c—lower eyelid and malar creases of the left and right side of a 49-year-old patient squinting before a treatment of onabotulinumtoxinA.

a

b

c

a

b

c

Figure 3.96 Different patterns of crow’s feet: a—upper eyelid; b—lateral canthal; and c—lower eyelid or malar eyelid creases.

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

a. Upper

b. Lateral

c. Lower or malar

72 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.99 (A,B) This 56-year-old patient at rest before and 3 weeks after an onabotulinumtoxinA treatment. Note the difference in pattern between the right and left crow’s feet. (C,D) Same patient at rest before and 3 weeks after an onabotulinumtoxinA treatment. Note the difference in pattern between the left and right crow’s feet.

3

33

Right side

(A)

(C) (D)

(B)

Left side

3

3

3

The duration of effect of onabotulinumtoxinA treatments of the lateral canthus usually is somewhat shorter than that seen in other areas of the face. At least 3 months and sometimes up to 4 months of diminished crow’s feet can be obtained with proper dosing and accu-rate placement of the injections. For some patients the duration of effect is extended with subsequent treatments of onabotulinumtoxinA ( 59 , 60 ).

Outcome (Results) If the treated crow’s feet are dynamic and the result of contractions of the orbital orbicularis oculi, there will be a significant improvement to the area ( Fig. 3.99A–D ). However, if the crow’s feet are mostly static and the result of photodamage and chronological aging, then the improvement will be disappointing, especially if the patient was not warned of this prior to treatment. It is important always to assess and

(A) (B)

Figure 3.98 Notice the shallow blood vessels that lie just beneath the surface of the skin in this 59-year-old female. Also, note the superficial boluses of injected onabotulinumtoxinA on the surface of the skin.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 73

Figure 3.100 Patient’s crow’s feet (A) before and (B) 2.5 months after a treatment with onabotulinumtoxinA and 2 months after full face CO2 laser resurfacing.

(A) (B)

discuss a particular problem and its solution in detail with the patient before initiating a course of treatment with onabotulinumtoxinA. It is also in the best interest of both patient and physician to document the pretreatment consultation both in writing and with photographs (see Appendix 3). The documentation should include any remarks the patient may have voiced during the interview. All too often, a patient’s memory of a physician’s concerns and predictions prior to treatment are easily forgotten by the patient after treatment.

Most of the time, the best way to diminish lateral canthal static wrin-kling is by some form of ablative resurfacing, whether by laser ablation, dermabrasion, or chemical peeling and the addition of a soft tissue filler when appropriate ( 62 ). The different types of non-ablative facial rejuvenation techniques still have not been able to eliminate completely the deep and dense solar elastotic changes that create the pronounced crow’s feet in the manner in which many patients over 50 years of age would like. In such cases, oftentimes a treatment regimen of regularly scheduled onabotulinumtoxinA injections after an ablative resurfacing procedure that is periodically augmented by injections of a soft tissue fillers is the only way many patients will be able to realize the kind of facial improvement they are seeking ( Fig. 3.100 ) ( 43 , 66 ). Prolongation of such improvements then can be accomplished regularly, albeit infre-quently throughout the year, with non-ablative laser, intense pulsed light, or similar types of superficial facial rejuvenation treatments and the daily application of topical retinoids, alpha hydroxy acids, or simi-lar cosmeceuticals.

When the lateral orbital orbicularis oculi is exceptionally hyperfunc-tional, causing deep and elongated crow’s feet that are recalcitrant and resist improvement with injections of onabotulinumtoxinA placed in the usual sites, additional injections placed posteriorly toward the lat-eral limits of the orbicularis oculi in the temporal area can be beneficial ( Fig. 3.101A–D ) ( 67 ).

Be cautious when treating the lower malar type of lateral canthal lines, because the majority of these lines may be produced by a hyperkinetic zygomaticus major. If the patient possesses redundant skin around the lateral canthus, then injecting onabotulinumtoxinA into the lower crow’s feet area can create additional skin folding over

the lateral malar prominence and exacerbate diagonal wrinkling of the mid and lateral cheeks. The propensity for this may be identified prior to treating the patient with onabotulinumtoxinA by having the patient smile forcibly and repeatedly. If their lower lateral canthal lines are con-tinuous with diagonal wrinkles of the mid and lateral cheeks, caution must be taken when injecting the lower malar crow’s feet ( Figs. 3.92 and 3.102 ). Soft tissue fillers or resurfacing may be the best way to rid the patient of these particular types of rhytides ( Fig. 3.100 ). Treating the zygomaticus major with onabotulinumtoxinA can easily result in an asymmetric smile and upper lip incompetence (see Complications below).

Complications (Adverse Sequelae) (see Appendix 5) When injecting the lateral orbital orbicularis oculi, onabotulinum-toxinA should be placed intradermally or subdermally. The injections should not be placed any more medially to an imaginary vertical line that passes through the lateral canthus, nor below the level of the supe-rior margin of the zygomatic arch. Otherwise, the muscle fibers of some of the levators of the lateral upper lip and corners of the mouth will be affected by the diffusion of the onabotulinumtoxinA, and result in lat-eral upper lip ptosis and possibly oral sphincter incompetence ( 67 , 68 ). This can occur because the zygomaticus major et minor originate at or near the lateral aspect of the superior margin of the zygomatic arch ( Fig. 3.92 ). If the zygomaticus major or minor is injected with onabotu-linumtoxinA, the lateral aspect of the ipsilateral upper lip will be weak-ened, causing a drooping of the upper oral commissure, an asymmetric smile, and possible drooling and incontinence of food and liquid. If onabotulinumtoxinA is injected or even diffuses more medially and inferiorly to the superior margin of the zygomatic arch, then the central and deep lip levators (levator labii superioris, levator labii superioris alaeque nasi, and levator anguli oris) can be affected, causing a more profound interference with upper lip competence and basic sphincteric functions, resulting in dysarthria and dysphagia.

Injecting subcutaneously small volumes of concentrated onabotu-linumtoxinA far enough (i.e., 1.0–1.5 cm) away from the lateral side wall of the bony orbit will prevent the unintended migration of

74 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.102 Lower crow’s feet extend down the mid and lateral cheeks in this 59-year-old patient.

onabotulinumtoxinA medially and into the superior or inferior, or both, palpebral orbicularis oculi. If this occurs, weakening of the lateral canthal tendon occurs, producing lower eyelid ectropion, which mani-fests as rounding of the lateral canthus ( Fig. 3.103 ). Rounding can lead

to secondary complications initially manifesting as epiphora (tearing) or even possibly prolonged corneal exposure, and secondary xeroph-thalmia (dry eye), which eventually can result in corneal damage (superficial punctate keratitis) ( 10 , 54 ). Because of their position within

Figure 3.101 (A) A 64-year-old patient at rest with deep, extensive, and recalcitrant crow’s feet before onabotulinumtoxinA. (B) Same patient at rest 1 month after onabotuli-numtoxinA. (C) Same patient squinting before onabotulinumtoxinA. (D) Same patient squinting 1 month after onabotulinumtoxinA.

22

22

2

33

3

22

2

2

2

3

33

(A) (B)

(C) (D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 75

the orbit, the lateral and inferior rectus, or inferior oblique are espe-cially disposed to accidental diffusion of injected onabotulinumtoxinA through the orbital septum. If any of the extraocular muscles are inadvertently weakened by onabotulinumtoxinA, diplopia and strabis-mus will result. If any of these serious complications does occur, immediate consultation with an ophthalmologist is imperative ( 54 ).

Overzealous treatments of onabotulinumtoxinA in the lateral peri-orbita that are either forcibly injected or given with high doses of high

volume onabotulinumtoxinA also can result in brow ptosis, ectropion, diplopia, xerophthalmia, lagophthalmos, and even superficial punctate keratitis because of corneal exposure. Brow ptosis is caused by the diffusion of onabotulinumtoxinA into the lower fibers of the frontalis when onabotulinumtoxinA is injected rapidly, or the area is massaged vigorously after injection ( Fig. 3.104A–D ). Patients can cause brow ptosis if they manipulate the injected area excessively, enough to dis-perse the onabotulinumtoxinA beyond the targeted area immediately

Figure 3.103 (A) Before 2 U of onabotulinumtoxinA were injected into each lower eyelid along with 9 U of onabotulinumtoxinA into the lateral canthus of this 55-year-old woman who is 8 years post blepharoplasty. (B) Same patient 3 weeks later with asymptomatic lateral canthal rounding and lower eyelid ectropion. Note the scleral show and unnatural and unattractive rounding of the lateral canthi.

22

333

333

Figure 3.104 This 49-year-old woman (A,C) before and (B,D) after she developed brow ptosis 2 weeks after onabotulinumtoxinA treatment for reasons unknown: patient manipulation or physician’s technique or both.

2

2

22

2

2

22

(A) (B)

(C) (D)

76 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

after a treatment session. Injecting large volumes of low concentrations of onabotulinumtoxinA also increases the risk of dispersion beyond the targeted muscle. Ectropion occurs when the muscular sling of the lateral orbicularis is inadvertently weakened by injections of onabotu-linumtoxinA, especially in someone who has had an interventional eyelid procedure, namely, blepharoplasty, deep chemical or laser resurfacing, etc. This is generally seen as excessive rounding of the con-tour of the lateral canthus ( Fig. 3.103 ).

In rare instances, when the lateral orbital orbicularis oculi is weak-ened with onabotulinumtoxinA and the lower crow’s feet are elimi-nated, a flattening of this periocular area can result. When the lateral upper lip levators (zygomatic major and minor) are still functioning normally and the patient smiles emphatically, there may appear a pecu-liarly abrupt change in contour from the fully rounded, finely corru-gated mid- and lateral cheek to the flattened wrinkleless periocular area ( 38 ). For these patients a soft tissue filler in the lateral malar deficit is the best way to temporarily correct the problem ( Fig. 3.105 ). Kane attributes this phenomenon to the fact that the orbicularis oculi is an accessory upper cheek levator ( 62 ). He also feels that when the lower lateral orbicularis oculi is completely denervated with injections of onabotulinumtoxinA, there is a loss of upper cheek elevation and lax skin will become redundant just inferior to the lower eyelid when a person smiles. In younger patients who still have tight and elastic periorbital skin, the excess lower eyelid skin folding and wrinkling does not always occur. There is just an abrupt contour difference between the lower lateral periorbita and the upper zygoma. However,

in older patients with loose, inelastic skin, a full smile may create an unnatural expression after injections of onabotulinumtoxinA because this area does not contract as it normally should. Especially when there is a complete elimination of periorbital wrinkling after an ona-botulinumtoxinA treatment, the lateral eyebrow is often left unnatu-rally elevated. Consequently, when such a patient smiles, there is a flattening of the normally occurring upper cheek bulge, because some of the natural cheek elevation is lost. Also, in severe cases, even at rest, there is an extra roll of skin, which becomes embarrassingly apparent at the junction of the lower eyelid and cheek skin. When this lateral portion of the muscle functions normally, it elevates the lateral eyelid skin and redistributes some of the excess skin of the lower eye-lid. When the orbicularis oculi is completely denervated by onabotu-linumtoxinA, this no longer occurs and the redundant lower eyelid skin forms a visible roll or folds of the skin ( Fig. 3.105 ) ( 62 ).

The incidence of the usual transient adverse sequelae that accompany a transcutaneous injection, including pain, erythema, edema, and ecchymoses can be mitigated with the use of ice and the application of a local topical anesthetic. The anatomy of the periocular area, however, makes occluding the topical anesthetic somewhat difficult and impractical. The patient also should be reminded to stop alcohol, aspi-rin, nonsteroidal anti-inflammatory drugs, anticoagulants, and other medications, and food supplements that increase coagulation time at least two weeks prior to treatment.

Figures 3.106 – 3.110 are some examples of different patients treated with onabotulinumtoxinA for crow’s feet (lateral canthal lines).

(A) (B)

(C) (D)

Figure 3.105 This 40 year old patient is seen (A) before and (B) 2 weeks after onabotulinumtoxinA treatment of the lateral canthal wrinkles. Note the flattening of the lateral canthal area due to weakening of the orbicularis oculi. Same patient seen with lateral malar deficit smiling (C) before and (D) immediately after a hyaluronic acid filler treatment.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 77

Figure 3.107 This 56-year-old squinting (A) before and (B) 2 weeks after an onabotulinumtoxinA treatment. Note the difference in the patterns between the left and right side crow’s feet. Same patient squinting (C) before and (D) 2 weeks after an onabotulinumtoxinA treatment. Note the difference in the patterns between the right and left side crow’s feet.

4

4

Left side

Right side

(A) (B)

(C) (D)

3

3

Figure 3.106 (A) This 48-year-old patient squinting before and 3 weeks after onabotulinumtoxinA treatment. Note the difference in wrinkle patterns between the right and left crow’s feet. (B) Same patient.

3

33

Right side(A)

(B)

2

Left side

4

4

4

2

78 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.108 This 46-year-old patient squinting before and 2 weeks after an onabotulinumtoxinA treatment.

3

33

2

Figure 3.109 This 41-year-old patient at rest before and 4 weeks after an onabotulinumtoxinA treatment.

3

22

Figure 3.110 This 64-year-old patient at rest before and 6 weeks after an onabotulinumtoxinA treatment.

3

33

2

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 79

Figure 3.111 This 49-year-old patient is shown (A) before and (B) 3 weeks after onabotulinumtoxinA was injected into the lateral aspect of the orbicularis oculi. Note the muscle fibers of the lower lateral frontalis raising the tail of the eyebrow and diminishing lateral hooding of the lateral aspect of the upper eyelid.

(A) (B)

Treatment Implications When Injecting the Lateral Orbicularis Oculi (Crow’s Feet)

1. All periocular injections of onabotulinumtoxinA should be

placed in the lower dermis or superfi cial subcutaneous tissue

and not any more deeply.

2. Inject onabotulinumtoxinA slowly placing the needle 1.0 to

1.5 cm lateral to the bony orbital rim and directing it away from

the globe into the lateral canthus to avoid diplopia and injury

to the eye.

3. Older patients will have varying degrees of improvement after a

treatment of onabotulinumtoxinA, depending on the amount of

photoaging, redundant skin, and static wrinkling present.

4. Posttreatment ecchymoses can last over one week, fallaciously

suggesting incompetence and a substandard injection technique

by the injector. Stop aspirin, NSAIDs, anticoagulants and other

medications, and all home remedies that increase coagulation

time at least two weeks before a treatment session. The applica-

tion of ice before and moderate point pressure to the skin after

an injection can reduce the extent of ecchymoses.

5. Upper lateral canthal injections of the orbital orbicularis oculi

also can be used to produce a lateral eyebrow lift when used in

conjunction with onabotulinumtoxinA injections of the glabel-

lar and forehead muscles (see next section).

6. Injecting the lower lateral canthus with large volumes of ona-

botulinumtoxinA can produce upper lip asymmetry and cheek

ptosis if the upper lip levators are inadvertently treated. Therefore,

inject onabotulinumtoxinA well above the superior margin of the

zygoma and remain 1.0 to 1.5 cm from the bony orbital rim.

7. Accurately dosed and precisely placed low-volume onabotu-

linumtoxinA injections are essential in order to avoid adverse

sequelae in the periorbital area.

PERIORBITAL AREA: LATERAL EYEBROW LIFT Introduction: Problem Assessment and Patient Selection With the progression of time and the accumulation of hours spent outdoors, the skin of the face as well as the rest of the body becomes more inelastic, causing it to sag and drape more loosely. This can

appear as hooding of the lateral brow with the uniquely character-istic appearance of ptosis of the lateral eyebrow ( Fig. 3.111 ). The thick skin of the lateral brow, when it becomes ptotic, gives the bearer a “heavy” down trodden look. It makes one appear tired, overburdened, and preoccupied with worries and concerns. High, arched lateral eyebrows convey an expression of happiness, vigor, approval, confidence, and sensuality. Depressed, low positioned or flat lateral eyebrows convey an expression of sadness, fatigue, anxi-ety, disdain, and disapproval. With advancing age, many individuals become ideal candidates for upper eyelid blepharoplasties and brow lifts. The physical appearance of this hooding generally affects men at a later age than women, but men as well as women with this prob-lem eventually will benefit from an upper eyelid blepharoplasty, brow lift or both when the hooding progresses and peripheral vision is impeded. In the meantime, chemodenervation with ona-botulinumtoxinA will forestall the inevitable by elevating the lateral brow and providing one with many more years of a more youthful, less tired appearance.

Functional Anatomy (see Appendix 1) The reason for lateral brow ptosis is multifactorial. As the skin and supportive soft tissues of the periorbita become inelastic and redun-dant, the lower lateral fibers of the frontalis become less efficient in elevating the heavy mass of periorbital skin above the lateral orbital bony rim. In addition, the antagonistic muscle movements of repeated frowning and the strong contractions (i.e., depressor action) of both the lateral aspect of the horizontal fibers of the upper orbital orbicu-laris oculi and the vertical fibers of the lateral orbital orbicularis oculi, in conjunction with the ineffective levator action of the lateral fronta-lis, progressively produce a downward drooping of the lateral eyebrow ( Fig. 3.112 ).

Dilution (see Appendix 2)

Treating the periocular area should be done with low volume, highly

concentrated onabotulinumtoxinA. Therefore, reconstituting a

100 U vial of onabotulinumtoxinA with 1 ml of normal saline is best

for precise injections with accurate dosing when a 3/10 ml Beckton-

Dickenson U-100 insulin syringe with a 31-gauge needle is used.

80 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Dosing: How to Correct the Problem(What to Do and What Not to Do) To elevate and enhance the arching of the lateral eyebrow, especially in women, 2 to 4 U of onabotulinumtoxinA can be injected intrader-mally or subdermally into the lateral depressor, that is, the lateral orbital orbicularis oculi, in the vicinity of maximal contraction. This often is seen clinically as corrugations in and around the tail of the eyebrow ( Fig. 3.113 ). They correspond to where the lateral aspect of the superciliary arch meets the lower aspect of the anterior temporal line at the zygomatic process of the frontal bone ( Figs. 3.69 and 3.114 ). Depending on the idiosyncratic anatomy of the patient being treated, intradermal injections can be placed just above or below the hairs of the lateral aspect (i.e., tail) of the eyebrow ( Fig. 3.115A,B ). One or multiple (usually no more than three) injections of 2 to 4 U of onabotulinumtoxinA can be given intradermally in this area of

maximal muscle contraction. Higher doses can be used with a lesser number of injection points. Injecting onabotulinumtoxinA in this area reduces the depressor action of the horizontal and vertical muscle fibers of the orbital orbicularis oculi at the lateral aspect of the brow, and allows the muscle fibers of the lower lateral aspect of the frontalis to elevate the lateral eyebrow ( Fig. 3.116A–D ) ( 51–53 , 69 , 70 ).

With the patient in the sitting or semireclined position, have the patient forcibly elevate and depress the eyebrows. This will allow one to assess the depressor strength of the lateral orbicularis oculi and the levator strength of the lateral frontalis. After determining the dose of onabotulinumtoxinA needed, have the patient once again forcibly ele-vate the eyebrows. Facilitate and maintain the upward movement by supporting the skin with the thumb and index finger of the nondomi-nant hand. This maneuver allows the lower muscle fibers of the frontalis

Figure 3.113 This 49-year-old patient with many wrinkles and corrugations of the upper lid and lateral eyebrow is shown before a treatment of onabotulinumtoxinA. Note how the corrugations vary from right-to-left. (X marks where 1 to 3 U of onabotulinumtoxinA can be injected intradermally in the lateral aspect of the upper eyelid).

XX

X

XX

XX

X

X

X

Figure 3.112 (A) This 40-year-old at rest before and (B) 3 weeks after onabotulinumtoxinA treatment. Note the difference in the lateral brow height.

3

22

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 81

Figure 3.114 Location of the main injection point (●) when attempting to elevate the lateral aspect of the eyebrow.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

to rise up, thereby uncovering and exposing the superficial muscle fibers of the upper orbital orbicularis oculi. With the bore of the needle point-ing upward and away from the orbit inject intradermally approximately 2 U to no more than a total of 8 U of onabotulinumtoxinA into one and usually no more than three injection sites along the lateral brow. Start the injections from the lateral aspect of the eyebrow and place them 1 cm apart from each other and finish at a point just lateral to the mid-pupillary line along the superciliary arch in patients with a strong orbicularis oculi who display lateral brow depression with or without hooding or corrugation ( Fig. 3.117 ). OnabotulinumtoxinA must be injected slowly and intradermally and no more deeply than subdermally

into the superficial subcutaneous tissue of each lateral brow. Raising a wheal at each injection point will guarantee the injection was given at the proper depth of the intradermal/subcutaneous interface ( Fig. 3.118 ). Ordinarily, one to three intradermal injections of 2 to 3 U of onabotu-linumtoxinA placed into the lateral aspect of the brow will suffice to produce an aesthetically pleasing lateral brow lift and a diminution of idiosyncratic lateral brow corrugations ( Figs. 3.119A–D and 3.120A–D). This superficial injection technique will reduce the risk of the onabotu-linumtoxinA dispersing beyond the intended area and producing adverse sequelae, that is, brow and eyelid ptosis, ectropion, strabismus, diplopia, or xerophthalmia (see Appendix 5).

Figure 3.115 The exact location of injection points on the skin of an individual’s lateral brow may vary according to the person’s anatomy.

82 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.117 Most lateral injection point along the superciliary arch.Figure 3.118 Raising a wheal at each injection point will guarantee the injection was given at the proper depth.

Outcomes (Results) (see Appendix 4) Lateral brow elevation is best appreciated as a decrease in hooding of the lateral aspect of the upper eyelid ( Figs. 3.120 and 3.121 ) ( 51–53 , 68–71 ). Elevating the eyebrows at their medial, central, or lateral aspects can be unpredictable when first attempted, but usu-ally reproducible when the proper technique is used and appropri-ate, specific clinical records and sequential photographs are kept

(see Appendix 3) ( 53 , 68–71 ). With the proper technique the complication rate is low and for some individuals the results might be subtle at best ( 65 ). Therefore, each patient’s clinical record must include diagrammatic as well as photographic documentation along with written or typed progress notes if reproducible results are expected. The desirability of lifting the eyebrows for one patient or another—that is, the medial, central, or lateral aspect—will

Figure 3.116 (A) Right lateral brow of this 45-year-old patient at rest and before a treatment of onabotulinumtoxinA. (B) Note brow elevation 3 weeks after a treatment of onabotulinumtoxinA of the lateral right brow. (C,D) Left lateral brow of this 45-year-old at rest and before a treatment of onabotulinumtoxinA. (C) Note brow elevation 3 weeks after a treatment of onabotulinumtoxinA of the lateral left brow.

(A) (B)

(C) (D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 83

Figure 3.119 (A) This 62-year-old patient before and (B) 2 weeks after treatment with onabotulinumtoxinA injection in the lateral aspect of her right brow. Note the lateral brow lift and diminution of the lateral brow corrugations. (C) This 62-year-old patient before and (D) 2 weeks after treatment with onabotulinumtoxinA injection in the lateral aspect of her left brow. Note the lateral brow lift and diminution of the lateral brow corrugations.

(A) (B)

(C) (D)

depend on current fashion trends and standards. The preference for lifting the eyebrows will depend on the patient’s overall physiognomy and idiosyncratic anatomy. The feasibility for doing so will depend on whether or not the physician is capable of injecting onabotulinumtoxinA with a reproducible technique. Typically, the effects of onabotulinumtoxinA in the area of the lat-eral brow last as long as those of the glabella.

It is important to identify and remind each patient that attempting to eliminate the horizontal forehead lines that are positioned immediately above and adjacent to or within the lateral eyebrows are impossible to eliminate without causing lateral brow ptosis ( Figs. 3.71A,B and 3.72A–D ). Those lines exist because they identify a person with inherent brow ptosis and compensatory brow lifting ( Fig. 3.39A–C ). It is the presence of functioning lower fibers of the lateral frontalis that is needed to raise the lateral brow. When there is excessive skin laxity (i.e., derma-tochalasis) in the area of the lower lateral forehead and lateral brow, the skin redundancy, creating lateral orbital hooding and horizontal wrin-kles immediately above the lateral brow may or may not be treatable by onabotulinumtoxinA to the patient’s satisfaction ( Fig. 3.122 ).

Complications (Adverse Sequelae) (See Appendix 5) It is important to keep in mind that when treating the forehead with onabotulinumtoxinA, injections in the lateral aspect of the frontalis

should not be done too high or too low. Injections that are too high can result in the excessively elevated lateral eyebrow, producing what is known as the Mephisto or “Mr. Spock” look. Injections that are too low will cause or accentuate brow ptosis and will negate any further attempt at lateral brow elevation until the strength of the lower lateral frontalis muscle fibers returns.

Xerophthalmia or dry eye can occur if onabotulinumtoxinA is injected too deeply in the upper lateral aspect of the periorbital area and it diffuses into the lacrimal gland and diminishes its secretion. When this occurs, regular and constant instillation of some form of commercially available artificial tears (i.e., ophthalmic normal saline) will be necessary until the lacrimal glands begin to function again. Consultation with an ophthalmologist also is recommended.

Forceful, deep, and rapid injections at the lateral canthus can cause the onabotulinumtoxinA to diffuse into the bony orbit and weaken the lateral extraocular muscles, causing strabismus and diplopia. The best way to avoid these complications and other adverse sequelae is to inject onabotulinumtoxinA slowly and intradermally with 2 to 3 U per injec-tion point in women and 3 to 4 U per injection point in men. The dos-age will depend on the strength of the frontalis and presence or absence of dermatochalasis and lateral orbital hooding.

Figures 3.123 – 3.129 are some examples of different patients treated with onabotulinumtoxinA to elevate the lateral brow.

84 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.121 (A) This 68-year-old patient before and (B) 3 weeks after onabotulinumtoxinA was injected into the lateral aspect of the orbicularis oculi. Note the elevation of the hooding of the lateral aspect of the upper eyelid.

1

22

(A) (B)

Figure 3.120 (A) This 58-year-old patient is shown at rest before and (B) 3 weeks after her onabotulinumtoxinA treatment. (C) Same patient is shown squinting before and (D) 3 weeks after her onabotulinumtoxinA treatment.

Before(C) (D) 3 weeks after

22

2

(A) (B)Before

2

22

3 weeks after

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 85

Figure 3.123 (A) This 57-year-old patient squinting before and (B) 3 weeks after onabotulinumtoxinA treatment on the right. Note the difference in the lateral brow height and hooding. (C) Same patient squinting before and (D) 3 weeks after onabotulinumtoxinA treatment of the left. Note the difference in lateral brow height and hooding.

3

32

2

3

3

2

2

(A) (B)

(C) (D)

Figure 3.122 (A) A 61-year-old woman with dermatochalasis causing skin redundancy and orbital hooding bilaterally before onabotulinumtoxinA. (B) Note the injection pattern and number of units used to treat this individual. (C) Same patient 3 weeks after onabotulinumtoxinA.

22

2 2 2 2

2

33

3

3

(A)

(C)

(B)

86 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.125 (A) This 57-year-old patient at rest before and (B) 2 weeks after onabotulinumtoxinA treatment. Note the difference in the lateral brow hooding.

2

2

2

2

(A) (B)

Figure 3.126 This 45-year-old patient is shown (A) before and (B) 2 weeks after onabotulinumtoxinA was injected into the lateral aspect of the orbital orbicularis oculi. Note the reduction in the lateral brow hooding.

(A) (B)

Figure 3.124 (A) This 52-year-old squinting before and (B) 3 weeks after onabotulinumtoxinA treatment on the left. Note the difference in lateral brow height and lateral brow hooding. (C) Same patient squinting before and (D) 3 weeks after onabotulinumtoxinA treatment on the right. Note the difference in lateral brow height and lateral brow hooding.

3

2

22

3

3

22

(A) (B)

(C) (D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 87

Figure 3.127 (A) This 53-year-old patient at rest before and (B) 3 weeks after onabotulinumtoxinA treatment. Note the difference in the lateral brow hooding.

(A) (B)

2

3

2

2

Figure 3.128 (A) This 49-year-old patient at rest before and (B) 3 weeks after onabotulinumtoxinA treatment. Note the difference in the lateral brow height and hooding.

2

2

22

(A) (B)

Figure 3.129 (A) This 48-year-old patient at rest before and (B) 2 weeks after onabotulinumtoxinA treatment on the left. Note the difference in the lateral brow height and hooding. (C) Same patient at rest before and (D) 2 weeks after onabotulinumtoxinA treatment. Note the difference in the lateral brow height and hooding.

2

2

2

2

2

2

(A) (B)

(C) (D)

88 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.130 (A) Early festoons and wrinkles of the lower eyelid in this 42-year-old patient at rest. (B) Same patient with periocular wrinkles exaggerated when she smiles. She also complained of dark circles under her eyes.

(A) (B)

PERIORBITAL AREA: LOWER EYELID LINES Introduction: Problem Assessment and Patient Selection Along with crow’s feet and lateral brow ptosis, many people have addi-tional folds and creases of the lower eyelids, which give them the appearance of being tired, sleep deprived, or even older than their cur-rent age. These “festoons” or “jelly rolls” are produced by a hyperkinetic palpebral (preseptal portion of the) orbicularis oculi and some degree of skin laxity and blepharochalasis ( Fig. 3.130A,B ). They also help

Treatment Implications when injecting the Lateral Eyebrows

1. Injecting 4 to 6 U of onabotulinumtoxinA in the upper lateral

eyebrow temporarily produces a lateral brow lift, increases the

vertical palpebral aperture, and corrects lateral canthal hooding

in older patients.

2. Injections must be performed intradermally over the tail of the eye-

brow; otherwise, the lacrimal gland will be affected and xerophthal-

mia may occur. Raising a wheal confi rms a superfi cial injection.

3. Before injecting onabotulinumtoxinA intradermally, have

patients raise their eyebrows elevating the lower fi bers of the

frontalis to uncover the upper fi bers of the orbital orbicularis

oculi in the vicinity of the lateral eyebrows.

4. Accurate dosing and precise superfi cial injection technique will

avoid diffusion of onabotulinumtoxinA into the lower frontalis

and the exacerbation of lateral orbital hooding.

5. Upper lateral orbicularis oculi injections placed intradermally

and along the superciliary arch but lateral to the mid papillary

line will diminish the skin corrugations of the lateral brow seen

in some patients.

6. Maintaining the strength of the lower lateral fi bers of the fronta-

lis and prevent worsening of lateral orbital hooding by injecting

onabotulinumtoxinA intradermally and 1.5 to 2.5 cm above the

bony orbital rim along the superciliary arch. Prevent a Mephisto

or “Mr. Spock” look by injecting onabotulinumtoxinA intramus-

cularly into the lowers fi bers of the frontalis, 2.5 to 3.5cm above

the lateral bony orbit.

7. In patients with excessive skin laxity (dermatochalasis) in the lateral

brow and lower forehead, injections of onabotulinumtoxinA may

not satisfactorily lift the lateral brow and relieve brow hooding.

create the appearance of “dark circles” and baggy eyes that women and even men would prefer not to have. Likewise, a tired, disinterested, downtrodden, and unambitious demeanor is projected when the pal-pebral aperture is narrowed because of a hyperfunctional pretarsal orbicularis oculi. Various facial movements, primarily smiling or laughing, also will narrow momentarily the palpebral aperture. Injec-tions of onabotulinumtoxinA in the lower palpebral orbicularis oculi will reduce excess wrinkling, widen the ocular aperture, and produce a more youthful, happy, and overall pleasant appearance.

Functional Anatomy (see Appendix 1) The orbicularis oculi helps protect the eyes from bright light, gusts of air, and fast flying projectiles. Those working outdoors or in a brightly lit environment automatically maintain their orbicularis oculi in a constant hyperkinetic state of partial closure, that is, they are continu-ously squinting. This can cause the muscle fibers of the orbicularis oculi to hypertrophy. In younger patients, hypertrophic palpebral orbi-cularis oculi can be observed as producing additional periocular folds, and are sometimes referred to as ‘jelly rolls,’ especially in the vicinity of the lower eyelid ( Fig. 3.130A,B ). These lower eyelid folds can be dimin-ished by onabotulinumtoxinA ( Fig. 3.131A–D ). In older patients, how-ever, the skin of the eyelids becomes thin, redundant, and inelastic. The orbital septum attenuates, becoming less effective. Because of a weak-ening of this anatomical bulwark, the inferior periorbital fat bulges from behind the preseptal orbicularis oculi and creates characteristic suborbital “festoons” ( Fig. 3.132A,B ). OnabotulinumtoxinA injections of the already weakened and incompetent preseptal orbicularis oculi invariably will enlarge this type of suborbital festooning, and therefore should not be performed ( 64 ).

A major function of the palpebral portion of the orbicularis oculi is its sphincteric blinking action, which aids in the maintenance of corneal moisture. It accomplishes this with each blink of the eye, which distributes over the anterior surface of the globe the drops of tears that are secreted from the main and accessory lacrimal glands ( Fig. 3.133 ). Opening and shutting the eyes activates the so-called lacrimal pump, shunting the secreted tears through the canalicular system into the lacrimal sac and down the nasolacrimal duct, where the accumulated fluid from the tears is then released into the nasal cavity from the inferior meatus under the inferior nasal turbinate. As the secreted tears flow from the lacrimal glands in the upper lateral aspect of the orbit, they collect in the lower medial corner of the orbit to form the lacrimal lake. With the eyelids open, the lacrimal portion of the orbicularis oculi compresses the lacrimal sac and positions the

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 89

Figure 3.131 (A) Left lower eyelid of a 42-year-old woman at rest and before 2 U of onabotulinumtoxinA were injected in the middle of the left lower eyelid. (B) Same patient at rest 3 weeks after onabotulinumtoxinA. (C) Same patient smiling before 2 U of onabotulinumtoxinA were injected in the middle of the left lower eyelid. (D) Same patient smiling 3 weeks after onabotulinumtoxinA.

2

2

(A) (B)

(C) (D)

patulous punctum in direct contact with the globe and the lacrimal lake. This allows the tears to flow into and through the patent cana-liculi. Contracting the superficial fibers of the pretarsal orbicularis oculi shuts the eyelids and distributes the tears over the anterior sur-face of the globe from a superior lateral to an inferior medial direc-tion. Opening the eyes again causes the deep fibers of the pretarsal orbicularis oculi to contract, shutting down the upper and lower canalicular system. Contemporaneously, the deep fibers of the prese-ptal orbicularis oculi pull on the lateral walls of the lacrimal sac,

Figure 3.132 (A) This 64-year-old woman has thinning of the preseptal orbicularis oculi, which is seen as festoons of the lower eyelids. (B) Same patient squinting causes the orbital and palpebral portions of the orbicularis oculi to contract. Injections of onabotulinumtoxinA in the lower eyelid will make the orbicularis oculi incompetent at rest and intensify her festooning and wrinkles with squinting. Therefore, onabotulinumtoxinA injections in this patient in the lower eyelids should not be performed.

(A) (B)

enlarging its lumen and contributing to the negative pressure gradi-ent within the nasolacrimal canalicular system, which causes the tears to be aspirated into the lacrimal sac ( Fig. 3.133 ). Upon reopening the eyelids, the positive pressure within the canalicular system is recre-ated and the lacrimal sac collapses, propelling the tears into the naso-lacrimal duct, then through the inferior meatus and into the nasal cavity. Simultaneously, the puncta and canaliculi reopen to collect more tears from the lacrimal lake and the process recycles with each opening and shutting of the eyelids.

90 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) Appropriate candidates for onabotulinumtoxinA treatment of the lower eyelids are those who have normal eyelid elasticity, determined by a normal snap test. Individuals who have not had any previous lower eyelid surgery, including blepharoplasty or some form of resur-facing, either by laser or chemical peeling usually display a normal snap test. To perform a lower eyelid snap test, grasp the skin of the lower eyelid between the thumb and index finger. Gently pull the lid away from the globe and then release it. If the eyelid recoils immedi-ately back against the globe, the snap test indicates that the eyelid’s elasticity is ostensibly normal, and it can be treated with injections of onabotulinumtoxinA. If the recoil is sluggish, indicating insufficient elasticity of eyelid skin, then the patient’s lower eyelids should not be injected with onabotulinumtoxinA, because the probability of post-injection ectropion is high.

Another way to test the competency of the lower palpebral orbicu-laris oculi is to have the patient look forward in a relaxed manner and then gaze upward. If the lower eyelid flattens and pushes the periorbital fat inward, the preseptal orbicularis oculi is competent, tight, and can be treated with onabotulinumtoxinA. If the lower eyelid bulge of fat

becomes more pronounced and projects even farther anteriorly, then the lower preseptal orbicularis oculi is probably weak and incompetent and injections of onabotulinumtoxinA will only exacerbate the fes-tooning of the lower eyelids.

The patient should be looking directly forward in a sitting or a semireclined position for the injections. To prevent frightening the patient with the sight of the needle, the physician should approach the patient from the side and stand on the same side of the patient directly adjacent to the lower eyelid to be treated. As the injector approaches the patient with the needle, the patient should be asked to gaze directly upward and to take a deep breath without moving. Contemporane-ously, the physician pulls the lower eyelid skin inferiorly with the index finger of the nondominant hand. The syringe barrel rests on the index finger while the needle tip is inserted at about a 45° angle into the pretarsal skin at a point 2 to 3 mm from the lower lid margin and 1 to 2mm lateral to the midpupillary line. The needle tip then is advanced approximately 2 to 3 mm deep through the skin. It should remain at the depth of the lower dermis and not be advanced any deeper than the dermal/subcutaneous interface ( Fig. 3.134A ). Even as the needle tip is advanced 2 to 3 mm within the skin, it should remain in its superficial position just lateral to the midpupillary line. When the tip of the needle is through the skin and has reached its proper depth and location lateral to the midpupillary line, an injection of 2 U (i.e., 0.02 ml) of onabotulinumtoxinA is given and will remain within the thin eyelid tissue and not leak through or track out along the path of the needle puncture. The injector should observe the rise of a wheal of fluid, which should reassure the physician that an adequate dose of onabotulinumtoxinA has been delivered ( Fig. 3.134B,C ). No addi-tional drops of onabotulinumtoxinA should escape from the needle as it is withdrawn out of the skin, provided there is no air within the bar-rel of the syringe. Air within the syringe causes a positive pressure gra-dient inside the barrel, forcing fluid out of the needle, even without any digital pressure on the plunger of the syringe ( Fig. 3.134D ).

Figure 3.133 Tears are produced by main and accessory lacrimal glands (1). The distribution of these tears over the surface of the eye is achieved by movements of the eyelids performing a squeegee action (2) of the marginal tear bead shown here in optical cross-section by a slit lamp beam. The passage of tears into the nose occurs via the lacrimal drain-age system (3). a, lacrimal lake; b, puncta; c, canaliculi; d, lacrimal sac; e, nasolacrimal duct; f, inferior meatus; g, turbinates. Source : Reproduced with permission from Zide B, Jelks G, eds. Surgical Anatomy, Philadelphia: Lippincott, 1985; 34.

1

2

3

a

b c

d

f

gg

g

b

e

Frontal boneOrbital part oflacrimal gland

Palpebral part oflacrimal gland

Excretory ducts oflacrimal gland

Plica semilunarisand lacrimal lake

Lacrimal caruncle

Inferior lacrimal papilla and punctum

Opening of nasolacrimal duct

Superior lacrimal papilla and punctum

Lacrimal canaliculiLacrimal sac

Nasolacrimal duct

Middle nasalconcha

Nasal cavity

Inferior nasalconchaInferior nasal meatus

Dilution (see Appendix 2)

When treating the periorbital area with onabotulinumtoxinA it

is imperative to be accurate with dosing and precise with injecting

minimal volumes of onabotulinumtoxinA. Therefore, a 100 U vial

of onabotulinumtoxinA should be reconstituted with only 1 ml of

normal saline (see Appendix 1).

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 91

Figure 3.134 (A) Technique of injecting the lower eyelid with onabotulinumtoxinA. Note the index finger of the nondominant hand pulling down on the skin of the lower eyelid making it taut. The needle tip is inserted at a 45° angle, and 2–3mm down from the lid margin and approximately 2–3mm deep within the deep dermal to subcutaneous layer. (B) Note the appearance of the wheal of onabotulinumtoxinA in the same patient. (C) The appearance of a wheal indicates that the bolus of onabotulinumtoxinA has been delivered successfully and at the correct depth. (D) A microdroplet of air within the syringe wastes a drop of onabotulinumtoxinA as it escapes out of the tip of the needle and onto the surface of the skin upon withdrawing the needle out of the skin.

(A) (B)

(C) (D)

Delicate massage of the injected area directed laterally will distract the patient and help disperse the onabotulinumtoxinA safely along the superficial fibers of the palpebral orbicularis oculi. When this tech-nique is executed in a calm and expeditious manner, the patient will not cower away from the needle pointed directly at his or her eye, and s/he may even compliment the physician on the painless fashion and ease with which the treatment was executed. An additional 1 to 2 U of onabotulinumtoxinA can be injected intradermally or at the dermal/subcutaneous interface and approximately 2 to 3 mm below the lid margin, at a point halfway from the lateral canthus and the midpupil-lary line ( Fig. 3.135 ) ( 61 , 62 ). For most patients this second injection in the lower eyelid is superfluous and not necessary. It may even lead to a lateral lower lid ectropion and other annoying adverse sequelae (Fig. 3.103).

Outcomes (Results) (see Appendix 4) It was discovered serendipitously that an injection of 2 to 4 U of ona-botulinumtoxinA placed subcutaneously in the pretarsal orbicularis oculi of the lower eyelid at the midpupillary line, approximately 2 to 3 mm below the lid margin, can improve the rolls of festooning redun-dant skin that occur on and just inferior to the lower eyelid ( Figs. 3.130A,B and 3.131A–D ) ( 72 ). Pretarsal injections of onabotulinum-toxinA in the lower eyelid also were found to produce a desirable

relaxation of the pretarsal orbicularis oculi, which consequently increased the palpebral aperture both at rest and during smiling, laugh-ing, and various other facial movements. The extent of the increase in palpebral aperture was dependent upon the amount of units injected pretarsally and whether or not crow’s feet were treated at the same time. For those patients who were treated with only 2 U of onabotu-linumtoxinA injected in only one site in the lower lid at the pretarsal midpupillary line, the average increase in palpebral aperture (IPA) was approximately 0.5 mm at rest and 1.3 mm at full smile ( Fig. 3.135 ). When combined with a fixed dose of 12U of onabotulinumtoxinA given in three separate doses 1.5 mm apart at the lateral canthus to treat concomitant crow’s feet, the average IPA was approximately 1.75 mm at rest and 2.9 mm at full smile ( Table 3.1 ). When 4 U of onabotu-linumtoxinA were injected pretarsally into the lower eyelid at two sepa-rate sites, equally positioned from the lateral canthus and the midpupillary line ( Fig. 3.135 ), the average IPA was approximately 1.75 mm at rest and 2.5 mm at full smile. When 2 U of onabotulinum-toxinA were injected pretarsally into the lower eyelid at two separate sites (total of 4 U) equally positioned, one at the midpupillary line (A1 in Fig. 3.135 ), the other midway from the midpupillary line and the lateral canthus (A2 in Fig. 3.135 ) in conjunction with treating the crow’s feet with 4 U of onabotulinumtoxinA injected in the lateral can-thus at three sites each equally spaced (total of 12 U), the average IPA at

92 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

rest was approximately 2.2 mm and 2.9 mm at full smile. When 8 U of onabotulinumtoxinA were injected pretarsally in the lower eyelid at two separate sites in the same manner that the 4U of onabotulinum-toxinA were given (A1 and A2 in Fig. 3.135 ), the average IPA was approximately 1.95 mm at rest and approximately 4.5 mm in full smile. When the 8 U of onabotulinumtoxinA were injected pretarsally into the lower eyelid at the two separate sites as above (A1 and A2 in Fig. 3.135 ) and in conjunction with treating the crow’s feet with 12 U of onabotulinumtoxinA injected in three equal (4 U) doses in the lateral

Table 3.1 Increase in Palpebral Aperture (IPA) at Rest and at Full Smile

Pretarsal area treated alone

Pretarsal area treated together with crow’s feet (12 U of

onabotulinumtoxinA)

OnabotulinumtoxinA

units

2 U 4 U 8 U 2 U 4 U 8 U

IPA at rest (mm) 0.5 1.75 1.95 1.75 2.2 1.5IPA at full smile

(mm)

1.3 2.5 4.5 2.9 2.9 4.0

Source : From Ref. 72.

Figure 3.135 When treating the lower eyelid folds and festoons, one (A1) injection at the midpupillary line or a second (A2) injection halfway between the midpupillary line and the lateral canthus can be performed depending on the strength of the palpebral orbicularis oculi and the depth of the folds. Additional injections (●) of onabotulinum-toxinA may be needed to treat crow’s feet, the dosage of which will depend on the strength of the lateral orbital orbicularis oculi.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

A1 A2

canthus ( Fig. 3.135 ), the average IPA was approximately 1.5 mm at rest and 4.0 mm at full smile. Interestingly, there appeared to be a synergis-tic effect to the response of the lower pretarsal orbicularis oculi when the lateral orbital orbicularis oculi was contemporaneously treated during the same session. This technique of injecting the pretarsal orbi-cularis oculi produces an “open-eyed look” that gives the patient the appearance of one who is vibrantly active and cheerfully youthful ( Fig. 3.136 ).

In most cases, the second intermediary injection of onabotulinum-toxinA between the lateral canthus and midpupillary line is not always necessary (A2 in Fig. 3.135 ). It may even increase the chance for lateral canthal rounding and lower eyelid ectropion ( Fig. 3.104A,B ). This technique of injecting the lower eyelids with ona-botulinumtoxinA also has been surprisingly popular among Asian patients who desire a more rounded, Western eyelid aperature ( 66 , 72 , 73 ).

Complications (Adverse Sequelae) (see Appendix 5) Rounding of the lateral canthus can be produced by excessively weaken-ing either the upper or lower, or both, pretarsal orbicularis oculi. Inject-ing crow’s feet at least 1.0 to 1.5 cm lateral to the lateral canthus also can help avoid such an unwanted outcome. The second intermediate injection of the lower pretarsal orbicularis oculi (A2 in Fig. 3.135 ) also has been found to cause rounding of the lateral canthus and ectropion of the adjacent lateral aspect of the lower lid margin, especially when a full treatment of onabotulinumtoxinA is injected into the adjacent

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 93

Figure 3.136 (A) This 56-year-old patient seen before and (B) after 2 U of onabotulinumtoxinA was injected into the lower eyelid at the midpupillary line 2–3 mm from the lid margin.

22

2

2

(A) (B)

Figure 3.137 Upper lip levators.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

94 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.139 (A) A 49-year-old patient at rest before and 3 weeks after onabotulinumtoxinA treatment of the lower eyelids. (B) Same patient at rest before and 3 weeks after onabotulinumtoxinA treatment of the lower eyelids seen from the left side. (C) Same patient at rest before and 3 weeks after onabotulinumtoxinA treatment of the lower eyelids seen from the right side.

2 2

(A)

(B)

(C)

Figure 3.138 Two days after 2 U of onabotulinumtoxinA were injected in both lower eyelids for the first time in this 53-year-old woman. The ecchymosis in the right eye-lid lasted for about 10 days.

upper and lower crow’s feet area ( Fig. 3.103A,B ). Therefore, unless the patient has recalcitrant lower eyelid festoons that wrap around the lateral canthus and are continuous with deep and resistant lateral can-thal lines, this second (A2 in Fig. 3.135 ), intermediate, lateral pretarsal injection of onabotulinumtoxinA should be withheld, and only the central pretarsal injection of the lower eyelid at the midpupillary line should be given (A1 in Fig. 3.135 ).

It is imperative that the pretarsal injections be placed into the deep dermis, barely reaching the subcutaneous tissue, and nowhere near the bony malar prominence, since most of the upper lip levators originate along the margin of the zygomatic arch ( Fig. 3.137 ). Otherwise, upper lip ptosis, asymmetry, and even sphincter incompetence of the upper lip can result, because the levators of the lateral aspect of the upper lip (zygomaticus major and levator anguli oris) and even the levators of the central aspect of the upper

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 95

Figure 3.140 (A) A 68-year-old patient at rest before and 5 weeks after onabotulinumtoxinA treatment of the lower eyelids and 1 month after superficial CO2 fractionated laser

ablation. (B) Same patient at rest before and 5 weeks after onabotulinumtoxinA treatment of the lower eyelids and 1 month after superficial CO2 fractionated laser ablation seen

from the left side. (C) Same patinet at rest before and 5 weeks after onabotulinumtoxinA treatment of the lower eyelids and 1 month after superficial CO2 fractionated laser

ablation seen from the right side.

2 2

(A)

(B)

(C)

lip (levator labii superioris, zygomaticus minor, and levator labii superioris alaeque nasi) can be weakened by diffusion of onabotulinumtoxinA.

Injecting onabotulinumtoxinA medial to the midpupillary line of the lower eyelid runs the risk of weakening the intentional and

involuntary sphincteric function of the palpebral orbicularis oculi, which would compromise forced eyelid closure and the blink reflex. This in turn could both diminish the action of the lacrimal pump and cause temporary epiphora ( 35 , 66 ) or even result in xerophthalmia because of supervening lagophthalmos and corneal exposure. This can

96 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 3.141 (A) A 38-year-old patient at rest before and 1 month after onabotulinumtoxinA treatment of the lower eyelids. (B) Same patient at rest before and 1 month after onabotulinumtoxinA treatment of the lower eyelids seen from the right side. (C) Same patient at rest before and 1 month after onabotulinumtoxinA treatment of the lower eyelids seen from the left side. Crow’s feet were also treated.

2 2

(A)

(B)

(C)

Figure 3.142 A 47-year-old patient at rest before and 2 weeks after onabotulinumtoxinA treatment of the lower eyelids and crow’s feet seen from the left side.

2

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 97

Figure 3.143 A 56-year-old patient at rest and 3 weeks after 2 U of onabotulinumtoxinA was injected into the lower eyelid at the midpupillary line 2–3 mm from the lid margin and 6 U of onabotulinumtoxinA for crow’s feet. Note the wide eyed look.

23

3

Figure 3.144 (A) This 58-year-old patient is shown at rest and forward gazing before and (B) 3 weeks after onabotulinumtoxinA injection of the lower lid and crow’s feet. Note the reduction of the lower lid festoons.

2

22

2

(A) (B)

Figure 3.145 This 42-year-old patient is shown at rest and forward gazing before and 3 weeks after onabotulinumtoxinA injection of the lower lid. Note the reduction in the lower eyelid wrinkling.

AfterBefore

occur more readily in older patients who have attenuated muscular strength and a thinned orbital septum.

Postinjection ecchymoses are practically inevitable whenever thin eyelid skin is injected ( Fig. 3.138 ). The use of a small insulin syringe with a fine needle (Becton-Dickinson U-100 Insulin 3/10 syringe with

a 31-gauge needle) and a slow, intradermal injection technique may help prevent or limit the extent of postinjection ecchymoses. Other maneuvers at preventing bruising include, pre- and posttreatment icing, ample overhead lighting, a slight stretch to the skin over the area to be treated and postinjection gentle massage and point pressure with

98 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

ice. Patients with fragile vasculature, as is commonly seen in older indi-viduals, contribute to the inevitability of frequently occurring lower eyelid ecchymoses, which should resolve in a few (approximately 10–15) days.

Pseudoherniation of the infraorbital fat pad can be enhanced when onabotulinumtoxinA is injected into the inferior palpebral (preseptal) orbicularis oculi in patients who have festooning caused by protruding periorbital fat in inelastic, incompetent lower eyelids. A worsening of pseudoherniation by onabotulinumtoxinA is easy to produce, particu-larly in older patients or in patients who have had a blepharoplasty or other type of lower eyelid surgery in the past, because the sling-like support of their preseptal orbicularis oculi is weak and ineffective ( Fig. 3.132A,B ). Injections of onabotulinumtoxinA in the inferior preseptal, inferolateral canthal, and superior malar areas of patients with lax lower eyelid skin can compromise further the integral strength of the orbicularis oculi, accentuating the infraorbital festoons, instead of reducing them ( 68 ). Lower eyelid injections of onabotulinumtoxinA in such individuals should not be performed ( 64 ).

In their dose-defining studies, Flynn et al. found no substantial adverse events in the patients treated with 2 U of onabotulinumtox-inA injected at one site pretarsally in the lower eyelid ( Fig. 3.135 ). In those patients who had 4 U of onabotulinumtoxinA injected pretar-sally in two divided doses of 2 U each (A1 and A2 in Fig. 3.135 ), less than half of them suffered from “dry eyes” and one patient could not wear her contact lenses ( 73 ). There were additional, temporary adverse events that were more of an annoyance than a serious complication and they occurred after 8 U of onabotulinumtoxinA were injected pretarsally in two divided doses of 4 U each into the lower eyelid (A1 and A2 in Fig. 3.135 ). These untoward side effects included transient lower eyelid edema, which gave the patient an increasing sense of lower eyelid fullness, persistently “dropped bags,” and a sensation of puffy lower eyelids, which became worse toward the end of the day ( 73 ). Also, there were patients who developed photophobia, and who were unable to go outdoors in bright light because they had difficulty with squinting and could not protect their eyes from sunlight. Still others were bothered by incomplete sphincteric eyelid closure, which caused stinging of their eyes when they washed their faces with or without soap. All of these annoyances remitted within 3 months from the time the 8 U of onabotulinumtoxinA were injected into the two sites in the mid and lateral aspects of the pretarsal orbicularis oculi of their lower eyelids.

Figures 3.139 – 3.146 are some examples of different patients treated with onabotulinumtoxinA for folds and creases of the lower lids.

Figure 3.146 (A) This 42-year-old patient is shown at rest and forward gazing before and (B) 3 weeks after an onabotulinumtoxinA injection of the right lower lid. Note the wide eyed open look.

2

22

2

(A) (B)

Treatment Implications When Injecting the Lower Eyelids

1. Lower eyelid injections of onabotulinumtoxinA produce a

“wide-eyed,” youthful appearance.

2. Inject only 1 to 3 U and no more than 4 U of onabotulinum-

toxinA intradermally or into the dermal/subcutaneous interface

2 to 3 mm inferior to the lid margin into the pretarsal orbicularis

oculi 1 to 2 mm lateral to the midpupillary line.

3. Pretarsal injections of onabotulinumtoxinA at the intermedi-

ate point between the lateral canthus and the midpupillary line

increases the risk for lower eyelid ectropion, a rounded lateral

canthus, epiphora, and various other adverse sequelae.

4. Pretarsal injections of onabotulinumtoxinA in the lower eyelid

medial to the midpupillary line may cause epiphora by weaken-

ing the blink refl ex, or dry eyes by creating persistent lagophthal-

mos and corneal exposure.

5. Deep injections of onabotulinumtoxinA lower than 3 to 4 mm

from the lower eyelid margin can result in lip asymmetry and

cheek ptosis because of upper lip levator weakening.

6. Low-volume, highly concentrated injections of low doses of ona-

botulinumtoxinA are recommended when injecting the superfi -

cial fi bers of the lower pretarsal or preseptal orbicularis oculi.

7. Anyone who has had other periorbital cosmetic procedures and

who has a sluggish snap test should not be treated with onabotu-

linumtoxinA injections in the lower pretarsal or preseptal orbi-

cularis oculi.

REFERENCES 1. Lowe NJ, Yamauchi PS, Lask GP, et al. Botulinum toxins types A

and B for brow furrows: preliminary experiences with type B toxin dosing. J Cosmet Laser Ther 2002; 4: 15–18.

2. Karsai, S, Raulin C. Current evidence on the unit equivalence of dif-ferent botulinum neurotoxin A formulations and recommendations for clinical practice in dermatology. Dermatol Surg 2009; 35: 1–8.

3. Carruthers JDA, Glogau RG, Blitzer A, et al. Advances in facial reju-venation: Botulinum toxin type A, hyaluronic acid dermal fillers, and combination therapies: consensus recommendations. Supple-ment to Plastic Reconstr Surg 2008; 121: 5S–30S.

COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE 99

4. Carruthers A, Carruthers J. Botulinum toxin type A: history and current cosmetic use in the upper face. Semin Cutan Med Surg 2001; 20: 71–84.

5. Fulton JE. Botulinum toxin. The Newport Beach experience. Der-matol Surg 1998; 24: 1219–24.

6. Carruthers A, Carruthers J. The treatment of glabellar furrow with botulinum A exotoxin. Dermatol Surg Oncol 1990; 16: 83.

7. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. Dermatol Surg Oncol 1992; 18: 17–21.

8. Blitzer A, Brin MF, Keen MS, Aviv JE. Botulinum toxin for the treatment of hyperfunctional lines of the face. Arch Otolaryngol Head Neck Surg 1993; 119: 1018–22.

9. Carruthers JD, Lowe NJ, Menter MA, et al. Double-blind, placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines. Plast Reconstr Surg 2003; 112: 1089–98.

10. Hankins CL, Strimling R, Rogers GS. Botulinum A toxin for glabel-lar wrinkles: dose and response. Dermatol Surg 1998; 24: 1181–3.

11. Carruthers A, Carruthers J, Cohen J. Dilution volume of botuli-num toxin type A for the treatment of glabellar rhytides: does it matter? Dermatolog Surg 2007; 33: S97–S104.

12. Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabel-lar folds; a double-blind, placebo-controlled study with a electro-myographic injection technique. Am Acad Dermatol 1996; 35: 569–72.

13. Pribitkin EA, Greco TM, Goode RL, Keane WM. Patient selection in the treatment of glabellar wrinkles with botulinum toxin type A injection. Arch Otolaryngol Head Neck Surg 1997; 123: 321–6.

14. Alam M, Dover JS, Klein AW, Arndt KA. Botulinum A exotoxin for hyperfunctional facial lines: where not to inject. Arch Dermatol 2002; 138: 1180–5.

15. Angres, GG. Blepharopigmentation and eyebrow enhancement techniques for maximum cosmetic results. Ann Ophthalmol 1985, 17: 605.

16. Gunter JP, Antrobus SD. Aesthetic analysis of the eyebrows. Plast Reconst Surg 1997; 99(7): 1808–16.

17. Basic Eyebrows Tutorial. [Available from: http://ricebunny.xanga.com/611662957/basic-eyebrows-tutorial/] (accessed June 14, 2010).

18. Baker SB, Dayan JH, Crane A, Kim S. The influence of brow shape on the perception of facial form and brow aesthetics. Plast Recon-str Surg 2007; 119(7): 2240–7.

19. Roth JM, Metzinger SE. Quantifying the arch position of the female eyebrow. Arch Facial Plast Surg 2003; 5: 235–9.

20. Trindade de Almeida ART. Patterns of glabellar contraction: a pre-liminary report. Surg Cosmet Dermatol 2010; 2(1): 23–8.

21. Benedetto AV, Lahti JG. Measurements of the anatomical position of the corrugator supercilii. Dermatol Surg 2005; 31: 923–7.

22. Wieder JM, Moy RL. Understanding botulinum toxin. Surgical anatomy of the frown, forehead, and periocular region. Dermatol Surg 1998; 24: 1172–4.

23. Macdonald MR, Spiegel J, Raven RB et al. An anatomical approach to glabellar rhytides. Arch Otolaryngol Head Neck Surg 1998; 124: 1315–20.

24. Ingallina F, Trévidic P. Anatomy and Botulinum Toxin Injections. E2E Medical Publishing, 2010. Available at www.expert2expert.co.uk.

25. Cook Jr. BE, Lucarelli MJ, Lemke BN. Depressor supercilii muscle: anatomy, histology, and cosmetic implications. Opthalmic PIast Reconstr Surg 2001; 17: 404–11.

26. Patrinely JR, Anderson RL. Anatomy of the orbicularis oculi and other facial muscles. In: Jankovic J, Tolosa E, eds. Facial Dyskinesias (Advances in Neurology, Vol. 49). New York: Raven Press, 1988.

27. Botox Cosmetic [package insert]. Irvine, CA: Allergan, 2009. 28. Alam M, Dover JS, Arndt KA. Pain associated with injection of

botulinum A exotoxin reconstituted using isotonic sodium chloride with and with out preservative: a double-blind, random-ized controlled trial. Arch Dermatol 2002; 138: 510–14.

29. Klein AW, Mantell A. Electromyographic guidance in injecting botulinum toxin. Dermatol Surg 1998; 24: 1184–6.

30. Jankivic, J. Needle EMG guidance for injection of botulinum toxin: needle EMG guidance is rarely required. Muslce Nerve 2001: 24; 1568.

31. Blitzer A, Binder WJ, Aviv JE. The management of hyperfunctional facial lines with botulinum toxin: a collaborative study of 210 injec-tion sites in 162 patients. Arch Otolaryngol Head Neck Surg 1997; 123: 389–92.

32. Fagien S. Botulinum toxin type A for facial aesthetic enhancement: role in facial shaping. Plast Reconstr Surg 2003; 112: 6S–18S.

33. Binder WJ, Blitzer A, Brin MF. Treatment of hyperfunctional lines of the face with botulinum toxin A. Dermatol Surg 1998; 24: 1198–205.

34. Carruthers J, Fagien S, Matarasso SV, et al. Consensus recommen-dations on the use of botulinum toxin type A in facial aesthetics. Supplement to Plastic Reconstr Surg 2004; 114: 1S–18S.

35. Carruthers A, Carruthers J. Botulinum A exotoxin in clinical oph-thalmology. Can J Ophthalmol 1996; 30: 389–400.

36. Carruthers J, Carruthers A. Prospective, double-blind, random-ized, parallel-group, dose-ranging study of botulinum toxin type A in men with glabellar rhytides. Dermatol Surg 2005; 31: 1297–1303.

37. Benedetto AV. The cosmetic uses of botulinum toxin type A. Int J Dermatol 1999; 38: 641–55.

38. Fagien S, Raspaldo H. Facial rejuvenation with botulinum neuro-toxin: an anatomical and experiential perspective. Cosmet Laser Ther 2007; 9(suppl 1): 23–31.

39. Rzany B, Aschner B, Fratila A, et al. Efficacy and safety of 3- and 5-injection patterns (30 and 50 U) of botulinum toxin A (Dysport) for the treatment of wrinkles in the glabella and the central forehead region. Arch Derm 2006: 142; 320–6.

40. Gassia V. Botulinum toxin A in the treatment of the wrinkles in the upper third of the face. Ann Dermatol Venereol 2008: 135; S175–S180.

41. Huang W, Rogachefsky AS, Foster JA. Browlift with botulinum toxin. Dermatol Surg 2000; 26: 55–60.

42. Frankel AS, Kamer FM. Chemical browlift. Arch Otolaryngol Head Neck Surg 1998; 124: 321–3.

43. Ahn MS, Cotton M, Maas CS. Temporal browlift using botulinum toxin A. Plast Reconstr Surg 2000; 105: 1129–35.

44. Carruthers A, Carruthers J. Clinical indications and injection tech-nique for the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998; 24: 1189–94.

45. Fagien S. Temporary management of upper lip ptosis, lid malposi-tion, and eyelid fissure asymmetry with botulinum toxin type A. Plast Reconstr Surg 2004; 114: 1892–902.

46. Northington ME, Huang CC. Dry eyes and superficial punctuate keratitis: a complication of treatment of glabellar dynamic rhytides with botulinum exotoxin A. Dermatol Surg 2004; 30: 1515–17.

47. Fagien S. Botox for the treatment of dynamic and hyperkinetic facial lines and furrows; adjunctive use in facial aesthetic surgery. Plast Reconstr Surg 1999; 103: 701–13.

48. Fagien S. Botulinum toxin type A for facial aesthetic enhancement: role in facial shaping. Plast Reconstr Surg 2003; 112 (Supple 5): 6S–18S.

49. Alam M, Arndt KA, Dover JS. Severe, intractable headache follow-ing injection with botulinum A exotoxin. J Am Acad Dermatol 2002; 46: 62–5.

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50. Hsu TS, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A. Arch Dermatol 2004; 140: 1351–4.

51. Carruthers A, Carruthers J, Cohen J. A prospective, double-blind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dematol Surg 2003; 29: 461–7.

52. Flynn TC, Clark RE. Botulinum toxin type B (Myobloc) versus botulinum toxin type A (Botox) frontalis study: rate of onset and radius of diffusion. Dermatol Surg 2003; 29: 519–22.

53. Rohrich RJ, Janis JE, Fagien S, Stuzin JM. The cosmetic use of bot-ulinum toxin. Plast Reconstr Surg 2003; 112; 117S–187S.

54. Le Louarn C. Botulinum toxin A and facial lines: the variable con-centration. Aesth Plast Surg 2001; 25: 73–84.

55. Ozsoy Z, Genc B, Gozu A. A new technique applying botulinum toxin in narrow and wide foreheads. Aesth Plast Surg 2005; 39: 368–72.

56. Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon 2002; 48: 336–56.

57. Klein AW. Dilution and storage of botulinum toxin. Dermatol Surg 1998; 24: 1179–80.

58. Lowe NJ, Lask G, Yamanchi P, et al. Bilateral, double-blind, ran-domized comparison of three doses of botulinum toxin type A and placebo in patient’s with crow’s feet. J Am Acad Dermatol 2002; 47: 834–40.

59. Guerrissi JO. Intraoperative injection of botulinum toxin A into the orbicularis oculi muscle for the treatment of crow’s feet. Plast Reconstr Surg 2003; 112(5 Suppl): 161S–163S.

60. Matarasso A, Glassman M. Effective use of Botox for lateral canthal rhytides. Aesth Surg 2001; 21: 61.

61. Matarasso SL. Comparison of botulinum toxin types A and B: bilateral and double-blind randomized evaluation in the treatment of canthal ryytides. Dermatol Surg 2003; 29: 7–13.

62. Kane MA. Classification of crow’s feet patterns among Caucasian women: the key to individualizing treatment. Plast Reconstr Surg 2003; 112: 33S–39S.

63. Matarasso SL, Matarasso A. Treatment guidelines for botulinum toxin type A for the periocular region and a report on partial upper lip ptosis following injections to the lateral canthal rhytides. Plast Reconstr Surg 2001; 108: 208.

64. Goldman M. Festoon formation after intraorbital botulinum A toxin: a case report. Dermatol Surg 2003; 29: 560–1.

65. Matarasso SL, Matarasso A. “M” marks the spot: update on treat-ment guidelines for botulinum toxin type A for the periocular area. Plast Reconstr Surg 2003; 112: 1470–72.

66. Yamauchi P, Lask G, Lowe NJ. Botulinum toxin type A gives adjunctive benefit to periorbital laser resurfacing. J Cosmet Laser Ther 2004; 6(3): 145–48.

67. Kadunc BV. Periorbital wrinkles. In: Hexsel D, Almeida AT de (eds) Cosmetic Use of Botulinum Toxin. Porto Alegre, Brazil: AGE Editora, 2002: 149–54.

68. Frankel AS. BOTOX for rejuvenation of the periorbital region. Facial Plast Surg 1999; 15: 255–62.

69. Huigol SC, Carruthers A, Carruthers J. Raising eyebrows with bot-ulinum toxin. Dermatol Surg 1999; 25: 373–5.

70. Chen AH, Frankel AS. Altering brow contour with botulinum toxin. Facial Plast Surg Clin N Am 2003; II: 457–64.

71. Matarasso SL. Complications of botulinum A exotoxin for hyper-funtional lines. Dermatol Surg 1998; 24: 1249–54.

72. Flynn TC, Carruthers J, Carruthers A. Botulinum A toxin treat-ment of the lower eyelids improves infraorbital rhytides and wid-ens the eye. Dermatol Surg 2001; 27: 703–8.

73. Flynn TC, Carruthers JA, Clark RE. Botulinum A toxin (BOTOX) in the lower eyelid: dose-finding study Dermatol Surg 2003; 29: 943–50 .

101

and indistinct borders, the mid and lower facial musculature should be treated with lower doses of onabotulinumtoxinA to gently weaken their activity and prevent diffusion. Wrinkles in the mid and lower face tend to be more static in nature as compared to those in the upper face, which are more dynamic in origin ( 3 , 4 ). Particularly in the mid face, wrinkles develop and are enhanced because of photodamage, volume loss, and soft tissue shifting ( 5 ). This is one of the reasons why deep longstanding wrinkles and furrows in the mid and lower face on many occasions cannot be totally effaced, no matter how much ona-botulinumtoxinA is used. Persistent treatments with escalating doses can result in anatomic aberrations and functional imbalance without satisfactorily diminishing the unwanted wrinkles. This must be made perfectly clear to the patient prior to treatment so as not to disappoint the patient and frustrate the injector. In order to maintain the func-tional as well as an anatomic balance in the mid and lower face when treating a patient with injections of onabotulinumtoxinA, it is abso-lutely necessary, more so than in the upper face, that accurately mea-sured, minimal volumes of low doses of onabotulinumtoxinA be precisely placed and injected into specifically targeted muscles. Par-ticularly during treatment of the mid face, the upper lip levators are easily affected by the slightest diffusion of onabotulinumtoxinA. This can readily cause a disruption in one or many of the complex motor functions of the lips (e.g., eating, drinking, speaking, and expressing emotion). Also, because of the intermingling of the orbicularis oris with the muscle fibers of the upper lip levators, which are invested with a thicker mass of subcutaneous soft tissue, onabotulinumtoxinA injections of the mid face should be performed only by an expert injector ( 6 ).

In many areas of the mid and lower face, however, better overall cos-metic results can be achieved with different soft tissue fillers, or with resurfacing techniques and many other types of invasive procedures (i.e. rhytidectomy, prosthetic implants, and different soft tissue suspen-sion techniques), while supplementary treatments with onabotu-linumtoxinA injections can be used to enhance and prolong the final aesthetic outcomes ( 7 ).

NASOGLABELLAR LINES (see Appendix 1) Introduction: Problem Assessment and Patient Selection There are many individuals who form diagonal nasoglabellar lines over the lateral walls of the nasal bridge near the root of the nose that radiate downward, toward the alae, and accentuate when they speak, smile, laugh, or frown. These wrinkles are produced by the contraction of the transverse nasalis and their depth and pattern can be different on either side of the midline ( Fig. 4.2A–D ). They are anatomically distinct both in location and source from the horizontal lines that span transversely across the nasal radix, which are produced by the downward pull of the procerus. When this radial fanning of longitudinal wrinkles of the upper lateral aspect of the nasal bridge occurs as a compensatory maneuver after treatment of glabellar frown lines with onabotulinum-toxinA, these lines have been identified as the “BOTOX ® sign” ( Fig. 4.3 ) ( 7 ). On the other hand, when these nasoglabellar lines occur naturally and without treatment, they are referred to as “bunny lines” or a “nasal scrunch” ( Fig. 4.4 ) ( 7 , 8 ). Women who idiosyncratically produce naso-glabellar wrinkles find them to be annoying and unsightly because they can unintentionally project an attitude of disdain or dislike. These lines should be treated with injections of onabotulinumtoxinA along with glabellar frown lines during the same treatment session. On the other

4 Cosmetic uses of Botulinum toxin A in the mid face Anthony V. Benedetto

MID FACE Introduction With the increased demand for facial rejuvenation done by noninva-sive techniques, many experienced injectors of onabotulinumtoxinA now are venturing below the upper face with their treatments ( 1 ). At this time, however, all of these treatments in the United States are not Food and Drug Administration (FDA)–approved and are performed in an off-label manner. As with any other part of the face, one must be completely knowledgeable of the levator and depressor action of the mimetic musculature. The reciprocating action of opposing mimetic muscles can prove to be a bit more complicated and chal-lenging in the mid and lower face than in the upper face. Specifically, the muscles of the upper face are easily distinguishable from one another because of various topographic landmarks, making it easy to inject them with onabotulinumtoxinA. However, in the mid and lower face, there is an interdependence of the superficial and deep mimetic muscles, which also are adjacent to some of the muscles sur-rounding the mouth that function in the articulation of sounds or in mastication and deglutition. These muscles of facial expression are interlaced with and help form the superficial muscular aponeurotic system (SMAS). Many of them perform complementary and, at times, unrelated functions. The mimetic muscles of the mid and lower face have very specific functions, which are mostly centered around the mouth. These muscles can sometimes act as agonists, sometimes as antagonists, but always in a complex, synergistic man-ner. They allow a person to smile, laugh, grimace, pucker the lips, or to make any other overt or subtle gesture with the mouth. These complex functions permit one to hold solids, liquid, or air within the mouth without loss of contents. They also allow one to release at will the contents out of the mouth slowly or forcibly. These muscles allow for the fine motor movements necessary to produce either subtle whispering sounds or thunderous clamor. They also facilitate the actions of chewing, swallowing, and a myriad of other simple and complex movements that either explicitly or implicitly function in deliberate and involuntary motor movements that are so particular of an individual’s mannerisms. In addition, many of these superficial and deep muscles overlie a thicker mass of soft tissue as well as each other, creating an anatomy that is quite different from the forehead and brow ( Fig. 4.1 ). Consequently, if onabotulinumtoxinA migrates beyond the targeted muscles when it is injected in the mid and lower face, unintended effects and adverse sequelae can easily occur. There-fore, when treating anyone with onabotulinumtoxinA in the mid and lower face, low doses usually are effective and higher doses are not necessarily better.

There are additional factors that contribute to the differences in the anatomy of the upper face as compared to that of the mid and lower face, which will reflect how one is to utilize injections of onabotu-linumtoxinA when rejuvenating the face ( 2 ). In the upper face, the skin can be thicker and more tightly adherent to the underlying mus-cles of facial expression. Adverse outcomes in the upper face, if and when they occur, often are related to diffusion of the injected ona-botulinumtoxinA and usually present as cosmetic inconveniences and asymmetries, which can be easily rectified most of the time. Generally, much higher doses of onabotulinumtoxinA are injected into the upper face musculature to produce more extensive muscle weakness, but onabotulinumtoxinA treatments here rarely cause functional imbal-ance. On the other hand, because of their compact spatial arrangement

102 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.1 Mimetic muscles of facial expression. Right side depicts the superficial and the left side depicts the deeper muscles.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Figure 4.2 “Nasal scrunch” or “bunny lines,” produced by the transverse nasalis, are those vertical lines emanating from the lateral sides of the root of the nose before a treatment with onabotulinumtoxinA. The transverse or horizontal lines across the root of the nose are produced by the procerus. Different patients have different wrinkle patterns. Note the commonly seen nasoglabellar lines caused by the contraction of the transverse nasalis, which are accompanied by (A) nasociliary rhytides, (B) nasoorbicular and nasoalar rhytides, (C) nasociliary and nasoalar rhytides, and (D) nasoorbicular and nasoalar rhytides (see pp. 106–107) .

(A) (B)

(C) (D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 103

Figure 4.3 “BOTOX® Sign.” (A) Patient frowning and without nasoglabellar lines prior to a treatment with onabotulinumtoxinA. (B) Same patient frowning 3 weeks after an onabotulinumtoxinA treatment of his glabellar frown lines. Note the compensatory nasoglabellar lines, i.e. “BOTOX® Sign”. (C) Two weeks after a touch-up injection of onabotulinumtoxinA in the transverse nasalis and 5 weeks after the original onabotulinumtoxinA treatment. Note the compensatory nasoglabellar lines are gone.

(A) (B)

(C)

Figure 4.4 A 49-year-old patient frowning before and 3 weeks after a treatment with onabotulinumtoxinA of both the glabella and nasoglabellar lines. Note the diminished nasoglabellar “bunny lines.”

(A) (B)

104 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

hand, there are some individuals with inelastic, lax, redundant skin who elevate skin and soft tissue of the midface when they forcibly squint and produce deeply corrugated nasoglabellar rhytides. For these patients, whose nasoglabellar lines are not produced by the contraction of the transverse nasalis, but by the elevation and pleating of submalar and lateral nasal skin, injections of onabotulinumtoxinA are not helpful ( Fig. 4.5 ).

Functional Anatomy (see Appendix 1) Nasoglabellar lines are the result of the contraction of the upper or transverse portion of the nasalis, also known as the compressor naris. The transverse nasalis originates from the maxilla, superior and lateral to the incisive fossa ( Fig. 4.6 ). Its fibers course medially and superiorly and expand into the aponeurosis over the bridge of the nose, inserting into the fibers of its paired muscle of the opposite side and into the aponeurosis of the procerus ( Fig. 4.7 ). The transverse nasalis or com-pressor naris depresses the cartilaginous part of the nose, drawing the ala inwardly toward the nasal septum. These nasoglabellar lines are pro-duced by asking the patient to squint forcibly, as if intense light is shin-ing in the eyes. If these lines become prominent without any upward movement of cheek skin, then the patient will most likely produce them readily after their glabellar lines are treated with onabotulinumtoxinA ( Fig. 4.4 ). Therefore, such naturally occurring nasoglabellar lines should be treated automatically with injections of onabotulinumtoxinA at the same treatment session when glabellar frown lines are treated. If the nasoglabellar lines are not treated, the patient more than likely will blame the physician and onabotulinumtoxinA for their presence after treatment whether or not the patient is aware of them before treatment. Therefore, it behooves the physician to disclose their presence to the patient prior to any treatment with onabotulinumtoxinA, underscoring the necessity to include these nasoglabellar frown lines as an integral part of the treatment of glabellar frown lines ( Fig. 4.4 ).

If the transverse nasalis does not overtly exhibit wrinkling and is not treated in conjunction with the glabellar frown lines, and when the

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) With the patient in the upright sitting or semireclined position, nasoglabellar lines can be relaxed by injecting 2 to 5 U of onabotu-linumtoxinA subcutaneously or intramuscularly into the lateral walls of the nasal bridge, just inferior to the nasal radix and anterior and superior to the nasofacial angle ( Fig. 4.8 ). This technique should posi-tion the needle well above the angular vessels and upper lip levators ( 9–12 ). The soft tissue is extremely thin and vascular in this area and advancing the needle tip a few millimeters here goes a long way. It is most important to avoid injecting too low along the nasal sidewalls and into the nasofacial sulcus ( Fig. 4.9 ). Otherwise, either the levator labii superioris alaeque nasi or the levator labii superioris, or both, may be weakened by the injected onabotulinumtoxinA, since they both origi-nate along the medial aspect of the malar prominence. If either of these levators is affected, then upper lip ptosis, asymmetry, and resultant functional changes of the mouth can occur.

nasoglabellar lines become evident after the patient’s glabellar frown lines are treated with onabotulinum toxinA (i.e. displays the “BOTOX sign”), then the nasoglabellar lines should be identified and treated during the obligatory follow-up visit 2 to 3 weeks after an onabotu-linumtoxinA treatment session ( Fig. 4.3 ).

Dilution (see Appendix 2)

In order to prevent the unintended widespread diffusion of

onabotulinumtoxinA beyond the point of injection, it is necessary

that a minimum amount of onabotulinumtoxinA be injected when

treating nasoglabellar lines. Therefore, 1 ml of normal saline should

be used to reconstitute the 100 U vial of onabotulinumtoxinA when

injecting nasoglabellar lines.

Figure 4.5 In this 49-year-old patient, not all the nasoglabellar lines are produced by the contraction of the transverse nasalis, but rather by the pleating of the submalar and lateral nasal skin. OnabotulinumtoxinA injections are not entirely helpful in this type of patient. Note their absence when the mid face skin is prevented from elevating.

Pre

Post

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 105

It appears men are not treated for this problem as frequently as women. The dose of onabotulinumtoxinA depends on the overall depth and location of the lines and strength of the transverse nasalis. Dose of 3 to 5 U of onabotulinumtoxinA injected on each side may be

necessary to diminish these lines. An additional 2 to 4 U may be required before the least amount of nasoglabellar wrinkling is totally eliminated, especially in those men and women who spend the better part of their day outdoors and whose nasalis is hypertrophic and

Figure 4.6 The compressor naris or transverse nasalis originates from the maxilla and inserts into the nasal bridge aponeurosis.

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labii superiorisalaeque nasi

NasalisAlar nasalis or

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

Transverse nasalisor Compressor naris

Figure 4.7 Compressor naris: its relationship to adjacent musculature.

Corrugator supercilii

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

NasalisAlar nasalis or

Dilator naris

Transverse nasalisor Compressor naris

Levator labii superiorisalaeque nasi

Levator labii superiorisalaeque nasi

106 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

hyperkinetic from constant squinting. The effects of onabotulinum-toxinA can last at least 3 months and usually longer. In patients who previously have had a rhinoplasty, the results may be somewhat less than expected ( 10–14 ).

Outcomes (Results) (see Appendix 4) Eliminating nasoglabellar lines along with glabellar frown lines gives an individual a relaxed, youthful appearance. When the nasoglabellar lines are not treated and the glabellar frown lines are, nasoglabellar lines in the presence of a smooth glabella produce an exceptionally unsightly effect ( Figs. 4.3 and 4.10A,B ). Recently, Tamura et al. ( 15 ) found that they were able to successfully treat approximately 40% of their patients with nasoglabellar lines by injecting them with 3 U of onabotulinumtoxinA on either side of the nasal side wall into the belly

of the transverse nasalis. The other 60% of the patients in their study had persistent bunny lines that exhibited different linear patterns along the proximal and distal nasal bridge. They found that in order to fur-ther diminish these persistent bunny lines an additional 2 U of ona-botulinumtoxinA needed to be injected at different sites along either side of the nasal bridge according to the three different patterns they identified. They named the recalcitrant bunny lines according to their anatomic location as the naso-alar rhytides, naso-orbicular rhytides, and naso-ciliary rhytides. The additional onabotulinumtoxinA treat-ments were given during the first follow-up visit, 4 weeks after the ini-tial treatment with onabotulinumtoxinA. There were approximately 30% of the patients who had persistent wrinkling at the root of the nose, which extended superiorly toward the medial margin of the eye-brow and glabella caused by the contraction of the orbital orbicularis

Figure 4.8 Injecting the transverse nasalis anterior and superior to the nasofacial angle. Note the wheal of injected onabotulinumtoxinA.

Figure 4.9 Point “●” at which injections should be placed when treating the compressor naris (transverse nasalis).

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

NasalisAlar nasalis or

Dilator naris

Transverse nasalisor Compressor naris

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 107

oculi adjacent to the ciliary arch, so they were identified as having naso-ciliary rhytides ( Figs. 4.2A,C and 4.11A,B ). Another 30% of the patients had persistent wrinkling of the root of the nose owing to con-traction of the nasal portion of the orbital orbicularis oculi, so these patients were identified as having naso-orbicular rhytides ( Figs. 4.2B,D and 4.11A,B ).The third pattern identified as persistent naso-alar wrin-kles occurred in both of the above subgroups and were felt to be the result of the contraction of the alar portion of the levator labii superi-oris alaeque nasi ( Figs. 4.2B–D and 4.11A,B ). Each area of persistent wrinkling was produced by unaffected fibers of the underlying mus-cles, which required the additional 2 U of onabotulinumtoxinA on either side of the nasal bridge to completely eliminate any residual nasoglabellar “bunny lines” ( Figs. 4.12 and 4.13 ) ( 15 ).

Patients who recruit cheek and submalar skin and elevate it toward the nasal radix forming corrugations of skin along the lateral aspect of the proximal nose will not be helped by onabotulinumtoxinA injec-tions ( Fig. 4.5 ). Only those rhytides that are formed by the contraction of the transverse nasalis will be diminished by injections of onabotu-linumtoxinA ( Figs. 4.4 , 4.12 , and 4.13 ). Usually, one can expect the effect of an onabotulinumtoxinA treatment of nasoglabellar lines to last at least 3 to 4 months, or however long the glabellar frown lines remain effaced.

Complications (Adverse Sequelae) (see Appendix 5) Injecting onabotulinumtoxinA too low along the nasal sidewalls and allowing it to diffuse into the upper lip levators (i.e. levator labii superioris alaeque nasi and levator labii superioris) can produce asym-metry and even ptosis of the upper lip, including sphincter incompe-tence and functional difficulties with speaking, eating, and drinking. Also, if the medial palpebral orbicularis oculi is weakened as the result of the unintended diffusion of onabotulinumtoxinA, a diminution in the action of the lacrimal pump can occur, causing epi phora (excessive tearing) ( 14 ). Diplopia also can result if the medial rectus is weakened by onabotulinumtoxinA. Vigorous massage to the area after the injec-tion of onabotulinumtoxinA can cause it to spread and diffuse beyond the targeted area and produce the same untoward adverse results, even if dosing is appropriate and the injection technique is flawless. There is no antidote for any of these untoward post-treatment sequelae, and the patient is obligated to endure them until the effects of the onabotu-linumtoxinA remit. In the meantime, consultation with an ophthalmol-ogist to help the patient cope with these ocular problems is advisable.

It is important also to keep in mind that the angular artery and vein sit in the nasofacial angle and injections placed too low along the nasal

sidewall and deeply into the skin can result in an intravascular injection of the onabotulinumtoxinA or injury to one of the vessels causing either ecchymoses (vein) or hematoma (artery). Therefore, intradermal or superficial subcutaneous placement of the needle tip is all that is necessary when injecting this area with onabotulinumtoxinA ( Fig. 4.8 ). There have been no reports of any adverse events from an intravascular injection of onabotulinumtoxinA when less than 10 U is injected.

Figures 4.14 to 4.16 are additional examples of different patients treated with onabotulinumtoxinA for nasoglabellar lines.

Figure 4.10 Note the presence of nasoglabellar “bunny lines” before ( A ) and their absence 3 weeks after ( B ) a onabotulinumtoxinA treatment of only glabellar frown lines.

(A) (B)

Treatment Implications When Injecting Nasoglabellar Lines

1. Squinting will reveal the presence or absence of nasoglabellar

lines and they should be elicited before treating glabellar frown

lines with onabotulinumtoxinA.

2. Nasoglabellar lines are present naturally in some individuals

when they squint and are identifi ed as “bunny lines.”

3. When nasoglabellar lines are produced as the result of compen-

satory contraction of the transverse nasalis after an onabotu-

linumtoxinA treatment, they are referred to as the “BOTOX® sign.”

4. Treat vertical nasoglabellar frown lines (i.e. those produced by

the contraction of the transverse nasalis) along with horizontal

glabellar frown lines (i.e. those produced by the contraction of

the procerus) during the same treatment session.

5. Injections of onabotulinumtoxinA should be performed intra-

dermally or subcutaneously into the lateral aspect of the nasal

bridge and radix.

6. Injections too low and deeply into the nasofacial sulcus may

result in ecchymoses, hematoma, upper lip ptosis and asym-

metry, or even upper lip incompetence and functional diffi cul-

ties of the sphincteric action of the mouth.

7. Additional units of onabotulinumtoxinA may be needed along

the lateral aspect of the nasal radix and the proximal and distal

nasal bridge in different patterns to efface all the nasoglabellar

lines in certain (∼60% of) patients.

8. Patients with inelastic, lax skin who squint excessively may

produce nasoglabellar lines that cannot be reduced by onabotu-

linumtoxinA injections.

108 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.11 (A,B) Standard injection point for transverse nasalis (●). Note the additional injection sites to diminish persistent nasoglabellar lines. Red dot (●) for nasociliary rhytides; green dot (●) for naso-orbicular rhytides; purple dot (●) for naso-alar rhytides.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Alar nasalis orDilator narisZygomaticus

minor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Transverse nasalisor Compressor naris

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculiCorrugator

supercilii

Procerus

Depressorsupercilii

alaeque nasi

Levator labiisuperioris

alaeque nasi

Alar nasalis orDilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

Transverse nasalisor Compressor naris

Nasalis

Nasalis

(A)

(B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 109

Figure 4.12 A 45-year-old patient frowning before and 3 weeks after a treatment with onabotulinumtoxinA of both the glabellar and nasoglabellar lines. Note the diminished “bunny lines.”

2 2

4

8

4

Figure 4.13 A 52-year-old patient frowning before and 2 weeks after a treatment with onabotulinumtoxinA of both the glabellar and nasoglabellar lines. Note the diminished “bunny lines.”

3 4

4

Figure 4.14 A 66-year-old patient frowning before and 1 week after a treatment with onabotulinumtoxinA of both the glabellar and nasoglabellar lines ( naso orbicular and naso alar ). Note the diminished “bunny lines.”

2 2

3 36

110 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

NASAL FLARE Introduction: Problem Assessment and Patient Selection There are some individuals who, either naturally or when they are under physical or emotional stress, flare their nostrils and widen their nasal aperture repeatedly as they inspire. Many individuals, who possess a broad nasal bridge with a wide nasal alar base, also may have well-developed muscles of the distal nose (i.e. alar nasalis) and the medial alar portion of the levator labii superioris alaeque nasi. They will allow such persons to dilate their nostrils deliberately and involuntarily. This noticeable movement of the nostrils with forced inspiration can impart to the casual observer, a negative attitude, which may include anger, fear, exhaustion, concern, dis approval, or personal distress. For some patients, active dilation of the nostrils also occurs while speaking, smiling, or laughing ( Fig. 4.17 ). For these patients, injections of onabotulinumtoxinA may diminish this embarrassing, idiosyncratic synkinesis.

Functional Anatomy (see Appendix 1) Nasal flaring is the result of the involuntary contraction of the lower por-tion of the nasalis or the alar nasalis also called the dilator naris, causing the alae nasi to dilate repeatedly ( Figs. 4.6 and 4.7 ). The alar nasalis origi-nates from the maxilla above the lateral incisor and canine, lateral to the bony origin of the depressor septi nasi, and medial to the transverse nasa-lis under the nasolabial fold ( Fig. 4.18 ). Its fibers travel superiorly and anteriorly and insert into the skin of the ala above the lateral crus of the lower lateral cartilage near the margin of the nasal aperature and to the posterior part of the mobile septum. Its medial fibers also can blend with

Figure 4.16 A 55-year-old patient frowning before and 4 weeks after a treatment with onabotulinumtoxinA of both the glabellar and nasoglabellar lines. Note the diminished “bunny lines.”

4 44

Figure 4.15 A 59-year-old patient frowning before and 3 weeks after a treatment with onabotulinumtoxinA of both the glabellar and nasoglabellar lines. Note the diminished “bunny lines.”

2 2

3 3

5

the fibers of the depressor septi nasi. The alar nasalis also contributes to the formation of the upper ridge of the philtrum. The alar nasalis or dila-tor naris draws the alae nasi and posterior aspect of the columella down-ward and laterally, dilating the nostrils and elongating the nose. The dilator naris contracts before inspiration thereby preventing the alae nasi from collapsing during inspiration.

An accessory dilator of the nares is the medial portion of the levator labii superioris alaeque nasi also known as the levator alae nasi. The levator labii superioris alaeque nasi originates from the upper part of the frontal process of the maxilla, divides into medial and lateral bun-dles of muscle as it passes obliquely along the nasal sidewall. The medial alar portion of the levator labii superioris alaeque nasi blends into the perichondrium of the lateral crus of the lower lateral cartilage and inserts into the overlying skin. In some individuals, the levator alae nasi pulls the lateral crus superiorly displacing the circumalar furrow laterally and dilating the nostrils. Because the levator alae nasi at times can function together with the nasal tip muscle fibers of the depressor septi nasi to retract the tip of the nose, they also are considered secondary nasal dilators ( 16 ) (see below).

Dilution (see Appendix 2)

Moderate diffusion of onabotulinumtoxinA can be advantageous

when treating the lower nasalis. Therefore, reconstituting a 100 U

vial of onabotulinumtoxinA with 1 to 2.5 ml of normal saline to

inject into this area is acceptable.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 111

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) Treat the patient in the sitting or semireclined position with subcuta-neous injections of 4 to 10 U of onabotulinumtoxinA into the center of each ala toward the alar rim along the lateral fibers of the alar nasalis. This will weaken involuntary muscle contractions of the nostrils ( 3 , 17 ). Such results can be useful in African-American patients or other ethnic groups who have a characteristically similar, broad nasal bridge and wide alae that flare easily because of a hyperkinetic alar nasalis ( Fig. 4.19 ). Only those patients who can deliberately and actively flare their nostrils are candidates for onabotulinumtoxinA injections. Patients of African and Asian descent or other individuals, who have a

characteristically broad nasal bridge and wide alar base, but who cannot deliberately flare their nostrils will not experience appreciable narrowing of their nasal aperature with injections of onabotulinum-toxinA, and therefore should not be treated ( Fig. 4.20 ).

Outcomes (Results) (see Appendix 4) For those individuals who can flare or dilate their alae nasi wilfully, injections of onabotulinumtoxinA will decrease the frontal diameter of the nostril and give their nose a narrower, more Caucasian appearance, without interfering with inspiration. Results can last up to 3 to 4 months and sometimes longer with repeat treatments. In patients who do not have a well-developed dilator naris and medial levator labii

Figure 4.17 This 72-year-old has a horizontal upper lip crease, gummy smile, and an active dilation of the nostrils when smiling.

Figure 4.18 Dilator naris is the inferior portion of the nasalis.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculiLevator labii

superiorisalaeque nasi

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

NasalisAlar nasalis or

Dilator naris

Transverse nasalisor Compressor naris

112 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Treatment Implications When Injecting the Nose For Nasal Flare

1. Treat only those patients who can actively and wilfully fl are their

nostrils.

2. Injections of 4 to 10 U of onabotulinumtoxinA in the center of

or along the alar rim of each ala nasi into the dilator naris will

relax the involuntary fl aring of the nostrils.

3. Treating hyperkinetic dilator naris with onabotulinumtoxinA

can produce an overall narrower nasal aperture without inter-

fering with inspiration.

4. No adverse side effects have been identifi ed with this injection

technique.

superioris alaeque nasi, and cannot dilate their nostrils at will, no amount of onabotulinumtoxinA will narrow their nasal aperature ( Fig. 4.20 ).

Complications (Adverse Sequelae) (see Appendix 5) If patients are not selected properly, injections of onabotulinumtoxinA might not be effective; then time, effort, and money will have been wasted. Otherwise, these patients experience no other adverse sequelae, except the usual ones that occur with transcutaneous injections, including pain, edema, erythema, and possible ecchymoses. There have been no reports of difficulty with inspiration in those patients who have been treated successfully or unsuccessfully with onabotulinumtoxinA for a nasal flare.

NASAL TIP PTOSIS Introduction: Problem Assessment and Patient Selection With age, the nasal tip in some individuals naturally rotates down-ward, partly because of the pull of gravity and partly because of the pull of a hyperkinetic muscle of the nasal septum (i.e. depressor septi nasi). When this occurs, a person may possess the appearance of senil-ity and decrepitude, projecting an evil and sinister demeanor. There are others who, because of idiosyncratic skeletal morphology, possess a downwardly rotated nasal tip since birth ( Fig. 4.21 ). Still there are others, whose nasal tip will noticeably and dynamically rotate down-ward in an up and down motion as they speak or pucker their lips, regardless of age ( Fig. 4.22 ). For those whose nasal tip actively moves and rotates downward when depressing the upper lip or when speaking, onabotulinumtoxinA injections have provided noninvasive means to elevate and project the nasal tip upward. Injections of ona-botulinumtoxinA will also stop the up and down movement of the nasal dome while talking, smiling, or drinking. For adynamic, static, inferiorly pointing nasal tips, only soft tissue fillers or surgical rhinoplasty can be corrective ( Fig. 4.23 ).

Dynamic nasal tip ptosis can be accompanied by excessive upper lip shortening and occasionally, the presence of a gummy smile and a transverse line across the upper lip and philtrum ( Fig. 4.22A–E ) ( 18 ). This horizontal upper lip crease can be exaggerated in older patients with dermatochalasis and skin laxity (Fig. 4.17). It also is found in younger patients when there is curling of a short upper lip with smiling ( Figs. 4.23– 4.25 ) ( 19 ). These patients typi-cally will also exhibit an excessive amount of alveolar gingiva when

Figure 4.19 This 57-year-old patient at rest before and 4 weeks after a treatment with onabotulinumtoxinA. A slight reduction of a nasal flare was achieved with 5 U of onabotulinumtoxinA injected into the dilator naris (alar nasalis) bilaterally.

Before After

Figure 4.20 This 47-year-old patient at rest before and 2 weeks after 6 U of onabotulinumtoxinA was injected into each ala. A slight reduction of a nasal flare was achieved.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 113

Figure 4.21 Downward rotated nasal tip in this 37-year-old patient.

smiling or laughing, known as a “gummy smile” ( Fig. 4.22B,D ) (see pp. 132–138) .

Functional Anatomy (see Appendix 1) The paired depressor septi nasi is often considered a component part of the dilator naris. It originates from the nasal spine at the center of the incisor fossa of the maxilla deep to the orbicularis oris and on the medial cartilaginous crura ( Fig. 4.26 ) ( 18 ). Its fibers course upward and insert into both the mobile cartilaginous nasal septum and the mucous membrane undersurface of the ala nasi, as well as the superfi-cial muscle fibers of the orbicularis oris and mucous membrane of the upper lip. A few muscle fibers may even continue upward between the medial crura and into the nasal tip ( Fig. 4.26 ) ( 20 ).

The depressor septi nasi pulls the nasal septum downward, draws the ala inferiorly, and narrows the nostril. In some individuals, fibers of the dilator naris have been found to interdigitate with those of the depres-sor septi nasi. Consequently, when the depressor septi nasi contracts in unison with the dilator naris as the upper lip is set in motion (e.g., when smiling or pursing the lips to whistle, kiss, or pronounce words containing w, o, u, j, m, g, b, p, q sounds), a paradoxical widening of the

Figure 4.22 (A,B) This 26-year-old has a dynamic nasal tip ptosis, an upper lip shortening, a gummy smile, and a transverse line across her upper lip when smiling before ona-botulinumtoxinA. (C,D) View of the profile of the same patient. Note the dynamic nasal tip ptosis, gummy smile, and downward turn of the nose when actively smiling. (E) Same patient seen 1 week after onabotulinumtoxin treatment. Note the reduction in the gummy smile and nasal tip ptosis with smiling.

(A) (B)

(C) (D) (E)

114 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.25 This 63-year-old patient curls the upper lip with smiling. Note the prominent lip crease and downward rotation of the nasal tip. Note the difference between this older patient and the younger one of Figure 4.22.

nasal aperture will then occur and the nasal tip will actively rotate downward and upward ( Figs. 4.22 and 4.27A,B ).

In some individuals, the lip and alar insertions are comingled with fibers of the levator labii superioris alaeque nasi. During animation when the nasal tip is pulled downward while the upper lip is pulled upward in a curling motion, a horizontal upper lip crease and gummy

Figure 4.24 A 52-year-old patient curls the upper lip with smiling. Note the visible lip crease and downward rotation of the nasal tip. Note the difference between this older patient and the younger one of Figure 4.22.

show is revealed ( Figs. 4.17 , 4.22, and 4.25) (see pp. 132–138). When the nostrils are simultaneously pulled downward, an ominous snarl is created ( Fig. 4.22D ). Because of the variability in the anatomy and the multifactorial etiology of nasal tip ptosis and dynamic nasal tip retrac-tion, injections of onabotulinumtoxinA to elevate and project the tip of the nose usually is not as easy to perform as one might think.

Figure 4.23 This 48-year-old patient has an adynamic, static, inferiorly rotated nasal tip, which could only be treated with a soft tissue filler. She is seen here before and 2 weeks after treatment with an intracolumella injection of calcium hydroxylapatite.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 115

Figure 4.26 Depressor septi nasi may intermingle with the dilator naris and superficial fibers of the orbicularis oris.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasiCompressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Figure 4.27 ( A ) This 52-year-old at rest with upward projection of the nasal tip. ( B ) Same patient. Note the nasal tip rotates downward when she puckers her lips while speaking.

(A) (B)

116 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) For those patients who can intentionally depress and rotate the tip of their nose downward by puckering or lowering their upper lip, injec-tions of onabotulinumtoxinA can be helpful in raising and projecting their nasal tip. To effectively treat a dropped nasal tip, have the patient depress their upper lip downward, widening the junction between the base of the nasal columella and the upper lip. This maneuver elongates the depressor septi nasi, separating it functionally and anatomically away from the orbicularis oris. This allows one to place the needle pre-cisely into the depressor septi nasi at the base of the columella, and not into fibers of the orbicularis oris, before injecting onabotulinumtoxinA ( Fig. 4.28A ).

With the patient in the sitting or semireclined position, grasp the columella between the thumb and index finger of the nondominant hand at the same time the patient is forcing the upper lip downward and underneath their incisors and canines. Another technique is to lift the tip of the nose superiorly and gently push it posteriorly with the thumb of the nondominant hand ( Fig. 4.28A,B ).

Depending on the strength of the depressor septi nasi, 2 to 4 U of onabotulinumtoxinA can be injected just superior (1–2 mm) to the labiocolumella boundary line ( Fig. 4.28B ). An additional 2 to 4 U of onabotulinumtoxinA also can be injected into the middle of the colu-mella and nasal tip, if the strength of the depressor septi nasi is visibly excessive and hyperfunctional ( Fig. 4.28A ). Stronger muscles will require higher doses of onabotulinumtoxinA ( 31 ). In some patients whose depressor septi nasi also interdigitates with the dilator naris, an additional injection of 2 to 6 U of onabotulinumtoxinA on both lat-eral aspects of the nasal tip, i.e. into the center of the ala just above its rim, will be necessary to effectively elevate and project the nasal tip.

To reduce the depth of the horizontal upper lip crease, injections of onabotulinumtoxinA should be placed lateral to the alae nasi and into the lateral labial fibers of the levator labii superioris alaeque nasi. This actually is the treatment for an exaggerate upper gummy smile and is discussed in detail on pages 132–138.

Outcomes (Results) (see Appendix 4) Injecting onabotulinumtoxinA into the depressor septi nasi will relax the muscle, lifting and projecting the nasal tip upward ( Fig. 4.29 ). The combination of injecting both the columella and the alae just lateral to the nasal tip with onabotulinumtoxinA will relax the lower end and base of the nose, producing additional lifting of the nasal tip by the medial (alar) fibers of the levator labii superioris alaeque nasi ( Fig. 4.30 ) ( 22 ). If one can see obvious movement and a downward rotation of the nasal tip when a patient smiles, speaks, depresses the upper lip or puckers the lips, then injections of onabotulinumtoxinA will be effec-tive ( Figs. 4.31A,B and 4.32A,B ). Results can last 3 to 4 months and slightly longer with repeat treatments. If there is no movement of the nasal tip when the upper lip is depressed or while the patient smiles, speaks, puckers, or purses the lips, onabotulinumtoxinA injections should not be given.

Atamoros has devised a therapeutic dosing scheme whereby he can predict the height change in the nasal tip elevation and projection in

patients he treats with onabotulinumtoxinA ( 22 ). Injecting 2 U of ona-botulinumtoxinA deeply into each of the right and left sides of the nasal tip dilator naris and 2 U of onabotulinumtoxinA into the depres-sor septi nasi (total of 6 U of onabotulinumtoxinA) produces a slight elevation of the nasal tip. Approximately 4 U of onabotulinumtoxinA injected into each of the right and left side of the nasal tip and the depressor septi nasi (total of 12 U of onabotulinumtoxinA) produce a medium elevation of the nasal tip. For a high elevation and projection of the nasal tip, 6 U of onabotulinumtoxinA into each of the right and left dilator naris and depressor septi nasi (total of 18 U of onabotu-linumtoxinA) may be needed ( Figs. 4.30 and 4.33 ) ( 22 ). Results lasted as long as 4 months. This is due presumably to the compensatory upward contraction of the secondary nasal dilator, i.e. medial (nasal) fibers of the levator labii superioris alaeque nasi.

When a horizontal upper lip midphiltral crease is accentuated with smiling, with or without a downward rotation of the nasal tip, an addi-tional 1 to 3 U of onabotulinumtoxinA can be placed into each levator labii superior alaeque nasi as described below on pages 132–138. Injecting the depressor septi nasi and the lateral (labial) fibers of the levator labii superoris alaeque nasi with onabotulinumtoxinA not only can diminish the transverse line of the upper lip, but it also can provide an apparent increase in the vertical distance between the columella and vermillion border, occasionally creating a fuller, more voluminous upper lip for some patients but otherwise, adversely elongate a thin upper lip and vermillion in others ( 21 ). Dayan and Kempiners ( 18 ) also found that with 5 U of onabotulinumtoxinA placed into each depressor septi nasi and 3 U placed into each levator labii superioris alaeque nasi, the nasal tip became less ptotic, the alar insertion remained in a more neutral position, and the nasolabial angle widened from 110 to 115 degrees. In addition, there was a relative elongation and a relaxation in the curling of the upper lip with smiling and laugh-ing that accompanied a diminution of the mid philtral horizontal crease, a more horizontal orientation to the alar base insertion and an attenuation in the appearance of a snarl. Consequently, the depressor septi nasi is one of the muscles that might need to be weakened when treating a patient for an exaggerated upper gummy smile. When there still is evidence of a horizontal upper lip crease after an appropriate treatment of onabotulinumtoxinA, injections of a strategically placed soft tissue filler may be the only solution for its complete elimination (see pp. 132–138).

Complications (Adverse Sequelae) (see Appendix 5) Higher doses of injected onabotulinumtoxinA produce a relaxation of the decussating fibers of the alar nasalis and depressor septi nasi, which can result in an unattractive, exaggerated widening of the nostrils along with the projection and elevation of the nasal tip ( Fig. 4.30 ). This forced widening of the nostrils is accompanied in some patients by per-sistent pain and soreness over the nasal tip that can last for over 2 weeks ( 22 ). The duration of the effect of the injected onabotulinumtoxinA in this area sometimes lasts for only 2 months, and even less in some patients.

Weakening only the depressor septi nasi may just elevate the nasal tip. However, if the onabotulinumtoxinA diffuses laterally from the midpoint of the base of the nasal columella and into the central upper lip levators (i.e. levator labii superioris, levator labii superioris alaeque nasi), then the upper lip can become elongated and thinned, obliterating the contour and depth of the philtrum. Asymmetry and alterations in functional buccal sphincteric control may also result, producing difficulty with eating, swallowing, and speaking. Unless there is an obvious downward displacement of the anterior aspect of the nose and nasal tip when a patient forcibly lowers their upper lip, puckers, speaks, or smiles, injections of the depressor septi nasi should not be attempted.

Dilution (see Appendix 2)

In the paranasal area, minimum amounts of onabotulinumtoxinA

should be used so as not to accidentally affect the levators of the

upper lip by the inadvertent diffusion of onabotulinumtoxinA. There-

fore, a 100 U vial of onabotulinumtoxinA should be reconstituted

with only 1 ml of normal saline.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 117

Figure 4.29 This 41-year-old at rest before and after 4 U of onabotulinumtoxinA were injected at the base and midsection of the nasal columella. Note the slight elevation of the ptotic nasal tip after treatment. Dynamic tip rotation with speaking and lip puckering was also reduced.

Figure 4.28 ( A ) Injection of the depressor septi nasi in the center of the columella. Note the pinching of the columella making it easy to inject. ( B ) Injection of the depressor septi nasi at the base of the columella. Note the placement of the needle, above the orbicularis oris while the thumb of the nondominant hand gently pushes the nasal tip upward and backward.

(A)

(B)

118 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.31 (A) The nasal tip of the 26-year-old actively rotated downward with speaking, smiling, and laughing before 4 U of onabotulinumtoxinA: 2 U at the base and 2 U in the center of the columella. (B) Same patient 1 week after onabotulinumtoxin treatment.

(A) (B)

Treatment Implications When Injecting the Nose for a Drop of the Nasal Tip

1. The tip of the nose may rotate downward because of muscle contraction, age, and gravity.

2. When the depressor septi nasi visibly depresses the tip of the nose when one smiles, speaks, puckers, or purses the lips, onabotulinumtoxinA

injections will elevate and project the nasal tip.

3. In some patients, additional deep injections of onabotulinumtoxinA into the dilator naris toward the nasal tip may be necessary to elevate

and project the tip of the nose.

4. Injecting onabotulinumtoxinA into the lateral aspect of the tip of the nose can cause an amplifi ed widening of the nostrils.

5. Overtreatment with onabotulinumtoxinA can cause excessive nostril widening, prolonged pain, an exaggerated elevation and a fl attening of

the nasal tip projection.

6. Diffusion of onabotulinumtoxinA lateral to the base of the columella can affect the upper lip levators, elongating the upper lip, blunting the

contour of the philtrum and causing lip asymmetry.

7. Upper lip asymmetry and oral sphincter weakness can result from injecting too high a dose of onabotulinumtoxinA at the base of the columella

which diffuses into the fi bers of the orbicularis oris.

Figure 4.30 Exaggerated elevation of the nasal tip, flattening of the tip projection and excessive widening of the nostralis can be seen in this patient who was injected with a total of 18 U of onabotulinumtoxinA (6 U into each dilator naris equally divided per side and 6 U into the depressor septi nasi in the base and mid columella). Source : Courtesy of Dr. Franciso Pérez-Atamoros.

Before

1 month after

2 weeks after

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 119

(A) (B)

Figure 4.32 (A) The nasal tip of the 52-year-old actively rotated downward with speaking, smiling, and laughing before 4 U of onabotulinumtoxinA: 2 U at the base and 2 U in the center of the columella. (B) Same patient 2 weeks after onabotulinumtoxinA treatment. Note the slight nasal tip elevation and projection.

Figure 4.33 Nasal tip before and 1 month after a treatment with onabotulinumtoxinA. An overall total of 16 U of onabotulinumtoxinA were injected: 8 U into the lower nasalis (4 U on each side) and 8 U (4 U at the base and 4 U into the mid portion of the columella) into the depressor septi nasi to achieve these results. Source: Courtesy of Dr. Francisco Pérez-Atamoros.

1 month after

4+4

8

Before

NASOLABIAL FOLDS Introduction: Problem Assessment and Patient Selection Chronological aging and a downward shift of soft tissue in the mid cheek area can deepen a nasolabial sulcus, which, in turn, augments its fold. Accentuated by side lighting and shadows, the nasolabial fold is enhanced by the overall diminution of structural skeletal and muscular support and intensified by the incessant effects of aging and the pull of gravity. The descent of soft tissue cheek mass occurs in the infraorbital and submalar area at different depths and stages in an inferiomedial direction and varies with each individual ( 23 , 24 ). The redistribution of facial soft tissue and fat is augmented with time and leads to the development of a characteristic vertical groove and fold that extend from the alar facial sulcus to the lateral labial commissures ( 21 ). The appearance of these so-called nasolabial folds probably is more frequently seen in genetically predisposed indi-viduals, but more than likely they also can be acquired by those whose mid facial movements are constant and excessively intense ( 25 ).

Usually absent in children, nasolabial folds emerge around the age of 25 years with longlasting expressions of emotion; laughter, fatigue, pain, etc. By age 35, the nasolabial fold becomes more fixed in those so predisposed and exhibit a great deal of morphologic variability ( 25 , 26 ). Deep, diagonal folds from the sides of the nose that progress downward toward the angle of the mouth, and at times even lower, project an attitude of disgust and dismay and are a characteristic sign of advanced age. These deep furrows and folds remain as one of the more difficult and still barely correctable harbingers of senes-cence in the treatment of the aging face. In the past, different surgi-cal procedures have attempted to efface the outline and depth of the groove, thereby flattening the fold. These procedures are fraught with scars and failure. Recently, injections of soft tissue fillers have been the most beneficial in achieving a modicum of success, and probably are still the best technique for elevating and softening this defect, considering the reasons for its presence. Nevertheless, injec-tions of onabotulinumtoxinA also have been employed in an attempt

120 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

to reduce the appearance of nasolabial folds. Unfortunately, intra-muscular injections of onabotulinumtoxinA appear not to be the long sought after panacea for this problem and they too have proven to be fraught with complications and failure in this area of the midface.

Functional Anatomy (see Appendix 1) There is significant variation in the anatomy that creates the nasolabial fold, which extends from a point lateral to the nasal ala to a point lateral to or lower than the oral commissure. The etiology of a prominent nasolabial fold is the result of multiple contributing alterations occur-ring in varying degrees and stages in the skin, bone, muscles, fat, and its retaining ligaments ( 23 , 24 ). The cutaneous insertions of the different mimetic facial muscles along this fold may promote the early appear-ance of the nasolabial fold and sulcus, starting in those so predisposed persons in their mid to late twenties ( 25 ). In older patients, a combi-nation of any of the following also may contribute to a prominent nasolabial fold:

• Loss of skin thickness over the sulcus

• Redundant skin lateral to the sulcus

• Excessive fat deposits lateral to the sulcus that are fixed in place by retaining ligaments, with or without

• Ptosis of the malar and submalar fat laterally as a result of a weakening of the SMAS in the mid upper cheek.

Aging and frequent mimetic action of the causative facial muscles can deepen the vertical sulcus that runs from the upper border of the nasofacial angle downward and laterally toward the commissures of the mouth. Depending on the idiosyncratic anatomic variations of an individual, it is a combination of any one of the mid face mimetic

Figure 4.34 Muscles that contribute to the formation of the nasolabial fold.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

muscles (zygomatic complex, the central upper lip levators, and the levator anguli oris and risorius) that are responsible for elevating the upper lip and producing a smile ( 25–27 ). They also contribute signifi-cantly either individually or as a group to the initial formation and the progressive intensification of the nasolabial folds ( Fig. 4.34 ).

Nasolabial folds can appear convex (60%), straight (30%), or concave (10%) ( Figs. 4.35–4.37 ). The length of a nasolabial fold also can vary from being one that is extended (42%), short (38%), or con-tinuous (20%) from the alar base to the mandible ( 25 , 26 ). With respect to an individual’s idiosyncratic facial morphology, the nasolabial fold can be divided into three sections: the upper or medial, middle, and lateral or lower section ( Fig. 4.38 ) ( 27 ). However, no significant corre-lation was found between the muscles present and their patterns of peribuccal attachments and the length and contour of the nasolabial crease and fold ( 26 ).

According to some authors, in many patients, it is the levator labii superioris alaeque nasi that is the muscle most responsible for producing the upper medial portion of the nasolabial fold and the levator labii superioris for deepening the middle of the nasolabial fold ( 3 , 4 , 25 , 27 , 28 ). It is the zygomatic muscle complex and the levator labii superioris that are primarily responsible for elevating the lip and producing a smile ( 4 , 29 ). In some individuals, however, the levator labii superioris alaeque nasi is less important in the for-mation of a smile, especially if elevating the medial aspect of the upper lip is minimal when they do smile. In many other individuals, the zygomaticus complex, along with a contribution from the levator labii superioris and levator anguli oris, can deepen the middle and lower lateral portions of the nasolabial fold and even exaggerate lateral canthal wrinkles, extending crow’s feet downward over the surface of the mid and lateral cheeks ( Fig. 4.39 ) (see pp. 64–79).

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 121

Figure 4.35 The different morphological types of nasolabial folds. Source : Adapted from Ref. 25 .

Convex(A) (B)

(C)

Straight

Concave

Figure 4.36 Clinical examples of the types of nasolabial folds: (A) convex; (B) straight; (C) concave. Source: From Refs. 25, 26.

Convex(A)

(B)

(C)

Straight

Concave

122 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.37 Different lengths of the nasolabial folds in relationship to the corner of the buccal commissures: (A) short; (B) extended; (C) continuous. Source : From Ref. 26.

Short(A)

(B)

(C)

Extended

Continuous

In most individuals the zygomaticus major and levator anguli oris help to elevate the corner of the mouth and move it laterally and slightly upward with smiling. In so doing, they also can mobilize mid cheek skin upward and laterally, extending the lower crow’s feet down the face, especially in individuals who have inelastic, loose, redundant skin.

The zygomaticus major originates on the lower aspect of the zygomatic bone, just anterior to the zygomaticotemporal suture line ( Fig. 4.34 ). It then continues downward toward the angle of the mouth and joins other muscle fibers of the modiolus before its fibers reach the oral commissure. There the zygomaticus major interdigitates with the fibers of the levator anguli oris and superficial and deep fibers of the orbicularis oris. In 66% of 50 cadavers dissected, the zygomaticus major was present as a single muscle ( 26 ). In the other 34% of the cadavers studied, the zygomaticus major appeared bifid with two separate muscle bundles and was more common in the female cadavers. The larger main bundle decussated into the modiolus and then inserted into or above the corner of the mouth, while the more superficial and narrower one inserted into the deep dermis below the corner of the mouth ( 25 , 26 ). When pulled upon separately, the superficial bundle created a concave nasolabial fold, and the main bundle created a convex nasolabial fold. On occasion, additional dermal insertions were found along the course of the smaller, more superficial bundle. This was thought to represent the reason for the presence of parabuccal dimples.

The zygomaticus minor, on the other hand, when present, originates more medially on the zygoma than the zygomaticus major just behind the zygomaticomaxillary suture line and deep to the orbicularis oculi ( Fig. 4.34 ). The fibers of the zygomaticus minor move downward to insert more medially and directly into the upper lip, interdigitating

Figure 4.38 Sections of the nasolabial fold: (A) medial (or upper) nasolabial fold; (B) middle nasolabial fold; (C) lateral (or lower) nasolabial fold. Source: From Ref. 27.

A

B

C

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 123

Figure 4.39 Lower crow’s feet, lateral cheek rhytides and deep nasolabial folds. Note also the horizontal wrinkle on the upper lip.

with fibers of the levator labii superioris. In the same cadaver dissec-tion study by Pessa et al., the zygomaticus minor was present in only 36% of the specimens ( 26 ). The zygomaticus minor helps elevate the center of the upper lip, exposing the maxillary teeth. Both muscles of the zygomaticus complex can deepen the nasolabial fold when they contract. In most individuals, when the zygomaticus minor contracts together with the central upper lip levators (i.e. levator labii superioris alaeque nasi and levator labii superioris), they will cause the upper lip to curl when expressing smugness, contempt, or disdain.

The levator labii superioris alaeque nasi originates from the supe-rior part of the frontal process of the maxilla close to the side of the nose (Fig. 4.40 ). It travels obliquely downward and laterally, dividing itself into two separate muscle bundles. The one smaller bundle inserts medially into the perichondrium of the lateral crus of the greater alar cartilage and skin of the nose, while interdigitating with fibers of the dilator naris. The other larger lateral bundle continues downward toward the medial aspect of the upper lip and crosses over the front of the levator labii superioris, merging its fibers with those of the levator labii superioris and orbicularis oris. It inserts under the dermis and into the overlying skin of the ipsilateral upper lip near the upper part of the nasolabial furrow and fold. The lateral labial muscle bundle raises and everts the upper lip and raises, deep-ens, and increases the curvature of the upper part of the nasolabial sulcus. The medial nasal muscle bundle pulls the lateral cartilagi-nous crus laterally and upward to dilate the nostrils. It also displaces the circumalar facial sulcus laterally, modifying its curvature and elevates the nasolabial sulcus and fold ( 30 ).

The levator labii superioris is the widest of all the lip levators and it originates from the maxilla at the lower margin of the orbit, just above the infraorbital foramen, deep to the orbicularis oculi (Fig. 4.41 ). Coursing downward between the lateral labial bundle of the levator labii superioris alaeque nasi, the zygomaticus minor, and the levator anguli oris, some of its fibers insert directly into the skin overlying

these muscles in the central and lateral aspect of the upper lip and other fibers interdigitate with those of the orbicularis oris. Its function is to raise and evert the central aspect of the upper lip. In conjunction with other muscles, it moves and deepens the middle of the nasolabial sulcus, especially during expressions of seriousness and sadness.

The levator anguli oris originates more deeply in the canine fossa of the maxilla, just below the infraorbital foramen (Fig. 4.42 ). It lies deeply beneath the upper lip levators and the zygomaticus complex. Its muscle fibers travel downward into the modiolus and then decussate with those of the zygomaticus major while wrapping around the oral commissure to interdigitate with the fibers of the orbicularis oris and the depressor anguli oris. The levator anguli oris then inserts into the overlying skin at and just below the angle of the mouth and the lower portion of the nasolabial sulcus. It raises the lateral aspect of the upper lip, and the corners of the mouth when smiling or laughing. In some patients, it also deepens and shifts the contour of the lower nasolabial sulcus ( Fig. 4.42 ).

The preceding group of four muscles was previously identified as the quadratus labii superioris , which, when contracted, was felt to cause the nasolabial sulcus to deepen. The quadratus labii superioris was described as comprising four muscle heads: the angular head or the levator labii superioris alaeque nasi, the infraorbital head or the levator labii superioris, the zygomatic head or the zygomaticus minor, and the canine head or the levator anguli oris ( Fig. 4.43 ).

Dilution (see Appendix 2)

Injecting minimal volumes of onabotulinumtoxinA in this area is

of paramount importance so as not to have unintended diffusion

of the onabotulinumtoxinA affect the surrounding muscles of the

midface. Therefore, a 100 U vial of onabotulinumtoxinA should be

reconstituted with only 1 ml of normal saline.

124 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.41 The levator labii superioris is a deeper muscle originating under the orbicularis oculi.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Figure 4.40 The levator labii superioris alaeque nasi is divided into two separate bundles of muscles distally; the medial bundle inserts into the skin over the ala nasi and interdigitates with the fibers of the dilator naris, and the lateral bundle inserts into the skin and mucosa of the center of the upper lip interdigitating with fibers of the orbicu-laris oris.

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 125

Figure 4.42 The levator anguli oris lies deep to the muscles of the midface.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Buccinator

Masseter

Depressor labiiinferiorisMentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Modiolus

Platysma

Depressor angulioris

Levator angulioris

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) Injecting 1 and not more than 2 U of onabotulinumtoxinA into the middle of the nasofacial angle just lateral to the upper border of the ala nasi will weaken the lateral fibers and some of the medial fibers of the levator labii superioris alaeque nasi and flatten the upper and medial aspect of the nasolabial fold ( Figs. 4.44 and 4.45 ). While sitting or in the semi reclined position, ask the patient to snarl or lift the upper lip forcibly in an upward direction as one does when sneering or expressing abhorrence, disgust or repugnance ( Fig. 4.46 ). With the index finger of the non-dominant hand directly over the nasofacial angle and palpating the area gently, one will feel the contracture of muscle fibers as the patient repeats the sneer maneuver. With the nee-dle pointed perpendicularly to the surface of the skin advance it approximately 3 to 5 mm deep and just before contacting bone as not to inflict undue pain on the patient. Inject only 1 or 2 U of onabotu-linumtoxinA directly into the thickest bulge of muscle contraction ( Fig. 4.47 ). Depending on the position and depth of the nasolabial sulcus and the height of the nasolabial fold, the bulge of muscle contracture palpated may actually correspond to the interdigitating lower fibers of the levator labii superioris and zygomaticus minor together with the lower lateral labial fibers of the levator labii superi-oris alaeque nasi ( Fig. 4.48 ). This also is the same technique used to inject onabotulinumtoxinA to reduce a gummy smile (see pp. 132–138). These injection techniques should be performed only by the very experienced physician whose patient possesses nasolabial folds that are deep and become exaggerated with a simple upward movement of the upper lip, as in sniffing, sneering, and smiling ( Fig. 4.49A,B ). Proper patient selection is of paramount importance, because untoward sequelae resulting in a lack of control of essential buccal sphincter functions can occur very easily and be devastating to the patient. The use of electromyographic guidance when treating this area can be helpful to the novice injector.

For those patients who produce innumerable wrinkles of the mid cheek with smiling or squinting, an intradermal injection of 1 to 2 U of onabotulinumtoxinA near the origins of the zygomaticus com-plex along the inferior lateral margin of the zygomatic arch at the infe-rior border of the orbicularis oculi of the lower eyelid can achieve an additive effect of diminishing lower lateral canthal rhytides along with effacing nasolabial folds ( Fig. 4.50 ) ( 31 ). Depending on the idiosyn-cratic anatomy of a particular individual, the shape of the face, and the strength of the muscles, it might be necessary to administer one, two, or multiple injections of onabotulinumtoxinA, each over the mid to lateral malar prominence, to obtain the consistent results desired (see pp. 64–79) ( 5 , 31 , 33 ). This technique is always accompanied by a drop of the upper lip or a reduction in the lateral excursion of the oral com-missures especially when smiling, laughing, or speaking ( Fig. 4.50 ) (see pp. 132–138 and 190–197).

Shao-Ping, et al injected a total of 20 to 25 U of onabotulinum-toxinA intradermally into the entire face lateral to the nasolabial fold, including the temples and cheeks from the infraorbital area to the jawline at 1 cm intervals ( 32 ). A 100 U vial of onabotulinumtoxinA was reconstituted with 10 mL of normal saline to achieve a concen-tration of 10 U of onabotulinumtoxinA for each 1 mL of solution. Each site on the face was injected with 0.02 mL of onabotulinum-toxinA solution. This technique of microBOTOX (also known as mesoBOTOX) injections is very popular in Asian countries where a subtle lifting and diminution of the fine facial wrinkling is in demand (see chapter 6).

Outcomes (Results) (see Appendix 4) There have been a few attempts to establish a fail-safe technique in which some of the upper lip levators could be treated with ona-botulinumtoxinA to reduce a deep nasolabial sulcus and fold with-out attendant adverse effects. If one considers the levator labii superioris alaeque nasi, the principal muscle that creates the

126 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

(A)

(B)

Figure 4.43 Quadratus labii superioris, (A) viewed from the side and (B) viewed from the front.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 127

nasolabial fold, and the other central and lateral lip levators (the levator labii superioris, zygomaticus complex, levator anguli oris, and risorius) responsible for deepening the nasolabial sulcus when they contract, then precisely placed low-volume injections of ona-botulinumtoxinA should be able to reduce the appearance of the nasolabial fold and the depth of its sulcus. Because this is not the only or primary function of these muscles, injections of onabotu-linumtoxinA can unwittingly produce secondary changes that

Figure 4.44 “●” marks the point where 1 U of onabotulinumtoxinA was injected into this 53-year-old to diminish the depth of the nasolabial sulcus. Note the elongation of the upper lip, flattening of the philtrum and thinning of the vermillion in this patient at rest.

∑ ∑

Figure 4.45 “●” marks the point where 1 to 2 U of onabotulinumtoxinA can be injected to weaken the lateral labial and some of the medial nasal fibers of the levator labii superioris alaeque nasi to diminish the depth of the nasolabial fold.

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

interfere with and diminish the primary functions of these muscles, i.e. elevating the upper lip and laterally abducting the corners of the mouth, which are necessary movements when one speaks, smiles, laughs, yawns, or forcibly breathes by mouth. Nasolabial fold efface-ment and its accompanying side effects can last up to 3 months or as long as the onabotulinumtoxinA treatment is effective.

Petchngaovila describes an intradermal injection technique of highly diluted onabotulinumtoxinA, which relaxes what she considers

128 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.46 Elevation of the upper lip when sneering, sniffing or smiling will contract the levator labii superioris alaeque nasi as well as the levator labii superioris and the zygomaticus minor in most patients. Note the deep nasolabial fold and gummy smile.

Complications (Adverse Sequlae) (see Appendix 5) Just 1 to 3 U of onabotulinumtoxinA into each lip levator complex in the lower nasofacial sulcus will collapse the upper extent of the naso-labial fold and also elongate the upper lip, with fairly long lasting results ( 1 ). However, injecting this area can result in a flat midface with elongation of the upper lip, effacement of the philtrum, and narrowing and diminishing the fullness of the upper lip vermillion. An appearance that is not well accepted by most individuals, especially those who already have a naturally longer upper lip ( Fig. 4.54 ). Over-zealous treatment of this area can result in an asymmetric smile and a ptotic upper lip, causing drooling and fluid incontinence when drink-ing from a glass or cup. It also can result in biting the upper lip when chewing. In most patients, these nasolabial lines are best treated with soft tissue fillers, implants, or surgical rhytidectomy, and not with onabotulinumtoxinA ( 3 ).

Injecting onabotulinumtoxinA any lower than the upper alar facial border, i.e. closer to the alar labial sulcus or along the nasal sill, can produce a weakening of the central upper lip levators and the orbicu-laris oris that can produce an inability to elevate the upper lip, elongating its overall dimensions. This is a common technique used to drop the upper lip and correct a gummy smile, but is not appropriate in most patients just seeking a reduction in the fullness of their nasolabial folds (see pp. 132–138).

Usually, injecting only 1 to 2 U of onabotulinumtoxinA intrader-mally away from the mouth, and near the origins of the zygomaticus major et minor and levator labii superioris at the inferior border of the lateral orbital orbicularis oculi, can help both diminish the nasolabial fold and efface the lower lateral canthal wrinkles and lower lateral cheek rhytides. This technique usually is accompanied by a reduction in the strength of the upper lip sphincter competence and smile sym-metry ( 3 , 5 ). It is extremely important, however, that minimal volume onabotulinumtoxinA is injected deeply and precisely into the fibers of the targeted muscles, to lightly weaken and not paralyze them. Even with a light weakening of the levator labii superioris and the zygomatic complex, a certain amount of lip ptosis will occur, and is actually expected. This should be discussed with the patient before treatment, and should not be considered a true adverse outcome or complication ( Figs. 4.44 and 4.54 ) ( 2 , 34 ) (see chapter 6 for similar results with the microinjection technique).

In older patients who have a large amount of excessive fat deposi-tion or ptotic malar fat along with redundant skin lateral to the nasolabial sulcus, weakening the central upper lip levators will have no effect on the extent and depth of the nasolabial folds. The nasola-bial folds might even be enhanced if the lateral upper lip levators are

Figure 4.47 Injecting onabotulinumtoxinA should be performed intramuscularly with the needle perpendicular to the skin surface.

the major depressors of the face (i.e. platysma and lateral orbicularis oculi) and allows the levators of the midface (zygomaticus complex, levator labii superioris alaeque nasi, levator labii superioris, levator anguli oris) and lateral frontalis to reverse the sagging and wrinkling of the upper and mid face ( 33 ). According to Petchngaovila, this intradermal midface lifting realigns the imbalance of the muscles of the midface by weakening the downward pull of the depressors ( platysma, lateral fibers of the orbicularis oculi) and allowing the levators of the midface and lateral frontalis to contract and lift the skin in a compensatory fashion. This treatment requires not only multiple repeat injections before obvious results are produced, but also frequent maintenance injections every 2 to 3 months. This procedure is best done for sheet-like muscles rather than for muscle bundles, and when the muscles are flaccid and poorly defined. This technique also is best suited for older patients with loose, lax skin who want to realign and uplift their midface, diminish the wrinkling of their cheeks and soften the nasolabial folds ( Figs. 4.51–4.53 ) (see chapter 6).

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 129

Figure 4.49 This 51-year-old has deep nasolabial folds at rest (A), which are exaggerated by smiling (B). Note the inversion and foreshortening of the upper lip with smiling.

(A) (B)

weakened, causing a reduction in the lateral muscle support, which in turn will allow the ptotic fat and redundant skin to sag even more so. On the other hand, in younger patients with good cutaneous elasticity and soft tissue support (i.e. those in their early thirties to late fifties) much of the appearance of the nasolabial fold is caused by mimetic muscle contraction, the bulk of which can be attributed to the levator labii superioris alaeque nasi. When this muscle is weakened in younger persons, the nasolabial fold is diminished, usually uneventfully. Attempting to weaken some of the other upper lip levators may cause

undesirable sequelae, e.g., upper lip ptosis, buccal asymmetry, and even oral sphincter incompetence. For example, also weakening the zygo-maticus muscles can soften the nasolabial folds, but the smile may be changed, reducing the extent of the upward and lateral excursion of one’s smile. However, for those patients displaying an excessive amount of gingiva when smiling or laughing, weakening of the central upper lip levators may actually be desirable, because it can reduce the full upward movement of the upper lip, that overexposes the crown and gums of the upper incisors and canines (see pp. 132–138).

Figure 4.48 “●” marks the point where 1 to 2 U of onabotulinumtoxinA can be injected to weaken the levator labii superioris and zygomatic minor along with the levator labii superioris alaeque nasi to diminish the nasolabial fold.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilli

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

130 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Injecting onabotulinumtoxinA in the midface in an attempt to diminish the nasolabial folds and to eliminate the random wrinkling of the lateral aspect and center of the cheeks produced by squinting or smiling should only be attempted by the most experienced physician injector ( 6 ). Selecting the right patient can be more important than any

Figure 4.51 This 40-year-old patient is seen (A) before, (B) 2 weeks after intramuscular treatments, and (C) 10 weeks after intradermal injections of BoNTA, giving her a slight lift of the total face. Source : Courtesy of Chariya Petchngaovila, MD.

(A) (B) (C)

other aspect of an onabotulinumtoxinA injection. Understanding how certain facial and cheek wrinkles and folds are produced, and how to palpate and identify the target muscles for injection, is the key to success or failure. Attempting to reduce midcheek wrinkling and nasolabial folds with injections of onabotulinumtoxinA can result in not only a

Figure 4.50 Intradermal injection of 1 to 2 U of onabotulinumtoxinA (●) at the lateral zygomatic arch near the origin of the zygomaticus complex can diminish lower crow’s feet lines, mid cheek wrinkles and help efface the upper and mid nasolabial sulcus and fold. Depending on the individual’s anatomy, shape of face and strength of the muscles, a second injection point (*) might be necessary to produce the same results. See chapter 6 on microinjections of BoNTA.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

* *

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 131

Figure 4.52 This 61-year-old is seen before and 2 weeks after intradermal injections of onabotulinumtoxinA. Note the overall appearance of a “facial lift.” Source: Courtesy of Chariya Petchngaovila, MD.

Figure 4.53 This 33-year-old is seen before and 10 days after intradermal injections of onabotulinumtoxinA giving her the appearance of a “facial lift.” Source: Courtesy of Chariya Petchngaovila, MD.

unconditionally the expected and inadvertent sequelae. Subcising deeply adherent nasolabial sulci, injecting them with a soft tissue filler and resurfacing the cheeks by chemical peeling, dermabrasion, or laser ablation (fractionated) is probably a more dependable way to address these problems and produce consistent, longer lasting results ( 5 ).

flattening of the nasolabial fold, but also an overall flattening of the cheek and an elongation of the upper lip, an eklabion or lip ptosis as well as lip asymmetry and lack of oral sphincter control ( 33 ). For these reasons, it is probably most advisable not to treat this area of the mid face with onabotulinumtoxinA unless the patient is willing to endure

132 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

EXAGGERATED UPPER GUMMY SMILE Introduction: Problem Assessment and Patient Selection Some individuals have a tendency to reveal an excessive amount of their upper gum mucosa when they smile or laugh. This commonly is seen as a familial trait, which is especially disconcerting in women who display this type of smile. Most of the time, since this is a source of considerable embarrassment, one can observe these individuals con-cealing with their fingertips the appearance of their teeth when they smile or laugh. Also, while speaking in an animated fashion which causes them to smile or laugh during conversation, they can be seen covering their mouths in whatever way possible. No matter how hard

they try, it is impossible for these individuals to smile or laugh without revealing their upper gingiva. Consequently, they attempt only to smile partially when being photographed or during social interactions, which creates a certain amount of anxiety for those who are more self-conscious. These individuals also tend to have sharply defined nas olabial folds with deep furrows ( Fig. 4.55 ).

Some patients, in conjunction with the inadvertent shortening of their upper lip causing an exaggerated gingival smile, also are plagued with exhibiting an involuntary lowering of the tip of their nose (see pp. 112–119). There are still others who also form a transverse furrow across the philtrum of their upper lip when they speak, laugh, or smile. Occasionally, the same person will exhibit a combination all of these changes ( Fig. 4.56 ). A horizontal furrow across the upper lip usually is seen in older individuals or in those whose photodamaged skin has reduced elasticity and soft tissue bulk, causing the lax upper lip skin to wrinkle easily with every lip movement ( Fig. 4.56 ). Many of these individuals also have a long history of smoking tobacco.

Functional Anatomy (see Appendix 1) The aesthetics of the ideal tooth exposure when smiling varies accord-ing to idiosyncratic structural and topographic anatomy, but has been loosely calculated to be three-quarters of the dental crown height of the upper incisors and no more exposure than 1 to 2 mm of upper gum mucosa ( 35 , 36 ). Generally, men show less gum and interlabial excur-sion than women ( 37 , 38 ). There are many reasons for a “gingival smile.” It can be the result of an increase in the interlabial space combined with an excessive contraction of the upper lip levators, producing an exces-sive amount of exposure of the gums upon smiling or laughing ( 37 , 38 ). Additional causes of an exaggerated upper gummy smile include an elongation of facial height created by an excessive vertical length of the maxilla, a genetically short upper lip, and a short crown length with or without malpositioning of the incisors ( 39 ).

Functionally, according to Rubin, there are three patterns of smiles by which an individual is identified ( 40 , 41 ). The first and most com-monly encountered type of smile (67% of the patients studied) is when the zygomaticus major dominates the movement of the lips. This is called the “Mona Lisa” smile and is initiated with a sharp elevation and outward pull of the corners of the mouth and then a soft elevation of the center of the upper lip, revealing approximately 80% of the incisors ( Fig. 4.57 ). This type of smile is produced predominantly by the pull of the zygomaticus major.

Figure 4.54 This 29-year-old patient smiling before and 2 weeks after a treatment with onabotulinumtoxinA to efface a deep nasolabial fold. Note the slight upper lip ptosis that is unavoidable with this treatment. Note the upward direction of the commissures, which is created by the untreated and unopposed action of the zygomaticus major, levator anguli oris, and risorius.

Treatment Implications When Injecting Nasolabial Folds

1. Successful treatment of the nasolabial fold is absolutely depen-

dent upon proper patient assessment of what actually is causing

and exaggerating the nasolabial fold and sulcus.

2. The levator labii superioris alaeque nasi is usually the muscle

primarily responsible for the creation of the upper medial por-

tion of the nasolabial sulcus and fold.

3. Nasolabial folds are best reduced by injections of soft tissue fi ll-

ers, implants, and surgical rhytidectomy and subcision rather

than with injections of onabotulinumtoxinA.

4. In the properly selected patient injections of 1 to 2 U of ona-

botulinumtoxinA should be given in the nasofacial or upper alar

facial sulcus in an attempt to fl atten the nasolabial fold.

5. Injections of onabotulinumtoxinA too low along the alar facial

angle will produce an elongation or ptosis of the upper lip, an

asymmetric smile, and functional incompetence of the oral

sphincter.

6. Injections of onabotulinumtoxinA too lateral to the nasofacial

angle will produce an overall fl attening of the midcheek and a

drop in the soft tissue support of the malar fat pad.

7. In the properly selected patient, a combination of injections of

onabotulinumtoxinA and either soft tissue fi llers or some form

of surgical intervention or both will produce longer lasting results

than if the nasolabial folds were treated solely with either alone.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 133

Figure 4.55 Individuals with a gummy smile commonly will have deep nasolabial folds and furrows as seen in this 23 year old.

The canine smile is the second most commonly identified smile pattern (35% of the patients studied) and is characterized by a high elevation of the center of the upper lip, exposing the canine teeth first before the rest of the upper lip is elevated ( Fig. 4.58A ). The canine smile can produce anywhere from a partial central dental reveal to an exagger-ated full denture show with a certain amount of gingival exposure ( Fig. 4.58B ). This pattern of smile is produced predominantly by the contraction of the levator labii superioris elevating the upper lip. When the contraction of the levator labii superioris is intense and severe, a gummy smile results ( Fig. 4.55 ).

The third and least commonly seen smile pattern is the full denture smile, which was seen in about 2% of the patients studied. The full denture smile is characterized by the simultaneous separation of both the upper and lower lips in which both the upper and lower dentures have partial or full exposure. This type of smile is the result of the con-traction of all the upper lip levators and lower lip depressors around the mouth all at the same time ( Figs. 4.59 and 4.60 ).

Commonly found with a simple canine or an exaggerated canine smile (i.e. a “gummy smile”) are individuals with deep nasolabial furrows and highly mounded nasolabial folds ( Figs. 4.55 – 4.57 ). These

two conditions usually are found together, because contraction of the levator labii superioris alaeque nasi creates an ascending steep medial nasolabial fold while lifting the central upper lip a few extra millime-ters, which also can expose alveolar gingiva. With such hyperkinetic upper lip levators, asymmetric smiles usually are not uncommon ( Figs. 4.60–4.62 ).

Figure 4.56 A transverse rhytide is seen across the philtrum of the upper lip at rest, which is intensified with smiling in this 68-year-old non-smoker with extensive photodamage. Note the minimal gummy smile, deep nasolabial folds and furrows, widening of the alar base, and the slight nasal tip downward rotation with smiling.

Dilution (see Appendix 2)

Injecting minimal amounts of low-volume onabotulinumtoxinA

in the midface is of paramount importance. The least amount of

diffusion of onabotulinumtoxinA in this area of stratifi ed lamellae

of different muscle bundles can be disastrous to the overall thera-

peutic success and cosmetic appearance of the patient. The repu-

tation of a physician injector who treats the midface is tenured in

the aesthetic outcomes of his efforts. Therefore, the most qualifi ed

physicians treating this area of the face will reconstitute a 100 U vial

of onabotulinumtoxinA with only 1 ml of normal saline.

Figure 4.57 The most common type of smile is produced primarily by the pull of the zygomaticus major.

134 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 4.59 The full denture smile is characterized by the simultaneous partial or full exposure of both upper and lower dentures.

Figure 4.60 The full denture smile is a result of the contraction of all the upper lip levators and lower lip depressors around the mouth, all at the same time. Note a slight ptosis of the upper left quadrant.

Figure 4.58 ( A ) The canine smile exposes the canine teeth before the rest of the upper lip is elevated. ( B ) An exaggerated canine smile in a younger patient.

(A) (B)

Figure 4.61 Hyperkinetic central upper lip levators create a slight gummy canine smile that is asymmetrically higher in the upper right quadrant of this 29 year old. Note the deep nasolabial folds.

Figure 4.62 Hyperkinetic lateral upper lip levators create a slightly gummy smile that is asymmetrically higher in the upper right quadrant of this 20 year old. Note the deep nasolabial folds.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 135

Figure 4.63 Place the needle perpendicular to the skin surface and inject 1 to 2 U of onabotulinumtoxinA deeply into the belly of the muscle at the nasomaxillary groove while the patient smiles excessively.

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) To nonsurgically elongate the upper lip, especially during a smile, the central upper lip levators (levator labii superioris alaeque nasi or levator labii superioris) need to be gently relaxed (not paralyzed) with injections of onabotulinumtoxinA. This can be accomplished with the patient in a sitting or semireclined position. Then palpate the nasomaxillary groove with the fingertip of the index finger of the non-dominant hand, until the finger tip pad straddles the lower lateral aspect of the alar facial sulcus and the superior edge of the maxillary alveolar process. Excessive pressure

with palpation in this area can cause some discomfort to the patient, so this maneuver should be done as expeditiously as possible. As the patient smiles with the index finger in this position, contraction of the levator labii superioris alaeque nasi can be felt. At the point of maximum thick-ness of the muscle, insert the needle perpendicularly to the surface of the skin and deeply into the nasofacial groove for about 3 to 5 mm. Inject 1 to 2 U of onabotulinumtoxinA intramuscularly and just above the peri-osteum of the canine fossa ( Fig. 4.63 ). An additional unit of onabotu-linumtoxinA may be required if the central lip levators are very strong and the center of the upper lip is lifted extremely high. Remember to reserve this injection technique only for those patients who have an exag-gerated gingival smile, and in whom the levator labii superioris alaeque nasi can be palpated. Also, remember that injecting onabotulinumtox-inA at this site may reduce the height and extent of the nasolabial fold by weakening the levator labii superioris and the levator labii superioris alaeque nasi ( Figs. 4.64 ). The more laterally located lip levators, i.e. zygo-maticus major and minor, levator anguli oris, and risorius, are to be avoided; otherwise, either an adynamic or asymmetric smile can result. Weakening the central upper lip levators without affecting these lateral upper lip levators allows the lateral levators full and uninhibited move-ment during a smile. This can be enhanced by also treating the depressor anguli oris with onabotulinumtoxinA, thereby removing any additional antagonistic depressor action against the lateral upper lip levators. The depressor septi nasi at times may require treatment with 1–2 U of ona-botulinumtoxinA along the length of the columella. This additional maneuver will help produce a more natural smile, while lowering the central aspect of the upper lip and reducing the depth of a horizontal upper lip crease and the extent of an exaggerated gummy smile. If migra-tion of onabotulinumtoxinA extends into the superficial fibers of the orbicularis oris an inability to fully pucker the lips also will occur. Another technique is to inject 1 to 2 U of onabotulinumtoxinA intra-orally into the bellies of the two central upper lip levators ( Fig. 4.65 ) ( 38 )

Figure 4.64 The central lip levators (i.e. direct tractors): levator labii superioris alaeque nasi and levator labii superioris can be treated with 1 or 2 U of onabotulinumtoxinA ● to diminish a gummy smile. The indirect tractor, depressor septi nasi, also may be treated with 1–2 U of onabotulinumtoxinA ● when upper lip retraction is extreme.

Frontalis

Procerus

Corrugator supercilli

Depressor supercilli

Orbicularis oculi

Compressor naris

Dilator naris

Zygomaticus minor

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Levator labii superioris

Levator labii superiorisalaeque nasi

136 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

by passing the needle through the gingivo-labial sulcus above the alveolar ridge at the same point in the nasofacial groove and canine fossa as described above. A minimum dose of low-volume onabotulinumtoxinA should just barely relax the central upper lip levators so that the upper lip cannot fully retract upward. If the excessive gummy show is at its highest in the center of the upper lip, then 1 U of onabotulinumtoxinA can be injected into the depressor septi nasi at the base of the columella ( Figs. 4.64 and 4.66 ).

Outcomes (Results) (see Appendix 4) Treating those patients with an exaggerated gingival smile can produce a variety of anatomic and functional changes. By limiting the exaggerated upward movement of the upper lip with injections of onabotulinum-toxinA, an obvious reduction in the amount of upper gingival and dental show will result, along with an elongation of the upper lip, a flattening of the philtrum, a thinning of the vermillion, and an effacement of the medial aspect of the nasolabial fold and sulcus ( Fig. 4.44 ).

Polo conducted a study to determine the doses required and the injection sites preferred to correct gummy smiles, and to provide consistent, statistically significant and aesthetically pleasing results ( 39 ). Thirty patients (29 female, 1 male) with an upper gummy smile caused by hyperfunctional upper lip levators received 2.5 U of ona-botulinumtoxinA at 2 sites per side (a total of 4 sites) in two distinct points lateral to the alar facial angle. The one injection point was more medial and at the alar facial angle where the levator labii superioris alaeque nasi overlaps with the levator labii superioris. The other injection point was more lateral and where the levator labii superioris overlaps with the zygomaticus minor. The injection sites were determined by palpation of contracting musculature while the patient smiled. No electromyographic guidance was used. A gummy smile was defined as an excessive gingival display above the tooth crown of at least 3.0 mm upon unrestricted, nonposed, “full-blown,” spontaneous smiling. There were more females (96%) than males (4%) who possessed a gummy smile. Preinjection gingival display averaged 5.2 mm ( ± 1.4 mm). Two weeks after treatment, the mean gingival display declined to 0.09 mm ( ± 1.06 mm). The mean reduc-tion in gingival display at 2 weeks for all 30 patients was 5.1 mm. Along with the anticipated relative lengthening of the upper lip upon

Figure 4.66 The central lip levators (i.e. direct tractors): levator superioris alaeque nasi and levator labii superioris can be treated with 1–2 U of onabotulinumtoxinA ● to diminish a gummy smile. The indirect tractor, depressor septi nasi, also may be treated with 1–2 U onabotulinumtoxinA ● when upper lip retraction is extreme.

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugatorsupercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

Figure 4.65 The intraoral injection of the central lip levators may be less painful to the patient, but a less precise way of injecting by the physician.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 137

smiling, Polo also reported a marked reduction of the nasolabial fold as the most frequently observed accompanying side effect. Other attendant sequelae included a reduction in the hypercontractibility of the transverse nasalis when smiling and an effacement of lower periocular rhytides of the orbital orbicularis oculi. This was thought to be caused by the relaxation of the decussating muscle fibers of the levator labii superioris alaeque nasi, levator labii superioris and zygo-maticus minor with the transverse nasalis and orbicularis oculi. The author also concluded that the dose of 5 U per side was best for

patients who had at least a 5.0 mm gingival display. For those who had less than a 5.0 mm gingival display, lower doses of onabotu-linumtoxinA were more appropriate. The results lasted 24 to 30 weeks.

In addition, it may be possible to diminish the appearance of an idiosyncratic horizontal rhytide when it is present across the upper lip ( Figs. 4.56 and 4.67 ). An additional 1 to 2 U of onabotulinumtoxinA at the base of the columella into the depressor septi nasi by the technique described above (page 136) may be necessary to further eliminate the central aspect of this horizontal upper lip rhytide

Figure 4.67 Note the transverse rhytide across the upper lip in this light complected 68-year-old individual both at rest and when smiling.

Figure 4.68 Properly functioning levator labii superioris alaeque nasi, zygomaticus major and minor, levator labii superioris, levator anguli oris, risorius and orbicularis oris are essential for buccal sphincter competence.

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Compressor naris

Dilator naris

Zygomaticus minor

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Levator labii superioris

Levator labii superiorisalaeque nasi

138 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

( Figs. 4.22 and 4.25 ). Most of the time, however, injections of a soft tissue filler is the only way to completely efface a deep, transverse upper lip wrinkle, especially when it persists after an onabotulinum-toxinA treatment of the central levators of the upper lip. No more than 2 U of onabotulinumtoxinA at each injection site should be attempted, especially during the initial treatment session. Remember to avoid injecting and affecting the deep fibers of the orbicularis oris; otherwise, lip incompetence and asymmetry will occur. In patients with extremely thin and atrophic lips, the transverse lip rhytide may not be amenable to treatments of onabotulinumtoxinA, because atro-phic skin will readily crease and develop wrinkling superficially with the least bit of lip movement. The majority of patients who develop the transverse rhytides across their upper lip seem to be those over the age of 60 years who are of light complexion (usually of skin type II and III), have spent a lot of time outdoors, and may or may not have a his-tory of smoking tobacco ( Figs. 4.56 and 4.67 ) .

Complications (Adverse Sequelae) (see Appendix 5) Because of the anatomy of the different codependent levator muscles and their attachments in both the upper lip skin and orbicularis oris, the risk–benefit ratio of treating a patient with a gingival smile is high and the potential comorbidity is significant. Assistance with an electro-myograph (EMG) might ensure more accurate needle placement and avoid untoward results when attempting to treat an exaggerated upper gummy smile with injections of onabotulinumtoxinA. Inaccurate nee-dle placement or overzealous dosing in this area is subject to upper lip ptosis and an asymmetric smile, which, in turn, might be coupled with buccal sphincter incompetence, difficulty with producing particular sounds and articulating certain words, and an inability to move the upper lip in a full smile or pucker. The upper lip levators (i.e. levator labii superioris alaeque, levator labii superioris, the zygomaticus com-plex, risorius, levator anguli oris, and orbicularis oris) ( Fig. 4.68 ) can easily be affected by the least amount of inadvertent diffusion of onabotulinumtoxinA. Buccal sphincter incompetence can result in an embarrassing public display of functional compromise, especially when incontinence of liquid or solids is the result.

REFERENCES 1. Carruthers J, Carruthers A. Botulinum toxin (BOTOX ® ) use in the

mid and lower face and neck. Semin Cutan Med Surg 2001; 20: 85–92

2. Matarasso A. Discussion: new indications for botulinum toxin type A in cosmetics: mouth and neck. Plast Reconstr Surg 2003; 110: 86S–87S

3. Rohrich RJ, Janis JE, Fagien S et al . The cosmetic use of botulinum toxin. Plast Reconstr Surg 2003; 112(Suppl): 177S–187S.

4. Fagien, S, Rasplado, H. Facial rejuvenation with botulinum neuro-toxin: An anatomical and experiential perspective. J Cos Laser Th 2007; 9 (suppl 1): 23–31.

5. Carruthers JD, Glogau, RG, Blitzer, A et al. Advances in facial reju-ventation: Botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies—consensus recommendations. Plast Reconstr Surg 2008; 121: 5S–30S.

6. Fagien, S. Botulinum toxin type a for facial aesthetic enhancement: role in facial shaping. Plast Reconstr Surg 2003; 112 (Suppl 1): 6S–18S.

7. Fagien S. BOTOX ® for the treatment of dynamic and hyperkinetic facial lines and furrows: adjunctive use in facial aesthetic surgery. Plast Reconstr Surg 1999; 103: 701–7.

8. Manaloto RM, Alster TS. Periorbital rejuvenation: a review of dermatologic treatments. Dermatol Surg 1999; 25: 1–9.

9. Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 1996; 34: 788–97.

10. Carruthers J, Carruthers A. Botulinum toxin (BOTOX ® ) chemo-denervation for facial rejuvenation. Facial Plast Surg 2001; 9: 197–204.

11. Carruthers J, Carruthers A. Practical cosmetic BOTOX ® techniques. J Cutaneous Med Surg 1999; 3 (Suppl 4): S49–59.

12. Blitzer A, Binder WJ. Current practices in the use of botulinum toxin in the management of facial lines and wrinkles. Facial Plast Surg 2001; 9: 395–404.

13. Matarasso SL. Complications of botulinum A exotoxin for hyper-functional lines. Derm Surg 1998; 24: 1249–54.

14. Goldwyn R, Rohrich R. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics. Supplement to Plast Reconstr Surg 2004; 114: 1S–22S.

15. Tamura BM, Odo MY, Changi B et al. Treatment of nasal wrinkles with botulinum toxin. Derm Surg 2005; 3: 271–5.

16. Arregui JS, Elejalde MV, Regalado J, et al. Dynamic rhinoplasty for the plunging nasal tip: functional unity of the inferior third of the nose. Plast Reconstr Surg . 2000: 106; 1624–9.

17. LeLouran C. Botulinum toxin A and facial lines: the variable con-centration. Aesthet Plast Surg 2001; 25: 73–84.

18. Dayan, SH, Kempiners, JJ. Treatment of the lower third of the nose and dynamic nasal tip ptosis with Botox. Plast Reconstr Surg 2005; 115: 1784.

19. Rohrich, RJ, Huynh B, Muzaffar AR, Adams WP and Robinson, JB. Importance of the depressor septi nasi muscle in rhinoplasty: Anatomic study and clinical application. Plast Reconstr Surg . 2000; 105: 376.

20. Standernig S, ed.. Gray’s Anatomy. The Anatomical Basis of Clinical Practice, 40th edn. New York: Elsevier, Churchill, Livingstone, 2008.

21. Almeida AT de Nose. In: Excel D, Almeida AT de, eds. Cosmetic Use of Botulinum Toxin. Porto Allergre, Brazil: AGE Editora, 2002: 158–63.

22. Atamoros, PF. Botulinum toxin in the lower one-third of the face. Clin Derm 2003; 21: 505–12.

23. Rohrich, RJ and Pessa JE. The fat compartments of the face: ana-tomy and clinical implications for cosmetic surgery. Plast Reconstr Surg 2007; 119: 2219–27.

Treatment Implications When Injecting a Gummy Smile

1. Injecting onabotulinumtoxinA into the levator labii superioris

alaeque nasi can reduce exaggerated gingival show by elongating

the upper lip.

2. Injecting onabotulinumtoxinA into the levator labii superioris

alaeque nasi also will efface the nasolabial sulcus and fold and

fl atten the philtrum and attenuate the vermillion.

3. Inject the levator labii superioris alaeque nasi only when it can

be defi nitely palpated; otherwise, adjacent, nontargeted mus-

cles will be affected, and lip competence and symmetry will be

compromised.

4. Inject only low volumes of low doses of onabotulinumtoxinA in

the perinasal area.

5. Prior to any treatment with onabotulinumtoxinA, inform the

patient of the potential risks, benefi ts, comorbidities, and inherent

functional and cosmetic changes expected when perioral mimetic

muscles are weakened.

6. Patients with either a zygomatic (“Mona Lisa”) smile, a full den-

ture or a canine smile without exaggerated gingival exposure

(i.e., at least a 3 mm gingival display) should not be treated with

onabotulinumtoxinA injections to reduce the nasolabial folds.

COSMETIC USES OF BOTULINUM TOXIN A IN THE MID FACE 139

24. Donofrio L, Weinkle S. The third dimension in facial rejuvenation: a review . J Cosmet Dermatol 2006; 5(4): 277–83.

25. Zufferey J. Anatomic variations of the nasolabial fold. Plast Recon-str Surg. 1992; 89(2): 225–31.

26. Pessa et al. Variability of the midfacial muscles: analysis of 50 hemifa-cial cadaver dissections. Plast Reconstr Surg . 1998; 102(6): 1888–93.

27. Pessa JE, Brown F. Independent effect of various facial mimetic muscles on the nasolabial fold. Aesth Plast Surg 1992; 16: 167–71.

28. Kane MA. The effect of botulinum toxin injections on the nasolabial fold. Plast Reconstr Surg 2003; 112(5): 66S–72S.

29. Hoefflin SM. Anatomy of the platysma and lip depressor muscles. A simplified mnemonic approach. Dermatol Surg 1998; 24: 1225–31.

30. Ingallina FM, Trevidic P. Anatomy and botulinum toxin injections. E2 e Medical Publishing/Master Collection I. www.expert2expert.co.uk

31. Fagien, S. Botox for the treatment of dynamic and hyperkinetic facial lines and furrows: adjunctive use in facial aesthetic surgery. Plast Reconstr Surg 2003; 112: 40S–52S.

32. Shao-Ping, C, et al. The wrinkles soothing effect on the middle and lower face by intradermal injection of botulinum toxin type A. Derm Surg 2008: 47, 1287–94.

33. Petchngaovila C. Midface lifting with botulinum toxin: intra-dermal technique. J Cos Derm 2009; 8: 312–316.

34. Matarasso SL, Matarasso A. Treatment guidelines for botulinum toxin type A for the periocular region and a report on partial upper lip ptosis following injections to the lateral canthal rhytides. Plast Reconstr Surg 2001; 108: 208–14.

35. Kokich VO Jr, Kiyak HA, Shapiro PA. Comparing the perception of dentists and lay people to altered dental esthetics. J Esthet Dent 1999; 11: 311–24.

36. Sarver DM. The importance of incisor positioning in the esthetic smile: the smile arc. Am J Orthod Dentofacial Orthop 2001; 120: 98–111.

37. Kokich V, Nappen D, Shapiro P. Gingival contour and clinical crown length: their effects on the esthetic appearance of maxillary anterior teeth. Am J Orthod 1984; 86: 89–94.

38. Arnett GW, Bergman RJ. Facial key to orthodontic diagnosis and treatment planning. Am J Orthod and Dentofac Orthop 1993; Part I 103: 299–312, Part II 395–411.

39. Polo, M. Botulinum toxin type a in the treatment of excessive gingival display. Am J Orthod and Dentofac Orthop 2005; 127(2): 214–18.

40. Rubin LR. The anatomy of a smile: its importance in the treatment of facial paralysis. Plast Reconstr Surg 1974; 53: 384–7.

41. Rubin LR. The anatomy of the nasolabial fold: the keystone of the smiling mechanism. Plast Reconstr Surg 1999; 103: 687–91.

140

and periorbital area. In the lower face, there is the one large depressor, the platysma that interdigitates with and opposes the levators of the perioral area. The platysma also interdigitates with and amplifies the functions of the lower face depressors. However, because of the func-tional differences and the complex muscle interactions in the lower face, only the experienced physician should attempt to reduce the vari-ous rhytides of the lower face or correct anatomic variations and asym-metries of this area with injections of onabotulinumtoxinA. Otherwise, what was intended to be remedied might very easily be exacerbated.

PERIORAL LIP LINES OR RHYTIDES Introduction: Problem Assessment and Patient Selection As the eyes are the center of focus for the upper face, enabling an indi-vidual to express deep felt emotions and personal sentiment, the mouth also is the center of focus for the lower face. A full lip with a smooth and distinct border of the vermillion delineating it from the rest of the cutaneous lip is the hallmark of youth with all its pristine beauty. With time and sun exposure, the lips become thin, flaccid, elongated, and wrinkled, lacking substance and contour. What once reflected a per-son’s vitality and sensuality now reveals the passing years of trials and tribulation, leaving one appearing weary and worn, evidenced by wrinkles on the face and betrayed by perioral rhytides.

Both static and dynamic wrinkling can be found around the mouth appearing as vertical lip lines perpendicular to the vermillion border. It has been shown that static perioral wrinkles are caused not only by intrinsic aging and photodamage, but also are precipitated by the smoking of tobacco ( 1 ). Frequent and chronic cigarette smoking also can augment perioral dynamic wrinkles, probably because of the per-sistent lip puckering and pursing needed to hold a cigarette in the mouth while inhaling and exhaling tobacco smoke ( Fig. 5.1A,B ). Dynamic perioral wrinkles are found in those who are genetically pre-disposed and frequently pout and repetitively purse their lips, whether deliberately or involuntarily. This is seen more commonly in women in the way they habitually move (i.e., pucker or purse) their lips during routine daily activities of eating, drinking, and speaking ( Fig. 5.2A ). Activities, such as cigarette smoking, sipping liquids from a straw, whistling and playing certain musical wind instruments, provide a supplemental cause in the formation of dynamic perioral rhytides. Repeated purse-string-like movements of the orbicularis oris exagger-ate and intensify the dynamic perioral lines on a daily basis. Men usu-ally are not in the habit of pursing or puckering their lips as is commonly done by women ( Fig. 5.2B ). They also are “blessed” with facial beard hair that might help preclude the fine infolding and wrin-kling of facial and labial skin. Consequently, men are less afflicted than women with perioral wrinkling, nor are they bothered by them when and if they occur. Women are particularly frustrated by these lines, especially when lipstick channels up and down these rhytides blurring the outline of the vermillion ( Fig. 5.3 ).

There are many other causes for these perioral vertical lines besides repetitive puckering of the orbicularis oris, which include chronological aging and environmental exposure, all of which can be manifested mostly as static wrinkling. Static wrinkles can be the result of identifiable causes, like chronologic aging and sun exposure, and unknown causes like genetics, gender differences, intrinsic soft tissue characteristics, and anatomic idiosyncrasies like the shape of the mouth and how it moves while functioning on a daily basis. Much of the static wrinkling of the

5 Cosmetic uses of Botulinum toxin A in the lower face, neck, and upper chest Anthony V. Benedetto

INTRODUCTION Anatomic delineation of the lower face for our purposes encompasses the perioral region, chin, and jaw line, which is the area that includes the remainder of the superficial muscles of facial expression. The orbicularis oris functions as a sphincter providing a combination of levator and depressor movements to the upper and lower lips, and the corners of the mouth. The remaining facial muscles consist mostly of the levators of the upper lip and the depressors of the lower lip. These muscles are not always antagonistic to each other, but often act syner-gistically with one another in a spontaneous, involuntary manner. They open and close the mouth and perform essential buccal functions in unison with the orbicularis oris, such as maintaining the sphincter control and lip competence that is necessary when the mouth is filled with solid material, liquid, or air. Other vital functions of the orbicu-laris oris together with its levators and depressors include the ability to make sounds and articulate them into speech, or chew and swallow solids and liquids. This is in direct contrast with the upper face where levators and depressors take on an antagonistic role and are in direct opposition to each other. In addition, by contracting the orbicularis oris along with its levators and depressors in a particularly idiosyn-cratic manner, a person deliberately or involuntarily can express various and sundry emotions.

In the lower face fibers of the orbicularis oris interdigitate with some, if not all of the upper lip levators and the lower lip depressors. Because of this interdependence of muscles, the orbicularis oris also can function as an antagonistic muscle and perform the opposite movement of either the levators and the depressors after they all have moved in unison to separate or approximate the lips when opening or closing the mouth. Upon the completion of a particular function by the labial levators and depressors, one intentionally can move the orbi-cularis oris in the opposite direction to open or shut the mouth as one does when eating or drinking, and to purse or pucker the lips as one does when blowing air, liquid or solids out of the mouth.

These subtle but functional differences in the way the various peri-oral muscles operate play a significant role in how to devise a treatment plan with onabotulinumtoxinA. One cannot just identify a levator or depressor in the lower face and weaken it as one does in the upper face with injections of onabotulinumtoxinA without affecting adjacent muscle fibers of different muscles and possibly producing adverse sequelae. Some of these untoward effects can include lip asymmetry, sphincter incompetence affecting mastication or deglutition, a distur-bance in sound production and word pronunciation and the inability to accurately convey nonverbal communication and emotions in a deliberate or a spontaneous, involuntary manner. However, as our injection techniques improve and our understanding of how the mus-cles in the lower one-third of the face respond to onabotulinumtoxinA, it is becoming increasingly obvious that the lower face and neck should be treated all together as a defined all-encompassing cosmetic unit. It is also advisable to remind patients prior to treatment that injecting ona-botulinumtoxinA for cosmetic purposes anywhere else on the face or body except in the glabella is done off-label and without FDA approval. The approach to treating the lower one-third of the face should be similar to that of the upper one-third of the face, i.e., to treat the area all-inclusively as a functional unit and not as separate, independent muscles. In the upper face, there is the one large levator, the frontalis, that interdigitates with and opposes the four depressors of the brow

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 141

perioral area can be reduced by invasive surgical procedures such as ablative skin resurfacing, (e.g., fractionated or nonfractionated laser resurfacing, mechanical dermabrasion, or chemical peeling) and other different types of surgical rhytidectomy procedures, subcision, excisions, and implants. Static wrinkling also can be reduced by noninvasive proce-dures such as injections of synthetic soft tissue fillers or autologous fat.

It is important to distinguish the dynamic wrinkles of the lips from those that are static. Static wrinkles usually are not affected by treatment with onabotulinumtoxinA. Static wrinkles can be easily distinguished from dynamic wrinkles by asking a person to purse their lips. If there are rhytides present in the lips prior to pursing them and there is minimal change or intensification of these wrinkles with movement, then their perioral rhytides are primarily static and generally not reducible by ona-botulinumtoxinA ( Fig. 5.4 ). Static wrinkles are more commonly found

(A) (B)

Figure 5.1 (A) Note the perioral wrinkles that are produced when this 56 year old inhales on a cigarette. (B) Same patient puckering one month after treatment with onabotulinumtoxinA. Note the absence of the intense perioral wrinkles in this smoker.

in someone over the age of 60 to 65 years or in a younger person who has acquired extensive solar elastosis of their exposed skin. If the wrin-kles accentuate and deepen with lip movement and puckering no matter how young or old a person is, then these are dynamic wrinkles and can be diminished with injections of onabotulinumtoxinA ( Figs. 5.5A–D and 5.6A–D ).

Functional Anatomy (see Appendix 1) The shape of the mouth and the position of the lips are controlled by a complex three-dimensional arrangement of interlacing and decussat-ing bundles of different facial muscles. These include various levators (tractors and evertors) of the upper lip (i.e., levator labii superioris alaeque nasi, levator labii superioris, zygomaticus major et minor, leva-tor anguli oris, and risorius), various depressors (tractors and evertors)

Figure 5.2 (A) Note the perioral wrinkles in this 57-year-old woman expressing her displeasure and exasperation by pursing her lips. She refused perioral onabotulinumtoxinA treatments because she sang in a professional choir. (B) Note the lack of perioral wrinkles produced when this 77-year-old inhales on a cigarette.

(A) (B)

142 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

of the lower lip (i.e., depressor labii inferioris, depressor anguli oris, mentalis, and platysma), a multilamellar, compound sphincter (i.e., the orbicularis oris), and the buccinator ( 2 ).

The orbicularis oris is not a simple sphincter like the orbicularis oculi. It is comprised of multiple lamellae of muscle fibers traversing in differ-ent directions around the orifice of the mouth. It is composed partly of muscle fibers from the labial levators and depressors that insert into the lips and partly from fibers intrinsic to the lips. The orbicularis oris, once felt to be a series of complete ellipses of striated muscle surrounding the buccal orifice and functioning as a sphincter, is now understood to con-sist of four independent quadrants (right, left, upper, and lower) of stri-ated muscle, each containing a larger pars peripheralis and a smaller pars marginalis (i.e., eight segments total). These four right and four left anatomic parts (upper and lower right and left partes peripheralis and upper and lower right and left partes marginalis) are juxtaposed to each other respectively, and roughly correspond to the exterior anatomic delineations of the free or unattached portion of the lip ( Fig. 5.7 ). The smaller pars marginalis corresponds to the vermillion of the lip and the larger pars peripheralis corresponds to the remainder of the free unat-tached portion of the cutaneous lip. Consequently, the orbicularis oris is perceived as being composed of eight segments, each resembling a fan, whose apex begins at the modiolus, one set on top of the other ( Fig. 5.7 ).

Most of the muscle fibers in the pars peripheralis are thought to origi-nate within the modiolus, as a direct continuation of the many modio-lar muscles. A considerable number of these muscle fibers also originate from the buccinator, an accessory muscle of mastication, which rein-forces the complex of deeper intrinsic muscle fibers of the orbicularis oris. Muscle fibers of the buccinator pass anteriorly and decussate at the angles of the mouth, crisscrossing each other as they continue on to their insertions in the upper and lower lips. Those fibers of the buccina-tor that arise from the area of the maxilla pass inferiorly around the angle of the mouth and insert into the lower lip. Those fibers that arise from the area of the mandible travel around the angle of the mouth and insert into the upper lip. The uppermost and lowermost muscle fibers of the buccinator, however, traverse across the lips from side to side in a purse string fashion without decussating ( Fig. 5.8 ).

Superficial to those deep intrinsic muscle fibers of the buccinator and orbicularis oris is another stratum of muscle fibers formed on either side of the mouth by the levator anguli oris and the depressor anguli oris. The fibers of both the levator and depressor crisscross each other at the corners of the mouth and continue away from each other. The muscle fibers of the levator anguli oris continue inferiorly into the lower lip and insert into the skin near the midline of the lower lip. The muscle fibers of the depressor anguli oris follow the same pattern into the upper lip, inserting into the skin at the midline. Reinforcing these superficial transverse fibers of the upper and lower lips are inter-digitating oblique muscle fibers from the levator labii superioris, the zygomaticus major, and the depressor labii inferioris. In addition, there are the intrinsic orbicularis oris muscle fibers of the lips, which run in an oblique direction and pass from the undersurface of the skin through the thickness of the lip and into the mucous membrane. Finally, there are additional slips of muscle fibers of the orbicularis oris which attach to the alveolar process of the maxilla, the nasolabial sulcus, and the nasal ala and septum superiorly and the alveolar process of the mandible inferiorly, anchoring the orbicularis oris in place as low as the mentolabial sulcus. All of these fibers decussate with the other muscle fibers at the angles of the mouth. Most muscle fibers also continue toward the midline, crossing it at least 5 mm into the opposite side of the lip. It is these interlacing and crisscrossing intrinsic fibers in the center of the upper lip that play a role in forming the lateral ridges of the philtrum with its central depression on the skin surface found at the base of the nose in the midline. These interlacing, crisscrossing intrinsic fibers also help form the depression found in the lower lip at the mentolabial sulcus. The pars marginalis of the orbicularis oris is unique to human lips and is crucial in the production of sound and speech.

Figure 5.3 Blunting of the vermillion border in this 62-year-old is offset by lipstick. Note lines of lipstick tracking up and down the perioral rhytides.

Figure 5.4 This 72-year-old with deep peribuccal rhytides and moderate solar elastosis of the face and lips at rest. Her peribuccal rhytides barely intensified with puckering. Note the persistence of the peribuccal rhytides 1 month after a treatment of onabotulinumtoxinA injections, because the bulk of her wrinkles were age related and of the static type. Note also the eversion and fullness of the upper lip at rest after treatment.

Before 1 month after

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 143

Figure 5.5 This 53-year-old with deep peribuccal rhytides and severe solar elastosis of the face and lips is shown at rest (A) and with puckering (B) before a treatment with onabotulinumtoxinA. Note the rhytides intensify with puckering. Same patient at rest (C) and puckering (D), 3 weeks after her first treatment with onabotulinumtoxinA. Note the rhytides at this early post-treatment time have only partially effaced. Note also the fullness and eversion of the vermillion after onabotulinumtoxinA.

At rest before

At rest 3 weeks after Pukering 3 weeks after

Puckering before(A) (B)

(D)(C)

Figure 5.6 This 66-year-old with deep peribuccal rhytides and moderate solar elastosis of the face and lips at rest (A) and puckering (B) before a treatment with onabotulinum-toxinA. Note that rhytides intensify with puckering. Same patient at rest (C) and puckering (D), 2 weeks after a treatment with onabotulinumtoxinA. Note the fullness of the vermillion at rest and the reduction of rhytides with puckering.

(A)

(C)

(B)

(D)

144 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

The function of the orbicularis oris is to close the mouth by approxi-mating the lips. By contracting the deep fibers and the superficial oblique ones, the orbicularis oris can apply the lips closely to the alveo-lar arch. The superficial interdigitating muscle fibers of the orbicularis oris, on the other hand, shape the lips in different configurations and either bring the lips together against the teeth or protrude the lips and the corners of the mouth forward to produce the maneuver of pursing or puckering the lips for certain functions such as whistling or kissing. Because of its mouth-closing function, the orbicularis oris can be con-sidered, in part, an antagonist to the lip levators and depressors.

Direct labial tractors are those levators and depressors that enter directly into the tissue of the lips without passing through and interlac-ing with the modiolus ( Fig. 5.7 ). For the most part, when these muscles

contract, they exert a vertical pull at right angles on the buccal aper-ture. That is, they either elevate or evert in part or entirely the upper lip and they depress or evert in part or entirely the lower lip ( Fig. 5.8 ). The direct lip tractors are from medial to lateral: the lateral labial portion of the levator labii superioris alaeque nasi, levator labii superioris, and zygomaticus minor in the upper lip, and the depressor labii inferioris and platysma (pars labialis) in the lower lip ( Fig. 5.7 ). The pars labialis of the platysma is in the same plane as the depressor anguli oris and depressor labii inferioris, and interdigitates its fibers with them, occu-pying any vacant space between them ( Fig. 5.9 ). In both the upper and lower lips, the direct labial tractors interlace their fibers into a continu-ous sheet of muscle superficial to the intrinsic fibers of the pars peripheralis and pars marginalis of the orbicularis oris as they travel

Figure 5.7 The four quadrants and eight segments of the orbicularis oris. Source: Courtesy of Gray’s Anatomy, 39th edn.

Orbicularis oris:pars peripheralis superioris

Orbicularis oris:pars marginalis inferiorispars peripheralis inferioris

pars marginalis superioris

Direct labial tractors:Levator labii superioris alaeque nasiLevator labii superiorisZygomaticus minor

Direct labial tractors:Depressor labii inferiorisPlatysma pars labialis

Modiolus:basis modulicornu moduli

Figure 5.8 Orbicularis Oris – The buccinator helps form the intrinsic muscle fibers of the orbicularis oris. Note the direct labial tractors: Levator labii superioris alaeque nasi, Levator labii superioris, Zygomaticus minor, Depressor labii inferioris, and platysma, pars labialis.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 145

through the substance of the free lip and sequentially attach to the undersurface of the dermis and mucous membrane. The movements of the direct tractors can be modified by the superseding activity of the modiolar muscles and the orbicularis oris. This produces the fine and delicate labial movements required to whistle, enunciate different sounds, express certain emotions and communicate nonverbally.

The buccinator, on the other hand, is not a typical mimetic muscle of the face. It is a deep, thin, quadrilateral muscle that spans the void between the maxilla and mandible and forms the deep muscular boundaries of the cheek ( Fig. 5.8 ). It originates from the posterior por-tion of the alveolar process of the maxilla, from the upper medial sur-face of the mandible at the junction of the body and ramus, just posteromedial to the last molar and from the pterygomandibular raphe or ligament. This raphe stretches from the medial pterygoid process to the inner surface of the mandible, and represents the line of juncture between the buccinator and the superior constrictor of the pharynx. The muscle fibers of the buccinator traverse forward toward the modi-olus near the angle of the mouth to become continuous with the intrinsic fibers of the orbicularis oris. The upper fibers of the buccina-tor continue as muscle fibers of the lower lip and the lower fibers of the buccinator merge with those of the upper lip without decussating and then insert into the mucous membrane and skin of the upper and lower lips. The buccinator’s function is to keep the cheek against the gums and teeth during mastication. It also keeps food in between the teeth and prevents it from becoming lodged between the teeth and cheek. It also assists the tongue in directing and maintaining food between the teeth while chewing. As the mouth closes, the teeth glide over the buccolabial mucosa, which must be continuously and progres-sively retracted away from the opposing surface of the teeth, otherwise a person constantly would inadvertently bite down on the inner surface of the buccal mucosa.

Contraction of the buccinator also prevents the cheeks from becom-ing overly distended by positive pressure when air, liquid, or solids fill the oral cavity. The buccinator also assists in gradually expelling from in between the lips accumulated liquid, solids or air within the oral cavity, as when spitting or playing a wind instrument or blowing up a balloon ( buccinator is Latin for trumpet player).

On either side of and just lateral to the oral commissures, a number of mimetic facial muscles converge toward a centralized anatomic loca-tion where they interlace their muscle fibers to form a dense, compact, mobile fibromuscular mass called the modiolus ( Fig. 5.10 ). As many as seven facial muscles, divided in different bundles within various ana-tomic planes, converge in a spiralling configuration into the modiolus, interlacing and attaching to it, each in their own distinctive way. Each person’s modiolus is subject to individual variation, predicated upon their age, sex, ethnic, and genetic background. The modiolus has no precisely delineated anatomic boundaries, nor does it have uniformly recognizable histologic features. The modiolus has the overall configu-ration of a blunt kidney-shaped cone ( Figs. 5.7 and 5.10 ). Its base (basis moduli) is adjacent and adherent to the buccal mucosa. It is located approximately 2 cm lateral to the center of the oral commissure and measures about 2 cm above and below an imaginary horizontal line that passes through the center of the oral commissure. From mucosa to der-mis, its vertical thickness is approximately 1 cm. The facial artery passes through an oblique fibrous cleft through its center. The cone-shaped modiolus is extended by two rounded edges or cornua, which give it its kidney shape and which extend into the lateral tissue margin of the free lip, above and below the angle of the mouth ( Figs. 5.7 and 5.10 ).

The subtle, three-dimensional movements of the modiolus, either bilaterally and symmetrically or unilaterally and asymmetrically, enable one to integrate common, routine movements of the cheeks, lips, jaws, oral aperture and vestibule into the daily activities of biting,

Figure 5.9 The depressor labii inferioris, depressor anguli oris and the platysma (pars labialis).

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculiCorrugator

supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti nasi

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

146 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

chewing, drinking, sucking, spitting, swallowing, whistling, and controlling changes in pressure and contents within the oral cavity. The modiolus facilitates the innumerable subtle variations in the fine movements involved in speech and word formation, as well as, the gen-eration and modulation of harmonious musical tones, subtle soft whis-pers, or the harsh sounds used in shouting, screaming, and crying. All the permutations of facial expression, ranging from mere hints to exag-gerated distortions, be they symmetric or asymmetric, are enabled by the intricately synergistic and precise displacements of the modiolus.

Many of the movements of the modiolus seem to involve most, if not all, of its associated muscles, whose actions are predicated upon the amount of separation between the upper and lower teeth (i.e., the gape of the mouth). The principal seven modiolar muscles include the zygo-maticus major, levator anguli oris, depressor anguli oris, platysma pars modiolus, risorius, and the main functional sphincteric effectors, the buccinator and orbicularis oris ( Fig. 5.10 ). As the interlabial and inter-dental distances approach their maximum separation of about 4 cm, the modiolus occupies the interdental space, moves anteriorly 1 cm closer to the oral commissure, and becomes immobile. With the mouth wide open, the nasolabial sulci elongate, becoming straighter and more vertical, and the inferior labiomandibular sulci (marionette lines) are less deep and curved. With the lips in contact with each other and the teeth in tight approximation, the modiolus can move only a few milli-meters in all directions. The mobility of the modiolus is maximized when the upper and lower teeth are separated by 2 to 3 mm, similar to its position when speaking. The muscular modiolar activities are enhanced by the partial separation of the jaws, integrating buccal func-tional movements with the direct labial tractors (levators of the upper lip and depressors of the lower lip) (Fig. 5.8). All of the delicate but intricate movements of the lips and mouth can be either intentionally or involuntarily set into motion from moment to moment by subtle and expeditious contractions of the diversely complex mimetic mus-cles of the perioral area.

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) Because of the complex nature of the orbicularis oris and the way it functions, injections of onabotulinumtoxinA in the perioral area should be performed only by an experienced physician injector. Each patient should be evaluated and treated individually, and standard injection points should not necessarily be adhered to in this area or any other area of the face for that matter. OnabotulinumtoxinA should be injected into an area of maximal muscle contraction. This is particu-larly important in the lips where the vertical lip lines may not be exactly symmetrical and do not always appear at the same depth or location in every patient. Perioral rhytides are dependent upon the particular

Dilution (see Appendix 2)

When injecting onabotulinumtoxinA intradermally into the lips

and the orbicularis oris, minimal dosages must be used (3). Because

there may be a multitude of vertical lines across the lips, concen-

trated onabotulinumtoxinA will not spread readily across the expan-

sive surface of the superfi cial fi bers of the orbicularis oris. In order

to have the onabotulinumtoxinA spread evenly, one can reconsti-

tute a 100 U vial of onabotulinumtoxinA with anywhere from 2 to

4 ml of normal saline. In this way, dilute, large volumes of onabotu-

linumtoxinA can spread across the surface of the superfi cial fi bers

of the orbicularis oris when only 1 or 2 U are injected into each

quadrant of the pars peripheralis of the upper and lower lips. Apply-

ing onabotulinumtoxinA intradermally and in low doses will avoid

any compromise in the sphincteric and synergistic functions of the

deeper muscle fi bers of the orbicularis oris and the labial tractors

and evertors (4,5).

Figure 5.10 The modiolus and its seven principal muscles: Levator anguli oris, zygomaticus major, risorius, platysma, depressor anguli oris, buccinator, and orbicularis oris.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 147

strength of the various superficial fibers of the orbicularis oris at that location (i.e., in the quadrant) along the lip, which are different from one patient to the next.

Place properly selected patients in the upright sitting or semireclined position and inject 1 to 2 U of onabotulinumtoxinA into each pars peripheralis of the upper and lower lips intradermally and no deeper than the dermosubcutaneous junction. At this level, the superficial fibers of the orbicularis oris can be found. The appearance of fluid-filled

wheals confirms the injections were preformed at the proper depth. Injections can be placed into the border between the pars peripheralis and pars marginalis ( Fig. 5.11 ). This technique can be more painful than when onabotulinumtoxinA is injected 2 and no more than 4 mm superior to the vermillion border ( Fig. 5.12 ). It is recommended that, at the initial treatment session, both quadrants of the pars peripheralis of the upper and lower lips be treated with no more than 2 U of onabotu-linumtoxinA injected into each site intradermally and applied sym-metrically into 1 to 3 sites depending on the severity of the wrinkling. The upper lip should not be injected with more than 8 U of onabotu-linumtoxinA at any given treatment session. OnabotulinumtoxinA should not be injected directly into the center of the philtrum, so as not to flatten the philtral columns. If the lower lip does not possess very deep rhytides, then it should be treated with only minimal amounts of onabotulinumtoxinA, i.e., no more than 2 units in each quadrant for a total of 4 U in the entire lower lip, especially at the initial treatment session. It is advisable to treat the lips symmetrically, injecting the four quadrants of the pars peripheralis to weaken the orbicularis oris in a relatively proportional and symmetric manner. Treating both the upper and lower lips at the same time will maintain the necessary peri-oral functional competence with a symmetric weakening of the overall sphincteric action of the lips. The dose in each quadrant can vary depending on the number and depth of rhytides present. Since only the superficial fibers of the orbicularis oris should be treated, then only 1 to 2 U of onabotulinumtoxinA in 2 sites per quadrant, injected intra-dermally, will suffice to produce the desired effect ( 3–5 ). In patients who have had treatments of onabotulinumtoxinA repeated over many years and, therefore, are well known to the physician injector, slightly higher doses, but not more than 3 U of onabotulinumtoxinA in each

Figure 5.11 Injections of onabotulinumtoxinA into the orbicularis oris at the junc-tion between the upper pars marginalis and pars peripheralis in this 59 year old patient were painful.

Figure 5.12 Injections of onabotulinumtoxinA placed 2 to 4mm above the vermillion border into the center of the pars peripheralis of the orbicularis oris were less painful for this 53 year old patient. Same patient as in Figure 5.5.

148 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

injection site on occasion, can be placed into each lip quadrant ( Figs. 5.13A,B and 5.14A,B ).

Some physicians use different patterns to inject the lips that include as many as 10 or 11 injection sites between the upper and lower lips, usually at the points of maximal muscle contraction ( Fig. 5.15 ) ( 5 , 6 ). However, this large amount of onabotulinumtoxinA and these many injection points are not appropriate for most patients. It is important that the patient returns 2 to 3 weeks after a treatment session with ona-botulinumtoxinA so that the physician can evaluate the patient for any asymmetry or aberration in lip function ( 5 ).

For those patients who also have their lips injected with soft tissue fillers, it has been found that injections of onabotulinumtoxinA may prolong the effects of the fillers, since the constant muscle contraction and stress on the filler material by normal, routine lip movement is reduced by the effects of the onabotulinumtoxinA ( 6 , 7 ). When other cosmetic procedures are performed during the same treatment session in which onabotulinumtoxinA needs to be injected, the onabotu-linumtoxinA treatment should be given first. This will allow the mus-cles to become saturated with the onabotulinumtoxinA, before a filler, laser, or surgical procedure is performed, and possibly modifying the anatomy and physiologic properties of that site.

The total dose for onabotulinumtoxinA injected into the upper lip should not exceed 8 U, and that for the lower lip should never exceed 6 U, unless the physician knows the patient very well and has treated the patient successfully without complications in the past with high doses of onabotulinumtoxinA ( Fig. 5.16 ).

Outcomes (Results) (see Appendix 4) Of all the areas of the face that are treated for wrinkling, the perioral area is the least predictable and responsive no matter what invasive or non-invasive modality is used, including injections of onabotulinum-toxinA. Even so, the perioral area is high on the treatment list when patients request cosmetic rejuvenation of the face.

When onabotulinumtoxinA injections of the lips are effective as intended, a pleasing effacement of the depth of the vertical lip lines occurs, which can dramatically improve the overall physical appear-ance and emotional outlook of the patient. In addition to relaxing the superficial fibers of the orbicularis oris and diminishing the wrinkles on the cutaneous surface of the lip, there also can be a widening of the philtrum and a slight eversion of the vermillion, producing an attrac-tive “pseudo” augmentation of the lips ( Figs. 5.13A,B , 5.14 , and 5.17A,B ) ( 4 , 5 , 8 ). Many feel that this pseudoaugmentation and eversion

3 2 2 3

2 2

2 weeks afterBefore

(A) (B)

Figure 5.13 This 47-year-old at rest before (A) and 2 weeks after (B) her 3rd onabotulinumtoxinA treatment of perioral vertical rhytides. Note the subtle fullness of the vermillion and eversion of its border.

Figure 5.14 This 47-year-old at rest before (A) and 2 weeks after (B) her 4th onabotulinumtoxinA treatment of perioral vertical rhytides. Note the subtle fullness of the vermillion and eversion of its border.

Before After

1

2 2

1 11

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 149

of the lips are best produced when onabotulinumtoxinA is injected directly into the cutaneovermillion border ( Fig. 5.11 ). However, this technique usually is very painful for the patient. Similar lip fullness and eversion can be realized when onabotulinumtoxinA is injected in a less painful way a few millimeters above the vermillion line ( Fig. 5.12 ). To maximize the augmentation and eversion of the lips without inflicting additional pain upon the patient, place the needle into the cutaneous lip 2 to 4mm superior to the vermillion border intradermally and advance the tip of the needle until it reaches the pars marginalis just under the vermillion of the lip. This maneuver is facilitated by standing behind the patient, grasping, and with moderate pressure, compressing

the lip between the index finger and thumb of the nondominant hand ( Fig. 5.18 ). The slight discomfort experienced by the patient when the lip is compressed between the fingers will help distract the patient from feeling the full impact of the pain experienced when the lips are injected. Injections must be intradermal to affect only the superficial fibers of the orbicularis oris and to avoid complications. The more superficial the injection, the more painful it is, no matter what product is injected or where on the lip it is placed.

Only dynamic perioral wrinkles can be attenuated by onabotu-linumtoxinA, not the static rhytides that result from photodamage and age ( Fig. 5.4 ). For correction of static wrinkles and solar

Figure 5.15 Point (x) should only be injected in extreme cases of excessively deep rhytides in the center of the lip (philtrum).

Frontalis

Procerus

Corrugator supercilii

Depressor supercilii

Orbicularis oculi

Levator labii superiorisalaeque nasi

Compressor naris

Dilator naris

Zygomaticus minor

Levator labii superioris

Zygomaticus major

Levator anguli oris

Depressor septi nasi

Masseter

Buccinator

Risorius

Orbicularis oris

Platysma

Depressor anguli oris

Depressor labii inferioris

Mentalis

Figure 5.16 This 56-year-old shown puckering before (A) and 3 weeks after (B) a treatment of onabotulinumtoxinA of the perioral rhytides.

Before After

11 12

2 2

(A) (B)

150 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

elastosis, various soft tissue fillers and different resurfacing proce-dures with adjunctive treatments of onabotulinumtoxinA when appropriate will give the best results. Because low doses are used to efface perioral rhytides, the usual duration of effect from injections

of onabotulinum toxinA is sometimes 2 and generally no longer than 3 months.

Complications (Adverse Sequelae) (see Appendix 5) The perioral area is probably the most difficult location on the face to treat with onabotulinumtoxinA without the frequent occurrence of adverse sequelae. This is because, unlike the sphincteric action of the orbicularis oculi, which has only one opposing levator muscle (i.e., the frontalis) and a few co-depressor muscles (i.e., the corrugator supercilii, procerus, and depressor supercilii), the orbicularis oris is interlaced with muscle fibers from the different groups of upper and lower lip levators and depressors, making it easy for the injected onabotulinumtoxinA to diffuse into an adjacent constituent interdigitating muscle or group of muscles that produce a different set of facial movements. Consequently, adverse sequelae or, at the very least, annoying functional disturbances are bound to occur.

Using a range of higher doses ( ≥ 6 to 8 U in the upper lip and ≥ 4 to 6 U in the lower lip) of onabotulinumtoxinA will subject the patient to difficulties with lip puckering when attempting to whistle or kiss ( Fig. 5.19 ). A slightly asymmetric smile is relatively common in the general population (see pp. 154–160). It also can be created or accen-tuated by unequal dosing and asymmetric placement of injections of onabotulinumtoxinA. In the case of overdosing, many different adverse functional changes can occur which can include, but are not limited to, the inability to form certain letters (e.g. b, p, f, w, o, and u), to articulate different sounds, and to pronounce certain words. Involuntary tongue, inner cheek, and lip biting may result, along with flattening of the philtrum or even lip paresthesias. There can be a disturbance in proprioception of the lips, which makes it difficult to apply lipstick, whistle, or kiss. There also can be a concomitant inability to approximate the lips tightly enough to prevent fluid or even food incontinence. Fluid incontinence causes one to drool or actively dribble liquid out of the mouth while drinking from a glass and cup, or sipping from a straw, or eating from a spoon ( 9–11 ). The inability to purse or pucker the lips can last beyond 2 to 4 weeks after a treatment of onabotulinumtoxinA. One should not be tempted to inject progressively higher doses of onabotulinumtoxinA into the lips similar to the way one can increase the injection dose in the peri-orbital area. Doing so will definitely lead to any number of the

2 2

2 2

2 21

(A) (B)

Figure 5.17 (A) This 59-year-old accentuating her dynamic perioral rhytides by puckering. She has had at least 4 onabotulinumtoxinA treatments in the past. (B) Same patient puckering 5 weeks after an onabotulinumtoxinA treatment. Note the subtle fullness of the lips and the eversion of the vermillion border.

Figure 5.18 Injection technique of the lip vermillion. Note the position of the fingers, compressing the lip between the index finger and thumb of the nondominant hand. The approach is from behind the patient. The needle is inserted into the cutaneous lip 2–4 mm above the vermillion and advanced under it.

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 151

adverse sequelae as identified above. It is important to understand that there is only a very narrow margin for the successful treatment of the orbicularis oris with onabotulinumtoxinA. If 2 U of onabotu-linumtoxinA per quadrant is injected into a patient’s lips effectively and without untoward sequelae, then as little as an additional 1 or 2 U of onabotulinumtoxinA in the upper or lower lip in that same individual may result in some or all of the adverse side effects previously enumerated. Those most intolerable are an asymmetric smile and lack of sphincter control, causing food and liquid inconti-nence, and difficulty with speech and sound articulation. So the temptation to inject even 1 U more in an upper or lower lip to improve the results or extend the duration of an onabotulinumtox-inA treatment must be overcome, unless visible ineffectiveness of a particular dose of a previous onabotulinumtoxinA treatment already has been experienced by the patient. Then either additional units at the 2- to 3-week follow-up visit can be given, or a gradual increase in dose (by no more than 1 U of onabotulinumtoxinA) and number of injection sites can be attempted with each subsequent onabotu-linumtoxinA treatment session. When onabotulinumtoxinA is inef-fectively injected, or there is some loss of product while injecting,

preventing a full complement of onabotulinumtoxinA to reach the targeted muscle fibers, then an uneven outcome can result ( Fig. 5.20 ). Avoid injecting onabotulinumtoxinA too close to the corners of the mouth. This can result in incompetent commissures, ekla-bion, an asymmetric smile, aberration in speech, drooling and dribbling, and even incontinence of solid food.

Of all the areas on the face to inject onabotulinumtoxinA, the lips are the most painful. The more superficial (i.e., intradermal) the injection, the more painful it will be. Icing and the prolonged application of a topical anesthetic with occlusion may alleviate some of the pain that accompanies such superficial injections in the lips. Forewarning the patient of the potential side effects and the particular painfulness of the treatment does not seem to dissuade those who are determined to rid themselves of these unsightly lipstick-trailing rhytides. In contradistinction, superficial injections in the perioral area do not elicit ecchymoses with the same ease and frequency that the superficial injections in the periorbital area do.

Figures 5.21 to 5.26 are additional examples of different patients treated with onabotulinumtoxinA for perioral rhytides.

Figure 5.19 This 68-year-old is seen puckering before (A) and 3 weeks after (B) a treatment of onabotulinumtoxinA. The patient experienced some difficulty puckering following the injections.

(A) (B)

Figure 5.20 This 43-year-old puckering before (A) and 3 weeks after (B) her 1st onabotulinumtoxinA treatment for perioral vertical rhytides. Note the persistence of wrinkles in the right upper quadrant due to inadequate treatment on that side.

(A) (B)

152 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

(A)

(B)

Figure 5.21 (A) This 53-year-old with deep peribuccal rhytides and severe solar elastosis of the face and lips at rest before and 2 weeks after treatment with onabotulinumtoxinA. Note the subtle fullness of the lips and the eversion of the vermillion border. (B) Same patient puckering before and 2 weeks after treatment with onabotulinumtoxinA. Many of the wrinkles are of the static type, caused by photoaging. Note the subtle fullness of the lips and the eversion of the vermillion border.

Figure 5.22 This 66-year-old is shown at rest with perioral rhytides, before (A) and 1 month after (B) a treatment with onabotulinumtoxinA in the upper and lower lips and a hyaluronic acid filler in the marionette lines, prementum, and prejowl areas.

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 153

(A)

(B)

Figure 5.23 (A) This 68-year-old is shown at rest with perioral rhytides, before and 2 weeks after a treatment with onabotulinumtoxinA. Note the subtle fullness of the lips and the eversion of the vermillion border. (B) Same patient puckering before and 2 weeks after treatment with onabotulinumtoxinA.

Figure 5.24 This 57-year-old is shown at rest with perioral rhytides, before (A) and 2 months after (B) a treatment with onabotulinumtoxinA of the upper and lower lips and a hyaluronic acid filler in the marionette lines, prementum, and prejowl areas.

(A) (B)

154 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

ASYMMETRIC SMILE Introduction: Problem Assessment and Patient Selection Many men and women are born with an asymmetric smile (idio-pathic asymmetry, see classification of asymmetries, pages 43–47) (Figs. 4.60–4.62 and 5.27–5.29 ). This also can be a manifestation of a family trait ( Fig. 5.30 ), which is especially disconcerting to women who display this type of smile. For many of these individuals, this is a source of considerable embarrassment, especially when they are in a socially interactive situation. Just like those with a gummy smile, they are reticent to freely grin in public, and seek different ways to hide their mouths when laughing or smiling in the presence of oth-ers (see pp. 132–138). Those who have a prominent position in the workplace or society are especially self-conscious of their obviously “crooked smile”. Many prefer not to smile when being photographed, and will avoid family and social events where photographs are being taken.

Functional Anatomy (see Appendix 1) No matter what type of smile one has (zygomatic, canine, or full denture) ( 12 ) if it is asymmetrical or “crooked” it is always a source of anxiety and self-consciousness for the bearer, whether male or female ( 13 ). Asymmetric smiles can occur because of segmentally weakened or hyperfunctioning muscles on either side of the upper or lower lips. If the asymmetry appears in the upper lip, one or more of the many upper lip levators or a segmental portion of the orbicu-laris oris may be involved unilaterally or bilaterally. If the asymmetry

Treatment Implications When Injecting Perioral Rhytides

1. Only dynamic wrinkles in the lips are reducible by onabotu-

linumtoxinA treatments. A thorough and accurate assessment of

the patient is the key to a successful outcome.

2. Treating hyperkinetic superfi cial fi bers of the orbicularis oris with

onabotulinumtoxinA will relax surface rhytides, evert the vermil-

lion, and create the appearance of fullness in the lips.

3. Inject low doses of high-volume onabotulinumtoxinA intradermally

in the lips, and see the patient 2 to 3 weeks after each treatment.

4. Treat the lips with symmetrically placed injections of onabotu-

linumtoxinA in all four quadrants of the pars peripheralis. Each

individual injection site can be dosed differently with the tip of

the needle advanced to just beneath the vermillion.

5. Inject the lower lip conservatively and with a slightly lower dose

of onabotulinumtoxinA than in the upper lip to avoid functional

aberrations. Injecting onabotulinumtoxinA into the base of the

philtrum may fl atten its contour.

6. Avoid injecting onabotulinumtoxinA close to the corners of the

mouth, for risk of creating incompetent commissures, eklabion,

an asymmetric smile, drooling, and even dribbling.

7. The pretreatment application of ice or a topical anaesthetic with

occlusion may reduce the particular pain experienced when lips

are injected.

Figure 5.26 This 47-year-old is shown puckering with perioral rhytides, before (A) and 3 weeks after (B) a treatment with onabotulinumtoxinA. Note the mentalis and platysma were not treated. Note the dimpling of the mentum and the perimental furrows.

(A) (B)

Figure 5.25 This 44-year-old is shown at rest with perioral rhytides, before (A) and 2 weeks after (B) a treatment with onabotulinumtoxinA. Note the subtle fullness of the lips and the eversion of the vermillion border.

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 155

Figure 5.27 In this 55-year-old female an asymmetric smile is caused by hyper-kinetic lateral levators of the left upper quadrant of the lips.

Figure 5.28 In this 62-year-old male an asymmetric smile is caused by hyperkinetic central levators of the right upper quadrant of the lips.

appears in the lower lip, a unilateral malfunctioning of a lower lip depressor occurs that is usually weaker or stronger than its contra-lateral paired muscle with or without the segmental involvement of the orbicularis oris. Lower lip asymmetries are more easily cor-rected because unlike the intricate network of the upper lip levators (see pp. 110–139), the problem commonly stems from a hyperki-netic depressor labii inferioris or occasionally a depressor anguli oris and rarely both ( 14 ). Isolated quadrants or portions of the muscle fibers of the lower orbicularis oris theoretically also can be involved.

The depressor labii inferioris is a quadrilateral muscle that origi-nates inferior to the mental foramen at the oblique line of the lower lateral surface of the body of the mandible between the symphysis menti and the mental foramen ( Fig. 5.31 ). As one of the direct labial tractors, its fibers travel upward and medially to insert directly into the skin and mucosa of the lower lip, decussating with fibers of its paired muscle from the contralateral side along with some muscle fibers of the lower orbicularis oris. Inferiorly and laterally, it is con-tinuous with the platysma (pars labialis) ( Fig. 5.32 ). At its origin, the depressor labii inferioris is approximately 3 cm wide, and covered lat-erally by the depressor anguli oris for about 1 to 2 cm. It then narrows to approximately 2 cm wide before it inserts in the superior aspect of the lower lip.

The function of the depressor labii inferioris is to pull the lower lip downward and laterally slightly everting the vermillion when a person is chewing, drinking, smiling, laughing, or speaking. Other-wise, one would bite or chew their lip while performing these func-tions. It should act in unison and symmetrically with its paired counterpart on the opposite side of the chin, which is not always the case in some individuals. The depressor labii inferioris is one of the muscles used when expressing sorrow, irony, melancholy, and doubt.

Dilution (see Appendix 2)

Because of the extensive interlacing of muscle fi bers in the perioral

area, the success of treating a particular muscle in the lower face is

predicated upon not having onabotulinumtoxinA diffuse beyond the

area of injection. Consequently, minimal amounts of low-volume,

highly concentrated onabotulinumtoxinA should be used when

targeting a perioral muscle for treatment. Therefore, experienced

physicians will reconstitute a 100 U vial of onabotulinumtoxinA

with only 1 ml of normal saline.

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) Ordinarily, the unilateral stronger muscle of the face is weakened with injections of onabotulinumtoxinA to correct an asymmetry ( Fig. 5.33A–F ). Depending on the type of asymmetry to be corrected and the location and strength of the muscle(s) to be weakened, it is usually advisable for the injector to determine the appropriate dose of onabotulinumtoxinA necessary for injection at the time of treatment. Each patient’s problem should be evaluated individually and a solution determined according to the patient’s idiosyncratic anatomy. When treating muscles in the lower face, very low doses of onabotulinumtoxinA are all that are necessary to produce a desired, long-lasting effect. Dramatic results can be obtained usually with less than 4 or 5 U of onabotulinumtoxinA.

Prior to injection the patient should be in the sitting or semire-clined position while forcibly contracting the muscle to be treated. Commonly it is the depressor labii inferioris that is hyperkinetic and

Figure 5.29 In this 61-year-old, an asymmetric smile is caused by a hyperkinetic depressor labii inferioris in the right lower quadrant.

156 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Figure 5.31 Depressor labii inferioris is a square, deeply situated muscle on the chin and it depresses the lateral aspect of the lower lip downward while gently everting the vermillion.

creating an asymmetric smile. As the patient smiles energetically, the location of the hyperkinetic muscle is easily visualized ( Fig. 5.33A,C ). The needle should pass perpendicular to the skin’s surface and enter directly into the belly (thickest part) of the muscle. This injection point is usually inferior to the mental crease and the inferior limit of the orbicularis oris. Generally 2 to 4 U of onabotulinumtoxinA will weaken the hyperfunctional depressor labii inferioris sufficiently enough to realign an asymmetric smile ( Figs. 5.33A–F and 5.34 ) ( 13 ).

Slow, deliberate injections will prevent pain and widespread diffusion of onabotulinumtoxinA, averting adverse sequelae.

Outcomes (Results) (see Appendix 4) When the problem has been correctly assessed, and the proper conser-vative dose of onabotulinumtoxinA determined, weakening the hyperkinetic muscle on the side of the face producing the asymmetry with injections of onabotulinumtoxinA will correct the asymmetry

Figure 5.30 (A) Father (55 years old) and (B) daughter (20 years old) demonstrate the same type of idiosyncratic, asymmetric smile caused by a hyperkinetic right depressor labii inferioris. The daughter also has an asymmetric smile on the upper right with deep nasolabial grooves and folds.

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 157

Depressorangulioris

Orbicularisoris

Buccinator Platysma Risorius Masseter

Frontalis

Orbicularis oculi

Corrugator supercilii

Procerus

Depressorsupercilii

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Depressorsepti

Levator labiisuperioris

Zygomaticusminor

Levator angulioris

Zygomaticusmajor

Depressor labiiinferioris

Mentalis

Figure 5.32 Depressor labii inferioris is one of the direct labial tractors inserting directly into the skin and mucosa while other fibers interdigitate with some of the lower fibers of the orbicularis oris and platysma (pars labialis).

( Figs. 5.33A–F and 5.34 ). The effect of a single treatment can last beyond 5 to 6 months. It is best to treat an asymmetry with a lower dose of onabotulinumtoxinA, which can be increased by a touch-up treatment 2 to 3 weeks later when the patient returns for his or her obligatory posttreatment evaluation. Correcting a problem conserva-tively, albeit possibly insufficiently, allows both the patient and the physician to assess clearly the appropriateness of the corrective action ( 15 ). Subsequently, additional units of onabotulinumtoxinA can then be injected with confidence to adequately treat the problem to the sat-isfaction of patient and physician. In the lower face, the muscles are small, intermingled with indistinct borders and do not always function in the same way in every patient. The shape and the contour of the mouth and whether or not it is symmetrical or asymmetrical will depend on how the perioral muscles function in a particular individ-ual. When there is an obvious asymmetry, 1 or 2 U of onabotulinum-toxinA can go a long way in modifying how perioral muscles contract and interact with each other.

In a study by Benedetto ( 13 ), four females and one male were treated for lower lip asymmetry. Four were caused by a hyperkinetic right depressor labii inferioris, one by a left one. Four of the patients were aware of their asymmetry which was present since birth or early childhood. One was not aware of having an asymmetric smile. OnabotulinumtoxinA was used to correct the asymmetric smile, with only 1 to 3 units. The smiles became level and symmetrical within one week of the treatments, which lasted anywhere from 6 to 7.5 months

with the first treatment session and even longer with subsequent treat-ments, even when a lower dose was used.

Complications (Adverse Sequelae) (see Appendix 5) An erroneous assessment and fallacious conclusion to a problem in the lower face can produce incomplete and even untoward results, which can become an intolerable annoyance and even a functional problem to the patient. Therefore, a thorough knowledge of the anat-omy and func tion of the muscles of the face in the area of the body to be treated is absolutely necessary when one is attempting to treat a patient with onabotulinumtoxinA. This is particularly important when the problem is not a recognized, commonly occurring com-plaint with well-established and approved techniques of treatment as is the case with glabellar frown lines. Idiosyncratic or iatrogenic asymmetries need to be corrected on a case-by-case basis and expert understanding of functional anatomy is paramount. Overzealous treatment of any problem can only lead to adverse sequelae, which are all dependent on the location and the particular muscle or mus-cles in which the problem resides. In the case of an asymmetric smile, one or two extra units of onabotulinumtoxinA can create the same complications of an adynamic smile and incompetent buccal sphinc-ter, causing difficulty with eating, drinking, swallowing, and speech articulation.

Figures 5.35 to 5.37 are additional examples of different patients treated with onabotulinumtoxinA for an asymmetric smile.

158 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

3

(A) (B)

(C) (D)

(E) (F)

Figure 5.33 (A,B) This 47-year-old with an idiosyncratic asymmetric smile before and 3 weeks after 3 U of onabotulinumtoxinA were injected into her left depressor labii inferioris. (C,D) Same patient seen 3 months after the 1st treatment of her left depressor labii inferioris. An additional 1U of onabotulinumtoxin was injected at this time (C). Same patient seen again 4 months after her 2nd touch-up treatment (D). (E,F) Same patient seen with lasting results 8 months after her 2nd treatment. An additional 1 U of onabotulinumtoxinA was injected to maintain these results (E). Patient seen again 7 months after her 3rd treatment (F).

Figure 5.34 This 22-year-old with an idiosyncratic asymmetric smile before (A) and 4 months after (B) 2 U of onabotulinumtoxinA were injected into her right depressor labii inferioris for the 2nd time. Note the absence of dental show of the lower teeth.

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 159

Figure 5.35 This 55-year-old with an idiosyncratic asymmetric smile before (A) and 3 weeks after (B) 2 U of onabotulinumtoxinA were injected into her right depressor labii inferioris. Note the eversion of the vermillion border.

(A) (B)

Figure 5.36 This 61-year-old with an idiosyncratic asymmetric smile before (A) and 5 months after (B) 1 U of onabotulinumtoxinA was injected into her right depressor labii inferioris.

(A) (B)

Figure 5.37 This patient with an idiosyncratic asymmetric smile before (A) and 2 months after (B) 2 U of onabotulinumtoxinA were injected into her left depressor labii inferioris.

(A) (B)

160 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

MELOMENTAL FOLDS Introduction Patients whose corners of the mouth chronically project downward commonly also will possess pronounced melomental folds. These superfluous folds of skin are created by deep furrows emanating away and downward from the oral commissures. They also are identified as a labiomandibular crease, “drool grooves,” or “marionette lines.” When these lines are present, they usually impart to others the negative expressions of sadness, disapproval, unpleasantness, and melancholy. When these “marionette lines” extend downward along the lateral sides of the mentum they reinforce the downward turn of the corners of the mouth creating an inverted smile or “Chinese moustache” and evoke the outward appearance of someone who is old and senile, no matter how young they might be chronologically ( Fig. 5.38 ). Marionette lines can be a source of frustration and embar-rassment, particularly for women during daily social interactions, or for those who maintain a prominent position in the workplace. Until recently, the only way to efface these lines was either by invasive surgi-cal procedures such as rhytidectomies, subcision, and skin resurfac-ing, or injections of soft tissue fillers which can produce results that are remedial but temporary. Injections of onabotulinumtoxinA can be given to supplement these procedures enhancing and even pro-longing their results, bringing the treatments of melomental folds a little closer to a more satisfactory outcome ( 6 ).

Functional Anatomy (see Appendix 1) Formation of an inverted smile because of the downward projection of the corners of the mouth is produced by the hyperkinetic activity of the depressor anguli oris pulling on the lateral oral commissures ( Fig. 5.39 ) ( 16 ). The depressor anguli oris is a small triangular muscle (also known as the triangularis) whose wide base originates at the mental tubercle and along the external oblique line of the body of the mandible below the canine premolar and first molar, lateral and superficial to the larger depressor labii inferioris ( Figs. 5.31 and 5.32 ). The muscle fibers of the depressor anguli oris narrow as they travel upward and converge onto the angle of the mouth, where some mus-cle fibers insert directly into the undersurface of the skin while other fibers insert into the modiolus and then interdigitate with muscle fibers of the risorius, orbicularis oris, and levator anguli oris near the upper lip and the zygomaticus major and buccinator at the oral com-missures ( Fig. 5.39 ). In addition, the lower posterior fibers of the depressor anguli oris interdigitate with those muscle fibers of the upper platysma (pars labialis) and cervical fascia that converge toward the lateral oral commissures. In some individuals, the depres-sor anguli oris will traverse the midline inferior to the mental tuber-cle and decussate with fibers of its paired muscle of the opposite side, creating the transversus menti or the “mental sling” (2).

The function of the depressor anguli oris is to depress the oral commissures slightly laterally and downward when opening the mouth. The depressor anguli oris is an antagonist to the levator anguli oris, risorius, and zygomaticus major, displacing the corners of the mouth downward and slightly laterally when it contracts in an expression of grief, sorrow, and sadness. In certain patients, the infe-rior aspect of the marionette line contributes to the formation of the pre jowl or labiomandibular sulcus. Upon opening the mouth, the labiomental sulcus across the chin becomes more horizontal and deeper in its center.

Dilution (see Appendix 2)

When treating the depressor anguli oris and the perioral area,

onabotulinumtoxinA should not be allowed to diffuse beyond the

targeted muscle fi bers; otherwise, cosmetic aberrations such as an

asymmetric smile, and functional disturbances such as drooling,

dribbling, and even dysarthria are sure to follow. Therefore, the high-

est volume of diluent that should be used to reconstitute a 100 U vial

of onabotulinumtoxinA is 1 ml of normal saline. Any volume of dilu-

ent higher than 1 ml is sure to invite adverse sequelae.

Treatment Implications When Injecting an Asymmetric Smile

1. Know the functional anatomy of the muscle(s) to be treated.

2. Inject low-volume, minimal doses of onabotulinumtoxinA

directly into the belly of the muscle(s) in question.

3. First treatments should be conservative with low doses of onabotu-

linumtoxinA to confi rm the appropriateness of the treatment.

4. All fi rst-time and subsequently treated patients must be re-evaluated

2 to 3 weeks after an onabotulinumtoxinA treatment to assess

their results and to monitor their satisfaction with the outcome.

5. Assess and treat each and every patient individually. No two patients

or their problems are alike and therefore cannot be treated the same.

6. Reevaluate each patient’s problem before every treatment, because

the dosage of subsequent injections may change depending on

how the treated muscle(s) respond and reanimate over time.

7. Treatment results are long lasting, and their duration can remain

even longer with each subsequent treatment.

Figure 5.38 (A) This 52-year-old at rest has marionette lines that extend down the lateral sides of the mentum creating an inverted smile because of hyperkinetic depressor anguli oris. (B) This 37-year-old grimacing displays a deep inverted smile, also because of hyperkinetic depressor anguli oris. Note the asymmetry in the depth and length of the marionette lines in both patients.

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 161

Figure 5.39 Depressor anguli oris inserts into the modiolus before interdigitating with the risorius, platysma (pars labialis), levator anguli oris, and the orbicularis oris. It pulls the corners of the mouth downward.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Figure 5.40 (A) The correct point of injection for the depressor anguli oris is not the anterior one that is directly inferior to the downward extension of the melomental crease, but slightly more posteriorly (arrow) at the most inferior point of an imaginary line that passes through the nasolabial sulcus. (B) Same patient, contralateral side.

(A) (B)

Dosing: How To Correct Problem (see Appendix 3)(What to Do and What Not to Do) The downward angling of the “marionette lines” can be improved by injecting 3 to 6 U of onabotulinumtoxinA intramuscularly in the cen-ter of the body of the mandible at a point that is most inferior to an imaginary vertical line that passes through the nasolabial sulcus ( Fig. 5.40 ). This point should be approximately 8 to 10 mm lateral to the oral commissure and 8 to 15 mm inferior to this point, depending on the idiosyncratic shape of the patient’s face. The appropriate injection point can be identified by palpating someone who is actively contract-ing the corners of the mouth downward (Fig. 5.41A) while pronounc-ing the letter “e” in an exaggerated fashion ( Fig. 5.41B ) ( 11 , 17 ). Another

maneuver to assist in the localization of the depressor anguli oris is to have the patient bite down, forcibly contracting the jaw muscles. This will contract and enlarge the belly of the masseter, which is a muscle very easily identified by palpation ( Fig. 5.42 ). In the majority of indi-viduals, the depressor anguli oris lies approximately 1 to 2 mm to 1 cm anterior to the masseter depending on the shape of the jaw. After the patient clenches their teeth and the anterior border of the masseter is identified, have the patient exaggerate the pronunciation of the letter “e” (Fig. 5.41B). The location of a hypertrophic depressor anguli oris should be easily palpated along the anterior border of the masseter and on the body of the mandible. At times, the depressor anguli oris can be detected more easily by palpating it intraorally along the inferior

162 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

alveololabial sulcus as the patient actively contracts it. Yet another way to identify the appropriate injection point of the depressor anguli oris is to have the patient forcibly contract their platysma (Fig. 5.41C). Those patients who possess platysmal neck bands frequently will form a lateral neck band that is directly beneath the point where fibers of the platysma and the depressor anguli oris decussate ( Fig. 5.41C ). Just cephalad to this lateral platysmal neck band on the superior aspect of the body of mandible is the general vicinity where onabotulinum-toxinA should be injected (Fig. 5.41D).

Place the patient in the upright sitting or semireclined position. At the point where the contracted and thickened belly of the depressor anguli oris can be felt, insert the needle perpendicular to the skin surface over the body of the mandible. Advance the needle until it passes through the subcutaneous tissue and into the muscle and inject 3 to 6 U of onabotulinumtoxinA ( Fig. 5.41D ). Remember, the depressor anguli oris lies on a plane superior to the depressor labii inferioris (Fig. 5.42). Advancing the needle too deeply may unavoid-ably expose some of the posterior fibers of the depressor labii inferi-oris to the injected onabotulinumtoxinA. If the depressor anguli oris cannot be palpated, then it should not be treated. Inject precise amounts of onabotulinumtoxinA accurately into the depressor anguli

oris, since the orbicularis oris and depressor labii inferioris are imme-diately adjacent to it, and unsightly and dysfunctional perioral changes can result if either one of these two muscles is inadvertently weakened along with the depressor anguli oris. Care should be taken not to inject into the marginal mandibular nerve and facial artery and vein that lie in this general vicinity in a bony groove just anterior to the masseter ( Fig. 5.42 ). If the depressor anguli oris is palpated over this bony groove, lift the skin and muscle with the nondominant hand before injecting onabotulinumtoxinA. With this technique, onabotulinumtoxinA can be injected directly into the fibers of the depressor anguli oris, while avoiding injecting the neurovascular structures of that area ( 18–20 ). Since the depressor anguli oris is wider at its origin along the body of the mandible, it is advisable to inject it in this location and not near its insertion close to the corners of the mouth where it narrows and interdigitates with other perioral muscles. In fact, when there is an obvious platysmal band just inferior to where the depressor anguli oris is injected, an additional 2 to 3 U of onabotulinumtoxinA can be injected into the apex of that platys-mal band approximately 1 to 2 cm inferior to the lower margin of the body of the mandible. This will insure a complete relaxation of the depressor anguli oris and an uplifting of the oral commissures.

Figure 5.41 The injection point can be identified by feeling the contraction of the depressor anguli oris as the patient actively contracts the corners of the mouth downward (A) and pronounces the letter “e” in an exaggerated manner (B). Note the lateral platysmal band (C). It points to where the depressor anguli oris can be injected with onabotulinum-toxinA (D). Injecting the depressor anguli oris at the most inferior point of the nasolabial sulcus in the center of the body of the mandible is approximately 1 cm lateral and 1 cm inferior to the corner of the mouth and usually corresponds to the uppermost aspect of a platysmal band.

(A)

(C)

(B)

(D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 163

Figure 5.43 (A) This 47-year-old possesses a deep labiomental furrow and downward projecting corners of the mouth before (A) and after (B) 4 U of onabotulinumtoxinA were injected into the depressor anguli oris bilaterally. Note the uplifted corners of the mouth and the patient’s more pleasant appearance after a treatment of onabotulinumtoxinA (B).

4 months after 2nd treatment Before(A) (B)

4 4

Figure 5.42 The masseter can be easily palpated when patients clench their teeth. Note the position of the depressor anguli oris on the left. It normally is found laterally and superficially to the depressor labii inferioris and anteriorly to the masseter.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator anguli oris

Buccinator

Masseter

Modiolus

Depressor labii inferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

Depressor angulioris

Outcomes (Results) (see Appendix 4) Injections of onabotulinumtoxinA will relax the depressor anguli oris and permit the unopposed elevation of the corners of the mouth to occur by the upward pull of the risorius, levator anguli oris, and the zygomaticus major. When the corners of the mouth are relaxed and elevated by injections of onabotulinumtoxinA, a person appears younger and naturally relaxed and pleasant ( Figs. 5.43A,B and 5.44A,B ).

Depending on the extent and depth of the marionette lines pres-ent, this area is best treated in combination with soft tissue fillers and some form of laser treatments whether ablative or nonablative.

OnabotulinumtoxinA then will usually prolong the beneficial effects of such rejuvenation procedures. The beneficial effects from injec-tions of onabotulinumtoxinA can last from 4 to 6 months.

Complications (Adverse Sequelae) (see Appendix 5) It is extremely important to inject inferior to and far enough away from the orbicularis oris when treating the depressor anguli oris. Otherwise, onabotulinumtoxinA can diffuse focally into the muscle fibers of the orbicularis oris and produce a localized area of inadequate sphincteric closure of the oral cavity (Fig. 5.44D) and a segmental inability to

164 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

pucker the lips ( Fig. 5.19 ). This will result in a localized area of ekla-bion, an asymmetric smile, drooling and even dribbling, and a change in speech and word pronunciation.

Injections given too medially also can weaken the depressor labii inferioris, causing a flattening of the contour of the lower lip and an

asymmetric smile ( Fig. 5.44D ). Additional adverse sequelae when the depressor labii inferioris is inadvertantly weakened include the inability also to purse or pucker the lips symmetrically, seal the lips to contain solid food or fluid in the mouth or to drink from a glass, sip from a straw, or eat from a spoon. Pronunciation of particular

Figure 5.45 This 45-year-old before (A) and 3 weeks after (B) 4 U of onabotulinumtoxinA were injected into each depressor anguli oris. Note the slight uplifting of the corners of the mouth.

(A) (B)

Figure 5.44 This 52-year-old at rest (A) and 3 weeks after (B) 4 U of onabotulinumtoxinA were injected into each depressor anguli oris. (C) Same patient frowning before and 3 weeks after (D) that same treatment. Note the slightly asymmetric smile with forced frowning (D), which lasted approximately 2–3 weeks after the initial onabotulinumtoxinA treatment, and of no concern to the patient. No other adverse sequelae was experienced by the patient.

After

44

Before

AfterBefore

44

(A) (B)

(C) (D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 165

(A) (B)

Figure 5.46 This 40-year-old before (A) and 2 weeks after (B) 4 U of onabotulinumtoxinA were injected into each depressor anguli oris. Note the slight uplifting of the corners of the mouth.

(A) (B)

Figure 5.47 This 53-year-old before (A) and 3 weeks after (B) 4 U of onabotulinumtoxinA were injected in each depressor anguli oris. Note the slight uplifting of the corners of the mouth.

sounds can be hampered and the articulation of certain words will be difficult. When the depressor labii inferioris is profoundly affected a disconcerting adynamic smile, is likely to occur, with only the upper lip moving. Overzealous injections with doses over 6 to 8 U of onabotulinumtoxinA into the depressor anguli oris also will place patients at risk for developing the adverse sequelae as described above, even when the injection technique is flawless, if onabotu-linumtoxinA diffuses into the adjacent depressor labii inferioris. Even when the appropriate dose is precisely injected, vigorous

massaging of the area after the injection can displace the onabotu-linumtoxinA into adjacent muscle fibers and cause similar adverse effects as described. For the first-time patient, treatment in this area can produce similar but mild and transient sequelae that may be overwhelming to the uninformed and unprepared patient so pretreatment warning of these potential side effects is mandatory ( Fig. 5.44A,B ).

Figures 5.45 to 5.48 are additional examples of different patients treated with onabotulinumtoxinA to uplift the oral commissures.

(A) (B)

Figure 5.48 This 78-year-old before (A) and after (B) 4 U of onabotulinumtoxinA were injected in each depressor anguli oris. Note the slight uplifting of the corners of the mouth. This patient also underwent ablative fractionated CO

2 resurfacing and injections of soft tissue fillers 2 weeks after the onabotulinumtoxinA injections.

166 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 5.49 (A,B) This 49-year-old woman was unaware of her chin dimples before treatment (A). She is also seen 3 weeks after treatment with onabotulinumtoxinA (B).

(A) (B)

Treatment Implications When Injecting Marionette Lines

1. Inject onabotulinumtoxinA only when the depressor anguli oris

can be accurately palpated and unmistakably identifi ed.

2. The depressor anguli oris usually can be identifi ed at the inferior

end of the nasolabial sulcus over the body of the mandible and

anterior to the masseter.

3. A lateral platysmal band can identify the location where the depres-

sor anguli oris and platysma decussate along the inferior border

of the mandible. It is at this point of maximal contraction of the

depressor anguli oris that is the recommended site for an injection

of onabotulinumtoxinA.

4. Avoid injecting onabotulinumtoxinA into the marginal mandibular

nerve and facial artery and vein by lifting the skin and soft tissue

before injecting.

5. Avoid injecting onabotulinumtoxinA into the depressor labii inferi-

oris and orbicularis oris by remaining at least 1 cm lateral and 1 to

1.5 cm inferior to the lateral oral commissure and in the center of or

just above the body of the mandible.

6. OnabotulinumtoxinA should be injected intramuscularly just

beneath the subcutaneous plane since the depressor anguli oris lies

in a superfi cial level above that of the depressor labii inferioris.

7. Always inject minimal volumes of highly concentrated

onabotulinumtoxinA in the perioral area.

CHIN PUCKERING AND A DEEP MENTAL CREASE Introduction: Problem Assessment and Patient Selection For some men and especially women, a hyperkinetic mentalis can produce involuntary localized dimpling ( Fig. 5.49A,B ) or an overall puckering of the chin, creating convolutions of deep ridges and furrows while they speak or convey a particular facial expression ( Fig. 5.50 ). For most individuals who consciously or involuntarily crinkle their chin during animation or even while at rest, these changes generally go undetected by the person producing them unless disclosed by others. Once identified, chin puckering then can be verified by the patient by personally viewing

these chin corrugations with a mirror while animating or speaking ( Fig. 5.51 ).

Any motion of the lower lip that causes the lip margin to evert as when pronouncing words that begin with the letter “F” will usually accentuate chin puckering ( Fig. 5.52A,B ). In other individuals, chin puckering can be a frustrating annoyance when it occurs postopera-tively as a secondary synkinesis of augmentation mentoplasty ( Fig. 5.53A ) ( 21,22 ). Because not all of the bony attachments of the muscle fibers of the mentalis can be repositioned and reapproximated exactly as they were prior to the instillation of a chin implant, the contracting fibers of the mentalis then become anomalously reattached to the mentum, producing an irregular crimping of the skin surface, either at rest or with each movement of the mentalis ( Fig. 5.53A,C ). This can be an unexpected and frustrating substitution for the correction of an inadequately projecting chin.

In still another group of people, a hyperkinetic mentalis produces an accentuated, deep transverse (labio)mental crease between the lower lip and the prominence of the chin that amplifies the forward projection of the apex of the mentum ( Figs. 5.54 and 5.55 ). This is viewed as a sign of dotage or senility by the casual observer, because with age the tip of the chin can elevate and project forward, produc-ing the so-called “wicked witch’s chin.” Men are not as frequently bothered by similar changes and even less often do they seek relief from them.

Functional Anatomy (see Appendix 1) Dynamic wrinkling and corrugations of the surface of the chin or the deep concavity of a (labio)mental crease is produced by a hyperki-netic mentalis. The mentalis is a short, stout, conical, two-bellied muscle that originates deeply to the depressor labii inferioris on the anterior aspect of the mandible on either side of the midline at the level of the incisive fossa and root of the lower lateral incisors ( Fig. 5.56 ). It travels downward, converging its two muscle bellies toward the midline to insert with multiple fibrous attachments into the skin of the apex of the chin on either side of the frenulum of the lower lip. Some of its fibers interdigitate superiorly with fibers of the orbicularis oris and laterally with the fibers of the depressor labii inferioris. The mentalis elevates the skin of the base of the lower lip upward, helping to force the lower lip against the gums. The mentalis assists other reciprocating synergistic perioral muscles (e.g., depres-sor labii inferioris and orbicularis oris) to depress, protrude, and

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 167

Figure 5.50 This 50-year-old was unaware that her chin puckered when she became animated or spoke. Forced contraction of her mentalis produced multidirectional corruga-tions before onabotulinumtoxinA (A), which disappeared 2 weeks after 8 U of onabotulinumtoxinA were injected in her mentalis (B).

2 weeks afterBefore

4 4

(A) (B)

Figure 5.51 This 30-year-old was unaware of her chin corrugations until she was actively animating and puckering in front of a mirror. Note the localized dimpling of her chin.

Dilution (see Appendix 2)

When treating the mentalis, lateral diffusion of the onabotulinum-

toxinA runs the risk of weakening the depressor labii inferioris and

producing sphincter and motor movement incompetence of the

mouth, causing an inability to depress the lower lip when smiling,

laughing, speaking, drinking, and eating. Therefore, accurately recon-

stituted, low volumes of concentrated onabotulinumtoxinA must be

precisely injected when treating the mentalis. The preferred way to

accomplish this is to reconstitute a 100 U vial of onabotulinumtoxinA

with only 1 ml of normal saline.

evert the lower lip during drinking, eating, and speaking. This maneuver also intensifies the indentation of the mentolabial crease. The mentalis also wrinkles the skin of the chin when it is contracted in pouting to produce an expression of doubt, displeasure, sadness, or disdain. With age, the loss of dermal collagen, elasticity, and soft tissue support, as well as diminution in the bone structure and sub-cutaneous fat along with a hyperkinetic mentalis can enhance the appearance of uncontrollable chin convolutions and dimpling. In most individuals, when frowning in displeasure or projecting an expression of sadness, doubt, or disdain, the depressor anguli oris contracts simultaneously with the mentalis, so the melomental (“marionette”) lines also are accentuated. This is why, for many patients, it is advisable to treat both the presence of marionette lines and chin dimpling at the same time during the same session.

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) A hyperactive mentalis can be relaxed by injecting 3 to 4 U of onabotulinumtoxinA deeply into the muscle at one point on each side of the midline of the mentum at the apex of its protuberance. This two-point injection technique is especially appropriate if the patient has a vertical mental cleft or a widely shaped, square chin ( Figs. 5.53A–D and 5.55 A,B). Injections are best done with the patient in the upright sitting or semireclined position. If the patient has a narrow, rounded or pointed chin, the insertion of the mentalis

into the undersurface of the skin with its paired muscle belly of the contralateral side probably is more centrally located. For these patients, an alternative one point injection technique is more appropriate. This is accomplished by injecting 4 to 6 U of onabotu-linumtoxinA deeply into one point only in the center of the mentum at the apex of the mental protuberance ( Figs. 5.57 and 5.58 ).

It is imperative to avoid inadvertent diffusion of onabotulinum-toxinA into any of the muscle fibers of the orbicularis oris, which can result in sphincter and motor movement irregularities. This can be accomplished by injecting onabotulinumtoxinA significantly inferiorly to the transverse mental crease and into the center of the apex of the mental protuberance. Light massage will relieve the pain of injection. Vigorous massage will displace the onabotulinumtox-inA laterally or superiorly, particularly if the two-injection point technique is used, and cause the onabotulinumtoxinA to diffuse into the fibers of the depressor labii inferioris and the orbicularis oris or both producing untoward sequelae.

168 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 5.52 This 63-year-old woman at rest before (A) 4 U of onabotulinumtoxinA were injected into her mentalis. Note the crimping of the chin and deep mental crease at rest and while pronouncing words containing the letter “F” (B). Same patient at rest (C) and animating 3 weeks after (D) the onabotulinumtoxinA treatment. Note the reduction of chin crimping and effacement of the mental crease.

(A) (B)

(C) (D)

Figure 5.53 This 67-year-old before (A) and 6 weeks after (B) her 3rd onabotulinumtoxinA treatment with 8 U of onabotulinimtoxinA into her mentalis for a synkinesis caused by an augmentation mentoplasty 2–3 years previously. Note the difference in the pattern of chin crimping before and after a treatment with onabotulinumtoxinA. The same patient was plagued with the appearance of chin crimping both at rest and during animation seen here before (C) and 3 weeks after (D) her 4th treatment of onabotulinumtoxinA.

(A) (B)

(C) (D)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 169

Outcomes (Results) (see Appendix 4) Relaxing the hyperkinetic muscle fibers of the mentalis can reduce or eliminate the involuntary convolutions and corrugations of the chin when one is at rest, speaking, or emotionally expressing oneself ( Figs. 5.55 and 5.58 ). A weakening of the mentalis also can drop the anterior projection of the skin of the chin slightly downward, attenuating an already deep transverse labiomental crease and possibly rotating the lower lip slightly upward ( Figs. 5.55A,B and 5.59 ). When the transverse labiomental crease is exceptionally deep and resistant to treatment with onabotulinumtoxinA, elevating and effacing it with soft tissue fillers is an advisable alternative. Deeply placed injections of soft tissue fillers across the anterior aspect of the mentum will recon-tour and rejuvenate the chin and injections of onabotulinumtoxinA into the mentalis will actively sustain and prolong the improvement.

For those patients who have a distorted convoluted chin as a result of a previous augmentation genioplasty with a chin implant, injections of onabotulinumtoxinA can produce a softening and a relaxation of the chin. This is much appreciated by those who are vexed by these anxiety provoking wrinkles and convolutions of the mentum and for whom addi-tional surgery is not an option ( Fig. 5.53A–D ). The addition of a soft tis-sue filler will augment and prolong the corrective effects produced by the injections of onabotulinumtoxinA. The effects of the injections of ona-botulinumtoxinA of the mentalis can last anywhere from 4 to 6 months.

Complications (Adverse Sequelae) (see Appendix 5) When injections of onabotulinumtoxinA are placed too high on the lower lip, i.e., above the transverse (labio)mental crease, the orbicularis oris, and even the depressor labii inferioris can certainly be weakened, particularly when using the two point injection technique. Diffusion of onabotulinumtoxinA into the depressor labii inferioris and orbicularis oris also can occur when vigorous massaging is performed immedi-ately after injection. If either the orbicularis oris or the depressor labii inferioris is inadvertently affected by onabotulinumtoxinA, a relax-ation of a tight oral sphincter, a reduction in lip competence, and a diminution in buccal motor movements will occur (Fig. 5.60). This can cause a patient to form certain letters, such as b, p, w, f, o, and u, and articulate certain sounds and words with embarrassing difficulty. Also, an asymmetric smile can be produced as a result of an adynamic or synkinetic lower lip. An overzealous treatment of the mentalis with too high a dose of onabotulinumtoxinA that virtually immobilizes the mentalis will cause an inability to approximate the lower lip tightly against the teeth, or a glass or cup, producing involuntary dribbling from the lower lip when drinking, or drooling from the corners of the mouth when at rest (Fig. 5.60).

Figures 5.61 to 5.65 are additional examples of different patients treated with onabotulinumtoxinA for chin puckering and a deep mental crease.

Figure 5.54 This 52-year-old patient seen before (A) and 1 month after (B) 6 U of onabotulinumtoxinA were injected into the mentalis. Note the slight diminution of the mental crease.

(A) (B)

Figure 5.55 This 58-year-old patient seen before (A) and 3 weeks after (B) 8 U of onabotulinumtoxinA were injected into the mentalis. Note the deep transverse labiomental crease prior to treatment and the diminution of it after treatment.

(A) (B)

170 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

(A) (B)

Figure 5.57 This 70-year-old woman accentuates chin puckering by pursing her lips before (A) and 1 month after (B) 4 U of onabotulinumtoxinA were injected into a single site at the apex of the mentum.

6

(A) (B)

Figure 5.58 This 53-year-old with chin puckering at rest that was exacerbated with animation, and is seen before (A) and 2 weeks after (B) 6 U of onabotulinumtoxinA were injected into a single site at the apex of the mentum. Note the narrowness of the apex of the mentum and the location of the single injection point.

Figure 5.56 The mentalis elevates the lower lip, indents the mentolabial crease, and creates surface corrugations over the mentum.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 171

(A) (B)

Figure 5.59 This 58-year-old patient seen before (A) and 1 month after (B) 4 U of onabotulinumtoxinA were injected into the mentalis. Note the deep transverse labiomental crease prior to treatment and the slight diminution of it after treatment.

(A) (B)

Figure 5.60 This 55-year-old patient smiling before (A) and after (B) 10 U of onabotulinumtoxinA were injected into her mentalis. Note the inability of the mentalis to lower the center of the lower lip after her high dose treatement. The patient had to manually lower her lip to avoid biting it while eating and drinking. She had incontinence of liquid and difficulty with articulating certain sounds and words.

(A) (B)

Figure 5.61 This 44-year-old with chin puckering and perioral rhytides is seen before (A) and 3 weeks after (B) 4 U of onabotulinumtoxinA were injected into the mentalis. Note the softening of the lower face and fullness of the lip vermillion with additional onabotulinumtoxinA injections of the perioral rhytides.

172 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

(A) (B)

Figure 5.63 This 53-year-old with chin puckering is seen before (A) and 6 weeks after (B) 4 U of onabotulinumtoxinA were injected into the mentalis. Note the softening of the lower face and a fullness of the lip vermillion with the additional treatment of her perioral rhytides.

Figure 5.62 This 53-year-old with chin puckering is seen before (A) and 2 months after (B) 4 U of onabotulinumtoxinA were injected into the mentalis. Note the transverse widening of the mentum. Perioral rhytides were also treated with onabotulinimtoxinA.

(A) (B)

(A) (B)

Figure 5.64 This 66-year-old is shown at rest with chin puckering and perioral rhytides, before (A) and 2 weeks after (B) 4 U of onabotulinumtoxinA were injected into the mentalis and additional onabotulinumtoxinA was injected in the perioral rhytides. Note the excessive wrinkling of the lower lip and chin before treatment that softened after treatment.

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 173

Treatment Implications When Injecting the Mentalis

1. Inject onabotulinumtoxinA far below the transverse mental

crease and at the apex of the mental protuberance.

2. Injections can be placed deeply and in one site centrally or in two

sites separately on either side of the midline depending on the

width of the chin.

3. High-volume injections or an improper heavy-handed tech-

nique can cause diffusion of onabotulinumtoxinA into the orbicu-

laris oris or depressor labii inferioris or both, and produce motor

dysfunction of the lower lip and sphincter incompetence of the

buccal aperture.

4. Immobilizing the mentalis with a high dose of low-volume ona-

botulinumtoxinA can prevent the lower lip from approximating

tightly against the teeth or a drinking vessel, resulting in dribbling

while drinking and drooling while at rest. Inability to articulate

words and sounds distinctly also can occur.

5. Injections of onabotulinumtoxinA can correct postoperative

chin puckering and distortions resulting from an augmentation

genioplasty.

6. The use of onabotulinumtoxinA can prolong the enhancement

produced by soft tissue fi ller injections of the perimental and

peribuccal areas.

7. OnabotulinumtoxinA treatment of the lower face should always

include injecting the mentalis.

JAWLINE BLUNTING AND WRINKLING OF THE UPPER PLATYSMA Introduction: Problem Assessment and Patient Selection With age, there is a descent of soft tissue from the mid face to the man-dibular border ( 23 ). With time, the platysma can become hyperkinetic and the skin of the face and neck becomes lax and drapes randomly in the lower face, over the mandibular border, overhanging and blunting the cervicofacial angle ( Fig. 5.66 ). Patients who can displace and elevate their platysma and make their mandibular border disappear by pulling down hard on their platysma are ideal candidates for treatment with onabotulinumtoxinA. In addition, there is a small subset of patients whose upper platysma is very active and hyperkinetic creating various perioral horizontal lines with the slightest bit of buccal movement ( Fig. 5.67A,B ). These lines in particular will deepen with smiling or laughing and are an annoyance to those who possess them. Lower facial

platysmal lines become more obtrusive when their bearer loses weight and the skin continues to become lax and inelastic with time and sun exposure ( Fig. 5.68A–D ).

Functional Anatomy (see Appendix 1) The platysma is composed of two separate broad, thin sheets of muscle running up the front and lateral aspects of the neck from the upper chest to the mandible, fusing and blending its muscle fibers with the superficial muscular aponeurotic system (SMAS) superiorly in the face ( 24–25 ). It can vary considerably in thickness and extent. In some individuals, the platysma may even be absent.

The platysma originates from the superficial fascia of the upper part of the thorax over the pectoralis major and deltoid. It ascends in a superomedial direction across the clavicle and acromion of the scapula and up the lateral neck. Its anterior fibers from both sheets of muscle on either side of the neck interdigitate with each other in various patterns at or near the symphysis menti of the mandible. The posterior fibers pass over the lower border of the body of the mandible superficial to the marginal mandibular branch of the facial nerve, artery, and vein. This upper part of the platysma is composed of three portions and is a con-tributor to the orbicularis oris complex ( Figs. 5.8 , 5.9 , and 5.69 ) ( 2 ).

The upper fibers of the platysma identified as the platysma pars mandibularis insert onto the lower border of the body of the mandible below the oblique line and into the skin and subcutaneous tissue of the lower part of the face. Posterior to the attachment, separate muscle fibers pass superomedially to interdigitate with the lateral fibers of the depressor anguli oris. Other fibers of the platysma travel deep to the depressor anguli oris and reemerge medial to it. Some additional platysmal fibers known as the platysma pars labialis continue within the tissue of the lateral half of the lower lip, as a direct labial tractor. They interdigitate and blend into the muscles around the angle of the mouth (orbicularis oris and risorius), the chin (mentalis), and the depressors of the lower lip (depressor labii inferioris and especially the depressor anguli oris) ( Fig. 5.69 ). It is the platysma pars labialis that occupies the space between the depressor labii inferioris and the depressor anguli oris. It is on the same tissue plane of these lower lip depressors and all three muscles have similar labial attachments. Occa-sionally, fibers of the platysma may be present as high as the ear or zygoma (i.e., near the origin of the zygomaticus major or up to the margin of the orbicularis oculi), participating in the formation of the SMAS in the lower and lateral aspects of the face. The platysma pars modiolaris is comprised of all the remaining fibers of the upper pla-tysma posterior to the platysma pars labialis and is posterolateral to the

Before 3 weeks after

4 4

(A) (B)

Figure 5.65 This 38-year-old at rest with a deep transverse mental crease before (A) and 3 weeks after (B) 8 U of onabotulinumtoxinA were injected into the mentalis. Note the effacement of the mental crease and upward rotation of the lower lip vermillion.

174 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 5.67 (A) This 68-year-old has a very active upper platysma which creates a set of perioral horizontal rhytides with the slightest buccal movement. Same patient is seen grimacing prior to (B) 20 U of onabotulinumtoxinA that were injected 2–4 mm above and below the inferior border of the body of the mandible. (C) Same patient shown 1 month after treatment.

(A) (B)

(C)

fibers of the depressor anguli oris. They pass superomedially deep to the risorius and into the apical and subapical modiolar attachments (see pages 145–146 and Figs. 5.9 and 5.10 ). The anterior portion and thickest fibers of the platysma can pull the lower lip and corners of the mouth downward and laterally, widening the buccal aperature at the corners of the mouth as in an expression of horror. The platysma also slightly depresses the mandible, partially opening the mouth during an expression of surprise. The platysma also is active during sudden, rapid, and deep inspiration. Contracting the platysma can increase negative pressure in the superficial jugular veins of the neck, facilitating venous circulation. Electromyographic studies have demonstrated that the platysma is not actively contracting during laughing, opening the mouth, or moving the head ( 24,25 ).

Dilution (see Appendix 2)

When treating the upper fi bers of the platysma, it is safer and results

will be more consistent if small volumes of onabotulinumtoxinA

are injected, thereby avoiding any unintended diffusion beyond the

targeted muscles. Therefore, a 100 U vial of onabotulinumtoxinA is

best reconstituted with 1 ml of normal saline. If a more far-reaching

technique simulating the “microbotox” technique (see chapter 6) is

desired, then a 100 U vial of onabotulinumtoxinA can be reconsti-

tuted with 2 to 5 U of normal saline. With this dilution, the small

volume intradermal microinjection technique is the only manner in

which it should be utilized.

Figure 5.66 This 58-year-old has a hyperkinetic platysma, creating a blunting of the cerviofacial angle.

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 175

Figure 5.68 This 55-year-old has lower face platysmal lines due to aging and weight loss. Patient is seen before (A,C) and 3 weeks after (B,D) 6 U of onabotulinumtoxinA were injected into the platysma, pars mandibularis along the inferior border of the mandible. The mentalis was injected with 5 U of onabotulinumtoxinA and a hyaluronic acid soft tissue filler was injected into the nasolabial folds during the same treatment session.

(A) (B)

(C) (D)

Figure 5.69 Platysma, pars labialis, pars mandibularis and pars modiolaris.

Corrugator supercilii

Levator labiisuperiorisalaeque nasi

Levator labiisuperioris

Levator angulioris

Buccinator

Masseter

Depressor labiiinferioris

Mentalis

Frontalis

Procerus

Depressor supercilii

Orbicularis oculi

Levator labiisuperioris

alaeque nasi

Compressor naris

Dilator naris

Zygomaticusminor

Zygomaticusmajor

Depressorsepti nasi

Risorius

Orbicularis oris

Modiolus

Platysma

Depressor angulioris

176 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Dosing: How to Correct the Problem (see Appendix 3)(What to Do and What Not to Do) The platysma plays a predominant roll in the overall contour of the mandibular border and the cervicofacial angle. It is responsible for the presence of horizontal wrinkles found in the vicinity of the modi-olus and lateral to the oral commissures ( Fig. 5.68A–D ). Treat the patient while in the sitting or semi reclined position. For the horizon-tal rhytides that appear adjacent to the commissures and are intensi-fied when the corners of the mouth are compressed, 2 U of onabotulinumtoxinA injected 1 to 2 cm below the inferior margin of the body of the mandible directly inferior to those horizontal wrin-kles in 1 to 3 points 1.5 to 2.0 cm apart from each other will diminish them ( Fig. 5.68A–D ). This treatment usually is performed at the same time the depressor anguli oris and mentalis are treated, since these muscles all interdigitate with each other and they function codependently with each other.

Levy recently found that he could delineate more sharply the man-dibulocervical angle by injecting 2 to 3 U of onabotulinumtoxinA at

Figure 5.70 Note the multiple injection points along the upper cervical border of the platysma, along the lateral aspect of the neck. Approximately 2 U of onabotulinumtoxinA were injected at each point (wheal).

Figure 5.71 The injection points are posterior to the lateral border of the depressor anguli oris and anterior to the belly of the sternocleidomastoid.

multiple sites along the upper cervical border of the platysma just adjacent and inferior to the body of the mandible along the lateral aspect of the neck ( Fig. 5.70 ) ( 26 ). Injections should be placed posterior to an imaginary line that is a continuation of the nasolabial fold that traverses the mandible and passes onto the lateral neck and is posterior to the lateral border of the depressor anguli oris and anterior to the belly of the sternocleidomastoid ( Fig. 5.71 ).

The total dose for each side of the neck should not exceed more than 15 to 20 U of onabotulinumtoxinA. If there is a prominent platysmal band in the lateral neck, this also should be included in the treatment of the “Nefertiti lift” ( Figs. 5.70 and 5.71 ). The platysma in the submandibular area and platysmal bands can be easily treated by grasping skin or the band with the nondominant hand and injecting onabotulinumtoxinA between the thumb and index finger in a “T”-like configuration along the lateral neck ( Figs. 5.70 and 5.71 ).

Outcomes (Results) (see Appendix 4) For those horizontal platysmal wrinkles lateral to the mentum and oral commissures, a treatment with 4 to 8 U of onabotulinumtox-inA will last 3 to 4 months. Levy, however, reports the effects of the “Nefertiti lift” to last on an average of 6 months ( 26 ). He named this technique the “Nefertiti lift” to emphasize the final visual effect of a perfectly recontoured jawline. Injections of onabotulinumtoxinA relax the platysma pars mandibularis , which then allows the levators of the face to lift the skin of the lower face. This in turn sharpens and redefines the mandibular border and angle by redraping the skin over the jawline and elevates the corners of the mouth. This technique gives the visual effect of a “mini lift” and the perfectly contoured mandibular angle that Nefertiti made so famous (see chapter 6).

Complications (Adverse Sequelae) (Appendix 5) Injecting the platysma pars mandibularis is no easy task and should only be performed by the expert injector. If there is diffusion of ona-botulinumtoxinA beyond the immediate site where it is injected, the depressor labii inferioris, the orbicularis oris, and other segments of the platysma will be affected, which can adversely impact upon the final results. In addition, if onabotulinumtoxinA is injected unevenly or if it is taken up by the different muscle fibers of the platysma that interdigitate with the lower lip depressors, then an asymmetry and a

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 177

Figure 5.72 This patient experienced asymmetry of the lower right quadrant of the lips and distortion of the lower face after submandibular injections of onabotulinumtoxinA diffused into the right depressor labii inferioris. Note the synkinesis of the levators in upper lateral quadrant.

Figure 5.73 (A) This 59-year-old patient is seen before (A) and 2 weeks after (B) 12 U of onabotulinumtoxinA were injected in her left platysma, pars mandibularis and left depressor anguli oris. Same patient is seen before (C) and 2 weeks after (D) the identical treatment with onabotulinumtoxinA was completed on the right.

(A)

(C)

(B)

(D)

178 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

malfunctioning of the mouth and distortion of the lower face will be experienced by the patient ( Fig. 5.72 ). This can occur when performing the Nefertiti lift or when one attempts to eliminate the horizontal lines of the lateral mentum and inferior oral commissures. Other predict-able adverse sequelae that can occur when the injections of onabotu-linumtoxinA are not placed properly are an asymmetric smile, disruption of lip competence causing incontinence of food and liquids, dysarthria, disphonia, and dysphagia. When treating the platysma pars mandibularis along the inferior mandibular border posteriorly, ona-botulinumtoxinA should not inadvertently penetrate the sternocleido-mastoid either by direct injection or diffusion. If this occurs, the patient will have difficulty with lateral and rotational movements of the neck, resulting in an instability of head positioning and difficulty raising it from a supine position.

When treating the lower face and the platysma, there is an exquisitely delicate balance of levators and depressors just like in the midface, i.e., a narrow margin of success. Increasing a proven efficacious dose of onabotulinumtoxinA by 1 or 2 U may cause adverse sequelae when a lower dose did not. Therefore, only a minimal amount of low volume onabotulinumtoxinA should be injected in the mid and lower face, if predictable and reproducible beneficial treatments are expected. Most importantly, when treating the platysma in the lower face, keep the injections superficial (i.e., intradermal) and far away from the orbicularis oris and depressor labii inferioris.

Figures 5.73 to 5.75 are additional examples of different patients treated with onabotulinumtoxinA in the submandibular area for perimental rhytides and to tighten the jawline.

(A) (B)

(C) (D)

2

4

22

2

22

Figure 5.74 (A) This 58-year-old patient is seen before (A) and 2 weeks after (B) 12 U of onabotulinumtoxinA were injected in her left platysma, pars mandibularis and left depressor anguli oris. (C) Same patient is seen before and 2 weeks after (D) the identical treatment with onabotulinumtoxinA was completed on the right.

Treatment Implications When Injecting the Jawline and Upper Platysma

1. Horizontal rhytides just lateral to the mentum and oral

commissures can be diminished by intradermal injections of

onabotulinumtoxinA along the undersurface of the mandible.

2. Hyperkinetic fi bers of the upper platysma (pars mandibularis)

can blunt the jawline.

3. Properly placed intradermal injections of onabotulinumtoxinA

along the underside of the mandible and down the lateral neck

can sharpen the jawline and lift the lower skin of the face.

4. Injections of the upper platysma with onabotulinumtoxinA should

be performed posterior to the origin of the depressor labii inferioris

and 2 to 3 cm inferior to the lower border of the body of the mandible.

5. For optimal results, the lower face should be treated as a cosmetic

unit with injections of onabotulinumtoxinA placed intrader-

mally in the superfi cial orbicularis oris, deeply into the mentalis,

subcutaneously and intradermally into the depressor anguli oris,

and intradermally in the upper platysma.

6. Avoid injecting the depressor labii inferioris and the deep fi bers

of the orbicularis oris with onabotulinumtoxinA to prevent oral

sphincter incompetence and a disruption in buccal function.

7. Avoid injecting the sternocleidomastoid with onabotulinumtoxinA

to prevent diffi culty with neck movements and head positioning.

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 179

HORIZONTAL LINES AND VERTICAL BANDS OF THE NECK Introduction: Problem Assessment and Patient Selection Frequently, the neck can be a more accurate gauge of a person’s chron-ologic age than the overall appearance of his or her face. This is espe-cially true in those individuals who have spent a lot of time outdoors and who have taken advantage of various cosmetic procedures avail-able for facial rejuvenation. The neck as well as the perioral region have remained the bane of aesthetic rejuvenation for most age-conscious individuals seeking relief from the ravages of time and the innumerable hours spent outdoors, whether for work or pleasure. None of the avail-able invasive surgical procedures (i.e., cervicoplasties or rhytidecto-mies) have ever eliminated satisfactorily and safely horizontal necklace lines, vertical platysmal bands, and cords for any substantial length of time ( 26 ). Since the 1990s, there has been the introduction of more aggressive approaches to neck rejuvenation, albeit not as invasive as a surgical intervention. These include superficial skin surface altering procedures, e.g. chemical peeling or ablative fractionated laser resur-facing and periodic nonablative laser or intense pulsed light treat-ments, thread-lifting, soft tissue fillers and implants or regular topical cosmeceutical treatments. However, all of these innovative procedures fall short of totally eliminating the usual skin surface damage of solar elastosis and the pigmentary and textural changes that are so character-istic of photodamage and aging.

Upon animation with different neck movements, vertical bands and cords may become prominent at an early age (in the fourth or fifth decade) in predisposed individuals or eventually in the sixth or seventh

decade for many others ( Figs. 5.76 and 5.77 ). With age, the skin of the neck progressively loses its elasticity, becomes increasingly lax and redundant. There is a diminution of soft tissue support, causing the skin of the neck to be susceptible to continuous horizontal creasing, which leads to persistent transverse wrinkles that are perpendicular to the normal vertical contractions of the platysma. These horizontal lines traverse the anterolateral aspect of the neck between the anterior borders of the right and left sternocleidomastoid from the subman-dibular area down to the clavicles like multiple parallel rings around the neck ( Fig. 5.76 ).

When the platysma becomes less elastic with age, it separates anteri-orly and can be appreciated clinically as two or more divergent bands or folds of skin that extend from the lower margin of the mandible to the medial aspect of the clavicles. These anterior neck bands often tighten and become more visible, especially when the patient turns the head from side to side as they speak or gesticulate ( Fig. 5.77 ) ( 27 ). Ver-tical bands and cords develop as the result of a hyperactive platysma attempting to support the ptotic structural changes so characteristic of a senescent neck. The anterior edges of the fibers eventually lose muscle tone, separate over time, and protrude anteriorly, creating the cords and bands that are sometimes referred to as the “turkey neck” defor-mity ( Fig. 5.78 ). For some carefully selected individuals who still pos-sess a reasonable amount of cutaneous elasticity, but who develop prominent platysmal neck bands because of idiosyncratic platysmal hyperactivity, injections of onabotulinumtoxinA have become a viable treatment option to reduce the prominence of those platysmal neck

(A) (B)

(C) (D)

Figure 5.75 (A) This 66-year-old patient is seen before (A) and 3 weeks after (B) 12 U of onabotulinumtoxinA were injected in her left platysma, pars mandibularis and left depressor anguli oris. (C) Same patient is seen before and 3 weeks after (D) treatment with onabotulinumtoxinA on the right.

180 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 5.76 This 55-year-old began to notice deep horizontal wrinkles of the anterior neck at age 40.

bands. For still others demonstrating a similar integrity of cutaneous elasticity, but who either are unable for medical reasons or are unwilling for other reasons to undergo the rigors and postoperative morbidity of an invasive surgical procedure such as a cervicoplasty or rhytidectomy, injections of onabotulinumtoxinA have become a frequently requested solution to their problem.

Functional Anatomy (see Appendix 1) The platysma is composed of two separate broad, thin sheets of mus-cle running up the front and lateral aspects of the neck from the upper chest to the mandible, fusing and blending its muscle fibers with the superficial muscular aponeurotic system (SMAS) superiorly in the face ( Fig. 5.69 ). It can vary considerably in thickness and extent. In some individuals, the platysma may even be absent. The platysma originates from the superficial fascia of the upper part of the thorax over the pectoralis major and deltoid. It ascends in a superomedial direction across the clavicle and acromion of the scapula and up the lateral neck. Its anterior fibers from both sheets of muscle on either side of the neck interdigitate with each other in various patterns at or near the symphysis menti of the mandible ( 28 , 29 ). The posterior fibers pass over the lower border of the body of the mandible superfi-cial to the marginal mandibular branch of the facial nerve, artery, and

Figure 5.77 This 52-year-old began to notice deep horizontal wrinkles of the anterior neck at age 38. Note the platysmal neck band when she forcibly contracts her platysma.

Figure 5.78 The pendulous “turkey neck deformity” in this 73-year-old woman.

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 181

vein ( Fig. 5.9 ). Occasionally, fibers of the platysma may be present as low as the fourth to sixth intercostal space in the chest and as high as the ear or zygoma (i.e., near the origin of the zygomaticus major or up to the margin of the orbicularis oculi), participating in the formation of the SMAS in the lower and lateral aspects of the face. With maxi-mum contraction the platysma pulls the skin lying over the clavicle upward and wrinkles the skin of the neck in an oblique direction increasing the diameter of the neck, as one does when relieving the pressure of a tight collar. The platysma also is active during sud-den, rapid, and deep inspiration. Contracting the platysma can increase negative pressure in the superficial jugular veins of the neck, facilitating venous circulation.

Some authors like to emphasize the different anatomic variations of the platysma based on the pattern of decussation of its interlacing fibers as they approach the submental region (Fig. 5.79) ( 27 , 30–33 ). The most common variant seen in approximately 75% of patients identified as type I is where the fibers of the platysma interdigitate with its counterpart on the opposite side of the neck 1 to 2 cm below the chin. In patients with the type II variant, seen approximately 15% of the time, the decussation of the fibers occurs at the level of the thyroid cartilage and becomes a unified sheet of muscle from thereon up and over the entire submental region. Approximately 10% of patients have the type III variant, which is seen as two separate straps of platysma that run parallel to each other up the neck, attaching to the mandible and skin without decussating its fibers ( Fig. 5.79 ) ( 24 , 32–36 ).

There are two distinctly separate depots of fat in the submental region of the neck that must be taken into consideration when plan-ning rejuvenation procedures for the aging neck. The more superficial one of the two is the submental or submandibular fat pad, which lies directly anterior to the platysma in the subcutaneous plane. The other, the subplatysmal fat pad, lies more deeply in the neck, residing behind and posterior to the platysma. Herniation and protrusion of the sub-platysmal fat pad in the aging neck are predicated upon the type of anatomic variant of the platysma present in an individual and whether or not there is a significantly wide enough separation of the two muscle sheets inferior to the mentum. In those individuals with excessive amounts of submental fat in the subplatysmal layer, the loss of platys-mal muscle tone permits the subplatysmal fat pad to herniate through the free borders of the platysma and establish a central fullness of sub-mental fat in between vertical columns of neck bands, the so-called turkey neck deformity ( Fig. 5.78 ).

Dilution (see Appendix 2)

Because the platysma is a large sheet of muscle that drapes over the

anterolateral aspect of the neck, injections of large volumes of dilute

onabotulinumtoxinA may be more expedient when the entire neck

needs to be treated. Therefore, reconstituting a 100 U vial of ona-

botulinumtoxinA with 2 to 4 ml of normal saline is more practi-

cal than reconstituting it with a smaller volume when injecting the

platysma.

Dosing: How to Correct The Problem (see Appendix 3)(What to Do and What Not to Do) To eliminate most of the dynamic horizontal lines of the neck, inject approximately 1 to 2 U of onabotulinumtoxinA above and below the main horizontal line at points 2 to 3 cm apart into the deep dermis, rather than the subcutaneous plane, using dilute volumes of onabotu-linumtoxinA. This is performed with the patient sitting upright or in a semireclined position and forcibly contracting their platysma by clenching their teeth ( Fig. 5.77 ). Depending on the size of the patient’s neck, no more than 25 to 35 U of onabotulinumtoxinA should be given per treatment session.

In the properly selected patient, onabotulinumtoxinA also can be used to reduce the appearance of vertical neck bands and cords ( 17–21 , 27 ). In those patients with extensive cutaneous laxity and flaccid platysmal cords, injections of onabotulinumtoxinA can actually cause the patient to appear worse, and therefore should not be attempted ( Fig. 5.78 ).

With the patient sitting upright or in a semireclined position and contracting their platysma, grasp the platysmal band between the thumb and index finger of the nondominant hand ( Fig. 5.80 ). Inject 2 to 3 U of onabotulinumtoxinA intradermally into each injection site along the vertical extent of the band, starting approximately 2 cm below the inferior border of the mandible centrally in the submental area, and approximately 1 cm below the inferior border of the mandible lat-eral to the origin of the depressor anguli oris. This technique avoids diffusion of onabotulinumtoxinA into the lower fibers of the depressor labii inferioris in the lateral mental area and may prevent unexpected visible distortions of the chin and functional disturbances of the lower lips. Repeat each injection at intervals of 1.5 to 2 cm from each other, descending down the neck toward the border of the clavicle ( 32 ).

Figure 5.79 Three types of decussating platysma. Source: From Ref. 45.

Type I Type II Type III

182 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Raising a visible wheal with each injection attests to the appropriately superficial placement of the injected onabotulinumtoxinA ( Fig. 5.81 ). Keeping the injections as superficial as possible will avoid postinjection ecchymoses that result from puncturing superficial muscular vasculature of the muscle. The application of ice to the area before and

Figure 5.81 Raising a wheal while injecting onabotulinumtoxinA in the neck attests to the superficial placement of the product.

Figure 5.80 Contracting the platysma makes the injecting of onabotulinumtoxinA into the lower dermis easier.

especially after injecting onabotulinumtoxinA as well as gentle massage immediately after injecting helps to alleviate some of the pain that accompanies an intracutaneous injection. It also may help reduce the potential for bruising. Most patients require three to five injection points to treat a platysmal band adequately, and some may require even more, depending on the length of their neck. It is advisable to inject no more than 10 to 15 U of onabotulinumtoxinA along the vertical extent of each platysmal band for a total of 30 to 50 U per treatment session when two or three neck bands are treated ( 24 ). When more than two platysmal bands are present in the neck, that is, two bands or more on each side of the neck, the other two or more platysmal bands should be treated at another treatment session 2 to 4 weeks later, especially when more than 50 U of onabotulinumtoxinA have already been injected. When the neck bands present as thick cords and a hypertrophic platysma can be palpated, an additional 1 or 2 units of onabotulinumtoxinA can be applied at each injection point. Some authors have injected as much as 200 U per treatment session, a practice that is not necessary in most cases ( 34,35 ). There are others who use electromyographic guidance to accurately place a minimum amount of onabotulinumtoxinA in a platysmal band when treating the neck. They typically use less than a total of 20 U of onabotulinumtoxinA in any given treatment session and for them, electromyographic guidance when treating the platysma is a necessity ( 36 ).

Outcomes (Results) (see Appendix 4) Relaxation of a hypertrophic platysma with diminution of horizontal neck lines and vertical bands will occur 5 to 7 days after a treatment with onabotulinumtoxinA. The effects can last anywhere from 3 to 5 or more months, depending on the precision of the injections, the strength of the platysma, and the frequency and intensity of the patient’s neck movements. Usually patients who are too young for rhytidectomies or older patients who have had rhytidectomies will have the best results when there is reasonably tight cutaneous elasticity and minimal ptosis of subplatysmal fat and soft tissue. It is advisable to

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 183

Figure 5.82 The significant amount of fat in between the horizontal bands of the neck of this 49-year-old may be more conducive to alternative treatment, i.e., liposuction.

have the patient return 2 to 3 weeks after a treatment session with ona-botulinumtoxinA to assess their response to the treatment and their satisfaction with the overall results. Touch-up injections always can be done to correct any asymmetry or lack of a response along a particular neck band or cord.

Treatment with onabotulinumtoxinA has been beneficial in pre-paring a patient for submental liposuction because, by relaxing the neck bands, a more even draping of the anterior neck skin can be achieved in the postoperative period after liposuction. When there is a significant amount of fat herniation from in between the two lateral sheets of platysma in certain patients, along with subman-dibular fat occupying the submental area, liposuction with or with-out a platysmaplasty and possibly a rhytidectomy, are the only treatments that will be corrective ( Fig. 5.82 ). Injections of onabotu-linumtoxinA in these patients are marginally helpful. On the other hand, when there is no herniation or protrusion of subplatysmal fat and the presence of submental fat is negligible, injections of ona-botulinumtoxinA will be effective in reducing the vertical neck bands and cords created by a hypertrophic platysma ( Fig. 5.83 ). In some authors’ experience, the anatomic type or configuration of pla-tysmal decussation ( Fig. 5.79 ) does not necessarily prove to be pre-dictive of whether or not a treatment of onabotulinumtoxinA will be successful ( 34 ). It is the length of the platysma, the extent of muscle flaccidity, and the degree of muscle hypertrophy that seem to be the predictive factors that mostly influence the success rate of a treatment

of onabotulinumtoxinA in the neck. In fact, flaccid neck bands that are heavy and loose can be made worse with injections of onabotulinumtoxinA ( Fig. 5.78 ).

In patients who experience suboptimal results with residual band-ing and asymmetric draping of the anterior neck skin after rhytidec-tomy, injections of onabotulinumtoxinA can help normalize these types of unwanted outcomes. The additional benefit of a slight eleva-tion of the lower lip and buccal commissures and a tightening of lower cheek jowels has been known to occur for quite some time ( 34–36 ). This effect of lower face lifting takes place when onabotu-linumtoxinA diffuses from the fibers of the upper platysma pars mandibularis into the decussating fibers of the depressor anguli oris and the platysma (pars labialis), immediately subjacent to the body of the mandible during injections of platysmal bands ( 34–36 ). This relaxation of the upper platysma (pars marginalis), along with a sec-ondary tightening of the cerviofacial angle ( 34–36 ) was recently described as the Nefertiti lift facil slim fightining (see pp. 173–178 and chapter 6) (26).

Complications (Adverse Sequelae) (see Appendix 5) Treatment of horizontal rhytides and vertical bands in the neck with onabotulinumtoxinA usually is very safe, and there is a very low incidence of untoward sequelae. When they do occur, however, they usually are the result of improper technique and overzealous dosing.

184 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Since the underlying nine muscles of deglutition, phonation, and neck flexion are also cholinergic in origin, overdosing with onabotulinumtox-inA when treating the neck can result in xerostomia, dysphagia, dyspho-nia, dysarthria, and neck weakness ( 38 , 39 ). The static wrinkles caused by solar elastosis and age usually are not affected by onabotulinumtoxinA.

Injections of more than 50 U of onabotulinumtoxinA in the neck increases the risk for temporary hoarseness and difficulty with swallowing (dysphagia). Older patients are more at risk for such complications, because they present with more wrinkling and banding of their necks and commonly require higher doses of onabotulinumtoxinA to achieve satisfactory results.

Figure 5.83 This 52-year-old patient is seen before (A) and 3 weeks after (B) treatment with onabotulinumtoxinA.

(A) (B)

Figure 5.84 This 71-year-old patient is seen before (A) and 3 weeks after (B) treatment with onabotulinumtoxinA.

(A) (B)

Figure 5.85 This 52-year-old patient is seen before (A) and 2 months after (B) treatment with onabotulinumtoxinA. Note the additional attenuation of the horizontal wrinkle lines. Same patient as in Fig. 5.77.

(A) (B)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 185

They also have a diminution in the soft tissue support of the neck, making it easier for the onabotulinumtoxinA to diffuse to other deeper muscles of the neck (e.g., sternocleidomastoid and other strap muscles of the neck), which will affect deglutition, speech, and the overall strength of the neck in keeping it upright. Similar complications can be produced in younger patients when onabotulinumtoxinA is injected too deeply, because it can affect the deeper musculature of the neck.

In patients treated for cervical dystonia in whom over 200 U of ona-botulinumtoxinA commonly are injected into the strap muscles of the

neck during one treatment session, dysphagia, hoarseness, dry mouth, and flu-like syndromes have been observed ( 39 , 40 ).

When onabotulinumtoxinA is injected in the neck only to reduce platysmal banding and transverse rhytides, mild and transient neck discomfort can occur 2 to 5 days after treatment, with only a rare occurrence of neck weakness experienced with head elevation and flex-ion ( 34 ). Only one patient out of 1500 in a multiple center treatment study experienced clinically significant dysphagia, which resolved spontaneously within 2 weeks. Profound dysphasia was reported in

Figure 5.86 This 66-year-old patient is seen before (A) and 2 weeks after (B) treatment with onabotulinumtoxinA. Note the mentalis was not treated in this patient.

(A) (B)

Figure 5.87 This 47-year-old patient is seen before (A) and 1 month after (B) treatment of the platysmal bands with onabotulinumtoxinA. The mentalis, depressor anguli oris, and perioral rhytides were also treated with onabotulinumtoxinA.

(A) (B)

186 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

1 patient when more than 75 to 100 U of onabotulinumtoxinA were used to treat platysmal bands during one treatment session ( 41 ). A nasogastric tube was temporarily required to feed the patient until she was able to swallow without assistance.

Commonly observed and expected side effects include transient edema and erythema, both of which usually resolve within 1 to 2 days. Post-injection ecchymoses may last a few days longer. Other less com-monly occurring adverse sequelae can include muscle soreness or neck discomfort and mild headache. A few patients complain of either difficulty or, in extreme cases, an inability to lift the head from the supine position and then to keep it still and upright. When onabotu-linumtoxinA injection are placed 1 to 2 cm beneath the inferior mar-gin of the mandible, centrally, fibers of the depressor labii inferioris can be weakened by diffusion. This can cause a dysfunction of the lower lip integrity and sphincteric balance ( Fig. 5.72 ). For many patients, the cost–benefit ratio is not significant enough to make this procedure a regularly sought after treatment.

Figures 5.84 to 5.87 are additional examples of different patients treated with onabotulinumtoxinA for horizontal lines and vertical bands of the neck.

Treatment Implications When Injecting the Neck

1. Superfi cial intradermal injections of onabotulinumtoxinA can

diminish horizontal wrinkles and vertical bands of the neck.

2. The platysma lies superfi cial to the muscles of deglutition and

neck fl exion and deep injections of large amounts of onabotu-

linumtoxinA can cause varying degrees of dysphagia and an

inability to raise the head and keep it upright.

3. Injecting the platysma pars mandibularis can affect the corners

of the mouth, lower lip, chin, and inferior border of the mandible

because of the interdigitation of platysmal fi bers into the mimetic

muscles of the lower face.

4. In older patients with lax, redundant skin and attenuated pla-

tysma fi bers that are separated and form fl accid neck bands and

cords, injections of onabotulinumtoxinA may enhance rather

than diminish the appearance of those neck bands.

5. Injections of onabotulinumtoxinA cannot correct the herniation

of subplatysmal fat or reduce the fullness of excessive amounts of

submental or submandibular fat.

6. Injections of onabotulinumtoxinA should begin at least 2 to

3 cm inferior to the origin of the depressor labii inferioris to

prevent distortions of the skin of the chin and dysfunction of

the lower lip.

7. Horizontal neck lines do not always completely efface with

injections of onabotulinumtoxinA, especially when the skin of

the neck is severely damaged by sun and time.

Dilution (see Appendix 2)

Because of the large surface area of the upper chest, a more extensive

coverage of onabotulinumtoxinA is necessary and widespread diffu-

sion is encouraged. Therefore, a 100 U vial of onabotulinumtoxinA

can be reconstituted with 2 to 4 ml of normal saline.

age, spoiling the youthful impression that is portrayed by a wrinkle-free face and neck. Recently, superficial and middepth wrinkles on the upper anterior chest wall have been successfully treated with onabotulinumtoxinA ( 3 , 42 ).

There also have been reports describing the use of onabotu-linumtoxinA to relax postsurgical myospasm of the fibers of the pectoralis complex after breast implantation surgery ( 43 , 44 ). Sub-sequently, there appeared a report describing the use of injections of abobotulinumtoxinA to reduce wrinkles of the lower anterior neck and upper chest wall attributed to the excessive contractions of the platysma ( 44 ).

Functional Anatomy (see Appendix 1) The platysma is a very thin, superficial, broad sheet of muscle of vary-ing prominence that originates from the fascia covering part of the upper pectoralis major and deltoid. In certain patients, the platysma can originate lower than the second, and as far down as the fourth to the sixth, intercostal space. If contraction of the platysma in these patients is hyperkinetic and constant, excessive horizontal and vertical wrinkling of the central, mid to the lower décolleté can occur ( 42 ) (see pp. 173–174 and 180–181).

Dosing: How To Correct the Problem (see Appendix 3)(What to Do and What Not to Do) The patient can be treated more comfortably in the semireclined rather than in the upright position. Approximately 2 to 4 U of onabotulinum-toxinA can be injected into each site on the anterior chest wall in several different treatment patterns. The key to a successful outcome is to have the onabotulinumtoxinA diffuse throughout the entire anterior expanse of the upper chest wall ( 42 ). Injections should be applied super-ficially into the deep dermis or at the dermosubcutaneous junction. The pattern of injection depends on the particular shape of an individual’s upper chest. Accordingly, the area to be treated is outlined as either an upside down isosceles or equilateral triangle, whose apex is at a point over the middle of the xiphoid process of the sternum and whose base is an imaginary line that connects two points placed over the middle of both clavicles ( Fig. 5.88 ) ( 42 ). This triangle corresponds to the points of inter-digitation of the clavicular portion and the sternocostal portion of the platysma and pectoralis major. Approximately 2 to 4 U of onabotulinum-toxinA are injected into the dermosubcutaneous plane at multiple sites that are roughly 1.5 to 2.0 cm apart from each other within the triangle. The total dose injected should range from 20 to 50 U (average is 35 U) of onabotulinumtoxinA, depending on the overall strength of the platysma, the number and depth of the wrinkling, and the size and expanse of the anterior chest wall of the patient being treated. Some chests will require anywhere from 6 to 12 injection sites to be successfully treated.

Gentle massage and point pressure with ice to the area injected can prevent post-injection bleeding and ecchymoses.

Outcomes (Results) (see Appendix 4) A smoothening of the surface of the central mid to lower décolleté usu-ally occurs within 1 to 3 weeks of a treatment session ( Figs. 5.89–5.91 ).

UPPER CHEST WRINKLING Introduction: Problem Assessment and Patient Selection When the fashion of women’s clothing becomes more revealing, the décolleté takes on an entirely new significance, revealing the tell-tale skin surface changes caused by the innumerable amount of hours one has spent in the sun, either at leisure or work. Inelastic, sagging facial skin that has been rejuvenated to a more youthful appearance by redraping and resurfacing techniques and with soft tissue fillers and implants will be marred by the appearance of the crepe paper-like wrinkling of the “V” of the upper chest. On the upper chest, both static and dynamic wrinkling can coexist. When they do, the person exhibiting them appears deceptively older than their stated

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 187

Figure 5.88 An upside-down triangle represents the area where onabotulinumtoxinA can be injected to reduce wrinkling (A). Note fine wrinkling on chest in close-up (B).

(A) (B)

Figure 5.90 Area of the central upper chest of a 56-year-old treated with onabotulinumtoxinA before (A) and 5 weeks after (B). Source : Courtesy of Dr. Francisco Pérez-Atamoros.

44 4

44

44

4

4

4

(A) (B)

The diminution of chest wrinkling usually commences more slowly than when onabotulinumtoxinA is injected in the face, and it may be effective for only 2 to 3 months (Fig. 5.92 and 5.93). Widespread diffu-sion of the injected onabotulinumtoxinA is necessary to achieve total

coverage and complete reduction in the wrinkling of the skin surface of the upper chest wall. Therefore, injections in the upper chest wall are performed preferably with high volumes of low concentration onabotulinum toxinA ( 3 ).

Figure 5.89 Asterisks represent points where 5 U of onabotulinumtoxinA were injected. Source : Courtesy of Dr. Francisco Pérez-Atamoros.

(A) (B)

188 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Complications (Adverse Sequelae) (see Appendix 5) The most common side effect reported is inadequate clinical results because of insufficient dosing. Additional adverse sequelae include a reduction in upper extremity muscle strength, especially upon adduc-tion and internal rotation as when performing a hugging motion. If onabotulinumtoxinA is injected too deeply and at higher doses, exceed-ing 75 to 100 U per treatment session, unintended weakening of the intercostal musculature can occur, which may interfere with deep res-piration. The clinical results of pectoral platysma weakening can take up to 15 days or longer to occur, a much slower onset of effect com-pared to that which occurs after onabotulinumtoxinA injections of facial muscles ( 44 ). The other frustrating adverse result is the quantity and the cost of so much onabotulinumtoxinA that results in so little appreciable changes. Therefore, for many, the cost–benefit ratio is not an incentive to have this procedure performed (45).

Figure 5.91 Area of the central upper chest of a 49-year-old treated with onabotulinumtoxinA before and 6 weeks after 42 U of onabotulinumtoxinA were injected. Source : Courtesy of Dr. Francisco Pérez-Atamoros.

AfterBefore

Treatment Implications When Injecting the Upper Chest

1. Injections of high-volume, low concentration onabotulinum-

toxinA in the upper “V” of the anterior chest wall can suppress

the fi ne surface wrinkling of the skin of that area.

2. Induction of effect in the upper chest takes longer and lasts for

a shorter amount of time compared to onabotulinumtoxinA

injections in the face.

3. Overdosing can cause diffi culty with deep inspiration or with adduct-

ing the upper extremities, as is done when one performs a hug.

4. Injections of onabotulinumtoxinA must be performed intrader-

mally to prevent weakening of the intercostal musculature and

diffi culty with deep inspirations.

Figure 5.92 Area of the central upper chest which has been treated with onabotulinumtoxinA before (A) and 4 weeks after (B).

(A) (B)

Figure 5.93 Area of the central upper chest which has been treated with onabotulinumtoxinA before (A), 2 weeks after (B), and 4 weeks after (C).

(A) (B) (C)

COSMETIC USES OF BOTULINUM TOXIN A IN THE LOWER FACE, NECK, AND UPPER CHEST 189

REFERENCES 1. Freiman A, Bird G, Metelitsa AI, et al. Cutaneous effects of

smoking. J Cutan Med Surg 2004; 8(6): 415–23. 2. Standernig S (ed.). Gray’s Anatomy. The Anatomical Basis of Clinical

Practice, 40th edn. New York: Elsevier, Churchill, Livingstone, 2008. 3. Atamoros FP. Botulinum toxin in the lower one third of the

face. Clinics in Dermatol: Botulinum Toxin in Clinical Medicine (Part I). 2003: 21; 505–12.

4. Fagien S. BOTOX ® for the treatment of dynamic and hyperkinetic facial lines and furrows: adjunctive use in facial aesthic surgery. Plast Reconstr Surg 1999; 103: 701–13.

5. Smychyshyn N, Sengelmann R. Botulinum toxin a treatment of perioral rhytides. Dermatol Surg 2003; 29: 490–5.

6. Carruthers JA, Glogau RG, Blitzer A and Consensus Group. Advances in facial rejuvenation: Botulinum toxin type A, hyluronic acid dermal fillers and combination therapies—Consensus Rec-ommendations. Plast Reconstr Surg 2008; 121(5S): 5S–30S.

7. Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhyt-ides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg 2003; 29: 802–9.

8. Carruthers J, Carruthers A. Aesthetic botulinum A toxin in the mid and lower face and neck. Dermatol Surg 2003; 29: 468–76.

9. Klein AW. Complications and adverse reactions with the use of botulinum toxin. Seminars Cut Med Surg 2001; 20: 109–20.

10. Alam M, Dover JS, Klein AW et al. Botulinum A exotoxin for hyperfunctional facial lines. Where not to inject. Arch Dermatol 2002; 138: 1180–5.

11. Mazzuco R. Perioral wrinkles. In: Hexel D, Almeida AT de (eds.). 12. Cosmetic Use of Botulinum Toxin. Porto Allegre, Brazil: AGE

Editora, 2002; 158–63. 13. Rubin LR. The anatomy of a smile: its importance in the treatment

of facial paralysis. Plast Reconstr Surg 1974; 53: 384–7. 14. Benedetto AV. Asymmetric smiles corrected by botulinum toxin

serotype A. Derm Surg 2007; 33(S1): S32–S36. 15. Lindsay RW, Edwards C, Smitson C, et al. A systematic algorithm

for the management of lower lip asymmetry. Am J Otolar 2009. [Epub ahead of print]

16. Alam M, Dover JS, Klein AW, Ardnt KA. Botulinum A exotoxin for hyperfunctional facial lines: where not to inject. Arch Derm 2002; 138: 1180–5.

17. Pessa Je et al. The anatomy of the labiomandibular fold. Plast Reconstr Surg 1998; 101(2): 482–86.

18. Biglan AW, Burnstine RA, Rogers GL et al. Management of strabis-mus with botulinum toxin A. Ophthalmol 1989; 96: 935–43.

19. Blitzer A, Brin MF, Green PE et al. Botulinum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol 1987; 98: 93–7.

20. Carruthers J, Carruthers A. Botulinum toxin (BOTOX ® ) chemodenervation for facial rejuvenation. Facial Plast Surg Clin N Am 2001; 9(2): 197–204.

21. Loos BM, Mass CS. Relevant anatomy for botulinum toxin in facial rejuventation. Facial Plast Surg Clin N Am 2003; 11: 439–43.

22. Papel ID, Capone RB. Botulinum toxin A for mentalis muscle dysfunction. Arch Facial Plast Surg 2001; 3: 268–9.

23. Rohrich RJ, Pessa JE. The fat compartments of the face: anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg. 2007; 119(7): 2219–27.

24. Sposito MM. New indications for botulinum toxin type A in cosmetics: mouth and neck. Plast Reconstr Surg 2002; 110(2): 601–11.

25. Carruthers A, Carruthers J. Clinical indications and injection tech-nique for the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998; 24: 1189–94.

26. Levy PM. The “Nefertiti lift”: A new technique for specific re-contouring of the jawline. J Cos Las Ther 2007; 9: 249–52.

27. Rohrich RJ, Rios JL, Smith PD, Gutowski KA. Neck rejuvenation revisited. Plast Reconstr Surg 2006; 118(5): 1251–63.

28. Hoefflin SM. The platysma aponeurosis. Plast Reconstr Surg 1996; 97: 1080–8.

29. Cardoso de Castro C. The anatomy of the platysma muscle. Plast Reconstr Surg 1980; 66(5): 680–3.

30. Pogrel AM et al. Anatomic evaluation of anterior platysma muscle. Int J Oral Maxillofac Surg 1994; 23: 170–3.

31. Janfaza P, Nadol JB, Galla HJ et al. Surgical Anatomy of the Head and Neck. Philadelphia, PA: Lippincott Williams and Wilkins, 2001: 520.

32. Cardoso de Castro C. The changing role of platysma in face lifting. Plast Reconstr Surg 2000; 105: 764–75.

33. Brandt FS, Boker A. Botulinum toxin for rejuvenation of the neck. Clin Dermatol 2003; 21: 513–20.

34. Matarasso A, Matarasso SL, Brandt FS et al. Botulinum A exotoxin for the management of platysma bands. Plast Reconstr Surg 1999; 103: 645–52.

35. Brandt FS, Bellman B. Cosmetic use of botulinum A exotoxin for the aging neck. Dermatol Surg 1999; 24: 1232–4.

36. Blitzer A, Binder WJ. Cosmetic uses of botulinum neurotoxin type A. Arch Facial Plast Surg 2002; 4: 212–20.

37. Hoefflin SM. Anatomy of the platysma and lip depressor muscles. A simplified mnemonic approach. Dermatol Surg 1998; 24: 1225–31.

38. Klein AW. Complications and adverse reactions with the use of botulinum toxin. Seminars Cut Med Surg 2001; 20: 109–20.

39. Blitzer A, Binder WJ, Aviv JE. The management of hyperfunctional facial lines with botulinum toxin: a collaborative study of 210 injec-tion sites in 162 patients. Arch Otolaryngol Head Neck Surg 1997; 123: 389–92.

40. Dayan S. Facial Plastic Surgery Clinics of North America; Botox. Philadelphia, PA: WB Saunders Company, 2003: 488–92.

41. Benedetto AV. In Thiers B (ed.). Dermatologic Clinics: The Clini-cal Use of Botulinum Toxin, Volume 22. Philadelphia, PA: WB Saunders Company, 2004.

42. Carruthers J, Fagien S, Matarasso S and the BOTOX ® Consensus Group. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics. Plast Reconstr Surg 2004; 114(Suppl): 15–25.

43. Isaac C, Gimenez R, Ruiz R de O. Breast wrinkles (décolleté folds). In: Hexel D, Almeida At de (eds). Cosmetic Use of Botulinum Toxin. Porto Allegre, Brazil: AGE Editora, 2002; 178–81.

44. Richards A, Ritz M, Donahoe S et al. BOTOX ® for contraction of pectoral muscles. Plast Reconstr Surg 2001; 108: 270–1.

45. Becker-Wegerich PM, Rauch L, Ruzicka T. Botulinum toxin A: suc-cessful décolleté rejuvenation. Dermatol Surg 2002; 28:168–71.

46. Benedetto AV. Botulinum toxin in clinical medicine. Clin Derma-tol 2003; 21(6): 465–8.

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area and to the hypertrophic muscle bundle of the lower lid. In some patients, the result can be pleasing with a slight opening of the orbital aperture, which makes the eye look bigger and more attractive. These are usually younger patients without significant lower eye bags. But in others, there can be distressing complications with resulting “bags” under the eyes, a waterlogged appearance and an unwelcome inanimate response of the lower lid to smiling. Patients feel they look worse than before the ona-botulinumtoxinA administration. These are invariably older patients who may have unrecognized eye bags or skin laxity in whom relaxation of the infraorbital orbicularis oculi muscle actually allows the eye bags to bulge and become more visible. The action of the muscles prior to onabotu-linumtoxinA administration helps to keep the skin tightened in a state of tension and push the eye bags inward, thus disguising them. This is unmasked once the muscles relax and are no longer able to provide any resistance to the eye bags as they herniate outward.

A third problem area was the neck. Early techniques advocated administering traditional onabotulinumtoxinA (i.e., onabotulinum-toxinA diluted with 2–2.5 ml of saline) into the anterior and lateral pla-tysmal bands without injecting into the muscle in between these bands, over the horizontal neck creases or above the jawline. Some patients had good results with softening of the platysmal bands and improvement of the cervicomental angle but none experienced a lifting of the jawline nor improvement of neck skin quality nor horizontal lines.

In looking for a solution to these three problems, the author drew on his experience with intradermal injections of onabotulinumtoxinA to the axilla to decrease hyperhydrosis ( 2–4 ) and odor and developed the Microbotox technique.

MICROBOTOX (MESOBOTOX) Microbotox is essentially an intradermal or subdermal injection of very dilute onabotulinumtoxinA to affect the sebaceous and sweat glands as well as the superficial layer of facial muscles. It requires care-ful preparation of the solution and a sensitive and refined injection technique, which is the key to a successful outcome. Injecting too large a bolus at any given point will flood the area with onabotulinumtoxinA and cause deep muscular paralysis, which may be undesired.

Although having performed this technique for over a year, in 2001 the author coined the term Mesobotox as the depth of injections in this technique correlated with the depth of injections used in traditional mesotherapy. Shortly after that however, the author felt that the dosage of onabotulinumtoxinA being significantly reduced and its application over a wide area of skin via multiple injections of small boluses made the term Microbotox more appropriate instead. The author has lectured extensively on this topic since then ( 5 ).

Physiologic Basis for Action OnabotulinumtoxinA is a very versatile drug that inhibits a variety of receptors including substance-p. In treating rhytides by blocking neuromuscular transmission, onabotulinumtoxinA works on cholin-ergic receptors. Sweating is also largely mediated through cholinergic receptors and is inhibited by onabotulinumtoxinA as well. However, onabotulinumtoxinA also has the ability to work on noradrenergic receptors, which partly mediate sweat and sebaceous secretions as well. Hence onabotulinumtoxinA is able to decrease muscular activity as well as bring about a change in quality of the overlying skin of the injected area through this double mode of action.

6 Skin resurfacing with Microbotox and the treatment of keloids Woffles T. L . Wu

INTRODUCTION Microbotox is a useful and versatile chemoresurfacing technique ( 1 ) using onabotulinumtoxinA that can improve the sheen and texture of skin, decrease sweat, oil and sebum production, improve acne, reduce the appearance of open pores, decrease fine lines without altering deep muscle movement, lift and sculpt the jawline, improve scars, smoothen the neck and undereye areas, and generally give a natural appearance to the face without an “overbotoxed” look. It can also be used to improve the appearance of scars and to treat established keloids when used in conjunction with intralesional triamcinolone and intense pulsed light (triple therapy).

It involves multiple injections of small boluses of diluted onabotu-linumtoxinA into the dermis or the interface between dermis and the superficial layer of facial or neck muscles over the affected area. There are a variety of refinements that can be achieved as the onabotulinumtoxinA exerts its effect on both muscle movement and on the skin itself.

In the muscle, the Microbotox is injected superficially so as to weaken the superficial layer of muscle fibers without compromising deep muscular activity. This decreases fine lines and wrinkles in difficult to treat areas such as the lateral forehead, the undereye area and the neck and jawline. In the skin, the effect of the onabotulinumtoxinA is to decrease the production of sweat (which is well documented), sebaceous secretions, and bring about a shrinkage of the sweat and sebaceous glands, which in turn causes a “tightening” of the skin envelope. Pores appear reduced in size and the skin becomes smooth and unlined. Acne is visibly improved.

The technique can be applied to the forehead, T-zone, cheeks, lower eyelids, jawline, neck, décolletage, and buttocks.

HISTORY When we started using onabotulinumtoxinA in the 1990s for intra-muscular injection of forehead rhytides, one of the common observations was that the overlying forehead skin would often become shiny, smooth, and tight with hardly a pore in sight. Many patients liked this “resurfaced” look. This effect was the result of onabotulinumtoxinA intended originally for the frontalis muscles diffusing back into the skin and affecting the sweat and sebaceous glands. It was usually seen when large boluses of onabotulinumtoxinA were administered to the forehead, allowing this diffusion to occur.

At the same time, there were many patients who also complained that the forehead felt too frozen and stiff and some had difficulty lifting their brows or even complained of droopy eyebrows and loss of definition of the eyelid crease. Our early experience saw us injecting too much ona-botulinumtoxinA into the forehead in the mistaken belief that a smooth forehead was the only desired ideal of patients. What patients actually want is a smooth forehead but one that is still able to move naturally and elevate. This seems a paradox since the muscles that create the forehead lines are the same muscles that are responsible for elevation. It therefore seemed obvious that we had to devise a technique of onabotulinumtox-inA administration that decreased visible forehead lines but yet still allowed the underlying muscles to move and the eyebrows to elevate.

Another clinical problem encountered was in achieving a smooth lower eyelid. After the traditionally placed onabotulinumtoxinA injections for the glabella, crow’s feet, and forehead regions, patients often experience enhanced “bunny lines” and wrinkles just under the lower lid eyelash margin. Some would complain that these “new” wrinkles were disturbing. Traditional onabotulinumtoxinA can be administered to the infraorbital

SKIN RESURFACING AND TREATMENT OF KELOIDS 191

Mechanism of Action In traditional onabotulinumtoxinA administration, the objective is to bring about muscle weakening or paralysis and in the case of onabotu-linumtoxinA facial sculpting ( 6 ), an atrophy of the masseteric muscle bulk. Therefore, the onabotulinumtoxinA should be injected into the muscle itself for best effect ( Fig. 6.1A–E ). This can sometimes lead to pain and bruising. Because the margin for error is higher when injecting into the muscle, we have tended to be more cavalier in the way we inject

into these traditional areas, often not ensuring that we are delivering the correct dose of onabotulinumtoxinA in a precise fashion.

For Microbotox, the delivery technique is very important as we are injecting multiple tiny boluses of onabotulinumtoxinA into the dermis or into the junction between the dermis and the superficial layer of the mus-cles of the face or neck. This weakens the superficial layer of the facial muscles, which are attached to the undersurface of the facial skin and are responsible for the fine lines and wrinkles that patients dislike.

Figure 6.1 (A) Standard onabotulinumtoxinA injection technique: onabotulinumtoxinA is injected into the muscles. (B) The injected onabotulinumtoxinA spreads and diffuses. (C) Muscle begins to weaken. (D) There may be some diffusion to the overlying skin. (E) Paralysis of the muscle is achieved.

(A) (B)

(C) (D)

(E)

192 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

In the skin, the sweat and sebaceous gland activity is reduced ( mediated through both cholinergic and noradrenergic receptors) and they become atrophic. This causes the skin envelope to shrink and patients feel tighter and lifted. Reduction of sebaceous secretion also helps in the control of acne but more importantly makes the “open” pores appear smaller and less in number. As a result, the skin looks more refined and has a smooth sheen to it ( Fig. 6.2A–E ).

Dilution and Injection Technique for Microbotox The author always uses a 100-unit bottle of onabotulinumtoxinA (Allergan, Irvine) diluted with 2.5 ml of normal saline. This dilution is used for all injections of onabotulinumtoxinA to the face or masseter muscles [onabotulinumtoxinA facial sculpting or facial slimming ( 6 )] or even to the axilla with 0.1 ml containing 4 units of onabotulinumtoxinA and 0.05 ml containing 2 units of onabotulinumtoxinA.

Figure 6.2 (A) Microbotox technique: onabotulinumtoxinA is injected as very tiny droplets into the dermis or junction between dermis and the superficial layer of facial muscles. (B) Microbotox technique: the onabotulinumtoxinA diffuses into the sweat and sebaceous glands. (C) Microbotox technique: decrease in sweating and sebaceous activity. (D) Microbotox technique: paralysis of superficial muscle layers. (E) Microbotox technique: contraction of the skin envelope due to gland atrophy.

(A) (B)

(C) (D)

(E)

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A 0.1 ml droplet is quite large and it is easy to see how an inaccurately placed droplet near the eyebrow (when treating for glabellar frown lines) can diffuse down to the levator muscles, thereby causing temporary ptosis of the upper eyelid.

A 0.05 ml droplet contains 2 units of onabotulinumtoxinA and is my usual volume of injectate when doing routine intramuscular injections. Where muscles are thicker or more dense, then 0.1 ml droplets are used.

For Microbotox, that same 0.05 ml droplet can be injected in multiple smaller droplets. Depending on the skill of the operator, 0.05 can be injected in 10 to 20 drops. In the clinical situation if the operator can inject 0.05 ml in 10 drops this is sufficient.

In different parts of the face, neck, and body, different dilutions of Microbotox are used especially when treating patient solely for pore closure or smoothening the skin and not wanting to affect the underly-ing muscle activity.

Injecting the small boluses of onabotulinumtoxinA should be done slowly and evenly, each injection spaced about 1 cm apart in a grid-like fashion. Once the injections can be done steadily and the boluses made even smaller, the injection distance can be reduced to 0.5 cm apart. All air bubbles must be carefully removed from the syringe prior to injection as this may compromise the injection accuracy.

THE FOREHEAD The objective is to retain as much muscular function and hence eyebrow elevation as possible but at the same time to smoothen the skin, reduce pore size, improve the sheen, and reduce rhytides especially those over the lateral forehead, which are a reflection of overactive frontalis muscle activity. Twenty-four to twenty-eight units are sufficient for the entire forehead including eight points of injection over the glabellar and eyebrow regions to decrease corrugator activity. If traditional onabotu-linumtoxinA has already been given to the glabellar, eyebrow, and central forehead regions to create a brow lift as described by this author, then 16 units is sufficient just for the lateral forehead alone. This usually lasts 4 months. On an average, the forehead will be covered with 40 to 50 injection points ( Fig. 6.4 ). To anesthetize the forehead, a supraorbital nerve block with a small bolus of Lignocaine 1% without adrenaline administered to the supraorbital nerves will provide adequate numbness and comfort for the patient. Additionally, Elamax 5 % (LMX 5) can be used to supplement the areas not covered by the nerve blocks. Surprisingly, because the injection bolus is so small patients seldom complain of pain even if an anesthetic is not used. It is better to underinject the lateral forehead to avoid any lowering of the eyebrow or sensation of heaviness. Patients should have a smooth forehead but still be able to elevate their eyebrows and look natural ( Fig. 6.5A,B ).

UNDEREYE REGION Patients often request a smoothening of the bunny lines and the fine lines under the eyelids, especially after onabotulinumtoxinA adminis-tration to the crow’s feet, glabella, and forehead regions, which makes the wrinkles of the undereye and paranasal regions relatively more prominent and noticeable ( Fig. 6.6 ). This part of the face is extremely delicate with a small margin for error. With too little onabotulinum-toxinA, the result is negligible. With too much administered, the entire lower lid can take on the complications already described above. The author usually uses 8 to 12 units for the infraorbital as well as nasal bunny line region. The results last approximately 3 to 4 months and the patients are warned that this area may wear out faster than other areas simply because there is less onabotulinumtoxinA spread out over a wide area. For patients who want a slight degree of movement over the lateral orbicularis (crow’s feet region), then 24 to 28 units can be used for this area and the infraorbital and bunny lines as well. Surprisingly, many patients who used to receive traditional onabotulinumtoxinA in

Figure 6.3 Microdroplet training: practice is required to enable the injector to release tiny droplets of diluted onabotulinumtoxinA regularly and evenly. Standard injections of 0.1 and 0.05 droplets are seen at the top left hand side. In comparison, the cluster of droplets below are both a single 0.05 ml droplet divided into multiple microdroplets. The cluster of droplets on the right is very fine (0.05 ml divided into 43 microdroplets) and realistically not achievable. The cluster on the left (0.05 ml divided into 12 microdroplets) is more practical.

0.1ml droplets

0.05ml droplets

0.05ml in multiplesmall droplets

0.05ml in muchsmaller droplets

Figure 6.4 Twenty-four units of Botulinum injected superficially into the entire fore-head as multiple small drops. Each drop should raise a small whitish bleb. If not it is too deep.

For the Microbotox technique, depending on the region of the face or neck to be injected, the required number of units are drawn up into a 1 cc syringe and then topped up to 1 ml with normal saline.

For example, if the forehead requires 24 units of onabotulinum-toxinA, then 0.6 ml of the prepared onabotulinumtoxinA (2.5 ml dilution) is drawn into a 1 ml syringe and an additional 0.4 ml saline is drawn up to make 1 cc of injectable solution. That is 24 units of onabotulinumtoxinA in 1 ml of solution.

For the injection technique, some practice is required, which can be gained by filling a 1 cc syringe with normal saline, attaching a 30G needle and then injecting small droplets onto a table top to practice delivering big and small boluses consistently. With this simple exer-cise, most physicians are surprised to learn that they are overinjecting the onabotulinumtoxinA many a time and not delivering evenly sized boluses with each injection ( Fig. 6.3 ).

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For the full Microbotox neck, the area of coverage should be from two fingerbreadths above the jawline to the clavicle below and from the pre-auricular region sweeping downward under the chin and across the mid-line ( Fig. 6.8 ). If the patient only wants elevation of the jawline, then two syringes of onabotulinumtoxinA are sufficient with the injections starting above the jawline and sweeping down over the neck up to the level of the thyroid cartilage. The distribution of the Microbotox is therefore in the form of a sling going under the chin and upper neck. Here the injection points can be closer together. Over the sternocleido-mastoid however, the injections should be spaced further apart to avoid weakening this muscle.

In those patients who have horizontal neck lines as their primary complaint, the injection points can be closer together along the lines themselves and in between the sternocleidomastoids but more dispersed over that muscle.

In all cases of neck and jawline Microbotox, care should be taken not to inject over the risorius or the depressor anguli oris as this can lead to an asymmetric smile or the lack of a full, broad smile.

If the patient also has horizontal neck lines and crepelike skin, then a third syringe of onabotulinumtoxinA can be used to resurface the entire anterolateral surface of the neck as well ( Figs. 6.9 and 6.10 ). Microbotox of the neck and jawline is a good complimentary treatment to the onabotulinumtoxinA facial slimming technique for masseteric hypertrophy where the initial rapid shrinkage of the masseteric bulk can lead to a temporary laxity of the jowl and upper neck skin. The microbotox of the neck and jawline helps to alleviate this by relaxing the superficial platysma fibers and allowing the skin to redrape more closely to the cervicomental angle.

MICROBOTOX FOR OILY FACIAL SKIN, ACNE, AND LARGE PORES In Asia, a common request is to smoothen the skin, decrease the inci-dence of acne over the cheeks and forehead and especially to reduce the appearance of large facial pores. While there are many other modalities that can help such as intense pulsed light, fractional lasers, chemical peels, and other nonablative laser systems. Microbotox has been an effective and efficient solution as patients can see visible results within a week ( Fig. 6.11 ).

The usual areas addressed are the forehead and central T-zone as well as the nose and both cheeks below the infraorbital skin. This is where the facial skin is at its thickest and most greasy and where the pores are most visible.

For facial and nose sweat and sebaceous gland reduction, great care has to be taken to ensure small boluses of the onabotulinumtoxinA solution are injected into the dermis with as little spillover into the facial muscles as possible. For initial dosing of the forehead and T zone area 20 units in 1 ml saline is sufficient to achieve a smoothening of the

Figure 6.6 Microbotox of the infraorbital and bunny line regions. The droplets should be evenly spaced out to prevent overrelaxation of the orbicularis muscle.

Figure 6.5 (A) Microbotox forehead—at rest. (B) Microbotox forehead—upon elevation. Eyebrows move freely with absence of forehead wrinkles.

(A) (B)

these areas now request Microbotox instead as they feel they look more natural and have less stiffness ( Fig. 6.7A,B ).

An infraorbital nerve block with a small bolus of anesthetic is used (to avoid any dilution and diffusion errors) although most patients can tolerate the infraorbital injections without any anes-thesia. About 25 injection points are used for the undereye and bunny line regions.

Patients are always enthusiastic to reduce the lines in this region and very small doses of onabotulinumtoxinA are in fact required to do so. Avoid overinjecting this area as it is easy to develop the complications of enhanced eye bags or festooning, lid laxity, a swollen waterlogged appearance and the “inanimate lower eyelid.”

THE NECK AND JAWLINE Microbotox is used here to elevate the jowls, smoothen the jawline, reduce the platysmal bands, reduce horizontal creases, decrease the crepelike appearance of the neck skin, and allow the neck skin to drape the cevicomental angle more acutely.

It does all of this by exerting its action on the sweat and sebaceous glands of the neck to smoothen and tighten the skin and on the platysmal muscle over its entire area as opposed to the technique of pinpoint injections to the platysmal bands alone. Elamax ointment applied to the whole neck for 20 minutes can be useful for patient comfort. Two to three syringes of onabotulinumtoxinA solution are prepared, each containing 24 to 28 units in 1 ml saline.

SKIN RESURFACING AND TREATMENT OF KELOIDS 195

Figure 6.7 (A,B) Microbotox of the infraorbital region; absence of fine lines and rhytides when smiling.

(A) (B)

Figure 6.8 Microbotox of the neck and jawline: injections start two fingerbreadths above the jawline and sweep downward over the entire neck to the clavicle but avoid-ing the sternocleidomastoid (where possible) and staying two fingerbreadths behind the angle of the mouth to avoid weakening the depressor angular oris.

Figure 6.9 Microbotox neck: a similar patient with complaints of horizontal neck lines.

skin for 4 months. In the nose and cheeks, 20 units in 1 ml saline can also cover the entire midfacial skin. If the patients come in for an early touch up at 2 to 3 months, then a single syringe of 24 U onabotulinumtoxinA in 1 ml saline can be adequately dispersed over forehead, T-zone, nose, and cheek areas to maintain and prolong the effect for another 3 months or so. Infraorbital and supraorbital nerve blocks using small amounts of lignocaine (0.2 ml at each point) provide sufficient anesthesia to keep the patient comfortable. Elamax can be used as well.

MICROBOTOX OF THE DÉCOLLETAGE, CHEST, AND HANDS The Microbotox technique can be used in other areas where the skin either has a crepelike, crumply appearance or where there are a lot of fine lines. The décolletage area depending on the extent of this condition can be treated with one or two syringes of onabotulinumtoxinA solution containing 28 units in 1 cc saline. The author has experienced several Figure 6.10 Microbotox neck (anterior view).

196 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 6.11 (A) Microbotox of the infraorbital and cheek region for oil and pore control: before and after administration of 16 units to both sides of the face showing the reduc-tion in porphyrin count which is a reflection of oil production. (B) Microbotox of the infraorbital and cheek region for oil and pore control: before and after administration of 16 units to both sides of the face showing improvement in evenness. A lower score denotes smoother appearing skin. (Continued)

(A)

(B)

SKIN RESURFACING AND TREATMENT OF KELOIDS 197

male bodybuilder patients who request a smooth décolletage/chest area devoid of sweating. This makes the chest area smooth, dry, and satiny for posing and photographic purposes. One cubic centimeter with 28 units is sufficient for this area. Interestingly, in these patients, the decrease of sweating in this area has lasted up to 10 months.

The back of the hands can be injected in a similar way with one syringe of 28 units onabotulinumtoxinA in 1 ml per hand. This makes the skin of the dorsum smoother and more lustrous.

MICROBOTOX IN TRADITIONAL AREAS An interesting spinoff of the microbotox technique has been that many patients now request Microbotox in the traditional areas of the crow’s feet, glabella, and central forehead regions, which otherwise would have received full-dose conventional onabotulinumtoxinA. These patients feel that the smoothness of the skin conferred by the Microbotox tech-nique is more important than the muscle weakening effect and in fact would prefer to have more muscle movement than when they were being treated with full-dose onabotulinumtoxinA. They feel they look more natural.

MICROBOTOX IN SCARS AND KELOIDS The author has for many years been using the Microbotox technique to treat fresh scars in order to speed up the resolution of the scar as well as to prevent keloid formation ( 7 ). Where there are established keloids, Microbotox injections have been especially useful and the technique will be described below. The use of onabotulinumtoxinA in scars is well established ( 8–12 ) but no reports exist so far in the use of onabotulinumtoxinA for keloids and hypertrophic scars.

While several papers have been written documenting the usefulness of Botulinum toxin type-A in the treatment of early scars or the

prophylactic prevention of visible scars developing ( 8–12 ), none actu-ally describes the successful treatment of established hypertrophic or keloid scars with botulinum toxin type-A. The following chapter exam-ines the author’s approach to treating keloids and the rationale in the development of the keloid triple therapy program, which includes the use of intense pulsed light (IPL), intralesional triamcinolone, and intra-lesional Microbotox injections.

Keloids remain a vexing problem to treat in any surgical field ( 19 , 20 ). In esthetic surgery in particular, the best surgical result can be unpre-dictably compromised by the development of a keloid and no amount of preoperative assessment can truly safeguard a patient from its devel-opment. A careful history of previous keloid development and an exam-ination of past scars can help determine if a patient has a keloid tendency. The parents of the patient should also be asked if they are prone. Keloids may develop as a result of factors that may be within a surgeon’s control such as site and location of scar, the way in which the wound was closed, the sutures used, and whether postoperative immo-bilization was used so the surgeon can exert some influence over its development. Even then with all these precautions, a keloid may still develop and spoil an otherwise good surgical outcome. It is known that tension across a wound has a stimulative effect on the process of wound healing and can trigger the development of a keloid. Keloids in the ster-num and over the deltoid regions are good examples of sites on the body where the wounds are subject to high skin tension forces across them and where the forces of nature can conspire to confound the surgeon.

Background Pathophysiology This chapter does not attempt to delve into the detailed pathophysiology of keloids and the numerous research studies that are ongoing but a broad summary of current understanding ( 14–16 ) is in order to provide

Figure 6.11 (Continued) (C) Microbotox of the infraorbital and cheek region for oil and pore control: before and after administration of 16 units to both sides of the face showing improvement in the pore count.

(C)

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a backdrop for why the triple therapy was devised and the rationale for using Microbotox.

Normal Physiology Wound healing goes through three phases: the inflammatory, fibro-blastic, and the maturation phases. In the first phase of wound healing, which is more correctly a wound “cleaning” phase, there is an inflam-matory reaction both in the wound and in the surrounding tissues as numerous cellular elements such as red blood cells, eosinophils, mast cells, plasma cells, lymphocytes, and others are recruited to mop up and devour all the traumatized cells and debris in the vicin-ity as well as to accumulate the cells such as fibroblasts, which will subsequently take part in the repair process. The inflammatory cas-cade is triggered and vascularity increases to provide the conduits for cellular transport.

In the second phase, the repair cells such as fibroblasts and other cell precursors continue to aggregate and proliferate, producing hyaluronic acid, ground substance, collagen, smooth muscle myofi-broblasts that are essentially the “glue” that holds the two wound edges together. This phase is one of rapid accumulation of higgledy piggledy disorganized cells and intercellular matrix and comes to a stop once there has been sufficient cellular accumulation and the wounds have closed.

In the maturation phase, all of these elements begin to organize and sort themselves out becoming linear sheets of collagen interspersed with the right amount of ground substance and the correct inter-cellular ratios. Muscles if they have been cut also begin to repair them-selves as cellular differentiation occurs. This is a slower more long drawn out phase, taking several weeks to months to complete.

All of these phases are controlled by growth factors and cytokines with the usual chemical or hormonal start and stop signals functioning normally.

Abnormal Physiology Most scars invariably go through an early phase where the wound is hypertrophic. This usually commences from the first 2 weeks after surgery and may last for several months. Here the scar is red, raised, mildly itchy and blanches to the touch but everything is confined to the wound itself. There is no encroachment of surrounding tissue. At a cellular level within the wound can be seen numerous nodules containing cells of collagen and plentiful smooth muscle myofibroblasts in the core of the scar but everything looks organized and neatly arranged. There is a moderate increase in basal collagen production but response to growth factors is still good. Clinically the hypertrophic scar responds to treat-ment with silicone gel, creams, massage, intralesional triamcinolone, and even intense pulsed light. Usually, three to four sessions of the above can suffice.

A keloid scar, however, behaves differently. It can follow from a hypertrophic scar or it can even develop months after a hypertrophic scar has subsided. It rapidly becomes raised, angry purple, hard, intensely itchy, or even painful to the touch and it grows beyond the confines of the original scar. In very aggressive cases, one can even see little fingers of advancing growth encroaching into the surrounding tissue. This is called the advancing edge of the keloid. The keloid may respond briefly to intralesional triamcinolone but invariably recurs after 3 to 4 weeks and patients have been known to be repeatedly injected for years—and even then with dismal results. Intense pulsed light may or may not work and numerous other treatments have been tried, which include interferon, radiation, cryotherapy, polytherapy, surgical excision, ultraviolet A1 radiation, 5-fluorouracil, Bleomycin, silicone gel sheeting, laser surgery, and pressure garments. The fact that there are so many different treatments only attests to the elusive and exasperating nature of the keloid.

At a cellular level, are seen large collagen (type 1) bundles, abundant eosinophils, mast cells, plasma cells, and lymphocytes, plentiful muco-polysachharide ground substance, high numbers of fibroblasts, fibro-nectin, elastin, and a high expression of proliferative cell nuclear antigen and ATP. In fact, it is as if the inflammatory and fibroblastic phases do not switch off and just continue with a disorganized cellular proliferation. It appears that the stop and start signals do not go off properly ( 21 ).

Current Thoughts on Keloid Formation There are currently several theories behind keloid formation but the most attractive theory is that there is abnormal fibroblastic activity and decreased apoptosis of cells, i.e., increased production versus decreased destruction or breakdown. This in turn is caused by increased levels of growth factors and other cytokines. Why this happens is still not clear ( 17 , 18 ).

While a detailed description of the technique is beyond the scope of this chapter, the author has successfully used Microbotox in the treatment of keloids and scars. The technique is called triple therapy and combines intense pulsed light (IPL) to reduce redness and vascularity of the keloid, intralesional triamcinolone (Kanakort) injections to rapidly flatten the keloid and intralesional Microbotox to induce cellular apoptosis ( 13 ) as well as to reduce the tension of actin and myosin across the wound edges and thus reduce keloid relapse and recurrence.

Twenty-eight units of onabotulinumtoxinA in 1 ml saline or 1% Lignocaine is used for all cases of scar or keloid therapy. One cubic cen-timeter is sufficient to inject bilateral inframammary incisions for breast augmentation or a Cesarean wound. An abdominoplasty scar will require three such vials and an inverted-T breast reduction would require four syringes of the Microbotox preparation. Where the scars are fresh and not keloidal, only Microbotox is required.

Where there is an established keloid, this is first treated with several pulses of IPL using a 640 nm crystal filter. The Microbotox is then injected into the keloid as well as into the skin around the keloid. It is important to locate and inject the skin immediately adjacent to the advancing edge of the keloid. The triamcinolone (Kanakort) is then injected into the keloid until it blanches.

Microbotox has a synergistic effect with triamcinolone. It not only reduces the dose requirement of triamcinolone (which is important as the drug has potential side effects of telengiectasia and hypopigmented skin atrophy) but also reduces the often rapid recurrence of keloid for-mation while the patient is on intralesional injections of triamcinolone alone. It also has the effect of reducing the redness of the scar. A common observation when using triamcinolone alone at monthly interval is that the keloid reduces in size and intensity for 2 to 3 weeks and then starts to reactivate in the third or fourth week, often growing back to its original size. The physician then gives another dose of triamcinolone and the cycle starts again. With concomitant administration of the Microbotox, the recurrence is slower and less intense such that at the subsequent injection of triamcinolone, this dose can be directed wholly at the resid-ual keloid rather than at a keloid, which has regained its original size. In this way, the keloid resolves at a faster rate and a more complete fashion.

Complications As can be expected, the main complications of the Microbotox technique are in allowing the onabotulinumtoxinA to spread and diffuse into unintended areas, thereby causing weakness of certain muscles and altering facial movements and expression.

In the forehead, it is important to judge how much onabotulinum-toxinA is to be injected not only in terms of volume but dosage as well since this is a very variable area. In someone with a low narrow fore-head, 1 cc may be too much volume whereas in a person with a high wide forehead, 1 cc is insufficient. It also depends on how skilled or dexterous the injector is. If too much is injected and diffuses deeply

SKIN RESURFACING AND TREATMENT OF KELOIDS 199

into the frontalis muscle, then the patient can experience an immobile, low brow with difficulty in elevating the eyebrows and hooding of the lateral brow and loss of the upper eyelid crease.

Infraorbital complications have already been discussed in detail above. Again great care has to be taken during the injection to make sure the boluses are small and uniformly delivered.

In the neck, some patients can complain of weakness of the neck, especially on getting up from bed or in performing sit-ups. This occurs if there has been too much Microbotox injected over the sternocleido-mastoid muscles. This can be avoided by either avoiding injecting over these muscles or increasing the spacing between the injection points to reduce the total load of onabotulinumtoxinA to that area. There have been no complications regarding phonation or swallowing.

At or above the jawline, if the injections are carried too far forward over the depressor anguli oris or too close to the risorius, then a weak or lop sided smile can result. Some patients feel they cannot smile broadly. This may be of concern and embarrassment to patients and may necessitate a small dose of Microbotox to the contralateral side to achieve symmetry. This same complication can be seen when injecting the cheeks for oil control and pore size reduction.

In general, it is best not to inject within two fingerbreadths from the angle of the mouth.

In the hands, a potential complication could be weakness of the intrinsic muscles but this has not been seen yet.

RESULTS Case 1 A 49-year-old woman with greasy skin, open visible pores, popply chin, and glabellar frown lines requested a happier, vibrant look, and smoother skin so that her make up would stay on better and look more even. She received traditional onabotulinumtoxinA to her glabellar/eye-brow, crow’s feet, central forehead, and chin areas. Each black injection point is between 2 and 4 units. The forehead, infraorbital, and cheek areas were then chemoresurfaced with Microbotox (green areas) using two 1 ml syringes of onabotulinumtoxinA, each syringe containing 24 units in 1 ml saline and injected at 1cm regular intervals. 1 ml was used for each side of the face and forehead ( Fig. 6.12A–C ).

Case 2 A 37-year-old man complained of oily skin, large pores, and minor acne scars. He disliked the oily appearance and said that he had to constantly blot his face with facial tissues and this irked him. He received 24 units to the forehead and T-zone area and another 28 units to the infraorbital and cheek area. One week later, he was happy with the smooth and even texture of his skin ( Fig. 6.13A–H ).

Case 3 A 42-year-old woman complained of crepelike appearance of her neck skin, a “chicken skin” appearance, some vertical banding, and some horizontal striations. She had tried chemical peels and ther-mage with little success. She received a full Microbotox of the neck and jawline using three syringes, each containing 28 units of ona-botulinumtoxinA. 0.7 cc in 1 ml of saline. Postinjection, she felt the skin was smoother, finer, tighter, the jawline was lifted and when she applied neck creams they now glided on and stayed on the neck skin more easily ( Fig. 6.14A–E ).

Case 4 This 33-year-old woman wanted the best possible result for her Cesarean scar. A small keloid scar on her left deltoid had been successfully treated by the author using triple therapy. At the time of delivery, the author closed the Cesarean scar in layers and then com-menced triple therapy from the third postoperative week; 28 units of onabotulinumtoxinA mixed with a small amount of Xylocaine 2% (Microbotox) was injected into the mildly hypertrophic scar. IPL using a wavelength of 640nm was also used to decrease redness, and 0.2 ml of triamcinolone was injected at the same time. She came monthly for 5 sessions and, at completion of therapy 6 months after the first treatment, the scar was barely visible and completely soft

(Fig. 6.15A–E).

Case 5 This was the author’s first case in which Microbotox was used to treat a keloid. A 16-year-old girl had suffered a laceration of her left neck following a bicycle injury. A large thick and painful keloid developed.

Figure 6.12 (A) Case 1: Oily, greasy skin with glabellar frown lines and popply chin. (B) Same patient. Areas of Microbotox (green) and traditional onabotulinumtoxinA (black dots). (C) Same patient. After Microbotox, 24 units per side and traditional onabotulinumtoxinA (2–6 units into each site marked by a black dot in B).

(A) (B) (C)

200 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 6.13 (A) Case 2: Before Microbotox to entire face and forehead region. (B) Same patient after 24 units Microbotox per side. (C) Same patient before (right, ¾ view). (D) Same patient after (right, ¾ view). (E) Same patient before (left, ¾ view). (F) Same patient after (left, ¾ view). (Continued)

(A) (B)

(C) (D)

(E) (F)

SKIN RESURFACING AND TREATMENT OF KELOIDS 201

Figure 6.13 (Continued) (G) Same patient before (left, ¾ view)—close-up view to show the numerous visible pores. (H) Same patient after (left, ¾ view)—close-up view to see improvement in visible pores and oil.

(G) (H)

Figure 6.14 (A) Case 3: Patient before showing horizontal lines, crepelike skin, fine crosshatching wrinkles, cervicomental skin laxity (anterior view). (B) Same patient: after 72 units Microbotox to entire neck, jawline, jowls, and side of face (anterior view). (C) Same patient: before Microbotox (left, ¾ view). (D) Same patient: after Microbotox (left, ¾ view). (E) Same patient: closeup view of the left neck showing the improvement in skin quality, horizontal lines and fine crosshatching wrinkles.

(A)

(C) (D) (E)

(B)

202 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

A previous surgeon treated it unsuccessfully with triamcinolone injections for several months and then resorted to excising the keloid. It recurred and the surgeon excised it once more only to see it recur yet again. More triamcinolone injections were administered with little success. The patient became extremely depressed, reclusive, and self-conscious, growing her hair to cover her neck. When she was first seen by the author in March 2003, the keloid was hard, large, and extremely tender. She had not received any treatment for 6 months. Intralesional triamcinolone was given weekly for three sessions, each session being traumatic for both patient and surgeon. It was then decided to inject Microbotox into the keloid and the surrounding skin to act as a “chemical splint” and combine this with the intralesional triamcinolone to potentiate its effects. As the keloid was very red and vascular, it was also decided to expose it to several pulses of IPL at 640 nm in order to decrease its color and vascularity. This triple therapy was performed under a short general anesthesia to aid

patient’s comfort. Twenty-eight units of Microbotox were adminis-tered in addition to 2 cc of triamcinolone. The patient was not seen till 11 months later when she returned for a second treatment. Most of the keloid had flattened, leaving only the superior edge still raised and slightly tender. A second treatment of IPL, 28 units Microbotox, and 2 cc triamcinolone were administered. One month later, there was complete flattening of the keloid. Over the next few months, the scar slowly improved in colour, texture, and softness until it appeared almost like normal skin ( Fig. 6.16A–E ).

DISCUSSION The Microbotox technique has been an interesting and serendipitous discovery that has greatly expanded the scope of onabotulinumtox-inA practice in the author’s clinic. The initial observation of smooth, clear, and slightly edematous turgid forehead skin with a satiny sheen following administration of onabotulinumtoxinA to the forehead

Figure 6.15 (A) Case 4: Patient with a Cesarean scar 3 weeks post operative: before triple therapy (December 8, 2006). (B) Same patient 2 weeks after commencing triple therapy. A second dose of triple therapy was given (December 29, 2006). (C) Same patient 2 months after initial treatment with triple therapy. A third dose was given (February 16, 2007). (D) Same patient 4 months after commencing therapy. Fourth dose given (April 4, 2007). (E) Same patient. Final result (June 7, 2007) showing completely smooth result with minimal scar.

(A) (B)

(C) (D)

(E)

SKIN RESURFACING AND TREATMENT OF KELOIDS 203

Figure 6.16 (A) Case 5: March 19, 2003—after several unsuccessful injections of triamcinolone to scar. Keloid at its thickest and most tender. First triple therapy given. (B) Same patient: February 13, 2004—significant reduction in keloid size and thickness as well as symptoms of pain. Second triple therapy given. (C) Same patient: May 3, 2004—keloid completely resolved leaving a slightly depressed but soft scar. No injections given. (D) Same patient: August 11, 2004—gradual maturing of scar. (Continued)

(C) (D)

(A) (B)

lines led us to realize that this was due to the intradermal effect of onabotulinumtoxinA that had diffused out from the muscle into the skin. Patient requests to have this smooth forehead skin without loss of forehead movement and expression gave the author the idea to deliver the onabotulinumtoxinA directly into the skin and not into the muscle.

The aim was to deliver the onabotulinumtoxinA as multiple microdroplets into the dermal layer of the skin at carefully spaced out intervals. However, because the injection of the microdroplet was technically challenging and impossible to confine to the dermis alone, there was bound to be diffusion into the underlying superficial muscle layer, which would cause relaxation of the fibers of frontalis that insert into the dermis and not the deeper layers of the muscle. This would allow a smoothening of the skin without affecting the function of the deep muscle and hence elevation of the eyebrows.

If a conventional preparation of onabotulinumtoxinA using 2 to 2.5 ml of saline were used, then each microdroplet would contain a higher concentration of onabotulinumtoxinA and if these microdrop-lets were to inadvertently diffuse into the deeper fibers of the muscle, then widespread paralysis of that muscle would result, leading to unwanted muscle weakness especially in the lateral forehead. This would in turn cause flattening of the brow, possibly lateral eyelid hooding and patients could complain of a “stiff” feeling over the eyebrow/forehead region.

The author therefore felt that if the concentration of onabotulinum-toxinA was reduced by further diluting it in the syringe so as to increase the total injection volume to 1 cc but retain the desired number of units (for example, 16, 24, or 28), then the actual dose of onabotulinumtox-inA to the skin would still be relatively high but with much less diffusion into the deep layers of the facial muscles. Only diffusion into the superficial

204 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

muscle fibers is desirable as it is this that gives the reduction of superficial and fine rhytides.

Practice with injecting the microdroplets was required to ensure a consistent and steady delivery of these microdroplets to the skin and superficial muscles of the target area. This practice was necessary as the markings of a standard 1 cc syringe are for 0.05 and 0.1 ml droplets only. With Microbotox, we are trying to achieve at least 10 microdroplets with every 0.05 ml. As described, this entailed squirting microdroplets of water onto a glass table top so as to correlate the amount of injection force with the emerging droplets. Developing this tactile sense was very useful as it also helped with a more precise delivery of onabotulinum-toxinA when using conventional 2.5 cc dilutions to the traditional areas.

The Microbotox technique was first used by the author for the improvement of forehead lines and for the fine lines under the lower eyelid. Patients were satisfied with the results in these two difficult areas to treat. Unwanted side effects of injecting normal dilution ona-botulinumtoxinA into these areas were significantly reduced and patients gave enthusiastic feedback.

The author then started using the technique to allow better draping of the neck skin and elevation of the jowls and jawline by the intradermal effects on the skin as well as on the superficial fibers of the plastysma. Microbotox of the neck was also seen to be beneficial to reducing the intensity of the horizontal neck lines, another difficult to treat problem.

Once the delivery of microdroplets was consistent and predictable, it was natural to extend this technique to the skin of the T-zone,

nose, and cheeks to decrease sweat and oil secretion and ultimately improve the appearance of open pores. It was also noted that acne in this area improved and patients had a more desirable “matt” finish to their skin instead of the “greasy, oily” look, which necessitated constant blotting.

Microbotox to the décolletage, chest, and hands were again natural extensions of employing this technique.

The use of Microbotox in the treatment of scars and keloids has been particularly rewarding. It arose from the simple idea to use the onabotu-linumtoxinA as a “chemical splint” to maximize the effect of the con-comitant injections of intralesional steroid and has now become part of an established protocol of three modalities (including IPL) all adminis-tered at the same session. Currently the author injects all fresh surgical scars with Microbotox on the sixth or seventh postoperative day just prior to removal of stitches. If the scars are already keloidal, then triple therapy is commenced at the initial consultation and continued monthly until the keloid is resolved. This may require 4 to 8 sessions.

CONCLUSION Microbotox has multiple uses in the face, neck, hands, and body as well as for scar and keloid therapy. It is a refinement in the use of onabotu-linumtoxinA and has allowed us to understand better the myriad effects of onabotulinumtoxinA. It has greatly increased the versatility of an already versatile and fascinating drug.

Figure 6.16 (Continued) (E) Same patient: February 11, 2005—scar almost imperceptible. (F) Same patient: October 12, 2005—soft, supple scar. Completely flat. No recurrence

of keloid. (G) Same patient: June 30, 2006—final result.

(G)

(E) (F)

SKIN RESURFACING AND TREATMENT OF KELOIDS 205

REFERENCES 1. Wu WTL. Nonsurgical facial rejuvenation with the 4R principle:

innovative uses of BOTOX and facelifting with the Woffles lift, a barbed suture sling (Chapter 72). In: Panfilov D, ed. Aes-thetic Surgery of the Facial Mosaic. Berlin: Springer, 2006: 636–49.

2. Bushara KO, Park DM, Jones JC, Schutta HS. Botulinum toxin—a possible new treatment for axillary hyperhydrosis. Clin Exp Dermatol 1996; 21: 276–8.

3. Glogau RG. Botulinum A neurotoxin for axillary hyperhydrosis: no sweat Botox. Dermatol Surg 1998; 24: 817–19.

4. Naumann M, Lowe NJ. Botulinum toxin type A in the treatment of bilateral primary axillary hyperhydrosis: a randomized, paral-lel group, double blind, placebo controlled trial. BMJ 2001; 323: 596–9.

5. Wu WTL. Facial rejuvenation without facelifts—personal strategies. Regional Conference in Dermotological Laser and Facial Cos-metic Surgery 2002, Hong Kong. 13–15 Sep 2002.

6. Wu WTL. Botox facial slimming/facial sculpting: the role of botu-linum toxin type A in the treatment of hypertrophic masseteric muscle and parotid gland enlargement to narrow the lower facial width. Facial Plast Surg Clin N Am 2010; 18: 133–40.

7. Wu WTL. The Role of BOTOX in Keloid Therapy. 14–16 Jun 2007, Annual Meeting of the MultiSpecialty Foundation, Las Vegas Bellagio Hotel, Las Vegas, USA.

8. Gassner HG, Sherris DA, Otley CC. Treatment of facial wounds with botulinum toxin A improves cosmetic outcome in Primates. Plast Reconstr Surg 2000; 105; 1948–53.

9. Gassner HG, et al. Botulinum toxin to improve facial wound heal-ing: a prospective, blinded, placebo controlled study. Mayo Clin Proc 2006; 81(8): 1023–8.

10. Giebler FRG, Giebler EF. Creating invisible scars. Int J Cosmet Surg Aesth Derm 2002; 4(2): 107–10.

11. Gassner HG, Sherris DA. Chemoimmobilisation: Improving pre-dictability in the treatment of facial scars. Plast Reconstr Surg 2003; 112(5): 1464–6.

12. Sherris DA, Gassner HG. Botulinum toxin to minimise facial scar-ring. Facial Plast Surg 2002; 18(1): 35–9.

13. Chuang YC, Huang CC, Kang HY, et al. Novel action of botulinum toxin on the stromal and epithelial components of the prostate gland. J Urol 2006; 175(3Pt 1): 1158–63.

14. Rockwell WB, Cohen IK, Ehrlich HP. Keloids and hypertrophic scars: a comprehensive review. Plast Reconstr Surg 1989; 84: 5, 827–37.

15. Mafong EA, Ashinoff R. Treatment of hypertrophic scar and keloids: a review. Aesth Surg J 2000; 20(2): 114–21.

16. Al-Attar A, Mess S, Thomassen JM, Kauffman L, Davison SP. Keloid pathogenesis and treatment. Plast Reconstr Surg 2006; 117: 286.

17. Luo SK, Benathan M, Raffoul W, Panizzon RG, Egloff DV. Abnormal balance between proliferation and apoptotic cell death in fibroblasts derived from keloid lesions. Plast Reconstr Surg 2001; 107: 87.

18. Lu F, Gao JH, Ogawa R, Hyakusoku H, Ou CQ. Biological differ-ences between fibroblasts derived from peripheral and central areas of keloid tissues. Plast Reconstr Surg 2007; 120: 625–30.

19. Rosen DJ, Patel MK, Freeman K, Weiss PR. A primary protocol for the management of ear keloids: results of excision combined with intraoperative and postoperative Steroid Injections. Plas Reconstr Surg 2007; 120: 1395.

20. Van de Kar AL, Kreulen M, van Zuijlen PPM, Oldenburger E. The results of surgical excision and adjuvant irradiation for therapy-resistant Keloids: a prospective clinical outcome study. Plast Reconstr Surg 2007; 119: 2248.

21. Lim IJ, Phan TT, Song C, Tan WTL, Longaker MT. Investigation of the influence of keloid-derived keratinocytes on fibroblast growth and proliferation in vitro. Plast Reconstr Surg 2001; 107: 797.

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YOUTH AND “SQUARE JAWS” A youthful face is characterized by healthy clear skin, a taut firmly projected mid face, a smooth unbroken contour from the lower lid eyelash margin to the upper lip, a relaxed appearance with absence of muscle imbalance or strain, and a generally triangular face with high-lights over the malar and chin prominences ( 8 ). Due to a myriad of reasons including volume depletion and soft tissue sagging, as the face ages, it takes on a more squarish appearance and eventually there is an inversion of the triangle of youth. Part of the rejuvenative process, whether by surgical or nonsurgical means, involves triangulating the face to restore the sharp, heart-shaped ideal of most cultures. This restores to some degree one aspect of a youthful look.

Even in youth, many individuals have square faces or “square jaws” due to masseteric muscle hypertrophy and in some cases due to benign and diffuse parotid gland enlargement. This gives the face the appear-ance of a boiled egg standing on its base. In a man, this confers on the individual a strong purposeful look provided he has the body size and proportions to match. If he is a thin person with a small body frame, the square face can look incongruous.

In a young woman, unless she is of striking beauty where a square jaw enhances her look, this squarish face can be undesirable making the face look too masculine or strong and in some cases much older as well.

For these reasons, reducing lower facial width is aesthetically necessary.

HISTORY The author started using BOTOX® (Allergan, Irvine) to treat patients with masseteric hypertrophy in 1998 initially for functional reasons and later purely for cosmetic indications. At that time, nothing had been written on the use of BOTOX® to achieve cosmetic reshaping of the lower face. Two papers had been published in 1994 by Moore and Wood ( 1 ), and by Smyth (2) detailing the use of BOTOX® in patients with medical symptoms arising from masseteric hypertrophy and this subsequently became the basis for the author to use BOTOX® to cosmetically reshape the lower face.

The first patient ( Fig. 7.1A,B ) treated complained of headaches, grinding, and occasional temporomandibular joint pain. She had large asymmetric masseter muscles, a square face, and palpable mandibular angle spurs. These were not part of her initial complaint. About 20 units of onabotulinumtoxinA were administered directly into the muscle mass using a 30 G needle. After 2 weeks, the patient was recalled and it was noted that her symptoms had reduced but not been totally elimi-nated. The masseter could still clench but was noticeably reduced in size and was softer. A further 20 units per side was administered and the patient returned a month later. This time she was relieved of headaches and grinding but the muscle could still clench weakly. A further 20 units was given as the third dose and she was seen a month later. At this point, she realized that she looked thinner and claimed that many of her friends and family had remarked on her physical change. She felt that she had improved aesthetically and requested further reduction of lower facial width solely for cosmetic reasons. A further 20 units was given two more times a month apart before she was able to achieve the degree of slimness she desired and where there was no further movement of the masseter muscle on clenching. She had received a total dose of 100 units of onabotulinumtoxinA per side over a 4-month period. After a further

7 Facial and lower limb contouring Woff les T. L . Wu

BOTOX FACIAL SCULPTING (FACIAL SLIMMING): REDUCTION OF INCREASED LOWER FACIAL WIDTH DUE TO MASSETERIC HYPERTROPHY AND PAROTID GLAND ENLARGEMENT WITH BOTULINUM TOXIN A Botulinum toxin type A has the profound ability to decrease lower facial width and to sculpt the lower face by inducing an atrophy and hence decreases volume of the masseter muscle (especially if it is ini-tially hypertrophied) ( 1–11 ). By reducing the volume occupied by the masseter muscle, the lower face is made narrower, there is better defi-nition of the zygomatic arch and malar eminence, and the jawline becomes sharper and better defined ( Fig. 7.1A,B ). Over time, it is felt that prolonged atrophy of the muscle may lead to remodeling and narrowing of the mandible itself ( 5 , 8 , 11 ).

Previously, the lower face could only be narrowed by surgical reduction of the mandibular angles and/or the masseter muscle itself. While beautiful results can be obtained, there are numerous potential complications some of which can be difficult to correct ( 12–14 ).

The term BOTOX facial sculpting ( 5 , 8 , 11 ) was chosen because the power of botulinum toxin type A goes beyond mere facial width reduction. Depending on how much the masseter muscle is reduced, a variety of results can be achieved and a spectrum of emotional responses to the new look can be evoked ranging from slight width reduction with the effect of “losing some weight and puppy fat” to more visible sculpting that brings out the shape of the zygomatic arch and infra-zygomatic hollows and confers a “supermodel-like” appearance. Con-versely, overcorrection can sometimes make the face look overly gaunt and unattractive so aesthetic judgment has to be carefully exercised.

Some patients deliberately wish to look extremely thin and almost cachexic with the intent to evoke a fragile, vulnerable look that brings about feelings of sympathy and “wanting to protect.” For actors wish-ing to portray starved prisoners or victims of torture, this technique provides a safe and reversible way of achieving that look and gives added meaning to the term “method acting.”

Another cause of a squarish lower face is the enlargement of the parotid gland. This has been a previously underappreciated anatomic occurrence simply because we did not assess for it and if we had we did not know what to do about it. It is naturally occurring and indi-cates no disease or tumorous state. Some people just have prominent parotids ( Fig. 7.2 ). This blunts the angles of the mandible and makes the lower face “heavy” and ponderous looking. In a man, it looks very beefy and in a woman, it looks very masculine and severe. Like every-thing else in aesthetic surgery, there must be an appropriateness of one’s features to one’s outlook, profession, and personality. In much the same way, as a low eyebrow looks correct in a younger individual and a higher more arched brow looks better in an older female, the width of the lower face also plays a role in creating the appropriate image for that person.

Hypertrophied parotid glands may look good in an older, authoritarian gentleman but a younger woman in the fashion industry may feel that this same look makes her appear older and more severe. Hence, botuli-num toxin type A has a tremendous ability to help selected patients achieve their appropriate “look” without surgery. Surgery merely to reduce the size of a normally functioning (but large) parotid gland would never otherwise be contemplated.

FACIAL AND LOWER LIMB CONTOURING 207

3 months, she returned with palpable movement of the muscle on clenching and a larger dose of 40 units was given. This time it lasted a further 5 months before she returned for another maintenance dose.

At the same time, a second patient ( Fig. 7.3A,B ) with a square face also requested nonsurgical reshaping and slimming of her face. She was com-menced with 40 units of onabotulinumtoxinA into each masseter and returned a month later for a second dose. Her rate of facial slimming was seen to be faster and the degree of muscle paralysis more complete in a shorter time than the first patient. It was decided to adopt a monthly schedule of onabotulinumtoxinA injections starting at 40 units per side until all muscle movement had stopped and then the patient observed the duration of time before muscle activity returned. Since then we have treated more than 700 patients who sought lower facial width reduction purely for aesthetic reasons.

ANATOMICAL CONSIDERATIONS The masseter muscle has three component parts or heads that arise from different sections of the length of the zygomatic arch and are inserted in a fan-like fashion into the ramus, condyle, angle, and lower border of the mandible ( Fig. 7.4A ). The deep head (yellow) arises from the inferior aspect of the posterior half of the zygomatic arch and is

inserted into the posterior half of the ascending ramus down to the angle of the mandible ( Fig. 7.4B ). The intermediate head (blue) arises from the middle third of the zygomatic arch and fans downward to insert into the anterior half of the ascending ramus, the condyle, and the angle of the mandible ( Fig. 7.4C ). The superficial head (red), which arises from the anterior half of the zygomatic arch including part of the malar eminence, is more strap-like and fans downward and backward to insert mainly into the angle of the mandible ( Fig. 7.4D ).

There is thus an overlapping of these three heads in the middle part of the muscle, which consequently is the thickest part that can be felt when a patient clenches their teeth. Palpation of the muscle on clenching firmly will also reveal a step-like, tiered form of the muscle. The anterior border of the muscle does not coincide with the anterior border of the mandibular ramus but in fact lies forward to this.

The surface markings are easy to identify as the anterior edge of the muscle is easily felt on clenching and the other borders are the zygo-matic arch, the posterior edge of the ramus, and the lower border of the mandible. Injections of botulinum toxin type A in to the muscle are therefore easily administered. Care should only be taken not to inject into the coronoid notch as the pterygoid muscles, which are on the inner side of the mandibular ramus, can become unduly weakened and give discomfort on chewing.

PHYSIOLOGIC BASIS FOR USING BOTULINUM TOXIN TYPE A Botulinum toxin type A not only causes a paralysis of muscles but also creates a temporary atrophy. We have seen this as an unwanted side effect of prolonged use in the lateral orbicularis oculi (crow’s feet region) where diffusion of the drug into the nearby temporalis muscle can create a wasted appearance of the temples.

In the masseter muscle, this atrophy is desired. What is interesting though is the long-term use of botulinum toxin type A to create not only muscular atrophy but also bony remodeling of the mandible and even the zygomatic arch itself. The author has noted in many patients on long-term botulinum toxin type A therapy of the masseter muscles, a gradual narrowing of the mandibular width over several months to years (15,16).

This is consistent with the findings of Moss, Enlow, and Rankow ( 17–20 ) who conceptualized the “bone-muscle-matrix” theory. Bones and the muscles that insert into them form an interrelated complex. If the muscles attached to that bone become weak or atrophic the bone also becomes less dense and thinner. This is seen in patients who have broken their legs and have had to endure a plaster cast for 12 weeks while the bone unites. As a result of muscle immobilization, when the cast is removed, the bone is invariably thinner and less radio dense.

(A) (B)

Figure 7.1 (A) Masseter hypertrophy. (B) After four sessions of onabotulinumtoxinA injections.

Figure 7.2 Normal and prominent parotid.

208 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Similarly, in people who constantly subject their bones to loading forces, the bones respond by becoming thicker and denser as can be seen in bodybuilders and manual workers. This is why we advise elderly patients to continue exercising in order to “strengthen” their bones.

Patients with masseteric hypertrophy invariably have mandibular angle spurs and it is interesting to note that with prolonged atrophy of

the muscle, these spurs become less prominent and the mandibular width more narrow.

INJECTION TECHNIQUE AND SCHEDULING While I have used all forms of botulinum toxin type A to induce atrophy of the masseter muscle, I am most familiar with and prefer using

(A) (B)

Figure 7.3 (A) Masseter hypertrophy. (B) After three sessions.

(A) (B)

(C) (D)

Figure 7.4 (A) Masseter origins. (B) Deep head. (C) Intermediate head. (D) Superficial head. The circle indicates the thickest part of the muscle upon clenching, which represents the point where all three muscle heads overlap.

FACIAL AND LOWER LIMB CONTOURING 209

In such cases, the parotid gland has to be treated at the same time in order to decrease lower facial width.

The author uses a loading dose of 40 units of onabotulinumtoxinA injected into the substance of each parotid gland, which lies one to two fingerbreadths in front of the ear, over and behind the mandibular angle, and tucking in under the earlobe. The gland can be felt as a dif-fuse, boggy “thickness.” Results can be seen within 3 weeks. Repeat injections of the same dose are given monthly until the gland has shrunk sufficiently and then maintenance injections of between 30 and 40 units of onabotulinumtoxinA are given every 4 to 6 months.

In 17 patients, we have not encountered any major side effects or signs of antibody development. There has been no clinical change in the amount of saliva produced and no complaints of “dry mouth.” We have not studied the composition of the saliva nor conducted any CT studies.

In patients, who are being treated for both the parotid gland and the masseter, they will receive 40 units into each parotid and 40 units into each masseter muscle bringing the total to 160 units of onabotulinumtoxinA at one sitting. This is much less than those patients who are being trea-ted for calf hypertrophy in which case they would be receiving a total of 400 units of onabotulinumtoxinA divided into both calves per session.

BOTULINUM TOXIN TYPE A AND THE SUBMANDIBULAR GLAND The author has used onabotulinumtoxinA to reduce the visibility of the submandibular gland in nine patients. These are patients who have noticed the gland as an unsightly bulge beneath the jawline or in those patients who have had a facelift and the gland has become more obvious.

The loading dose is much less at 25 to 32 units per side and the regime of monthly injections remains the same as for the parotid and masseter. The submandibular gland is much more difficult to isolate and immobilize as it tends to slip away. The patient should bend the head forward and turn to the contralateral side in order to make the gland pop out from under the border of the mandible.

While visible reduction has been seen in all cases, the degree and rapidity of reduction is not as dramatic as for the parotid glands. This may be a reflection of different receptor types within the different glands. It could also indicate that the submandibular gland although visible may not actually be enlarged and hence cannot be reduced any further than its base state and size.

COMPLICATIONS The most frequent complications are as follows:

1. Loss of full smile and 2. Asymmetric smile. Both are due to diffusion of the botulinum toxin

A forward to the risorius and levator anguli oris. This typically occurs when the onabotulinumtoxinA is injected too close to the anterior border of the muscle or when the injected volume is too much. I would not inject more than 1.5 cc volume into the masseter as there is a higher risk of diffusion beyond the muscle borders.

3. Weakness of and an aching sensation on chewing. Typically the patient finds difficulty in opening the mouth widely and then initiating biting such as in eating a hamburger or thick juicy steak. This occurs in the first 2 to 3 months of treatment and may disturb the patients but this then gradually recovers and seldom are patients bothered by this subsequently even with repeated and continued injections ( 7 , 26 ).

4. Jowling due to overrapid volume reduction and sagging of the over-lying skin envelope. This occurs because the muscle atrophies faster than the overlying skin can accommodate. After 2 to 3 months, the skin contraction “catches up” with the devolumized muscle.

5. Overhollowing of the infrazygomatic region giving a cachexic appearance. This was explained above and may be desirable in some patients.

onabotulinumtoxinA. About 2.5 ml of saline is used to reconstitute the bottle of 100 units and therefore 1 cc will contain 40 units, 1.5 cc will be 60 units, etc. All injections use a normal half-inch 30-G Precision Glide needle (Becton Dickinson, Franklin Lakes, NJ). This is more than enough to make contact with the lateral mandibular surface even in patients with huge masseter muscles.

There are two parameters to consider in achieving a good result—dose and frequency.

The usual starting dose is 40 IU (1 cc) into each side in five to eight spaced out injections. This is repeated a month later and again a month after that. The patient should be assessed for residual muscle move-ment and/or bulk each time. If the muscle is still able to clench or feels bulky, then more onabotulinumtoxinA is given until no movement and atrophy has occurred.

Some patients may not wish to maximally reduce the size of the masseters and want only a slight thinning of the face. If they are satisfied with the result after the first one or two sessions they can then go into the maintenance phase of treatment.

For maintenance, the patient is asked to monitor the size of the muscle and is told to return either at 3 to 4 month intervals or if the muscle is able to clench strongly again, whichever is earlier. The usual maintenance dose is 32 to 40 units per side every 4 to 6 months.

When injecting the onabotulinumtoxinA into the muscle, more can be given to the lower half and the region of the overlap zone where the muscle is thickest. Care must be taken not to inject through the coro-noid notch as this leads to unwanted weakening of the pterygoid mus-cles leading to difficulty in chewing. One should also avoid injecting too heavily into the upper half of the muscle as this will lead to accen-tuated scalloping out of the lateral side of the face. Even if the ona-botulinumtoxinA is evenly distributed throughout, as the muscle begins to shrink, there is a natural tendency for this scalloping to develop because of two reasons: Firstly, the mandibular angle and spurs have yet to remodel so may appear to bulge and secondly, the skin over the jawline and jowls takes several months before it contracts fully and so may appear heavy and droopy.

In patients with very large masseters, up to 60 units (1.5 ml) can be injected in the initial setting. Beyond this it is risky as more than 1.5 cc would have to be injected into each side and this can lead to diffusion of the drug beyond the borders of the muscle thus giving rise to side effects as listed below.

It is preferable to see the patients monthly and adjust the dosage according to the result that is obtained from the previous treatment session. In a very large hypertrophic masseter, it is better to bring it down slowly over several months than to try to reduce it too aggres-sively. The result and side effect profile for giving 40 units every month for 5 months (40+40+40+40+40) is different from administering 60 units every month for 3 to 4 months.

BOTULINUM TOXIN TYPE A AND THE PAROTID GLAND The use of botulinum toxin type A to decrease salivary production in the parotid and submandibular glands is documented in several articles ( 21–25 ). However, none have dealt with its use in reducing the size of the parotid gland for pure cosmetic sculpting or shaping of the face.

The parotid gland can be diffusely enlarged as part of a normal variation without any symptoms of either decreased or increased salivary pro-duction (Fig. 7.2). This broadens the lower face and gives a “bull-necked” appearance with blunting of the mandibular angle and sometimes a visible bulge that lifts the lobe of the ear upward.

Botulinum toxin type A can be used to shrink the size of the parotid in much the same way as the hypertrophic masseter muscle, the dose depending on the initial size of the parotid. Sometimes, the enlarged parotid only becomes noticeable after treating the masseter muscle and as the size of the muscle shrinks the parotid then becomes more evident.

210 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

(A) (B)

Figure 7.5 Case 1: (A) Model with complaint of face being “too big on camera.” (B) After 80 units of onabotulinumtoxinA.

6. Bruising seldom occurs. 7. Hematoma is rare and I have encountered one instance only that

resolved within a week. 8. Visible fasciculations of the muscles can sometimes occur in

the first 2 to 3 weeks and represents an insufficient dose of onabotulinumtoxinA.

9. Neuropraxia is extremely rare.

RESULTS OnabotulinumtoxinA and the Parotid Glands Case 1 A 32-year-old Caucasian woman working as a model felt her face was “too big on camera” and desired cosmetic slimming of the face in order to look more fashionable and slimmer. She had no symptoms of grind-ing or headaches, etc. About 40 units of onabotulinumtoxinA into each side of the maasseter were given on two occasions a month apart. The patient is seen 1 month after the second dose ( Fig. 7.5A,B ).

Case 2 A 35-year-old male also complained that his face looked too chunky and did not photograph well. He wished to have a more defined jawline and a more sculpted appearance. About 40 units of onabotulinumtoxinA were injected at monthly intervals on three occasions before he achieved his desired “look” ( Fig. 7.6A–F ).

Case 3 This 38-year-old woman previously had an augmentation rhinoplasty, chin augmentation, blepharoplasty, and correction of prominent ears between the years 2002 and 2004 ( Fig. 7.7A ). In November of 2007, she complained of a “fat” face and was puzzled as to why her face looked so broad and “egg-like” when her body remained thin and her weight con-stant. Examination revealed bilateral grossly enlarged parotid glands, which classically lifted the lobes of her ears ( Fig. 6B.7B ). There were no symptoms of increased or decreased salivary flow and no alteration of taste. There was no evidence of tumor. Ultrasound examination showed enlarged parotid glands with normal architecture. All hemato-logic tests for parotid disease were negative including erythrocyte sedi-mentation rate (ESR), antinuclear factor (ANF), and antirheumatoid antibodies. Having treated other patients with diffusely enlarged parotid glands successfully with onabotulinumtoxinA, this was offered to the patient as a treatment option. Not wishing to undergo any addi-tional surgery, she received her first injection of 60 units into each parotid gland as well as 40 units of onabotulinumtoxinA into each of the masseter muscles in December 2007. A second dose was given in

January 2008 where she received 40 units of onabotulinumtoxinA into each masseter as well as 40 units into each of the parotid glands. Sig-nificant shrinkage of the parotid gland was seen in February 2008. The lower facial width had improved and she felt she looked more normal. A third dose of onabotulinumtoxinA was given in February 2008 and when she returned in May 2008, there was further normalization of her facial contours. A fourth dose of 40 units was given into each parotid and masseter muscle at this time and this shrank her parotid to a normal size. She was seen in April 2009 with minimal recurrence of the parotid enlargement and an increase in volume of the masse-ter muscle. She was given a maintenance dose of 40 units onabotu-linumtoxinA into each of the parotid glands and masseter muscles. She remained stable and only noticed slight enlargement of the glands and her masseter muscle in December 2009. She returned in January 2010 for a further maintenance dose of 40/40/40/40 units. It would appear that this dose of 160 units each session gives adequate shrinkage of parotid gland as well as masseter muscle for approxi-mately 9 months ( Figs. 7.7A–F , 7.8A–F , 7.9A–D ).

Case 4 A 40-year-old man felt his lower face was too heavy and wanted facial slimming to look more aesthetic as well as younger. Clinically, he appeared to have an indistinct jawline and a widened lower face due to hypertrophic masseter muscles. A dose of 40 units of onabotulinum-toxinA was injected into each masseter muscle. A month later, despite a slight infrazygomatic hollow appearing to indicate muscle shrinkage, he still felt his face had not improved much and was still broad. A sec-ond dose of onabotulinumtoxinA 40 units into each masseter was given again. When he returned a month later, he still complained of a broad lower face despite further shrinkage of the masseter muscle. He pointed to the masses just under his earlobes and in front of the ear. Clinically, his parotid glands were also large and this continued to widen and enhance his mandibular angles and gave him a broad lower face. The large parotid glands had been missed at initial examination and only became unmasked after the masseter muscle volume had reduced. About 40 units of onabotulinumtoxinA were injected into each parotid on two separate occasions a month apart and this reduced their size to improve his facial balance ( Figs. 7.10A–D and 7.11A–D ).

Case 5 Submandibular gland injection ( Fig. 7.12A,B ): This 51-year-old woman had received a long threadlift (Woffles lift) to improve her jowling as well as to elevate her mid face. She subsequently complained of prominent submandibular glands ( Fig. 7.12A ) and received 28 units of

FACIAL AND LOWER LIMB CONTOURING 211

(A)

(B)

(C)

(E)

(F)

(D)

Figure 7.6 Case 2. (A, front view; D, ¾ view): Male model with “chunky face” after some weight gain. (B, front view; E, ¾ view) Same patient 1 month after 40 units onabotulinum-toxinA to both masseters. (C, front view; F, ¾ view) Same patient 1 month after second dose of 40 units to each masseter muscle and 28 units Microbotox to the upper neck and jawline.

onabotulinumtoxinA into each gland every month for 3 months. Although visibly smaller the glands could not be reduced any further ( Fig. 7.12B ). However, the patient was satisfied with the reduction in size.

DISCUSSION This chapter does not attempt to make a case that all faces look good or more youthful with narrower lower facial width but rather to illustrate that a nonsurgical technique exists for those who desire triangulation of the face or a slimming effect.

In fact, in some cultures, a squarish jaw can be desirable and cer-tainly can make the face look younger provided other features of

the face are in harmony and consistent with the overall look. The use of mandibular body onlay grafts or implants made of silicone or calcium hydroxyl apatite attest to this flip side of the aesthetic ideal.

CONCLUSION Botulinum toxin type A is a useful tool for reducing facial width by inducing an atrophy of the masseter muscle. It can also be used to good effect to reduce the size of benignly diffused and enlarged parotid glands as well as to a lesser degree the submandibular gland.

212 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 7.7 Case 3: (A) Before parotid enlargement. (B) After enlargement. (C) After first onabotulinumtoxinA treatment. (Continued)

(A)

(B)

(C)

Figure 7.8 Case 3: (A) Before parotid enlargement. (B) After enlargement. (C) After first onabotulinumtoxinA treatment, as seen from below. (Continued)

(A)

(B)

(C)

FACIAL AND LOWER LIMB CONTOURING 213

(D)

(E)

(F)

Figure 7.8 (Continued) Case 3: (D) After second onabotulinumtoxinA treatment. (E) After third onabotulinumtoxinA treatment. (F) Parotid January 2010, as seen from below.

Figure 7.7 (Continued) Case 3: (D) After second onabotulinumtoxinA treatment. (E) After third onabotulinumtoxinA treatment. (F) January 2010.

(D)

(E)

(F)

214 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

THE ROLE OF BOTULINUM TOXIN A IN COSMETIC CALF SLIMMING AND CONTOURING As the world moves toward nonsurgical, minimal pain, no-downtime procedures, simple and effective techniques delivered via injection have become increasingly popular and are most well tolerated by patients ( 15 , 16 ). In the last decade, onabotulinumtoxinA has become an important and viable option for achieving cosmetic calf contour-ing or reduction of calf size ( 27 , 28 ) and together with liposuction, partial resection of the gastrocnemius muscle ( 29–32 ), and selective denervation of the gastrocnemius muscles ( 33 , 34 ) has increased the palette of treatments for thick and bulky calves.

Patients who seek cosmetic calf reduction are predominantly females who wish to achieve esthetically sleek lower limbs where the legs appear as long, continuous fusiform columns flowing down from the pelvis to the ankles with only the slightest of undulations. These legs appear youthful and feminine in addition to being healthy and firm. Above all, they should look sensuous. The desired legs should also look good in and enhance the effects of high heeled shoes which are an essential part of a woman’s wardrobe ( Fig. 7.13A,B ). Popular culture and the media also places great emphasis on such legs, which are featured as selling points in movie billboards and contemporary art.

This treatment is more popular in Asia ( 35 ) than the West and there are several reasons for this. Firstly, Asian body morphology generalizes toward individuals with a higher trunk–lower limb height ratio, that is, Asian females tend to have shorter legs in relation to their torso. This is an unfortunate esthetic feature and causes Asian females to look more stumpy than their Western or African sisters. If the calves are thick and bulky, this further accentuates the physical disproportion and makes for a stocky, heavyset appearance of the legs.

Among many Asian females, thick or muscular calves are perceived as unrefined, inelegant, and masculine. “Radish” legs, “obese” legs, and “fat” legs are some of the common terms used for these thick, bulky calves ( Fig. 7.14A,B ). They also have connotations of belonging to the “working class”. This mind-set also explains why cosmetic skin whiten-ing is so popular in Asian females as having a darker skin tone is also perceived in the same way.

Previously, the only options available to patients seeking cosmetic slimming of their calves was liposuction, partial resection of the gas-trocnemius muscles, or denervation of the medial head of the gastroc-nemius muscle, all three techniques having their own limitations and risks. These procedures are operations and can leave unsightly scars (to the patients). Wounds on the lower limbs do not heal well. Despite

Figure 7.9 (A) Parotid enlargement. (B) After second onabotulinumtoxinA treatment. (C) After three doses of onabotulinumtoxinA. (D) January 2010.

(A) (B)

(C) (D)

FACIAL AND LOWER LIMB CONTOURING 215

(A) (B)

(C) (D)

Figure 7.10 Case 4: A man with increased lower facial width due to enlarged masseters and parotid glands: (A) Front view at initial presentation. (B) Same patient one month after 40 units had been injected into each masseter. He appears slightly thinner. (C) Same patient one month after a second dose of 40 units was injected into each masseter. There is little improvement in lower facial width as it is now discovered he has large parotid glands as well. (D) Same patient one month after 40 units had been injected into each parotid gland. Here he appears significantly narrower as the onabotulinumtoxinA exerts its effects on both the masseters and parotid glands.

the scars of liposuction and denervation being short, they invariably can be seen. The scar from partial debulking of the muscle is even more obvi-ous. These wounds often result in hyperpigmented and/or keloid scars, which can prove to be a persistent nuisance to patients. These are patients who are concerned enough about the shape of their calves to seek treat-ment. Therefore, a small dark scar is instantly spotted and complained about despite good cosmetic improvement of the calf shape.

As a result, onabotulinumtoxinA calf slimming has become an excel-lent alternative as it leaves no scars and is potentially reversible should the patient have a change of heart. Its only drawback is its cost.

ASSESSMENT OF THE PATIENT WITH THICK CALVES When a patient seeks cosmetic calf slimming, it has to be determined how much of this is contributed by fat and how much by muscle bulk.

The patient is first asked to stand on tip toes. In a lean individual, the definition of the two gastrocnemius muscles can be easily seen and delineated for treatment. In a fatty calf, the muscle definition is obscured and the calf looks doughy and shapeless. This fat usually con-tinues down into the ankles blunting the esthetic hollows above and below the malleoli. If the skin is then pinched, the thickness of the fat can be felt and one can see a “cellulite” orange peel appearance.

If the patient has predominantly fatty calves and ankles, then liposuction is discussed including the possibility of visible and persistent scars. Due to the convexity of the calves, it has always been necessary to have sev-eral access points on either sides of the calf if a thorough liposuction is to be achieved. Limiting the number of scars limits the esthetic result of the contouring so potential scarring is a real issue that must be made known to patients.

216 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

(A) (B)

(C) (D)

Figure 7.11 Case 4: A man with increased lower facial width due to enlarged masseters and parotid glands. (A) Inferior view at initial presentation. (B) Same patient one month after 40 units had been injected into each masseter. He appears slightly thinner. (C) Same patient one month after a second dose of 40 units was injected into each masseter. There is little improvement in lower facial width as it is now discovered he has large parotid glands as well. (D) Same patient one month after 40 units had been injected into each parotid gland. Here he appears significantly narrower as the onabotulinumtoxinA exerts its effects on both the masseters and parotid glands.

If the calf bulk is due to hypertrophic or enlarged gastrocnemius muscles, then the alternatives of selective muscle denervation, partial muscle debulking, and onabotulinumtoxinA injection treatment are discussed.

My preference for those patients who can afford the long-term cost is to use onabotulinumtoxinA primarily because it is simple to per-form but also because it lends itself to easily adjusting and refining the final result. With partial debulking of the gastrocnemius muscles, not only is it potentially bloody, the sural nerve can be accidentally severed and it has significant downtime, it is not easy to control the shape and the final esthetic outcome. In denervation of the medial gastrocnemius alone, a compensatory hypertrophy of the lateral head can occur, creating a distorted or bow legged appearance. This is in turn has to be addressed either surgically or with the use of

onabotulinumtoxinA. If onabotulinumtoxinA is used, any residual unsightly bulges can be targeted until a smooth appearance is achieved ( Fig. 7.15 ).

PHYSIOLOGIC BASIS AND MECHANISM OF ACTION OnabotulinumtoxinA in calf reduction works in exactly the same way as onabotulinumtoxinA in masseteric hypertrophy ( 26 ), bring-ing about a state of chemically induced “disuse atrophy” of the gas-trocnemius muscles. The objective is to bring about muscle weakening or paralysis and finally an atrophy of the gastrocnemius muscle bulk.

The onabotulinumtoxinA can be injected into the medial, lateral, or both heads of the gastrocnemius muscle to selectively reduce its bulk. Even within each muscle, the onabotulinumtoxinA can be distributed in

FACIAL AND LOWER LIMB CONTOURING 217

(A) (B)

Figure 7.13 Young 20-year-old girl with ideal slim Asian legs. (A) Posterior view in high heels. (B) Side view.

Figure 7.12 Case 5: A woman with enlarged submandibular glands (A) at initial presentation and (B) 4 months later. She had received 28 units onabotulinumtoxinA into each submandibular gland monthly for three months (that is, a total dose of 84 units per gland). The gland could not be reduced beyond this size. The patient seemed satisfied.

(A) (B)

such a way (either higher or lower) as to achieve the most fusiform appearance for the patient. Some patients have a more bulky medial head, others have hypertrophy of both.

The injections should be delivered directly into the muscle with a minimum of pain, bruising or swelling.

DILUTION AND INJECTION TECHNIQUE FOR ONABOTULINUMTOXINA CALF SLIMMING The author always uses a 100-unit bottle of onabotulinumtoxinA diluted with 2.5 ml of normal saline. The usual dose is 100 to 120 units per gastrocnemius head—a total of 400 to 480 units for both calves. This is repeated 4 to 6 weeks later to consolidate the atro-phy and refine any residual bulges. An additional third dose can be given 8 to 12 weeks later. This gives a more thorough atrophy and

thus shaping of the gastrocnemius muscles. The result can last up to 18 months ( 36 ).

If only the initial dose is given without a second dose, the atrophy of the gastrocnemius muscles will be partial. A reduction in size of the calves will be seen but it will not be dramatic and it will only last for about 6 months before reverting to the preinjection size. The author’s intention is to achieve maximum slimming of the calves and to main-tain it at this level rather than allow it to revert to a thickened state again. The same approach is used in the treatment of masseteric hyper-trophy where repeated injections bring about maximal muscle size reduction after which maintenance doses are used to keep the muscles in their atrophied state ( 37 ).

Five 1 ml syringes containing 40 units each are prepared for each calf. Occasionally, a small amount of local anesthesia (2% lignocaine

218 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Semitendinosus Semimembranosus

Gracilis

Medial head ofgastrocnemius muscle

Lateral head ofgastrocnemius muscle

SoleusSoleus

PlantarisBiceps femoris

Aponeurosis ofgastrocnemius

Figure 7.15 Anatomy of the posterior compartment of the leg, highlighting the prominent gastrocnemius muscles.

Figure 7.14 (A) Asian woman with muscular “radish” legs—side profile. (B) Posterior view.

(A) (B)

and 1:200,000 adrenaline) can be included in the syringe. In such a case, 32 units (0.8 cc) is drawn into the 1 ml syringe and topped up with the anesthetic to make 1 ml of solution. Six such syringes are prepared in this way.

The patient is first asked to stand on tip toes and the muscle heads outlined. With the patient then lying supine and the muscles in a flaccid state, onabotulinumtoxinA is injected into the muscle in two vertical rows, each injection spaced about 1 to 2 cm apart.

A 30g needle is used. Although short, this needle with slight pressure more than adequately penetrates the gastrocnemius muscle. It is also less painful and seldom bruises. Larger needles are not necessary and

can leave the patient with a degree of soreness which they do not appre-ciate. The 30g needle also prevents any onabotulinumtoxinA from being injected deeply into the soleus muscle, which would leave the patient with a noticeable weakness of the calves especially when standing upright as it is the soleus, which is responsible for maintaining balance and not the gastrocnemius.

The patient can resume activities immediately. Initially the author used to inject only the medial gastrocnemius

with 80 to 100 units of onabotulinumtoxinA but compensatory hyper-trophy of the lateral head with a “bow legged appearance” ( 38 ) occurred in several patients requiring subsequent contouring of this muscle as well. As a result, it was felt that concomitant treatment of both heads from the outset led to a better and more uniformly sleek result. Smaller dosages of onabotulinumtoxinA (40–70 units per gastrocnemius), as quoted by Lee et al. ( 3 ), did not yield a good result.

RESULTS Patients can notice a reduction in muscle strength within two weeks and see a visible reduction in size within 3 to 4 weeks ( Fig. 7.16A–D ). Within 6 to 8 weeks, the muscle reduction is maximal and this is the best time to add a second dose to target any areas that may have been missed with the first session. Sometimes due to the lack of diffusion and placement of the initial injections, there may be asymmetric bulges or undulations in which case these areas can be targeted during the second session. If after 3 months, the muscle bulk is not sufficiently reduced, a further dose can be given ( Fig. 7.17 ).

Patients are still able to engage in gym or sporting activities and none has reported any difficulty with running or diminished ability although slight weakness has been felt in the first 2 to 3 weeks.

COMPLICATIONS AND ADVERSE EVENTS As with other onabotulinumtoxinA techniques, most complications are due to the injection of the product into muscles for which they are not intended. In this case, injecting the soleus muscle is to be avoided as this can give a noticeable weakness of the calves and potentially problems with balance in the upright position. The author has not encountered this complication.

FACIAL AND LOWER LIMB CONTOURING 219

Figure 7.16 A 33-year-old woman desiring cosmetic calf slimming was injected with 100 units of onabotulinumtoxinA into each gastrocnemius head for a total of 400 units for both calves. Patient is shown 3 weeks after the first injection. (A) Posterior view before onabotulinumtoxinA. (B) Posterior view after onabotulinumtoxinA. (C) Side view before onabotulinumtoxinA. (D) Side view after onabotulinumtoxinA.

(A) (B)

(C) (D)

Some other reported complications have included the following:

1. Ecchymoses and myalgia at the injection sites, usually lasting a few days only. This can be reduced by using the 30g needle as recommended by the author.

2. Transient weakness of the calf muscles for the first 2 weeks after the initial injection and fatigue of the calf muscles when hearing high heeled shoes, both of which improve after 2 to 3 weeks.

3. Compensatory hypertrophy of the lateral gastrocnemius if the medial head alone was injected. This can be avoided by injecting the lateral gastrocnemius at the same time. It increases the cost but the overall result is much better.

There have been no other adverse effects of note.

DISCUSSION The use of Botulinum toxin type A to bring about cosmetic slimming of the calves is now well established. The dosing regimes among differ-ent authors are variable though. Lee et al. in 2004 conducted a study on

the effects of different doses of onabotulinumtoxinA on the medial gastrocnemius muscle. He used doses of 32, 48, and 72 units of ona-botulinumtoxinA into each muscle and concluded that doses of up to 72 units are safe without major complications. In the author’s experi-ence, these dosages are too low to achieve a significant clinical improve-ment that satisfies the patient’s esthetic requirements. Originally commencing with 80 units per gastrocnemius muscle head, the results were unsatisfactory and had to be increased to between 100 and 120 units per head (i.e., 200–240 units per leg). In some patients, even this dose was insufficient and whilst maintaining the dosage, the frequency of injections had to be increased.

In the treatment of masseteric hypertrophy, the author uses doses of 40 to 60 units per side and repeats this at monthly intervals (usu-ally two or three times) until complete atrophy and lack of muscle movement is achieved. This allows the lower face to achieve maximal slimming. The gastrocnemius muscles are much larger in compari-son to the masseter muscles and they are also subjected to much greater loads on a daily basis than the latter. It is therefore only logical that doses of anywhere from 32 to 80 units per muscle head would

220 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Figure 7.17 A 37-year-old woman desining thinner calves was injected with 400 units of onabotulinumtoxinA into both calves at each session. The photographs show her pro-gression after several injections and 18 months after the last injection, demonstrating the long lasting nature of the result. (A–C) The patient is seen before 400 units of onabotu-linumtoxinA were injected into both sides of the calves. Posterior and both side views. (D–F) Same patient. After 6 weeks, there is slight reduction in the contours of the calves. A further 400 units per calf is injected. (G–I) Same patient. After a further 4 weeks (10 weeks post first injection) the patient sees good slimming but wishes to have a third injection.

(A) (B) (C)

(D) (E) (F)

(G) (H) (I)

FACIAL AND LOWER LIMB CONTOURING 221

not yield good clinical results and that much greater doses of ona-botulinumtoxinA would be required. Another possible reason why greater doses of onabotulinumtoxinA are required is because of its lack of diffusion in muscles, a clinical feature useful when injecting in the face and neck but perhaps less so in the voluminous muscle bulk of the gastrocnemius where diffusion of the product may in fact be desirable ( 39 , 40 ).

Han et al. ( 4 ) has been able to achieve very good results for patients using 300 to 360 units of abobotulinumtoxinA per side and this may be due to the fact that it has a greater diffusibility in muscles than onabotulinumtoxinA.

The recurring cost is a significant consideration in this technique as between four and five bottles of onabotulinumtoxinA (100 units/bottle) are used each time and a patient may require two to three sessions to achieve the desired esthetic goals. While all patients have been delighted

with the initial results, fewer than half of the patients have continued with the technique beyond two years and the reason has invariably been about recurring costs. These same patients are however resistant to sur-gical alternatives for reasons of scarring and morbidity. As a result, they have allowed the calves to revert to their normal state.

CONCLUSION Botulinum toxin A again demonstrates its versatility as a therapeutic and cosmetic product for calf slimming. It is a successful and viable alternative to traditional, surgical options for treating thick and bulky calves. The treatment is easy to administer, has no appreciable downtime, nor adverse effects profile and gives extremely pleasing results after several months of usage. It needs to be repeated periodically and its only drawback is the high recurring cost of the treatments.

Figure 7.17 (Continued) (J–L) Same patient. She is seen 7 months after the third set of injections. She is satisfied with the cosmetic outcome and wishes to maintain the result. A fourth dose is given. (M–O) Same patient. The patient is seen 18 months after the fourth injection showing little recurrence of the original bulky calves despite the long duration without any maintenance injections. She is very happy.

(J) (K) (L)

(M) (N) (O)

222 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

REFERENCES 1. Moore AP, Wood GD. The medical management of masseteric

hypertrophy with botulinum toxin type A. Br J Oral Maxillofac Surg 1994; 32: 26–8.

2. Smyth AG. Botulinum toxin type A treatment of bilateral masseteric hypertrophy. Br J Oral Maxillofac Surg 1994; 32: 29–33.

3. Mandel L, Tharakan M. Treatment of unilateral masseteric hyper-trophy with botulinum toxin: Case report. J Oral Maxillofac Surg 1999; 57: 1017–9.

4. Von Lindern JJ, Niederhagen B, Appel T, Berge S, Reich R. Type A botulinum toxin for the treatment of hypertrophy of the masseter and temporal muscles: An alternative treatment. Plast Rec Surg 2001; 107(2): 327–32.

5. Wu WTL. Facial rejuvenation without facelifts—personal strategies. Regional Conference in Dermatological Laser and Facial Cos-metic Surgery 2002, Hong Kong. 13–15 Sep 2002.

6. Park MY, Ahn KY, Jung DS. Botulinum toxin type A treatment for contouring of lower face. Dermatolog Surg 2003; 29: 477–83.

7. Yu C, Chen PKT, Chen YR. Botulinum toxin A for lower facial con-touring: A prospective study. Aesthetic Plast Surg 2007; 5: 445–51.

8. Wu WTL. Innovative uses of BOTOX and the Woffles lift. In: Panfilov D, ed. Aesthetic Surgery of the Facial Mosaic. Berlin Heidelberg: Springer, 2006: 636–49.

9. Kim HJ, Yum KW, Lee SS, Heo MS, Seo K. Effects of botulinum toxin type A on bilateral masseteric hypertrophy evaluated with computer tomographic measurement. Dermatol Surg 2003; 29: 484–9.

10. Kim KS, Byun YS, Kim YJ, Kim ST. Muscle weakness after repeated injection of botulinum toxin type A evaluated according to bite force measurement of human masseter muscle. Dermatol Surg 2009; 35: 1902–7.

11. Wu WTL. Botox facial slimming/facial sculpting: The role of botu-linumtoxin-A in the treatment of hypertrophic masseteric muscle and parotid enlargement to narrow the lower facial width. Facial Plas Surg Clin N Amer 2010; 18(1): 133–40.

12. Gurney C. Chronic bilateral benign hypertrophy of the masseter muscle. Am J Surg 1947; 78: 137.

13. Adams W. Bilateral hypertrophy of the masseter muscle: An oper-ation for correction. Br J Plast Surg 1949; 2: 78.

14. Baek SM, Kim S, Bindinger A. The prominent mandibular angle: Preoperative management, operative technique and results. Plast Reconstr Surg 1989; 83: 272.

15. Wu WTL. Nonsurgical facial rejuvenation with the 4R principle: innovative uses of BOTOX and facelifting with the Woffles lift, a barbed suture sling (Chapter 72). In: Panfilov D, ed. Aesthetic Surgery of the Facial Mosaic. Berlin: Springer, 2006: 636–49.

16. Wu WTL. Botox facialslimming/facialsculpting: The role of botuli-num toxin type A in the treatment of hypertrophic masseteric muscle and parotid gland enlargement to narrow the lower facial width. Facial Plast Surg Clin N Am 2010; 18: 133–40.

17. Moss ML. The primacy of functional matrices in orofacial growth. Dent Pract Dent Rec 1968; 19(2): 65–73.

18. Moss ML, Rankow RM. The role of the functional matrix in man-dibular growth. Angle Orthod 1968; 38(2): 95–103.

19. Moss ML. The functional matrix hypothesis revisited. The role of an osseous connected cellular network. Am J Orthod Dentofacial Orthop 1997; 112(2): 221–6.

20. Enlow DH. Facial Growth, 3rd edn. Philadelphia: Saunders, 1990. 21. Fuster-Torres MA, Berini-Aytes L, Gay-Escoda C. Salivary gland

application of botulinum toxin for the treatment of sialorrhea. Med Oral Patol Oral Cir Bucal 2007; 12(7): E511–E17.

22. Vargas H, Galati LT, Parnes SM. A pilot study evaluating the treat-ment of postparotidectomy sialoceles with botulinum toxin type A. Arch Otolaryngol Head Neck Surg 2000; 126: 421–4.

23. Chow TL, Kwok SPY. Use of botulinum toxin type A in a case of persistent parotid sialocele. Hong Kong Med J 2003; 9: 293–4.

24. Giess R, Naumann M, Werner E, et al. Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2000; 69: 121–3.

25. Manrique D. Application of botulinum toxin to reduce the saliva in patients with amyotrophic lateral sclerosis. Rev Bras Otorri-nolaringol 2005; 71(5): 566–9.

26. Kim ST, Choi JH, Park MY, Ahn KY. The change of the maxi-mal bite-force after botulinum toxin A injection for lower face contouring. J Korean Soc Aesthetic Plast Surg 2005; 11(1): 45–50.

27. Lee HJ, Lee DW, Park YH, et al. Botulinum toxin type A for aesthetic contouring of enlarged medial gastrocnemius muscle. Dermatol Surg. 2004; 30(6): 867–71; discussion 871.

28. Han KH, Joo YH, Moon SE, Kim KH. Botulinum toxin A treatment for contouring of the lower leg. J Dermatol Treat 2006; 17(4): 250–4.

29. Lemperle G, Exner K. The resection of gastrocnemius muscles in aesthetically disturbing calf hypertrophy. Plast Reconstr Surg 1998; 102: 2230–6.

30. Kim IG, Hwang SH, Lew JM, Lee HY. Endoscope-assisted calf reduction in Orientals. Plast Reconstr Surg. 2000; 106: 713–18.

31. Tsai CC, Lee SS, Lai CS, Lin SD, Chiou CS. Aesthetic resection of the gastrocnemius muscle in postpoliomyelitis calf hypertrophy: an uncommon case report. Aesthetic Plast Surg 2001; 25: 111–13.

32. Lee JT, Wang CH, Cheng LF, et al. Subtotal resection of gastrocne-mius muscles for hypertrophic muscular calves in Asians. Plast Reconstr Surg. 2006; 118(6): 1472–83.

33. Tsai FC, Mardini S, Fong TH, Kan JH, Chou CM. Selective neurec-tomy of the gastrocnemius and soleus muscles for calf hypertro-phy: an anatomical study and 700 clinical cases. Plast Reconstr Surg 2008; 122(1): 178–87.

34. Kim SC, Kang MH, Ock JJ. Calf-contouring surgery of gastrocne-mius hypertrophy: selective neurectomy of the sural nerve. Aesthetic Plast Surg 2008; 32(6): 889–93.

35. Schuman M. Some Korean women go to great lengths to show a little leg. Wall Street Journal . February 21, 2001.

36. Schroeder AS, Erti-Wagner B, Britsch S, et al. Muscle biopsy sub-stantiates long term MRI alterations one year after a single dose of botulinum toxin injected into the lateral gastrocnemius of healthy volunteers. Mov Disord. 2009; 24(10): 1494–503.

37. Tsai FC, Hsieh MS, Chou CM. Comparison between neurectomy and botulinum toxin A injection for denervated skeletal muscle with clinical implications. J Neurotrauma 2010 Jun 7 (Epub ahead of print).

38. Lee CJ, Park JH, Park SW. Compensatory hypertrophy of calf mus-cles after selective neurectomy. Aesthetic Plast Surg. 2006; 30(1): 108–12.

39. Aoki KR. Preclinical update on Botox-purified neurotoxin com-plex relative to other botulinum neurotoxin preparations. Eur J Neurol 1999; 6: S3–10.

40. Aoki KR. Pharmacology and immunology of botulinum toxin type A. Clin Dermatol. 2003; 21: 476–80.

223

warm-up time after exposure to cold ( 5 ), controls rest pain, shortens and reduces frequency and severity attacks ( 6 ) including stiffness, numbness, acute pain, color change, and swelling ( 7 ), prevents impending infarction of digits and successfully heals ischemic ulcerations caused by pro-found vasospasm in the majority of patients ( 1 ). These favorable changes of improved perfusion are quantified using visual analogue scale (VAS) and confirmed by digital surface temperature readings ( 1 , 2 ), imaging studies with laser Doppler interferometry ( 3 ), intra-vascular arteriography, or high-resolution digital magnetic reso-nance angiography ( 1 ). The adverse events reported are rare and include mild and temporary hand weakness. Amelioration of pain improves hand function despite occasional muscle weakness ( 1 ).

PHYSIOLOGICAL BASIS OF BoNTA FOR RAYNAUD’S PHENOMENON Autonomic: Vasodilator and Vasoconstrictor In addition to the widely recognized inhibitory effects on the release of acetylcholine (Ach) from neurons innervating striated muscle and sweat glands, BoNTA has been shown to produce a neuromodulating effect on autonomic nerves ( 8 ). Cutaneous vasoconstriction and vaso-dilation are regulated by modulation of sympathetic and parasympa-thetic neuronal inputs and the complex actions of released ACh, NE, peptides like NPY, and small molecules such as nitric oxide on vascular smooth muscle.

In an animal model of significantly constricted uterine arteries, BoNTA has been shown to reduce the amplitude of sympathetic NE-mediated vasoconstriction by 80% ( 9 ). Likewise, isometric contrac-tions of venae cavae mediated by NE acting on alpha-adrenoceptors are substantially reduced by BoNTA administration ( 10 ). Concur-rently, in parasympathetic neurons, BoNTA is found to significantly reduce the autocrine acetylcholine-mediated inhibition of vascular relaxation and also to reduce the slow component of neurogenic vaso-dilation mediated by the peptides VIP and CGRP ( 11 ). Thus, a differ-ential effect of BoNTA on different classes of neurotransmitters is observed, whereby it may reduce neurotransmitter and neuromodula-tor release from vasoconstrictor and vasodilator neurons depending on various regulatory mechanisms.

Local BoNTA injection consistently shows an ability to improve per-fusion of the injected tissue by both substantial opening of the vascular bed and an increase in aerobic metabolism. BoNTA inhibits the neuro-genic contractions of tumor vessels by blocking NE, thus improving tumor perfusion and oxygenation and thus aiding in delivery of cancer therapy ( 11 , 12 ). In inflammatory muscle states due to decreased micro-circulation, such as in lateral epicondylitis secondary to low intramus-cular blood flow in extensor carpi radialis brevis, BoNTA injection allows for muscle relaxation, a shift toward aerobic metabolism and a decrease in lactate production, restoration in intramuscular blood flow, decreased pain, improved muscle strength, and function ( 13 ).

BoNTA Has Anti-Inflammatory and Antinociceptive Effects BoNTA also acts on the nociceptive portion of the sensory system to reduce pain and neurogenic inflammation by attenuating the periph-eral release of neuroactive compounds such as SP and glutamate from C-fibers, as well as reducing central sensitization ( 6 ). BoNTA does not directly decrease excitability of nociceptors, but acts by reducing inflammatory pain ( 14 ) and thus pathological pain ( 15 ).

8 Botulinum toxin type A treatment for Raynaud’s phenomenon and other novel dermatologic therapeutic applications Irèn Kossintseva , Benjamin Barankin , and Kevin C. Smith

INTRODUCTION This chapter will discuss the use of botulinum neurotoxin type A (BoNTA) in dermatology for the treatment of painful conditions including Raynaud’s phenomenon, postherpetic neuralgia, headache, reflex sympathetic dystrophy (or complex regional pain syndrome), and a variety of other conditions. The use of BoNTA to improve upper thoracic posture and thus improve the appearance and presentation of female breasts will be discussed. An approach to the management of acute overdoses of BoNTA will also be described.

Since BoNTA was first reported to be useful for the reduction in the pain of spasmodic torticollis in 1985 ( 1 ), the number of references in Medline™ to “botulinum” and “pain” have been growing at an increas-ing rate, and by the end of 2009 there were over 1,130 references. The list of painful conditions reported to respond well to BoNTA is also growing, and now includes some dermatologic conditions, and other conditions like headache, which are treated by some dermatologists who have expertise in the use of BoNTA ( 2 , 3 ).

It is important to note that the BoNTA used by the authors in the management of these conditions was BOTOX ® , and the doses described in this chapter refer to BOTOX®. Because the diffusion characteristics and dosing of other forms of BoNTA differ from BOTOX®, it is not possible to establish a simple ratio for the conversion of BOTOX® doses to other formulations of BoNTA, or to other botulinum neurotoxins serotypes, for example, BoNTB or BoNTE (chapter 1). To reduce the risk of confusion, the recently designated generic instead of the trade name of the BoNTA actually injected will be used throughout this chapter, which is onabotulinumtoxinA for Allergan’s BOTOX ® ; abobo-tulinumtoxinA for Medicis’ Dysport ® ; and incobotulinumtoxinA for Merz’s Xeomin ® . The term BoNTA will be used to refer to the general class and serotype of neurotoxin.

BoNTA TREATMENT IN RAYNAUD’S PHENOMENON Raynaud’s phenomenon is defined as an episodic digital asphyxia caused by vasospasm of the digital arteries triggered by cold exposure or stress. It is either idiopathic and known as Raynaud’s disease, or sec-ondary to diseases such as scleroderma, lupus erythematosus, rheuma-toid arthritis, and occlusive arterial disease. Its symptoms include a progression from digital blanching and cyanosis to reactive hyperemia, to pain and dysesthesias, which if prolonged, can result in severe digital vascular compromise, ulceration, digital infarction, and may even necessitate amputation. The etiology of Raynaud’s disease is complex, but both vasospasm and nociception appear to play a major role. The inhibitory effects of BoNTA on somatic and autonomic neurotrans-mission are well documented. BoNTA inhibits norepinephrine (NE)-mediated sympathetic vasoconstriction, thus improving perfusion of digits by opening up the vasculature and allowing for better oxygen-ation. It concurrently inhibits pain-mediating neuropeptides, namely substance P (SP), neuropeptide-Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and glutamate, thus interfering with nociception, both peripheral and central sensitization, and decreasing swelling and inflammation.

BoNTA is successfully used in Raynaud’s phenomenon as a safer and easier alternative to surgical sympathectomy ( 4 ). It essentially pro-duces a chemical sympathectomy that lasts for months and effectively improves hand temperature within 1 to 2 days as well as shortens

224 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Substance P BoNTA inhibits substance P (SP), a peptide released both peripherally and centrally by nociceptive primary afferent C-fibers, thus producing the analgesic effect seen in treating primary headache disorders ( 16 ). It markedly inhibits SP secretion in dorsal root ganglia neurons ( 17 ) within hours and lasts for at least 2 weeks. Local inflammation sensi-tizes peripheral nociceptive neurons, and as the increase in peripheral pain input causes increased release of SP in the spinal cord, it induces central sensitization ( 6 ). BoNTA thus attenuates both the peripheral and central sensitization by its inhibition of SP.

CGRP BoNTA inhibits the release of calcitonin gene-related peptide (CGRP), an inflammatory neuropeptide found on its own as well as colocalized with SP in sensory ganglia neurons, when pain stimulus is present, but not basally. It reduces bladder pain response by 62% through inhibition of CGRP release from afferent nerve terminals ( 18 ), and in trigeminal nerves ( 19 ), explaining the observed efficacy of BoNTA in migraine and cluster headache therapy. Curiously, CGRP released during inflamma-tion causes vasodilation, thus BoNTA’s analgesic effect in migraines may be secondary to vasoconstriction of the meningeal vasculature.

Glutamate BoNTA dose-dependently inhibits inflammatory pain by decreasing glutamate release. Glutamate is a stimulant of local nociceptive neu-rons through activation of receptors on primary afferents ( 20 ). Periph-eral glutamate release results in edema, pain, and inflammation ( 21 ), which is abolished by local BoNTA injection at doses below ones that would elicit muscle paralysis ( 15 ).

PRACTICAL TIPS Assessment Assessment of disability caused by Raynaud’s phenomenon or disease should be performed prior to and after the BoNTA treatment at 1 week, 1 month, and then routine follow-up. This is done by asking patients to evaluate the level of their (a) pain and (b) hand function using the 10-point visual analogue scale (VAS) , as well as the dermatology quality of life scale. If digital ulcerations are present, a photographic record is useful.

Injection Parameters There is no consensus of how many injection sites should be adminis-tered per affected hand, and whether the entire hand should be treated or just the most affected digits. The clinical decision will be based on the extent and severity of the patient’s Raynaud’s phenomenon/disease, with consideration given to the pharmacoeconomics of using BoNTA and also consideration of how best to avoid causing unwanted muscle weakness in the treated hand.

The authors consider that it is reasonable to administer up to 100 units of onabotulinumtoxinA per hand being treated, reconstituted in 3 to 6 cc of normal saline/100 U vial ( 1 , 4 ). This relatively high reconstitution volume is presently preferred as the increased volume may facilitate spread of the injected onabotulinumtoxinA from the injection point to the vessels we wish to relax. The trend is to inject the palm and all fingers at their base, with the exception of thumb unless it is specifically symptomatic (since thumb ischemia is uncommon in Raynaud’s). Targeted anatomy includes the superficial palmar arch, common digital arteries, and proper digital arteries, with injections being just adjacent to the tar-geted vasculature (in order to avoid injury to vessels) and needle tip perpendicular to the palm and deep to the palmar fascia ( Fig. 8.1 ) ( 1 ).

Figure 8.1 Typical injection points when BoNTA is administered for Raynaud’s phenomenon. Each subcutaneous dose of onabotulinumtoxinA is 5 to 10 units.

Proper palmardigital arteries

Radial arteryof index finger

Princepspollicis artery

Radialartery Ulnar

artery

Deeppalmar arch

Superficialpalmar arch

Commonpalmardigital

arteries

Injection points whenBoNTA is used tocontrol Raynaud’s. Eachsubcutaneous injectionis 5–10 units of BOTOX®

BOTULINUM TOXIN TYPE A TREATMENT FOR RAYNAUD’S 225

A 30, 31, or 32G needle is used to infiltrate the soft tissues, with 10 to 40 injection sites spaced approximately 1 cm apart, of equally dis-tributed volume of reconstituted 100 U of onabotulinumtoxinA ( 1 , 4 ). This is followed by a massage of the injected tissues to help distribute the medication throughout the region. Due to the discomfort associ-ated with palmar injections, sufficient anesthesia (e.g., ice, vibration, or nerve blocks) is necessary to make the procedure tolerable (see chapter 11). To minimize weakness of the thumb, it is important to avoid injection into the thenar muscle group on the radial side of the proximal part of the palm (flexor, extensor and abductor pollicis longus, and extensor pollicis brevis).

OTHER NOVEL DERMATOLOGIC USES OF BoNTA Targeting Hypersecretion Based on the positive results seen with treatment of hyperhydrosis using onabotulinumtoxinA injections, onabotulinumtoxinA has been found to be helpful for other conditions made worse by increased sweating. These conditions include persistent facial flushing with or without localized sweating, gustatory sweating (Frey’s syndrome), localized uni-lateral hyperhydrosis, Ross’ syndrome ( 22 ), familial benign pemphigus (Hailey-Hailey disease), and dishydrotic eczema ( 23 ).

Frey’s syndrome is facial hyperhidrosis in the preauricular region from gustatory stimulus, observed commonly after parotidectomy. On aver-age, 40 units of onabotulinumtoxinA effectively alleviates the symptoms within days after injection and remission has been reported to persist for 15 to 18 months ( 24 ). Other glandular hypersecretory disorders, including sialorrhea, excessive lacrimation, chronic rhinitis ( 25 , 26 ) and parotid fistulas ( 27–29 ) also have been reported to respond to treatment with onabotulinumtoxinA.

Hailey-Hailey disease is an autosomal-dominant acantholytic blis-tering disease affecting the intertriginous skin and is exacerbated by heat, sweat, moisture, friction, and infection. Intertriginous injections of BoNTA have been reported to induce significant improvement within 2 weeks with onabotulinumtoxinA ( 30 ) and improvement can be maintained for many months with abobotulinumtoxinA ( 31 ). Dys-hidrotic hand eczema (pompholyx) is a chronic, relapsing inflamma-tory vesiculo bullous disease also aggravated by hyperhidrosis ( 32 ). The addition of onabotulinumtoxinA injection to topical steroid therapy

has shown significant benefit in managing pompholyx eruptions and the associated symptoms of pruritus ( 33 , 34 ). Inverse psoriasis is exac-erbated by maceration, secondary infection, and inflammatory pain; onabotulinumtoxinA injections to affected intertriginous regions also improve the symptoms and eruptions of inverse psoriasis ( 35 ).

Targeting Pain OnabotulinumtoxinA’s antinociceptive properties have been used in the treatment of multiple cutaneous piloleiomyomas, with effective rapid and sustained resolution of pain ( 36 ). It has also shown substan-tial benefit in the treatment of notalgia paresthetica ( 37 ).

BoNTA enters neurons by binding to the synaptic vesicle protein SV2 receptor (isoforms A, B, and C) ( 38 ). SV2 is transiently exposed when synaptic vesicles fuse with the presynaptic membrane to dis-charge neurotransmitter into the synaptic junction ( Fig. 8.2 ). This is the physiological basis for the important clinical observation that gen-erally the most effective and efficient way to administer BoNTA for painful conditions is to inject BoNTA in the points and areas of maxi-mum discomfort indicated by the patient, because it is in these areas that there is maximum discharge of pain mediating neurotransmitter and thus maximal exposure of the SV2 protein, which mediates uptake of BoNTA. This method of administration of BoNTA is commonly referred to as the “follow the pain” approach. Clinical trials of onabotu-linumtoxinA for painful conditions sometimes use a rigid protocol of doses and injection sites rather than the “follow the pain” approach, which customizes the treatment to the needs of each individual patient, and this difference may explain why some clinical trials (in particular for headache) do not obtain the degree of improvement which is commonly achieved in clinical practice ( 39–42 ).

BoNTA for Postherpetic Neuralgia Perhaps the first to use onabotulinumtoxinA for the treatment of posther-petic neuralgia (PHN) were Dr. Arnold Klein ( 43 ) and, later, Drs. Mariusz Sapijaszko and Richard Glogau (personal communication) who used onabotulinumtoxinA to treat PHN on the trunk. Their informal oral reports, together with a consideration of the well-established role of SP in the pathogenesis of PHN, and considering reports that BoNTA blocked the release of SP from vesicles in nerve terminals, provided the rationale

Figure 8.2 SV2 receptors for the binding domain (i.e., heavy chain) of BoNTA are exposed when the contents of vesicles of neurotransmitter are released at the presynaptic membrane.

Presynaptic motor nerve terminal orperipheral terminal of nociceptiveprimary afferent neuron (C-fibre)

After stimulation of the nerve terminal,vesicles containing NT (for exampleacetylcholine, substance P, calcitonin gene-related peptide, or glutamate) fuse with theneuronal membrane (via the SNAREcomplex), releasing NT and exposing SV2receptors to BoNTA.

NT

NT

NT

NT

SV2 receptors onneurotransmitter(NT) vesicles arethe binding site forBoNTA

NTNT

226 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

in areas of PHN, it is best to use BD-II 0.3 ml insulin syringes with attached 31G needles (Becton Dickinson, Franklin Lakes, NJ). It is not usually necessary to pretreat patients with a topical anesthetic, but this could be used in cases where there is a likelihood of intolerable injec-tion discomfort.

Patients should be informed that there will very likely be some unwanted relaxation of muscles in the treated area. Injecting BoNTA intradermally can minimize muscle weakness. Injections for the pain of PHN seem to be equally effective whether given intradermally, subdermally, or intramuscularly.

The maximum analgesic effect of BoNTA treatment for PHN often occurs at around 3 to 4 weeks. For this reason, patients are asked to return for reassessment and possibly additional treatment every 3 to 4 weeks until they are pain free.

While the occasional patient will respond in a dramatic manner to a single session of treatment with BoNTA, it is more typical for patients to improve in a stepwise manner. Patients generally need between one and four treatment sessions to become pain-free. Objective quantification of the area of involvement, medication intake, Likert pain score, and patient’s and physician’s global assessment will help both the patient and the physician to determine whether or not additional treatment is jus-tified. The author (KCS) has only had success treating PHN on the face and scalp with BoNTA, and has not found BoNTA useful for the treatment of PHN on the trunk or extremities. The reasons for treatment failure on the trunk and extremities are not known, and further studies are warranted.

Usually, serial photographs of the involved area demonstrate progres-sive reduction of the surface area ( Fig. 8.5 ). Patients find this encour-aging. There is often a paradoxical increase in the patient’s Likert pain score as the total area of involvement shrinks. The reason for this phenomenon is not well understood. It could be that the mildest areas of PHN resolve first, with the result that because of “averaging” by the patient, the pain score in the residual area of involvement

for additional trials of treatment with BoNTA for severe, intractable PHN ( 44 ). One author (KCS) has found onabotulinumtoxinA to be a very reliable treatment for PHN on the face and scalp, but has had only treatment failures when attempting to use onabotulinumtoxinA to treat PHN on the trunk and extremities. The reason for this difference in responses is not known, and additional investigations are warranted.

It is important clinically, for communication with other physicians and with third party payers, and in terms of pharmacoeconomics to objectively quantify a patient’s condition at baseline and in response to therapy. The four tools which are helpful include:

1. Likert pain scale and global assessment ( Fig. 8.3 ). 2. Physician’s global assessment ( Fig. 8.4 ). 3. Number of doses of pain medication taken in the 7 days preceding

evaluation, and the number of doses taken since the last visit. 4. Marking and photographing the boundaries of the area or areas

of PHN before treatment and then marking and photographing the involved areas at every subsequent visit ( Fig. 8.5 ).

Patients are advised to continue their usual pain medications, and only to reduce the dose of pain medication as they respond to their BoNTA treatment.

The patient identifies the area or areas of involvement. The boundaries of the area(s) of involvement are marked with washable pink fluorescent marker, photographed ( Fig. 8.5 ), then injected with onabotulinumtoxinA intradermally or subdermally at doses ranging from 2.5 to 5 units per injection site, with the injections spaced 2 to 3 cm apart. The total dose of onabotulinumtoxinA is generally in the range of 1 to 2 units per cm or cm 2 .

BoNTA is reconstituted using normal saline with benzyl alcohol preservative (which has local anesthetic properties and reduces injection discomfort). A reconstitution volume of 1 ml per 100 units of onabotulinumtoxinA is used by the author (KCS), but the reconstitution volume does not seem to influence efficacy—the only thing that matters is how many units of BoNTA are administered ( 45 ). Because there is commonly hyperalgesia

Figure 8.3 Visual analog scale used to measure patients’ perception of their pain and of their global well-being.

Last Name First Name Chart # Date

Patient’s rating scale:

Please circle the number which best describes the amount of pain you are having todayin the involved area:When you are not touching the area:

NO Pain 0 1 2 3 4 5 6 7 8 9 10 WORST possible pain

When the area is touched or rubbed:

NO Pain 0 1 2 3 4 5 6 7 8 9 10 WORST possible pain

Please circle the number which best describes your PAIN in the involved area isBETTER or WORSE compared with how it was at your last visit:

BETTER 5 4 3 2 1 0 1 2 3 4 5 WORSE

Please circle the number which best describes your OVERALL impression of how you are doing,compared with the previous visit:

BETTER 5 4 3 2 1 0 1 2 3 4 5 WORSE

BOTULINUM TOXIN TYPE A TREATMENT FOR RAYNAUD’S 227

Figure 8.4 Visual analog scale used to measure the physician’s assessment of the patient’s pain and of the patient’s global well-being.

Last Name First Name Chart # Date

Patient’s rating scale:

Please circle the number which best describes the amount of pain the patient appears to be having todayin the involved area:When the area is not touched:

NO Pain 0 1 2 3 4 5 6 7 8 9 10 WORST possible pain

When the area is touched or rubbed:

NO Pain 0 1 2 3 4 5 6 7 8 9 10 WORST possible pain

Please circle the number which best describes whether the patient’s pain in the involved areaappears to be BETTER or WORSE compared with how it was at the patient’s last visit:

BETTER 5 4 3 2 1 0 1 2 3 4 5 WORSE

Please circle the number which best describes your OVERALL impression of how this patient is doing,compared with the previous visit:

BETTER 5 4 3 2 1 0 1 2 3 4 5 WORSE

Figure 8.5 The area identified by the patient is marked and photographed, the patient completes a visual analog pain score (Fig. 8.3), and then the painful area is injected with onabotulinumtoxinA.

90

80

70

60

50

40

30

20

10

0DayZero

Day21

Day49

Day59

84

Pain at rest

Pain with rubbing

Pain in residual areaof involvement:visual analog scorerises as area ofinvolvement shrinks.

228 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

would tend to rise. When the patient with PHN has been rendered pain-free by treatment with BoNTA, there is usually a long-term drug-free remission of pain.

BoNTA in the Management of Painful Scars Immunohistochemistry has demonstrated substantial numbers of nerves staining for SP and CGRP in some scars ( 46 ). This observation, together with successful experience treating PHN, formed the rationale for offer-ing a trial of treatment with injections of BoNTA to patients suffering from chronic intractable painful scars. Objective quantification of the patient’s pain is of great importance in the management of painful scars. Tools that are useful for this purpose are essentially the same as those used in the assessment of patients who have PHN.

1. Likert pain scale and global assessment ( Fig. 8.3 ). 2. Physician’s global assessment ( Fig. 8.4 ). 3. Marking the boundaries of the area or areas of pain prior to

treatment and then marking and photographing the involved areas at every subsequent visit ( Figs. 8.5 and 8.6 ).

Injections are usually performed using a 30G 1-inch needle, or a BD-II 0.3 ml insulin syringe with 31G needle, inserted into the scar. In the case of a thick scar (for example, a keloid on the central chest after thoracotomy ( Fig. 8.6 ), the patient may offer advice about whether the pain is deep or superficial and the injection can be adjusted to take this into account. Application of ice for 30 to 60 seconds, or injection of lidocaine around and below the scar, are generally not necessary but could be used in a very sensitive patient to reduce the pain of injection. The author (KCS) has successfully used injections of onabotulinum-toxinA to treat pain associated with keloid scarring, hypertrophic scar-ring, and normal scarring.

The author (KCS) uses a reconstitution of 1 ml in 100 units of ona-botulinumtoxinA. The amount of onabotulinumtoxinA administered in each treatment has ranged from 10 to 50 units per ml (cubic volume) of scar tissue.

As with the treatment of PHN, the antinociceptive effect of BoNTA for painful scars seems to reach a maximum at around 3 weeks, so it is

advisable to have patients return for reassessment and retreatment every 3 to 4 weeks until the patient is pain-free. The required number of treatments has ranged from one to four. As with PHN, the visual analog or Likert pain score may rise in residual areas of involvement even as the patient globally improves ( Fig. 8.7 ), and patients typically remain pain-free for a long time once they have been rendered pain-free by treatment with BoNTA. In one case, there have been partial relapses at 6 to 12-month intervals, and these have responded within 5 to 10 days to additional injections of BoNTA.

There has been no clinically significant improvement in the appearance (assessed by serial photography) of the scars injected by the author (KCS) with onabotulinumtoxinA, but one hypertrophic scar on the breast ( Fig. 8.8 ) seemed much softer 6 months after two injections with onabotulinumtoxinA. Because SP and CGRP interact with some of the cytokines involved in collagen remodeling and collagen deposition ( 47–49 ), it is conceivable that treatment with BoNTA could affect the physical properties of some scars, perhaps with repeated treatments or after longer follow-up.

BoNTA in the Management of Reflex Sympathetic Dystrophy (Complex Regional Pain Syndrome) Reflex sympathetic dystrophy syndrome (RSDS) is characterized by constant burning pain and hyperesthesia in an extremity. Swelling, sweating, vasomotor instability, and sometimes trophic changes often accompany pain. There is often a history of injury or other trauma. Muscle spasms, myoclonus, or focal dystonia may occur. Diffuse pain, loss of function, and autonomic dysfunction are three main criteria suggested for diagnosis. Successful use of BoNTA for this entity has been reported ( 50 , 51 ).

Over the past five years, the author (KCS) has treated a 41-year-old woman who had an 8-year history of severe, refractory RSDS rendering her right arm and leg useless since injuries in a motor vehicle accident. She also had posttraumatic headaches with muscle spasm pulling her head to the right. The headaches and muscle spasm were also treated with onabotulinumtoxinA. Initially injections were exceptionally pain-ful and anxiety provoking. Anxiety was reduced in subsequent injection

Figure 8.6 Keloid scar on the chest of a woman who had 8 years previously had a coronary artery bypass grafting procedure, and whose pain had not responded adequately for surgical resection of the keloid, or to injections of triamcinolone acetonide, or to the application of silicone gel.

Week zero Week zero Week 4

BOTULINUM TOXIN TYPE A TREATMENT FOR RAYNAUD’S 229

of particular benefit. Subcutaneous and intramuscular injections of onabotulinumtoxinA (a total of 120–400 units per session, about once a month) into the areas of discomfort in the right hand and arm gave substantial pain relief (for which the patient was very grateful) and also normalized skin color and temperature in the right hand and forearm within several minutes, but after one year of treatments there has not been any improvement in her ability to use the right hand. Even though the right hand remains useless, it is less of an impediment. It should be noted that reduction in pain and sensitivity has allowed this patient to take part in a greater range of activities of daily living and to participate more fully and effectively in physiotherapy and in society, so there has

sessions by pretreating this patient with 80 mg of oxyprenolol (a very lipid-soluble beta blocker, which crosses the blood–brain barrier quite well and attenuates the central effects of adrenaline) together with 4 mg of lorazepam, 1 to 2 hours before injection of onabotulinumtoxinA. Over the past several years, fentanyl 100 to 150 mcg administered intravenously 10 minutes before the injection sessions has been very helpful to reduce both anxiety and pain. Gradual improvement in the hyperalgesic component of her RSDS has also contributed to improved tolerance of the BoNTA injections.

The patient characterized her pain as coming predominantly from bone, and deep injections close to bone using a 30G 1-inch needle were

Figure 8.8 Pain in a hypertrophic scar on the upper chest after breast biopsy resolved in response to intralesional injection of onabotulinumtoxinA.

Week Zero - 3 cm painful and hypersensitivehypertrophic scar with a volume of about0.4 cc 10 months after breast biopsy.Injected with 20 units of onabotulinumtoxinA@ 1ml/100 units, 30 ga 1 inch needle.

Week 8 - 1 week after relapse of discomfort,8 weeks after 20 units of onabotulinumtoxinAinjected into a total volume of about 0.5 ml of scar.

Week 12 - 4 weeks after a second dose of20 units of onabotulinumtoxinA @ 1 ml/100 units.Completely pain free.

Onabotulinumtoxin A for painful hypertrophic scar

Figure 8.7 Chart illustrating gradual reduction in visual analog pain scores in response to injection of painful areas in the keloid scar with onabotulinumtoxinA.

100

90

80

70

60

50

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30

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0Pain with touch Pain at rest

Week Zero - 45units of Botoxentire scar

Week 4Painful sternal keloid: visual-analog pain scale

Week 4 Botox™25 units superior1/3 of scar only

Week 10 Botox™25 units superior1/3 of scar

Week 13 Botox™25 units superior1/3 of scar

Week 27 Botox™25 units superficial foritch only

Week 17 completely painfree - thrilled

230 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

3. the muscles are not antagonistic in action, as are the frontalis and the orbicularis oculi, but rather synergistic,

4. there is no way to determine how much, if any, of the onabotu-linumtoxinA is actually acting on the pectoralis minor as the onabotulinumtoxinA can diffuse widely in a three-dimensional plane unlike the forehead where there is the bony skull limiting diffusion.

Dr. Doris Hexsel (personal communication, July 2004), in a study of six women, was not able to obtain satisfactory results, and in two cases noted that the nipples hung lower.

On the other hand, Pérez-Atamoros has successfully achieved eleva-tion of the breasts when the nipples are projecting downward by inject-ing three doses of 15 units of onabotulinumtoxinA into the part of the pectoralis major which lies medial and inferior to the pectoralis minor (Fig. 8.10). In a series of 100 female patients between 30 and 55 years of age with different degrees of breast ptosis, elevation of the ptotic breast has been achieved, averaging 1.1 cm with the maximum elevation being 1.8 cm. Each patient was injected with onabotulinumtoxinA on only one side in this pilot study, with the contralateral side as control. Sixty-five of the 100 patients rated the results as good to very good, and 73 of the 100 patients would repeat the procedure. Pérez-Atamoros has noted that the best candidates are physically fit women between the ages of 30 and 55 years, with small or moderate-sized breasts. The dose recommended per breast is three injections ranging from 15 to 30 units of onabotulinumtoxinA each. The total dose in one application is 90 to 180 U. Approximately 89% of the study patients presented with asym-metry of the breasts before the treatment. It is important not to correct naturally occurring breast asymmetry by giving higher doses on one side of the chest or the other, but to inject the same total dose of ona-botulinumtoxinA on each side. Five patients had pain lasting longer than a week after treatment. Pérez-Atamoros has suggested that relax-ation of the inferior medial portion of the pectoralis major muscle allows the superior portion to lift the ptotic breast (Fig. 8.11). For a comparison of the injection sites used by Pérez-Atamoros and one of the authors (KCS) see Fig. 8.9.

The ideal candidates for this treatment seem to be non-obese women with slightly rounded shoulders or who are slightly stooped forward, with breasts of cup-size A or B. Older women, and those with larger breasts, tend to respond more slowly and to a lesser extent (Fig. 8.10).

The benefits of onabotulinumtoxinA treatment usually develop over a period of 1 to 2 weeks, and persist for 3 to 4 months (Fig. 8.12). The dura-tion of effect is somewhat longer than might be expected considering the

been an overall improvement in general functional ability. Treatment of the involved areas in the right lower leg and foot were also helpful. At times the total dose of onabotulinumtoxinA for treatment of headache and for treatment of RSDS in the right arm and leg reached 1,200 units per month. This was well tolerated. After about four years of treatment, her headaches, neck spasm, and RSDS in the right arm and lower leg improved to the point where onabotulinumtoxinA in those areas was stopped, and the dose of onabotulinumtoxinA declined to about 400 units every 2 to 3 months to control her headaches, neck spasm, and pain in the right shoulder.

This is consistent with the observations of Cordivari et al. ( 45 ), who noted that four out of four of their patients with dystonia-complex regional pain syndrome affecting the hand had pain relief after treat-ment with abobotulinumtoxinA, but only one of the four had func-tional improvement.

There is less concern now than in the past about the risk that a patient such as this, who was treated with high doses of onabotulinumtoxinA, will develop antibodies against the onabotulinumtoxinA formulation of BoNTA. Jankovic et al. ( 21 ) found that blocking antibodies were detected in 4 of 42 (9.5%) cervical dystonia patients treated only with the original onabotulinumtoxinA, but in none of the 119 patients ( p < 0.004) treated exclusively with the current onabotulinumtoxinA, which has been on the market since late 1997.

BoNTA for Improvement of Upper Thoracic Posture and “BOTOX ® Breast Lift” BoNTA has a long history of being used to improve posture in a variety of conditions ( 52 , 53 ). The position of the shoulders is determined largely by the balance of forces between the pectoralis minor and pectoralis major muscles ( Fig. 8.9 ), which tend to rotate the shoulders medially and to depress the shoulders and the opposing muscles of the back, for example the rhomboids. The use of onabotulinumtoxinA to improve upper thoracic posture and so improve the presentation of the female breast has been detailed in the previous edition of this textbook ( 54 ) by the present author (KCS) and by Dr. Francisco Pérez-Atamoros .

This proposed mechanism of action has been criticized by Dr Otto Wegelin (personal communication, April 2004), who argues that

1. the muscles (pectoralis minor and rhomboid minor) invoked to carry out the postural changes are far too small to do what is expected of them,

2. the muscles do not in fact rotate the shoulder but rather act primarily to stabilize the scapula,an entirely different function,

Figure 8.9 Typical injection sites for onabotulinumtoxinA treatment of the pectoralis minor and pectoralis major muscles.

Typical injection points fortreatment of pectoralisminor (10 units ofonabotulinumtoxinAat each point.) Kevin C. Smith, MD

Injection points fortreatment of pectoralismajor (15 units ofonabotulinumtoxinA at each point.)Francisco Pérez-Atamoros, MD

BOTULINUM TOXIN TYPE A TREATMENT FOR RAYNAUD’S 231

Some women have noted that not only are the breasts and nipples elevated by their more erect posture with shoulders back, but also that there is a pleasing outward projection of the nipples which develops about a week after the onabotulinumtoxinA treatment and persists for 3 to 4 months. The reasons for this are not known. Perhaps projection

relatively low doses of onabotulinumtoxinA in proportion to the size of the muscles. It may be that improvements in shoulder posture persist for a while once posture has been improved by onabotulinumtoxinA, alter-ing the balance of forces between the pectoralis minor and/or major muscles and the opposing muscles in the back (Fig. 8.11).

Figure 8.10 (A) A patient with symmetrically positioned breasts and nipples before receiving three injections of 15 units each of onabotulinumtoxinA into the right lower and medial aspect of the pectoralis major as indicated by the stars. (B) The same patient one month after the injection of onabotulinumtoxinA. Note the elevation of the right breast and nipple at approximately 1.1 cm elevation.

(A) (B)

Figure 8.12 (A) A patient with symmetrically positioned breasts but with the right breast slightly rotated laterally. She received 3 injections of 15 units each of onabotulinumtoxinA in the right lower and medial aspect of the pectoralis major. (B) Same patient one month after the injection of onabotulinumtoxinA. Notice the elevation of the breast and nipple on the side of approximately 1.3 cm.

(A) (B)

Figure 8.11 The areas in which onabotulinumtoxinA can be injected into the lower and medial aspect of the pectoralis major.

232 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

of the breasts as a result of improved shoulder posture leads to increased mechanical stimulation of the nipples under some circumstances. Another more speculative hypothesis is as follows: SP and CGRP have been demonstrated in neurovascular structures related to the nipple–areolar complex in animals (55) and in humans (56). BoNTA has been shown to block the release of SP and CGRP from nerve terminals. If some of the injected onabotulinumtoxinA makes its way from the injection sites to the nipple–areolar complex, it might affect smooth muscle in the nipples by way of its effect on the release of SP and CGRP.

OnabotulinumtoxinA is administered using a 30G 1-inch needle. Pneumothorax or bleeding has not been seen, and would not be expected with a 30G needle. The risk of entering the pleural space can be reduced by limiting needle insertion depth to less than 2 cm.

Recently it has been reported that the combination of BoNTA to relax muscles in the chest, when combined with a program of stretch-ing to relax the chest muscles and exercises to strengthen muscles in the back, can produce a higher response rate and a greater duration of effect on upper thoracic posture than treatment with BoNTA alone ( 57–59 ).

Issues which remain to be resolved include optimization of patient selection, onabotulinumtoxinA dosing, injection placement, the issue of placebo effect versus biomechanical effect, and elucidation of the mechanism of action if indeed there is a biomechanical effect from onabotulinum toxin A treatment of the pectoralis minor and/or pecto-ralis major muscles with onabotulinum toxin A ( 60 , 61 ). It is our posi-tion that until these issues have been addressed, the “BOTOX ® breast lift” will not be ready for commercialization as a medical procedure ( 62 ). T-2-weighted magnetic resonance imaging (MRI) before and immediately after exercise is being evaluated as a technique to visualize and perhaps partially quantify the degree of flaccid paralysis induced by onabotulinumtoxinA treatment ( 63 ).

Management of BoNTA OverdoseOverdoses of BoNTA are most commonly the result of accidental injec-tion of small quantities of BoNTA, causing unintended localized mus-cle weakness. In some cases this will be annoying for the patient, but will resolve in a matter of weeks or months without treatment. Resolu-tion in such cases may be accelerated if the patient tries to exercise the affected muscle as hard as possible for 5 minutes, five times a day.

If the local overdose is more serious (e.g., if an extraocular muscle has been injected) and if the mistake was immediately recognized, it might be possible to limit the uptake of BoNTA into the affected neu-rons by flooding the area with lidocaine. This might both dilute and wash away the injected BoNTA, and would also reduce or stop depolar-ization of the affected motor neurons, and so greatly reduces the expo-sure of the SV2 receptors that BoNTA binds to.

Because the uptake of BoNTA into motor neurons is an energy-dependent process, and considering that the rate of metabolic pro-cesses drops by about 50% for every 10°C reduction in temperature, it can also be useful in some circumstances to apply ice immediately after flooding the injected area with lidocaine, and to keep the injected area iced for a couple of hours. Pretreatment with lidocaine can directly reduce uptake of BoNTA as discussed above, and also reduces the dis-comfort that can result from the application of ice. Icing may reduce the temperature of the affected tissue from about 37°C to around 7°C, resulting in perhaps an eightfold reduction in the metabolic rate in the treated area (KCS, D Schachter, R Schachter, unpublished observations).

In a severe systemic intoxication with BoNTA, if the exposure was recognized almost immediately (e.g., in a laboratory or industrial accident), it might be beneficial to paralyze the patient temporarily in an intensive care unit setting using a medication like Pavulon®, and perhaps also to reduce the patient’s body temperature as much as possible while the BoNTA was being flushed out of the patient’s

system and while awaiting delivery of immunoglobin directed against BoNTA.

REFERENCES 1. Tsui JK, Eisen A, Mak E, et al. A pilot study on the use of botulinum

toxin in spasmodic torticollis. Can J Neurol Sci 1985; 12(4): 314–6. 2. Smith K, Alam M Botulinum toxin for pain relief and treatment of

headache. In: Carruthers A, Carruthers J, eds. Botulinum Toxin, 2nd edn. Philadelphia, PA: Elsevier, 2008: 93–104.

3. Smith KC, Goldberg D: Dermatologists Can Use Botulinum Toxin to Treat Headache. Point/Counterpoint. Practical Dermatology. August 2004.

4. Van Beek AL, Lim PK, Gear AJ, Pritzker MR. Management of vasospastic disorders with botulinum toxin A. Plast Reconstr Surg. 2007; 119(1): 217–26.

5. Stadlmaier E, Muller T, Hermann J, Graninger W. Raynaud’s phenomenon: Treatment with Botulinum toxin. Ann Rheum Dis 2005; 64 (supple III): 275.

6. Sycha T, Graninger M, Auff E, Schnider P. Botulinum toxin in the treatment of Raynaud’s phenomenon: a pilot study. Eur J Clin Invest. 2004; 34(4): 312–3.

7. Kossintseva I, Barankin B. Improvement in both Raynaud disease and hyperhidrosis in response to botulinum toxin type A treatment. J Cutan Med Surg 2008; 12(4): 189–93.

8. MacKenzie I, Burnstock G, Dolly JO. The effects of purified botu-linum neurotoxin type A on cholinergic, edrenergic and non-adrenergic, atropine-resistant autonomic neuromuscular transmission. Neuroscience 1982; 7: 997–1006.

9. Morris JL, Jobling P, Gibbins IL. Differential inhibition by botuli-num neurotoxin A of cotransmitters released from autonomic vasodilatior neurons. Am J Physiol Heart Circ Physiol 2001; 281: H2124–32.

10. Morris JL, Jobling P, Gibbins IL. Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons. Am J Physiol Heart Circ Physiol 2002; 283(6): H2627–35.

11. Ansiaux R, Baudelet C, Cron GO, et al. Botulinum toxin potentiates cancer radiotherapy and chemotherapy. Clin Cancer Res. 2006; 12(4): 1276–83.

12. Matic DB, Lee TY, Wells RG, Gan BS. The effects of botulinum toxin type A on muscle blood perfusion and metabolism. Plast Reconstr Surg. 2007; 120(7): 1823–33.

13. Oskarsson E, Piehl Aulin K, Gustafsson BE, Pettersson K. Improved intramuscular blood flow and normalized metabolism in lateral epicondylitis after botulinum toxin treatment. Scand J Med Sci Sports 2009; 19(3): 323–8.

14. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004; 107: 125–33.

15. Türk N., Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia Clin Neuropharmacol 2005;28(4):161–2.

16. Aurora S. Botulinum toxin type A for the treatment of migraine. Expert Opin Pharmacother 2006; 7(8): 1085–95.

17. Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000; 38: 245–58.

18. Rapp DE, Turk KW, Bales GT, Coock SP. Botulinum Toxin Type A inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 2006; 175: 1138–42.

19. Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 2004; 44: 35–43.

20. Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 1995; 197(1): 25–8.

BOTULINUM TOXIN TYPE A TREATMENT FOR RAYNAUD’S 233

21. Wheeler-Aceto H, Porreca F, Cowan A. The rat paw formalin test: comparison of noxious agents. Pain. 1990; 40(2): 229–38.

22. Kreyden OP, Scheidegger EP. Anatomy of the sweat glands, pharma-cology of botulinum toxin, and distinctive syndromes associated with hyperhidrosis. Clin Dermatol 2004; 22(1): 40–4.

23. Bansal C, Omlin KJ, Hayes CM, Rohrer TE. Novel cutaneous uses for botulinum toxin type A. J Cosmet Dermatol. 2006; 5(3): 268–72.

24. Martos Díaz P, Bances del Castillo R, Mancha de la Plata M. Clinical results in the management of Frey’s syndrome with injections of Botulinum toxin. Med Oral Patol Oral Cir Bucal 2008; 13(4): E248–52.

25. Capaccio P, Torretta S, Osio M, et al. Botulinum toxin therapy: a tempting tool in the management of salivary secretory disorders. Am J Otolaryngol 2008; 29(5): 333–8.

26. Laing TA, Laing ME, O’Sullivan ST. Botulinum toxin for treatment of glandular hypersecretory disorders. J Plast Reconstr Aesthet Surg. 2008; 61(9): 1024–8.

27. Hill SE, Mortimer NJ, Hitchcock B, Salmon PJ. Parotid fistula compli-cating surgical excision of a basal cell carcinoma: successful treatment with botulinum toxin type A. Dermatol Surg 2007; 33(11): 1365–7.

28. Lim YC, Choi EC. Treatment of an acute salivary fistula after parotid surgery: botulinum toxin type A injection as primary treatment. Eur Arch Otorhinolaryngol 2008; 265(2): 243–5.

29. Marchese-Ragona R, Marioni G, Restivo DA, Staffieri A. The role of botulinum toxin in postparotidectomy fistula treatment. A technical note. Am J Otolaryngol 2006; 27(3): 221–4.

30. Konrad H, Karamfilov T, Wollina U. Intracutaneous botulinum toxin A versus ablative therapy of Hailey-Hailey disease—a case report. J Cosmet Laser Ther 2001; 3(4): 181–4.

31. Koeyers WJ, Van Der Geer S, Krekels G. Botulinum toxin type A as an adjuvant treatment modality for extensive Hailey-Hailey disease. J Dermatolog Treat 2008; 19(4): 251–4.

32. Swartling C, Naver H, Lindberg M, Anveden I. Treatment of dyshidrotic hand dermatitis with intradermal botulinum toxin. J Am Acad Dermatol 2002; 47(5): 667–71.

33. Wollina U, Karamfilov T. Adjuvant botulinum toxin A in dyshidrotic hand eczema: a controlled prospective pilot study with left-right comparison. J Eur Acad Dermatol Venereol 2002; 16(1): 40–2.

34. Kontochristopoulos G, Gregoriou S, Agiasofitou E, et al. Letter: regression of relapsing dyshidrotic eczema after treatment of concomitant hyperhidrosis with botulinum toxin-A. Dermatol Surg 2007; 33(10): 1289–90.

35. Zanchi M, Favot F, Bizzarini M, et al. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol 2008; 22(4): 431–6.

36. Sifaki MK, Krueger-Krasagakis S, Koutsopoulos A, Evangelou GI, Tosca AD. Botulinum toxin type A—treatment of a patient with multiple cutaneous piloleiomyomas. Dermatology 2009; 218(1): 44–7.

37. Weinfeld PK. Successful treatment of notalgia paresthetica with botulinum toxin type A. Arch Dermatol. 2007;143(8):980–2.

38. Dong M, Yeh F, Tepp WH et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006; 312(5773): 592–6.

39. Hamdy S, Samir H, El-Sayed M, et al. Botulinum toxin: could it be an effective treatment for chronic tension-type headache? J Headache Pain 2009; 10: 27–34.

40. Mathew NT, Kailasam J, Meadors L. Predictors of response to botu-linum toxin type A (BoNTA) in chronic daily headache. Headache 2008; 4: 194–200.

41. Aurora SK, Gawel M, Brandes JL, et al. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, dou-ble-blind, placebo-controlled exploratory study. Headache 2007; 4: 486–99.

42. Blumenfeld A: Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders. Headache. 2003; 4:853–60.

43. Klein AW. The therapeutic potential of botulinum toxin. Dermatol Surg 2004; 30(3): 452–5.

44. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2003; 43 Suppl 1: S9–15.

45. Carruthers A, Carruthers J, Cohen J. Dilution volume of botulinum toxin type A for the treatment of glabellar rhytides: does it matter? Dermatol Surg. 2007; 33: S97–104.

46. Crowe R, Parkhouse N, McGrouther D. Neuropeptide-containing nerves in painful hypertrophic human scar tissue. Br J Dermatol 1994; 130(4): 444–52.

47. Takeba Y, Suzuki N, Kaneko A et al. Evidence for neural regula-tion of inflammatory synovial cell functions by secreting calcito-nin gene-related peptide and vasoactive intestinal peptide in patients with rheumatoid arthritis. Arthritis Rheum 1999; 42(11): 2418–29.

48. Hart DA, Reno C. Pregnancy alters the in vitro responsiveness of the rabbit medial collateral ligament to neuropeptides: effect on mRNA levels for growth factors, cytokines, iNOS, COX-2, metalloproteinases and TIMPs. Biochim Biophys Acta 1998; 1408(1): 35–43.

49. Jorgensen C, Sany J. Modulation of the immune response by the neuro-endocrine axis in rheumatoid arthritis. Clin Exp Rheumatol 1994; 12(4): 435–41.

50. Cordivari C, Misra VP, Catania S et al. Treatment of dystonic clenched fist with botulinum toxin. Mov Disord 2001; 16(5): 907–13.

51. Saenz A, Avellanet M, Garreta R. Use of botulinum toxin type A on orthopedics: a case report. Arch Phys Med Rehabil 2003; 84(7): 1085–6.

52. Traba Lopez A, Esteban A. Botulinum toxin in motor disorders: practical considerations with emphasis on interventional neuro-physiology. Neurophysiol Clin 2001; 31(4): 220–9.

53. Gallien P, Nicolas B, Petrilli S et al. Role for botulinum toxin in back pain treatment in adults with cerebral palsy: report of a case. Joint Bone Spine 2004; 71(1): 76–8.

54. Smith KC, Pérez-Atamoros F. Other dermatologic uses of botulinum toxin. In: Benedetto AV, ed. Botulinum Toxin in Clinical Dermatology. London: Taylor & Francis, 2006: 219–36.

55. Thulesen J, Rasmussen TN, Schmidt P, et al. Calcitonin gene-related peptide (CGRP) in the nipple of the rat mammary gland. Histo-chemistry 1994; 102(6): 437–44.

56. Eriksson M, Lindh B, Uvnas-Moberg K, et al. Distribution and origin of peptide-containing nerve fibres in the rat and human mammary gland. Neuroscience 1996; 70(1): 227–45.

57. Lang AM. Considerations for the use of Botulinum toxin in pain management. Case Management 2006; 11: 279–82.

58. Finkelstein I, Katsis E: Botulinum toxin type A (BotoxR) improves chronic tension-type headache by altering biomechanics in the cer-vico-thoracic area: a case study. Cephalalgia 2005; 25: 1189–1205.

59. Vad VB, Donatelli RA, Joshi M, Lang AM, Sims V. O.N.E.U.P. Cervico-thoracic and Lumbar Pain Syndromes Program. Beth Israel Medical Center, Office of Continuing Medical Education, 1st Avenue at 16 th St., New York, NY, 10003. Accessed January 2008.

60. Smith KC, Arndt KA. In: Alam M, Dover J, eds. Lifting with Neuro-modulators in Non-Surgical Skin Tightening and Lifting. Elsevier, 2008; 107–16.

61. Smith KC. Botulinum toxin A for upper thoracic posture and the appearance of a “breast lift.” In: Alam A, ed. Body Rejuvenation. London: Taylor and Francis, 2010; 77–82.

62. Cosmetic Injections Expand to Points Below the Chin, New York Times, January 26, 2006, http://www.nytimes.com/2006/01/26/fashion/thursdaystyles/26sside.html?_r=1&oref=slogin. Accessed October 7, 2007.

63. Smith KC, Ludwig D, Price T. Unpublished observations, August 2005.

234

750 kDa ( 9 ). The influence of the complexes once injected is really unknown, especially since dissociation occurs at physiologic pH. Ques-tions concerning field of effect, diffusion and onset of action of each toxin are not fully answered. We do know that each has different units of potency (BOTOX® units versus Dysport® units) and this has a major impact on its clinical significance.

Technical differences in the two products are less than the similari-ties. The complex size is as follows:

1. BOTOX® (onabotulinumtoxinA): 900 kDa 2. Dysport® (abobotulinumtoxinA): 500 to 700 kDa 3. Xeomin (oncobotulinumtoxinA): 150 kDa-naked neurotoxin 4. Purtox: 150 kDa-naked neurotoxin

Other differences are in the composition of the product, which is sum-marized in Table 8A.1 . Protein content is slightly greater in onabotulinum-toxinA with more serum albumin, but the carriers—NaCl and lactose—do differ; whether or not this makes a clinical difference is unknown.

THE CLINICAL STUDIES AbobotulinumtoxinA (i.e., Dysport ® ) was first studied for aesthetic usage in Europe by Ascher in the later 1990s and again by Ascher and Rzany in 2004 and 2006 ( 10 ). Ascher performed a multicenter, random-ized double-blind placebo controlled study of efficacy and safety of each dilutional doses of abobotulinumtoxinA for the treatment of glabellar lines. The 119 patients were from 18 to 70 years of age, with moderate to severe glabellar frown lines and no prior aesthetic treatment. The dos-ages used were placebo, 25, 50, and 75 units in a double-blind control. They were injected in five controlled glabellar sites targeting the obicu-laris oculi pars frontalis, the corrugators and the procerus muscle, each with appropriate divided units. Outcome measurements were assessed from blinded standardized photographs, investigator assessments, and patient evaluation. These were compared to a rating scale 0 to 4 of gla-bellar lines as follows: 0 = no lines; 1 = mild lines; 2 = moderate lines; 3 = severe lines. A responder was defined as 0:1 on the rating scale. The results indicated that all groups except placebo showed a response at 1 month and at 3 months. At 6 months, approximately two-thirds of the abobotulinumtoxinA-treated patients were still responders. Though the primary statistical analysis was performed at rest, the assessment at maximal frown was similar up to 3 months confirming the activity of abobotulinumtoxinA on the glabellar musculature.

The safety protocol was favorable with a 7.0% rate of adverse events, all mild and reversible. Headache was the most common with all resolv-ing within 2 to 10 days. There were no reported cases of blepharoptosis or diplopia. The conclusions indicated the abobotulinumtoxinA was an effective cosmetic treatment for glabellar lines as evaluated by indepen-dent photographic analysis and investigator assessment. The result suggested that 50 units was the optimal dosage for the glabella and with 10 units injected into each of five glabellar sites. Most interesting was the long-term result indicating that one-third of the patients treated were still responders at 6 months ( 11 ). Other studies by Asher have indicated similar results of efficacy and safety for abobotulinumtoxinA in other locations including the forehead and crow’s feet ( 12 ).

This was followed by the U.S. studies beginning in 2003 extending to the present. The Inamed, Ipsen, and Medicis studies included phase II, phase III single, and repeat dosage studies with at total of 2,300 patients assessed for efficacy and safety. All studies evaluate efficacy and safety of

9 Botulinum toxins-A other than BOTOX ® Gary D. Monheit

Botulinum toxin (BoNT) has evolved from the “most poisonous of all poisons” ( 1 ) to one of the most widely applied medical drugs within the last 60 years ( 2 ). The muscle-paralyzing activity of BoNT was first noticed in 1817 and subsequently has led to the hypothesis that small doses of BoNT could be beneficial in therapeutic uses. By now, several commercial preparations of botulinum toxin serotype A (BoNT-A) products are widely used for the treatment of strabismus, blepharo-spasm, cervical dystonia, and other conditions of excessive muscle con-traction. In recent years, the aesthetic uses have expanded remarkably since the Carruthers first investigated the usefulness of BoNT-A for glabellar frown lines ( 3 ).

Onabotulinum toxin (BOTOX ® , Allergan, Irvine, California) was first approved by the Food and Drug Administration (FDA) in 2002 for glabellar lines, but since then it has been applied off-label for other facial dynamic wrinkles and other aesthetic indications ( 4 ).

Abobotulinum toxin (Dysport ® ; Ipsen, Medicis US and Azzalure, Galderma, Europe) was first licensed for medical usage in Europe in 1990 ( 5 ). Clinical studies for esthetic indications were first performed in Europe 2002 and 2003, followed by U.S. FDA studies until 2009. FDA approval for treatment of glabellar frown lines occurred in May 2009.

Other BoNTA preparations now under consideration for aesthetic, usage include NT-201, now oncobotulinumtoxinA (Xeomin, Merz), Purtox (Mentor, California) and a topical BoNTA (Revance, California).

All of the preparations are BoNTA molecules, but there are some technical differences in the formulations. Most clinical properties seem to act the same. There may be some subtle differences the clinician must understand. It is thus important to review the science of the mol-ecule, its formulations, and its physiologic action to use each of the preparations correctly.

To use the new products correctly, it is necessary to understand the following points:

1. The science of the BoNTA molecule and its differences 2. The clinical studies demonstrating efficacy and safety 3. Differences in the two products 4. Experience in world wide usage

SCIENCE OF BOTULINUM TOXIN A The BoNTA molecule is a polypeptide with a light and a heavy chain actuated by “nicking” at the junction of the disulfide bond. This acti-vates the molecule to irreversibly bind to the presynaptic terminal of the neuromuscular junction, cleaving specific membrane proteins, thus blocking the exocytosis of acetylcholine. The BoNTA cleaves the SNAP-25 protein blocking the neuromuscular junction ( 6 ).

The toxin exists as a complex with a surrounding coat of protective proteins: the hemagglutinin and nontoxic nonhemagglutinin proteins. The surrounding complex protein can serve to protect the neurotoxin from its potential destruction by the low pH of stomach acid. On absorption as the pH becomes physiological the outer protein coat releases the neurotoxin ( 7 ). Similarly, the full complex found in the vial prior to injection (750 or 900 kDa) and upon injection dissociates to the naked 150 kDa neurotoxin molecule ( 8 ).

Though both the BOTOX® and Dysport® neurotoxin molecules are the same weight (150 kDa), the complexes are different sizes due to variations in production. BOTOX® is 900 kDa and Dysport® is

BOTULINUM TOXINS-A OTHER THAN BOTOX 235

glabellar frown lines with rating scales at rest and at maximal frown. The U.S. studies used the same injection points as the U.S. onabotulinum-toxinA trials and were evaluated at maximal frown as its end points. In Europe, end points for response were determined at rest for efficacy and the lateral corrugator injection points were placed 0.5 cm more medial. The results though for efficacy and safety for both studies were similar.

Phase II trials were a dosage ranging study including placebo, 20 units, 50 units, and 75 units. There was a 90% responder rate at both 50 and 75 U. All doses were well tolerated with only minor side effects including headache, needle pricks, and bruising but blepharop-tosis was observed in only three patients. Of those reported cases, only one demonstrated a true clinical ptosis to the investigator. Ptosis had been reported in other product studies but not in other studies involving abobotulinumtoxinA ( 13 ).

Antibody production has always been of concern with clinical usage of BoNTA, but studied only with cervical dystonia ( 14 ). None of the patients in this study showed any evidence of neutralizing antibodies either at baseline or on follow-up evaluations. From these observations, the 50-U dosage was recommended as the optimal dose for safety and efficacy. The lower dosage of 50 U was chosen for all of the phase III trials ( 15 ).

The initial single dosage, placebo-controlled, double-blinded, ran-domized trial of glabellar frown lines included over 400 subjects fol-lowed for 150 days ( 16 ). The patients were then enrolled in a repeat dosage trial for 23 months including four cycles of repeat dosage when the patient’s frown lines returned to baseline. The patients were evalu-ated for efficacy (i.e., number of responders at 30 days and duration of response) and safety. Over 90% responder rate was recorded at 30 days with duration at 4 months of 40% responders and at 5 months; 25% were still full responders ( 17 ). This produced a very similar efficacy case for responders and duration as onabotulinumtoxinA.

One factor reported by the subjects was an onset of action within 1 to 2 days. Subsequent studies have included a diary that the patient recorded when an onset of effect was first noted. In three of the studies the onset was recorded. Fifty percent of subjects noted an onset within 2 days and 80% noted it within 3 days ( 18 ). Though this was felt to be different from prior neurotoxins, true onset studies were not performed

to date with onabotulinumtoxinA. Reinjection treatment studies were performed to ensure that repeated exposure to the toxin did not influ-ence efficacy or duration.

The repeat administration studies involved 768 individuals from phase III clinical trials who received up to six repeated treatments over 17 months. A patient was reinjected when glabellar wrinkle lines returned to baseline. The patients were followed for efficacy and safety including adverse effects and assessment of serum-neutralizing anti-bodies to abobotulinumtoxinA. Results confirmed continued effective-ness throughout the study with no increase of active events and no patients developed neutralizing antibodies.

The possibility of blocking antibodies influencing efficacy and toxin action has been noted with large therapeutic doses given over years for treatment of spastic torticolis and cerebral palsy. Antibody blocking effect, as of this time, has not been recorded with the cosmetic use of abobotulinumtoxinA ( 19 ).

As the data of these initial trials were reviewed, it was noted that efficacy and duration of action for men was less than that for women on a 50-U dosage for treating the glabella. This observation stimulated a variable dose study, which stratified patients by race/ethnicity, sex, and random-ized by muscle mass. The muscle mass groups were to receive a single treatment of various doses of abobotulinumtoxinA. Abobotulinumtox-inA was administered as a single dose of 50, 60 or 70 U for women and 60, 70, or 80 U for men. This is based on procerus/corrugator muscle mass, small, medium, or large. Efficacy and duration was evaluated during a 5-month period. The results indicated that 87% of men and women had full efficacy at 30 days with a mean duration of 109 days for both men and women with no difference in ethnicity or gender ( 20 ).

Though clinicians have individualized abobotulinumtoxinA glabellar treatment as to sex, ethnicity, and muscle mass in clinical practice, this is the first controlled clinical study to verify this common practice.

DIFFERENCES IN THE BoNTA PRODUCTS As the science of BoNTA and the clinical studies are very similar, what are the differences? The real differences have to do with manufacturing, dosage measurement, and what is in the vial.

The first real difference is in how treatment units are measured. The Dysport® units (DU) are measured differently from the BOTOX ® units (BU) and are not interchangeable. Because these are proprietary mea-surements, a unit-to-unit measurement is an estimate. The current assessment is 2.5 DU versus 1.0 BU with a range of 2 or 3 to 1. This can give some guidance to the novice user but one should learn to think and treat using individual units—as one learns a foreign language—and not convert for usage.

The vial of each product is slightly different ( Table 9.1 ). The major difference is the number of units in each. AbobotulinumtoxinA has 300 DUs in the United States and 500 U throughout the rest of the world, while onabotulinumtoxinA has 100 BUs. Both have albumin while abobotulinumtoxinA has lactose as a carrier and onabotulinumtoxinA has NaCl.

Most other differences found with treatment have to do with the clinicians’ injection technique when utilizing the product in individual patients. This produces variability as to dosage, dilution, and technique of injection. These variables are pertinent to both products.

Questions still asked concern a direct unit to unit ratio and differences of effect with similar units injected. As of this time, there are no direct comparisons of the units of biologic activity. Because of this the “head to head” studies performed for duration, efficacy and “diffusion” are imper-fect and results are difficult to interpret. The anhidrotic halo study by De Almeida was a 3 to1 ratio giving a greater field of effect for abobotu-linumtoxinA ( 21 ) while a similar study by Hexsel using a 2.5 to 1 ratio revealed similar fields of effect ( 22 ). The answer probably lies in the fact

Table 9.1 Constituent of Botulinum Toxin A

Dysport® BOTOX® cosmetic

Vial Size 300 U 100 Ua

Composition Clostridium botulinum toxin

type A hemagglutinin

complex

Clostridium botulinum toxin

type A hemagglutinin

complex125 µg (0.125 mg) human

serum albumin

500 µg (0.5 mg) human

serum albumin2.5 mg lactose 0.9 mg sodium chloride

Molecular

Weight

(neurotoxin)

150 kDa 150 kDa

Bulk active

substance

(total protein

content)

∼3 ng ∼5 ng

Storage

(post-

reconstitution)

2°C to 8°C/until vial expiration

(2°C to 8°C/use within

4 hours)

2°C to 8°C/36 months

(2°C to 8°C / use within

4 hours)

aBOTOX® Cosmetic is also available in a 50 U vial. The 100 U vial is referenced in this comparison.

Dysport® [package insert]. Scottsdale, AZ: Medicis Aesthetics Inc. 2009.BOTOX® Cosmetic [package insert]. Irvine, CA: Allergan, Inc. 2002.

236 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

that spread in field of effect is related more to dosage, dilution, and tech-nique rather than intrinsic differences in the toxin or its preparation.

PRODUCT EXPERIENCE AbobotulinumtoxinA has been used world wide for aesthetic needs for over 10 years. Those clinicians who have the greatest experience have defined injection points, minimal dosage, and a range of doses for each of the facial areas.

Both glabella and crow’s feet have been well studied by Asher with results comparable to onabotulinumtoxinA ( 23 ). Forehead, eyebrows, and full upper face are successfully treated with abobotulinumtoxinA in a similar fashion to onabotulinumtoxinA.

Volume injected is an important variable and varies as to physician preference. Common dilutions for 1 vial, 300 U of abobotulinum-toxinA are 1.5 ml or 2.5 ml, though some physicians prefer 3.0 ml. A 1.5 ml dilution will give 20 units on the 0.1 ml scale of a 1.0 ml tuber-culin syringe, while a 3.0 ml dilution yields 10 units on the 0.1 ml scale, similar to onabotulinumtoxinA. It is recommended that the physician beginning abobotulinumtoxinA treatment use the 1.5 ml dilution, the most concentrated form to limit field of effect until he is familiar with the product. Experienced practitioners though use many off-label dilu-tions from 1.5 to 3.0 ml successfully. It is best for the physician to keep dilution a constant and vary the dosage as to patient needs.

AbobotulinumtoxinA has been used in clinical cosmetic practice worldwide over the last 10 years with similar injection points and tech-niques as onabotulinumtoxinA, but with different dosages. A full understanding of anatomy and product effect on distinctive facial muscles is essential for ensuring optimal treatment results and should be acquired through proper training. Since there are only a few clinical studies concerning off-label indications, an international consensus conference was held in Paris in January 2009, which provided general guidelines for effective and safe use of abobotulinumtoxinA on the generally useful yet off-label sites for injection. These have included the common upper face sites: the glabella, forehead, brow, crow’s feet and eyelid; and other less common facial sites including bunny lines, depressor angularis oris, obicularis oris, mentalis, and platysma. These recommendations gave guidelines to beginning dosage and range for each site as well as injection points and technique. Those physicians attending the summit include the following:

on practice experience of the physician using onabotulinumtoxinA. The author has preferred the more concentrated dilution as experience with U.S. clinical trials has used the 1.5 cc dilution. Table 9.2 lists the dosages recommended for upper face with injection points described in the figures ( Figs. 9.1–9.5 ) .

The forehead is best treated through five injection sites located at midforehead at a distance of at least 2.5 cm above the brow. A dosage of 40 to 60 DU of abobotulinumtoxinA is effective for forehead wrinkle relaxation. The lateral forehead injection site should be above the highest point of the outer one-third of the brow. This will prevent an undesirable lateral brow elevation, the “Mephisto look” ( 24 ).

Laugh lines or crow’s feet are treated with 30 abobotulinumtoxinA injected lateral to each orbital rim, but not inferior to the orbital rim. The injection sites are 1.0 cm lateral to the orbital rim in the three posi-tions, representing the muscle bulges, superior, mid, and inferior. Care must be taken not to inject below the orbital rim as lip ptosis or asym-metry may result from the zygomaticus muscle.

Lower eyelid wrinkles formed from an overactive or hypertrophic orbicularis oculi can be treated judiciously with 3 to 4 DU of abotu-linumtoxinA injected in the lower lid at the mid papillary line 2 to 3 mm below the tarsal plate. This will flatten the bulging muscle and create an image of “open eye.” Overaggressive treatment may, though, create an unwanted ectropion ( 24 ).

Treatment of the lower face should be performed with more precau-tion as overdosage leads to significant dysfunction of obicularis oris creating an asymmetric smile and oral aperture. I would also recom-mend the more concentrated dilution of 1.5 cc saline per 300 unit vial to titrate, the toxin for contouring within appropriated muscles. Dosage recommendations in the lower face are given in Table 9.3 .

As with onabotulinumtoxinA treatment, the physician must have a thorough understanding of facial musculature and the balance between elevator and depressor muscles. It is especially important in the lower face to be familiar with the anatomy and function of the facial muscles. Injections in or near many perioral muscles can cause facial asymmetry with expression. Because the field of effect is influenced by volume, the 1.5 cc dilution is recommended to limit abobotulinumtoxinA effect to the muscles injected.

AbobotulinumtoxinA can be used for elevation of the oral commis-sure by injecting the depressor angularis oris (DAO) with 10 DU of abobotulinumtoxinA (Fig. 9.6). The mentalis can be treated with 10 U to suppress chin dimpling (Fig. 9.7). Care is taken to keep both of these injections away form the depressor labialis inferioris. Platysma injec-tions for bands use 5 DUs of abobotulinumtoxinA per injection with a total of 20 DU per band. This is a superficial injection spaced out at 1 cm intervals along the platysmal band (Fig. 9.8).

As aesthetic physicians become familiar with this second botulinum toxin product in the United States, new innovations and techniques will evolve and new data beyond the clinical trials will emerge. It is said the real clinical trial for a drug or device occurs in the first 2 years after release. It is with the large usage numbers that we gain a further under-standing of both efficacy and safety.

International Board of Botulinum Toxin January 12–13, 2009

Paris, France

1. Benjamin Ascher: Chairman, France

2. Sergio Talarico: Co-Chairman, Brazil

3. Daniel Cassuto: Italy

4. Sergio Escobar: Argentina

5. Doris Hexsel: Brazil

6. Pedro Jaen Olasolo: Spain

7. Gary Monheit: United States

8. Berthold Rzany: Germany

9. Maurizio Viel: London

10. Alexandre Kaoukhov: France/Galderma Research

Sponsoring: Galderma

Ipsen

Table 9.2 Recommended Dysport® Dosage for Upper Face

IndicationsTotal usual dose (Dysport® units)

Dose range (Dysport® units)

Glabella 50 30–70Forehead 40–50 40–70Crows’ feet 30 × 2 20–50 × 2Lateral eyebrow lift 20 × 2 20–40 × 2Glabella and forehead 90–100 70–140Glabella and lateral eyebrow

lift

90 50–110

Complete upper third face 150 110–240

Conversion ratio and dilution should be a constant for a physician’s practice and dosage adjusted to individual needs. Dilution for a 300 U vial of abobotulinumtoxinA has been 1.5 cc of nonpreserved saline for the clinical trials. Other dilutions have been 2.5 and 3.0 cc, depending

BOTULINUM TOXINS-A OTHER THAN BOTOX 237

Figure 9.1 Glabella dosage dependent on muscle mass.

Mild Moderate

Severe

= 5 DUs= 10 DUs

DU = Dysport® units

Figure 9.3 Injection sites for forehead.

= 10 DUs= 5 DUs

DU = Dysport® units

Figure 9.4 Injection sites for crows’ feet.

= 10 DUs

DU = Dysport® units

Figure 9.5 Injection sites for lateral eyebrow lift and upper face.

Dilution = 1.5= 5 DUs= 10 DUs

DU = Dysport® units

Figure 9.2 Injection sites for glabella.

= 10 DUsDU = Dysport® units

238 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

NON-COMPLEXED (NAKED) AND TOPICAL BOTULINUM TOXIN Other BoNTA products under development include Xeomin/NT-201 (Merz Pharmaceuticals, Frankfurt, Germany) and Purtox (Mentor, Santa Barbara, California). Both products are naked 150 kDa molecules without accessory proteins. Advantages may be the lack of accessory proteins, which may be antigenic. Immune response to the proteins can lead to a lack of clinical response, thus the use of the “pure” 150 kDa molecules may prevent this.

OncobotulinumtoxinA has been studied in Europe with clinical tri-als and now has been released for cosmetic usage in Germany and Eng-land. It is undergoing phase II trial in the United States. Trials in Europe have found oncobotulinumtoxinA similar in units, dosage, and potency as onabotulinumtoxinA. It has an onset within 2 days and a duration of 110 days and there was very little difference in adverse events compared to onabotulinum toxinA and abobotulinumtoxinA.

Purtox also is a 150 kDa pure neurotoxin without accessory proteins. It has undergone Phase I and Phase II clinical trials in the United States and found to have a 1- to 2-day onset with similar duration, efficacy, and safety record similar to the other toxins discussed. It is now under-going phase III clinical trials.

A topically applied botulinum toxin without accessory proteins is currently under development by Revance Therapeutics Company. The botulinum molecule is transported through the skin by a proprietary, noncovalently bonded transport peptide. This molecular biology-based approach to topical drug delivery utilized a positively charged peptide combined with protein transduction domains (PTD). Through an active cellular transport mechanism, the peptide/PTD complex facilitates the transdermal flux of the naked BoNTA molecule across epidermis and then passively through dermis to muscle ( 25 ).

The very first studies were performed in 2007 by Dr. Richard Glogau using crow’s feet or lateral canthal wrinkle lines. The in-patient study of 12 subjects using the opposing side as a control demonstrated an active decrease in muscle activity by 65%.

The Phase II study for facial aesthetics comprised 532 subjects (377 with the active compound-RT001 and 155 subjects as control) evalu-ated for efficacy and safety. The FDA study demonstrated 70% 1-point improvement on the wrinkle severity scale at rest 4 weeks post treat-ment with a 30% 2-point improvement at therapeutic dosages. The safety profile revealed no significant adverse events ( 26 ). The Phase III trials are now underway.

Though the topical approach may not be applicable for dynamic wrinkles controlled by deeper muscles such as glabella, the superficial muscle penetration alone may play a significant role in treating eyelids, forehead, and lips without muscular side-effects from deeper penetra-tion. In addition, its usage for hyperhidrosis, skin texture from pores and acne control all are uses the topical preparation may correct.

Within the last year, there are now two neurotoxins available for the aesthetic physician in the United States to treat cosmetic patients. Two additional toxins will be available within the next five years. Physicians will have a choice of products to use in specific facial areas.

Table 9.3 Recommended Dysport® Dosage for Lower Face

IndicationsTotal usual dose (Dysport® units)

Dose range (Dysport® units)

Obicularis oris 2.5 per injection point 10–15 units totalDepressor angularis

oris

5–10 units per site 10–20 units

Mentalis 5–10 units per site 10–20 unitsPlatysma 5–10 units per injection

point

20–40 units. Maximum

total dosage 50/side

Figure 9.6 Injection sites for depressor angularis oris.

= 5–10 DUsDU = Dysport® units

Figure 9.7 Injection sites for mentalis, (either the two blue sites or the one red site would be used).

= 5–10 DUs= 10 DUs

DU = Dysport® units

Figure 9.8 Injection sites for platysma.

= 5–10 DUsDU = Dysport® units

BOTULINUM TOXINS-A OTHER THAN BOTOX 239

REFERENCES 1. Schantz EJ, Johnson EA. Botulinum toxin: the story of its devel-

opment for the treatment of human disease. Perspect Biol Med 1997; 40(3): 317–27.

2. American Society for Aesthetic Plastic Surgery 2008 Cosmetic Surgery National Data Bank Statistics. Accessed at www.surgery.org. Accessed July 7, 2009.

3. Carruthers JA, Lowe NJ, Menter MA, et al., BOTOX Glabellar Lines I Study Group. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Der-matol 2002; 46(6): 840–9.

4. BOTOX Cosmetic [package insert]. Irvine, CA: Allergan, Inc. 2008.

5. DYSPORT [package insert]. Scottsdale, AZ: Medicis Aesthetics Inc. 2009.

6. Simpson LL. Peripheral actions of the botulinum toxins. In: LL Simpson, ed. Botulinum Neurotoxin and Tetanus Toxin. San Diego, CA: Academic Press, 1989: 153–78.

7. Eisele KH, Taylor HV. Dissociation of the 900 kDa neurotoxin complex from C. botulinum under physiological conditions. Poster presented at: Toxins 2008; June 12–14, 2008; Baveno, Lake Maggiore, Italy.

8. Pickett A. Diffusion of Type A Botulinum Toxin. Presented at the International Masters Course on Aging Skin; January 8–11, 2009. Paris, France.

9. Hasegawa K, Watanabe T, Suzuki T, et al. A novel subunit struc-ture of Clostridium botulinum serotype D toxin complex with three extended arms. J Biol Chem 2007; 282(34): 24777–83.

10. Ascher B, Zakine B, Kestemont P, et al. A multicenter, random-ized, double-blind, placebo-controlled study of efficacy and safety of 3 doses of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2004; 51(2): 223–33.

11. Vandenbergh PYK, Lison DF. Dose standardization of botulinum toxin. Adv Neurol 1998; 78: 231–5.

12. Ascher B, Klop P, Marion MH. Botulinum toxin in the treat-ment of frontoglabellar and periorbital wrinkles. J Med Est Chir Dermatol 1994; 21(XX1): 161–8.

13. Kessler KR, Skutta M, Benecke R. Long-term treatment of cervi-cal dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group. J Neurol. 1999; 246(4): 265–74.

14. Carruthers J, Lowe NJ, Mentor MA, Gibson J. Double-blind placebo-controlled study of the safety and efficacy of Botulinum

toxin type A for patients with glabellar lines. Plastic Reconstr Surg 2003; 112: 1089–98.

15. Monheit G, Carruthers A, Brandt F, Rand R. A Randomized, dou-ble blind, placebo controlled study of botulinum toxin A for the treatment of glabellar lines: Determination of optimal dose. Der-matologic Surgery. 2007; 33: 51–9.

16. Carruthers J, Fagien S, Matarasso SL. Consensus recommenda-tions on the use of botulinum toxin type A in facial aesthetics. Plast Reconstr Surg 2004; 114 (Suppl 1): S1–22.

17. Ascher B, Rzany BJ, Grover R. Efficacy and safety of botulinum toxin type A in the treatment of lateral crow’s feet: double-blind, placebo-controlled, dose-ranging study. Dermatol Surg 2009; 35: 1478–86.

18. Monheit G, Cohen J, Reloxin Investigational Group. Long-term safety of repeated administration of a new formulation of botuli-num toxin type A in the treatment of glabellar lines: Interim analysis from an open-label extension study. J Am Acad Derm 2009; 61(3): 421–5.

19. Rubin M, Dover J, Glogau R, et al. The efficacy and safety of a new US botulinum toxin type A in the retreatment of glabellar lines fol-lowing open-label treatment. J Drugs Dermatol 2009; 8(5): 439–44.

20. Kane MA, Brandt F, Rohrich RJ, et al. Reloxin Investigational Group. Evaluation of variable-dose treatment with a new U.S. Botulinum Toxin Type A (Dysport) for correction of moderate to severe glabellar lines: results from a phase III, randomized, double-blind, placebo-controlled study. In press.

21. De Almeida A, Marques E, De Almeida J, Cunha T, Boraso R. Pilot study comparing the diffusion of two formulations of botulinum toxin type A in patients with forehead hyperhidrosis. Dermatol Surg 2007; 33(1 Spec No.): S37–43.

22. Hexsel D, Dal’Forno T, Hexsel C, Do Prado DZ, Lima MM. A ran-domized pilot study comparing the action halos of two commercial preparations of botulinum toxin type A. Dermatol Surg 2008; 34(1): 52–9.

23. Ascher B, Zakine B, Kestemont P, et al. A multicenter, randomized, double-blind, placebo-controlled study of efficacy and safety of 3 doses of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2004; 51(2): 223–33.

24. Rzany B. Botulinum toxin A in cosmetic dermatology. Kosmetische Medizin 2003; 24:2: 72–9.

25. Kane M. Topical Botulinum Toxin. Oral Presentation. Interna-tional Master Course on Aging Skin, Paris, January 9, 2010.

26. Monheit GD. USA Botulinum Toxin Trials. Oral Presentation. International Master Course on Aging Skin, Paris, January 10, 2010.

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fusion to the presynaptic membrane of human motor neurons Tis responsible for flaccid paralysis associated with botulism. Each sero-type cleaves a specific residue on one of the SNARE proteins. RimabotulinumtoxinB cleaves vesicle associated membrane protein (VAMP) also known as synaptobrevin. Serotypes F, G, D also cleave VAMP, but at different locations ( Table 10.1 ) ( 19 ). Different cites of action of various serotypes may contribute to the differences in clini-cal efficacy. SNARE proteins are thought to be the primary and per-haps only intracellular targets of BoNT serotypes. The remarkable specificity of the BoNT light chain cleavage results from the LC’s rec-ognition of unusually long SNARE sequences ( ∼ 30 to 50 residues depending on the serotype) ( Fig. 10.1 ).

The medical applications of rimabotulinumtoxinB are not limited to motor neurons, and this toxin can enter many types of neurons in the central nervous system. A major focus has been to identify the recep-tors and pathways for rimabotulinumtoxinB recognition and entry into neurons. Research done by Dong et al. has established synaptotag-mins (Syts) I and II function as protein receptors for rimabotulinum-toxinB utilizing Syt I and II knockout mice ( 53 ). Additionally the same group established that mice lacking gangliosides are less sensitive to rimabotulinumtoxinB entry, supporting the theory that gangliosides act as a coreceptor with Syt I and II for rimabotulinumtoxinB entry into neurons ( 53 ).

IMMUNORESISTANCE As an injected foreign protein, any botulinum toxin is capable of elicit-ing an immune response ( 20 ). Treated patients can potentially develop neutralizing antibodies that inactivate the toxin’s clinical effects. When neutralizing antibodies are formed against either BoNT molecule, the therapeutic effect of the BoNT may be considerably or completely reduced. Clinical resistance has been reported in 3% to 5% of patients with cervical dystonia who were treated with BoNTA doses of 100 to 1,200 U, based on retrospective studies ( 21 , 22 ). Antibody formation to other parts of the complex is not believed to affect clinical performance of these products. The risk of antibody formation is expected to be much lower in patients treated for aesthetic purposes because they require significantly lower doses than do patients with cervical dysto-nia. Since the botulinum toxin serotypes were not believed to cross-neutralize, patients who become resistant to one serotype may benefit from treatment with another serotype. In studies of patients with cer-vical dystonia, BoNTA-resistant patients have been found to respond to treatment with rimabotulinumtoxinB. It should also follow that patients resistant to rimabotulinumtoxinB can benefit from BoNTA or any other botulinum toxin serotype. However, recent research has pointed to the possibility of the resistance to one serotype potentiating the development of resistance to the other with a series of injections. The most significant risk factors associated with development of cross-resistant antibodies include injections of high doses of neurotoxin, increased frequency of administration, and the amount of neurotoxin protein delivered in each injection ( 23–27 ).

A summary of immunogenicity factors associated with rimabotu-linumtoxinB is presented in Table 10.2 .

FORMULATION RimabotulinumtoxinB is produced as a ready-to-use liquid formulation set at a pH of 5.6 to stabilize the complex. Due to elevated acidity

10 Botulinum toxin B Neil S. Sadick and Yekaterina Kupava

INTRODUCTION The formation of glabellar lines is associated with repeated pulling of the skin by the underlying musculature. Movement of the transverse head of the corrugator supercilii muscle produces the vertical glabellar line, while the oblique head of the corrugator supercilii and the depres-sor supercilii and orbicularis oculi muscles contribute to the formation of the oblique glabellar line ( 1–3 ). Treatments designed to minimize the appearance of glabellar lines include dermabrasion, chemical peel, and injection of collagen, silicone, autologous fat or dermis, or polytetra fluoroethylene. Surgical options include endoscopy or limited incision to modify function of the corrugator supercilii and procerus muscles, and direct excision of the glabellar line ( 1 , 4 ).

In 1992, the Carruthers’ evaluated the use of Clostridium botulinum type A purified neurotoxin complex (onabotulinumtoxinA; BOTOX ® , Allergan Inc., Irvine, CA) to chemically denervate the corrugator super-cilii to treat glabellar wrinkles ( 5 ). Botulinum toxin blocks the release of acetylcholine from motor nerve endings, producing decrease in muscle tone, causing weakness or paralysis depending on dose and subsequent reduction of muscle overactivity. The Carruthers’ determined that botulinum toxin provided a safe treatment that addressed the underly-ing muscle activity contributing to the formation of wrinkle lines. Their results have been corroborated by other studies, and BoNTA is now cleared by the Food and Drug Administration (FDA) for use in improv-ing the appearance of moderate to severe glabellar lines ( 6–8 ).

An antigenically distinct serotype, botulinum toxin type B (BoNTB; Myobloc ® in the USA and Neurobloc ® in Europe; otherwise identified as rimabotulinumtoxinB henceforth, Solstice Neurosciences, South San Francisco, CA) was cleared in 2000 for treating the abnormal head position and related pain of cervical dystonia. It is currently being investigated in a variety of other disorders as well as in the setting of cosmetic dermatology. RimabotulinumtoxinB is available as a ready-to-use liquid formulation (requiring no reconstitution as is necessary with BoNTA) ( 9–14 ).

PHARMACOLOGY OF BOTULINUM TOXIN B The BoNTA complex has a total molecular weight of approximately 900 kDa, whereas rimabotulinumtoxinB is approximately 700 kDa. These large botulinum toxin complexes are most stable in slightly acidic conditions (pH 5 to 7) and dissociate in alkaline conditions ( Table 10.1 ). Within the large neurotoxin complex, which includes associated proteins (a hemagglutinin and a nontoxic, nonhemaggluti-nin moiety) the active neurotoxin exists as a 150 kDa dichain molecule consisting of a heavy chain (approximately 100 kDa) and a light chain (LC) (approximately 50 kDa) linked by a disulfide bond ( 15 ).

The action of rimabotulinumtoxinB upon neurons has features which all BoNTs share. Cellular intoxication is a three-step process that includes binding, internalization, and inhibition of acetylcholine release ( Fig. 10.1 ). The heavy chain is responsible for irreversible bind-ing of the toxin to serotype-specific acceptor sites on the neuronal cell membrane ( 16 ). Next, the toxin is internalized through receptor- mediated endocytosis ( 17 ). Once inside the cell, the light chain of toxin is released and targets a specific protein within the soluble N -ethyl maleimide-sensitive factor attachment protein receptor (SNARE) complex, which is involved in release of acetylcholine-containing vesi-cles from the presynaptic neuron ( 18 ). The light chain-mediated prote-olysis of SNARE proteins and consequent inhibition of synaptic vesicle

BOTULINUM TOXIN B 241

Table 10.1 Pharmacology of Botulinum Toxin Serotypes by Target Size and Cleavage Sites

Serotype Target size Cleaves at

A SNAP-25a Gln197–Arg198B VAMPb Glu76–Phe77C Syntaxin Lys253–Ala254

Lys252–Ala252SNAP-25a Arg198–Ala199

D VAMPb Ala67–Asp68Lys59–Leu60

E SNAP-25a Arg180–Ile181F VAMPb Gln58–Lys59G VAMPb Ala81–Ala82

aSNAP-25 is soluble NSF attachment protein of 25,000 kDa.bVAMP is vesicle-associated membrane protein (synaptobrevin).

injections with rimabotulinumtoxinB may be slightly more painful than with BoNTA. RimabotulinumtoxinB is available in vials of 2,500, 5,000 and 10,000 U each with a concentration of 5,000 U/ml or 500 U per 0.1 ml ( Table 10.3 ). This preparation can be diluted up to sixfold without losing any activity ( 20 ). Specifically, one unit is defined as the amount of toxin that is lethal in 50% of female Swiss-Webster mice after intraperitoneal injection (Mouse LD50 bioassay). However, because of variations between products in the sensitivity of different species to each toxin serotype, as well as differences in the potency assays used, different toxin products cannot be directly compared on a unit by unit basis. Individualized dose-ranging studies in humans are necessary for each toxin serotype, for each indication, and dose conver-sion should not be attempted (see package inserts for both BoNTA and rimabotulinumtoxinB).

RimabotulinumtoxinB is stored refrigerated at 2 ° C to 8 ° C and is stable in this environment for up to 3 years. Studies have also shown that when stored at room temperature (25 ° C), rimabotulinumtoxinB

is stable for at least 9 months. In addition, rimabotulinumtoxinB has been found to retain activity when stored refrigerated for 21 months and then moved to room temperature for 6 months, or then stored at room temperature for 6 months and then moved to 4 ° C. Rimabotu-linumtoxinB diluted up to sixfold with either nonpreserved or pre-served saline remains stable and retains potency for at least 24 hours at room temperature, even though the package insert suggests that it be used within 4 hours.

AESTHETIC USE OF BOTULINUM TOXIN B RimabotulinumtoxinB has many proposed therapeutic indications, all of which are off label except for cervical dystonia. The bulk of data and experience resides with BoNTA and has confirmed the effectiveness of this agent for facial wrinkles ( 28–39 ). Recently rimabotulinumtoxinB has also been investigated in the treatment for facial wrinkles, with results demonstrating efficacy for this indication ( Fig. 10.2 ). Highlights of some of the key clinical studies with respect to the use of these agents for aesthetic purposes are reviewed below.

CLINICAL STUDIES OF BOTULINUM TOXIN B Despite its FDA clearance solely for cervical dystonia, rimabotulinum-toxinB has been evaluated in several clinical trials for use in aesthetic medicine. Clinical trials in this setting have mostly been dose ranging and open label in terms of study design ( 40–45 ).

Ramirez et al. evaluated rimabotulinumtoxinB in 24 subjects with facial wrinkles. Most subjects (82%) had been treated with BoNTA previously, although not within the 6 months before the study ( 40 ). Subjects received 200 to 400 U of rimabotulinumtoxinB per unilateral injection site (total dose, 400 to 800 U). Three sites were injected, including the frontalis, the corrugators, and the orbicularis oculi. Improvement in facial wrinkles was assessed using two scales: the Wrinkle Improvement Scale (WIS; 0 indicates no improvement and 3 indicates significant improvement) and the Rated Numeric Kinetic Line Scale (RNKLS). During the study, the RNKLS was added to more objectively characterize wrinkle severity. This scale encompasses a

Figure 10.1 Pharmacology of botulinum toxins at the neuromuscular junction. SNAP-25 is the target for the type A toxin (red arrow), synaptobrevin is the target for the type B toxin (black arrow).

Botulinum toxin sites of action

SNARE Proteins

Pre-synapticnerve

surface

BoNT-E C AA

Acetylcholinevesicle

BoNT-D, F

BoNT-CSynapse Nerve terminal

SNAP-25

Syntaxin

Synaptobrevin-2 (VAMP)

BoNT-G

BoNT- B

242 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

description of wrinkles both at rest and at maximum frown. It ranges from a score of 1, reflecting no wrinkles at rest, which become fine lines with facial animation, to a score of 4, denoting deep lines at rest, which become deep furrows with facial animation. Subjects were eval-uated in repose and animation before injection and after injection at weeks 1, 2, 4, 8, and 12. Photographs were also obtained. All subjects had a relatively rapid onset of nearly complete paresis within 72 hours and, in many cases, within 24 hours. Scores on the WIS and RNKLS were moderately to significantly improved by 2 to 3 points after

rimabotulinumtoxinB treatment. However, the duration of effect was suboptimal (mean of 8 weeks). No subjects reported dysphagia, dyspepsia, or dry mouth, which are common side effects seen in treat-ment of cervical dystonia. Eyelid ptosis, brow ptosis, and dry eye were not measured. This preliminary study showed that rimabotulinum-toxinB is effective in treating facial lines of the glabella, forehead, and crow’s feet areas, but the authors concluded that doses higher than 400 to 800 U would be necessary for a longer duration of action.

The above study also evaluated the subjects for pain associated with injection, using the McGill Pain Scale. Pain on injection, usually described as a slight stinging sensation, has been reported to occur with BoNT injections. The McGill Pain Scale is a validated scale rang-ing from 0, signifying no pain to 5, signifying excruciating pain. At the time of treatment, subjects were asked to rate the pain of rimabotulinumtoxinB injection and to rate by memory the pain of BoNTA injection. On average, rimabotulinumtoxinB was found to be slightly more painful than the memory of BoNTA injection (2.3 vs. 1.6 respectively), although all subjects indicated that the injection pain would not prevent them from undergoing a repeat injection with rimabotulinumtoxinB.

A much smaller open-label study investigated preliminary doses of rimabotulinumtoxinB and also compared the effects of the drug with those of BoNTA in the treatment of glabellar lines ( 41 ). Subjects received 1,000 U ( N = 4) or 2,000 U ( N = 4) of rimabotulinumtoxinB or 20 U of BoNTA ( N = 5), divided equally over five sites (one injection at the procerus muscle and two injections each at the inferior-medial and superior-lateral aspects of the corrugator muscles). Subjects were pho-tographed before and after injection, and glabellar line severity was rated as absent, mild, moderate, or severe, both in the relaxed state and at maximum frowning. Results showed that both BoNTA and rimabotulinumtoxinB were both effective in treating glabellar frown lines. However, rimabotulinumtoxinB had a more rapid onset of action (by 1 to 2 days) as compared with BoNTA. At the doses used, BoNTA had a longer duration of effect than did rimabotulinumtoxinB. The duration of effect of BoNTA 20 U was at least 16 weeks, whereas that of rimabotulinumtoxinB was 8 to 10 weeks at the 1,000 U dose and 10 to 12 weeks with the 2,000 U dose. Although the study consisted of a small

Table 10.2 Protein Immunogenicity Factors

RimabotulinumtoxinB OnabotulinumtoxinAForeign ForeignLarge LargeNative DenaturedNonaggregated Aggregated2–3 months 3–4 months pH 5.6 Neutral

Cross-neutralizing antibodies between the serotypes are not expected based on single exposure. Multiple exposures may lead to cross sensitivity between toxins.

Patients who are resistant to BoNTA respond to rimabotulinumtoxinB therapy

and vice versa.

Table 10.3 Botulinum Neurotoxin Formulation

Parameter RimabotulinumtoxinBFormulation Stable liquid

Native proteinNonaggregatedNo reconstitutionpH 5.6

Vials 2,500 U, 5,000 U, and 10,000 UStorage Refrigerator (2–8°C)Mechanism of action Unique receptors for type B

Targets synaptobrevin

Figure 10.2 Schemata showing the most common sites of botulinum toxin injections in the upper face. (A) Yellow, injections in the glabella. (B) Red, injections in the frontalis. (C) Green, injections in lateral canthal lines. The authors prefer to use the conversion of 150 U of type B toxin for 1 U of type A toxin.

Common sites of BoNT therapy

Corrugator

Procerus

Depressor supercilii

Orbicularis oculi

BOTULINUM TOXIN B 243

group of patients, its results suggest that rimabotulinumtoxinB’s dura-tion of efficacy may be dose-dependent. Because limited adverse events were reported at doses used, the investigators concluded that higher doses of rimabotulinumtoxinB should be studied.

The lead author, Neil Sadick, conducted two open-label studies using higher doses of rimabotulinumtoxinB for treatment of glabellar wrinkles ( 42–44 ). Both studies were similar in design, but the first study evaluated rimabotulinumtoxinB 1,800 U ( N = 30), and the sec-ond study evaluated 2,400 U ( N = 16) and 3,000 U ( N = 18). Doses were divided equally among six sites; two in the procerus and two in each corrugator supercilii and orbicularis oculi muscle bilaterally. Most subjects in all treatment groups had not been previously treated with BoNTA. In the first study, efficacy was assessed using photography and a clinical scoring system that was used by both subjects and physicians; 0 denoted marked frowning ability, 1 denoted partial frowning ability, and 2 denoted complete inability to frown because of paralysis. The second study also used the RNKLS. Subjects returned to the office daily postinjection until the effects of rimabotulinumtoxinB were observed and then weekly thereafter. Both studies found rimabotulinumtoxinB to be effective in treating glabellar frown lines, based on photography, patient satisfaction, and improvements in assessment scores. Overall, rimabotulinumtoxinB had a very rapid onset of action. When viewed together, the results of both studies also suggest that the duration of response is dose related. The mean duration of effect was 8 weeks with 1,800 U, 9.6 weeks with 2,400 U, and 10.4 weeks with 3,000 U. Lid pto-sis was reported in one patient who received 2,400 U and in one patient who received 3,000 U. Headache and mild pain on injection were also reported. Overall, rimabotulinumtoxinB was very safe, and there was no increase in adverse effects with the higher doses.

Alster and Lupton chose 20 female patients with vertical glabellar rhytids showing minimal response to BoNTA, which was defined as less than 50% reduction in contraction of the muscles treated with BoNTA. These patients were treated with rimabotulinumtoxinB at a total dose of 2,500 U into five standardized intramuscular sites (procerus, inferome-dial corrugators, and superior medial corrugators). Improvement of wrinkles occurred in all individuals with peak response at 1 month and complete dissolution of effect at month 4 ( 45 ).

Flynn and Clark showed an increased rate of onset and more wide-spread diffusion of rimabotulinumtoxinB vs. BoNTA in a single center study of 24 patients with symmetrical, moderate to severe forehead wrinkles. Subjects received onabotulinumtoxinA 5 U on one side and rimabotulinumtoxinB 500 U on the other side of the forehead. Radius of diffusion and time until full effect were measured. Rimabotulinum-toxinB was found to have a slightly faster rate of onset than onabotu-linumtoxinA. A greater radius of diffusion was consistently observed with rimabotulinumtoxinB as measured by the greater area of wrinkle reduction at the doses used ( 46 ).

Spencer et al. ( 47 ) investigated the dose–response of rimabotu-linumtoxinB in 26 patients. Three different dosage schedules, i.e., low-dose (1,875 U), medium-dose (2,500 U), and high-dose (3,125 U) were followed for the glabellar study group for duration of effect. In the frontalis-treated group, low-dose regimen (2,250 U), medium-dose group (3,000 U), and a high-dose subgroup (3,750 U) were studied. Results showed that in the glabellar group most subjects showed evi-dence of paralysis at 2 months. However, only the high-dose group showed a continued effect at 3 months after treatment. In the frontalis group, response was often still present at 2 months, however it had totally dissipated by month 3 ( 47 ).

In a double-blinded, randomized, placebo-controlled pilot study by Bauman et al. on the safety and efficacy of rimabotulinumtoxinB for the treatment of crow’s feet utilizing 3,000 U in 20 patients, the maxi-mal effect was seen at day 30. Results began to wane by day 60, although the patients were not seen between day 30 and day 60, and most

patients had returned to baseline by their day 90 visit. Adverse side effects were reported as flu-like symptoms (55%), dry mouth (45%), and dry eye (25%) ( 48 ).

Matarasso completed a study of 10 female patients comparing rimabotulinumtoxinB and onabotulinumtoxinA in the lateral ocular canthal region ( 52 ). All patients had been without BoNT treatment in all areas for at least 6 months before undertaking the study. Based on the neurologic literature with cervical dystonia patients and the reported lowest conversion ratio of 1 unit onabotulinumtoxinA to 50 units rimabotulinumtoxinB, a double-blind trial was undertaken pri-marily to evaluate duration of rhytid reduction. Three aliquots of 5 units (total 15 units) of onabotulinumtoxinA were injected into one set of lateral canthal lines, and three aliquots of 250 units of rimabotu-linumtoxinB (750) units were similarly injected into the contralateral canthal rhytides. The injections were blinded to both the physician and patient. Evaluation was undertaken at 7, 30, 60, and 90 days, and results were based on photographic images at rest and maximal muscle cor-rection, and by physician and patient assessment. On unblinding of the solutions, the side treated with rimabotulinumtoxinB was found to have quicker onset of action (mean 2.3 days) and shorter duration of actions (mean 6.4 weeks). Conversely, the rhytids treated with ona-botulinumtoxinA had a mean onset of action of 3.7 days and an aver-age duration of 12.7 weeks. Other than a slightly higher degree of discomfort on injection at a rimabotulinumtoxinB-treated site, there were no reported adverse events ( 52 ).

Kim and investigators using an escalating dosage formula of 400 to 800 U to 1,600 to 2,000 U, and 2,500 to 3,000 U per site treating the bilateral frontalis, corrugator or orbicularis oculi using a wrinkle improvement scale and rated numerical kinetic line scales, found rimabotulinumtoxinB to be clinically effective for up to 8 weeks in the management of hyperkinetic facial lines and up to week 12 at the higher dosage. In this study, the authors report that patients exhibited excellent skin smoothing, which was felt to be secondary to an enhanced diffusion effect of the rimabotulinumtoxinB toxin. Reported side effects were headaches (40%), brow ptosis (7%), dry eyes (5%), and dry mouth (13%) ( 49 ).

An exploratory study by Carruthers et al. evaluated the dose response of subjects to rimabotulinumtoxinB treatment for hyperfunctional gla-bellar lines ( 54 ). This double-blind, randomized, placebo-controlled, sequential dose-escalation study evaluated the safety and tolerability of seven rimabotulinumtoxinB doses ranging from 250 to 3,000 U in the treatment of hyperfunctional glabellar lines. The study consisted of a single treatment of either rimabotulinumtoxinB or placebo with a 12-week follow-up period. One hundred and thirty six participants were assigned to seven sequential-dose treatment groups to receive 250, 500, 1,000, 1,500, 2,000, 2,500, or 3,000 U of rimabotulinumtoxinB, adminis-tered by intramuscular injection or equivalent volumes of placebo. The primary efficacy outcome measure was the Investigator Global Scale or Hyperfunctional Facial Line Scale (HFLS). The investigator scores dem-onstrated a statistically significant dose–response trend at weeks 1 to 12. But by week 8, only the 1,500-, 2,000-, 2,500-, and 3,000-U treatment groups has significantly larger decreased HFLS at rest and full frown compared to the placebo group. By week 12, no significant differences were observed for all rimabotulinumtoxinB groups compared to the pla-cebo. To extend the duration of subject response to treatment of hyper-functional glabellar lines, additional studies evaluating even higher doses of rimabotulinumtoxinB were recommended. When the rimabotu-linumtoxinB dosage was increased, the time to treatment effect decreased, indicating a dose-dependent time to onset of effect. The mean number of days after treatment with rimabotulinumtoxinB until effect on muscle movement was 5.3 days for the 1,500-U group to 2.0 days for the 3,000-U group. A dose-dependent trend was also observed in the patients’ subjec-tive assessment of improvement. Moderate to great improvement was

244 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

frontalis region, as reported in an open-label study ( 47 ). At the doses used, there were no reports of lid ptosis. Of note, rimabotulinumtoxinB was reported to yield a very uniform paralysis and a smooth aesthetic effect. This effect has also been observed by the authors, as well as by oth-ers, and may reflect the diffusion characteristics of rimabotulinumtoxinB, which may differ from those of BoNTA. Compared with BoNTA, rimabotulinumtoxinB appears to diffuse more within the injected muscle.

Taken together, the studies of rimabotulinumtoxinB for the treat-ment of facial wrinkles show that it is effective, has a very rapid onset of effect, and has a dose-related duration of effect. In clinical studies of cervical dystonia, the calculated duration of the effect of rimabotu-linumtoxinB was 12 to 16 weeks, which is comparable to that seen with BoNTA. These trials demonstrated a dose–response relationship in the duration of effect when treating glabellar lines. It is anticipated that higher doses of rimabotulinumtoxinB can be safely and effectively administered to produce an even longer duration of response in the

Table 10.4 Provisional Dosing Guidelines for BoNTB Injections for Facial Rhytides

Muscle site

RimabotulinumtoxinB

Units No. of injections

Glabella 2,000–3,000 3Frontalis 1,000–2,500 3–6Brow lift 300–500 per side 1 per sidePeriorbital 1,000–1,500 per side 1–2 per side

reported by 18.2 % in the 250-U group compared to 93.8% in the 3,000-U group. The experience of adverse events was low, with the most common reported adverse event being headache not otherwise specified, experienced by 19 subjects (13.7%) ( 54 ).

To date, the highest doses of rimabotulinumtoxinB to be used for aesthetic purposes are 3,125 U for glabellar lines and 3,750 U for the

Figure 10.3. Injection of rimabotulinumtoxinB. (A) Glabella, use nondominant hand to pinch muscle. Inject into center of muscle belly. About 2 injection points in the pro-cerus, 1 injection point into each corrugator. (B) Lateral canthal lines, use two-hand traction technique to tighten skin. Enter at about a 30º angle. Space out injections into 5 points along lateral orbicularis oculi.

(A) (B)

Figure 10.4 Before and after rimabotulinumtoxinB treatment to the frontalis. (A) Brows raised before treatment (top), 8 weeks after treatment with 3,000 U of rimabotulinum-toxinB to the frontalis (bottom). (B) Brows raised before treatment (top), 8 weeks after treatment with 2,400 U of rimabotulinumtoxinB to the frontalis (bottom).

(A) (B)

BOTULINUM TOXIN B 245

treatment of facial wrinkles. Further studies at higher doses are rec-ommended to determine optimal dosing of rimabotulinumtoxinB, with an acceptable level of adverse effects ( 50 , 51 ).

BOTULINUM TOXIN B USAGE CONSIDERATIONS Preliminary estimates of effective doses of rimabotulinumtoxinB based on the studies for the treatment of facial wrinkles are speci-fied in Table 10.4 . Results from these studies have clearly shown efficacy at these doses.

For the glabella, the relevant musculature includes the procerus complex and corrugator supercilii. A total of 20 to 30 U of onabotu-linumtoxinA may be divided equally and injected into five sites, where rimabotulinumtoxinB treatment with 2,000 to 3,000 U divided among only four sites appears to produce similar results. For frontalis injection 15 to 30 U of onabotulinumtoxinA divided among five to six injection sites produced adequate results while rimabotu-linumtoxinB in doses of 1,000 to 2,500 U per side produced similar results. Lifting of the brow can be achieved by treatment of the cor-rugator supercilii, the procerus complex, and the medial portion of the orbicularis oculi muscle. In the authors’ experience, 1,500 U of rimabotulinumtoxinB are employed in this setting. For lateral canthal

lines, the authors inject 10 to 15 U of onabotulinumtoxinA divided into three to four injections per side. Because of the proposed diffu-sion characteristics of rimabotulinumtoxinB, the authors employ a single injection of 1,000 to 1,500 U per side to treat the crow’s feet. The representative patients treated by the authors are presented in Figures 10.3 to 10.5 .

COMPLICATION PROFILES Complication profiles for BoNTA vs. rimabotulinumtoxinB are quite similar with eyelid and brow ptosis, mild bruising, and asymmetric brow elevation ( Fig. 10.6 ).

CONCLUSION Facial wrinkles involving the forehead, glabellar, and/or periorbital regions are a common aesthetic problem, and are directly related to overactivity of the underlying facial musculature. BoNT, which acts by causing flaccid paralysis or weakening of the muscles of facial expres-sion, has become a popular treatment for the management of hyper-functional facial lines. Three serotypes have been formulated and are currently available for commercial use in the United States: onabotuli-numtoxinA, abotulinumtoxinA, and rimabotulinumtoxinB. The major differences bet ween the two toxins in terms of pharmacologic mecha-nism are that each binds to its own serotype-specific acceptors on the neuronal cell membrane, and each targets different specific intracellu-lar proteins. The major differences in formulation are that onabotu-linumtoxinA and abobotulinumtoxinA are lyophilized. Both require reconstitution before use. RimabotulinumtoxinB is a ready-to-use liq-uid. As bacterial proteins, both BoNTA and BoNTB can elicit an immune response in treated patients. It is currently unknown whether one BoNT is more likely than the other to cause antibody formation and subsequent development of resistance.

The bulk of clinical data exists with onabotulinumtoxinA, due to over 20 years of clinical use in the U.S. marketplace versus 2 years with rimabotulinumtoxinB. These data confirm the effectiveness of ona-botulinumtoxinA in the treatment of facial wrinkles. Preliminary data with rimabotulinumtoxinB show that it too is effective in this regard. In these preliminary studies, rimabotulinumtoxinB, as compared with onabotulinumtoxinA, appears to have a faster onset of effect and potentially a more even, and smoother paralysis.

Both BoNTs are among the most potent neurotoxins known, and caution in dose escalation is appropriate in any indication and espe-cially in off-label use. At dermatological doses, the likelihood of serious adverse events is low with both products. However, as we become more aggressive with our aesthetic treatments (especially in the lower face), the side effects become more common and more worrisome. In an aesthetic practice, patient safety and satisfaction are paramount. Avoid-ance of posttreatment complications is crucial.

With further studies and clinical experience, it is likely that each product will have uses for which it is preferable based on its own indi-vidual efficacy and safety profile. This may also widen the scope of indications cleared by the FDA, ultimately benefiting a larger group of patients.

REFERENCES 1. Knize D. Muscles that act on glabellar skin: a closer look. Plast

Recon Surg 2000; 105(1): 350–61. 2. Kock RJ, Troell RJ, Goode RL. Contemporary management of the

aging brow and forehead. Laryngoscope 1997; 107(6): 710–15. 3. Pierard GE, Lapiere CM. The microanatomical basis of facial

frown lines. Arch Dermatol 1989; 125: 1090–2. 4. Vecchione TR. Glabellar frown lines: direct excision, an evaluation

of the scars. Plast Recom Surg 1990; 86(1): 46–52.

Figure 10.5 Patient frowning (top) before, and (bottom) 10 weeks after treatment with 2,400 U of rimabotulinumtoxinB to the glabella.

Figure 10.6 Drooping of the left upper eyelid after rimabotulinumtoxinB injection in the glabella. Apraclonidine (0.5%) drops, 3 drops to the affected eye three times a day produces temporary relief of this problem until it completely resolves.

246 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

28. Brandt F, Bellman B. Cosmetic uses of botulinum A exotoxin for the aging neck. Dermatol Surg 1998; 24: 1232–4.

29. Carucci J. Botulinum exotoxin A for rejuvenation of the upper third of the face. Facial Plast Surg 2001; 17: 11–20.

30. Carruthers J, Carruthers A. Botox use in the mid and lower face and neck. Semin Cutan Med Surg 2001; 20: 85–92.

31. Foster J, Barnhorst D, Papay F, et al. The use of botulinum A toxin to ameliorate facial kinetic frown lines. Ophthalmology 1996; 103: 618–22.

32. Flynn T, Carruthers J, Carruthers A. Botulinum A toxin treatment of the lower eyelid improves infraorbital rhytides and widens the eye. Dermatol Surg 2001; 27: 703–8.

33. Hankins C, Strimling R, Rogers G. Botulinum A toxin for glabel-lar wrinkles, dose and response. Dermatol Surg 1998; 24: 1181–3.

34. Huilgol S, Carruthers A, Carruthers J. Raising eyebrows with botu-linum toxin. Dermatol Surg 1999; 25: 373–6.

35. Matarasso A. Botulinum A exotoxin for the management of platys-mal bands. Plast Reconstr Surg 1999; 103: 645–52.

36. West T, Alster T. Effect of botulinum toxin type A on movement-associated rhytides following CO

2 laser resurfacing. Dermatol Surg

1999; 25: 260–1. 37. Carruthers A, Carruthers JDA. The use of botulinum toxin to treat

glabellar frown lines and other facial wrinkles. Cosmet Dermatol 1994; 7: 11–15.

38. Lew MF, Adornato BT, Duane DD et al. Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia. Neurology 1997; 49: 701–7.

39. Hexsel DM, De Almeida AT, Rutowitsch M, et al. Multicenter, dou-ble-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to 6 consecutive weeks before application. Dermatol Surg 2004; 30(5): 823.

40. Ramirez AL, Reeck J, Maas CS. Botulinum toxin type B (Myobloc ® ) in the management of hyperkinetic facial lines. Otolaryngol Head Neck Surg 2002; 126: 459–67.

41. Lowe NJ, Yamauchi PS, Lask GP, et al. Botulinum toxin types A and B for brow furrows: preliminary experiences with type B toxin dosing. J Cosmet Laser Ther 2002; 4: 15–18.

42. Sadick NS. Botulinum toxin type B (Myobloc) for glabellar wrin-kles: a prospective open-label response study. Dermatol Surg 2002; 29: 817–21.

43. Sadick NS. Prospective open-label study of botulinum toxin type B (Myobloc) at doses of 2,400 and 3,000 units for the treatment of gla-bellar wrinkles. Dermatol Surg 2003; 29(5): 501–7; discussion 507.

44. Sadick NS. Botulinum toxin type B for glabellar wrinkles: a prospec-tive open-label response study. Dermatol Surg 2002; 28: 817–21.

45. Alster TS, Lupton JR. Botulinum toxin type B for dynamic glabel-lar rhytides refractory to botulinum toxin type A. Dermatol Surg 2003; 29: 516–18.

46. Flynn TC, Clark RE. Botulinum toxin type B (Myobloc) versus botulinum toxin type A (Botox) frontalis study: rate of onset and radius of diffusion. Dermatol Surg 2003; 29(5): 519–22.

47. Spencer JM, Gooden M, Goldberg DJ. Botulinum B treatment of glabellar and frontalis regions: a dose response analysis. J Cos Laser Ther 2002; 4: 19–23.

48. Bauman L, Slezinger A, Vujevich J et al. A double-blinded random-ized placebo-controlled pilot study of the safety and efficacy of Myobloc (botulinum toxin type B)-purified neurotoxin complex for the treatment of crow’s feet: a double-blinded placebo- controlled trial. Dermatol Surg 2003; 29: 508–15.

49. Kim EJ, Ramirez AL, Reeck JB, Maas CS. The role of botulinum toxin type B (Myobloc) in the treatment of hyperkinetic facial lines. Plast Reconstr Surg 2003; 112 (5 Suppl): 88S–93S; discussion 94S–97S.

5. Carruthers JDA, Carruthers JA. Treatment of glabellar frown lines with botulinum-A exotoxin. J Dermatol Surg Oncol 1992; 18: 17–21.

6. Blitzer A, Brin MF Keen MF, et al. Botulinum toxin for the treat-ment of hyperfunctional lines of the face. Arch Otolaryngol Head Neck Surg 1993; 119: 1018–22.

7. Guyron B, Huddleston SW. Aesthetic indications for botulinum toxin injection. Plast Reconstr Surg 1994; 93: 913–18.

8. Keen M, Blitzer A, Aviv J, et al. Botulinum toxin A for hyperkinetic facial lines: results of a double-blind placebo-controlled study. Plast Reconstr Surg 1994; 94: 94–9.

9. Brashear A, Lew MF, Dykstra DD, et al. Safety and efficacy of Neurobloc ™ (botulinum toxin type B) in type A-responsive cervi-cal dystonia. Neurology 1999; 53: 1439–46.

10. Brin M, Lew MF, Adler CH, et al. Safety and efficacy of Neurob-loc ™ (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999; 53: 1431–8.

11. Sakaguchi G. Clostridium botulinum toxins. Pharmacol Ther 1983;19:165–94.

12. Callaway JE, Arezzo JC, Grethlein AJ. Botulinum toxin type B: an overview of its biochemistry and preclinical pharmacology. Semin Cutan Med Surg 2001; 20: 127–36.

13. Simpson LL. Molecular pharmacology of botulinum toxin and tetanus toxin. Annu Rev Pharmacol Toxicol 1986; 26: 427–53.

14. Oguma K, Fujinaga Y, Inoue K. Structure and function of Clos-tridium botulinum toxins. Microbiol Immunol 1995; 39: 161–8.

15. Olney RK, Aminoff MJ, Gelb DJ, Lowenstein DH. Neuromuscular effects distant from the site of botulinum neurotoxin injection. Neurology 1998; 38: 1780–3.

16. Fagien S, Brandt FS. Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic surgery. Clin Plast Surg 2001; 28: 127–48.

17. Setler P. The biochemistry of botulinum toxin type B. Neurology 2000; 55 (Suppl 5): S23–8.

18. Greene P, Fahn S, Diamond B. Development of resistance to botuli-num toxin type A patients with torticollis. Mov Disord 1994; 9: 213–17.

19. Jankovic J, Schwartz KS. Response and immunoresistance to botulinum toxin injections. Neurology 1995; 45: 1743–6.

20. Berman B, Seeberger L, Kumar R. Long-term safety, efficacy, dos-ing, and development of resistance with botulinum toxin type B in cervical dystonia. Mov Disord 2005; 20(2): 233–7.

21. Dressler D, Bigalke H. Botulinum toxin type B de novo therapy of cervical dystonia frequency of antibody induced therapy failure. J Neurol 2005; 252(8): 904–7.

22. Dolimbek BZ, Jankovic J, Atassi MZ. Cross reaction of tetanus and botulinum neurotoxins A and B, and the boosting effect of botuli-num neurotoxins A and B on a primary anti-tetanus antibody response. Immunol Invest 2002; 31(3–4): 247–62.

23. Aoki KR. Pharmacology and immunology of botulinum neurotox-ins. Int Ophthalmol Clin 2005; 45(3): 25–37.

24. Zuber M, Sebald M, Bathien N, et al. Botulinum antibodies in dys-tonic patients treated with type A botulinum toxin: frequency and significance. Neurology 1993; 43: 1715–18.

25. Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds: a double-blind, placebo-controlled study with an electromyo-graphic injection technique. J Am Acad Dermatol 1996; 35: 569–72.

26. Carruthers JA, Lowe NJ, Menter MA et al. A multicenter, double-blind, randomized placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002; 46: 840–9.

27. Blitzer A, Binder W, Aviv J, et al. The management of hyperfunc-tional facial lines with botulinum toxin: a collaborative study of 210 injection sites in 162 patients. Arch Otolaryngol Head Neck Surg 1997; 123: 389–92.

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50. Jacob CI. Botulinum toxin type B—onset duration and efficacy: comparing dilution with preserved versus un preserved saline. Cos Dermatol 2003; 16: 25–30.

51. Jacob CI. Botulinum neurotoxin type B—a rapid wrinkle reducer. Sem Cutan Med Surg 2003; 22: 131–5.

52. Matarasso SL. Comparison of botulinum toxin types A and B: a bilateral double-blind randomized evaluation in the treatment of cantahl rhytides. Derm Surg 2003; 29: 7–13.

53. Dong M, Tepp W, Johnson E, Chapman E. Mechanism of botuli-num neurotoxin B and G entry into hippocampal neurons. J Cell Biol 2007; 179: 1511–22.

54. Carruthers A, Carruthers J, Flynn TC, Leong MS. Dose-finding, safety and tolerability study of botulism toxin type B for the treatment of hyperfunctional glabellar lines. Dermatol Surg 2007; 33: S60–8.

248

characterized by excessive sweating of small areas of the skin, usually the axilla, palms, soles, face, or groin ( Fig. 11.1 ) ( 11 ). The onset is usu-ally in adolescence to early adulthood but can begin in early childhood, especially the palmar-plantar variants ( 7 ) ( Table 11.3 ). The differential diagnosis for excessive sweating is extensive, and an underlying cause must be considered, especially when the hyperhidrosis is generalized, asymmetrically distributed, or has a late onset ( 6 , 12 ). A detailed history with comprehensive review of symptoms and thorough physical exam-ination is the first step to identifying the type and cause of hyperhidro-sis of a patient presenting with excessive sweating. The types or extent of further testing is based on the findings from the history and physical exam.

This chapter will focus on primary focal hyperhidrosis henceforth identified simply as hyperhidrosis (HH). The prevalence of HH is reported to be 2.8% although it may be higher. It most commonly pres-ents in the second or third decade of life and a family history has been reported in 30 to 50% of patients ( 13 ). The prevalence is similar for men and women, although interestingly, women are more likely to seek evaluation and treatment ( 11 ). Patients may sweat on a continuous basis throughout the day, but more commonly, there are episodes of profuse sweating with a sudden onset. Trigger factors include emo-tional stress, stress at work or in the public, higher environmental tem-peratures, and stimulants such as caffeine and exercise. However, patients also often have episodes of HH without a known initiating factor or trigger when they are cool, comfortable, and calm.

Hyperhidrosis has a negative impact on many aspects of patients’ daily living: physically, psychologically, and occupationally ( 14–16 ). There is limited and mixed information on any real increase in cutane-ous infections or other problems such as skin maceration with idio-pathic hyperhidrosis ( 17 , 18 ). The greatest impact of HH is the significant reduction in the quality of life and the alterations it has on daily functioning ( 19 ). Patients report a lack of confidence, feeling depressed, refraining from meeting new people, and avoiding intimate activities. Work limitations are reported because of excessive sweating and patients describe having to change clothes during the day.

MEASURING HYPERHIDROSIS The Minor’s iodine-starch test is a simple way to detect the presence of sweat ( Fig. 11.2 ). The hyperhidrotic area to be treated is dried thor-oughly, an iodine solution is painted over the area and when thor-oughly dried, a starch powder such as corn starch is sprinkled on the surface. With the interaction of sweat, a purple to black color develops. Decolorized iodine solutions do not perform the colorimetric change properly and should not be used for this test. Many physicians today use surgical preparations such as Betadine™ solution or swabs to per-form the iodine-starch test. A plain corn starch that is used for cooking is readily available and inexpensive. The starch may be applied with a brush, cottonball, sifter or loose gauze. The iodine-starch test is useful in localizing the areas of sweat production but is not a quantitative test. For iodine-sensitive patients, Alizarin or Ponceau red dye and starch can be used. The pink powder turns to a bright red color when wet. Ninhydrin is another variant, but regardless of which variant is used, they all achieve a colorimetric outline of the sweating area ( 20–22 ).

Gravimetric testing measures the amount of sweat produced dur-ing a given time. It can be performed using a preweighed filter paper that is placed on the affected area (typically for 5 minutes) and then

11 Botulinum toxin in the management of focal hyperhidrosis Dee Anna Glaser

Botulinum toxins can be used to treat secretory problems such as hyperhidrosis, chromhidrosis, sialorrhea, and Frey’s syndrome. This chapter will focus on the rationale for and the practical application of using botulinum toxins to treat patients with such problems.

SWEATING Sweating is a normal physiological response to increased body tem-perature and is an important mechanism in releasing heat produced from endogenous as well as exogenous sources. The heat regulatory center is located within the hypothalamus, particularly involving the preoptic and anterior nuclei. Sweating is controlled by the sympathetic nervous system ( 1 ). Nerve fibers exit the preoptic or anterior nuclei and descend ipsilaterally through the spinal cord until they reach the intermediolateral column, where they exit the cord and enter the sym-pathetic chain. Although the neurotransmitter for the sympathetic nervous system is generally norepinephrine, acetylcholine is the neurotransmitter mainly involved in the sweating response. Other chemical mediators found in periglandular nerves include vasoactive intestinal peptide (VIP), atrial natriuretic peptide (ANP), galanin, and calcitonin gene peptide (CGP) ( 2 ).

The eccrine glands, responsible for producing sweat, are distributed around the body, with high concentrations in areas such as the palms, soles, and forehead ( Table 11.1 ). They are located at the junction of the dermis and subcutaneous fat and their function is to secrete water while conserving sodium chloride for electrolyte maintenance. Although they continually produce secretions, they are stimulated by heat, exercise, anxiety, and stress ( 3 , 4 ). Under severe heat stress, up to 10 l of sweat can be produced in a day; however, the normal rate is 0.5 to 1.0 ml/min. While rates vary among individuals, men generally sweat more than women ( 5 ).

The apocrine gland opens into the hair follicle and is located mostly in the axillae and perineum. They become functional around puberty and are not important for thermoregulation. The scant viscous secre-tions are thought to function as chemical attractants or signals, as an odor is produced when the secretions reach the skin surface and inter-act with bacteria ( 1 , 3 ). The apocrine glands respond to adrenergic stimuli, epinephrine more than norepinephrine.

HYPERHIDROSIS Hyperhidrosis simply describes excess sweating beyond that necessary for physiological thermoregulation and homeostasis ( 6 ). Problems can occur within any portion of the system: from the hypothalamus to the sweat gland or duct ( 2 ). The amount of sweat necessary to be consid-ered “excessive” is not well-defined and is variable between individuals. Patients with hyperhidrosis do not demonstrate any histopathologic changes in their sweat glands, nor are there any changes in the numbers of sweat glands ( 7 ).

Hyperhidrosis may be generalized or focal, bilateral or unilateral, symmetric or asymmetric, primary or secondary in origin. Generalized hyperhidrosis affects the entire body whereas focal hyperhidrosis occ-urs in discrete sections of the body ( 8 ). Generalized hyperhidrosis is usu ally secondary in nature, and the differential diagnosis is exten sive ( Table 11.2 ). Focal or localized hyperhidrosis may result from a sec-ondary process including lesions or tumors of the central or peripheral nervous system ( 9 , 10 ). More commonly however, it is idiopathic (pri-mary) focal and is usually referred to simply as “hyperhidrosis.” It is

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 249

reweighing the paper. Evaporation must be prevented. There is no standard or validated quantity that separates hyperhidrosis from euhidrosis, although it can exceed 30 times that of normal nonhy-perhidrotic individuals. Hund suggests a minimum of 100 mg/5 min for men and 50 mg/5 min for women will identify axillary hyperhidrosis ( 5 ). A study of 60 patients demonstrated that the

mean axillary sweat production was 346 mg/5 min for men and 186 mg/5 min for women with HH (healthy control subjects had values of 72 and 46, respectively). Likewise, the mean palmar gravimetric measurement was 300 mg/5 min ( 23 ). Gravimetric eval-uation is typically reserved for research purposes and is not routinely used in clinical practices.

A third method used to measure disease severity is with question-naires and quality of life scales. Several such tools are available, including the Dermatology Life Quality Index (DLQI), the Hyperhi-drosis Impact Questionnaire (HHIQ), and the Hyperhidrosis Disease Severity Scale (HDSS). The DLQI has 10 items that form six domains such that a total score of zero is best and 30 demonstrates the worst quality of life. The HHIQ has items for a baseline evaluation and ten items used to assess treatment follow-up. It too is most commonly used in clinical trials ( 24 ). The HDSS is based on one question that the patient can answer in the office ( Table 11.4 ). The HDSS is a simple tool to use in the clinical setting and is responsive to treatment with a one-point HDSS improvement corresponding with approximately a 50% reduction in sweat. This validated scale can aid in selecting patients appropriate for therapy and for assessing effectiveness of treatment ( 25 ).

THERAPY Many treatments are available for HH, and therapy should be tailored to the needs of the individual based on factors such as age and health status, location, and severity of the disease, occupation, and lifestyle ( Table 11.5 ).

Antiperspirants are used as first-line therapy and function by decreasing sweat secretion through blockage of the distal eccrine ducts. Over-the-counter (OTC) products very rarely control patients with severe disease (HDSS 3 or 4) (see above) ( 7 , 11 , 26 , 27 ). Prescription strength products containing high concentrations of metal salts, most commonly aluminum chloride, are more effective than OTC prepara-tions ( 28 ). Efficacy is still limited, and side effects are frequent with skin irritation, erythema, dryness, and pruritus.

Systemic anticholinergic drugs such as glycopyrrolate, atropine, or oxbutynin provide a generalized acetylcholine blockade ( Table 11.6 ) ( 26 , 29 , 30 , 31 ). Adverse effects such as dry eyes, dry mouth, and urinary retention are frequently encountered at the doses required to achieve symptom relief. Additionally, the generalized reduction in sweat pro-duction can be dangerous in individuals who engage in exercise, sports, or work in hot environments.

Iontophoresis is an electrical device that uses direct current and tap water. The mechanism of action is unknown but may change the ability of the pores to secrete sweat, or physically block the release of sweat via ions that enter the ducts. It is most suited for treatment of the hands and feet. Anticholinergic agents can also be added to the tap water ( 32 ). Side effects are relatively minimal but is relatively time-consuming, limiting its use for many patients ( Fig. 11.3 ) ( 33 ).

Table 11.2 Forms of Hyperhidrosis

Generalized Focal/Localized

Fever Primary focal hyperhidrosisInfections Intrathoracic tumorsMalignancy Rheumatoid arthritisTumors Spinal cord disease or injuryThyrotoxicosis StrokePheochromocytoma SyringomeliaDiabetes mellitus Ross syndromeDiabetes insipidus Atrioventricular fistulaHypoglycemia Gustatory sweatingHypopituitiarism Frey’s syndromeEndocarditis Localized unilateral hyperhidrosisa

Gout Cold-induced hyperhidrosisMedications Eccrine nevusMenopause Social anxiety disorderAnxiety Granulosis Rubra NasiDrug withdrawal

aAlso referred to as unilateral circumscribed idiopathic hyperhidrosis.

Table 11.1 Eccrine Sweat Glands: Area and Quantity

Area Quantity (cm2)

Sole of foot 620Forehead 360Palms 300Axillae 300Thigh 120Scrotum 80Back 65Lips NoneNail bed NoneNipple NoneInner preputial surface NoneLabia majora NoneGlans penis NoneGlans clitoridis None

Source: From Ref. 68, p. 263.

Table 11.3 Criteria for Establishing the Diagnosis of Primary Focal Hyperhidrosis (6)

Focal, visible excessive sweating of at least 6 monthsNo apparent secondary causeAt least two of the following characteristics

• Bilateral and relatively symmetric• Age on onset <25 years• Positive family history of primary focal hyperhidrosis• Cessation of focal sweating during sleep• Frequency of at least one episode per week• Impairs daily activities

Figure 11.1 Sites of hyperhidrosis in patients seeking medical evaluation. Source : From Ref. 11, p. 263.

0

Axilla

ry

Palm

ar

Plan

tar

Face

/sca

lp

Gro

in

Oth

er

1020304050607080

250 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

Table 11.4 Hyperhidrosis Disease Severity Scale

“Which best describes the impact of sweating on your daily activity?”

1 My (underarm) sweating is never noticeable and never interferes with my

daily activity2 My (underarm) sweating is tolerable but sometimes interferes with my daily

activity 3 My (underarm) sweating is barely tolerable and frequently interferes with

my daily activity4 My (underarm) sweating is intolerable and always interferes with my daily

activity

Source: From Ref. 25.

Local surgical excision and liposuction or curettage techniques can be used to remove eccrine units ( 34 ). The outcome is technique depen-dant and is typically limited to the axilla. Endoscopic thoracic sympa-thectomy (ETS) offers long-term improvement but is not universally accepted. The sympathetic chain is interrupted at the T2, T3, and sometimes the T4 ganglion ( 35 , 36 ). Success rates for palmar disease approximate 95% but is less for axillary HH. Surgical and anesthetic-related adverse events are relatively rare, but the major issue with ETS surgery for HH is the potential for patients to develop compensatory sweating ( Fig. 11.4 ) ( 37 ). The incidence varies, but approximately 60 to 70% of patients seem to develop it, with its occurrence and severity being unpredictable ( 35 , 38 , 39 ).

Figure 11.2 Performance of the Minor’s iodine-starch test. The hyperhidrotic area is doused with iodine solution (a) and after drying covered with starch powder (b). The hyperhidrotic area becomes clearly demarcated as a purple surface. Then the hyperhidrotic area is outlined (c). After removing the excess purple color from the center of the outline each injection site can be marked with gentian violet (d) to achieve the best results; (e) shows how the injections are placed. Source: From Ref. 68, p. 276.

(A) (B)

(C)

(E)

(D)

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 251

BOTULINUM TOXIN THERAPY Since sweating is mediated by acetylcholine the use of botulinum neurotoxin (BoNT) to treat focal HH is a logical choice. The chemo-denervation is localized, reversible, and yet long-lasting. Botulinum neurotoxin type A (BoNTA) has been most extensively studied and used clinically to treat HH, but botulinum neurotoxin type B (BoNTB) has also been reported to work.

The basic principle for using BoNTs to treat excessive sweating is to treat any underlying etiology as already discussed. Then the area of

sweating should be identified using a colorimetric test such as the Minor’s iodine-starch test ( Fig. 11.2 ). Since the sweat glands are typi-cally located at the junction of the dermis and subcutaneous fat, BoNT is usually placed as a deep intradermal injection. It is important to avoid injecting deeper structures such as muscle to prevent unwanted affects on the underlying muscles and for optimal BoNT interaction at the neuron–eccrine interface. Injections are generally placed 1 to 2 cm apart to allow for diffusion to the entire area. Although this basic tech-nique is used to treat all areas of the body, the more commonly treated sites will be covered in more detail. Due to the differences using the different BoNTA products, the newly assigned nonproprietary names will be listed when necessary.

AXILLARY HYPERHIDROSIS No area has been as extensively studied as the axilla ( 14 , 40–45 ) with numerous studies showing the benefit of BoNTA, including large mul-ticenter randomized, placebo-controlled trials in Europe and the United States. Naumann et al. reported on 320 patients with axillary HH that received 50 U of BoNTA (BOTOX® or onabotulinumtoxinA) per axilla or placebo ( 44 ). At 4 weeks, 94% of the onabotulinumtoxinA group had responded compared with 36% of the placebo group as measured by ≥ 50% reduction of sweat production from baseline. By 16 weeks, the response rates were 82% and 21%, respectively. Repeated injections with onabotulinumtoxinA over 16 months continued to produce similar results ( 40 ). The mean duration between onabotu-linumtoxinA treatments was approximately 7 months and patient sat-isfaction was high. Similar results were published in a large phase III double-blind trial in North America ( 45 ). Subjects with axillary HH were randomized to receive placebo, 50 U, or 75 U onabotulinum-toxinA into each axilla. The HDSS was the primary efficacy in this study with gravimetric measurements being secondary. Successful response was seen in 75% of patients in both treatment groups com-pared with 25% in the placebo group (defined as ≥ 2 point reduction in HDSS) while 80 to 85% of the treated subjects had >75% reduction in sweat production. No significant differences were noted between the two doses of onabotulinumtoxinA and the durability of therapy was approximately 7 months for both. A 3-year open label extension study revealed continued effectiveness and with similar duration of results ( 46 ). Specifically, the researchers were able to show a significant sus-tained improvement in the quality of life of subjects. The DLQI

Table 11.5 Therapies Most Commonly Used for Hyperhidrosis

Antiperspirants, over the counterAntiperspirants, prescription strengthIontophoresisOral medicationsBoNTA or BoNTBLocal excision of eccrine glandsLiposuction and/or curettage Endoscopic transthoracic sympathectomy

Table 11.6 Anticholinergics Commonly Used to Suppress Hyperhidrosis

Medication Dosage

Glycopyrrolate 1% cream Apply 1% solution to affected area once dailyGlycopyrrolate (1 mg tablet) 1–2 mg PO bid/tid, titrate to effectOxybutnin 5 mg PO bid/tid; not to exceed 5 mg qidPropantheline bromide 15 mg PO bid/tid 30 min ac initially; gradually

titrate to effectBenzotropine 1–2 mg/day PO; not to exceed 6 mg/day

Source: From Ref. 68, p. 268.

Figure 11.3 Iontophoresis procedure for palmar hyperhidrosis. To achieve satisfac-tory anhidrosis on both hands, it is important that both hands are treated in the anodal bath (red current). Therefore, after 10 minutes the red current plug has to be switched from one hand to the other and the treatment has to be repeated in the same manner. For palmoplantar therapy the treatment principles remain the same, but both hands are bathed in one and the feet in the other pan. Source : From Ref. 68, p. 270.

Figure 11.4 Increased sweating of the entire trunk after mild exercise or even after men-tal stress as a result of severe compensatory hyperhidrosis occurring after endoscopic thoracic sympathectomy for hyperhidrosis of the head. Source : From Ref. 68, p. 271.

252 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

hands such as choosing optimal doses, control of pain during injection, and side effects which include muscle weakness ( 23 , 56–60 ).

The optimum dose of BoNTA to control palmar HH is unknown and the issue is complicated by large variations in hand size ( Fig. 11.5 ). Published data report doses as low as 50 U per hand and as high as 200 U onabotulinumtoxinA per hand ( 55 , 61 ). Doses of abobotulinum-toxinA have ranged from 120 U per hand to 500 U per hand ( 22 , 54 , 62 ). Some authors have suggested using a defined dose per injection, with Swartling’s group using 0.8 U/cm 2 , and Naumann’s group using 2 U onabotulinumtoxinA injected every 1.5 cm on the palm but 3 injec-tions per fingertip and two injections into each of the middle and prox-imal phalanx using 1 to 2 U per injection ( 55 , 63 ). The Canadian advisory committee recommends 1.5 to 2 U/cm 2 with a mean dose of 100 U onabotulinumtoxinA per palm ( 7 ). It is unclear whether or not larger doses add to the duration of symptom relief or increase the risk of developing muscle weakness. When Wollina used 200 U of onabotu-linumtoxinA per hand in 10 patients, his relapse time varied from 3 to 22 months ( 61 ). Saadia studied 24 patients: 11 received 50 U onabotu-linumtoxinA per hand and 13 received 100 U/ hand. There was higher patient satisfaction reported in the high-dose group, but no difference in terms of duration (measured as a percentage of the palm area sweat-ing) for the two doses. There were more patients with hand and finger weakness in the high-dose treatment group ( 55 ). Until larger studies are available to address this issue, 75 to 100 U onabotulinumtoxinA per hand is a good starting point with adjustments being made as needed based on the size of the hand and past responses ( 27 ).

Another challenge with palmar BoNT therapy is an apparent shorter duration of response when compared with axillary injections ( 56 ).

revealed significant improvement in overall quality of life and occupa-tion and work-specific improvements were noted as well.

The efficacy of Dysport ® (abobotulinumtoxinA) has been shown in several studies. A multicenter trial of 145 subjects was performed with 200 U abobotulinumtoxinA in one axilla while the contralateral axilla was injected with placebo ( 41 ). After 2 weeks, the placebo-treated axilla was injected with 100 U abobotulinumtoxinA. Axillary sweating decreased within 2 weeks in both treatment sides and results were maintained for 6 months. There were no significant differences gravi-metrically between the two doses used. Therapy was well-tolerated and 98% of subjects said they would recommend the therapy to others.

Although studies have consistently shown that 50 U onabotulinum-toxinA per axilla provides safe and durable results (averaging ∼ 7 months), there is some debate whether higher doses of onabotulinumtoxinA can provide prolonged efficacy ( 47 , 48 ). One small open label study of 200 U onabotulinumtoxinA per axilla in 47 patients found prolonged results (over 19 months) in half of the patients, although the methodology was very different from other studies; starch iodine and telephone calls were used to assess patients ( 47 ). Likewise, 250 U of abobotulinumtoxinA ( 42 ) in each axilla resulted in prolonged benefit in a small study of 12 patients. Half remained symptom-free for 12 months and 9 months was achieved for 25% of the subjects ( 42 ). Currently the standard dose in the United States, and that listed in the package insert for onabotulinumtoxinA is 50 U per axilla. This achieves excellent results, high patient satisfaction, and helps to keep costs down. There is no such dosing consensus on other brands of BoNTA products.

To optimize treatment, the area of axillary involvement should be identified before treatment by a Minor’s iodine-starch test (as previ-ously reviewed) so that the BoNTA can be concentrated into the affected area. The key to performing a high-quality iodine-starch test is to thoroughly dry the region before beginning the test ( Fig. 11.2 ). The axilla does not need to be shaved prior to performing an iodine-starch test or to injecting BoNTA. The BoNTA is injected into the deep dermis at the dermal subcutaneous level and placed 1.5 to 2 cm apart. Because the axillary skin is thin, a wheal should be seen with each injection. An average of 10 to 11 injections per axilla are required, but will depend on the size of the axilla and hyperhidrodic area ( 49 ). In the event that an iodine-starch test cannot be performed prior to treatment or is equivo-cal, the physician should treat the hair-bearing areas as descried above. Should symptoms fail to be alleviated within 2 weeks, the patient can return to the office and an iodine-starch test performed to identify any “active” eccrine glands. The skin should be injected with 3 to 5 U of onabotulinumtoxinA for each 1 cm surface area identified.

Pain is minimal and the procedure is well tolerated. Although the package insert describes the use of unpreserved saline to reconstitute BoNTA, many physicians have found that the use of preserved saline reduces pain without altering efficacy ( 50 , 51 ). The use of 2% lidocaine to reconstitute BoNTA has been reported in one small study to be less painful than the use of unpreserved saline when injecting axillary HH and with equal efficacy ( 52 ). Side effects noted in studies include pain, hematoma, bruising, headache, muscle soreness, increased facial sweating, perceived compensatory sweating, and axillary pruritus.

Treatment intervals are mandated by the longevity of an individual’s treatment response but will average every 6 to 7 months. Some clini-cians have advocated that patients use a topical therapy twice a week when the sweating starts to return to try and extend the time interval between injections and help to keep costs to a minimum ( 53 ).

PALMAR HYPERHIDROSIS BoNT injections are useful in the treatment of palmar HH. No large-scale studies have been published but multiple small studies have dem-onstrated the ability of BoNT to establish clinical improvement in patients’ symptoms ( 23 , 54 , 55 ). Several challenges exist when treating

Figure 11.5 Variations in hand size. The larger hand is that of a 17-year-old male while the smaller hand is that of a 16-year-old girl. Hand size variations need to be taken into consideration when dosing BoNTA for palmar hyperhidrosis.

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 253

Responses range from 3 to 12 months ( 64 ). Aghaei found that anhidro-sis lasted up to 5 months for his patients treated with 500 U abobotu-linumtoxinA per hand ( 62 ), although he observed hypohidrosis lasting an average of 10 months ( 62 ). The reason for this shorter duration is unknown but may be ( 64 ) related to a smaller diffusion radius in the thicker palm skin and compartmentalized areas of the phalanges, a higher number of cholinergic nerve endings or a differential recovery rate of the nerves in the hands compared with the axilla. Backflow of the BoNT solution upon injection can be an issue with palmar injections and perhaps this plays a role as well ( 65 ).

Injection of the hand can be quite painful due to the density of nerve receptors and the large numbers of injections that are required. Pain during injection of the palm has been rated an average 68.1 ± 31.8 compared to 29.9 ± 24.5 for axillary treatment (using a visual analogue scale 1–100) ( 15 ). Several methods of pain control have been tried ( Table 11.7 ), although a rare patient will not require anesthesia. Topical anesthetic containing lidocaine and cold packs tend not to provide adequate pain control. More intensive cold exposure can be helpful: the use of dichlorotetrafluoroethane or liquid nitrogen, submersion of the hand in an ice bath, direct exposure of an ice cube or ice pack ( 66 , 67 ). Machines that emit chilled air or utilize a chilled tip can be beneficial but more expensive. Kreyden describes a technique of iontophoresis with 2% lidocaine for 30 minutes, followed by a light spray of liquid nitrogen just prior to inserting the needle to inject BoNTA ( 68 ). The use of a dermojet to inject BoNTA was found to be less painful than standard needle injections, but was much less effective in controlling the sweating and thus not recommended as a useful tool to treat the palms ( 69 ). Benohanian has described the used of a pressure unit to inject lidocaine into the palms and soles without the use of needles, before injecting BoNTA ( 70 ). The Med-JetMBX II (MIT Canada) ( 71 ) device system consists of a CO

2 -powered variable dose injector to

which a 12 cc disposable syringe is attached containing lidocaine. When the trigger is pulled, a volume of 0.02 to 0.3 cc anesthesia is injected to the targeted depth within the skin. The starting pressure is typically around 130 psi (with a range of 1 to 350 psi) depending on the epidermal thickness. The device is approved by Health Canada and the European Union. After the anesthetic wheals appear, BoNT can be administered with a standard needle system.

Nerve blocks are effective and can be performed in the office ( 63 , 72–74 ). The palm is innervated by three nerves, median, ulnar and radial nerves. All can be anesthetized at the level of the wrist using 1% or 2% lidocaine ( Fig. 11.6 ). Risks of a nerve block include infiltration of the nerve with subsequent nerve injury and vascular puncture. In addition, temporary hand weakness after the nerve blocks may limit the patients’ activities and ability to have both hands treated at one session. A 30G 0.5-inch needle should be used to minimize any nerve trauma. Approximately 2 cc of 1% or 2% lidocaine is injected around each of the nerves. If the patient feels any unusual tingling or sensation during the injection, the needle should be withdrawn slightly. Twenty minutes or more may be necessary for the full effect to develop. Intravenous

Table 11.7 Anesthesia Techniques Used for Palmar Injections

Topical anesthesiaNerve blocksCryoanalgesia Dichloretetrafluoroethane

Liquid nitrogen sprayIce cubes, ice pack, or ice bathCold packsMachine-assisted cold air

VibrationIntravenous regional anesthesia (Bier’s block)General anesthesia or sedation anesthesia

regional anesthesia (IVRA), also known as a Bier’s block is effective ( 75 , 76 ). An anesthetic such as prilocaine is injected intravenously following the application of a tourniquet cuff on the forearm. Exsanguination of the extremity is performed and an electronic double cuff is applied. Complete anesthesia is obtained in 20 minutes using 40 to 60 ml of 0.5% prilocaine. The total tourniquet time for IVRA ranges from 50 to 80 minutes and is well-tolerated. Due to the risk of toxic cardiovascular and central nervous system reactions, blood pressure and electrocardiogram are monitored during the IVRA and for about 30 minutes after the procedure.

Vibratory anesthesia is gaining popularity ( 77 ). The theory is that the nervous system is unable to perceive fully two different types of sensory inputs simultaneously. A handheld vibrator is applied to the volar and dorsal surface of the hand near the site of BoNTA injection. This requires an assistant and there is some movement of the patient’s hand, which can make injections challenging. The use of one vibrator to the volar aspect does not diminish pain as much as the use of two vibrators (personal experience). Neither technique results in a pain-free injection, but rather a diminishment of perceived pain. A study by Sherer found that pain threshold is significantly higher during vibra-tion compare to pre- or postvibration, and that vibration applied distal to the site of pain provided better analgesia than vibration applied proximal to the site of pain ( 78 ).

The author most commonly uses ice with pressure at this time for palmar injections. An ice cube is applied firmly to the planned injec-tion site for 7 to 10 seconds ( Fig. 11.7 ). If the patient requires additional pain control, a combination of ice and vibration is used. Ice is applied firmly to the area for 7 to 10 seconds and then the vibrator is firmly applied immediately adjacent to the injection site simultaneous to the injection (no more than 2–3 seconds). This technique does require an assistant and coordinated timing to optimize pain control. A 30G 0.5-inch needle with a leur lock syringe or insulin type syringe is especially helpful because of the thicker skin and higher pressures needed to inject the palm. Injections should be placed every 1 to 1.5 cm but the digits will usually need two to three injection sites per phalangeal unit ( Fig. 11.8 ).

Bruising is common with injections into the palm, but it is tempo-rary. Weakness of the hand or fingers is possible but is usually minor and of limited duration. The incidence varies in published series, but ranges from 0 to 77% ( 23 , 55–57 , 79 ). The most commonly affected area of weakness is the thenar eminence and can be measured in the thumb-index finger pinch, whereas gross strength or grip strength of the hand

Figure 11.6 The palm is innervated by the ulnar, median, and radial nerves. Nerve blocks are usually performed at the wrist.

Ulnar nerve distribution

Median nerve distribution

Radial nerve distribution

Radial injection site

Median injection site

Ulnar injection site

254 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

11 years with palmar HH successfully treated with onabotulinum-toxinA. Nerve blocks were used for pain control and doses of 75 to 150 units were given per palm ( 83 ).

PLANTAR HYPERHIDROSIS Very little has been published on BoNT therapy for plantar HH. Like the palms, there is no consensus on the optimal dose, the duration is variable and the injections are painful. Naumann used 42 and 48 units of onabotulinumtoxinA to treat two soles by injecting 3 U onabotu-linumtoxinA (0.15 ml) into each 2 × 2 cm squares ( 84 ). Blaheta’s group used 100 U onabotulinumtoxinA per sole (100 U/5 ml saline) in a study of eight patients with severe plantar hyperhidrosis ( 85 ). Cam-panati studied 10 patients with plantar hyperhidrosis using 100 U ona-botulinumtoxinA per foot. All patients had an improvement in symptoms and a “significant decrease of Minor’s test” for 12 weeks without significant side effects ( 86 ).

An iodine-starch test will delineate the hyperhidrotic area, which can extend up the sides and onto the dorsum of the foot. BoNTA should be evenly distributed every 1 to 2 cm using small gauge needles and inject-ing into the deep dermis. Injections of the plantar surface can be tech-nically more challenging due to the thickness of the stratum corneum in some areas, especially if calloused. The physician has to adjust for the variation in depth to accurately place BoNTA into the appropriate cutaneous level.

The need for pain control has to be addressed like with palmar injec-tions. IVRA can provide sufficient anesthesia for the sole and has been reported to be effective when administering BoNTA. In a small series of eight patients, IVRA was found to be more effective than nerve blocks in reducing the pain of BoNTA injections ( 87 ). However, nerve blocks can also be used and are generally performed at the level of the ankle ( Fig. 11.9 ). The tibial and sural nerves need to be blocked, and if the dorsum of the foot must be injected, the superficial peroneal nerve can be anesthetized ( 82 ).

Vadoud-Seyedi reported on using the Dermojet to inject BoNTA for plantar HH. Ten patients were treated with 50 U onabotulinum-toxinA/5 ml saline per foot. Fifteen to twenty points were injected per foot and no analgesia was used. The injections were tolerated well by all patients, although one developed a localized hematoma. The duration of benefit lasted 3 to 6 months, however, 20% of patients reported the treatment had no effect on their condition ( 88 ).

At this time, the author’s preferred method of pain control is ice combined with vibration as described earlier ( Fig. 11.10 ). Doses of 100 to 200 U onabotulinumtoxinA per foot are typically required.

Bruising and pain with injection are the most common side effects. In the published literature, one patient reported weakness of plantar flexor muscles in both feet following BoNTA injections, with resolu-tion in 10 days ( 89 ).

FACIAL HYPERHIDROSIS Primary facial HH has several patterns, but most commonly involves the forehead plus or minus the scalp. Patients with craniofacial HH may present with involvement of the forehead, scalp perimeter, entire scalp, cheeks, nose, upper lip, chin, or a combination of the areas ( Fig. 11.11 ). Gustatory sweating is a relatively common complication after surgery or injury in the region of the parotid gland and will be discussed later in the chapter. All forms of facial HH can respond to BoNTA, with gustatory sweating responding for very long periods of time.

There is a paucity of literature published on craniofacial hyper-hidrosis. Kinkelin’s group injected a mean of 86 U onabotulinumtoxinA (3 U BoNTA per injection site) over the forehead at equidistant locations (1–1.5 cm) in 10 men with frontal hyperhidrosis ( 90 ). The injections were kept 1 cm superior to the eyebrow to help prevent drooping of the

is not usually affected ( 55 , 58 ). Rarely, patients report numbness, tingling, or decreased dexterity. Injections of BoNTA should be in the dermal layer, especially over the thenar eminence to limit the chance that the drug will come in contact with the muscle layer. Subepidermal injections may increase the incidence of hematoma ( 57 ). There is one report of atrophy of the intrinsic musculature of the hands with “ debilitating” weakness associated with BoNTA injections for palmar HH, after five treatment sessions using 500 U abobotulinumtoxinA per palmar basin every nine months ( 80 ). Patients should be ade-quately counseled on the risks of weakness, which is usually mild and transient.

In an attempt to prevent muscle weakness, Zaiac advocates the use of the ADG® needle, a device designed for the injection of collagen ( 81 ). He found the average depth of the eccrine glands in 10 consecutive palmar biopsies to be 2.6 mm. By adjusting the needle to a length of 2.6 mm and using a total of 60 to 70 U onabotulinumtoxinA per palm, he had no weakness in a series of 10 patients. Likewise, Almeida uses an adapter to shorten her 7 mm 30G needle to measure 2.5 to 3.0 mm for palmar injections ( 60 , 82 ).

Children with palmar hyperhidrosis can be treated with BoNTs but pain control remains the biggest challenge. Less is known about the dosing, duration, and adverse events associated with pediatric use. Coutinho dos Santos published a series of nine children aged 6.5 to

Figure 11.7 Ice is firmly applied to the palm for 7–10 seconds before injection of botulinum toxin.

Figure 11.8 Typical injection pattern of palm and digits.

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 255

Böger treated 12 men suffering from bilateral craniofacial hyperhi-drosis with abobotulinumtoxinA 0.1 ng per injection ( 91 ). Half of the forehead was treated using a total of 2.5 to 4 ng injected equidis-tantly with a total of 25 to 40 injections given. Decreased sweating was seen within 1 to 7 days after injection and lasted a minimum of 3 months, but one patient experienced anhidrosis for 27 months. Side effects were limited to temporary weakness of the frontalis muscle (100%), and brow asymmetry that lasted 1 to 12 months in 17% of subjects.

It is the observation of the author that patients typically present with forehead sweating that may be combined with scalp sweating in a diffuse pattern or in an ophiasis pattern. OnabotulinumtoxinA injections are performed with 2 to 3 U every 1 to 2 cm avoiding the inferior 1 to 2 cm of the forehead to reduce the risk of brow ptosis ( 92 ) ( Figs. 11.12 and 11.13 ) The forehead can be treated more inferiorly if the response is not suffi-cient and the patient is willing to accept brow ptosis. Doses range from 50 U (forehead) to 250 to 300 U for the forehead and entire scalp ( 92 ).

GUSTATORY SWEATING (FREY’S SYNDROME) Gustatory sweating occurs on the cheek in response to salivation or anticipation of food. It may result from misdirection of autonomic nerve fibers after surgery and is frequently observed in diseases of the parotid gland and in diabetes.

BoNT is a highly effective treatment option for gustatory sweating as shown by several uncontrolled studies ( 93–97 ) ( Table 11.8 ). In a large

eyelid; injections were intracutaneous. Five of 10 patients had partial disability in frowning of the forehead, but was limited to a maximum of 8 weeks. There was no ptosis noted and satisfaction was good or excellent in 90% of the subjects. The benefits were maintained for 5 months in 90% of patients. Similarly, Tan and Solish report that symp-toms return on average 4 12 months after treatment of the forehead ( 15 ).

Figure 11.9 The injection point of tibialis. (a) Saphenous block, 1 = medial malleolus, 2 = posterior tibialis artery, 3 = injection points for tibialis block, 4 = area of subcutane-ous infiltration for saphenous block; (b) Fibularis block, 1 = lateralis malleolus, 2 = area of subcutaneous infiltration for saphenous block; (c) Profundus block, 1 = dorsalis pedis artery, 2= injection points for fibularis profundus block. Source : From Ref. 68, p. 282.

(A)

(B)

(C)

Figure 11.10 When ice and vibration is combined, ice is applied with firm pressure for 7–10 seconds before applying vibration to the immediate treatment area.

256 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

open study of 45 patients, there was a significant reduction of local facial sweating after injection of onabotulinumtoxinA using a mean dose of 21 U (range 5–72 U) and no recurrence of sweating was obser-ved during the follow-up period of 6 months. A marked long-lasting benefit of 11 to 36 months was also observed in three other open stud-ies ( 95–97 ). Thus, BoNT appears to have a particularly long-lasting effect on gustatory sweating. The reason for this is unclear.

In clinical practice, the Minor’s iodine-starch test should be performed before injection to visualize the affected area that has to be injected ( Fig. 11.14 ). After the iodine and starch have been applied to the area, the patient should chew on a piece of candy or food to stimulate the facial sweating. Injections with 2 to 3 U onabotulinumtoxinA or 8 U abobotu-linumtoxinA are given intradermally at sites 2.0 to 2.5 cm apart and evenly distributed over the affected area. Specific side-effects of the injec-tion of BoNT include pain on injection, local hematomas, and local muscle weakness due to diffusion of the toxin to adjacent muscles (particularly, the zygomatic muscle).

Figure 11.11 Cranio-facial hyperhidrosis. Right side of face Minor’s iodine-starch test prior to treatment. (a) Right side of face, (b) forehead, and (c) left side of face. Source : Photographs courtesy of Anthony V. Benedetto, DO, FACP.

(A)

(B)

(C)

Figure 11.12 Injection pattern for craniofacial hyperhidrosis. Injections should be intradermal to avoid muscular affect.

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 257

OTHER SWEATING DISORDERS Inguinal HH affects 2 to 10% of individuals with primary HH ( 14 ). It usually develops in adolescence and can be associated with excessive sweating at other body sites. Intradermal injections of BoNTA can con-trol symptoms for 6 months or more. Identifying the surface areas that needs injection by the iodine-starch test can be technically challenging due to the body location, but is valuable ( Fig. 11.15 ). Two to three units onabotulinumtoxinA are injected every 1 to 2 cm within the affected area; typical doses range from 60 to 100 U per side ( 98 ).

Compensatory sweating is the most common complication of endo-scopic transthoracic sympathectomy (ETS), ranging from 44% to 91% ( 99 ) ( Figs. 11.4 and 11.16 ) Treatment has been particularly difficult but a couple of reports noted success using BoNTA. Huh used 300 U abo-botulinumtoxinA to treat the chest and abdomen after identifying the area with an iodine-starch test ( 99 ). He diluted each 100 U of onabotu-linumtoxinA with 10 ml saline and injected 0.1 ml into each square centimeter. The effects gradually reduced but were reported to remain for 8 months. Belin and Polo reported good results treating the upper abdomen with onabotulinumtoxinA, but unfortunately their patient’s compensatory sweating was from the nipple line down to his knees and the entire area was not treated ( 37 ). Kim and colleagues reported on 17 patients with severe compensatory hyperhidrosis being treated with BoNTA ( 100 ). One hundred to 500 units of onabotulinumtoxinA were used, administering 2 units every 1.5 cm. The injections were

Table 11.8 Selected Studies on BoNTA Treatment of Gustatory Sweating

Author Year Design n Dose (mean)Duration

(mo)

Naumann et al. (94) 1997 Open 45 21 mu

onabotulinum-

toxinA

6

Bjerkhoel

and Trobbe (95)

1997 Open 15 37 mu

onabotulinum-

toxinA

13

Laskawi et al. (96) 1998 Open 19 31 mu

onabotulinum-

toxinA

11–27

Laccourreye et al. (97) 1999 Open 33 86 mu

abobotulinum-

toxinA

12–36

well-tolerated, but the authors noted incomplete resolution of the sweat-ing due to insufficient dosing, and the duration lasted only 4 months.

Chromhidrosis is a rare disorder characterized by the excretion of colored or pigmented sweat. It is most commonly confined to the face or axilla but has been noted elsewhere on the body. Matarasso used 15 U onabotulinumtoxinA into the affected area of each cheek which measured 3 cm in diameter. Within 48 hours, the patient had a marked reduction in the amount of discharged black sweat ( 101 ).

ROSS SYNDROME Ross syndrome was first described by the neurologist Alexander T. Ross in 1958 ( 102 ). It is characterized by the triad of unilateral

Figure 11.13 Injection into the hairline for therapy of forehead hyperhidrosis. Figure 11.14 Patient with Frey syndrome. Distinct hyperhidrosis of a confined area of the cheek during or after eating due to misdirected re-sprouting of postsynaptic salivomotor parasympathetic fibers after parotid gland surgery or infection. Source : From Ref. 68, p. 288.

Figure 11.15 Hyperhidrosis of the left groin area after a Minor’s iodine-starch test. As shown the affected area can be extensive, which has to be considered before treatment. Source : From Ref. 68, p. 290.

258 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

causes ( 102 ). There is no histologic evidence of nerve fiber destruc-tion. Therefore Ross postulated a defect in acetylcholine cholinester-ase activity, rather than the degeneration of sweat glands. The progression of Ross syndrome is very slow. There is no therapy for the segmental progressive anhidrosis. The bothersome compensatory hyperhidrosis can be improved, however, with systemic antimusca-rinic drugs or with injections of BoNTA into the affected areas, usu-ally the face. In 1992 Itin et al. ( 104 ) presented a case study of a patient suffering from Ross syndrome with a defined area of anhidro-sis in the right hand, the right axilla, and the right side of the face. In follow-up, after 11 years, the patient presented with additional anhi-drotic areas in the right hemithorax and the underside of the left arm ( Fig. 11.17 ). Unfortunately the patient refused treatment with ona-botulinumtoxinA, even though the hyperhidrosis was so severe that electrolyte replacement was necessary (unpublished data).

Localized Unilateral Hyperhidrosis Localized unilateral hyperhidrosis (LUH) is a rare form of idiopathic localized hyperhidrosis and is defined as a confined area of hyperhidro-sis of less than 10 × 10 cm, mainly found on the forehead or the fore-arm, whose pathogenesis is unknown ( Fig. 11.18 ). Beside the unusual localization, the major difference from essential hyperhidrosis is that LUH has no typical triggering factor and occurs even while patients are asleep. The etiology of LUH is unknown but may be due to a misdi-rected reconnection of the sympathetic nerve fiber network after injury, similar to the Frey syndrome ( 105 ). Before onabotulinumtoxinA, no treatment was available for this distinctive but enigmatic skin disorder. However, excellent results have been experienced following injection of 30 U onabotulinumtoxinA in a patient suffering from LUH ( 105 ).

USE OF BOTULINUM TOXIN TYPE B FOR HYPERHIDROSIS Botulinum neurotoxin type B (BoNTB) use has been primarily limited to treatment of cervical dystonia, but there are a few reports of its use for treating HH. Injection of BoNTB can induce focal anhidrosis in a dose-dependant fashion. Birklein found that a threshold dose of 8 U Neurobloc®/Myobloc® (rimabotulinumtoxinB) led to anhidrotic skin

tonic pupils, generalized areflexia (Holmes–Adie syndrome), and progressive segmental anhidrosis with a compensatory band of exces-sive perspiration. Patients suffering from Ross syndrome usually do not perceive the hypohidrosis; instead, it is the compensatory seg-mental hyperhidrosis that is bothersome. In addition, many patients suffer from several symptoms of vegetative dysfunction, such as palpitation, stenocardia, orthostatic hypotonia, and irritable colon ( 103 ). The pathogenesis of Ross syndrome is unknown. Multiple neuropathies of the autonomic nervous system or a failure in the syn-thesis or release of neurotransmitters have been suggested as possible

Figure 11.16 Typical Minor’s iodine-starch test of a patient with compensatory hyperhidrosis after endoscopic thoracic sympathectomy for hyperhidrosis of the forehead. Note the anhidrotic area of the upper trunk (no coloration) and the (com-pensatory) hyperhidrotic purple area of the chest. Source: From Ref. 68, p. 290.

Figure 11.17 Patient with Ross syndrome characterized by progressive segmental anhidrosis with a compensatory band of excessive perspiration leading the patient to the physician. This is the very same patient 11 years after Itin et al. (46) first published their case study, showing extensive progression of the disease (unpublished data). Source: From Ref. 68, p. 289.

Figure 11.18 Patient with localized unilateral hyperhidrosis on his right wrist, show-ing the dripping hyperhidrosis after the Minor’s iodine-starch test. Source: From Ref. 68, p. 291.

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 259

areas greater than 4 cm after 3 weeks. The duration was prolonged for 3 months when 15 U BoNT-B were injected, and for 6 months when 125 U were injected ( 106 ).

Despite its ability to induce anhidrosis, the use of BoNTB is limited by the occurrence of systemic adverse events ( 107 ). Dressler reported that 100 U onabotulinumtoxinA, 2000 U rimabotulinumtoxinB, and 4000 U rimabotulinumtoxinB were equally effective in blocking axillary sweating when studying 19 HH patients ( 108 ). The extent of improvement was similar (16 weeks) in all groups, but the onset of action was earlier with the rimabotulinumtoxinB and there was greater discomfort with the rimabotulinumtoxinB compared with onabotu-linumtoxinA. One patient developed severe dryness of the mouth starting 1 week after injection, lasting 5 weeks as well as accommoda-tion difficulties and conjunctival irritation that lasted 3 weeks. Likewise, patients treated with 5000 U rimabotulinumtoxinB in each axilla achieved excellent reduction in sweating, but the incidence of side effects was high and included dry mouth, headache, and sensory motor symptoms of the hand ( 109 ).

A patient treated with 2500 U BoNTB to each palm for HH devel-oped bilateral blurred vision, indigestion, dry sore throat, and dyspha-gia ( 110 ). The largest published study to date on BoNTB to treat palmar HH included 20 subjects used 5000 U per palm ( 111 ). Adverse events were common: dry mouth or throat (90%), indigestion (60%), excessively dry hands (60%), muscle weakness (60%), and decreased grip strength (50%).

Lower dosing may be the key to reducing the high incidence of side effects ( 112 ). However, because of the incidence of systemic side effects using BoNTB and the high safety profile using BoNTA to treat focal hyperhidrosis, to date, BoNTA is the neurotoxin of choice.

FUTURE DIRECTIONS The use of botulinum toxins has revolutionized the treatment of HH and other secretory disorders. Compared with other treatments, it is unmatched in its efficacy, ease of administration, and patient satisfac-tion. Development of quick, safe, and effective pain control is needed for the treatment of more tender areas such as the palms and soles. New delivery devices are already being researched to help provide the most comfortable and efficient therapy. Kavanagh and colleagues have successfully used a small iontophoresis machine to deliver BoNTA to two patients with severe palmar hyperhidrosis, sparing them the injections ( 113 ). Glogau demonstrated that onabotulinumtoxinA can be successfully delivered into the axillary skin when combined with a proprietary transport peptide molecule (see chap. 9) ( 114 ). Research is ongoing looking at the clinical applications of different BoNT serotypes. Another area of potential research is with combination therapy. For the present, BoNT therapy is a valuable, well- tolerated therapy and can provide meaningful improvement in the quality of life of patients with HH and other secretory disorders.

REFERENCES 1. Goldsmith L. Biology of eccrine and apocrine sweat glands. In:

Freedberg I, Eisen A, Wolff K, Goldsmith L, Katz S, Fitzpatrick T, eds. Fitzpatrick’s Dermatology in General Medicine. New York: McGraw-Hill, 1999: 157–164.

2. Goldsmith L. Goldsmith disorders of the eccrine sweat gland. In: Freedberg I, Eisen A, Wolff K, Goldsmith L, Katz SI, Fitzpatrick T, eds. Fitzpatrick’s Dermatology in General Medicine. New York: McGraw-Hill, 1999: 800–809.

3. Stenn K, Bhawan J. The normal histology of the skin. In: Farmer E, Hood A, eds. Pathology of the Skin. New York: McGraw-Hill, 2000.

4. Glogau R. Botulinum A neurotoxin for axillary hyperhidrosis: no sweat Botox. Dermatol Surg 1998; 24: 817–19.

5. Hund M, Kinkelin I, Naumann M, Hamm H. Definition of axil-lary hyperhidrosis by gravimetric assessment. Arch Dermatol 2002; 138: 539–41.

6. Hornberger J, Grimes K, Naumann M, et al. Recognition, diagno-sis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol 2004; 51: 274–86.

7. Solish N, Bertucci V, Dansereau A, et al. A comprehensive approach to the recognition, diagnosis, and severity-based treatment of focal hyperhidrosis: Recommendations of the Canadian Hyperhi-drosis Advisory Committee. Dermatol Surg 2007; 33: 908–23.

8. Kreyden O, Scheidegger E. Anatomy of the sweat glands, pharma-cology of botulinum toxin, and distinctive syndromes associated with hyperhidrosis. Clin Dermatol 2004; 22: 40–4.

9. Cheshire W, Freeman R. Disorders of sweating. Semin Neurol 2003; 23(4): 399–406.

10. Grazziotin T, Buffon R, Manzoni A, Libis A, Weber M. Treatment of granulosis rubra nasi with botulinum toxin type A. Dermatol Surg 2009; 35: 1298–9.

11. Lear W, Kessler E, Solish N, Glaser D. An epidermiological study of hyperhidrosis. Dermatol Surg 2007; 33: S69–75.

12. Seline P, Jaskierny D. Cutaneous metastases from a chondroblas-toma initially presenting as unilateral palmar hyperhidrosis. J Am Acad Dermatol 1999; 40: 325–7.

13. Strutton D, Kowalski J, Glaser D, Stang P. US Prevalence of hyper-hidrosis and impact on individuals with axillary hyperhidrosis: Results from a national survey. J Am Acad Dermatol 2004; 51: 241–8.

14. Naumann M, Hamm H, Lowe NJ. Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomized controlled trial. Br J Dermatol 2002; 147: 1218–26.

15. Tan S, Solish N. Long-term efficacy and quality of life in the treat-ment of focal hyperhidrosis with botulinum toxin A. Dermatol Surg 2002; 28: 495–9.

16. Kowalski J, Ravelo A, Glaser D, Lowe NJ. Quality-of-life effect of botulinum toxin type A on patients with primary axillary hyper-hidrosis: Results from a North American clinical study popula-tion. P196. 2-7-2003. American Academy of Dermatology Annual Meeting.

17. Walling H. Primary hyperhidrosis increases the risk of cutaneous infection: a case–control study of 387 patients. J Am Acad Der-matol 2009; 61(2): 242–6.

18. Ingordo V, Naldi L, Fracchiolla S, Colecchia B. Prevalence and risk factors for superficial fungal infections among Italian Navy Cadets. Dermatology 2004; 209(3): 190–6.

19. Hamm H, Naumann M, Kowalski J, et al. Primary focal hyperhi-drosis: Disease characteristics and functional impairment. Der-matology 2006; 212: 343–53.

20. Bushara K, Park D. Botulinum toxin and sweating. J Neurol Neu-ros Psy 1994; 57(11): 1437–8.

21. Tugnoli A, Ragona R, Eleopra R, De Grandis D, Montecucco C. Treatment of Frey syndrome with botulinum toxin type F. Arch Otolaryngol Head Neck Surg 2001; 127: 339–40.

22. Schnider P, Binder M, Auff E, et al. Double-blind trial of botuli-num A toxin for the treatment of focal hyperhidrosis of the palms. Br J Dermatol 1997; 136: 548–52.

23. Lowe N, Yamauchi P, Lask G, Patnaik R, Iyer S. Efficacy and safety of botulinum toxin type a in the treatment of palmar hyperhi-drosis: A double-blind, randomized, placebo-controlled study. Dermatol Surg 2002; 28: 822–7.

24. Swartling C, Naver H, Lindberg M. Botulinum A toxin improves life quality in severe primary focal hyperhidrosis. Eur J Neurol 2001; 8(3): 247–52.

260 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

25. Glaser DA, Kowalski J, Eadie N, et al. Hyperhidrosis disease severity scale (HDSS): Validity and reliability results from three studies. Presented at the annual meeting of the American Acad-emy of Dermatology, Washington, DC, 2004.

26. Stolman L. Treatment of hyperhidrosis. Dermatol Clin 1998; 16(4): 863–9.

27. Glaser D, Hebert A, Parlser D, Solish N. Palmar and plantar hyperhidrosis: Best practice recommendations and special considerations. Cutis 2007; 79 (sup 5): 18–28.

28. Benohanian A, Dansereau A, Bolduc C, Bloom E. Localized hyperhidrosis treated with aluminum chloride in a salicylic acid gel base. Int J Dermatol 1998; 37: 701–3.

29. Praharaj SK, Arora M. Paroxetine useful for palmar-plantar hyperhidrosis. Ann Pharmacother 2006; 40: 1884–6.

30. Bajaj V, Langtry JAA. Use of oral glycopyrronium bromide in hyperhidrosis. Br J Dermatol 2007; 157: 118–21.

31. Klaber M, Catterall M. Treating hyperhidrosis: anticholinergic drugs were not mentioned. BMJ 2000; 321(7262): 703.

32. Naumann M, Davidson J, Glaser D. Hyperhidrosis: current understanding, current therapy CME. Medscape 2002.

33. Stolman L. Treatment of excess sweating of the palms by ionto-phoresis. Arch Dermatol 1987; 123: 893–6.

34. Swinehart J. Treatment of axillary hyperhidrosis: combination of the starch-iodine test with the tumescent liposuction technique. Dermatol Surg 2000; 26: 392–6.

35. Gossot D, Galetta D, Pascal A, et al. Long-term results of endo-scopic thoracic sympathectomy for upper limb hyperhidrosis. Ann Thoracic Surg 2003; 75: 1075–9.

36. Kim B, Oh B, Park Y, et al. Microinvasive video-assisted thoraco-scopic sympathicotomy for primary palmar hyperhidrosis. Am J Surg 2001; 181(6): 540–2.

37. Belin E, Polo J. Treatment of compensatory hyperhidrosis with botulinum toxin type A. Cutis 2003; 71: 68–70.

38. Andrews B, Rennie J. Predicting changes in the distribution of sweating following thoracoscopic sympathectomy. Br J Surg 1997; 84(12): 1702–4.

39. Kao M, Chen Y, Lin J, Hsieh C, Tsai J. Endoscopic sympathec-tomy treatment for craniofacial hyperhidrosis. Arch Surg 1996; 131(10): 1091–4.

40. Naumann M, Lowe N, Kumar C, Hamm H. Botulinum toxin type A is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. Arch Dermatol 2003; 139(6): 731–6.

41. Heckmann M, Ceballos-Baumann A, Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Eng J Med 2001; 344(7): 488–93.

42. Heckmann M, Breit S, Ceballos-Baumann A, Schaller M, Plewig G. Side-controlled intradermal injection of botulinum toxin A in recalcitrant axillary hyperhidrosis. J Am Acad Dermatol 1999; 41: 987–90.

43. Schnider P, Binder M, Kittler P, et al. A randomized, double-blind, placebo-controlled trial of botulinum A toxin for severe axillary hyperhidrosis. Br J Dermatol 1999; 140: 677–80.

44. Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. Br Med J 2001; 323: 596–9.

45. Lowe N, Glaser D, Eadie N, et al. Botulinum toxin type A in the treatment of primary axillary hyperhidrosis: a 52-week multi-center double-blind, randomized, placebo-controlled study of efficacy and safety. J Am Acad Dermatol 2007; 56: 604–11.

46. Glaser D, Kowalski J, Ravelo A, Weng EY, Beddingfield F. Func-tional and dermatology-specific quality of life benefits with

repeated botulinum toxin type A treatment of primary axillary hyperhidrosis. Presented at the annual meeting of the American Academy of Dermatology, San Francisco, 2006.

47. Wollina U, Karamfilov T, Konrad H. High-dose botulinum toxin type A therapy for axillary hyperhidrosis markedly prolongs the relapse-free interval. J Am Acad Dermatol 2002; 46: 536–40.

48. Karamfilov T, Konrad H, Karte K, Wollina U. Lower relapse rate of botulinum toxin A therapy for axillary hyperhidrosis by dose increase. Arch Dermatol 2000; 136(4): 487–90.

49. Glaser D. Treatment of axillary hyperhidrosis by chemodenerva-tion of sweat glands using botulinum toxin type A. J Drugs Dermatol 2004; 3: 627–31.

50. Alam M, Dover J, Arndt K. Pain associated with injection of botulinum A exotoxin reconstituted using isotonic sodium chlo-ride with and without preservative: a double-blind, randomized controlled trial. Arch Dermatol 2002; 138: 510–4.

51. Sarifakioglu N, Sarifakioglu E. Evaluating effects of preservative-containing saline solution on pain perception during botulinum toxin type-A injections at different locations: a prospective, sin-gle-blinded, randomized controlled trial. Aesth Plast Surg 2005; 29: 113–5.

52. Vadoud-Seyedi J, Simonart T. Treatment of axillary hyperhidrosis with botulinum toxin type A reconstituted in lidocaine or in nor-mal saline: a randomized, side-by-side, double-blind study. Br J Dermatol 2007; 156: 986–9.

53. Lowe N, Campanati A, Bodokh I, et al. The place of botulinum toxin type A in the treatment of focal hyperhidrosis. Br J Derma-tol 2004; 151: 1115–22.

54. Moreau M, Cauhepe C, Magues J, Senard J. Therapeutics: A double-blind, randomized, comparative study of Dysport vs. Botox in primary palmar hyperhidrosis. Br J Dermatol 2002; 149: 1041–5.

55. Saadia D, Voustianiouk A, Wang A, Kaufmann H. Botulinum toxin type A in primary palmar hyperhidrosis: randomized, single-blind, two-dose study. Neurology 2001; 57: 2095–9.

56. Naver H, Swartling C, Aquilonius S. Treatment of focal hyper-hidrosis with botulinum toxin type A. Brief overview of meth-odology and 2 years’ experience. Eur J Neurol 1999; 6(4): S117–120.

57. Vadoud-Seyedi J, Heenen M, Simonart T. Treatment of idiopathic palmar hyperhidrosis with botulinum toxin. Dermatology 2001; 203: 318–21.

58. Glaser D, Kokoska M, Kardesch C. Botulinum toxin type A in the treatment of palmar hyperhidrosis: the effect of dilution and number of injection sites. American Academy of Dermatology Annual Meeting , Poster. 2001.

59. Baumann L, Frankel S, Esperanza W, Halem M. Cryoanalgesia with dichlorotetrafluoroethane lessens the pain of botulinum toxin injections for the treatment of palmar hyperhidrosis. Der-matol Surg 2003; 29(10): 1057–62.

60. Trindade de Almeida A, Kadunc B, Martins de Oliveira E. Improv-ing botulinum toxin therapy for palmar hyperhidrosis: wrist block and technical considerations. Dermatol Surg 2001; 27: 34–6.

61. Wollina U, Karamfilov T. Botulinum toxin A for palmar hyperhi-drosis. J Eur Acad Dermatol Venereol 2001; 15: 555–8.

62. Aghaei S. Botulinum toxin therapy for palmar hyperhidrosis: experience in an Iranian population. Int J Dermatol 2007; 46: 212–4.

63. Hund M, Rickert S, Kinkelin I, Naumann M, Hamm H. Does wrist nerve block influence the result of botulinum toxin A treatment in palmar hyperhidrosis. J Am Acad Dermatol 2004; 50: 61–2.

BOTULINUM TOXIN IN THE MANAGEMENT OF FOCAL HYPERHIDROSIS 261

64. Perez BA, Avalos-Peralta P, Moreno-Ramirez D, Camacho F. Treatment of palmar hyperhidrosis with botulinum toxin type A: 44 months of experience. J Cosmetic Dermatol 2005; 4: 163–6.

65. Glogau R. Treatment of hyperhidrosis with botulinum toxin. Dermatologic Clinics 2004; 22: 177–85.

66. Kontochristopoulos G, Gregoriou S, Zakopoulou N, Rigopoulos D. Cryoanalgesia with dichlorotetrafluoroethane spray versus ice packs in patients treated with botulinum toxin a for palmar hyperhidrosis: self-controlled study. Dermatol Surg 2006; 32(6): 873–4.

67. Smith K, Comite SL, Storwick GS. Ice minimizes discomfort asso-ciated with injection of botulinum toxin type A for the treatment of palmar and plantar hyperhidrosis. Dermatol Surg 2007; 33: S88–91.

68. Kreyden OP. Botulinum Toxin in the Management of Focal Hyperhidrosis. In: Benedetto, AV, ed. Botulinum Toxin in Clinical Dermatology. Taylor & Francis, 2006; Chapter 10: pp. 281–285.

69. Naumann M, Bergmann I, Hofmann U, Hamm H, Reiners K. Botulinum toxin for focal hyperhidrosis: technical considerations and improvements in application. Br J Dermatol 1998; 139: 1123–4.

70. Benohanian A. Needle-free anaesthesia prior to botulinum toxin type A injection treatment of palmar and plantar hyperhidrosis. Br J Dermatol 2007; 156(3): 593–6.

71. Benohanian A. What stands in the way of treating palmar hyper-hidrosis as effectively as axillary hyperhidrosis with botulinum toxin type A. Dermatol Online J 2009; 15(4): 12.

72. Trindade de Almeida AR, Kandunc BV, Martins de Oliveira. Improving botulinum toxin therapy for palmar hyperhidrosis. Derm Surg 2001; 27: 34–36.

73. Hayton MJ, Stanley JK, Lowe, NJ. A review of peripheral nerve blockade as local anaesthesia in the treatment of palmar hyperhi-drosis. Br J Dermatol. 2003; 149: 447–451.

74. Campanati A, Lagalla G, Penna L, Gesuita R, Offidani A. Local neural block at the wrist for treatment of palmar hyperhidrosis with botulinum toxin: technical improvements. JAAD 2004; 51(3): 345–348.

75. Vollert B, Blaheta H, Moehrle E, Juenger M, Rassner G. Intrave-nous regional anaesthesia for treatment of palmar hyperhidrosis with botulinum toxin type A. Br J Dermatol 2001; 144: 632–3.

76. Ponce-Olivera RM, Tirado-Sanchez A, Arellano-Mendoza MI, Leon-Dorantes G, Kassian-Rank S. Palmar hyperhidrosis. Safety efficacy of two anaesthetic techniques for botulinum toxin ther-apy. Dermatology Online J 2006; 12(2): 9.

77. Reed M. Surgical pearl: mechanoanesthesia to reduce the pain of local injections. J Am Acad Dermatol 2001; 44: 671–2.

78. Scherer C, Clelland J, O’Sullivan P, Doleys D, Canan B. The effect of two sites of high frequency vibration on cutaneous pain threshold. Pain 1986; 25(1): 133–8.

79. Solomon B, Hayman R. Botulinum toxin type A therapy for palmar and digital hyperhidrosis. J Am Acad Dermatol 2000; 42: 1026–9.

80. Glass GE, Hussain M, Fleming AN, Powell BW. Atrophy of the intrinsic musculature of the hands associated with the use of botulinum toxin-A injections for hyperhidrosis: a case report and review of the literature. J Plastic Reconstr Aesthetic Surg 2009; 62(8): 274–6.

81. Zaiac M, Weiss E, Elgart G. Botulinum toxin therapy for palmar hyperhidrosis with ADG needle. Dermatol Surg 2000; 26: 230.

82. Trindade de Almeida A, Boraso R. Palmar hyperhidrosis. In: Trin-dade de Almeida A, Hexsel D, eds. Hyperhidrosis and Botulinum Toxin. Sao Paulo: Know-how Editorial Ltd, 2004: 155–62.

83. Coutinho dos Santos C, Gomes A, Giraldi S, Abagge K, Marinoni L. Palmar hyperhidrosis: long-term follow-up of nine children

and adolescents treated with botulinum toxin type A. Pediatr Dermatol 2009; 26(4): 439–44.

84. Naumann M, Hofmann U, Bergmann I, et al. Focal hyperhidro-sis: effective treatment with intracutaneous botulinum toxin. Arch Dermatol 1998; 134(3): 301–4.

85. Blaheta H, Deusch H, Rasner G, Vollert B. Intravenous regional anesthesia (Bier’s block) is superior to a peripheral nerve block for painless treatment of plantar hyperhidrosis with botulinum toxin. J Am Acad Dermatol 2003; 48(2): 302–4.

86. Campanati A, Bernardini M, Gesuita R, Offidani A. Plantar focal idiopathic hyperhidrosis and botulinum toxin: a pilot study. Eur J Dermatol 2007; 17(1): 52–4.

87. Blaheta H, Deusch H, Rassner G, Vollert B. Intravenous regional anesthesia (Bier’s block) is superior to a peripheral nerve block for painless treatment of plantar hyperhidrosis. J Am Acad Dermatol 2003; 48(2): 301–3.

88. Vadoud-Seyedi J. Treatment of plantar hyperhidrosis with botuli-num toxin type A. Int J Dermatol 2004; 43: 969–71.

89. Sevim S, Dogu O, Kaleagasi H. Botulinum toxin-A therapy for palmar and plantar hyperhidrosis. Acta Neurol Belg 2002; 102: 167–70.

90. Kinkelin I, Hund M, Naumann M, Hamm H. Effective treatment of frontal hyperhidrosis with botulinum toxin A. Br J Dermatol 2000; 143: 824–7.

91. Boger A, Herath H, Rompel R, Ferbert A. Botulinum toxin for treatment of craniofacial hyperhidrosis. J Neurol 2000; 247(11): 857–61.

92. Glaser DA, Herbert AA, Pariser DM, Solish N. Facial hyperhidro-sis: best practice recommendations and special considerations. Cutis 2007; 79(5 Suppl): 29–32.

93. Drobik C, Laskawi R. Frey’s syndrome: treatment with botulinum toxin. Acta Otolaryngol (Stockh) 1995; 115: 459–61.

94. Naumann M, Zellner M, Toyka K, Reiners K. Treatment of gusta-tory sweating with botulinum toxin. Ann Neurol 1997; 42(6): 973–75.

95. Bjerkhoel A, Trobbe O. Frey’s syndrome: treatment with botuli-num toxin. J Laryngol Otol 1997; 111(9): 839–44.

96. Laskawi R, Drobik C, Schonebeck C. Up-to-date report of botuli-num toxin type A treatment in patients with gustatory sweating (Frey’s syndrome). Laryngoscope 1998; 108: 381–4.

97. Laccourreye O, Akl E, Gutierrez-Fonseca R, et al. Recurrent gusta-tory sweating (Frey syndrome) after intracutaneous injection of botulinum toxin type A: incidence, management, and outcome. Arch Otolaryngol Head Neck Surg 1999; 125: 283–6.

98. Hexsel D, Dal’forno T, Hexsel C. Inguinal, or Hexsel’s hyperhi-drosis. Clin Dermatol 2004; 22(1): 53–9.

99. Huh C, Han K, Deo K, Eun H. Botulinum toxin treatment fore compensatory hyperhidrosis subsequent to an upper thoracic sympathectomy. J Dermatol Treat 2002; 13: 91–3.

100. Kim W, Kil H, Yoon K, Noh K. Botulinum toxin: a treatment for compensatory hyperhidrosis in the trunk. Dermatol Surg 2009; 35(5): 833–8.

101. Matarasso S. Treatment of facial chromhidrosis with botulinum toxin type A. J Am Acad Dermatol 2005; 52(1): 89–91.

102. Ross AT. Progressive selective sudomotordenervation. Neurology 1958; 8: 808–17.

103. Kreyden OP. Rare forms of hyperhidrosis. In: Kreyden OP, et al., eds. Hyperhidrosis and Botulinum Toxin in Dermatology. Basel: Karger, 2002; 30: 178–87.

104. Itin P, Hirsbrunner P, Rufli T, et al. Das Ross Syndrom. Hautarzt 1992; 43: 359–60.

105. Kreyden OP, Schmid-Grendelmeier P, Burg G. Idiopathic local-ized unilateral hyperhidrosis. Case report of successful treatment

262 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

with botulinum toxin type A and review of the literature. Arch Dermatology 2001; 137: 1622–5.

106. Birklein F, Eisenbarth G, Erbguth F, Winterholler M. Botulinum toxin type B blocks sudomotor function effectively: a 6 month follow up. J Invest Dermatol 2003; 121(6): 1312–6.

107. Schlereth T, Mouka I, Eisenbarth G, Winterholler M, Birklein F. Botulinum toxin A (Botox) and sweating-dose efficacy and com-parison to other BoNT preparations. Autonom Neurosci 2005; 117: 120–6.

108. Dressler D, Abid Saberi F, Benecke R. Botulinum toxin type B for treatment of axillary hyperhidrosis. J Neurol 2002; 249: 1729–32.

109. Nelson L, Bachoo P, Holmes J. Botulinum toxin type B: a new therapy for axillary hyperhidrosis. Br J Plastic Surg 2005; 58: 228–32.

110. Baumann L, Halem M. Systemic adverse effects after botulinum toxin type B (myobloc) injections for the treatment of palmar hyperhidrosis. Arch Dermatol 2003; 139: 226–7.

111. Baumann L, Slezinger A, Halem M, et al. Double-blind, random-ized placebo-controlled pilot study of the safety and efficacy of myobloc (botulinum toxin type B) for the treatment of palmar hyperhidrosis. Dermatol Surg 2005; 31: 263–70.

112. Hecht M, Birklein F, Winterholler M. Successful treatment of axillary hyperhidrosis with very low doses of botulinum toxin B: a pilot study. Arch Dermatol 2003; 295: 318–9.

113. Kavanagh G, Oh C, Shams K. BOTOX delivery by iontophoresis. Br J Dermatol 2004; 151: 1093–5.

114. Glogau R. Topically applied botulinum toxin type a for the treat-ment of primary axillary hyperhidrosis: results of a randomized, blinded, vehicle-controlled study. Dermatol Surg 2007; 33: S76–80.

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failure to reschedule treatment, and clinical effect falling short of expectations. In short, most of the reasons given (except possibly cost) are seemingly directly related to poor patient–physician communication ( 6 ).

To improve communication, the practice decided to institute a man-datory 2-week posttreatment office evaluation for new BoNTA patients to determine treatment effect, to administer touch-ups if needed, and to address patient expectations and treatment-related concerns. Since initiating this mandatory follow-up, retention rate of BoNTA patients in the practice increased from 55% to 67%.

Thankfully, BoNTA dissatisfaction leading to discontinuation of BoNTA injections does not usually have associated medicolegal con-siderations. However, some patients dissatisfied with BoNTA may actually have BoNTA-induced associated complications. A recent review of BoNTA adverse reactions occurring after treatments for medical and not cosmetic purposes reported 28 deaths and 17 seizures among 406 reports of serious adverse events ( 7 ). All of these patients treated for their medical conditions, received significantly higher dos-ages of BoNTA than is commonly used for cosmetic treatments. Among the 28 deaths, 6 were attributed to respiratory arrest, 5 to myocardial infarction, 3 to cerebrovascular accident, 2 to pulmonary embolism, 2 to pneumonia (1 known to be aspiration pneumonia), 5 to other known causes, and 5 to unknown causes of death. Death occurred a median of 3 days after BoNTA injection (range: <1 hour–120 days). The median age of BoNTA recipients who died was 44 years (range: 3–91 years). Of the 28 patients who died, 26 had underlying systemic diseases with elevated risk of mortality, in addition to the symptoms for which they received BoNTA. The possibility of a causal role for underlying diseases made it difficult to evaluate the role of BoNTA in the fatalities. It would seem, based on these facts, that warning patients of the risk of seizures and death after BoNTA used for cosmetic procedures is not legally required.

The more serious reported events associated with onabotulinum-toxinA include dysphasia, muscle weakness, allergic reactions, and flu-like symptoms ( 7 ). These have all been extraordinarily rare reported events, and may not always be directly related to the BoNTA injection, and probably are not reasonable risks to discuss with patients who are seeking facial cosmetic BoNTA injections.

Among 995 reported cosmetic cases with a nonserious compli-cation, lack of intended cosmetic effect was most commonly noted. Injection site reaction, ptosis muscle weakness, and headache were frequently reported complications ( 7 ).

What should be clear is that there are some obvious contraindica-tions to BoNTA use for cosmetic purposes. These would include prior allergic reaction, injection into areas of infection or inflammation, pregnancy (safety for use during pregnancy has not been established), or breastfeeding. Women who inadvertently have been injected during pregnancy thus far have had uneventful deliveries, and to date no tera-togenicity has been attributed to botulinum toxin. Nonetheless, delay of injections would be the likely recommendation until pregnancy is complete and breastfeeding has ended.

Relative contraindications to BoNTA treatment would include patients with diseases of the neuromuscular junction (e.g., myasthenia gravis) because of the underlying generalized muscle weakness seen with such diseases. Local weakness at injection sites would be expected in such patients. In addition, some medications decrease neuromuscular transmission and generally should be avoided in patients treated with

12 Medicolegal considerations of cosmetic treatment with botulinum toxin injections David J. Goldberg

Botulinum toxin injections have become one of the most popular cosmetic treatments throughout the world over the past decade. How-ever, the recognition of the effects of this toxin has been known for over a century. It was Justinus Kerner, a German physician, who first studied the potent effects of botulinum toxins during the Napoleonic Wars, after a reported increase in food-poisoning deaths in persons eating sausages. After a series of experiments on animals and self, he hypoth-esized that the toxin was produced under anaerobic conditions, that it acted on the autonomic and motor nervous system, and that it was lethal in small doses ( 1 ). The use of botulinum toxins, for modern day medical purposes, began in the 1960s, when Scott et al. investigated the therapeutic uses of this drug in humans suffering from strabismus and blepharospasm ( 2–4 ). In the United States, the Food and Drug Admin-istration (FDA) approved botulinum toxin type A (BoNTA) for these conditions in 1989. In 2000, the FDA expanded the approved indica-tions to include cervical dystonia. In 2002, FDA approved the use of BoNTA for cosmetic uses.

Independent surveys by the American Society for Aesthetic Plastic Surgery and the American Society of Plastic Surgeons suggest that, in 2002, between 1.1 and 1.6 million patients in the United States received cosmetic injections with BoNTA. In 2008 the number had increased to 2.5 million patients. These numbers clearly are increasing yearly both in the United States and elsewhere throughout the world ( 5 ).

Although a very safe substance when used with appropriate dosing, BoNTA injections can be associated with complications. Such compli-cations may be associated with medicolegal considerations. This chap-ter will review the reported BoNTA-associated complications and the legal impact these implications may have on the injecting physician. A wide variety of complications may occur. It should be noted though that the most common complication, that of patient dissatisfaction, may have nothing to do with actual physician technique.

Patient dissatisfaction can, and should be, of concern to physicians who perform BoNTA injections. The disgruntled patient typically fails to return for further treatment or, less commonly, may assert negli-gence and sue for economic damages.

Why do some patients fail to return for BoNTA injections? There are few published studies evaluating patient satisfaction and retention in dermatology for cosmetic procedures. One recently published study explored why a high percentage of patients may not return for repeat botulinum toxin injections ( 6 ).

In the study, a private cosmetic dermatology practice reviewed the charts of all patients who had received BoNTA injections over a 2-year period to determine the patient retention rate, defined as the percent-age of patients who returned for BoNTA treatment within 6 months after the initial injection ( 6 ). In particular, patients who had discontin-ued BoNTA treatment after a single session were surveyed to learn their reasons for termination.

Between November 2002 and October 2004, 361 patients received BoNTA cosmetic treatments for the first time. Chart review revealed that 55% (198/361) of these patients returned for additional BoNTA injections, but that 45% (163/361) discontinued BoNTA treatment, although 67% (109/163) of these patients continued to receive other cosmetic procedures. A retention rate of 55% was not as high as was expected.

The practice surveyed 50 patients who had discontinued BoNTA treatments after an initial injection. The most common reasons cited were procedural cost, perceived lack of product longevity, patient

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botulinum toxin. These include aminoglycosides, penicillamine, quinine, and calcium channel blockers ( 8 ).

The most common reactions to botulinum toxin injections are gen-erally mild and transient and they are discussed in detail in their respective chapters on injection techniques (chapters 3–5). These include nausea, fatigue, malaise, flu-like symptoms, and rashes at sites distant from the injections. Untoward sequelae commonly caused by a percutaneous injection include pain, edema, erythema, ecchymosis, headache, and hypesthesia. These also are generally mild and transient. The most common meaningful adverse effect is unwanted weakness in nontargeted muscles. Fortunately, unwanted weakness caused by the action of the toxin usually resolves in several months and in some patients in a few weeks, depending on the site, strength of the injec-tions, and the muscles made excessively weak ( 8 ). More infrequently experienced reactions to BoNTA injections include nausea, fatigue, malaise, flu-like symptoms, and rashes at sites distant from the injection sites (see Appendix 5).

Muscle weakness is the result of the desired toxin effect on injected musculature. This can be a desired goal in most and a problem with imagined or presumptive medical legal overtones for others. For exam-ple, patients who depend on emotive expression, such as actors and politicians, can be significantly negatively impacted by a potential reduction in expression. Excess weakness following frontalis injection may cause paralysis rather than weakening of the muscle. Patients may report they appear masklike and their brow feels heavy. If brow ptosis occurs, a hooded appearance may be present, and occasionally vision may be partially obstructed. If the lateral fibers of the frontalis have not been injected appropriately, a quizzical appearance may result in which the lateral brow is pulled up while the central brow is lowered. This can be improved by simply injecting a small amount of toxin into the lateral frontalis fibers.

Since brow depressors are generally weakened when treating glabel-lar lines, ptosis of the upper eyelid can occasionally result following improper injection technique in this region. This may occur as late as 2 weeks after injection. Ptosis is caused by migration of toxin through the orbital septum weakening the levator palpebrae superioris. Patients who are instructed to and remain in an upright position for 3–4 hours following injection while avoiding manual manipulation of the area may be at less risk of eyelid ptosis. Active contraction of the muscles under treatment may increase the uptake of toxin and decrease its dif-fusion. Ptosis can be treated with apraclonidine 0.5% eye drops. Apra-clonidine is an alpha2-adrenergic agonist, which causes Müller’s muscles to contract. It should be noted that apraclonidine is contrain-dicated in patients with documented hypersensitivity. Phenylephrine 2.5% can be used when apraclonidine is not available. Phenylephrine is contraindicated in patients with narrow-angle glaucoma and in patients with aneurysms.

Weakness of the lower eyelid or lateral rectus can occur following injection of the lateral orbicularis oculi. If severe lower lid weakness occurs, an exposure keratitis may result. If the lateral rectus is weak-ened, diplopia results. Treatment is symptomatic. This complication is best avoided by injecting at least 1 cm lateral to the lateral canthus and above the zygomatic arch.

Injection of platysma muscles can result in dysphagia from diffusion of toxin into muscles of deglutition. When this occurs, it usually lasts only a few days or weeks. Some patients may require soft foods. Although a swallowing weakness does not necessarily herald systemic toxicity. However, if it is severe, patients may be at theoretical risk of aspiration.

Some patients experience neck weakness after botulinum toxin injections into the neck. This may be especially noticeable when attempting to raise the head from a supine position. This is thought to occur from a weakening of the sternocleidomastoid muscles, either

from direct injection or diffusion. This rare complication appears to be more common in women with long, thin necks.

Any discussion of complications induced by botulinum toxin injec-tions raises the issue of what is required in an informed consent ( 9 ). Generally, in the United States reasonable risks must be detailed to the prospective patient. What is a reasonable risk may be open to discus-sion. It represents the “standard of care.” The duty of a physician using botulinum toxin is to use botulinum toxin in accordance with the stan-dard of care. The standard of care is somewhat simplistically defined as “what would a reasonable physician do if in an identical situation with an identical patient.” Although the elements of a cause of action in neg-ligence are derived from formal legal textbooks, the standard of care is not necessarily derived from some well-known textbook ( 10 ). It is also not articulated by any judge. The standard of care is defined by some, as whatever an expert witness says it is in the confines of the court-room, and what a jury will believe. In a case against any cosmetic physi-cian, the specialist must have the knowledge and skill ordinarily possessed by a specialist in that field, and has used the care and skill ordinarily possessed by a specialist in that particular field of specialty in the same or similar locality under similar circumstances. A derma-tologist, plastic surgeon, otolaryngologist, internist, or aesthetic medi-cine physician will all be held to an equal standard. A failure to fulfill such a duty may lead to loss of a lawsuit by the physician. If the jury accepts the suggestion that the doctor mismanaged the case and that the negligence led to damage of the patient, then the physician will be liable. In the case of botulinum toxin injections mistreatment may both lead to damages and physician liability. Conversely, if the jury believes an expert who testifies for the defendant doctor, then the stan-dard of care, in that particular case has been met. In this view, the stan-dard of care is a pragmatic concept, decided case by case, and based on the testimony of an expert physician. The physician injecting botuli-num toxin is expected to do this in the manner of a reasonable physi-cian. He need not be the best in his field; he need only perform the procedure in a manner that is considered by an objective standard as reasonable. This objective standard, although seemingly subjective, is determined by expert witness during in-court testimony. For example, if a physician chose to use a dilution of BoNTA that is not in accor-dance with the manufacturer’s suggested dilution but works well and gives optimal results, then this dilution would be considered reason-able and would not lead to loss of a medical malpractice lawsuit.

It is important to note that where there are two or more recognized approaches to injecting botulinum toxins, a physician does not fall below the standard of care by using any of the acceptable methods even if one method turns out to be less effective than another method. Finally, in many jurisdictions, an unfavorable result due to an “error in judgment” by a physician is not in and of itself a violation of the stan-dard of care if the physician acted appropriately prior to exercising his professional judgment.

Evidence of the standard of care in a specific malpractice case includes laws, regulations, and guidelines for practice, which represent a consensus among professionals on a topic involving diagnosis or treatment, and the medical literature including peer-reviewed articles and authoritative texts. In addition, obviously, the view of an expert is crucial. Although the standard of care may vary from state to state in the United States, it is typically defined as a national standard by and for physicians ( 11 ).

Most commonly for litigation purposes, as described above, expert witnesses articulate, in court, the standard of care. The basis of the expert witness testimony, and therefore the origin of the standard of care, is grounded in the following:

1. The witness’ personal practice; 2. The practice of others that he has observed in his experience;

MEDICOLEGAL CONSIDERATIONS OF COSMETIC TREATMENT WITH BOTULINUM TOXIN INJECTIONS 265

3. Medical literature in recognized publications; 4. Statutes and/or legislative rules; and/or 5. Courses where the subject is discussed and taught in a

well-defined manner.

The standard of care is the way in which the majority of the physi-cians in a similar medical community would practice. If, in fact, the expert personally does not practice like the majority of other physi-cians, then the expert will have a difficult time explaining why the majority of the medical community does not practice according to his or her ways ( 12 ).

It would seem then that in the perfect world, the standard of care in every case would be a clearly definable level of care agreed upon by all physicians and patients. Unfortunately, in the typical situation the standard of care is an ephemeral concept resulting from differences and inconsistencies among the medical profession, the legal system, and the public.

At one polar extreme, the medical profession is dominant in deter-mining the standard of care in the practice of medicine. In such a situ-ation, recommendations, guidelines, and policies regarding varying treatment modalities for different clinical situations published by nationally recognized boards, societies, and commissions establish the appropriate standard of care. Even in some of these cases, however, fac-tual disputes may arise because more than one such organization will publish conflicting standards concerning the same medical condition. Adding to the confusion, local societies may publish their own rules applicable to a particular claim of malpractice.

Thus, in most situations the standard of care is neither clearly defin-able nor consistently defined. It is a legal fiction to suggest that a gener-ally accepted standard of care exists for any area of practice. At best there are parameters within which experts will testify. The cosmetic physician’s best defense that he is acting in accordance with the stan-dard of care is to document appropriate risk assessment of the patient, provide appropriate medical record documentation, appropriate informed consent, and finally to utilize appropriate diagnostic and treatment approaches ( 13 ).

American physicians have in recent years put forth substantial efforts toward standard setting, and specifying treatment approaches to vari-ous conditions. Clinical practice guidelines have been developed by specialty societies such as the American Academy of Dermatology, the American Society for Dermatologic Surgery, and the American Society of Aesthetic Plastic Surgery. The Institute of Medicine has defined such clinical guidelines as “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.” Such guidelines represent standardized specifications for performing a procedure or managing a particular clinical problem.

Clinical guidelines raise thorny legal issues ( 11 ). They have the potential to offer an authoritative and settled statement of what the standard of care should be for a given skin condition. A court would have several options when such guidelines are offered as evidence. Such a guideline might be evidence of the customary practice in the medical profession. A doctor acting in accordance with the guidelines would be shielded from liability to the same extent as one who can establish that she or he followed professional customs. The guidelines could play the role of an authoritative expert witness or a well-accepted review article. Using guidelines as evidence of professional custom, however, is prob-lematic if they are ahead of prevailing medical practice.

Clinical guidelines have already had an effect on settlement, accord-ing to surveys of malpractice lawyers. A widely accepted clinical stan-dard may be presumptive evidence of due care, but expert testimony will still be required to introduce the standard and establish its sources and its relevancy.

Professional societies often attach disclaimers to their guidelines, thereby undercutting their defensive use in litigation. The American Medical Association, for example, calls its guidelines “parameters” instead of protocols intended to significantly impact on physician dis-cretion. The AMA further suggests that all such guidelines contain disclaimers stating that they are not intended to displace physician discretion. Such guidelines, in such a situation, could not be treated as conclusive.

Plaintiffs usually will use their own expert, as opposed to the physi-cian’s expert, to define the standard of care. Although such a plaintiff ’s expert may also refer to clinical practice guidelines, the physician’s neg-ligence can be established in other manners as well. These methods include (1) examination of the physician defendant’s expert witness, (2) an admission by the defendant that he or she was negligent, (3) testimony by the plaintiff, in a rare case where s/he is a medical expert qualified to evaluate the allegedly negligent physician’s conduct, and (4) common knowledge in situations where a layperson could under-stand the negligence without the assistance of an expert.

It is clear then that although complications may occur following botulinum toxin injections, the plaintiff, in order to win his or her neg-ligence cause of action against an aesthetic physician, must establish that his or her physician had a duty of reasonable care in treating him or her and had in fact breached that duty. However, that breach must also lead to some form of damages. A mere inconvenience to the plain-tiff, even in the setting of a physician’s breach, will usually not lead to physician liability in a cause of action for negligence. In general, most botulinum toxin induced complications are temporary and nothing more than an inconvenience. However, in those rare situations, where a patient was not warned of a potential complication, and the ensuing complication led to damages (such as the inability to work), there may be legal implications from the botulinum toxin–induced complication.

In the United States, thankfully lawsuits brought against physicians for negligent use of BoNTA are quite rare. It is because the effects of BoNTA wear off long before a court trial would begin that such claims are so rare. We discuss two examples of such lawsuits.. In one case, a television anchorwoman was given BoNTA in her frontalis region. Because of negligent technique, her eyebrows were lifted in the so-called mephisto pattern. Even though the deformity was treated to cor-rection some weeks after the injection, she missed out on 2 weeks of work with its economic impact and associated embarrassment. She sued her physician. Although the case never went to trial, she settled for economic damages. Similarly a musician working in a jazz band had BoNTA injected in his lip and for almost 1 month was unable to suc-cessfully blow into his musical instrument. As in the previous case, he settled for monies after bringing a lawsuit because of economic dam-ages ensuing from his inability to play his instrument. A similar case occurred in which a patient claimed dysphagia after injections of BoNTA into her neck. In all cases, the plaintiffs contended they were never warned that this complication might happen—clearly a breach in the standard of care.

BoNTA injections into either the forehead or upper lip would be considered off-label since the FDA labeling (FDA-approval process) is for glabellar folds. In contrast to some countries in Europe where the physician use of a drug off-label is restricted, the FDA has traditionally encouraged such behaviors by U.S. physicians and looks at this as a way of further developing medical research and care in the United States. However, the use of any drug (including BoNTs) for off-label purposes can lead to problems for the physician. In one case brought to trial in the United States, a dermatologist was using onabotulinumtoxinA off-label for the treatment of headaches. The plaintiff subsequently devel-oped a disabling illness and contended that it was caused by the off-label use of the onabotulinumtoxinA by a physician who would not

266 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

CONCLUSION In 1959 Lammana referred to botulinum toxin as “the most poisonous poison” ( 16 ). Written long before the notion of the aesthetic use of botulinum neurotoxins was conceived and its safety well established, Lammana’s opinion of BoNTA today could be used as ammunition by aggressive lawyers and their dissatisfied clients. Also, given the high rates of medical malpractice in the United States, physicians perform-ing cosmetic dermatologic procedures are advised to institute certain measures when treating patients to reduce the likelihood of patient dis-satisfaction and potential litigation. These include establishing a good rapport with their patients; prescreening patients prior to performing procedures, not only for obvious contraindications to treatment but for any “warning signs” that might indicate the patient is looking for something that may not satisfy him or her; using appropriate consent forms that outline reasonable risks (see Appendix 4); and taking action to correct any potential adverse outcomes, should they occur. These steps are part of good medical care and should be performed at all times. Understanding the medicolegal considerations of the cosmetic treatment with botulinum toxin injections remains an important part of the everyday cosmetic practice.

REFERENCES 1. Erbguth F. Botulinum toxin, a historical note. Lancet 1998; 351:

1280. 2. Scott AB, Rosenbaum A, Collins CC. Pharmacological weakening

of extraocular muscles. Invest Ophthalmol Vis Sci 1973; 12:924–7. 3. Scott AB, Suzuki D. Systemic toxicity of botulinum toxin by intra-

muscular injection in the monkey. Mov Disord 1988; 3: 333–5. 4. Scott AB. Botulinum toxin injection of eye muscle to correct

strabismus. Trans Am Ophthalmol Soc 1981; 79: 734–70. 5. American Society of Plastic Surgeons. [Available at http://www.

plasticsurgery.org/Patients_and_Consumers/Procedures/ Cosmetic_Procedures/Botulinum_Toxin.html]

6. White L, Tanzi EL, Alster TS. Improving patient retention after botulinum toxin type A treatment. Dermatol Surg 2006; 32: 212–15.

7. Coté TR, Mohan AK, Polder JA, Walton MK, Braun M. Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. JAAD 2005; 53: 407–15.

8. Glogau RG. Review of the use of botulinum toxin for hyperhidro-sis and cosmetic purposes. Clin J Pain 2002; 18 (Suppl); S191–7.

9. Gershon SK, Wise RP, Braun MM. Adverse events reported with cosmetic use of botulinum toxin A. Pharmacoepidemiology Drug Safety 2001; 10 (Suppl): S135–6.

10. Furrow BF, Greaney TL, Johnson SH, Jost TS, Schwartz RL. Liability in Health Care Law, 5th edn. St. Paul, MN: West Publishing , 2004.

11. Hyams AL, Shapiro DW, Brennan TA. Medical practice guidelines in malpractice litigation: an early retrospective. J. Health Policy Law 1996; 21: 289.

12. Lamont v. Brookwood Health Service, Inc., 446 So.2d 1018 (Ala.1983).

13. Gannon v. Elliot, 19 Cal.App.4th 1 (1993). 14. Botox lawsuit is raising eyebrows. NY Times, April 4, 2004 15. Jesitus J. Bogus botox sounds wake-up call. Dermatology Times

February 1, 2005. [Available at: http://www.dermatologytimes.com/dermatologytimes/article/articleDetail.jsp?id=146023]

16. Lamanna C. The most poisonous poison. Science 1959;130: 763–72.

in general be treating headaches. Although the dermatologist, at trial, was not found to be culpable, the case is an example of what can hap-pen when products are used off-label. Some physicians are concerned that there will be increasing restrictions for off-label use. This has yet to be decided ( 14 ).

Recently the FDA mandated a “black box warning” for manufactur-ers selling botulinum toxins in the United States. This information, mandated by the FDA, must be provided with every vial of sold botuli-num toxin. The warning contains the following:

• Read this information this time and every time you get botuli-num toxin.

• Share this information with your family and caregivers.

• Problems with swallowing, speaking, or breathing may occur.

• These problems may occur weeks after the injections.

• Swallowing problems may require a feeding tube.

• Muscle weakness may occur all over the body.

• Loss over bladder control may occur.

• Death can happen.

• These problems could make it unsafe for you to drive a car or do other dangerous activities.

• This medication guide has been approved by the FDA.

Although it is clear that such a warning must be contained within the manufacturer packaging, the obvious question remains. Is it necessary to warn patients of dire complications that have never been reported with the cosmetic use of this product? Most clinicians are convinced that such a warning would preclude patients from seeking this elective cosmetic treatment. Unfortunately there is no easy legal answer to the question. What can be advised is a practical approach of mentioning the “black box” warning in the consent and encouraging discussion with patients regarding the issue. Currently a coalition of cosmetic dermatology, plastic surgery, and oculoplastic surgical societies is attempting to discuss the issue with the FDA.

Finally, it should be noted that one rare serious adverse event follow-ing the cosmetic use of BoNTA has been wrongly associated with the FDA-approved product (BOTOX ® ; onabotulinumtoxinA) ( 15 ). In a 2004 case, a physician administered a high dose of unregulated and unlicensed research-grade BoNTA to himself and three others to treat wrinkles ( 15 ). All developed respiratory paralysis but eventually recov-ered; the physician’s license to practice medicine was suspended. Given that this became a well-publicized media case, it once again begs the question whether respiratory collapse needs to be included as a possi-ble adverse event in the cosmetic use of BoNTA. Certainly this serious adverse event, if it were to occur, would result from a breach of physi-cian duty and would be grounds for a lawsuit claiming major economic damages. However, any reasonable cosmetic dermatologist recognizes that this situation was unique to this case. The possibility of respiratory paralysis is virtually nonexistent when licensed, FDA-approved BoNTA is used in established doses for cosmetic purposes. Therefore, this adverse event need not be included on the consent form.

This case also highlights the need for physicians to be cognizant of “bootlegged” BoNTA. Sellers of these products claim that they pro-vide similar results when compared to licensed BoNTA, but at a sub-stantially reduced cost. Use of these products is a breach of the physician’s professional duty to provide care. In addition to a poten-tial lawsuit by a dissatisfied patient, other adverse outcomes include medical license suspension or revocation in one’s state, and federal consequences.

267

appendix 1 Muscles of facial expression

Muscle Origin Insertion Action Function

I. Forehead Frontalis (s) Galea aponeurotica Skin of forehead and brow Raises eyebrow;

retracts scalp

Wrinkles forehead; used in

frowning and to express

surprise and astonishmentII. Glabella a. Corrugator supercilii (d) Medial superciliary arch

(nasal process of

frontal bone)

Skin in the mid portion

of brow

Adducts and draws

brow down

Used to squint and protect eyes

b. Orbicularis oculi (s)

i. Orbital portion

Medial and anterior

orbital margin

Surrounds orbital opening

as a sphincter: fibers are

over temple, cheek and

into eyebrow

Shuts eyelid Wrinkles brow to produce

a frown; used to wink,

squint and protect eyes

ii. Palpebral portion (s) Medial palpebral ligament Lateral palpebral raphe Closes eye

involuntarily

Produces sphincteric action

of the eyelidsiii. Lacrimal portion (d) Lacrimal crest Upper and lower tarsal

plates

Draws eyelids

posteriorly

Facilitates the lacrimal pump

c. Depressor supercilii (s) Nasal process of frontal

bone

Skin of brow Pulls down

medial brow

Pulls eyebrows down, closes

eyelids, facilitates the

lacrimal pumpd. Procerus (s) Nasal bone and cartilage Skin of forehead between

eyebrows

Pulls down

medial brow

Wrinkles central brow to

produce frown; used to

squint and shield eyes

(conveys disdain or dislike)III. Nose a. Compressor naris

(transverse nasalis) (s)

Canine eminence of

maxilla

Nasal bridge aponeurosis Compresses

nasal aperture

Slows exhaled air

b. Dilator naris

(alar nasalis) (s)

Maxilla above lateral

incisor and alar cartilage

Nasal tip and alar skin and

cartilage

Widens nasal

aperture

Prevents alar collapse in

forceful breathing; flares

nostrils during anger or

exertionc. Depressor septi nasi (s) Incisive fossa of maxilla Lower nasal septum and

under surface of lower

lateral alar cartilage

Draws nasal tip and

alae downward

Narrows the nostrils

IV. Mouth a. Orbicularis oris (s) Medial maxilla, mandible

and many muscles that

converge around mouth;

deep surface or perioral

skin; angle of the mouth

(via modiolus)

Mucous membrane of lips Closes lips Forms a sphincter around

mouth; closes oral aperture;

protrudes, puckers and

shapes lips (kissing); resists

distension when blowing

b. Levator labii superioris

alaeque nasi (s)

Frontal process of maxilla Alar cartilage and

lateral upper lip

Dilates nares and

everts and elevates

lateral upper lip

Deepens the upper nasolabial

fold, dilates nasal aperature

and used in scowlingc. Levator labii superioris

(d and s)

Lower margin of orbit,

above infraorbital

foramen on maxilla

Angle of mouth and

upper lip

Elevates and everts

upper lip

Used in expressing seriousness

and sadness and deepens

nasolabial foldd. Zygomaticus minor

(d and s)

Malar surface of zygomatic

bone (near maxillary

suture line)

Upper lip at angle of

mouth into orbicularis

oris and levator labii

superioris

Draws mouth

upward and

laterally

Elevates and everts upper lip

used in expressing sadness

(see next above)

e. Zygomaticus major

(d and s)

Lateral surface of

zygomatic bone

Angle of mouth

(via modiolus)

Draws mouth

upward and

laterally

Elevates oral commissures used

in laughing or smiling

(bilateral); sneering and to

show disdain (unilateral)f. Levator anguli oris (d) Canine fossa below

infraorbital foramen

of maxilla

Angle of mouth

(via modiolus) and

upper lip musculature

Raises angle of

mouth and

lateral upper lip

Widens oral aperature to grin

or grimace and used in

smiling and laughing; it

deepens nasolabial furrow as

in contempt or disdaing. Risorius (s) Fascia of masseter,

buccal skin and

parotid gland

Angle of mouth

(via modiolus)

Retracts angle of

mouth laterally

Used in smiling and laughing

when present

(Continued)

268 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

(Continued)

Muscle Origin Insertion Action Function

h. Depressor anguli

oris (s)

Oblique line of mandible Angle of mouth

(via modiolus), upper

and lower lip

Depresses angle of

mouth downward

and laterally

Used in grimacing and

snarling; used in expressing

sadnessi. Depressor labii

inferioris (d)

Between symphysis menti

and mental foramen;

platysma

Skin of lower lip and

orbicularis oris

Draws lower lip

downward and

laterally

Everts the lower lip, used in

drinking, pouting and

expressing irony; sorrow and

doubtj. Mentalis (d) Incisive fossa of mandible Skin of chin

(mentolabial sulcus)

Raises and protrudes

lower lip and

wrinkles skin of chin

Used in pouting and to elevate

skin of chin when expressing

doubt or disdaink. Buccinator (d) Outer surface of mandible;

alveolar process of

maxilla and mandible;

pterygomandubular

raphe

Angle of mouth (via modiolus);

upper and lower lips;

interdigitates with

orbicularis oris

Flattens cheek against

gums; used when

distending cheeks

with air and

compresses them to

force air out of

mouth

Presses cheek against molar

teeth; works with tongue to

keep food between occlusal

surfaces and out of oral

vestibule when chewing; used

in sucking and to puff up

cheeks and blow air out of

the mouth as when blowing

up a balloon or playing a

wind instrumentl. Platysma (s) Pectoralis fascia of second

to fourth rib, deltoid

fascia and subcutaneous

tissue of infraclavicular

and supraclavicular

regions

Lower jaw, angle of mouth

(via modiolus), parotid

fascia, skin of cheek and

lower lip; orbicularis oris

Widens mouth

aperture at

commissures; pulls

skin of lower face

and neck taught

Used in expressing horror,

tension and stress; assists in

shaving or in relieving

pressure of a tight collar; and

depresses lower lip and

mandible against resistance

Abbreviations : s, superficial; d, deep.

MUSCLES OF FACIAL EXPRESSION IN ACTION

Frontalis Corrugator supercilii Procerus and transverse

part of nasalis

Orbicularis oculi and

depressor superciliiAlar part of levator labii

superioris alaeque nasi

and alar part of nasalis

Buccinator and orbicularis oris Levator labii superioris alaeque

nasi and levator labii superioris

Risorius Risorius and orbicularis oris Levator labii superioris alaeque

nasi and zygomaticus minor

MUSCLES OF FACIAL EXPRESSION 269

Risorius plus levator labii

superioris and depressor

labii inferioris (asymmetry)

Orbicularis oris Depressor anguli oris and

mentalis

Mentalis Platysma and depressor

anguli oris

Right platysma, labialis,

right depressor anguli oris, left

levator labii superioris, left

zygomaticus major and

mentalis

Depressor anguli oris, mentalis,

and platysma

Left levator labii superioris,

levator labii superioris alaeque

nasi, zygomaticus major,

risorius, and levator anguli oris

Right depressor anguli oris,

right depressor labii inferioris,

mentalis, and right

platysma, labialis

Levator anguli oris, zygomaticus

major and minor, risorius, and

mentalis

Right zygomaticus major and

minor, right depressor labii

inferioris, right levator labii

superioris and mentalis

Zygomaticus major, risorius,

and depressor labii inferioris

(asymmetry)

Levator labii superioris,

zygomaticus minor, risorius,

depressor labii infeioris,

platysma, partes mandibularis

et labialis et modiolaris, and

dilator naris

Depressor anguli oris, mentalis,

right depressor labii inferioris,

and platysma pars mandibularis

Left levator labii superioris,

levator labii superioris alaeque

nasi, and risorius

270 BOTULINUM TOXINS IN CLINICAL AESTHETIC PRACTICE

The bony origins of the muscles of facial expressions; their insertions are in soft tissue. 1, Corrugator supercilli; 2, Orbicularis oculi: 2a, Upper orbital part; 2b, Palpebral part; 3, Medial palpebral ligament; 4, Procerus; 5, Levator labii superioris alaeque nasi; 6, Levator labii superioris; 7, Zygomaticus minor; 8, Zygomaticus major; 9, Levator anguli oris; 10, Nasalis, transverse; 11, Nasalis, alar; 12, Depressor septi; 13, Buccinator; 14, Depressor labii inferioris; 15, Depressor anguli oris; 16, Platysma; 17, Mentalis; 18, Masseter; 19, Temporalis; 20, Incisivus labii superioris; 21, Incisivus labii inferioris; 22, Sternocleidomastoid; 23, Levator palpebrae superioris; 24, Inferior oblique; 25, Inferior rectus; 26, Lateral rectus; 27, Superior oblique; 28, Medial rectus; 29, Superior oblique.

1928

27 232926 4

1

2a

32b

25

24

18

22

5

6 78

9

1011

2012

13

2117 14

15 16

13

19

18

26

MUSCLES OF FACIAL EXPRESSION 271

The bony origins of the muscles of facial expressions; their insertions are in soft tissue. 1, Corrugator supercilli; 2, Orbicularis oculi (orbital and palpebral parts), 3, Orbicularis oculi (lacrimal parts); 4, Medial palpebral ligament; 5, Procerus; 6, Levator labii superioris alaeque nasi; 7, Levator labii superioris; 8, Nasalis, transverse; 9, Nasalis, alar; 10, Depressor septi; 11, Levator anguli oris; 12, Buccinator; 13, Mentalis; 14, Depressor labii inferioris; 15, Depressor anguli oris; 16, Platysma; 17, Masseter; 18, Temporalis; 19, Zygomaticus major; 20, Zygomaticus minor; 21, Sternocleidomastoid; 22, Occipital belly of occipitafrontalis; 23, Incisivus labii inferioris; 24, Incisivus labii superioris.

18

22

21

17

18 1224

12

16 1514

23 13

109

8

11

71920

3 42 6

5

1

2

272

that was not agitated ( 8 ). There was no difference in muscle relaxation between the two sides treated, and the duration of effect remained constant on both sides for approximately 16 weeks. Similar results were anecdotally confirmed by the majority of those present at the 2004 consensus conference ( 4 ).

INJECTION TECHNIQUE OF ONABOTULINUMTOXINA OnabotulinumtoxinA should be injected with sterile, plastic, single-use syringes. In order to minimize the pain and bruising of injection, the use of tuberculin syringes with a 30 to 32G needle is recommended. For those injectors who want to reconstitute onabotulinumtoxinA with a minimum amount of diluent (1 ml or less) and be able to control the minutest amount of solution injected, an insulin syringe with an attached 29 or 31G needle can be used ( 9 ) (Becton-Dickinson, Franklin Lakes, New Jersey). Insulin syringes (0.5 or 0.3 ml) have no potential space at the hub where the needle is preattached, thereby minimizing any wastage of solution ( 10 ). In addition, the barrel of the syringe is scored with markings representing 0.01 ml that can be easily seen and which will correspond to 1 U of onabotulinumtoxinA when a 100 U vial is reconstituted with 1 ml of diluent ( 9 ). To further reduce some of the discomfort associated with any type of intramuscular injection, the pretreatment application of either a topical anesthetic, ice, or both on the skin surface at the injec-tion site can help provide a more comfortable, positive experience for some patients.

Although there are no controlled studies to support certain com-monly prescribed posttreatment recommendations made to prevent local diffusion of the onabotulinumtoxinA beyond the injection site, many expert physician injectors still recommend the following for their patients:

1. DO NOT massage the onabotulinumtoxinA treated areas for 2 to 3 hours.

2. DO NOT bend over (e.g., to tie shoes or pick up something from the floor) for 2 to 3 hours after a onabotulinumtoxinA treatment of the upper face.

3. LIMIT heavy physical activity, and lying down or sleeping for 2 to 3 hours after a an onabotulinumtoxinA treatment of the upper face.

4. DO contract treated muscles for 2 to 3 hours immediately after an onabotulinumtoxinA treatment. This promotes the uptake of onabotulinumtoxinA by the receptor sites at the neuromuscular junctions.

Postmarketing reports indicate that the effects of onabotulinum-toxinA and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects ( 1 ). These symptoms have been reported hours to weeks after injection. The risk of symptoms is probably greatest in children treated for spas-ticity but symptoms also can occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unap-proved uses and approved indications, cases of the spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses but not at the lower doses generally used for

appendix 2 The preparation, handling, storage, and mode of injection of onabotulinumtoxinA

STORAGE OF ONABOTULINUMTOXINA BOTOX ® /BOTOX ® Cosmetic (onabotulinumtoxinA) is a purified neurotoxin complex distributed in vials of 100 U or 50 U of sterile, vacuum-dried crystalline powder without preservative. The vials of onabotulinumtoxinA have a holographic film on the vial label with the name “Allergan” within the horizontal lines of rainbow color. They are shipped frozen in insulated, styrofoam containers containing dry ice. When they reach their destination, the vials of onabotulinumtoxinA can be stored in their dry, powdered form in the refrigerator at a con-stant temperature of 2°C to 8°C for up to 36 months for the 100 U vial and 24 months for the 50 U vial ( 1 ). Once reconstituted, the solution of onabotulinumtoxinA can be stored again in the refrigerator at a con-stant temperature of 2°C to 8°C. DO NOT REFREEZE RECONSTI-TUTED ONABOTULINUMTOXINA. Although the package insert for onabotulinumtoxinA recommends the reconstituted product be used within 4 hours, studies have shown that after reconstitution, the potency of onabotulinumtoxinA should remain consistent and unchanged for up to 6 weeks, and can be used without any noticeable change in clinical efficacy ( 2 , 3 ).

PREPARATION OF ONABOTULINUMTOXINA The package insert for onabotulinumtoxinA suggests that the 100 U vial be reconstituted with 2.5 ml of 0.9% nonpreserved saline for a final concentration of 4 U/0.1 ml and the 50 U vial with 2.25 ml of the same ( 1 ). The report of a consensus conference of key physician injec-tors held in 2004 recommended that a 100 U vial of onabotulinum-toxinA be reconstituted at a “dilution that minimizes the likelihood of diffusion to neighboring muscle groups”, and can be anywhere from 1 to 10 ml of normal saline for each 100 U vial of product ( 4 ). Anecdotal and published reports suggest that volume may influence duration of effect, in that the greater the volume, the shorter the duration of effect ( 5 ). A recent study treating the glabella with onabotulinumtoxinA diluted with 1 ml/vial, 3 ml/vial, 5 ml/vial, and 10 ml/vial resulted in no significant differences on the Facial Wrinkle Scale as assessed by trained observers. However, subject assessment of the duration of effect was felt to be longer with the more concentrated onabotulinum-toxinA that was injected ( 6 ). The 2004 consensus conference report also attested to the fact that the majority of dermatologic and esthetic physician injectors reconstitute onabotulinumtoxinA with preserved normal saline instead of nonpreserved diluent. The result of a bilateral, comparative prospective study has shown that there is less pain with injection when preserved isotonic saline is used instead of nonpreserved isotonic saline ( 4,5,7 ). There was no loss of efficacy nor duration of potency whether onabotulinumtoxinA was reconstituted with preserved or unpreserved normal saline. Once reconstituted, the vial of onabotulinumtoxinA should be clear, colorless, and free of particulate matter, regardless of diluent and amount used ( 1 ).

HANDLING OF ONABOTULINUMTOXINA Concerns over a potential loss of potency resulting from rough handling, agitation, and foaming during reconstitution were also addressed at the 2004 consensus conference ( 4 ). Trindade de Almeida et al. treated one side of six patients in the glabella and periocular area with onabotu-linumtoxinA that was reconstituted by agitation to the point of bub-bling and foaming, and the opposite side with onabotulinumtoxinA

THE PREPARATION, HANDLING, STORAGE, AND MODE OF INJECTION OF ONABOTULINUMTOXINA 273

cosmetic purposes. Furthermore, using currently available analytical technology, it is not possible to detect onabotulinumtoxinA in the peripheral blood following intramuscular injection at the recom-mended doses ( 1 ). A thorough review and understanding of the cur-rent package insert for the brand of BoNTA to be used is recommended before treating patients.

CURRENT POPULAR MODE OF PREPARING, HANDLING, AND STORING ONABOTULINUMTOXINA

Popular methodsManufacturer’s

recommendations ( 1 )

Storage • Before reconstitution ≤ 36 months at 2–8°C

(100 U vial)

≤ 36 months at 2–8°C

(100 U vial) ≤ 24 months at 2–8°C

(50 U vial)

≤ 24 months at 2–8°C

(50 U vial)• After reconstitution ≤ 16 weeks at 2–8°C3 4 hours at 2–8°C

Preparation • Diluent Preserved normal saline

(0.9% saline with 0.9%

benzyl alcohol) ( 7 )

Non-preserved normal

saline (0.9% saline)

• ConcentrationConcentrations

1–10 ml/100 U vial as

needed for appropriate

uptake and diffusion

( 2 , 4 , 10 )

2.5 ml/100 U vial

Handling No special precautions

( 8 , 10 )

Do NOT agitate or cause

foaming Injection technique Insulin syringe with 30G

needle ( 9 ) or tuberculin

syringe with 30–32G

needle ( 4 )

None recommended

REFERENCES 1. Allergan, Inc. Botox Cosmetic (botulinum toxin type A) purified

neurotoxin complex (Package Insert). Irvin, CA: Allergan, Inc., revised August 2009.

2. Garcia A, Fulton JE Jr. Cosmetic denervation of the muscles of facial expression with botulinum toxin: a dose-response study. Dermatol Surg 1996; 22: 39.

3. Hexsel DM, de Almeida AT, Rutowitsch M et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003; 29: 523.

4. Carruthers J, Fagien S, Matarasso SL. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics, Suppl Plast Reconstr Surg 2004; 114: 2S.

5. Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon 2002; 48: 336.

6. Carruthers A, Carruthers J, Cohen J. Dilution volume of botulinum toxin type A for the treatment of glabellar rhytides: does it matter? Dermatol Surg 2007; 33: S97–S104.

7. Alam M, Dover JS, Arndt KA. Pain associated with injection of botu-linum A exotoxin reconstituted using isotonic sodium chloride with and without preservative: a double-blind, randomized controlled trial. Arch Dermatol 2002; 138: 510.

8. Trindade de Almeida AR, Kadunc BV, Di Chiacchio N, Neto DR. Foam during reconstitution does not affect the potency of botu-linum toxin type A. Dermatol Surg 2003; 29: 530.

9. Flynn TC, Carruthers A, Carruthers J. Surgical pearl: the use of the Ultra-Fine II short needle 0.3 cc insulin syringe for botulinum toxin injections. J Am Acad Dermatol 2002; 46: 931–3.

10. Hsu, JS, Dover, JS, and Arndt, KA. Effect of volume and concentra-tion on the diffusion of botulinum exotoxin A. Arch Dermatol 2004; 140: 1351–4.

274

appendix 3 Patient treatment record

Doctor’s name and address

BOTOX ® COSMETIC INJECTION SITE RECORD

PATIENT NAME: _________________________

CHART #: _________________________

DATE OF TREATMENT: _________________________

NOTES :

Botox Lot # __________

N. S. Lot #: __________

Dilution used: _____ mL/100U_____ Units/0.1cc

Photos

Total Units/Site

Pre Rx Post Rx

Expires: __________

Expires:__________ Date Date

Forehead

Glabella

Crow’s feet

Eyelids: (lower); (upper)

Nose: bunny lines

Nose: (alar flare); (tip lift)

Mouth corners (DAO)

Lips: (lower); (upper)

Lips: (Asymmetry); (Gummy smile)

Chin: (apex)

Neck: (Horizontal lines); (Bands)

Mandibulocervical angle

MicroBoNTA

Decolletee

Breast Lift

Other:

Total Units Injected

The nature and purpose of the treatments have been explained to me and questions I had regarding the treatments have been answered to my satisfac-tion. I understand that these treatments may involve risks of complications both from known and unknown causes, and I freely assume these risks.

PATIENT SIGNATURE: WITNESS:

DOCTOR’S SIGNATURE: DATE:

275

Adverse event information may be reported directly either to Allergan Inc. by phone to 800-433-8871, by facsimile to 714-246-5295 or by email to IR-Pharmacovigilance@allergan.com or to Medicis Aesthetics, Inc., by phone to 877-397-7671, depending on which product is used. In addition, adverse events may also be reported to the FDA MedWatch Reporting System by the following methods:

• Online at www.fda.gov/medwatch/report.htm

• Phone at 1-800-FDA-1088

• Facsimile at 1-800-FDA-0718, using the MedWatch Form 3500 ( available at www.fda.gove/medwatch.getforms.htm)

• Mail, using the postage-paid MedWatch Form 3500 to: MedWatch, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787

PREGNANCY, NEUROLOGIC DISEASE, AND MEDICATIONS I am aware that BoNTA is absolutely contraindicated in all preg-nant women and must not be injected if I am not sure whether or not I am pregnant. If I am trying to conceive, BoNTA should not be injected for three months prior to conception. BoNTA should not be injected if I am breastfeeding or if I have any neurologic disease such as multiple sclerosis or myasthenia gravis. The effect of BoNTA may be potentiated by aminoglycoside antibiotics such as spectinomycin, tobramycin, neomycin, gentamycin, kanamycin, or amikacin. Please notify the doctor or nurse if you are currently on such medications. I am not nursing nor am I aware I am pregnant nor do I have any sig-nificant neurologic disease. (_____) (initial) Today’s treatment will be performed with (circle one used): BOTOX ® Cosmetic (onabotulinumtoxinA) or Dysport™ (abobotulinum toxinA) or (Name of other product): _______________.

PHOTOGRAPHS I authorize the taking of photographs and videos and their use for sci-entific and medical purposes both in publications and presentations. I understand that my identity will be protected.

PAYMENT I understand this is a cosmetic procedure and payment is my respon-sibility and due at the time of treatment.

I have read and completely understand all of the above. All of my questions have been answered satisfactorily by the doctor and nurse. I accept the risks, benefits, and potential complications of this procedure and hereby give my informed consent to be treated with (circle one): BOTOX ® Cosmetic (onabotulinumtoxinA) or DYSPORT™ (abobotu-linumtoxinA) or (Name of other product): _______________. Signed __________________________ Date __________________ __ Name ___________________________ Witness _____________ ____ Treating Physician: _________________________________________

appendix 4 Informed consent for the treatment of facial and body wrinkles with BoNTA

RATIONALE I am aware that when a small amount of purified Botulinum neurotoxin A (BoNTA) is injected into a muscle, it causes weakness of that muscle. This occurs in 3 to 5 days or even later, and usually lasts 3 to 5 months but can last for shorter or longer amounts of time, depending on which BoNTA product is used and where it is injected.

Frown lines between the eyebrows are due to contraction of muscles around and between the eyebrows. Injecting BoNTA into this area will temporarily weaken these muscles causing a reduction or disappear-ance of the frown lines. Similarly, crow’s feet and horizontal forehead lines can be improved by injecting BoNTA into these areas, weakening the muscles that cause the wrinkles on the forehead and around the eyes. Many other areas of the central and lower face, neck, and chest also can be treated successfully with BoNTA, but treatment of any area other than between the eyebrows is currently not approved by the Food and Drug Administration (FDA) and is performed off-label.

RESULTS AND AFTER TREATMENT CARE 1. I understand that I will not be able to “frown” or see certain

wrinkles while the injections of BoNTA into this area and other areas are effective. After a period of months wrinkles will return, at which time retreatment is appropriate and needed in order to maintain the previously treated area(s) without wrinkles.

2. I understand that I must remain upright and not bend or lower my head (i.e., to tie my shoes or pick up something), and I must not manipulate or rub the treated areas for 2 to 3 hours after my treatment session.

3. I understand I might experience quicker results if I repeatedly contract and use (e.g., frown) the injected muscles for the 2 to 3 hours after my treatment session.

RISKS AND COMPLICATIONS The most common side effects associated with BoNTA injections for wrinkle correction are bruising and swelling. These local reactions are temporary. Less commonly, headache, numbness, temporary drooping of one or both eyebrows or eyelids, the enlargement of skin folds under the eyelids, or asymmetry can occur in 2% of those injected. Any of these side effects can last for a few hours up to 2 to 4 weeks and possibly longer.

In a very small number of individuals the injections may not work as completely as they do in others nor may they last as long as they do in oth-ers. Everyone responds to injections of BoNTA in their own way. Results also may vary depending on which BoNTA product is used. At times a touch-up injection 2 to 3 weeks later can improve the initial results.

You should inform the doctor if you develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing), or if any similar existing symptom worsens.

If loss of strength, muscle weakness, or impaired vision occurs, you should avoid driving a car or engaging in other potentially hazardous activities.

276

III. Adverse effects of longer duration that can be serious and are not technique-dependent Immediate hypersensitivity reactions

• Urticaria, pruritus, rash, or generalized erythema

• Dyspnea, wheezing, or exacerbation of asthma

• Soft tissue edema

• Anaphylaxis

Contraindications to OnabotulinumtoxinA Injections Patients should not be treated or otherwise treated with extreme caution who are

• Psychologically unstable or who have questionable motives and unrealistic expectations

• Dependent on intact facial movements and expressions for their livelihood (e.g., actors, singers, musicians and other media personalities)

• Afflicted with peripheral motor neuropathic disease, amyo-trophic lateral sclerosis, or neuromuscular junctional disorders (e.g. myasthenia gravis, or Lambert-Eaton syndrome)

• Allergic to any of the component ingredients of BoNTA or BoNTB (i.e., BoNT, human albumin, saline, lactose and sodium succinate)

• Taking certain medications that can interfere with neuromus-cular impulse transmission and potentiate the effects of BoNT (e.g. aminoglycosides, penicillamine, quinine, and calcium channel blockers)

• Pregnant or lactating (BoNTs are classified as pregnancy category C drugs)

• Experiencing an active skin infection at the planned injection site

POTENTIAL BENEFICIAL EFFECTS OF ONABOTULINUMTOXINA OR ABOBOTULINUMTOXINA INJECTIONS

• Relief of frontal or occipital “tension headaches”

• Relief of migraine headaches

• Compensatory muscle strengthening of the same muscles when segmentally treated (e.g., strengthening of the lower frontalis and elevation of the eyebrows when the upper frontalis is treated or improvement of posture and projection of breasts when the lower pectoralis major or minor are treated)

• Compensatory muscle strengthening of synergistic muscles (e.g., strengthening of the lip levators and depressors when the orbicularis oris is treated)

• Compensatory muscle strengthening of antagonistic muscles (e.g., strengthening of the lower frontalis and medial brow lift when the medial brow depressors are treated or lateral brow lift when lateral brow depressors are treated

RISK EVALUATION AND MITIGATION STRATEGY In 2009, when another BoNTA (DysportTM; abobotulinumtoxinA) was approved by the FDA for use in the United States, Allergan, Inc. instituted a surveillance program called Risk Evaluation and Mitigation Strategy (REMS) to update its physician injectors on safety issues regarding the use of BOTOX ® /BOTOX ® Cosmetic

appendix 5 Side-effects and contraindications to BoNTA injections

Physicians are instructed to have their patients read the Medication Guide that is packaged with onabotulinumtoxinA before treatment and before each subsequent treatment. This information does not take the place of the patient talking with their physician about their medical condition or their treatment. Patients are encouraged to share this information with their family members and caregivers.

OnabotulinumtoxinA (BOTOX ® Cosmetic) is approved by the Food and Drug Administration (FDA) only to treat and temporarily improve moderate to severe glabellar frown lines in adults younger than 65 years of age. It is not known whether onabotulinumtoxinA is safe or effective in children younger than 18 years of age for the treatment of axillary hyperhidrosis, the only area on the body FDA approved for the treat-ment of hyperhidrosis. OnabotulinumtoxinA or abobotulinumtoxinA is not recommended for use in children younger than 18 years of age.

POTENTIAL SIDE-EFFECTS OF ONABOTULINUMTOXINA INJECTIONS ( 1 , 2 )

I. Adverse effects of limited duration that are common, localized, and not of a serious nature: Common with any percutaneous injection

• Mild stinging, burning or pain with injection

• Edema around injection site

• Erythema around injection site

• Mild headache, localized and transient

Technique-dependent

• Ecchymosis lasting 3 to 10 days

• Asymmetry

• Oral incompetence and asymmetric smile

• Lack of neck strength

• Lack of intended cosmetic effect

Rare and idiosyncratic

• Numbness and paresthesias, localized and transient

• Focal tonic movements (twitching)

• Mild nausea and occasional vomiting

• Dizziness or syncope

• Mild malaise and myalgias (localized and generalized)

• Dry mouth

• Periorbital edema

II. Adverse effects of longer duration that can be serious and are technique-dependent

• Blepharoptosis

• Brow ptosis

• Diplopia

• Blurred vision or diminished visual acuity

• Diminished tearing and xeropthalmia with or without keratitis

• Ectropion (can lead to xeropthalmia)

• Lagopthalmus (can lead to exposure keratitis)

• Dysphagia

• Dysarthria

• Dysphonia

SIDE-EFFECTS AND CONTRAINDICATIONS TO BONTA INJECTIONS 277

( onabotulinumtoxinA). The goals of the REMS program are to minimize the risks of medication errors related to the lack of interchangeability of onabotulinumtoxinA units with those of licensed botulinum toxins of other manufacturers and to inform prescribers and patients about the potential occurrence of spread of toxin effect beyond the injection site.

Physician injectors are advised to discuss the risks associated with onabotulinumtoxinA therapy outlined above and in the Medication Guide for onabotulinumtoxinA with patients and all the health care personnel who are involved in the preparation, prescribing, and/or injection of onabotulinumtoxinA. According to FDA regulations, a copy of the Medication Guide must be distributed directly to each patient every time he or she receives an onabotulinumtoxinA injection. Copies of the onabotulinumtoxinA Medical Guide can be obtained by calling 1-800-433-8871 or printing copies directly from the websites www.botoxmedical.com or www.botoxcosmetic.com. A copy of the Medication Guide also is included in every carton of onabotulinumtoxinA.

Because there are currently multiple marketed botulinum toxin products with different dose to potency ratios, there is a concern about medication errors such as overdosing based on incorrect unit administration from interchanging different BoNTA products ( 3 ). It is important to understand that BOTOX ® /BOTOX ® Cosmetic (ona-botulinumtoxinA; Allergan, Inc.), MYOBLOC TM (rimabotulinumtox-inB, Solstice), and Dysport TM (abobotulinumtoxinA; Ipsen Biopharm Limited/Medicis Corporation) are unique biologic products that are not interchangeable with each other. The potency units of onabotu-linumtoxinA are specific to the preparation and assay method utilized. Therefore, units of biological activity of onabotulinumtoxinA cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method. Additionally, onabotulinumtoxinA has multiple indications which all require spe-cific dosing. Caution should be taken to ensure that the dosing, dilu-tion, injection volume, and injection patterns are appropriate for the product and the patient.

No definitive reports of serious adverse events of distant spread of toxin effect associated with the cosmetic and dermatologic use of ona-botulinumtoxinA have been reported when the recommended labelled dose of 20 units for glabellar lines or 100 units for severe primary axillary hyperhidrosis have been used.

Distant Spread of Toxin Effect (3)

Postmarketing reports indicate that the effect of onabotulinumtoxinA

and all botulinum toxin products may spread from the area of injec-

tion to produce symptoms consistent with botulinum toxin effects.

These may include asthenia, generalized muscle weakness, diplopia,

blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary in-

continence, and breathing diffi culties. These symptoms have been

reported hours to weeks after injection. Swallowing and breathing dif-

fi culties can be life-threatening and there have been reports of death.

This risk of symptoms is probably greatest in children treated for

spasticity but symptoms can also occur in adults treated for spasticity

and other conditions particularly in those patients who have under-

lying conditions that would predispose them to these symptoms. In

unapproved uses, including spasticity in children and adults, and in

approved indications, cases of spread of effect have occurred at doses

comparable to those used to treat cervical dystonia and at lower doses.

However, at the lower doses generally used for cosmetic purposes,

there have been no substantiated reports of life-threatening adverse

results. Furthermore, using currently available analytical technology, it

is not possible to detect onabotulinumtoxinA in the peripheral blood

following intramuscular injections at the currently recommended

doses found in this compendium on the BoNTs. A thorough review

and understanding of the current package insert for the brand of

BoNT to be used is highly recommended before treating patients.

REFERENCES 1. Coté TR, Mohan AK, Polder JA, Walton MK, Bruan MM. Botuli-

num toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. JAAD 2005; 53: 407–15.

2. Gershon SK, Wise RP, Braun MM. Adverse events reported with cosmetic use of Botulinum toxin A. Pharmacoepidemiol Drug Safety 2001; 10(Suppl): S135–6.

3. Allergan, Inc. Botox Cosmetic (botulinum toxin type A) purified neurotoxin complex (Package Insert). Irvin, California: Allergan, Inc., revised August 2009.

279

accessory dilator, 110acne: Microbotox technique, 194–5acquired asymmetry, 44aging: chronological, 119alar nasalis, 110anesthesia: vibratory, 253antiperspirant, 249apocrine glands, 248apraclonidine, 264asymmetric smile, 209

complications, 157–9dilution, 155dosing, 155–6functional anatomy, 154–5outcomes, 156–7problem assessment and patient

selection, 154asymmetry, 43–4axillary hyperhidrosis, 251–2

bands: vertical, 179–86black box warning, 266blepharoptosis, 42–3body dysmorphic disorder, xiiibody image, xiibone-muscle-matrix theory, 207BOTOX®, 24, 103

handling, 272injection technique, 272–3preparation, 272storage, 272

botulinum neurotoxinsclinical pharmacology, 7–8history, 1, 2immunology, 8–9pharmacology, 2–5serotypes, 1structure, 1–2, 3synthesis, 1–2

botulinum neurotoxin type A (BoNTA)anatomical considerations, 207anti-infl ammatory effects, 223antinociceptive effects, 223assessment of disability, 224calcitonin gene-related peptide

(CGRP), 224complications, 209–10consent, informed, 275constituent of, 235in cosmetic calf slimming, 214–15cosmetic use, 15differences in products, 235–6glutamate, 224hypersecretion, 225injection parameters, 224–5injection technique, 208–9

intravascular injection, 23overdose management, 232painful scars, 228parotid gland, 209physiologic basis, 207–8postherpetic neuralgia, 225–8Raynaud’s phenomenon, 223–4refl ex sympathetic dystrophy

syndrome, 228–30results, 210–11scheduling, 208–9side-effects of, 276submandibular gland, 209substance P (SP), 224upper thoracic posture, 230–2

botulinum neurotoxin type B (BoNTB)aesthetic use of, 241clinical studies of, 241–5complication profi les, 245formulation, 240–1hyperhidrosis, 258–9immunoresistance, 240pharmacology, 240, 241

breast lift, 230–2brow depressor, 264brow elevation, 58brow ptosis, 16bruising, 253buccal sphincter incompetence, 138buccinator, 145bunny lines, 18, 101, 109, 110

calcitonin gene-related peptide (CGRP), 9, 224

canine smile, 133, 134care: post-operative, 275cellular intoxication, 240central brow frown lines

complications, 42–51dilution, 30dosing, 31–41functional anatomy, 26–9outcomes, 41–2problem assessment and patient

selection, 25–6central lip levators, 135, 136Cesarean scar, 199chemical splint, 202, 204chest

Microbotox technique, 195, 197wrinkling, 186–8

chin puckeringcomplications, 169–73dilution, 167dosing, 167functional anatomy, 166–7

outcomes, 169problem assessment and patient

selection, 166Chinese moustache, 160chromhidrosis, 257clinical pharmacology

approved and unlicensed products, 7intradermal injection, 8neuromuscular injection, 7–8

compensatory sweating, 257complex regional pain syndrome, 228–30complications

asymmetric smile, 157–9central brow frown lines, 42–51chest wrinkling, 188chin puckering, 169–73cosmetic calf slimming, 218–19deep mental crease, 169–73exaggerated upper gummy smile, 138forehead lines, 59–61jawline blunting, 176–9keloid formation, 198–9lateral canthal lines, 73–8lateral eyebrow lift, 83–8lower eyelid lines, 92–8melomental folds, 163–6nasal fl are, 112nasal tip ptosis, 116–8nasoglabellar lines, 107nasolabial folds, 128–32perioral rhytides, 150–4platysma, 176–9

compressor naris, 104, 105, 106consent, 275converging arrows, 38corrugator supercilii, 26–7, 30cosmetic calf slimming

adverse events, 218–21botulinum toxin type A, 214–15complications, 218–19dilution and injection technique, 217–18physiologic basis, 216results, 218thick calves, 215–16

cranial nervefi fth, 21seventh, 22

cranio-facial hyperhidrosis, 256crooked smile, 154crow’s feet, 64, 65, 69, 71

injection sites, 236, 237lower, 74

dark circles, 88deep mental crease

complications, 169–73

Index

280 INDEX

deep mental crease (Continued)dilution, 167dosing, 167functional anatomy, 166–7outcomes, 169problem assessment and patient

selection, 166delicate massage, 91depressor anguli oris, 19, 160, 161depressor labii inferioris, 19, 155, 156depressor septinasi, 18, 112–13, 115–16, 117depressor supercilii, 18, 28, 32, 65depressors of lip, 19, 20dilator naris, 110, 111dilution

asymmetric smile, 155central brow frown lines, 30chest wrinkling, 186chin puckering, 167cosmetic calf slimming, 217–18deep mental crease, 167exaggerated upper gummy smile, 133forehead lines, 52jawline blunting, 174lateral canthal lines, 69lateral eyebrow lift, 79lower eyelid lines, 90melomental folds, 160Microbotox technique, 192–3nasal fl are, 110nasal tip ptosis, 116nasoglabellar lines, 104nasolabial folds, 123perioral rhytides, 146platysma, 174

diplopia, 107dosing

asymmetric smile, 155–6central brow frown lines, 31–41chest wrinkling, 186chin puckering, 167deep mental crease, 167exaggerated upper gummy smile, 135–6forehead lines, 53–8jawline blunting, 176lateral canthal lines, 69–72lateral eyebrow lift, 80–2lower eyelid lines, 90–1melomental folds, 161–2nasal fl are, 111nasal tip ptosis, 116nasoglabellar lines, 104–6nasolabial folds, 125perioral rhytides, 146–8platysma, 176

drool grooves, 160dynamic wrinkles, 140–1dyshidrotic hand eczema

(pompholyx), 225Dysport®, 25, 234

ecchymosis, 23eccrine glands, 248, 249

ectropion, 76endoscopic thoracic sympathectomy

(ETS), 250exaggerated upper gummy smile

complications, 138dilution, 133dosing, 135–6functional anatomy, 132–3outcomes, 136–8problem assessment and patient

selection, 132external carotid artery, 23extrafusal fi bers, 6eyebrows, 26

arching of, 41medial brow dip, 43shapes of, 27

eyelid: ptosis, 42

facial anatomylower face, 19mid face, 18–19neck, 19, 21nerves, 21–2upper face, 15–16, 18vascular supply, 23

facial expressionmimetic muscles, 102muscles of, 15, 267–71

facial hyperhidrosis, 254–5facial sculpting, 206Food and Drug Administration (FDA),

101, 240forehead

injection sites, 236, 237Microbotox technique, 193, 194wrinkles, 55, 59

forehead linescomplications, 59–61dilution, 52dosing, 53–8functional anatomy, 51–2outcomes, 58–9problem assessment and patient

selection, 51Frey syndrome, 225, 255–6frontalis, 15, 16, 51, 53full denture smile, 133, 134functional anatomy

asymmetric smile, 154–5central brow frown lines, 26–9chest wrinkling, 186chin puckering, 166–7deep mental crease, 166–7exaggerated upper gummy smile, 132–3forehead lines, 51–2jawline blunting, 173–4lateral canthal lines, 64–9lateral eyebrow lift, 79lower eyelid lines, 88–9melomental folds, 160nasal fl are, 110nasal tip ptosis, 113–15

nasoglabellar lines, 104nasolabial folds, 120–3perioral rhytides, 141–6platysma, 173–4

generalized hyperhidrosis, 248gingival smile, 132glabella

contraction patterns, 29injection, 30

glabellar frown lines, 25–51glutamate, 224gravimetric testing, 248–9gummy smile, 113, 133gustatory sweating, 255–6

habitual scowling, 47Hailey-Hailey disease, 225handling: BOTOX®, 272heavy-handed massage, 58horizontal neck lines, 179–86Hyperfunctional Facial Line Scale

(HFLS), 243hyperhidrosis (HH)

axillary, 251–2botulinum toxin type B, 258–9cranio-facial, 256facial, 254–5forms, 249generalized, 248localized, 248measuring, 248–9palmar, 252–4plantar, 254primary focal, 248therapy, 249–50

Hyperhidrosis Disease Severity Scale (HDSS), 249, 250

hyperkinetic depressor, 26hyperkinetic mentalis, 166–7hyperkinetic upper lip levators, 134hypertrophied parotid glands, 206

iatrogenic asymmetry, 47, 157ideal eyebrow, 26, 28idiosyncratic asymmetric smile, 158–9idiosyncratic asymmetry, 44idiosyncratic facial morphology, 120immunoresistance, 240incidental asymmetry, 44incobotulinumtoxinA, 1, 7increase in palpebral aperture (IPA), 91, 92injection

intradermal, 8neuromuscular, 7–8parameters, 224–5sites, 237, 238

injection technique: BOTOX®, 272–3insulin syringe, 30intrafusal fi bers, 6intravenous regional anesthesia

(IVRA), 253Investigator Global Scale, 243

INDEX 281

iontophoresis, 249, 251Iopidine®, 42

jawline bluntingcomplications, 176–9dilution, 174dosing, 176functional anatomy, 173–4outcomes, 176problem assessment and patient

selection, 173jelly rolls (festoons), 88

keloidabnormal physiology, 198complications, 198–9normal physiology, 198pathophysiology, 197–8results, 199–202scar, 228

Lagophthalmos, 43lateral brow elevation, 82lateral canthal lines

complications, 73–8dilution, 69dosing, 69–72functional anatomy, 64–9outcomes, 72–3problem assessment and patient

selection, 64lateral eyebrow lift

complications, 83–8dilution, 79dosing, 80–2functional anatomy, 79outcomes, 82–3problem assessment and patient

selection, 79levator alae nasi, 110levator anguli oris, 123, 125levator labii superioris, 123, 124levator labii superioris alaeque nasi, 64–5,

116, 123, 124localized hyperhidrosis, 248localized unilateral hyperhidrosis

(LUH), 258lower crow’s feet, 74lower eyelid lines

complications, 92–8dilution, 90dosing, 90–1functional anatomy, 88–9outcomes, 91–2problem assessment and patient

selection, 88lower face, 19lower urinary tract disorders, 10–11

marionette lines, 160–1masseter, 161, 163masseteric hypertrophy, 207, 208, 221mastication, 15

McGill Pain Scale, 242medicolegal considerations, 263–6melomental folds

complications, 163–6dilution, 160dosing, 161–2functional anatomy, 160outcomes, 163patient selection, 160

mental sling, 160mentalis

hyperkinetic, 166–7injection sites, 238

Mephisto pattern, 53Microbotox

acne, 194–5chest, 195, 197dilution, 192–3décolletage, 195, 197forehead, 193, 194hands, 197injection technique, 192–3jawline, 194, 195keloid treatment, 197–204large pores, 194–5mechanism of action, 191–2neck, 194, 195oily facial skin, 194–5physiologic basis, 190in scars, 197undereye region, 193–4

mid face, 18–19, 20mimetic muscles, 24, 102Minor’s iodine-starch test, 248, 250, 258modiolus, 19, 146Mona Lisa smile, 132Müller’s muscle, 29muscles

brow, 26facial expression, 15, 267–71fi bers, 142lower face, 19mastication, 15spindle structure, 6weakness, 264

Myobloc™, 25

Naphazoline, 42nasal fl are

complications, 112dilution, 110dosing, 111functional anatomy, 110outcomes, 111–12problem assessment and patient

selection, 110nasal scrunch (bunny lines), 101, 102nasal tip ptosis

complications, 116–18dilution, 116dosing, 116functional anatomy, 113–15outcomes, 116

problem assessment and patient selection, 112–13

naso-alar wrinkles, 106–7nasociliary rhytides, 102, 106–7nasoglabellar lines

complications, 107dilution, 104dosing, 104–6functional anatomy, 104outcomes, 106–7problem assessment and patient

selection, 101, 104nasolabial folds

complications, 128–32dilution, 123dosing, 125functional anatomy, 120–3lengths of, 122morphological types of, 121outcomes, 125–8problem assessment and patient

selection, 119–20naso-orbicular rhytides, 106–7neck

facial anatomy, 19, 21horizontal lines, 179–86Microbotox technique, 194, 195vertical bands, 179–86

Nefertiti lift, 176nerves: face, 21–2

oculinum, 24orbicularis oculi, 16, 17, 18, 28, 31, 64, 65,

67, 88orbicularis oris, 142, 144

pain, 9palmar hyperhidrosis, 252–4palpebral orbicularis oculi, 66, 67parallel lines, 38, 41parotid gland, 209pars labialis, 144, 145, 173, 175pars mandibularis, 173, 175pars modiolaris, 173, 175patient selection

asymmetric smile, 154central brow frown lines, 25–6chest wrinkling, 186chin puckering, 166deep mental crease, 166exaggerated upper gummy smile, 132forehead lines, 51jawline blunting, 173lateral canthal lines, 64lateral eyebrow lift, 79lower eyelid lines, 88melomental folds, 160nasal fl are, 110nasal tip ptosis, 112–13nasoglabellar lines, 101, 104nasolabial folds, 119–20perioral rhytides, 140–1platysma, 173

282 INDEX

perioral rhytidescomplications, 150–4dilution, 146dosing, 146–8functional anatomy, 141–6outcomes, 148–50problem assessment and patient

selection, 140–1pharmocology

mechanism of action, 2–5nonmotor anticholinergic effects, 5retrograde transport, 5

physician’s negligence, 265plantar hyperhidrosis, 254platysma, 19, 140, 144

complications, 176–9decussating, 181dilution, 174dosing, 176functional anatomy, 173–4injection sites, 238outcomes, 176problem assessment and patient

selection, 173postherpetic neuralgia (PHN),

225–28postinjection ecchymoses, 97preparation: BOTOX®, 272primary focal hyperhidrosis, 248procerus, 31prolonged massage, 58pseudoaugmentation, 148–9pseudoblepharoptosis, 45pseudoherniation, 98Purtox, 238

quadratus labii superioris, 123, 126

Rated Numeric Kinetic Line Scale (RNKLS), 241–2

Raynaud’s phenomenon, 223–4refl ex sympathetic dystrophy syndrome

(RSDS), 228–30results

asymmetric smile, 156–7

central brow frown lines, 41–2chest wrinkling, 186–7chin puckering, 169cosmetic calf slimming, 218deep mental crease, 169exaggerated upper gummy smile, 136–8forehead lines, 58–9jawline blunting, 176keloid formation, 199–202lateral canthal lines, 72–3lateral eyebrow lift, 82–3lower eyelid lines, 91–2melomental folds, 163nasal fl are, 111–12nasal tip ptosis, 116nasoglabellar lines, 106–7nasolabial folds, 125–8perioral rhytides, 148–50platysma, 176

rimabotulinumtoxinB, 240–5Risk Evaluation and Mitigation Strategy

(REMS), 276–7risorius (laughter muscle), 68, 69Ross syndrome, 257–8

scarhypertrophic, 229keloid, 197–8, 228Microbotox technique, 197

self-esteem, XIIserotypes, 1, 240, 241Smith-Kettlewell Eye Research Institute, 1soluble N-ethylmaleimide-sensitive factor

attachment protein receptor (SNARE), 15

sphincteric type muscle, 66square jaws, 206squinting, 66standard of care, 264–5static wrinkles, 140–1, 184storage: BOTOX®, 272submandibular gland, 209substance P (SP), 224superfi cial muscular aponeurotic system

(SMAS), 15, 173

sweating, 190, 248compensatory, 257gustatory, 255–6

synaptobrevin, 240systemic anticholinergic

drugs, 249

topical botulinum toxin, 238transient receptor potential vanilloid

receptor-1 (TRPV1), 11translocation, 3transverse nasalis, 104, 105, 106transverse rhytide, 133triamcinolone, 198turkey neck deformity, 180

upper face, 15–16, 18upper gum mucosa, 132upper lip levators, 138

vascular supply, 23vasoconstrictor, 223vasodilator, 223vesicle associated membrane protein

(VAMP), 240vibratory anesthesia, 253visual analog scale (VAS), 223,

226, 227

wicked witch’s chin, 166wound healing, 198Wrinkle Improvement Scale (WIS), 241wrinkling

chest, 186–8static and dynamic, 140

xerophthalmia (dry eye), 83

younger patients: forehead lines, 51youthful face, 206

zygomatic arch, 73, 94, 130, 206, 207zygomaticus muscles, 129