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samueljFile Attachment2000dfe1coverv05b.jpgBotulinum Toxin in Clinical Dermatology Botulinum Toxin in Clinical Dermatology edited by Anthony V Benedetto DO FACP Clinical Assistant Professor of Dermatology University of Pennsylvania School of Medicine Philadelphia PA, USA and Dermatologic SurgiCenter 1200 Locust Street Philadelphia PA, USA LONDON AND NEW YORK First published in the United Kingdom in 2006 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park, Abingdon, Oxfordshire, OX14 4RN. Tel.: +44 (0) 20 7017 6000 Fax.: +44 (0) 20 7017 6699 Website: http://www.tandf.co.uk/medicine E-mail: info.medicine@tandf.co.uk “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P OLP. 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. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN 0-203-49505-5 Master e-book ISBN ISBN 1 84214 2445 (Print Edition) ISBN 978 1 84214 2448 (Print Edition) Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel: 800 272 7737; Fax: 800 374 3401 Outside Continental USA Tel: 561 994 0555; Fax: 561 361 6018 E-mail: orders@crcpress.com Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424 E-mail: salesorder.tandf@thomsonpublishingservices.co.uk Composition by Expo Holdings, Malaysia © 2006 Taylor & Francis, an imprint of the Taylor & Francis Group Dedication This book is dedicated to all those who have mentored and supported me throughout my past endeavors. Also to those who have given me the confidence and their invaluable assistance which has helped bring this challenging project to fruition, including friends, colleagues, family, and most of all Dianne. CONTENTS Foreword Jean Carruthers xiii Preface Anthony Benedetto xv Prologue The psychology of cosmetic treatment Matthew Silvan 1 Chapter 1 Pharmacology, immunology and current developments Roger Aoki 16 Chapter 2 Facial anatomy and the use of botulinum toxin James Spencer 36 Chapter 3 Cosmetic uses of botulinum toxin A in the upper face Anthony V Benedetto 50 Chapter 4 Cosmetic uses of botulinum toxin A in the mid face Anthony V Benedetto 152 Chapter 5 Cosmetic uses of botulinum toxin A in the lower face, neck and upper chest Anthony V Benedetto 201 Chapter 6 Muscle contouring with botulinum toxin Michael S Lehrer 254 Chapter 7 Other dermatologic uses of botulinum toxin Kevin Smith and Francisco Pérez-Atamoros 270 Chapter 8 Dysport®: a European botulinum type A neurotoxin Gary Monheit 291 Chapter 9 Botulinum toxin B Neil Sadick 305 Chapter 10 Botulinum toxin in the management of focal hyperhidrosis Oliver Kreyden 321 Appendix 1 The preparation, handling, storage and mode of injection of Botox® 364 Appendix 2 Consent to have botulinum treatments for facial and body wrinkles 368 Appendix 3 Patient treatment record 371 Appendix 4 Muscles of facial expression 373 Appendix 5 Side-effects and contraindications to BOTOX® injections 377 Index 379 CONTRIBUTORS K Roger Aoki PhD Vice President, Neurotoxins Research Program Biological Sciences Allergan, Inc 2525 Dupont Drive Irvine CA 92612 USA Anthony V Benedetto DO FACP Clinical Assistant Professor of Dermatology University of Pennsylvania School of Medicine Philadelphia PA USA Oliver P Kreyden MD Praxis Methiniserhof Baselstrasse 9 Muttenz 4132 Switzerland Michael S Lehrer MD Clinical Assistant Professor Department of Dermatology Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia PA 19104 USA Gary D Monheit MD Monheit Dermatology Associates Ash Place, Suite 202 2100 16th Avenue South Birmingham AL 35202 USA Francisco Pérez-Atamoros, MD Centre Dermatologico Tennyson Tennyson 241 Polanco Mexico City 11550 Mexico Neil Sadick MD Sadick Dermatology & Aesthetic Surgery 772 Park Avenue New York NY 10021 USA Matthew E Silvan PhD Department of Dermatology St. Luke’s-Roosevelt Hospital Medical Center 1090 Amsterdam Avenue New York NY 10021 USA Kevin C Smith MD FACP FRCPC Suite 201–6453 Morrison St. Niagara Falls Ontario L2E 7H1 Canada James M Spencer MD MS Professor of Clinical Dermatology Mt. Sinai School of Medicine 1 Gustave L.Levy Place, Box 1047 New York NY 10029 USA FOREWORD Botulinum toxin A is the most exciting new drug from the past century. Dr Alan Scott deserves the credit for the originality of his idea to use a drug rather than a surgical procedure to repair misaligned eyes. Alastair and I have seen our idea of using it for a cosmetic treatment flower from a rather strange ‘fringe’ idea to seeing BTX-A injections becoming the world’s most frequently administered aesthetic procedure. Groups of physicians who were once skeptical of its rationale and effects now are ardent users and supporters. In the wake of the wildly unsafe use of a non-human-approved botulinum neurotoxin in Florida in late 2004, this book is a very timely addition to the scientific literature. Safety and predictable efficacy are of paramount concern to aesthetic physicians. None of these goals can be reached without the knowledge of anatomy, aesthetics, physiology, injection technique, numbers and placement of units of BTX-A which are all stressed in this excellent book. The aesthetic physician authors who have contributed to this work are well respected and authoritative and deserve to be read and studied. One of the great results of the cosmetic revolution started by BTX-A is that many physician groups who did not traditionally learn from each other now greatly value the modern hybrid aesthetic approach—as exemplified by this book. Jean Carruthers Clinical Professor Department of Opthalmology University of British Columbia Vancouver Canada February 2005 PREFACE It is quickly becoming very difficult to remain up to date with what is being published about botulinum toxin. This small instructional manual was written to organize what dermatologists and other physicians need to know about treating patients for cosmetic purposes with injections of botulinum toxin A. Recently,also the reproducibility of labeled units. The process used to stabilize the neurotoxin protein (e.g. lyophilization, vacuum drying, low pH) can also affect the product’s clinical pharmacology, as can excipients added during the manufacturing process. The general process by which botulinum neurotoxins are manufactured is shown in Figure 1.4. Botulinum neurotoxins are produced by several different clostridial bacterial species and strains. Clostridium botulinum is the best known species, although Clostridium butyricum, Pharmacology, immunology and current developments 19 Figure 1.4 General methods of manufacture of botulinum neurotoxins for therapeutic use. Each step in the manufacturing process has the potential to affect clinical profile Clostridium baratii, and Clostridium argentinese also produce botulinum neurotoxins3. The different strains of organisms that produce botulinum neurotoxins exhibit variable characteristics, such as temperature needed for growth and proteolytic activity3. The particular bacterial strain from which the botulinum neurotoxin is obtained determines many of its properties, including neurotoxin complex size and extent of nicking3. Each preparation of botulinum neurotoxin designed for clinical use is synthesized by a different strain of bacteria. For all botulinum neurotoxin preparations approved for clinical use in the United States, the neurotoxin complex is isolated and purified from the bacterial media using state of the art, pharmaceutical level techniques. Next, excipients are added that comprise the formulation of the botulinum neurotoxin preparation. As shown in Table 1.1, the commercially available TABLE 1.1 FORMULATIONS OF DIFFERENT BOTULINUM NEUROTOXIN PREPARATIONS4–7 BOTOX® (Allergan) (100-U vial) Dysport® (Ipsen) (500-U vial) Myobloc® (Elan) (10,000-U vial) • ~5 ng botulinum toxin type A 900-kDa protein • ~12.5 ng botulinum toxin type A 900-kDa protein • ~100 ng botulinum toxin type B 500–700-kDa protein • 500,000 ng serum albumin • 125,000 ng serum albumin • 0.05% serum albumin • 900,000 ng sodium chloride • 2,500,000 ng lactose • 0.1 M sodium chloride • Vacuum dried • Lyophilized • 0.01 M sodium succinate • Liquid formulation, pH 5.6 Botulinum toxin in clinical dermatology 20botulinum neurotoxin products have different formulations and vary according to serotype and amount of neurotoxin complex protein, sodium chloride or lactose, and serum albumin. As can be seen from the table, the amount of neurotoxin complex protein that is present in these products is extremely small compared with the amounts of other ingredients. Each product’s distinct formulation results in a unique interaction with biologic systems following injection. The system is exposed to different ingredients and different numbers of molecules that likely influence local osmotic gradients and diffusion. The precise effects of such potentially different interactions have not been adequately studied, but the identity and amount of the diluent used can alter biologic potency8,9. The preparation is then stabilized using one of several different available methods, depending on the manufacturer. All botulinum toxins begin the finished product manufacturing process as solutions that must be converted into more stable forms for therapeutic use. Botulinum toxin type A BONT-A. (Allergan) is vacuum dried in a lyophilizer, BONT-A (Ipsen) is stabilized by freeze-drying in a lyophilizer, and BONT-B (Elan) is stabilized as a low pH (5.6) solution. The units are then tested. For all botulinum neurotoxin preparations, 1 unit (U) is defined as the amount of neurotoxin complex protein administered intraperitoneally in a biological assay I.P. LD50) of a group of 18- to 20-gram female Swiss Webster mice10. Even though the same definition of units applies to all botulinum toxin preparations, it is now widely accepted that units of the various preparations are not equal11,12. This is most likely due to differences in the way the lethality tests are performed (especially the diluent used) and differences among serotypes. For the final potency testing step, BONT-A (Ipsen) is dissolved in gelatin phosphate buffer, whereas BONT-A (Allergan) is dissolved in saline. For clinical use, the product labels for both BONT-A preparations recommend dilution with sterile unpreserved saline. The addition of gelatin to the diluent affects the number of LD50 units obtained, which may be one reason that more units of BONT-A (Ipsen) than BONT-A (Allergan) are needed for clinical efficacy. Structure There are seven serotypes of botulinum neurotoxins (A, B, C1, D, E, F, and G) produced by different strains of C. botulinum with serotype C2 being cytotoxic and not neurotoxic. All of the botulinum neurotoxins are synthesized as single-chain proteins of approximately 150 kDa that must be nicked or cleaved by proteases into di-chain molecules of approximately 100-kDa and 50-kDa subunits in order to be active13 (Figure 1.5). 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 bond14. Botulinum-producing organisms may be classified as proteolytic or non-proteolytic, denoting the presence or absence of endogenous enzymes that cleave the 150-kDa single-chain neurotoxin into the active di-chain neurotoxin15. Type A-producing strains are proteolytic and nearly all of the toxin recovered from these organisms (>95 per cent) exists in the di-chain form16. Pharmacology, immunology and current developments 21Type B-producing strains may be either proteolytic or non-proteolytic. Proteolytic type B strains have been found to cleave approximately 30 per cent of the single-chain proteins, although the percentage nicked in the commercial product based on the B serotype may be significantly higher17. Clostridial strains that synthesize toxin serotypes E and F are nonproteolytic and the toxin they produce must be exposed to exogenous proteases in order to exert its activity15,18,19 Figure 1.5 Structure of botulinum neurotoxin unnicked, inactive single-chain protein (150 kDa) and nicked, activated di-chain protein (100-kDa and 50-kDa chains) Botulinum neurotoxins are produced as part of a multimeric protein complex consisting of the neurotoxin and associated hemagglutinin and non-hemagglutinin proteins. The number and identity of the associated proteins vary by serotype and organism13. The associated proteins serve to stabilize and protect the neurotoxin molecule from degradation20. The crystal structure of botulinum toxin type A was first reported by Professor Raymond Stevens and colleagues21, which confirmed many of the predictions gleaned from studies of physiology 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 type B is similar to that of type A22. The crystal structures of the other serotypes have not yet been reported, although work is proceeding toward this end. Botulinum toxin in clinical dermatology 22Pharmacology Mechanism(s) of action Botulinum neurotoxins exert their activity through a multistep process that involves binding to nerve terminals, internalization, and inhibition of calcium-dependent neurotransmitter release23. The heavy chain (~100 kDa) subunit of the botulinum neurotoxin molecule binds to acceptors on nerve terminal membranes23, located primarily but not exclusively on cholinergic neurons24,25. The specificity of these acceptors appears to be different between different botulinum serotypes24–26. Although the precise identities of the botulinum neurotoxin acceptors are not known, they are thought to comprise proteins and gangliosides.Progress in identifying the type B acceptor has recently been reported: in PC 12 cells and rat diaphragm motor nerve terminals, the entry of botulinum toxin type B (but not type A or E) appears to be mediated by the secretory vesicle proteins synaptotagmins I and II26. A recent study has identified two critical carbohydrate interaction sites on the He fragment of tetanus toxin that participate in the binding and uptake process of this protein into neurons27. Mutation of residues in the binding pocket markedly decreases the binding affinity of tetanus toxin in vitro and significantly attenuates the effects of tetanus toxin on exocytosis27. In comparison, botulinum toxin serotypes A and B bind only a single molecule of ganglioside GT1 b, with critical residues located within the carboxyl terminal half of the He fragment28. Following binding, botulinum neurotoxins are translocated into the neuronal cytosol via acceptor-mediated endocytosis29. 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 neurotoxins24. Upon acidification of the endosome, it is hypothesized that a pH-dependent change in the translocation domain of the heavy chain facilitates the translocation of the light chain to the cytoplasmic 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 pass29. Inside the endocytotic vesicles, the neurotoxin structure undergoes a conformational change in the presence of a low pH, and the L chain is released into the cytosol accompanied by reduction of the disulfide bond that linked it to the heavy chain. 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 (Figure 1.6). Each serotype cleaves a specific peptide bond on one or more of the SNARE proteins29. The enzymatic activity of the light chain requires the presence of the intramolecular zinc. Botulinum neurotoxins reduce quantal neurotransmitter release elicited by action potentials, as well as spontaneous quantal acetylcholine release, as determined by an inhibition of miniature endplate potentials30. In response to reduced neurotransmitter release, sprouts appear at motor-nerve terminals and nodes of Ranvier, which have been noted within 2 days after injection of type A into mammalian soleus muscles. These Pharmacology, immunology and current developments 23sprouts persist and become more complex for at least 50 days following intramuscular injection of type A30. Sprouts may establish functional synaptic contacts30,31. Eventually, exocytosis is restored, the original terminals recover and the sprouts regress32. After re-innervation is complete, the target tissue is fully functional30 and there is no clinical indication that post-botulinum re-innervation produces functionally substandard synapses. Botulinum neurotoxins act not only on efferent motor pathways but also on autonomic efferent pathways, which also utilize acetylcholine as a neurotransmitter. The inhibitory effects of botulinum toxin type A on autonomic terminals have led to its successful use in conditions of autonomic hyperactivity such as hyperhidrosis and gustatory sweating33. Although the effects Figure 1.6 Mechanism of action of botulinum neurotoxins Amon et al. JAMA 2001, 285; 8:1059–70; copyright© 2001, 285; 1059 American Medical Association on autonomic and motor terminals are thought to occur by a similar mechanism (i.e. binding, internalization, and inhibition of neurotransmitter release), the clinical effects are of longer duration in autonomic conditions than in neuromuscular conditions33. The reason for this difference is unknown. Direct evidence from preclinical studies and indirect evidence from clinical studies indicate that botulinum toxin type A affects afferent pathways via inhibition of neural input to intrafusal fibers34,35. Intrafusal fibers are encapsulated fibers that make up muscle spindles (Figure 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 la sensory afferents. The Botulinum toxin in clinical dermatology 24inhibition of gamma motor neurons decreases activation of muscle spindles, which effectively changes the sensory afferent system by reducing the la traffic. Filippi et al.34 confirmed this hypothesis by establishing that local injections of botulinum toxin type A directly reduce afferent la fiber traffic in rats, thereby modulating sensory feedback. Histologic support for the direct effect of botulinum toxin type A on the rat muscle spindles supported the electrophysiologic results35. Thus, the overall effect of botulinum toxin type A therapy is a combination of a direct effect on the primary nerve-end organ communication coupled with an indirect effect on the overall system. In recent years, there has been an upsurge in research focus on possible actions of botulinum neurotoxins on neurotransmitters other than acetylcholine. The current developments in this area are discussed in the last section of this chapter. Figure 1.7 Muscle spindle structure showing intrafusal and extrafusal fibers Clinical pharmacology The initial preclinical studies conducted with botulinum toxin type A formed the basis for our understanding of its actions at the neuromuscular junction, including mechanism of action, potency, onset and duration of action, and recovery of function36,37. The well-characterized nature of this protein in inhibiting neurotransmitter release at the neuromuscular junction ultimately led Professor Schantz to suggest to Dr Scott that it might be useful for weakening the extraocular muscles of his patients, as previously described. Neuromuscular injection In the clinic, botulinum toxin type A is most often injected into overactive muscles that vary depending on the condition to be treated and the patient’s individual presentation. Pharmacology, immunology and current developments 25Onset of action following intramuscular injection is approximately 3 to 7 days38. The beneficial effects of each treatment with botulinum toxin type A last approximately 3 to 5 months in neuromuscular conditions38–40. The duration of botulinum toxin type B (Elan) is somewhat shorter than that of type A41,42, and has been reported as 6 to 8 weeks with 1000 units and 10 to 12 weeks with 2000 units in the management of facial lines38. Due to the chronic nature of most of the neuromuscular conditions that botulinum neurotoxins are used to treat, repeated injections are typically required over the course of many years. The results of numerous studies indicate that most patients respond to botulinum toxin type A for many years without decrements in safety, responsiveness, or quality of life, and without increased doses43–48. Some studies have reported enhanced benefits with botulinum toxin type A following repeated injections, showing increased duration49,50, decreased adverse events50, or greater functional improvements (e.g. gait in children with cerebral palsy51) with successive injections. In the case of improved gait, this may be due to adaptation of the patient to reduced tone. However, the increased duration and other benefits may also be due to altered sensory feedback from the periphery to the central nervous system52. The effects of botulinum toxin type A on gamma motor neurons that innervate intrafusalfibers lead to changes in muscle spindle activity34 that may ultimately lead to central nervous system adaptation53. Intradermal injection In the treatment of focal hyperhidrosis, botulinum toxin type A is injected intradermally instead of intramuscularly54. The onset of action of botulinum toxin type A in various forms of hyperhidrosis is within 1 week55, and benefits last approximately 7 months56. Benefits are maintained following repeated injections for at least 16 months56; longer studies have not yet been conducted for this indication, although there is no a priori reason to expect that patients with hyperhidrosis would not continue to respond over many years given the results in other similarly dosed indications43,44,50. Several studies have examined the use of botulinum toxin type B for axillary hyperhidrosis57,58. 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 difficulties and dry mouth57,58. Immunology Like most foreign proteins introduced into the body, botulinum neurotoxins can be antigenic and, under the right circumstances (i.e. dose and frequency), elicit immune responses designed to inactivate the protein. The antigenicity of botulinum neurotoxins has been recognized since the late 1800s when an inactive form of the substance produced by van Ermengem’s cultures was subsequently injected into goats and found to elicit antitoxin1. During the next decade, differences in the antitoxins produced to botulinum neurotoxins from various clostridial strains led to the discovery and identification of different botulinum neurotoxin serotypes59,60. Subsequent studies have identified some similar epitopes within the Botulinum toxin in clinical dermatology 26sequences of different botulinum neurotoxin serotypes61, suggesting a basis for cross-reactivity. Only antibodies formed against the 150-kDa neurotoxin neutralize its activity62. Antibodies may occasionally be formed against the non-toxin proteins in the botulinum neurotoxin complex, but these do not affect clinical responsiveness62. Within the botulinum toxin type A molecule, antibodies directed against the receptor-binding region in the heavy chain are neutralizing61,63. Despite the antigenic nature of botulinum neurotoxin proteins, antibody formation that interferes with the clinical responsiveness to botulinum toxin type A (BOTOX®) is infrequent64–67. This is probably because of the high potency of botulinum toxin type A, which produces clinical effects in extremely small quantities. However, frequent injections (i.e. more than every 3 months) or booster injections may increase the likelihood of an immune response against the neurotoxin67. Due to differences in manufacturing methods, different botulinum toxin preparations may show different antigenicity profiles even if they are based on the same serotype. The low rate of neutralizing antibody formation with botulinum toxin type A (BOTOX®, Allergan) has been confirmed in a recent study of 119 cervical dystonia patients68. None of these patients had detectable neutralizing antibodies in their serum after a mean of four treatments. The finding of primary or secondary clinical non-responsiveness without evidence of neutralizing antibodies suggests that there may be other reasons for lack of response to botulinum neurotoxins. These reasons include patient perception; for example, subsequent injections may appear to have a less dramatic effect than the first69, either because patients continue to experience some benefit from the previous 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 adaptation70,71. These changes may require a modification of injection sites, dose, or both in order to maintain optimal treatment benefit. Current developments Possible mechanism(s) of action in pain For many years it has been known that botulinum toxin type A reduces pain associated with cervical dystonia72. This observation led to additional study of the effects of botulinum toxin type A in pain associated with spasticity73, myofascial pain74, and certain headache disorders75. Investigations into the effects of botulinum toxin type A on migraine were prompted by reports of improvement in headaches following injection for facial lines76,77. 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, long-lasting 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 Pharmacology, immunology and current developments 27innervate 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 substance P, somatostatin, and other neuropeptides from both central and peripheral terminals. These peptides mediate pain and inflammatory reactions. The effects of botulinum toxin type A in migraine78 and the lack of direct concordance between its effects on muscle relaxation and improvement in pain in neuromuscular conditions79 suggest that pain relief may not be strictly secondary to the reduction of muscle contractions. This has led to an increase in research directed at identifying possible mechanisms by which botulinum toxin type A may act to reduce pain. Botulinum toxin type A has been found to inhibit substance P release from cultured dorsal root ganglion neurons80. Substance P is a peptide neurotransmitter released by primary nociceptive afferents (C fibers). Additionally, recent results from our laboratory indicate that subcutaneous injection of botulinum toxin type A dose-dependently inhibits formalin-induced nociceptive behavior in rats (phase 2 but not phase 1), in the absence of any measurable effects on muscle weakness81. Additionally, botulinum toxin type A reduced formalin-evoked glutamate release in this model81. In another study, 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 neurons82. CGRP is an inflammatory neuropeptide that is contained within dorsal root ganglia neurons and co-localized with substance P in most trigeminal and other sensory ganglia neurons. Current views of migraine pathophysiology emphasize the role of the trigeminovascular system, with trigeminal afferents thought to release CGRP, substance P, and possibly other neuropeptides that cause painful neurogenic inflammation of the meningeal vasculature83,84. Taken together, these results suggest a basis for non-cholinergic actions of botulinum toxin type A that may play a role in its analgesic effects. Botulinum toxin type A inhibits the release of acetylcholine from both alpha and gamma motor neurons. Alpha motor neurons innervate extrafusal fibers of skeletal muscles and stimulate muscular contractions that lead to movement. Gamma motor neurons innervate the ends of intrafusal muscle fibers, which make up muscle spindles, and stimulate their contraction. Muscle spindles are proprioceptive organs situated among skeletal muscle fibers. Sensory fibers termed la afferents innervate the center of the intrafusal fibers. When the muscle spindle is stretched, the primary sensory ending sends impulsesto the spinal cord. Potential effects of botulinum toxin type A on pain may be relevant for dermatologists who encounter patients with neuropathic pain localized to facial regions such as post-herpetic neuralgia85. Intradermal injections of botulinum toxin type A have been reported to benefit such patients86 although further study is needed (see Chapter 7). Other current basic research findings In order for botulinum neurotoxin preparations to be useful as therapeutics, the active neurotoxin molecule must remain at the site of injection. Uncontrolled diffusion leads to unwanted side effects through the weakening of nearby uninjected muscles or diffusion into the systemic circulation to induce more generalized or distant autonomic effects. Botulinum toxin in clinical dermatology 28Recent results suggest that the botulinum toxin type A 900-kDa complex may diffuse to a lesser extent than the free 150-kDa neurotoxin molecule87, which suggests that the non-toxin proteins may play a role in the side-effect profiles of botulinum neurotoxin preparations. The various botulinum neurotoxin serotypes are known to have different durations of action, with types A and C1 exhibiting the longest durations, types E and F much shorter durations, and type B an intermediate duration88. The longer duration of type A than other serotypes has been related to the persistence of the type A protease within the affected cell88 and the prolonged turnover time of the type A cleavage product designated SNAP-25A89. Recent results indicate that the protease domain of the type A light chain localizes in a punctate manner to the plasma membrane, in association with the cleaved product, SNAP-25A or SNAP-25(197)90. In contrast, the botulinum toxin type E light chain is localized to the cytoplasm. It has been hypothesized that localization of the type A protease to the plasma membrane and/or its interaction with the cleaved protein may partially protect it from degradation, thereby contributing to its extended duration of action compared with other serotypes90. In contrast, the cytoplasmic location of type E protease may make it more susceptible to degradation. This hypothesis is consistent with the much longer duration of type A than type E noted in humans and preclinical models91,92. Although much research has attempted to identify a protein binding site for botulinum toxin type A, polysialyated gangliosides remain the only well characterized acceptor/receptor candidates93. A recent study examined the binding of botulinum toxin type A to ganglioside GT1b using surface plasmon resonance, a technique that permits measurement of binding kinetics without the use of fluorescence or radiolabels93. This study found that the binding of botulinum toxin type A to GT1b in a phospholipid monolayer depended on ionic strength and proceeded at NaCl concentrations up to 150 mM. Binding did not follow a 1:1 model. Additional study indicated that the stability of the botulinum toxin type A-GT1b complex increased over time and that the conformation of botulinum toxin type A changed following incubation with GT1 b. Using circular dichroism, a 25 per cent increase in alpha helix content and 23 per cent decrease in beta sheet content was observed over time93. In other research, Dong and colleagues reported that botulinum toxin type B binds to gangliosides as well as synaptotagmins I and II26. These molecules are thought to constitute co receptors for botulinum toxin type B. However, botulinum toxin type A did not bind to synaptotagmins26, although the possibility of another co-receptor protein for type A has not been ruled out. Yowler and Schengrund have hypothesized that the conformational change they observed following botulinum toxin type A binding to GT1b may permit subsequent binding to a protein co-receptor93. Summary Botulinum toxin type A has a rich history of study that was first based on its identification as a toxin and later on its application as a potent medicine. Botulinum toxin type A and the six additional botulinum neurotoxin serotypes (B through G) share a similar molecular structure and basic mechanism of action. However, differences in the Pharmacology, immunology and current developments 29intracellular protein target or target site cleaved by the light chain of each serotype lead to variations in duration of action and possibly other effects. Evidence suggests that the clinical benefits of botulinum toxin type A may not only be due to its inhibition of acetylcholine release from motor efferent fibers, but also due to an indirect reduction in sensory feedback through the inhibition of acetylcholine release from gamma motor neurons. The onset and duration of botulinum toxin type A have been well characterized in many different disorders, with effects lasting longer in autonomic than neuromuscular conditions. Based on the available research, botulinum toxin type B appears to have a shorter duration of action than type A, as well as more autonomic side effects. Basic and clinical research on botulinum neurotoxins is progressing rapidly, particularly in the area of pain. Evidence suggests that botulinum toxin type A inhibits release of neurotransmitters involved in the generation of pain, such as glutamate, substance P, and calcitonin gene-related peptide, which may form the basis for its beneficial effects in migraine and other painful conditions. Along with the frequent reports of potential novel uses of botulinum toxin, the developments in pain continue to make botulinum neurotoxin research a high priority. References 1. Schantz EJ, Johnson EA. Botulinum toxin: the story of its development 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. Hatheway CL. Bacterial sources of clostridial neurotoxins. In: Simpson LL, ed. Botulinum Neurotoxin and Tetanus Toxin. San Diego: Academic Press, 1989:3–24 4. Botox Prescribing Information, Allergan Inc., 2004 5. 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Biochemistry 2004; 43(30):9725–31 Botulinum toxin in clinical dermatology 34 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 cosmetic physicians to soften or eliminate rhytides caused by hyperfunctional 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 complex is responsible for fusing, docking, and release of acetylcholine from their vesicles. Botulinum toxin (BOTOX®) 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 BOTOX® are temporary. For cosmetic use, the target of BOTOX® has principally been the muscles of facial expression. The muscles of the face can be divided into two groups: the muscles of facial expression, and the muscles of mastication1. 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 structures 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 body2. With age, the muscles of the face tend to atrophy,resulting in sagging of the face. This sagging is addressed through surgical lifting procedures. However, with repeated contraction of the muscles, areas of the skin overlying the muscle can develop creases from repeated mechanical 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 (Figure 2.1). The fibers of the frontalis are vertically oriented, and thus contraction of this muscle shortens the forehead 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 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. However, 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 hyperfunctional 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 resting 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 function of the frontalis is completely lost, such as is seen with severing of the temporal branch of the 7th cranial nerve, the eyebrow will droop Facial anatomy and the use of botulinum toxin 37 Figure 2.1 Frontalis. This is the largest muscle of the upper face and a frequent site of botulinum toxin therapy downward (eyebrow ptosis) (Figure 2.2). Often, normal position results from the dynamic exchange of opposing muscle groups. Careful use of BOTOX® to alter such relationships can be used to alter the position 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 BOTOX® therapy (Figure 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 frontalis extend vertically downward where they mesh with the skin and muscles at the eyebrow and glabella. The muscle actually has two halves, each separately Botulinum toxin in clinical dermatology 38innervated by the right and left temporal branches of the 7th cranial nerve. Thus in the superior aspect of the midline forehead there is no muscle, but rather a fascial band or aponiurosis separating the two halves of the frontalis3. 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 7th 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 (Figure 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 lateral portions of the obicularis oculi muscle, 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 Figure 2.2 Brow ptosis resulting from cutting the temporal branch of the 7th cranial nerve Facial anatomy and the use of botulinum toxin 39tension and the eyebrow will rise. This effect can be enhanced by selective use of BOTOX® 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 non-verbal emotional communication, but with repeated overuse, horizontal rhytides will develop. By weakening the middle and upper portions of the frontalis, these rhytides can be softened or eliminated. However, caution must be used to not paralyze too close to the eyebrows. If the portion immediately above the eyebrows is paralyzed, a brow ptosis may result. As a general principle, injections should always be at least 1 cm above the eyebrow, so functionality will remain to hold the eyebrows up. The glabellar complex is composed of the paired corrugator supercilii and the single procerus (Figure 2.3). The corrugators roughly define a V, with the base at the nasal root. At its base, it is attached 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 Figure 2.3 Glabellar complex; paired corrugator supercilii and the midline procerus Botulinum toxin in clinical dermatology 40and 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 contracture closes the eyelids (Figure 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 superiorly 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 palprebral 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 BOTOX®. 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 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 Facial anatomy and the use of botulinum toxin 41they function as depressors of the eyebrow Figure 2.5 Muscles of the nose: procerus nasalis (compressor naris and dilator naris) and depressor septi nasi contracture produce perpendicularly oriented ‘crow’s feet’ rhytides. The application of BOTOX® to the lateral portion of the Orbicularis oculi muscle will treat crow’s feet. Treatment must be given outside the orbital rim (injection approximately 1 cm lateral to the orbital rim) to avoid unwantedtreatment 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 eyebrow down. Since these medial vertical fibers are so closely associated with the corrugator supercilii, treatment of the corrugators most likely provides some therapy 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 supercilii4,5. As mentioned previously, in nature the fibers of the corrugators, procerus, and medial Orbicularis oculi are fused and intertwined, making clean and separate dissection of these muscles difficult at best. It Botulinum toxin in clinical dermatology 42may 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. Figure 2.6 Levators of the upper lip In the midline of the lower portion of the globe, the fibers of the Orbicularis oculi are horizontally oriented and are vital for closing the eyelids. However, by selectively weakening this lower portion, it can help to soften 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 BOTOX®. 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 eye6. The location of the Orbicularis oculi in relationship to other structures 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, 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), 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. Facial anatomy and the use of botulinum toxin 43Mid face The mid face contains few muscles amenable to therapy with BOTOX®, 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 muscle (Figure 2.5). The nasalis is shaped roughly like an upside-down horseshoe, 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 BOTOX® 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 columella from the upper lip, where it can pull the nasal tip down with smiling. It has been suggested that BOTOX® injection into to this location could elevate the nasal tip. There are multiple levators of the upper lip, which generally originate from bony attachments and travel down to insert in the lip (Figure 2.6). In the midline is the depressor septi muscle, which attaches to the midline upper lip and runs up the columella of the nose. Extending laterally on both sides are a series of paired muscles required for the complex functions of the upper lip. Just lateral to the midline of the upper lip is the paired levator labii superioris alaque nasi, which inserts bilaterally to 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 attaches to 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 is the levator anguli oris, which originates superiorly at the canine fossa. Lastly, the risorus muscle also inserts at the lateral portion of the upper lip and travels obliquely upward towards the ear. As several muscles come together to insert at the lateral commisure of the lips, this area is known as the modiolus, and can be thought of as a dense, fibromuscular interface that acts as a scaffold for the various muscles to pull on. The number of muscles in this area shows the complex functions performed by the mouth: eating, speaking, and emotional expression. As a general principle, none of the lip levators are targets for BOTOX® because of the importance of these functions, even though one could entertain the idea in order to soften the nasolabial folds. Lower face The muscles of the lower face are increasingly becoming targets for BOTOX® 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 Botulinum toxin in clinical dermatology 44attachments above and below respectively. Contracture of the upper, horizontally oriented fibers that travel along the upper lip is responsible for the vertical rhytides seen above the upper lip. However, complete paralysis of this portion of the orbicularis oris would interfere with eating and speaking and is to be avoided. However, very slight weakening of this upper portion, while still preserving overall function, can be used to soften upper lip vertical rhytides. Figure 2.7 Depressors of the lip There are two depressors of the lips, the depressor anguli oris, and the depressor labii inferioris (Figure 2.7). 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 muscle inserts medially to the lower lip under the depressor labii muscle and travels straight down to attach at the midline of the Facial anatomy and the use of botulinum toxin 45chin. It is responsible for protrusion of the lower lip. It is also responsible 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 muscle can softenthe 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. The platysma is a broad, thin muscle originating below the clavicle and extending upward to cover the entire anterior neck. Superiorly at the level of the mandible it meshes with 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 contracture, as well as vertically oriented platysmal bands, seen as the sheet-like muscle separates into cords with time. Multiple superficial injections of BOTOX® into this muscle can soften both of these cosmetic problems. Nerves of the face Use of BOTOX® 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 5th cranial nerve and the 7th cranial nerve, which provide sensation and motor function respectively. The 5th cranial nerve is the trigeminal 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. 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 both are a potential target for direct trauma from the needle used for BOTOX® 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 BOTOX® in the middle of the 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 midface. 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 foramen of these nerves are not in locations where direct trauma from needle injection is likely. Botulinum toxin in clinical dermatology 46The mandibular branch (V3) provides both a sensory and a motor function. The motor portion of the mandibular nerve provides function 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 BOTOX®, the mental branch, which provides sensation to the lower lip and chin, exits the skull at the mental foramen, which is on the lower lateral aspect of the chin, and theoretically could be traumatized if the injection needle entered the foramen during injection of the depressor anguli oris. Motor function of the face is provided by the 7th cranial nerve, the facial nerve. Although the action of BOTOX® 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 temporal branch travels superiorly to innervate the orbicularis oculi, the frontalis, and the corrugator supercilii all targets of BOTOX® therapy. The zygomatic branch travels upwards towards the lateral canthus to further 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. Vascular supply The consequence of intravascular injection of BOTOX® 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 BOTOX® would be in the range of 2800 units, or 28 vials of BOTOX®7. However, hitting a vessel may produce an unsightly ecchymosis, and the BOTOX® 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 internal 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. The internal carotid enters the skull at the carotid canal, travels anteriomedially towards the cavernous sinus and ultimately towards the circle of Willis. From inside the skull it gives off the ophthalmic arteries, which in turn give rise to branches relevant to a discussion of BOTOX®. 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 supratrochlear branch emerges in the area of the corrugators Facial anatomy and the use of botulinum toxin 47deep to muscle with the supratrochlear branch of the 5th 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 BOTOX® injection. The supraorbital branch exits the orbit in the midline of the superior orbital rim with the supraorbital branch of the 5th cranial nerve and travels superiorly deep to the frontalis muscle. Midline injection at the orbital rim with BOTOX® is 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. However, there are a few points that merit special attention when injecting BOTOX®. 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 a roughly 60° angle toward the nasal ala. At the level of the oral commissure it gives off two labial arteries that encircle the lips. The facial artery continues superiorly to the base of the nasal ala, where it anastomoses 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 terminateinto 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 temple 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 external carotid is the internal maxillary artery, which travels deep and is not relevant to BOTOX® injections. Venous drainage of the face generally follows the arterial pattern. 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 supratrochlear 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 theoretic risk, infection has not been a reported problem with BOTOX® injections. Botulinum toxin has rapidly become one of, if not the most, popular non-invasive cosmetic treatments currently available. Its cosmetic benefit derives from its ability to selectively relax or paralyze localized areas of facial muscle. A complete understanding of these muscles allows the physician to successfully utilize this medication. Bibliography 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 Botulinum toxin in clinical dermatology 486. Flynn TC, Carruthers J, Carruthers A. Botulinum A toxin treatment of the lower eyelids improves infraorbital rhytides and widens the eye. Dermatol Surg 2001; 27:703–8 7. BOTOX® cosmetic (package insert). Irvine, CA: Allergan Inc., 2002 Facial anatomy and the use of botulinum toxin 493 COSMETIC USES OF BOTULINUM TOXIN A IN THE UPPER FACE Anthony V Benedetto Introduction Botulinum toxin (BTX) has taken the practice of medicine by surprise and with a furor. Rarely can one find such a simple protein that in its natural form is so deadly, but by purification and minor extraction techniques can be utilized for therapeutic purposes by both physicians and surgeons. The application of BTX in neuromuscular 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 BTX in medicine are on the verge of being discovered. From neurologists and physiatrists, to ophthalmologists and otolaryngologists, and now for gastroenterologists and even the cosmetic surgeons, BTX has proven to be a powerful adjunctive modality for a multitude of disorders. Although this text is not the first concerning itself with the use of BTX, it is one of the few texts to address using BTX solely for dermatologic purposes. In the United States injecting BTX-A, specifically BOTOX® Cosmetic for any reason other than to diminish glabellar frown lines is considered off-label use and not FDA approved. Whether or not the FDA and other governmental regulatory agencies will ever approve every single indication for which BTX has proven to be efficacious, the fact remains that it is extremely reliable and non-toxic when administered as prescribed. Consequently, BTX is quickly becoming a part of the armamentarium of many physicians and surgeons worldwide. In the subsequent four chapters any reference to BTX-A will denote explicitly BOTOX® Cosmetic unless stated otherwise. The dermatologic uses of BTX-A or BOTOX® Cosmetic in these chapters are presented in a systematic fashion, first by identifying the anatomical basis of different aesthetic changes acquired by men and women as they ‘age’ and ‘wrinkle’. Next, normal functional anatomy is discussed to elucidate the reasons for these aesthetic changes so that a suitable plan of correction with BOTOX® Cosmetic can be initiated. Functional anatomy is emphasized because the only way to utilize any type of BTX properly is to have an in depth understanding of how to modify the normal movements of the mimetic muscles of the face. When injections of BOTOX® Cosmetic are appropriately performed, desirable and reproducible results without adverse sequelae are created. Various dilutions recommended for BOTOX® Cosmetic (henceforth identified simply as BOTOX®) also are presented so that precise dosing of the product can be applied to modify facial muscle movements, which in turn can improve a given esthetic problem. Emphasis is placed on what to do and what not to do when injecting BOTOX®. Outcomes and results of different injection techniques are discussed in order 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 BOTOX® to inject is necessary to understand when treating a certain problem in a particular area of the body, and therefore was done intentionally. On the other hand, 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. This text strives to provide both the neophyte and experienced physician the rationale for why and how a patient should be treated with a particular amount of BOTOX® in one area or another for a distinct outcome. By explicitly presenting certain techniques and the reasons for their use, the reader also should understand that this is only the author’s perception of a given esthetic problem and his approach to managing that problem, for that patient, who may or may not present again in the future in exactly the same way. Consequently, when a physician is preparing to treat a patient with BOTOX®, no 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 BOTOX® for the first time. The physician must comprehensively evaluate the patient’s current esthetic problem prior to commencing with the injections of BOTOX® and not necessarily rely totally on past treatment dosing. The physician shoud be flexible and treat the patient’s concerns and specific esthetic changes that are present at the time. Clinical examples and solutions presented in the next few chapters are only paradigms of reasonably acceptable clinical outcomes. The reader therefore should be able to extrapolate for him or herself a preferred approach and injection technique when treating similar clinical problems, provided there is sound justification for such a manner of treatment. In the not too distant future, we will be able to use new formulations of BTX-A in addition to new products of different serotypes of BTX. BTX-A of different formulations and brand names are currently in use in other parts of the world outside of the United States. Their equivalency to BOTOX® is still being measured and defined. It is extremely important to understand that the specific units and dosages of BTX-A indicated in this text, particularly in the next four chapters, are only for BOTOX® unless explicitly denoted otherwise. The same number of units of BOTOX® detailed in this text absolutely cannot be used to treat patients with BTX-A of another source or manufacturer, even if a ratio of equivalency is provided. Injectors of BOTOX® have quickly learnedseveral therapeutic indications for the use of botulinum toxin in dermatology have also been proposed. Many of these indications have been included in this text. Currently, the only FDA approved botulinum toxin A for cosmetic use in the USA is BOTOX® Cosmetic. It is approved only for the treatment of glabellar frown lines. However, the majority of the cosmetic corrections that are done with BOTOX® Cosmetic are performed on an off-label basis. Consequently, prior to the printing of this book, there has been no established text detailing the many different injection techniques presently available. Who are the patients who seek cosmetic enhancement, and why should we treat them? Dr Matthew Silvan presents us with a glimpse into the psychological aspects of someone seeking to cosmetically improve their outward appearance. Why does one seek the help of others to modify, and hopefully, improve upon their natural appearance? Is it a means to create a façade of deception for others, or is it a way to transform themselves inwardly and improve their self image? With some insight into the mind of the ‘cosmetic patient’, this textbook begins with a historical perspective on the development of the medical use of botulinum toxin presented by Dr Roger Aoki, Vice President of Neurotoxins Research Program in Biological Sciences at Allergan, Inc. Over the years, Roger has helped me and a score of others understand the essential concepts concerning the pharmacology and immunology of botulinum toxin. There is much emphasis on anatomy in this text. No one should attempt to administer botulinum toxin unless they possess a solid working knowledge of the mimetic muscles of the face. Ideally one should be able to visualize the functional anatomy of a particular facial muscle or set of muscles while gazing upon a patient and deciding where to place the needle and inject the next unit of botulinum toxin. Not only is there a full chapter dedicated solely to the muscular anatomy of the face by Dr James Spencer, but anatomy is again discussed in the ‘Functional Anatomy’ section of the individual chapters dealing with how to inject BOTOX® Cosmetic. Many physicians have their favorite manner in which they inject botulinum toxin, some of which are reliable and reproducible, others of which are not so reliable and reproducible. This text attempts to cull the many different techniques of well-known physician injectors who use botulinum toxin regularly, and who get excellent and reproducible results. By emphasizing the proper way to inject BOTOX Cosmetic®, we can alert the neophyte injector on how to carefully select the appropriate patients, produce acceptable results, and avoid complications. The chapter written by Dr Michael Lehrer describes a technique of reducing muscle bulk and girth with botulinum toxin. These techniques are practiced by physicians in areas of the world where oversized muscles create an unacceptable cosmetic dilemma for which invasive interventions occasionally are performed. Botulinum toxin now provides a non-invasive way to accomplish similar results. Drs Kevin Smith and Francisco Pérez-Atamoros then give us a glimpse of what may be in store for us in the future. They discuss controversial uses of botulinum toxin A that are in the purview of a practicing dermatologist, some therapeutic, and some cosmetic, but they all seem to work and produce remarkable outcomes. Next Dr Gary Monheit gives us an overview of Dysport®, the other botulinum toxin A that is currently being used in other parts of the world outside the United States. Soon Dysport® will be available for use by physicians in the United States under the tradename of Reloxin®. A chapter on the comparative uses of botulinum toxin serotypes B and A is presented by Dr Neil Sadick, who puts into perspective our understanding of the currently available botulinum toxins. Dr Oliver Kreyden, one of the first and foremost users of botulinum toxin for hyperhidrosis in Europe, concludes our compilation of dermatologic uses of botulinum toxin by contributing a detailed chapter on the pathophysiologic rationale and the therapeutic use of botulinum toxin in suppressing localized hyperhidrosis. Finally if it were not for Drs Jean and Alastair Carruthers, many of us in dermatology would not be injecting botulinum toxin for cosmetic and therapeutic purposes. It is because of them and their many disciples that most of us continue to learn and develop different ways to treat various problems in different areas of the body with botulinum toxin. Thank you Drs Carruthers for your insight, genius, and encouragement. Anthony V Benedetto DO, FACP March 2005 Notes on the text Chapters 2, 3, 4, 5 and 9 Please note that each line drawing of facial muscles in the above chapters depict superficial muscles on the left hand side of the diagram, and deep muscles on the right hand side of the diagram. Prologue THE PSYCOLOGY OF COSMETIC TREATMENT Matthew Silvan Introduction A consideration of the psychological issues related to cosmetic treatments, from surgical face lifts to non-invasive procedures such as BOTOX®, forces us to look at ourselves in a deeper way. It makes us confront our vanity and look at who we are and who we want to be. In addition, since cosmetic treatments are often used to stave off the effects of aging, their usage is intimately connected to our sense of our bodies, our sexuality, and even to our mortality. But how can we understand the differences between vanity and wanting to look our best? What does it mean to grow old gracefully? To pathologize the search for beauty and any effort to make one look younger, healthier, or just be more physically attractive seems contrary to a physician’s clinical and personal experience. However, to see the use of BOTOX® and other cosmetic treatments as divorced from psychological meaning is also problematic and avoids the complex and subtle nuances of how we think about ourselves and how we look at our patients. Ultimately, the individual decision to change one’s looks is complex and multidetermined. It is influenced by our culture, our sense of our selves, and the ubiquitous wishes, fears, and conflicts that are in all of us. As the reader of this book is primarily concerned with the science and therapeutic uses of botulinum toxin, the following comments are applicable to that specific population. However there are currently no experimental data yet published in peer review journals that can tell us specifically who are seeking BOTOX® treatments. We do not know what their psychological motivations are, with what conflicts they struggle, or what psychiatric diagnosis they carry. We may presume that, since BOTOX® is a less invasive medical intervention than cosmetic surgery, this group of patients may differ somewhat from the cosmetic surgery population. However, more than likely psychological factors are present in all patients who seek even the least invasive cosmetic treatments. Placing cosmetic treatments in a psychological and social context, illustrates that regardless of what one actually does there are core motivations and pressures that drive our patients to us to alter their appearance. Individual differences may exist, but the central psychodynamics that drive us and our patients are still quite generalizable. In addition, this chapter will describe how psychopathology may be assessed and, more importantly, how the presence of conflict and motivation is distinguishable from the pathology that may preclude cosmetic treatment. Let us begin with some anthropologic and historic observations about beauty, age, and the use of cosmetics. Culture, in terms of how it values and defines beauty either directly or indirectly, influences behavior. By exploring the use of cosmetic treatments in more depth, dermatologists can more effectively understand patients and the often complex and subtle expressionsfrom their recently frustrating experience using BTX-B that comparative equivalencies are not easily extrapolated. Not only was it difficult to establish a conversion dosage for equating BTX-B with BTX-A, 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 BTX-B with BTX-A. The dose conversion 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 BTX-B to units of BTX-A) when treating the frontalis with BTX-B, then one would assume the same equivalency ratio would be applicable for treating any of the other mimetic muscles of the face. However, when BTX-B was used for another facial muscle, e.g. the orbicularis oculi or corruagator supercilii, the equivalency of BTX-B to BTX-A was not the same, but namely 125:1, or thereabouts. Diffussion characteristics and rates also seem to influence Cosmetic uses of botulinum 51the inability to establish any type of fixed conversion ratio between BTX-B with BTX-A. Therefore the dose equivalent ratio for BTX-B could not be fixed, at least in the author’s personal experience. This confounding of equivalencies using BOTOX® as the standard to which all other serotypes of BTX are measured will only become compounded when different formulations of BTX-A or other serotypes are administered, and the reasons for this are briefly touched upon in chapters 1, 8 and 9. Therefore, it appears that when using any other type of BTX other than BOTOX®, it is better to learn how to administer that particular type of BTX independently of any conversion ratios, as individual muscles may respond 46 in a distinctly different manner with certain formulations and specific serotypes of BTX. The understanding of the pharmacokinetics and pharmacodynamics of BTX is still only in its early phase, and the possibilities for future developments are boundless. It is intriguing to understand that all of this was started by the insight and convictions of two astute and courageous physicians, an ophthalmologist and a dermatologist. If it were not for the Carruthers’ persistence in promoting their ingenious observations, many other perceptive and insightful physicians would not have had the opportunity or confidence to learn more about BTX and how to inject it. The challenge now being passed onto the reader is that with some basic knowledge of how to inject a few drops of BOTOX® safely and appropriately and treating patients with compassion and professionalism, additional innovative uses of BTX can be uncovered. Horizontal forehead lines Introduction: problem assessment and patient selection The easiest area of the face to treat with injections of botulinum toxin (BTX) is the forehead1. 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 individuals 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 individuals a properly functioning frontalis is essential, 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 (Figure 3.1). 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 surprise or even fear: emotions that one usually may not want to express too readily or frequently (Figure 3.2). When done properly, injections of Botulinum toxin in clinical dermatology 52BOTOX® can diminish forehead wrinkling and replace one’s negative expressions with those that are more positive. Figure 3.1 Patient before a BOTOX® treatment; note the fringe of hair concealing her forehead wrinkles. Bangs were separated for the photograph Cosmetic uses of botulinum 53 Figure 3.2 Contracting the frontalis expresses surprise or even fear 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 frequently are determined to eliminate any vestige of the appearance of a forehead wrinkle. A cautious and empathetic cosmetic physician will remind such patients that the absolute absence of a forehead wrinkle, especially at full contracture while expressing an emotion, may not be particularly appropriate for any reason, because it portrays an individual as too artificial and stone-like in appearance, and thus should not be desirable. Because of the various functions of the frontalis, its interaction with the depressor muscles of the glabella, and the potential risk of overtreatment causing brow ptosis, there are many who believe treating the frontalis with BOTOX® is not really as easy as one imagines2. Functional anatomy 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 (Figure 3.3). The function of the frontalis is to elevate the skin of the brow, the eyebrows, and the skin of the forehead, and to oppose the depressor action of the muscles of the glabella and brow. It also retracts the scalp. Botulinum toxin in clinical dermatology 54The 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 originates from the epicranial, membranous galea aponeurotica superiorly and inserts at the level of the superciliary ridge (or arch) of the frontal bone into the subcutaneous tissue and skin of the brow. The fibers of the frontalis also interdigitate with the muscle fibers of the brow depressors, i.e. the procerus, -corrugator supercilii, the depressor supercilii, and orbicularis oculi. In some patients there can be Figure 3.3 Frontalis, the only levator of the forehead a downward extension of the membranous galea aponeurotica in the midline composed of little or no muscle fibers3 (Figure 3.3). When present, injections of BOTOX® into this area are unnecessary. However, in some men and even women, there are well-developed muscle fibers in the center of the forehead. They can be detected by light palpation over the area while the patient actively raises and lowers the eyebrows. When functional Cosmetic uses of botulinum 55muscle fibers of the frontalis can be detected in the center of the forehead, injections of BOTOX® in the midline of the forehead are needed to produce the desired effect (Figure 3.4). (see Appendix 4) Dilution Controlled, widespread diffusion of BOTOX® can be a desired effect when injecting BOTOX® in the forehead. To avoid brow ptosis, the muscle fibers of the frontalis must remain fully functional 1.5–2.5 cm above the brow (i.e. 3–4 cm above actual bony orbital margin). Then higher dilutions and larger volumes of BOTOX® canbe injected into the upper forehead. Consequently, some injectors use from 1–2.5 ml of non-preserved saline to reconstitute a 100 U vial of BOTOX® when treating the forehead4 (see Appendix 1). Figure 3.4 Men and women who spend a lot of time outdoors have a well-developed frontalisBotulinum toxin in clinical dermatology 56 Figure 3.5 Typical injection sites in a woman with an average size forehead Dosing: how to correct the problem (what to do and what not to do) A typical dose for injecting the forehead in women is approximately 8–12 U of BOTOX®. (see Appendix 1). This can be injected either subcutaneously or intramuscularly at four to six sites across the forehead with 2–4 U of BOTOX® placed in each site at intervals of 1.5–2 cm apart on either side of a deep crease5,6 (Figure 3.5). For men, the typical dose is approximately 16–30 U of BOTOX® and occasionally higher. 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 4–5 U of BOTOX® placed in each site, depending on the strength of the frontalis7 (Figure 3.6a, b). 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 BOTOX® 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 forehead3,4. More often than expected, and unbeknownst to the individual, a patient will present with asymmetrical eyebrows prior to their first treatment with BOTOX®. Patients must be made aware of their idiosyncratic differences and their anatomic particulars 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 BOTOX® (Figure 3.7a) and sometimes they cannot (Figure 3.7b). Cosmetic uses of botulinum 57 Figure 3.6b Random pattern injections into a forehead that is high and wide with multiple parallel wrinkles. This patient had 2 U of BOTOX® injected at each site Figure 3.6a Typical injection sites in a man with an average size forehead. This patient had 3 U of BOTOX® injected at each site The patient can be injected in an upright sitting position or even in a semireclined position. The pattern of injection across the forehead also can vary. One can randomly inject 2–4 U of BOTOX® subcutaneously or intramuscularly at any point on the forehead, Botulinum toxin in clinical dermatology 58that is at least 2–2½ finger breadths (i.e. 2–3 cm) above the margin of the bony orbit (Figures 3.6 and 3.7). One also can inject as much as 24 U of BOTOX® or more subcutaneously across the forehead in a horizontal plane parallel to the wrinkles present3 (Figure 3.5). Another pattern that can be used is to inject 2–4 U of BOTOX® subcutaneously in a V configuration, whose arms diverge upward toward the lateral frontal hairline recession. This is accomplished by starting at a point in the midline approximately 2 cm above the medial aspect of the eyebrows, and injecting at three or four sites moving upwardly and laterally in a diagonal pattern, finishing toward the frontal Figure 3.7a 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 BOTOX® treatment they were symmetrical Figure 3.7b This 36-year-old patient has a high and narrow forehead and multiple rows of forehead wrinkles. Cosmetic uses of botulinum 59Note the left eyebrow is higher than the right before and after treatment with BOTOX® hairline recession and 4–5 cm above the lateral side of the eyebrows, depending on the height of the forehead2 (Figures 3.7b and 3.8). This pattern is best for women who have a relatively short rise to the height of their forehead. This pattern will keep BTX high above the eyebrows so they can form a peaked arch. Another technique is to inject subcutaneously approximately 2–4 U of BOTOX® at sites approximately 2 cm apart and across the entire forehead horizontally at a point midway between the brow and the hairline (Figure 3.5). This is advisable if the hairline is set low and if there are only one or two rows of horizontal wrinkles across the forehead (Figure 3.9). If the width of the forehead is narrow, i.e. less than 12 cm between the superior temporal lines, then four or five injections subcutaneously of 2–4 U of BOTOX® at each injection site Figure 3.8 This 40-year-old patient has a low and wide forehead with the right eyebrow higher than the left one before treatment with BOTOX®. Note the position of the right eyebrow one week after treatment with BOTOX® Botulinum toxin in clinical dermatology 60 Figure 3.9 This 36-year-old patient has an average low and narrow forehead with the right eyebrow higher than the left across the forehead are sufficient (Figures 3.7b and 3.9). One can feel the superior 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 (Figure 3.10). Its posterior edge continues upward, as a palpable protruding ridge up along the lateral edge of the frontal bone, and arches upward and backward, delineating the superior boundary of the temporal fossa. If an individual has a wider brow, i.e. more than 12 cm between the right and left superior temporal lines, then five, six, or possibly more injection sites across the forehead are probably necessary, with 2–4 U of BOTOX® injected at each site subcutaneously (Figures 3.7a and 3.11). The stronger the frontalis is, the more units of BOTOX® 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 can help disperse the toxin locally. Prolonged or heavy-handed massage can disperse the liquid BTX beyond the intended area of injection, weakening adjacent muscles and producing unwanted results, e.g. brow ptosis. Cosmetic uses of botulinum 61 Figure 3.10 Anatomic photo of skull illustrating the location and extent of the superior temporal line Figure 3.11 This 38-year-old patient has a high and wide forehead and an asymmetrically lower right eyebrow Outcomes (results) An adequate result when treating the frontalis is to completely eliminate 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 (see Appendix 1). Ideally, weakening of the frontalis should last at least 3 full months when a sufficient dose of BOTOX® is injected. Frequently, after repeat treatments and occasionally after the first treatment session in some patients, the effects Botulinum toxin in clinical dermatology 62of BOTOX® weakening can last as long as 4 to 6 months after BOTOX® is injected2. Overgenerous intramuscular injections of the frontalis with high doses of BOTOX® will eliminate totally all movement of the muscle, even with forced contraction, creating a flat and motionless forehead. There usually is never a good cosmetic reason for such total paralysis of the frontalis or any other muscle of facial expression. In addition, the overall duration of results is usually not extended in any area when a higher dose than that adequate for the individual’s problem is injected. Often, especially with the initial treatment of forehead wrinkles, the effect of BOTOX® 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 thatthe physician warn the patient of this before treatment and require the patient to return 2–3 weeks after a treatment session so that any minor asymmetries can be corrected. This is accomplished by injecting 1–2 U of BOTOX® in the vicinity of the persistent wrinkling. Remember, this should always be at least 2–2.5 cm above the brow, so as not to produce brow ptosis inadvertently. This is particularly important for those patients who have multiple rows of low-lying horizontal forehead lines. By allowing the lower fibers of the frontalis to remain active, there typically may be a wrinkle or two immediately above the eyebrow that might persist that cannot be reduced without causing brow ptosis. 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 management planning (Figure 3.12a–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 BOTOX®. These minor horizontal forehead lines usually are the manifestation of excessively lax skin and the frontalis being recruited to elevate a weighty brow to prevent brow hooding. One runs the risk of brow ptosis if total reduction of these lower forehead lines is attempted. Consequently, the patient is better off totally ignoring these lines or, if they remain after treatment with BOTOX® and are obtrusively bothersome to the patient, having them treated with a soft tissue filler after the injection of BOTOX® has completely taken effect.Cosmetic uses of botulinum 63 Figure 3.12a A 54-year-old patient with forehead wrinkles directly over the left eyebrow (arrow) observed with forced brow elevation before treatment Figure 3.12b Same patient 2 weeks after initial treatment with BOTOX®. Note the left brow is now higher than the right brow with forced eyebrow elevation. An additional 2 U of Botulinum toxin in clinical dermatology 64BOTOX® were injected during this follow-up visit Figure 3.12c Same patient 5 weeks after the initial treatment with BOTOX® and 3 weeks after a touch-up of 2 U of BOTOX®. The left eyebrow remains slightly elevated laterally at rest with eyes wide open, but not with eyes closedCosmetic uses of botulinum 65 Figure 3.12d Same patient 5 weeks after the initial treatment with BOTOX® and 3 weeks after a touch-up of 2 U of BOTOX®. The left eyebrow remains slightly elevated laterally at rest with eyes wide open, but not with eyes closed Complications (adverb sequelae) (see Appendix 5) When treating the frontalis with BOTOX®, there does not appear to be a particular injection pattern or technique that might provide clinical results better than another. However, what does seem to be most important is avoiding brow ptosis8–9. This is best accomplished by remaining at least 2–3 cm above the supraorbital margin or 1.5–2.5 cm above the eyebrow when injecting the frontalis with BOTOX®. This will enable the muscle fibers of the frontalis to remain functional in the area directly above the brow so that the eyebrows will not droop and produce hooding over the upper eyelids (Figure 3.13a–c). In most patients, horizontal forehead lines are present in conjunction with glabellar frown lines. In these patients, it is imperative that the glabellar 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. There is no antidote for brow ptosis, which can last as long as the BOTOX® injection is effective. Injections of low-dose, Botulinum toxin in clinical dermatology 66 Figure 3.13a Unintentional ptosis of the right brow 3 weeks after a treatment of BOTOX®, in this 53-year-old, which lasted the entire 5 months of treatment efficacy Figure 3.13b Same patient with an asymmetric left brow elevation found with forced raising of eyebrows. A touch-up of 2 U of BOTOX® was Cosmetic uses of botulinum 67injected over the left eyebrow 3 weeks after the treatment of BOTOX® Figure 3.13c Same patient 8 weeks after the initial BOTOX® treatment and 6 weeks after the touch-up low-volume BOTOX® precisely placed in the superficial fibers of the upper, orbital portion of the orbicularis oculi may help to reduce the extent of brow ptosis (see below). Clinical experience has indicated that when a more concentrated dose of BOTOX® is used (i.e. dilutions of 1 ml per 100 U vial of BOTOX®) there is minimal volume injected and migration of the BOTOX® is negligible, and the results also seem to last longer9. On the other hand, to prevent total paralysis of muscle movement, especially with the forced contraction of the frontalis, a different approach can be utilized when attempting to esthetically 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 BOTOX®, or which dosage regimens are most effective, one then can inject the forehead with the same number of units of BOTOX®, but with a more dilute solution10,11. Namely, a 100 U vial of BOTOX® can be reconstituted with 2–4 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 paralyzing4. However, injecting large volumes of diluted BOTOX® possibly might limit the duration of its effectiveness10,12. 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 technique, especially for the neophyte injector. Other more common adverse sequelae that occur with an injection of BOTOX® are related more to the actual injection rather than to the material injected. All of these adverse events are transient and generally do not last longer than 24–36 hours. They include local edema, erythema and pain at the injection and adjacent sites. For some patients, a dull and transient headache with or without general body malaise occurs after Botulinum toxin in clinical dermatology 68multiple injections of BOTOX® that can last beyond 24–72 hours. The occurrence of headache immediately after a BOTOX® injection seems paradoxical since BOTOX® injections are used to treat tension and migraine headaches by neurologists and many other medical specialists and subspecialists. Serious reactions, particularly 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) Additional illustrations of injection techniques are shown in Figures 3.14 to 3.17. Treatment implications when injecting the frontalis 1. Identify and document brow or forehead asymmetries prior to treatment with BOTOX®. 2. Inject the forehead 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. Post-treatment forehead asymmetry can be corrected with a few units of BOTOX® given into the active fibers of the frontalis, 2–4 weeks after a treatment session. 6. Counteract brow ptosis and elevate the eyebrows by injecting the superficial fibers of the upper orbital portion of the orbicularis oculi with 1–2 units of low-volume BOTOX® injected into the medial and lateral aspects of the brow (see below). Otherwise, brow ptosis will remain as long as the current BOTOX® treatment is effective. 7. The frontalisis best treated after or in conjunction with glabellar frown lines. Figure 3.14a This 52-year-old has mild forehead wrinkling at rest before and 3 weeks after a BOTOX® treatment of only the forehead Cosmetic uses of botulinum 69 Figure 3.14b Same patient raising her eyebrows, before and 3 weeks after a BOTOX® treatment of only the forehead Figure 3.15 This 45-year-old patient is raising her eyebrows before and 3 weeks after BOTOX® treatment of only the forehead Figure 3.16 This 35-year-old is shown at rest before and 2 weeks after a Botulinum toxin in clinical dermatology 70BOTOX® treatment of only the forehead Figure 3.17a This 40-year-old patient is shown at rest before and 3 months after a BOTOX® treatment of only the forehead Figure 3.17b Same patient raising his eyebrows before and 3 months after a BOTOX® treatment of only the foreheadCosmetic uses of botulinum 71 Figure 3.17c Same patient at rest before and one week after his fourth BOTOX® treatment of only the forehead Figure 3.17d Same patient raising his eyebrows before and one week after his fourth BOTOX® treatment of only the forehead Central brow (glabellar) frown lines Introduction: problem assessment and patient selection The area most frequently treated with BTX is the central brow or glabella and its frown lines11–20. The glabella is the smooth, flat, triangular elevation of the frontal bone superior to the nasal radix positioned between the two superciliary ridges or arches. The muscles of the ‘glabellar complex’ are the first and currently the only muscles of the face or body into which BOTOX® can be injected for cosmetic purposes that have been approved in the USA by the FDA. Treatment of all other muscles in any other part of the face or body Botulinum toxin in clinical dermatology 72with injections of BOTOX® for cosmetic reasons is done solely and explicitly in an off label manner. There are four depressor muscles of the brow that cause the horizontal and vertical creases of the glabella. These muscles allow one to squint to protect the eyes from the elements (i.e. Figure 3.18a This 53-year-old patient, with unintentional frowning during intense concentration, is shown before a BOTOX® treatment Figure 3.18b Same patient frowning 3 weeks after BOTOX® injections in the forehead and glabellar area Cosmetic uses of botulinum 73glaring light, gusts of air and wind, etc.), flying objects, and projectiles 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 concentration can be misinterpreted by others as a frown, which can express negative feelings of concern, tiredness, disappointment, frustration, anger, pain, and suffering, etc. (Figure 3.18a). Weakening the four depressors of the glabella with injections of BOTOX® can raise the eyebrows and virtually eliminate the frown lines of the central brow. This allows a person to appear more relaxed, conveying a positive sentiment when one ordinarily might be frowning and expressing a negative demeanor (Figure 3.18b). An elevated brow 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. In contrast, men in general prefer more horizontal eyebrows rather than arched or peaked eyebrows, which usually are more attractive in women. 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. A detailed pretreatment assessment of how an individual’s eyebrow position and shape conforms to the ‘ideal brow’ contour is key to producing acceptable results with injections of BOTOX®. The ideal contour of the female eyebrow is arched and positioned over the superciliary arch. The peak of the arch should be located just above the lateral limbus of the iris of the eye and sloping downward as far lateral as the lateral canthus, depending on the overall shape of a person’s face and what is currently fashionable21. The tail of the eyebrow should lie on a horizontal plane 1–2 mm above the lowest point of its medial end. The overall silhouette of a female eyebrow should be that of the wing of a gull (Figure 3.19). The male eyebrow should have less of an arched contour and is positioned lower on the superciliary arch at about the level of the superior bony orbital margin (Figure 3.20). The pretreatment position and symmetry of Botulinum toxin in clinical dermatology 74 Figure 3.19 The ideal eyebrow of a woman outlines the wing of a gull Figure 3.20 The ideal eyebrow of a man is less arched and lower set than a woman’s 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 BOTOX® can elevate them by allowing the lower fibers of the frontalis to raise the eyebrows unopposed by the decussating fibers of the corrugator supercilii and the superficial fibers of the orbital portion of the orbicularis oculi (Figure 3.21a, b). Cosmetic uses of botulinum 75Functional anatomy Contracting any of the mimetic muscles of facial expression will cause wrinkling of the skin perpendicular to the direction of the muscle fibers. Therefore, the muscles that produce the vertical lines of the glabella because their fibers are oriented more or less horizontally are the Figure 3.21 a Arching an eyebrow with strategically placed BOTOX® injections in this 53-year-old patient with relatively flat arches Figure 3.21 b Arching an eyebrow with strategically placed BOTOX® injections in this 53-year-old patient 2 weeks after treatment Botulinum toxin in clinical dermatology 76medial brow depressors, i.e. the corrugator supercilii and the medial fibers of the orbital portion of the orbicularis oculi. The corrugator supercilii is a small, narrow, deeply situated paired muscle that arises just inferior to the medial aspect of the superciliary arch approximately 4 mm lateral to the nasion (Figure 3.22). The nasion is the point of juncture of the nasofrontal with the internasal bony sutures22. Clinically it can be palpated as the center of the concavity at the nasal root. The corrugator extends laterally and upwardly through the palpebral and orbital fibers of the orbicularis oculi, inserting into the soft tissue and skin above the middle of the eyebrow in the vicinity of the supraorbital notch, overlying the inferior aspect of the superciliary arch3,22. It lies directly against the bone, and just beneath the interdigitating muscle fibers of the orbicularis oculi, procerus, depressor supercilii, and frontalis medially and beneath interdigitating fibers of the frontalis and orbicularis oculi laterally (Figure 3.22). Anatomic studies have demonstrated that the thickest portion of the belly of the corrugator is at or above a plane drawn through the middle of the eyebrow and approximately 1.6 cm from the nasion (i.e. the bony center of the nasal radix)21–23. (see Appendix 4) The outer portion of the 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 Figure 3.22 The corrugator supercilii lies on the bone and beneath the other glabellar muscles Cosmetic uses of botulinum 77 Figure 3.23 The Orbicularis oculi has different subdivisions and interdigitates with the other depressors and elevator of the glabella inferiorly, forming a wide sphincteric ring around the bony orbitthat extends beyond the edges of the bony orbital rim and into the eyelids (Figure 3.23). The inner portion of the Orbicularis oculi, identified as the palpebral portion of the muscle, is subdivided into preseptal and pretarsal portions (Figure 3.23). The medial aspect of the Orbicularis oculi occasionally is referred to as the depressor supercilii by some authors. Contraction of the orbital portion of the orbicularis oculi approximates the upper with the lower eyelids, either voluntarily or involuntarily, (see Appendix 4) The horizontal lines of the glabella and nasal root are produced by the contraction of the vertically oriented fibers of the procerus and the depressor supercilii, which are also medial brow depressors. The procerus is a thin, pyramidal muscle centrally located in the midline between the two eyebrows and lying 1–4 mm beneath the surface of the skin (Figure 3.24). 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 and 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 Botulinum toxin in clinical dermatology 78 Figure 3.24 The procerus is the midline, deep muscle of the glabella frown lines across the root of the nose. Anatomic studies have demonstrated that the procerus can be longer in women than in men23,24. The depressor supercilii is considered by many as a component part of the medial fibers of the orbital portion of the Orbicularis oculi21 (Figure 3.25). Yet others consider it a separate and distinct muscle from the Orbicularis oculi and corrugator supercilii25. 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 tendon25. In cadaver dissections where the depressor supercilii originated as two separate heads, the angular vessels passed in between the two bundles of muscles25. In cadavers 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, approximately 13–14 mm superior to the medial canthal tendon, which was superior in orientation to the medial aspect of the orbital portion of the Orbicularis oculi25. Not only does it help move the eyebrow downward and close the eyelid, but it also participates in the functioning of the physiologic lacrimal pump by compressing the lacrimal sac (see below). (See Appendix 4) Cosmetic uses of botulinum 79 Figure 3.25 The depressor supercilii is the diminutive muscle of the glabella Dilution Different clinicians have their favorite pattern of injecting the glabella with varying doses of different concentrations of BOTOX®18. The manufacturer’s package insert recommends reconstituting the 100 U vial of BOTOX® with 2.5 ml of unpreserved normal saline26. However, since the brow depressors decussate with each other and are in close proximity in a very small and confined area, it is extremely important to accurately inject precise amounts of BOTOX® in this area. Therefore, many seasoned and long time injectors of BOTOX® still dilute the 100 U vial of BOTOX® with only 1 ml of normal saline, and most have now switched to using preserved saline with 0.9% benzyl alcohol27 (see Appendix 1). In this way, only minimal volumes of BOTOX® will be needed to produce the desired effects. Dosing: how to correct the problem (what to do and what not to do) The pretreatment evaluation should include examining the patient at rest and in full motion, lightly palpating the area with the palmar surface of the finger tips. This will help determine the location, size, and strength of the individual muscles of the glabella. A Botulinum toxin in clinical dermatology 80frequently used and standardized technique for treating the glabella is to inject BOTOX® into five different sites with doses that range anywhere from 4–10 U at each site (Figure 3.26)14–20,26. Electromyographic guidance in this area has not particularly improved treatment outcomes because these facial muscles are superficial and easily localized by topographical landmarks19,22,23,28,29. Patients who are hard to treat because they are less responsive to the effects of BOTOX® seem to be those who possess 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. On the other hand, patients who possess thinner, less sebaceous skin with finer wrinkles and shallower skin folds that can be spread apart and reduced with the fingers (‘glabellar spread test’) seem to have better, longer-lasting results20. Figure 3.26 Standard five injection points for treating glabellar frown lines Cosmetic uses of botulinum 81 Figure 3.27 Standard five injection points for treating glabellar frown lines in a female frowning Generally, glabellar frown lines in women can be satisfactorily treated with a total dose of 25–40 U of BOTOX® injected into the standard five injection sites (Figure 3.27)2,17,28–32. Men, on the other hand, usually require a significantly higher dose of BOTOX® (40–80 U or even higher) injected at seven sites to produce a reasonable effect that lasts at least 3–4 months2,31,33 (Figure 3.28). When glabellar lines are deeper, longer, or thicker on one side of the midline, that set of muscles (e.g. corrugator and medial aspect of the orbicularis oculi) should receive a slightly higher dose of BOTOX® than those 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 midbrow does not elevate and become more arched than is generally the case naturally (Figure 3.29a–d)1. Remember to remain at least 1–2 cm above the orbital rim at the midpupillary line to avoid blepharoptosis. Figure 3.28 Standard seven injection points for treating stronger glabellar muscles causing deeper furrows and frown lines in a male frowning Botulinum toxin in clinical dermatology 82 Figure 3.29a Typical injection points and number 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 BOTOX® injections Figure 3.29b Same patient: an additional 6 U of BOTOX® were necessary to lower the lateral tail of the Cosmetic uses of botulinum 83eyebrows in this man who usually has straight eyebrows. Two weeks after the initial BOTOX® treatment (note elevated lateral eyebrows and points where additional 3 U of BOTOX® were injected) Figure 3.29c Injection of touch-up dose of 3 U of BOTOX® 2 weeks after initial BOTOX® treatment Figure 3.29d Five weeks after the initial BOTOX® treatment and 3 weeks after a touch-up treatment with the Botulinum toxin in clinical dermatology 84patient frowning (note the flatter, less arched lateral eyebrows) In order to treat the glabellar frown lines and produce optimal results with the least amount of complications, it is recommended that multiple injections of relatively concentrated doses and low volumes be used on both sides of the midline. With the patient sitting up or in the semireclined position gently palpate the medial aspect of the eyebrows as the patient squints and frowns. After locating the belly of the corrugator with the tips of the secondand third fingers of the non-dominant hand, ask the patient to raise the eyebrows as high as possible, keeping the tip of your index finger positioned over the thickest part of the belly of the corrugator supercilii. Then 4–10 U of BOTOX® can be injected into the strongest portion of the Figure 3.30 Technique of injecting the corrugator supercilii (note the position of the thumb and index finger of the nondominant hand) muscle, which is located approximately 12 mm lateral and 10 mm superior to the nasion or the center of the concavity at the nasal root22. Prior to inserting the needle, the index finger of the non-dominant 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 lower margin of the supraorbital rim (or margin). 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 60–90° angle until penetration into the corrugator supercilii can be felt22,31. 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 bone. If it does, the patient will sense sharp pain. The needle should then be withdrawn gently enough to Cosmetic uses of botulinum 85move 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 muscles and medial to the supraorbital notch and approximately 1.5–2.0 cm superior to the bony supraorbital margin (Figure 3.30). 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 non-dominant thumb and index finger on the brow just above and below the eyebrow prior to injecting BOTOX® serves many purposes. It prevents injecting BOTOX® too low and close to the orbital rim. By applying direct pressure inferior to the border of the supraorbital rim, Binder et al. felt that they were able to reduce migration of BOTOX® behind the orbital septum22,31. This maneuver also assists in identifying the location and direction of the corrugator supercilii, because it can be felt by light palpation. It is important to inject slowly to avoid dispersing the BOTOX® to surrounding, non-targeted muscles. The medial orbital portion of the orbicularis oculi is injected with another 4–10 U of BOTOX® at a point just above the medial end of the eyebrow. The level of the needle tip is directed away from the orbit and perpendicular to the skin surface and advanced slightly upward toward the hair line, always avoiding contact with the frontal bone and remaining 1–1.5 cm above the medial aspect of the superorbital margin (Figure 3.31)32,33. Because the Figure 3.31 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) Botulinum toxin in clinical dermatology 86fibers of the orbicularis oculi are closely adherent to the overlying skin, injections can be given subcutaneously at this site, which also should affect the depressor supercilii. A pleasing vertically upward lift to the medial brow can be accomplished by this technique, if fibers of the frontalis are not affected34,35. Gentle massage in an upward and lateral direction for a few seconds immediately after the injection helps relieve the acute pain of injection the patient might experience, and can disperse the toxin into the areas intended for treatment. Heavy-handed massage will definitely disperse the BOTOX® beyond the area and into muscle fibers not intended for the treatment, i.e. into the fibers of the lower frontalis, which can produce brow ptosis. When present, do not forget to identify, photograph, and indicate to the patient prior to any BOTOX® injection any variation in the anatomy that might cause the patient’s eyebrows to be asymmetric. Documentation of the conversation and the patient’s response is absolutely necessary and must always be completed prior to initiating treatment with BOTOX®. Next, an injection of approximately 4–10 U of BOTOX® is given between the eyebrows at the nasal root into the belly of the procerus and into the interdigitating fibers of the depressor supercilii. The dose needed for this injection of BOTOX® will depend on the overall muscle strength and depth of the horizontal glabellar wrinkles that are present23. The strength of the procerus can be determined by gently palpating the glabellar area 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 BTX 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 BOTOX® into the procerus can be done. This can be accomplished by grasping the soft tissue of the root of the nose between the thumb and the index finger of the non-dominant hand, elevating skin and muscle before placing the needle between the two fingers and injecting into one or two sites in the center of the nasal radix (Figure 3.32). The site of injection should be anywhere from 1–3 mm above or below the center of the horizontal plane that intersects both medial canthi. The weaker muscle fibers of the procerus are injected with at least 4 U of BOTOX®, while the stronger ones can be injected with up to 10 U and possibly more. The depressor supercilii already will have been partially treated by the injections given at the medial aspect of the eyebrows when the medial portion of the orbicularis oculi is treated. Likewise, when the procerus is injected some diffusion of the BOTOX® into the interdigitating fibers of the Cosmetic uses of botulinum 87 Figure 3.32 Technique of injecting the procerus (note the position of the index finger and the thumb of the non-dominant hand) depressor supercilii will occur, particularly when gentle massage upward and laterally toward the procerus is performed immediately after injection (see Appendix 1). Outcomes (results) There can be a noticeably high arching of the eyebrows, approximately 2–3 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 not34–36. Accentuated high arching eyebrows may be attractive in most women, but usually are not in men. In order to avoid a high arching brow in men, an additional 4–6 U of BOTOX® can be injected subcutaneously 1–1.5 cm above the supraorbital margin at the midpupillary line (Figures 3.28, 3.29)8,13. 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 BOTOX® because of the dynamic relationship between the brow depressors and levator30,34–36. On the other hand, to enhance and elevate the arching of the lateral eyebrow, especially in women, 2–4 U of BOTOX® can be injected subcutaneously into the lateral depressor, i.e. the lateral orbital portion of the orbicularis oculi, at a point of maximal contraction which usually is in the vicinity where the lateralaspect of the superciliary arch meets the lower aspect of the superior temporal line (Figure 3.33a). Depending on the idiosyncratic anatomy of the patient being treated, this point can be just above or below the hairs of the lateral aspect of the eyebrows (Figure 3.33b). One or multiple (usually no more than three) injections of 2–4 U of BOTOX® can be given at points of maximal muscle contraction (higher doses can be used for a lesser number of injections). Injecting BOTOX® in this area reduces the depressor action of the vertical muscle fibers Botulinum toxin in clinical dermatology 88of the orbicularis oculi at the lateral aspect of the brow, and allows the muscle fibers of the lateral aspect of the frontalis to elevate the lateral eyebrow34–38 (Figure 3.34a, b and c). Approximately 2 U to no more than 8 U of BOTOX® should be injected into one and usually no more than three injection sites, starting from the lateral aspect of the eyebrow and finishing at a point just lateral to the midpupillary line in patients with a strong orbicularis oculi who warrant such an injection (Figure 3.35). Ordinarily, one to three injections of 2–3 U of BOTOX® placed into the lateral aspect of the brow and upper eyelid will suffice to produce an esthetically pleasing lateral brow lift (Figures 3.35 and 3.36). With the bore of the needle Figure 3.33a Location of the main injection point when attempting to elevate the lateral aspect of the eyebrow Cosmetic uses of botulinum 89 Figure 3.33b Injection point for a lateral lift. The exact location on the skin in relationship to an individual’s eyebrow may vary according to the person’s anatomy Figure 3.34a This 49-year-old patient is shown before and 3 weeks after BOTOX® was injected into the lateral aspect of the orbicularis oculi (note muscle fibers of the lower lateral frontalis raising the tail of the eyebrow and diminished lateral hooding of the lateral aspect of the upper eyelid) Botulinum toxin in clinical dermatology 90 Figure 3.34b This 56-year-old patient is shown before and 3 weeks after BOTOX® was injected into the lateral aspect of the orbicularis oculi (note muscle fibers of the lower lateral frontalis raising the tail of the eyebrow) pointing upward and away from the orbit, BOTOX® must be injected slowly and subcutaneously into each lateral brow (Figure 3.33b). This technique might help reduce the risk of the BTX dispersing beyond the intended area and producing adverse sequelae, i.e. brow and eyelid ptosis, ectropion, diplopia, and xerophthalmia or dry eye. (see Appendix 5) High lateral eyebrows convey an expression of surprise, happiness, or approval. Depressed, or low positioned lateral eyebrows convey an expression of sadness, fatigue, anxiety, disdain and disapproval. Lateral brow elevation is best appreciated as a decrease in hooding of the lateral aspect of the upper eyelid34–40 (Figure 3.34 and 3.36). Elevating the eyebrows at their medial, central, or lateral aspects can be unpredictable when first attempted, but usually reproducible when the proper technique is used and appropriate specific clinical records and sequential Cosmetic uses of botulinum 91 Figure 3.34c This 45-year-old patient is shown before and 2 weeks after BOTOX® was injected into the lateral aspect of the orbicularis oculi (note the reduction in the lateral brow hooding) photographs are kept36–40. (see Appendix 3) With the proper technique the complication rate is low and the results may be subtle at best. Each patient’s clinical record must include diagrammatic as well as photographic documentation along with their written or typed progress notes if reproducible results are desired and expected. The preference of lifting the eyebrows for one patient or another, i.e. the medial, central, or lateral aspect, will depend on current fashion standards, the patient’s overall physiognomy and idiosyncratic anatomy, and whether or not the physician is capable of injecting BOTOX® with a reproducible technique. Ordinarily, one can expect the effect of a BOTOX® treatment of glabellar frown lines to last at least 3–4 months, with progressively longer-lasting results with each subsequent treatment session. Patients who are treated for the very first time with BOTOX® may experience some asymmetry and therefore should return for an evaluation and possible touch-up treatment within 2–3 weeks. Ordinarily, the effects of a BOTOX® treatment last longer with each sequential treatment. Therefore, after the first 1–2 years of treatment sessions regularly scheduled every 3–5 months, the patient may prefer to return for their next retreatment on an as-need basis (see Appendix 2). Botulinum toxin in clinical dermatology 92Complications (adverse sequelae) (see Appendix 5) Ptosis of the upper eyelid is the most significant complication seen when injecting BOTOX® in and around the glabella16,17 (Figure 3.37). It is felt by some that blepharoptosis is caused by the Figure 3.35 This 49-year-old patient with many wrinkles of the upper lid and lateral eye is shown before a treatment of BOTOX®. (× marks where 1 to 3 U of BOTOX® can be injected subcutaneously in the lateral aspect of the upper eyelid) migration of injected BOTOX® through the orbital septum, weakening the levator palpebrae superioris. This is found to occur more frequently when BOTOX® is injected close to the bony supraorbital margin at the midpupillary line. Only at this point do some of the muscle fibers of the levator palpebrae superioris insert inferiorly to the bony attachment of the orbital septum, allowing for easy diffusion and access of BOTOX® into the fibers of the upper eyelid levator, and producing ptosis of the upper eyelid. Blepharoptosis, when it occurs, is seen as a 1–2 mm or more drop in the upper eyelid, obscuring the upper border of the iris (Figure 3.37). Ptosis can appear up to 7–10 days after a BOTOX® injection and can last 2–4 weeks or even longer8,11,16,17. Blepharoptosis seems to occur more frequently when large volumes of highly diluted BOTOX® are injected into the glabellar complex. An antidote for blepharoptosis is apraclonidine 0.5% eye drops (lopidine®, Alcon Laboratories, Inc., Fort Worth, TX, USA). The ocular instillation of lopidine®, an alpha-2-adrenergic agonist with mild alpha-1 activity, causes Mueller’s muscle (a non-striated Cosmetic uses of botulinum 93sympathomimetic levator muscle of the upper eyelid) to contract, temporarily raising the upper eyelid approximately 1–2 mm. One or two drops should be instilled into the affected eye. If ptosis persists after 15–20 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 apraclondine eyedrops only when absolutely necessary, Figure 3.36 This 68-year-old patient is shown before and 3 weeks after BOTOX® was injected into the lateral aspect of the orbicularis oculi (note the elevation of the hooding of the lateral aspect of the upper eyelid). The numbers indicate the amount of BOTOX® units injected Botulinum toxin in clinical dermatology 94 Figure 3.37 Brow and eyelid ptosis in this 67-year-old patient. Note a drop of 2 mm of the right brow and the upper eyelid that occurred approximately 10 days after BOTOX® was used to treat forehead and glabellar wrinkles. Patient is actively blinking because approximately 20% of patients can develop a contact conjunctivitis with frequent use. The mydriatic and vasoconstrictor phenylephrine (Neo-Synephrine® HCI, 2.5% ophthalmic solution, Sanofi Pharmaceuticals, Inc., New York, NY USA or 2.5%, Alcon Laboratories, Inc., Fort Worth, TX, USA) is an alpha-1 agonist that also can be used when lopidine® is not available33. However, there are more potentialside effects associated with its use than with lopidine®. Specifically, even when only the 2.5% ophthalmic solution is used, phenylephrine can acutely exacerbate narrow angle glaucoma, cardiac arrhythmias, and hypertension. Because it also is a mydriatic, even one drop of Neo-Synephrine® will prevent the patient from accommodating as usual and visual acuity can be compromised. Naphazoline (Naphcon®, Alcon Laboratories, Inc., Fort Worth, TX, USA) is another ophthalmic solution that can be used to stimulate Mueller’s muscle to contract, temporarily lifting a ptotic upper eyelid. 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. This seems to occur more frequently in older patients who possess dermatochalasis of the skin of the eyelids and brow. In order to compensate for a heavy, lax brow, they unconsciously use the lower fibers of their frontalis to lift the soft tissue of the brow, which also maintains their upper eyelids in a raised position22. When this compensatory action of the frontalis is weakened by BOTOX®, a secondary blepharoptosis is created. Cosmetic uses of botulinum 95Overzealous treatments of BOTOX® in the area of the lateral canthus that are either forcibly injected or given with high doses of high volume BOTOX® can result in brow ptosis, ectropion, diplopia, xerophthalmia, or lagophthalmos and even superficial punctate keratosis because of corneal exposure. Brow ptosis is caused by the diffusion of BOTOX® into the lower fibers of the frontalis when BOTOX® is injected rapidly, or the area is massaged vigorously (Figure 3.13). Patients can cause brow ptosis if they manipulate the injected area excessively, enough to disperse the BOTOX® beyond the targeted area. Injecting large volumes of low concentrations of BOTOX® also increases the risk of dispersion beyond the targeted muscle. Ectropion occurs when the muscular sling of the lateral orbicularis is inadvertently weakened. This is generally seen as excessive rounding of the contour of the lateral canthus. Diplopia occurs when the lateral rectus or other extraocular muscles are weakened because BOTOX® has diffused through the orbital septum. Xerophthalmia or dry eye will occur if BOTOX® is injected too deeply in the upper lateral aspect of the periocular area and affects the secretion of the lacrimal glands. 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 functions of the orbicularis oculi either with involuntary blinking or with voluntary forced eye closure can occur when BOTOX® diffuses onto the palpebral portion of the orbicularis oculi, causing undue eyelid weakness. Incomplete eyelid closure or lagophthalmos has been seen more frequently in patients treated for strabismus when extraocular muscles are treated with substantial doses of BOTOX® than when patients are treated for cosmetic reasons, especially if minimal volume BOTOX® is injected47. 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 the 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 remain as long as the effects of the BOTOX® are present, or it can remit sooner. So protecting the patient from developing secondary dry eyes is extremely important, because excessive corneal exposure will lead to desiccation of the cornea and superficial punctate keratosis. Immediate consultation with an ophthalmologist at the first sign of lagophthalmos will prevent any additional, unintended eye injury. Botulinum toxin in clinical dermatology 96 Figure 3.38 This 70-year-old with compensatory brow lifting and an undetected left eyelid droop at rest (a) and frowning (b) before BOTOX®. Blepharoptosis (c) is seen at rest one month after BOTOX®. The patient and treating physician assumed the blepharoptosis was caused by BOTOX® until the before and after treatment pictures were compared which then prompted the diagnosis of ‘pseudoblepharoptosis’ Asymmetry is a minor adverse sequela that sometimes is unavoidable, particularly when a patient is treated for the first time with BOTOX® (Figure 3.38). There are three types of asymmetry that can be corrected with injections of BOTOX®; iatrogenic; idiosyncratic; and incidental or acquired. An example of incidental 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 a crooked, asymmetric smile (see Chapter 5), or one eyebrow or eyelid higher than the other (see above). Many of those individuals who possess, unbeknownst to them, a lower lying asymmetric brow on one side, commonly will also possess a lower lying upper eyelid on the same side. With age, compensatory brow lifting will lift the brows to maintain Cosmetic uses of botulinum 97unobstructed vision. When these patients are treated with injections of BOTOX® to such a degree that the lower fibers of the frontalis are weakened, the patient’s compensatory brow lifting is interrupted. With a drop in brow height comes a drop in upper eyelid height, and those patients who already have an asymmetrically lower upper eyelid on one side now appear to have blepharoptosis or pseudoblepharoptosis (Figure 3.38). When the patient first realizes that one upper eyelid is lower than the other, blame on the injector and the product is a foregone conclusion41. However, the astute and conscientious physician will evaluate the patient carefully and document his or her findings with pretreatment photographs. This will enable the physician to discuss the true problem with the patient and graphically demonstrate its presence prior to embarking on a perilous path to treatment failure. So instead of the physician being led to believe that the patient developed blepharoptosis because of his or her poor injection technique, the physician will be able to identify that the patient always has had an idiosyncratic subclinical upper eyelid asymmetry that can be unmasked and even exaggerated with injections of BOTOX®. This manifestation of pseudoblepharoptosis frequently occurs in patients over the age of 65–70 years who are treated for glabellar frown lines with injections of BOTOX®. 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 iodiosyncratic asymmetries, anatomical differences, and potential outcomes prior to treatment. Informing 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. latrogenic asymmetry arises when an injection of BOTOX® causes one side of the face to become weaker than the other. 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 BOTOX® is when thestronger side is not injected with the equivalent dose of BOTOX® as the contralateral side. This could be the result of the BOTOX® not diffusing completely through all the muscle fibers. Another reason could be that some of the fibers might have been physically resistant to the BOTOX®, because those particular fibers were idiosyncratically thicker or stronger than the rest of the area and may have required a higher dose of BOTOX®. Another possibility is that the injection 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, latrogenic asymmetry is probably the easiest to rectify. Generally with a few additional units of BOTOX® injected into the appropriate area, iatrogenic asymmetry can be easily and expeditiously ameliorated (Figure 3.39a, b). 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 (Figure 3.40), 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. Also, for the first time recipient of a periocular BOTOX® treatment, the presence of periocular edema lasting a few hours to days may occur. This could be Botulinum toxin in clinical dermatology 98attributed 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 lenses, 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 eyebrow hair from the medial end of their brow. This will widen the Figure 3.39a This 42-year-old patient is seen at rest with a higher right eyebrow 2 weeks after BOTOX® injections of the glabella and forehead and just before an additional 2 U of BOTOX® were given Cosmetic uses of botulinum 99 Figure 3.39b Same patient at rest 3 weeks after the additional 2 U of BOTOX® were given and 5 weeks after her initial treatment with BOTOX®. Notice the relative asymmetry of both eyebrowsBotulinum toxin in clinical dermatology 100 Figure 3.40 Patient 5 to 10 minutes after a BOTOX® treatment for forehead, glabellar and lateral canthal wrinkles. Note the erythema and edema in the pattern of the injections glabellar interbrow space, so they do not look like they are habitually scowling, when they actually are. After injections of BOTOX® are given to reduce the number and extent of glabellar frown lines, the corrugators are no longer contracting repeatedly and adducting the eyebrows toward each other, narrowing the interbrow glabellar space. In fact, the transverse width of the glabella returns to normal because the corrugators are in a more relaxed state at rest. However, those women who have plucked the medial portion of their eyebrows to visually widen a scowling brow before BOTOX®, now complain after BOTOX® that they look practically hyperteloric because their eyebrows are now widely separated, when in fact it is only that the medial aspects of their eyebrows have been excessively plucked. Such an adverse sequela 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 that day may not necessarily correspond to the natural anatomical position of that person’s brow. Injections of BOTOX® may return the area to its natural anatomic position, which paradoxically may appear to be distorting the glabellar area, when in reality it is not. Patients with permanent eyebrow tattooing may present similar challenges and treatment disappointments. Cosmetic uses of botulinum 101Figures 3.41–3.48 are some examples of different patients treated with BOTOX® for glabellar frown lines. Some had simultaneous treatment of their forehead frown lines. Figure 3.41 a This 56-year-old patient is shown at rest before and one month after a BOTOX® treatment for forehead and frown lines. Note the different dosages for areas of stronger muscle contraction Figure 3.41 b Same patient frowning before and one month after BOTOX® treatment for forehead and frown lines. Note the different dosages for areas of stronger muscle contraction Botulinum toxin in clinical dermatology 102 Figure 3.42 This 43-year-old patient is shown at rest before and 2 weeks after a BOTOX® treatment of frown lines only Figure 3.43 This 53-year-old patient is shown frowning before and 3 weeks after a BOTOX® treatment of glabellar frown lines only Figure 3.44 This 66-year-old patient is shown frowning before and 4 weeks Cosmetic uses of botulinum 103after a BOTOX® treatment of forehead and glabellar frown lines Figure 3.45 This 57-year-old patient is shown at rest before and frowning 2 weeks after a BOTOX® treatment of forehead and glabellar frown lines Figure 3.46 This 52-year-old patient is shown before and 3 weeks after a BOTOX® treatment of glabellar frown lines onlyBotulinum toxin in clinical dermatology 104 Figure 3.47 This 48-year-old patient is shown frowning before and 3 weeks after a BOTOX® treatment of forehead and glabellar frown lines Figure 3.48 This 56-year-old patient is shown frowning before and 2 weeks after a BOTOX® treatment of forehead and frown lines Treatment implications when injecting the glabella 1. Precise amounts of accurately placed injections of minimal volume BOTOX® reduce the incidence of brow and eyelid ptosis. 2. Men may need higher doses of BOTOX® than women for comparable results. 3. Women prefer arched eyebrows; men prefer straight, non-arched eyebrows. 4. BOTOX® injections should remain medial to the midpupillary line and 1.5–2.0 cm above the supraorbital margin, placed deeply into the corrugator supercilii. 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 BOTOX® diminish. 6 Patients with inelastic redundant skin of the brow develop brow ptosis and secondaryCosmetic uses of botulinum 105blepharoptosis easily with injections of BOTOX®. 7. Pre-existing asymmetry of the brow and eyelids should be discussed with the patient before treatment, and might be corrected by accurately injecting appropriate doses of BOTOX® on the affected side. Periocular lines—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” (Figure 3.49). Depending on a person’s skin type, history of sun exposure, and muscle strength, crow’s feet can appear in someone as young as 20 years of age. The natural thinness and abundance of the skin in the lateral periorbital area make this area 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. Theirpresence causes one to appear perpetually tired and fatigued and even older than one’s current age. For a woman, crow’s feet Botulinum toxin in clinical dermatology 106 Figure 3.49 Crow’s feet accentuated by squinting in a person who is 68 years old are the bane to 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. Functional anatomy Lateral canthal wrinkles are caused by the contraction of the lateral side of the orbital portion of the orbicularis oculi and therefore are referred to as dynamic wrinkles. They are the result of infolding and pleating of the overlying skin, which radiate away from the lateral canthus (Figure 3.49). These wrinkles are perpendicular to the direction of the lateral muscle fibers of the orbital portion of the orbicularis oculi, which run mostly in a vertical direction around the lateral canthus (Figure 3.50). These types of wrinkles can be diminished by injections of BOTOX®42,43. In some patients, however, age and photodamage are the major contributing factors that produce lateral canthal wrinkles. Cosmetic uses of botulinum 107These types of wrinkles are always present whether a person is actively animating or not and therefore are referred to as static wrinkles. When the bulk of crow’s feet are produced by static wrinkles, then injections of BOTOX® will be less effective. Only a resurfacing procedure or a soft tissue filler might help modify static wrinkling of the lateral canthus. When the bulk of crow’s feet are produced by the hyperactivity of the lateral orbital portion of the orbicularis oculi, then injections of BOTOX® can play a significant role in diminishing the wrinkling (Figure 3.51a, b). Figure 3.50 Lateral side of the orbital portion of the Orbicularis oculi The Orbicularis oculi is divided into three parts, the orbital, palpebral, and lacrimal portions. The orbital part is the outermost portion of the muscle that forms a complete ellipse around the bony orbit (Figure 3.52). In its superior aspect it 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, and medial and lateral canthal tendons. Contraction of the orbital portion of the Orbicularis oculi approximates the upper with the lower eyelids, as with forced, volitional eyelid closure, and depresses the medial and lateral aspects of the eyebrow. Certain Botulinum toxin in clinical dermatology 108medial fibers of the orbital portion of the 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 undersurface of the skin at the medial aspect of the eyebrows. They pull the eyebrows downward when they contract24,25. (see Appendix 4) The fibers of the palpebral part of the Orbicularis oculi are subdivided into preseptal and pretarsal portions (Figure 3.53). The pretarsal portion courses over the eyelids and the preseptal Figure 3.51 a Squinting produces a myriad of lateral orbital wrinkles in this 64-year-old before a treatment of BOTOX® into her crow’s feetCosmetic uses of botulinum 109 Figure 3.51 b Same patient squinting 3 weeks after BOTOX® injections Figure 3.52 The Orbicularis oculi is a sphincteric type muscle Botulinum toxin in clinical dermatology 110 Figure 3.53 Orbicularis oculi: the palpebral orbicularis oculi is divided into the preseptal and pretarsal portions portion lies superficial to the orbital septum. 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 part of the orbicularis oculi provides the sphincteric action of the eyelids and gently closes them involuntarily, as occurs with blinking or sleep. The palpebral portion of the orbicularis oculi should not be treated with BOTOX®, because it can cause loss of the voluntary and involuntary functions of eyelid closure. The lacrimal part of the orbicularis oculi is located posterior to the medial palpebral ligament and lacrimal sac (Figure 3.54). Its fibers arise from the posterior lacrimal crest and travel posteriorly to the lacrimal sac and insert onto the upper and lower tarsal plates medial to the lacrimal punctum. Contraction of the lacrimal portion of the orbicularis oculi draws the eyelids posteriorly against the globe, compressing the lacrimal sac and facilitating the lacrimal pump (see p 107) by creating negative back pressure within the canalicular system, and allowing tears to flow into the nasolacrimal duct. Cosmetic uses of botulinum 111Because crow’s feet are enhanced during smiling or laughing, the contraction of the risorius and zygomaticus major et minor also contributes to the formation of these lateral canthal Figure 3.54 Orbicularis oculi: third subdivision lies posterior to the medial canthal ligament rhytides. The zygomaticus major originates anterior to the zygomatic temporal suture deep to the orbicularis oculi and travels diagonally toward the corner of the mouth (Figure 3.55). 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 superiorly, laterally, and posteriorly when a person laughs, smiles, or chews. The zygomaticus minor originates from the zygomatic bone posterior to the zygomaticomaxillary suture, just anterior to the origin of the zygomaticus major, travels downward and forward and inserts into the lateral aspect of the upper lip (Figure 3.56). The zygomaticus minor helps to create and elevate the nasolabial fold and to elevate the lateral aspect of the upper lip, producing the expression of disdain. The risorius is bandlike, usually poorly developed, and lies at the upper border of the facial platysma (Figure 3.57). It does not originate from bone, but from the connective tissue overlying the parotid gland and the fascia of the masseter. The risorius travels Botulinum toxin in clinical dermatology 112horizontally across the face, superficially to the platysma, decussates with the modiolus, and inserts into the skin of the oral commissure. 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 or smiling, Figure 3.55 Zygomaticus major assists in lifting the lateral oral commissure producing dimples in some individuals. Along with the platysma, the risorius can move the oral commissures 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 (Figures 3.36 and 3.51a). (See Appendix 4). Dilution When injecting BOTOX® in the periocular area, it is imperative that minimal volumes be accurately placed. This will necessitate diluting a 100 U vial of BOTOX® with only 1 ml of normal saline (see Appendix 1). Cosmetic uses of botulinum 113Dosing: how to correct the problem (what to do and what not to do) When one performs injections of BOTOX® or any other pharmaceutical in the periocular area, both the patient and the physician should remain unencumbered, comfortable, and without Figure 3.56 Zygomaticus minor elevates the upper lip more centrally distractions. The patient should be in a sitting or semireclined position, approachable from both the left and right sides. When injecting BOTOX® in the lateral canthal area, one shouldof the needs and wishes that bring them to the office. By articulating a more comprehensive and complex understanding of a patient’s psychology, dermatologists are in a better position to assess whether the treatment they are offering will be what their patient actually wants and needs. By listening more acutely to their patient’s words, dermatologists are also better able to recognize those patients for whom cosmetic treatment is contraindicated and even dangerous. In covering this wide range of issues it behooves the cosmetic practitioner to recognize the psychological complexity of the work s/he is doing, the multi-determined motivations with which patients arrive, and the way in which this perspective can enhance the practice of their profession. History The search for beauty is not new or specific to this time in history. These concerns have been with us for millennia, although how they are expressed may shift from one extreme to the other. A review of sociologic, anthropologic, and literary sources can be extremely useful in helping us reflect on who our patients are today. Fossil records show that Neanderthals used ochre as a deodorant and later primitive man used vegetable dies and mineral pigments for adornment and make up1. So even before Narcissus looked at himself in a pool of water we have been concerned, consumed, and even obsessed with beauty. Simon2 reports on a seventh century physician from Alexandria who practiced a form of cosmetic surgery. De Gama sought the fountain of youth and Oscar Wilde’s Dorian Gray was willing to sacrifice much to look young and beautiful. As Kligman3 notes, Cinderella was probably the first ‘extreme makeover’. In the mid 1900s Pope Pious XII said that cosmetic procedures used to increase the powers of seduction or vanity were sinful and morally unlawful4. Today you cannot turn on the television or open a magazine without reading about beauty, cosmetics and which star had what plastic surgery. While it may be tempting to think that the media is driving this issue, history tells us otherwise. However, it is true that far more people are having cosmetic treatment. Yet this seems more a function of an improvement in technology, an increased availability of affordable options for invasive and non-invasive procedures, and a change in the social acceptability of cosmetic treatment than a change in who we actually are. While our conceptualizations of what is beautiful may have changed over time, the psychological motivations that drive us to alter our appearance have not. While some might long for the imagined simplicity of the past, others race full speed into the future. Yet, as Sullivan5 said, ‘we are all more human than otherwise’ and it would appear that an aspect of being human is to be concerned about one’s appearance. Cultural influences Surveys have shown that some cultures or groups seem far more focused on their appearance than others6. For example, 61 per cent of Brazilians think that physical attractiveness is very important as compared to 32 per cent in the US and 27 per cent in France. Even within the US, regional variations are noted. Southerners are far more Botulinum toxin in clinical dermatology 2concerned with their appearance than Northerners. Moreover, cultural factors profoundly influence what is considered beautiful and what people are willing to go through to make themselves that way. In some cultures, at some times, foot binding, grinding and blackening the teeth7, as well as scarring and piercing8, have all been considered acceptable body modifications that increased attractiveness. Are the cosmetic procedures we do today in our culture such as breast augmentation and rhinoplasty any different? On a conceptual level, the smoothing out of a few wrinkles does not seem like such a big thing. In fact can this even be considered body modification since it does not fundamentally change the way we look but only returns our skin and our appearance to a previous state? In this sense one could place cosmetic procedures along a continuum. At one end is the use of make up, at the other, complex cosmetic surgery that changes and modifies the body. In between are things like dieting, going to the gym, whitening teeth, and treatments such as BOTOX®. However, the search for beauty is more than skin deep. Data show that there are distinct advantages to being beautiful aside from being asked to the prom. Researchers have found that people with good looks are more likely to be hired9,10, promoted faster11, and paid more12. In a dramatic study about the benefits of being beautiful, Hamermesh and Biddle13 found that men with above-average looks are paid 5 per cent more than those with average appearance, while those with below-average looks are paid 9 per cent less. Finally, Graham14 reports on studies that show that good looks improve one’s chances in court, make you less likely to get referred to a therapist and generally mean you will get treated as different or special by the world around you. Age Maybe our cultural obsession with beauty and cosmetics is due to the unconscious drive of the species to propagate. Those who look beautiful are thought to be more youthful and thus more fertile. Maybe this is a reflection of a change in society such that age and wisdom are no longer revered in the way that they were. Nevertheless, agism is quite evident in the US. For example, single women of a certain age still despair of being able to find a partner and older workers frequently are fired or treated less favorably than younger ones. In an interesting and relevant study, Johnson15 looked at perceptions of the elderly. Analysis of the data revealed that attractive features are associated with youthfulness and unattractive features are associated with aging. His findings also indicated that, even in the elderly, beauty is associated with more socially desirable personality characteristics, more positive life experiences, and greater occupational status. He concludes that ‘maintaining or recapturing youthful vigor is an important determinant of judged attractiveness’. Growing old is something that few people do without some degree of psychological conflict. In part it may be that focusing on one’s wrinkles, receding hairline, or growing paunch is a displacement for no longer being fertile or able to hunt effectively. As we age, doubts about one’s ability to work or make love appear even in the absence of any ‘real’ evidence to the contrary. In addition, there is an almost universal fear of death and dying which all of us deny to a greater or lesser extent. As we struggle with getting older, Prologue 3most people try a variety of surgical and non-surgical measures to stave off the inevitable. Anne, a 53-year-old executive with a large textile firm, dressed in elegant suits by a famous designer. Trim and fit, with understated gold jewelry, she began jogging after the birth of her daughter, now 20. She thought the highlights in her hair softened her face, although she was having second thoughts on whitening her teeth. ‘The Hollywood look just isn’t me.’ She sought BOTOX® for some wrinkles around her eyes after seeing what the procedure had done for a friend. ‘It just made her look better. I can’t explain it. It’s not fake or too dramatic.’ Anne easily admitted she didn’t like getting old and while she knew she couldn’t turn back the clock she wished to ‘slow the process down some’. For Anne there seemed to be the unspoken hope that what she was doing would help recapture lost time. While this is obviously untrue, it does seem that looking younger helped her feel younger. For those patients who choose non-invasive treatments like BOTOX®, the dermatologists I spoke with report that few are interested in major cosmetic surgery but, like Anne, seem to want to ‘take a few years off’. However, what are these cosmetic treatments, either facestand 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 area to be treated with the tip of the needle pointed lateral to and away from the patient’s eye. Stretching the skin over the area to be injected with the non-dominant hand enables the physician to visualize most of the blood vessels that lie just beneath the surface of the skin in this area (Figure 3.58). Since the skin of the periorbital area is thin, the tip of the needle should be inserted no more deeply than 2–3 mm below the skin surface. This will allow the BOTOX® to diffuse slowly and evenly into the underlying muscle fibers. While injecting BOTOX® into the lateral canthus, it is important to remain at least 1–1.5 cm lateral to the lateral bony orbital rim. Approximately 2–4 U of BOTOX® can be injected into each of two to four Botulinum toxin in clinical dermatology 114sites subcutaneously at the lateral orbital area 1.0–1.5 cm apart from each other for a total of 4–16 U of BOTOX® on each side (Figure 3.51a, b). Men may need slightly higher dosing, approximately 10–20 U per side for comparable results2. Because there can be variable patterning of the lateral canthal lines from one person to the next, BOTOX® 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 Figure 3.57 Risorius is the muscle of laughter creases (Figure 3.59a). Characteristically, a patient can possess any one or multiple patterns of creases that can even be different from the left to right side of the face (Figure 3.59b). 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 BOTOX®. The number of injection sites and the Cosmetic uses of botulinum 115 Figure 3.58 Technique of injecting the crow’s feet or lateral 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 non-dominant hand assists in visualizing superficial periocular vasculature Botulinum toxin in clinical dermatology 116 Figure 3.59a Different patterns of crow’s feet: a, upper b, lateral and c, lower or malar eyelid creases amount of BOTOX® injected will depend on the patterning and severity of the lateral canthal wrinkling as well as the thickness of the skin and the presence or absence of blood vessels36,43–47,49. 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 BOTOX® can be injected subcutaneously at one or two sites as a single or double bolus, producing one or two wheals on the surface of the skin. The wheals of BOTOX® are then gently massaged laterally and away from the orbital fossa in an upward and downward direction. By carefully kneading a bolus of BOTOX® around the lateral canthus, the injected BOTOX® is dispersed subcutaneously and over the muscle fibers of the lateral Orbicularis oculi. This maneuver can prevent post-injection ecchymoses if none of the many periocular vessels found at the lateral Cosmetic uses of botulinum 117canthus are punctured. The bolus of BOTOX® is always injected 1–1.5 cm lateral to the lateral bony orbital margin. Figure 3.59b Different patterns of crow’s feet: a, upper b, lateral and c, lower or malar eyelid creases of the left and right side of a 49-year-old patient squinting before a treatment of BOTOX® When treating crow’s feet, especially at the level of the lower eyelid and lateral malar prominence, it is extremely important to inject BOTOX® in the subcutaneous plane, where the superficial muscle fibers of the orbicularis oculi can be found. The duration of effect of BOTOX® treatments of the lateral canthus usually are 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 accurate placement of the injections. For some patients the duration of effect is extended with subsequent treatments of BOTOX®43. (see Appendix 2). Outcome (results) If the treated crow’s feet are dynamic and the result of the contraction of the orbicularis oculi, there will be a significant improvement to the area (Figures 3.60 and 3.61). 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 discuss a particular problem and its solution in detail with the patient before commencing a course of treatment. 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, memory of a physician’s concerns and predictions are easily forgotten by patients. Most of the time, the best way to diminish lateral canthal static wrinkling is by some form of ablative resurfacing, whether by laser ablation, dermabrasion, or chemical Botulinum toxin in clinical dermatology 118peeling. The different types of non-ablative facial rejuvenation techniques still have not been able to eliminate completely the deep and dense solar elastosis that creates 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 BOTOX® injections and ablative resurfacing, and even injections of a soft tissue filler and daily applications of topical retinoids, alpha-hydroxy acids, or similar type products, is the only way many patients will be able to realize the kind of facial improvement Figure 3.60 This 46-year-old patient is shown at rest and 6 weeks after treatment with BOTOX® Figure 3.61 This 56-year-old man is shown squinting before and 2 weeks after a treatment with BOTOX® Cosmetic uses of botulinum 119they are seeking30,49 (Figure 3.62). Maintenance of such improvements then can be accomplished regularly, albeit infrequently throughout the year, with non-ablative laser, intense pulsed light, or similar types of superficial facial rejuvenation treatments. Figure 3.62 Patient’s crow’s feet before a treatment with BOTOX® and 2½ months after BOTOX® and 2 months after full face CO2 laser resurfacing When the orbicularis oculi is exceptionally hyperfunctional, causing deep and elongated crow’s feet that are recalcitrant and resist improvement with injections of BOTOX® placed in the usual sites, additional injections placed posteriorly toward the lateral limits of the orbicularis oculi in the temporal area can be beneficial50 (Figure 3.63a–d). 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 BOTOX® 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 BOTOX® by having the patient smile repeatedly. If their lower lateral canthal lines are continuous with diagonal wrinkles of the mid and lateral cheeks, caution must be taken when injecting the lower malar crow’s feet (Figure 3.64). Soft tissue fillers orresurfacing may be the best way to rid the patient of these types of rhytids. Treating the zygomaticus major with BOTOX® can easily result in an asymmetric smile and upper lip incompetence (see below) (see Appendix 1). Botulinum toxin in clinical dermatology 120Complications (adverse sequelae) (see Appendix 5) BOTOX® should be injected subdermally and not any more medially to an imaginary vertical line that passes through the lateral canthus, nor below the level of the superior margin of the Figure 3.63a A 64-year-old patient at rest with deep, extensive and recalcitrant crow’s feet before BOTOX® Figure 3.63b Same patient at rest 1 month after BOTOX® Cosmetic uses of botulinum 121 Figure 3.63c Same patient squinting before BOTOX® Figure 3.63d Same patient squinting 1 month after BOTOX® Botulinum toxin in clinical dermatology 122 Figure 3.64 Lower crow’s feet extend down the mid and lateral cheeks in this smiling 42-year-old patient 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 BOTOX®, and result in lateral upper lip ptosis and possibly oral sphincter incompetence40,47. This can occur because the zygomaticus major et minor originate at or near the lateral aspect of the superior margin of the zygomatic arch. If the zygomaticus major is injected with BOTOX®, the lateral edge of the upper lip will be weakened, causing a drooping of the affected side of the upper oral commissure, an asymmetric smile, and possible drooling and incontinence of food and liquid. If BOTOX® 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, including speaking and eating. Figure 3.65a This 56-year-old patient is shown at rest before and 3 weeks Cosmetic uses of botulinum 123after a BOTOX® treatment. Note the difference in pattern between the left and right crow’s feet Figure 3.65b Same patient at rest before and 3 weeks after a BOTOX® treatment. Note the difference in pattern between the left and right crow’s feet Figure 3.66a This 54-year-old patient is shown at rest before and 2 weeks after a BOTOX® treatment. Note the Botulinum toxin in clinical dermatology 124difference in the pattern of wrinkles between the left and right crow’s feet Figure 3.66b Same patient at rest before and 2 weeks after a BOTOX® treatment. Note the difference in the pattern of wrinkles between the left and right crow’s feet Figure 3.67a This 37-year-old patient is shown squinting before and 2 months after a BOTOX® treatment. Note the difference in the pattern of Cosmetic uses of botulinum 125wrinkles between the left and right crow’s feet Figure 3.67b Same patient squinting before and 2 months after a BOTOX® treatment. Note the difference in the pattern of wrinkles between the left and right crow’s feet Figure 3.68a This 58-year-old patient is shown at rest before and 3 weeks after a BOTOX® treatment. Botulinum toxin in clinical dermatology 126 Figure 3.68b Same patient squinting before and 3 weeks after a BOTOX® treatment. Injecting small volumes of concentrated BOTOX® 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 BOTOX® medially and into the superior or inferior, or both, palpebral portion of the orbicularis oculi. If this occurs, weakening of the lateral canthal tendon occurs, producing lower eyelid ectropion which manifests as rounding of the lateral canthus. Rounding can lead to secondary complications of possible prolonged corneal exposure, secondary dry eye, and eventually corneal damage (superficial punctuate keratitis). If any of the extraocular muscles are inadvertantly weakened by BOTOX®, diplopia will result. Because of their position within the orbit the lateral and inferior rectus or inferior oblique are especially disposed to accidental diffusion of injected BTX. If any of these serious complications does occur, immediate consultation with an ophthalmologist is imperative47. Figure 3.69a This 48-year-old patient is shown squinting before and 3 weeks after a BOTOX® treatment. Note the difference in pattern between the left and right crow’s feet Cosmetic uses of botulinum 127 Figure 3.69b Same patient squinting before and 3 weeks after a BOTOX® treatment. Note the difference in pattern between the left and right crow’s feet Loss of the sphincteric function of the orbicularis oculi with either involuntary blinking or voluntary forced eye closure can occur when BOTOX® diffuses onto the palpebral portion of the orbicularis oculi. Lagophthalmos has been seen more frequently in patients treated for strabismus than when they are treated for cosmetic reasons, especially if minimal volume BOTOX® is injected. 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. There is no antidote for lagophthalmos, which will resolve when the effects of the BOTOX® remit. So protecting the patient from developing secondary dry eyes is extremely important. Consultation with an ophthalmologist will prevent any additional, unintended eye injury. Figures 3.65–3.70 are some examples of different patients treated with BOTOX® for crow’s feet. Figure 3.70a This 56-year-old patient is shown squinting before and 2 weeks after a BOTOX® treatment. Note the difference in the pattern between the right and left crow’s feet Botulinum toxin in clinical dermatology 128 Figure 3.70b Same patient squinting before and 2 weeks after a BOTOX® treatment. Note the difference in the pattern between the right and left crow’s feet Treatment implications when injecting the lateral orbicularis oculi (crow’s feet) 1. Older patients will have varying degrees of improvement, depending on the amount of photoaging, redundant skin, and static wrinkling present. 2. Injecting the lateral canthus can produce upper lip asymmetry and cheek ptosis. Inject well above the superior margin of the zygoma and remain 1.0–1.5 cm lateral to the lateral canthus. 3. All periocular injections of BOTOX® should be placed in the lower dermis or subcutaneously, and not any more deeply. 4. Inject 1–1.5 cm lateral to the lateral canthus (bony orbital rim) to avoid diplopia. 5. Post-treatment ecchymoses can last over one week, fallaciously suggesting a substandard injection technique by an incompetent injector. 6. Upper lateral canthal injections of the orbicularis oculi also can be used to produce a lateral eyebrow lift when used in conjunction with BOTOX® injections of the glabellar and forehead muscles. 7. Accurately placed and precisely dosed low-volume BOTOX® injections are essential in order to avoid untoward sequelae in the periocular area. Lower eyelids Introduction: problem assessment and patient selection Along with crow’s feet, many people have additional folds and creases of the lower eyelids, which give them the appearance of being tired, sleep deprived, or even older than their current age. These ‘festoons’ or ‘jelly rolls’ are produced by hyperkinetic palpebral (preseptal and pretarsal) orbicularis oculi (Figure 3.71a, b). They also help create the appearance of dark, baggy eyes that women and even men alike would prefer not to have. Cosmetic uses of botulinum 129Likewise, a tired, disinterested, downtrodden, and unambitious demeanor is projected when the palpebral aperture is narrowed because of a hyperfunctional pretarsal orbicularis oculi.Various facial movements, primarily smiling or laughing, also will narrow momentarily the palpebral aperture. Functional anatomy The orbicularis oculi helps protect the eyes from bright light and fast flying projectiles and, when contracted abruptly, causes one to shut the eyes completely or partially, i.e. to squint. Those working outdoors or in a brightly lit environment maintain their orbicularis oculi in a constant hyperkinetic state, causing the muscle fibers of the orbicularis oculi to hypertrophy. In younger patients, hypertrophic palpebral orbicularis 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 (Figure 3.71b). These lower eyelid folds can be diminished by BOTOX® (Figure 3.72a–d). In older patients, however, the skin of the eyelids becomes thin and less elastic and the orbital septum attenuates, making it less effective. Because of a weakening of this anatomical bulwark, the inferior periorbital fat bulges from behind the preseptal orbicularis oculi and creates characteristic suborbital ‘festoons’ (Figure 3.73a,b). BOTOX® injections of the already weakened and incompetent preseptal orbicularis oculi invariably will enlarge this type of suborbital festooning, and therefore should not be performed48. Figure 3.71a Early festoons and wrinkles of the lower eyelid in this 42 year old patient at rest Botulinum toxin in clinical dermatology 130 Figure 3.71b Same patient with periocular wrinkles exaggerated when she smiles. She also complained of dark circles under her eyes Figure 3.72a Left lower eyelid of a 42-year-old woman at rest and before BOTOX® Cosmetic uses of botulinum 131 Figure 3.72b Same patient at rest 3 weeks after BOTOX® Figure 3.72c Same patient smiling before BOTOX® Botulinum toxin in clinical dermatology 132 Figure 3.72d Same patient smiling 3 weeks after BOTOX® Figure 3.73a This 75-year-old woman has thinning of the preseptal orbicularis oculi which is seen as festoons of the lower eyelids Cosmetic uses of botulinum 133 Figure 3.73b Same patient squinting causes the orbital and palpebral portions of the orbicularis oculi to contract. Injections of BOTOX® in the lower eyelid will make the orbicularis oculi incompetent at rest and intensify her festooning and wrinkles with squinting. Therefore, BOTOX® injections in the lower eyelids should not be performed in this patient A major function of the palpebral portion of the orbicularis oculi is its sphincteric action that 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 (Figure 3.74). 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 they are then released into the nasal cavity from the inferior meatus under the inferior nasal turbinate. As the secreted tears flow from 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 patulous punctum in direct contact with the globe and the lacrimal lake. This allows the tears to flow into and through the patent canaliculi. Contracting the superficial fibers of the pretarsal orbicularis oculi shuts the eyelids and distributes the tears over the anterior surface of the globe from a superior lateral to an inferior medial direction. 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 preseptal orbicularis oculi pull on the lateral walls of the lacrimal sac, enlarging its lumen and contributing to the negative pressure gradient within the nasolacrimal canalicular system, which causes the tears to be aspirated into the lacrimal sac (Figure 3.74). Upon reopening the eyelids, the positive pressure within the canalicular Botulinum toxin in clinical dermatology 134system is recreated and the lacrimal sac collapses, propelling the tears into the nasolacrimal duct, then through the inferior Figure 3.74 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 crosssection by a slit lamp beam (inset). The passage of tears into the nose occurs via the lacrimal drainage system (3) (Reproduced with permission from Zide B, Jelks G (eds) 1985 Surgical Anatomy, p.34. Philadelphia: Lippincott) a. Lacrimal late b. Puncta c. Canaliculi d. Lacrimal Cosmetic uses of botulinum 135sac e. Nasolacrimal duct f. Inferior meatus g. Turbi nates meatus and into the nasal cavity. Simultaneously, the puncta and canaliculi reopen to collect more tears from the lacrimal lake and the cycle recreates itself with each opening and shuting of the eyelids. Dilution When treating the periocular area with BOTOX® it is imperative to be precise with dosing and accurate with injecting minimal volumes of the BTX. Therefore, a 100 U vial of BOTOX® should be reconstituted with only 1 ml of normal saline, (see Appendix 1). Dosing: how to correct the problem (what to do and what not to do) Appropriate candidates for BOTOX® treatment of the lower eyelids are those who have normal eyelid elasticity, determined by a normal snap test, and who have not had any previous lower eyelid surgery, including blepharoplasty or some form of resurfacing, either by laser or chemical peeling. 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 immediately back against the globe, the snap test indicates that the eyelid’s elasticity is ostensibly normal, and it can be treated with injections of BOTOX®. If the recoil is sluggish, indicating insufficient elasticity of eyelid skin, then the patient’s lower eyelids should not be injected with BOTOX®, because the probability of post-injection ectropion is high. If the patient is in a sitting or a semireclined position for the injection, it will be easier for the physician to approach the patient with a needle head-on toward the eye. The physician injector should stand on the side of the lower eyelid to be treated, and the patient should gaze directly forward. 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. Contemporaneously, the physician pulls the lower eyelid skin inferiorly with the nondominant hand and inserts the needle tip through the skin at a point 2–3 mm from the lower lid margin at the midpupillary line. The needle tip should be advanced at about a 45° angle and approximately 2–3 mm deep through the skin, but remaining at the depth of the lower dermis and no deeper than the subcutaneous layer (Figure 3.75a, b). Even with the needle tip advanced 2–3 mm into the skin, it should maintain its superficial position. When the tip of the needle is through the skin and has reached its proper depth, an injection of 2 U (i.e. 0.02 ml) of BOTOX® will remain within the tissue and not leak or track out along the path of the needle puncture, provided there is no air within the barrel of the syringe. The injector should observe the rise of a wheal of fluid, which should reassure the physician that an adequate dose of BOTOX® has been delivered as intended (Figure3.75b). Delicate massage of the injected area directed laterally will distract the patient and help disperse the BOTOX® safely along the superficial fibers of the pretarsal orbicularis oculi. When this technique is Botulinum toxin in clinical dermatology 136 Figure 3.75a Technique of injecting the lower eyelid with BOTOX®. Note the index finger of the non-dominant hand pulling down on the skin of the lower eyelid making it taut. The needle tip is inserted at a 45° angle, 2–3 mm from the lid margin and approximately 2–3 mm deep within the deep dermal to subcutaneous layer Cosmetic uses of botulinum 137 Figure 3.75b The appearance of a wheal indicates that the bolus of BOTOX® has been delivered successfully 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 1–2 U of BOTOX® can be injected intradermally or subcutaneously and approximately 2–3 mm below the lid margin, at a point halfway from the lateral canthus and the midpupillary line52,53. 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 (see Appendix 2). Outcomes (results) It was discovered serendipitously that an injection of 1–2 U of BOTOX® subcutaneously in the pretarsal portion of the orbicularis oculi of the lower eyelid at the midpupillary line, approximately 2–3 mm below the lid margin, can improve the rolls of festooning redundant skin that occur on and just inferior to the lower eyelid51 (Figures 3.71 and 3.72). Lower eyelid TABLE 3.1 IPA—INCREASE IN PALPEBRAL APERTURE AT REST AND AT FULL SMILE Pretarsal area treated alone Pretarsal area treated together with crow’s feet BOTOX® 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 1.5 IPA at full smile (mm) 1.3 2.5 4.5 2.9 2.9 4.0 Botulinum toxin in clinical dermatology 138Adapted from Flynn TC, Carruthers J, Carruthers A. Botulinum A toxin treatment of the lower eyelids improves infraorbital rhytides and widens the eye. Dermatol Surg 2001; 27:703–8 Figure 3.76 When treating the lower eyelid folds and festoons, depending on the depth of the folds, one (A1) injection at the midpupillary line or a second (A2) injection midway between A1 and the lateral canthus can be performed, depending on the strength of the palpebral Orbicularis oculi. Additional injections (●) of BOTOX® may be needed to treat crow’s feet, the dosage of which will depend on the strength of the lateral Orbicularis oculi Cosmetic uses of botulinum 139pretarsal injections of BOTOX® also were found to produce a desirable relaxation of the palpebral aperture both at rest and during smiling, laughing, and various other facial movements, especially when they were applied in conjunction with BOTOX® treatments of lateral canthal rhytides (crow’s feet). The increase in palpebral aperture was dependent on the amount of units injected pretarsally and whether simultaneous treatment of crow’s feet was performed. For those patients who were treated with only 2 U of BOTOX® injected at only one site in the lower lid pretarsal midpupillary line, the average increase in palpebral aperture (IPA) was approximately 0.5 mm at rest and 1.3 mm at full smile (Figure 3.76). When combined with a fixed dose of 12 U of BOTOX® 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 BOTOX® were injected pretarsally into the lower eyelid at two separate sites, equally positioned from the lateral canthus and the midpupillary line (Figure 3.76), the average IPA was approximately 1.75 mm at rest and 2.5 mm at full smile. When 2 U of BOTOX® were injected pretarsally into the lower eyelid at two separate sites (total of 4 U) equally positioned, one at the midpupillary line (Figure 3.76 A1), the other midway from the midpupillary line and the lateral canthus (Figure 3.76 A2) in conjunction with treating the crow’s feet with 4 U of BOTOX® injected in the lateral canthus at three sites each equally spaced (total of 12 U), the average IPA at rest was approximately 2.2 mm and 2.9 mm at full smile. When 8 U of BOTOX® were injected pretarsally in the lower eyelid at two separate sites in the same manner that the 4 U of BOTOX® were given (Figure 3.76 A1, A2), the average IPA was approximately 1.95 mm at rest and approximately 4.5 mm in full smile. When the 8 U of BOTOX® were injected pretarsally into the lower eyelid at the two separate sites as above (A1 and A2 in Figure 3.76) and in conjunction with treating the crow’s feet with 12 U of BOTOX® injected in three equal (4 U) doses in the lateral canthus (Figure 3.76), the average IPA was approximately 1.5 mm at rest and 4.0 mm at full smile. Interestingly, there appeared to be a synergistic effect to the response of the lower pretarsal orbicularis oculi when the lateral orbital orbicularis oculi was simultaneously treated during the same session. This technique of injecting the pretarsal orbicularis oculi produces an ‘open-eyed look’ that gives the patient the appearance of one who is vibrantly active and cheerfully youthful (Figure 3.77). In most cases, the second intermediary injection of BOTOX® between the lateral canthus and midpupillary line is not necessary (Figure 3.76 A2). It may even increase the chance for lateral canthal rounding and lower eyelid ectropion. This technique of injecting the lower eyelids with BOTOX® also has been surprisingly popular among Asian patients who desire a more rounded, Western eyelid aperature49,52,53. Figures 3.78–3.82 are some examples of different patients treated with BOTOX® for folds and creases of the lower lids. Complications (adverse sequelae) (see Appendix 5) Rounding of the lateral canthus can be produced by the weakening of either the upper or lower, or both, pretarsal orbicularis oculi. Injecting at least 1.0–1.5 cm lateral to the lateral canthus can help avoid such an unwanted outcome. The second intermediate injection of the lower pretarsal orbicularis oculi (Figure 3.76 A2) also has been found to cause rounding of the lateral canthus and ectropion of the adjacent lateral aspect of the Botulinum toxin in clinical dermatology 140lower lid margin, especially when a full treatment of BOTOX® is injected into the adjacent upper and lower crow’s feet area (Figure 3.83). Therefore, unless the patient has recalcitrant lower eyelid festoons that wrap around the lateral canthus and Figure 3.77 This 56-year-old patient seen at rest before and after 2 U of BOTOX® were injected into the lower eyelid at the midpupillary line 2–3 mm from the lid margin and 6 U of BOTOX® for crow’s feet. Note the wide eyed open look Figure 3.78 This 49-year-old patient is shown at rest and forward gazing before and 3 weeks after a BOTOX® Cosmetic uses of botulinum 141of the lower lid. Note the wide eyed open look Figure 3.79a, b This 58-year-old patient is shown at rest and forward gazing before and 3 weeks after a BOTOX® treatment of the lower lid and crow’s feet. Note the reduction of the lower lid festoons Figure 3.80 The same patient is shown at rest and forward gazing before and 3 weeks after a BOTOX® treatment of the lower lid and crow’s feet. Note the reduction of the lower lid festoons are continuous with deep and resistant lateral canthal lines, this second (Figure 3.76 A2), intermediate, lateral pretarsal injection of BOTOX® should be withheld, and only the central pretarsal injection of the lower eyelid at the midpupillary line should be given (Figure 3.76 A1,). It is imperativethat the pretarsal injections be placed into the deep dermis, barely reaching the subcutaneous tissue, and nowhere near the bony malar prominence, since Botulinum toxin in clinical dermatology 142most of the upper lip levators originate along the superior margin of the zygomatic arch (Figure 3.84). 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 lip (levator labii superioris, zygomaticus minor and levator labii superioris alaeque nasi) can be weakened by diffusion of the BOTOX®. Figure 3.81 a This 50-year-old patient is shown at rest and forward gazing before and 3 weeks after a BOTOX® injection of the lower lid. Note the wide eyed open look Figure 3.81 b Same patient at rest and forward gazing before and 3 weeks after a BOTOX® of the lower lid. Note the wide eyed open look Cosmetic uses of botulinum 143 Figure 3.82 This 42-year-old patient is shown at rest and forward gazing before and 3 weeks after a BOTOX® injection of the lower lid. Note the wide eyed open look Figure 3.83 2 U of BOTOX® were injected into each lower eyelid at the mid pupillary line 2 mm from the lid margin along with 9 U of BOTOX® into the lateral canthus of this 55-year-old woman who is 8 years post-blepharoplasty. Although she had a normal Snap test her previous blopharoplasty may have contributed to this patient’s asymptomatic lateral canthal rounding and lower eyelid ectropion. Note the scleral show and Botulinum toxin in clinical dermatology 144unnatural and unattractive rounding of the lateral canthi Injecting BOTOX® medial to the midpupillary line of the lower eyelid runs the risk of weakening the voluntary and involuntary sphincteric function of the palpebral orbicularis oculi which would compromise forced eyelid closure and the blink reflex. This in turn could either diminish the action of the lacrimal pump and cause temporary epiphora23,49 or even result in xerophthalmia or dry eyes because of supervening lagophthalmos and corneal exposure. This can occur more readily in older patients who have attenuated muscular strength and a thinned orbital septum. Post-injection ecchymoses are more commonly produced whenever thin eyelid skin is injected (Figure 3.85). The use of small insulin syringes and fine 30-gauge needles, a slow injection technique, pre- and post-treatment icing, and gentle massage and point pressure all may help to prevent or limit the extent of post-injection ecchymoses, which otherwise should resolve in a few (approximately 10–15) days. Pseudoherniation of the infraorbital fat pad can be enhanced when BOTOX® is injected into the inferior palpebral orbicularis oculi in patients who have festooning caused by protruding periorbital fat in inelastic, incompetent lower eyelids. A worsening of pseudoherniation by BOTOX® is easy to produce, particularly 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 (Figure 3.73). Injections of BOTOX® in the inferior palpebral, inferolateral canthal, and high 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 them40. Lower eyelid injections of BOTOX® in such individuals should not be performed48. In their dose-defining studies, Flynn et al. found no substantial adverse events in the patients treated with 2 U of BOTOX® injected at one site pretarsally in the lower eyelid (Figure 3.76). In Cosmetic uses of botulinum 145 Figure 3.84 Upper lip levators Figure 3.85 Two days after 2 U of BOTOX® were injected in both lower eyelids for the first time in this 53-year-old woman. The ecchymosis in the right eyelid lasted for about 10 days Botulinum toxin in clinical dermatology 146those patients who had 4 U of BOTOX® injected pretarsally in two divided doses of 2 U each (Figure 3.76 A1, A2), less than half of them suffered from ‘dry eyes’ and one patient could not wear her contact lenses52,53. There were additional, temporary adverse events that were more of an annoyance than a serious complication and they occurred after 8 U of BOTOX® were injected pretarsally in two divided doses of 4 U each into the lower eyelid (Figure 3.76 A1, A2). They 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 day52. 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 BOTOX® were injected into the two sites in the mid and lateral aspects of the pretarsal portion of their lower eyelids. Treatment implications when injecting the lower eyelids 1. Lower eyelid injections of BOTOX® produce a ‘wide-eyed’, actively youthful appearance. 2. Inject only 1–2 U and no more than 3 U of BOTOX® into the lower dermis or the upper subcutaneous tissue in the pretarsal midpupillary line. 3. Pretarsal injections of BOTOX® at the intermediate point between the lateral canthus and the midpupillary line increases the risk for lower eyelid ectropion, rounded lateral canthus, and various other adverse sequelae. 4. Pretarsal injections of BOTOX® in the lower eyelid medial to the midpupillary line may cause epiphora by weakening the blink reflex, or dry eyes by creating persistent lagophthalmos and corneal exposure. 5. Injections of BOTOX® lower than 2–3 mm from the lower eyelid margin can result in lip asymmetry and cheek ptosis. 6. Low-volume, highly concentrated injections of BOTOX® are best when injecting the superficial fibers of the lower pretarsal portion of the orbicularis oculi. 7. Anyone who has had other periocular cosmetic procedures and who has a sluggish snap test should not be treated with BOTOX® injections in the lower pretarsal orbicularis oculi. References 1. Benedetto AV. The cosmetic uses of botulinum toxin type A. Int J Dermatol 1999; 38:641–55 2. Carruthers J, Fagien S, Matarasso, SV et al. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics. Supplement to Plastic Reconstr Surg 2004; 114:1S–18S 3. Wieder JM, Moy RL. Understanding botulinum toxin. Surgical anatomy of the frown, forehead, and periocular region. Dermatol Surg 1998; 24:1172–4 4. Hsu TS, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A. Arch Dermatol 2004; 140:1351–4 Cosmetic uses of botulinum 1475. Carruthers A, Carruthers J, Cohen J. A prospective, double-blind, randomized, parallel-group, doseranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dematol Surg 2003; 29:461–7 6. 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, 7. Le Louarn C. Botulinum toxin A and facial lines: the variable concentration. Aesthetic Plast Surg 2001; 25:73–84 8. Carruthers A, Carruthers J. Clinical indications and injection technique for the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998; 24:1189–94 9. Klein AW. Complications and adverse reactions with the use of botulinum toxin.Dis Mon 2002; 48;336–56 10. Klein AW. Dilution and storage of botulinum toxin. Dermatol Surg 1998; 24:1179–80 11. 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 12. Fulton JE. Botulinum toxin. The Newport Beach experience. Dermatol Surg 1998; 24:1219–24 13. Carruthers A, Carruthers J. The treatment of glabellar furrow with botulinum A exotoxin. J Dermatol Surg Oncol 1990; 16:83 14. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 1992; 18:17–21 15. 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 16. Carruthers JD, Lowe NJ, Menter MA, Gibson J, Eadie N for the Botox Galbellar Lines II Study Group. 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 17. Carruthers JA, Lowe NJ, Meneter Ma et al. A muliticanter, double-blind, randomized, placebocontrolled 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 18. Hankins CL, Strimling R, Rogers GS. Botulinum A toxin for glabellar wrinkles: dose and response. Dermatol Surg 1998; 24:1181–3 19. Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds; a double-blind, placebocontrolled study with a electromyographic injection technique. J Am Acad Dermatol 1996; 35:569–72 20. 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 21. Roth JM, Metzinger SE. Quantifying the arch position of the female eyebrow. Arch Facial Plast Surg 2003; 5:235–9 22. Benedetto AV, Lahti JG. Measurements of the anatomical position of the corrugator supercilii. Derm Surg 2005; 31:923–7 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. Daniel RK, Landon B. Endoscopic forehead lift. Anatomic basis. Aesthet Surg 1997; 17:97–104 25. Cook, Jr. BE, Lucarelli MJ, Lemke BN. Depressor supercilii muscle: anatomy, histology, and cosmetic implications. Opthalmic Plast Reconstr Surg 2001; 17:404–11 26. Botox Cosmetic [package insert]. Irvine, CA: Allergan, Inc., 2002 27. 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, randomized controlled trial. Arch Dermatol 2002; 138:510–14 28. Klein AW, Mantell A. Electromyographic guidance in injecting botulinum toxin. Dermatol Surg 1998; 24:1184–6 Botulinum toxin in clinical dermatology 14829. Blitzer A, Binder WJ, Aviv JE. The management of hyperfunctional facial lines with botulinum toxin: a collaborative study of 210 injection sites in 162 patients. Arch Otolaryngol Head Neck Surg 1997; 123:389–92 30. Fagien S. Botulinum toxin type A for facial aesthetic enhancement: role in facial shaping. Plast Reconstr Surg 2003; 112:6S–18S 31. Binder WJ, Blitzer A, Brin MF. Treatment of hyperfunctional lines of the face with botulinum toxin A. Derm Surg 1998; 24:1198–205 32. Carruthers A, Carruthers J. Botulinum A exotoxin in clinical ophthalmology. Can J Ophthalmol 1996; 30:389–400 33. Carruthers J, Fagien S, Matarasso SL. The Botox Consensus Group: Consensus Recommendations on the use of Botulinum Toxin Type A in facial aestletics. Plast Reconstr Surg 2004(6) supp. 1S–22S. 34. Huang W, Rogachefsky AS, Foster JA. Browlift with botulinum toxin. Dermatol Surg 2000; 26:55–60 35. Frankel AS, Kamer FM. Chemical browlift. Arch Otolaryngol Head Neck Surg 1998; 124:321–3 36. Ahn MS, Cotton M, Maas CS. Temporal browlift using botulinum toxin A. Plast Reconstr Surg 2000; 105:1129–35 37. Huigol SC, Carruthers A, Carruthers J. Raising eyebrows with botulinum toxin. Dermatol Surg 1999; 25:373–5 38. Chen AH, Frankel AS. Altering brow contour with botulinum toxin. Facial Plast Surg Clin N Am 2003; ll:457–64 39. Matarasso SL. Complications of botulinum A exotoxin for hyperfuntional lines. Derm Surg 1998; 24:1249–54 40. Frankel AS. BOTOX for rejuvenation of the periorbital region. Facial Plast Surg 1999; 15:255–62 41. 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 42. Lowe NJ, Lask G, Yamanchi P et al. Bilateral, double-blind, randomized 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 43. 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 44. 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 45. Kane MA. Classification of crow’s feet patterns among Caucasian women: the key to individualizing treatment. Plast Reconstr Surg 2003; 112:33S-39S 46. 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 47. 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 48. Goldman M. Festoon formation after intraorbital botulinum A toxin: a case report. Dermatol Surg 2003; 29:560–1 49. 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 50. Kadunc BV. Periorbital wrinkles. In: Hexsel D, Almeida AT de (eds) Cosmetic Use of Botulinum Toxin. Porto Alegre, Brazil: AGE Editora, 2002:149–54 51. Flynn TC, Carruthers J, Carruthers A. Botulinum A toxin treatment of the lower eyelids improves infraorbital rhytides and widens the eye. Dermatol Surg 2001; 27:703–8 Cosmetic uses of botulinum 14952. Flynn TC, Carruthers JA, Clark RE. Botulinum A toxin (BOTOX) in the lower eyelid: dose-finding study Dermatol Surg 2003; 29:943–50 Botulinum toxin in clinical dermatology 150 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 non-invasive techniques, many experienced injectors of BOTOX® now are venturing below the upper face with their treatments1. As with any other part of the face, one must be completely knowledgeable of the levator and depressor action of the mimetic musculature. In the mid and lower face the reciprocating action of opposing mimetic muscles can prove to be a bit more complicated and challenging 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 BOTOX®. However, in the mid and lower face, there is an interdependence of the superficial and deep muscles of facial expression, which also are adjacent to some of the muscles surrounding the mouth that function in the articulation of sounds or in mastication and deglutition. These muscles of facial expression are interlaced with and even help form the superficial muscular aponeurotic system (SMAS) and many of them perform complementary and, at times, unrelated functions. Nevertheless, the mimetic muscles of the mid and lower face have very specific functions, mostlycentered around the mouth, sometimes acting as agonists, sometimes as antagonists, but always in a complex, synergistic manner. This allows a person to smile and laugh, grimace, or pucker the lips, or to make any other overt or subtle gesture with the mouth, or even to hold solids, liquid, and air within the mouth without loss of contents or to release at will the contents slowly or forcibly out of the mouth. These muscles allow for the fine motor movements necessary to produce subtle whispering sounds or thunderous clammer. They also facilitate the actions of chewing and swallowing and a myriad of other simple and complex movements that either explicitly or implicitly function in voluntary 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 (Figure 4.1). Consequently, in the mid and lower face, it then is understandable why, if injected BOTOX® migrates beyond the targeted muscles, unintended results and complications can occur more readily. Therefore, when treating anyone with BOTOX® in the mid and lower face, a little bit of BOTOX® may be good, but a little bit more usually is 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 BOTOX® when rejuvenating the face2. In the upper face the skin can be thicker and more tightly adherent to the underlying muscles of facial expression and complications, if and Figure 4.1 Mimetic muscles of facial expression. Right side depicts the superficial and left side depicts the deeper muscles when they occur, often are related to BOTOX® diffusion. Usually much higher doses of BOTOX® are injected into the upper face musculature to produce more extensive muscle weakness, but BOTOX® treatments there rarely cause functional imbalance. On the other hand, the lower facial musculature should be treated with lower doses of BOTOX® to lightly weaken their activity. Deep longstanding wrinkles and furrows on many occasions cannot be totally effaced; otherwise, anatomic aberrations and functional imbalance can result. In order to maintain the functional as well as an anatomic balance in the mid and lower face when treating a patient with injections of BOTOX®, it is absolutely necessary, more so than in the upper face, that minimal volumes, accurately measured, of low doses of BOTOX® be precisely placed and injected into specifically targeted muscles. Cosmetic uses of botulinum toxin 153Particularly during treatment of the mid face, the upper lip levators are easily affected by the slightest diffusion of BOTOX®, which can readily cause a disruption in one or many of the complex motor functions of the lips (e.g. eating, drinking, and speaking). Also, because of the intermingling of the muscle fibers of the upper lip levators with the orbicularis oris, which overlie a thicker mass of subcutaneous soft tissue, BOTOX® injections to the mid face usually are best performed with electromyographic guidance. In many areas of the mid and lower face, however, better overall cosmetic results can be achieved with soft tissue implants and fillers, or resurfacing techniques and many other types of invasive procedures (i.e. rhytidectomy and different soft tissue suspension techniques), while supplementary treatments with BOTOX® injections can be used to enhance and prolong the final esthetic outcomes3. Nasoglabellar lines 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 radix 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 (Figure 4.2). They are anatomically different 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 BOTOX®, these lines are identified as the ‘BOTOX® sign’ (Figure 4.3a). On the other hand, when these nasoglabellar lines occur naturally, they are referred to as ‘bunny lines’ or a ‘nasal scrunch’3,4 (Figure 4.3b). They are annoyingly unsightly and unwanted by those 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 the nose before a treatment with BOTOX®. The transverse or horizontal Botulinum toxin in clinical dermatology 154lines across the root of the nose are produced by the procerus. Different patients have different wrinkle patterns Figure 4.3a ‘BOTOX® sign’, a) This 52 year old patient frowning and without nasoglabellar lines prior to a treatment with BOTOX®. b) Same patient frowning 3 weeks after BOTOX® treatment of his glabellar frown lines. Note the compensatory nasoglabellar lines, i.e. BOTOX® sign, c) Two weeks after a touch-up injection of BOTOX® in the transverse nasalis and 5 weeks after the original BOTOX® treatment. Note the compensatory nasoglabellar lines are gone women who possess nasoglabellar wrinkles, and they should be treated with injections of BOTOX® along with the glabellar frown lines. Functional anatomy 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 (Figure 4.4). Its fibers course medially and superiorly and expand into the aponeurosis over the bridge of the nose, Cosmetic uses of botulinum toxin 155inserting into the fibers of its paired muscle of the opposite side and into the aponeurosis of the procerus (Figure 4.5). The transverse nasalis or compressor naris depresses the cartilaginous part of the nose, drawing the ala toward the nasal septum. These nasoglabellar lines are produced by asking the patient to squint forcibly, as if intense light is shining in the eyes. If these lines become prominent, the patient will most likely produce them readily after their glabellar lines are treated with BOTOX® (Figure 4.3b). Therefore, such naturally occurring nasoglabellar lines should be treated automatically with injections of BOTOX® at the same treatment session when glabellar frown lines are treated. If they are not treated, whether or not the patient is aware of the existence of their nasoglabellar lines before a treatment of BOTOX®, the patient more than likely will blame the physician and BOTOX® for their presence after treatment. Therefore, it behooves the physician to disclose their presence to the patient prior to any treatment with BOTOX®, underscoring the necessity to include these nasoglabellar frown lines as part and parcel of the treatment of glabellar frown lines. Figure 4.3b This 49-year-old patient is shown frowning before and 3 weeks after a treatment with BOTOX®. Note the diminished nasoglabellar ‘bunny lines’ If these lines become evident after the patient’s glabellar frown lines are treated with BOTOX®, then they should be identified and treated during the obligatory follow-up visit 2–3 weeks after a BOTOX® treatment session (Figure 4.3a). (See Appendix 4). Botulinum toxin in clinical dermatology 156Dilution In order to prevent the unintended widespread diffusion of BOTOX®, it is necessary that a minimum amount of BOTOX® be injected when treating the nasoglabellar lines.Therefore, 1 ml of normal saline should be used to reconstitute the 100 U vial of BOTOX® when injecting nasoglabellar lines (see Appendix 1). Dosing: how to correct the problem (what to do and what not to do) With the patient in the upright sitting or semirecumbent position, nasoglabellar lines can be relaxed by injecting 2–5 U of BOTOX® 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 (Figure 4.6). This technique should position the needle well above the angular vessels5–8. The soft Figure 4.4 The compressor naris or transverse nasalis originates from the Cosmetic uses of botulinum toxin 157maxilla and inserts into the nasal bridge aponeurosis 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 (Figure 4.7a). Otherwise, either the levator labii superioris alaeque nasi or the levator labii superioris, or both, may be weakened by the injected BOTOX®, since they both originate 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. It appears men are not treated for this problem as frequently as women. Dose of BOTOX® depends on the overall depth and location of the lines and strength of the transverse nasalis. Higher doses by 1 or 2 U more than 5 U of BOTOX® injected on each side may be necessary to diminish these lines, especially in those men and women who spend the better part of the day outdoors and whose nasalis is hypertrophic and hyperkinetic from constant squinting. The effects of BOTOX® can last at least 3 months and usually longer. In patients who previously have had a rhinoplasty, the results may be somewhat less than expected6–10 (see Appendix 2). Figure 4.5 Compressor naris or transverse nasalis—its relationship to adjacent musculature Botulinum toxin in clinical dermatology 158 Figure 4.6 Injecting the transverse nasalis anterior and superior to the nasofacial angle. Note the wheal of injected BOTOX® Figure 4.7a Point • at which injections should be placed when treating the compressor naris (transverse nasalis) Cosmetic uses of botulinum toxin 159Outcomes (results) 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 (Figure 4.3a, b) (see Appendix 3). Recently, Tamuro et al11 found that they were able to successfully treat approximately 40% of their patients with nasoglabellar lines by injecting them with 3 U of BOTOX® on either side of the nasal side wall in 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 further diminish these persistent bunny lines an additional 2 U of BOTOX® needed to be injected at different sites along either side of the nasal bridge according to the three different patterns they identified as the naso-alar rhytides, naso-orbicular rhytides, and naso-ciliary rhytides. These additional BOTOX® treatments were given at four weeks during the first follow up visit. There Figure 4.7b Additional injection sites to diminish persistent nasoglabellar lines. Red dot for nasodlliary rhytides; green dot for nasoorbicular rhytides; purple dot for naso-alar rhytides Botulinum toxin in clinical dermatology 160were approximately 30% of the patients who had persistent wrinkling of the root of the nose owing to contraction of the nasal portion of the Orbicularis oculi, so these patients were identified as having naso-orbicular rhytides (Figures 4.7b, c). Another 30% of the patients had persistent wrinkling at the root of the nose which extended superiorly toward the medial margin of the eyebrow and glabella caused also by contraction of the Orbicularis oculi, but adjacent to the ciliary arch so they were identified as having naso-ciliary rhytides (Figures 4.7b, c). The third pattern identified as naso-alar persistent wrinkles occured in both subgroups and were felt to be the result of the contraction of the alar portion of the levator labii superioris alaeque nasi. Each area of persistent wrinkling, was produced by unaffected fibers of the underlying muscles which required the additional 2 U of BOTOX® on either side of the nasal bridge to completely eliminate any residual nasoglabellar ‘bunny lines’11. Complications (adverse sequelae) (see Appendix 5) Injecting BOTOX® 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 asymmetry and even ptosis of the upper lip, including sphincter incompetence and functional Figure 4.7c Additional injection sites to diminish persistent nasoglabellar lines. Red dot for nasocilliary rhytides; Cosmetic uses of botulinum toxin 161green dot for naso orbicular rhytides; purple dot for naso-alar rhytides difficulties with speaking and eating. Also, if the medial palpebral portion of the Orbicularis oculi is weakened as the result of the unintended diffusion of BOTOX®, a diminution in the action of the lacrimal pump can occur, causing epiphora (excessive tearing)10. Diplopia also can result if the medial rectus is weakened by the BOTOX®. Vigorous massage to the area after the injection of BOTOX® can produce the same adverse results, even if dosing and the injection technique are flawless. There is no antidote for any of these unwanted post-treatment adverse sequelae, and the patient is obligated to endure them until the effects of the BOTOX® remit. In the meantime, consultation with an ophthalmologist 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 deeply can result in an intravascular injection of the BOTOX®. Therefore, subcutaneous placement of the needle tip is all that is necessary when injecting this area with BOTOX®. Treatment implications when injecting nasoglabellar lines 1. Nasoglabellar lines can occur naturally In some individuals or they can be produced by treating glabellar frown lines with injections of BOTOX®. 2. Squinting will elicit the presence or absence of nasoglabellar lines before treating the glabellar frown lines with BOTOX®. 3. Treat nasoglabellar frown lines along with horizontal glabellar frown lines (i.e. those produced by the contraction of the procerus). 4. Injections too low and into the nasofacial sulcus may result in upper lip ptosis, asymmetry, or even upper lip incompetence and functional difficulties of the sphincteric action of the mouth. 5. Inject additional units of BOTOX® along the proximal and distal nasal bridge in different patterns to attenuate all the nasoglabellar lines in certain patients. 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 wide nasal alae, also may have a well-developed muscle of the distal nose (i.e. nasalis), which will allow them to dilate their nostrils voluntarily and involuntarily. This noticeable movement of the nostrils can impart a negative sentiment to observers whichmay include anger, fear, exhaustion, concern, disapproval, or personal distress. Botulinum toxin in clinical dermatology 162Functional anatomy Nasal flaring is the result of the involuntary contraction of the lower portion of the nasalis or the alar nasalis also called the dilator naris, causing the alae nasi to dilate repeatedly (Figure 4.8). The alar nasalis originates from the maxilla above the lateral incisor and medial to the transverse nasalis under the nasolabial fold, and inserts into the lower portion of the nasal cartilage and skin near the margin of the nasal aperature. Its medial fibers can blend with the fibers of the depressor septi nasi. The alar nasalis or dilator naris draws the ala of the nose downward and laterally, dilating the nostrils, thereby preventing the alae nasi from collapsing during inspiration. (See Appendix 4). Dilution Moderate diffusion of BOTOX® is encouraged when treating the lower nasalis. Therefore, reconstituting a 100 U vial of BOTOX® with 1–2.5 ml of normal saline to inject into this area is acceptable (see Appendix 1). Dosing: how to correct the problem (what to do and what not to do) Injections of 5–10 U of BOTOX® subcutaneously into the center of each ala toward the alar rim along the lateral fibers of the alar nasalis will weaken involuntary muscle contractions of the nostrils12. This can be useful in African-American patients or other ethnic groups who have a Cosmetic uses of botulinum toxin 163 Figure 4.8 Dilator naris is the inferior portion of the nasalis Figure 4.9 Patient at rest before and 4 weeks after a treatment with BOTOX®. A slight reduction of a nasal flare was achieved with 5 U of BOTOX® injected into the dilator naris (alar nasalis) bilaterally Botulinum toxin in clinical dermatology 164characteristically similar, broad nasal bridge and wide alae that flare easily because of a hyperkinetic alar nasalis (Figure 4.9). For some individuals, 10–15 U of BOTOX® may be necessary to relax each ala nasi. Only those patients who can voluntarily and actively flare their nostrils are candidates for BOTOX® injections. For those individuals, especially patients of African and Asian descent, who have a characteristically broad nasal bridge and wide alar base, but who cannot actively flare their nostrils at will, injections of BOTOX® will have no effect in narrowing the nasal aperture and should not be performed (see Appendix 1). Outcomes (results) For those individuals who voluntarily can flare or dilate their alae nasi, injections of BOTOX® will decrease the frontal diameter of the nostril and give their nose a narrower, more Caucasian appearance, without interfering with inspiration (see Appendix 1). Complications (adverse sequelae) (see Appendix 5) If patients are not selected properly, injections of BOTOX® will produce no effect, and time, effort, and expense will have been wasted. Otherwise, these patients experience no other adverse sequelae, except the usual ones that occur with intracutaneous injections, including pain, edema, and possible ecchymoses. Treatment implications when injecting the nose for nasal flare 1. Treat only those patients who can actively flare their nostrils. 2. Injections of 5–10 U of BOTOX® in the center or along the alar rim of each ala nasi into the dilator naris will relax flaring nostrils. 3. No adverse side effects have been identified with this injection technique. Nasal tip drop Introduction: problem assessment and patient selection With age, the nasal tip in some individuals naturally rotates downward, 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 senility and decrepitude, projecting an evil and sinister demeanor (Figure 4.10). Recently, BOTOX® therapy has provided a non-invasive means to elevate the nasal tip and produce tip projection, an effect that usually only can be accomplished by surgical rhinoplasty. Cosmetic uses of botulinum toxin 165Functional anatomy The depressor septi nasi is often considered a component part of the dilator naris, which originates from the center of the incisor fossa of the maxilla deep to the orbicularis oris. Its fibers course upward and insert into both the cartilaginous nasal septum (its mobile part) and the mucous membrane undersurface of the ala nasi, and the superficial muscle fibers of the orbicularis oris and mucous membrane of the upper lip (Figure 4.11). Figure 4.10 Downward projected nasal tip Botulinum toxin in clinical dermatology 166 Figure 4.11 Depressor septi nasi may intermingle with the dilator naris The depressor septi nasi pulls the nasal septum downward, draws the ala inferiorly, and narrows the nostril. In some individuals, on the other hand, fibers of the dilator naris have been found to interdigitate with those of the depressor septi nasi. Consequently, when the depressor septi nasi contracts in unison with the dilator naris, a paradoxical widening of the nasal aperture will then occur. Because of the variability in the anatomy and the multifactorial etiology of nasal tip depression, elevation and projection of the nasal tip usually is not as simple to produce with injections of BOTOX® as might be thought. (See Appendix 4). Dilution In the paranasal area, minimum amounts of BOTOX® should be used so as not to accidentally affect the levators of the upper lip by inadvertent diffusion of BOTOX®. Therefore, a 100 U vial of BOTOX® should be reconstituted with 1 ml of normal saline (see Appendix 1). Cosmetic uses of botulinum toxin 167Dosing: how to correct the problem (what to do and what not to do) For those patients who can intentionally depress the tip of their nose downward by lowering their upper lip, injections of BOTOX® 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 precisely into the depressor septi nasi, and not into fibers of the orbicularis oris, before injecting the BOTOX®. Depending on the strength of the depressor septi nasi, 2–4 U of BOTOX® can be injected just superior to this columella-labial juncture. An additional 2–4 U of BOTOX® also can be injected into the middle of the columella, depending on the strength and whether or not the depressor septi nasi is visibly functional. Stronger muscles can be injected with higher doses of BOTOX®13. In some patients whose dilator naris also interdigitates with the depressor septi nasi, an additional injection of 4–5 U of BOTOX® into each side of the dorsum of the ala nasi, i.e. into the dilator naris (as described previously on page 132), will be necessary to effectively project the nasal tip. The combination of injecting both the depressor septi nasi and the dilator naris with BOTOX® will relax the lower end and base of the nose, producing additional lifting of the nasal tip14. If, when depressing the upper lip, one can see an obvious downward rotation of the nasal tip, then injections of BOTOX® will be effective. If there is no movement of the nasal tip when the upper lip is depressed, BOTOX® injections should not be performed. Atamoros has devised a therapeutic dosing scheme whereby he can predict the height change in the nasal tip elevation in the patients he treats with BOTOX®14. Injecting 2 U of BOTOX® into each of the right and left dilator naris and 2 U of BOTOX® into the depressor septi nasi (total of 6 U of BOTOX®) produces a slight elevation of the nasal tip. Approximately 4 U of BOTOX® injected into each ofthe right and left alae nasi and the depressor septi (total of 12 U of BOTOX®) produces a medium elevation of the nasal tip. For a high elevation and projection of the nasal tip, 6 U of BOTOX® into each of the right and left dilator naris and depressor septi (total of 18 U of BOTOX®) may be needed14 (Figure 4.12) (see Appendix 3). Outcomes (results) Injecting BOTOX® into the depressor septi nasi will relax the muscle, lifting and projecting the nasal tip (Figure 4.13). Injecting the depressor septi nasi with BOTOX® also can provide an apparent increase in the distance between the columella and vermillion border, occasionally creating a fuller, more voluminous upper lip for some patients13. Consequently, the depressor septi nasi is one of the muscles which might need to be weakened when treating a patient for exaggerated upper gum smile (see p. 148) (see Appendix 3). Botulinum toxin in clinical dermatology 168 Figure 4.12 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 BOTOX® (6 U into each dilator naris and 6 U into the depressor septi nasi). (Courtesy of Dr Francisco Atamoros Perez) Figure 4.13 Nasal tip before and 1 month after a treatment with BOTOX®. To achieve these results, a total of 8 U of BOTOX® was injected Cosmetic uses of botulinum toxin 169into the lower nasalis (4 U on each side) and 8 U into the depressor septi nasi, for an overall total of 16 U. (Courtesy of Dr Francisco Atamoros Perez) Treatment implications when injecting the nose for a drop of the nasal tip 1. The tip of the nose can drop because of muscle contraction, age, and gravity. 2. BOTOX® injections of the depressor septi nasi will elevate and project the nasal tip. 3. In some patients, the dilator naris also may need to be injected with BOTOX® for nasal tip elevation and projection. 4. Overtreatment with BOTOX® can cause excessive nostril widening and an exaggerated elevation and a flattening of the nasal tip projection. 5. Diffusion of BOTOX® lateral to the columella can affect the upper lip levators, elongating the upper lip and blunting the contour of the philtrum. Upper lip asymmetry and oral sphincter weakness can result from injecting too high a dose of BOTOX® at the base of the columella. Complications (adverse sequelae) (see Appendix 5) Higher doses of injected BOTOX® produce a relaxation of the alar nasalis and depressor septi nasi which can result in an unattractive, prolonged widening of the nostrils along with the projection and elevation of the nasal tip (Figure 4.12). This forced widening of the nostrils was accompanied in some patients by persistent pain and soreness over the nasal tip that lasted for over 2 weeks14. The duration of the effect of the injected BOTOX® in this area sometimes can last 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 BOTOX® 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. 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, injections of the depressor septi nasi should not be attempted. Melolabial grooves and folds Introduction: problem assessment and patient selection Chronological aging and a downward shift of soft tissue can deepen a nasolabial sulcus, which, in turn, augments its fold. Accentuated by side lighting and shadows, the nasolabial fold is enhanced by the descent of the soft tissue mass of the cheek by the Botulinum toxin in clinical dermatology 170incessant effects of gravity. This descent of cheek mass is in the infraorbital area at different depths and shapes and varies with each individual. As the descent of the soft tissue mass intensifies, hooding or folds over the lateral labial commissures appears. The appearance of the so-called nasolabial folds probably is more frequently seen in genetically predisposed individuals, but more than likely they also can be acquired by those whose mid facial movements are constant and excessively intense. Deep, diagonal folds from the sides of the nose that progress downward toward the angle of the mouth, and at times even lower, portray an attitude of disgust and dismay and are a characteristic sign of senescence and dotage. These deep furrows and folds remain as one of the still barely correctable harbingers of decrepitude in the treatment of the aging face. In the past, different surgical procedures have been attempted to efface the outline of the groove, thereby flattening the fold. These procedures were fraught with scars and failure. Recently, injections of permanent and absorbable soft tissue fillers have been the most useful in achieving a modicum of success, and probably are still the best technique for softening and filling this defect, considering the reason for its presence. Nevertheless, injections of BOTOX® also have been employed in an attempt to reduce the appearance of the nasolabial folds. Unfortunately, intramuscular injections of BOTOX® 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 mid face. Functional anatomy There is significant variation in the anatomy that creates the nasolabial fold, which extends from the lateral nasal ala to a point lateral to or lower than the oral commissure. A prominent nasolabial fold may have a mutifactorial etiology with contributing influences of varying degrees from skin, bone, muscles, and fat. The cutaneous insertions of the different mimetic facial muscles along this fold may promote the early appearance of the nasolabial fold and sulcus, starting in those so predisposed persons in their mid to late thirties. In older patients, a combination of any of the following also may contribute to their prominent appearance: • Loss of skin thickness over the sulcus; • Redundant skin lateral to the sulcus; Cosmetic uses of botulinum toxin 171 Figure 4.14 Muscles that contribute to the formation of the nasolabial fold • Excessive fat deposits or ptosis of the malar 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 intensify the vertical sulcus that runs from the upper border of the nasofacial angle downward and laterally toward the commissures of the mouth. Dependent on idiosyncratic and anatomic variations of an individual, it is the set of facial muscles responsible for elevating the upper lip and producing a smile (zygomatic complex, the central upper lip elevators, and the risorius) that contributes significantly to the initial formation and perpetuation of the nasolabial folds (Figure 4.14). 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 fold15. It is the zygomatic muscle complex and the levator labii superioris that are primarily responsible for elevating the lip and producing a smile16. In some individuals, however, the levator labii superioris alaeque nasi is less important in the formation 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, can deepen the middle portion of the nasolabial fold and even exaggerate lateral canthal wrinkles, extending crow’slifts or BOTOX®, actually treating? Is it an illness? A medical condition? Is aging pathological? What are the moral and ethical implications of trying to combat a normal process of human development? Ringel16 raises some of these questions in a very provocative paper that questions the morality of cosmetic treatment. She notes that in defining aging skin as an illness we imply that life itself is an illness. In her view, doctors instead have a responsibility to fight agism and the stigma attached to getting old. She argues that all cosmetic treatments promote an inauthentic enhancement of the self. In doing so they promote a false sense of who one is and serve to perpetuate the denial of the true self. For Ringle, self esteem is clearly better served by embracing maturity rather than denying it. However, while considering this viewpoint is useful, there can be a temptation to fall too quickly not only into pathologizing but dichotomizing. To say that cosmetic treatments, including BOTOX®, are either moral or immoral, bad or good, indicative of a psychiatric illness or not simplifies the issue and misses the point. Focusing on one side of the debate or the other only obscures the more subtle but infinitely more important question of what is best for the patient. These psychological and philosophic questions are both relevant and useful to orient clinicians in assessing patients who come for BOTOX® treatment. They also help to place these specialized medical efforts in the larger context of how to help the ‘whole person’. It is critical to find out what our patients want and whether their goals are realistic and within our power to gratify. Part of the cosmetic dermatologists’ moral, ethical, and professional responsibility is to co-operatively work with patients to determine when treatment is appropriate. To do so, practitioners must enhance their ability to better understand the complex motivations of patients and assess when treatment will actually address the concerns they have. This is crucial to developing and maintaining a good doctor-patient relationship and assuring that patients come away satisfied with the treatment they receive. Patients like Anne abound, but others are unlikely to be pleased with the outcome of their treatment if their expectations and motivations are not well clarified. Botulinum toxin in clinical dermatology 4Motivation In simple terms, the majority of those who choose to have cosmetic treatment are motivated to look younger, healthier, and sexier and, by extension, feel better about themselves. Jim, a 48-year-old lawyer, was determined not to be outdone by the young hotshots coming into the firm now. Since getting divorced three years ago he had been a beast at the gym and had taken two inches off his waist and added them to his chest ‘Fixing all my suits was a pain but it was worth it. You should see the women I meet now’. He showed up like clockwork every three months to get his BOTOX® shot. When he did, he had already circled in black ink any age spots or moles he also wanted lasered off. He told his dermatologist he made a day of it by spending the rest of the afternoon at the spa getting a haircut, massage, and manicure, and generally pampering himself. People like Jim care about how they look and are invested psychologically in their bodies. As they worry about the effect of age, they are beginning to doubt they can still compete with their younger colleagues at work or in the dating game. They hope that making some change in their appearance will increase their self esteem, lift their low mood, and make it easier for them to interact with others. This interest is not necessarily pathologic. In fact, its absence is often one of the first signs of psychiatric illness. Those with major psychiatric illness frequently have little or no interest in their appearance. Yet there is also a tendency to say that such concerns about appearance are shallow. That professional success or a loving family is the true measure of one’s worth. It may even be that a more intense concern about appearance represents a displacement of other thoughts and feelings. It is probably true that worries about the skin and the face can often represent deeper unconscious thoughts, feelings and fantasies about ourselves. Although concentration on physical flaws may reflect deeper psychopathology, it is also reasonable to be upset with the blotchy skin or acne breakout that one sees in the mirror. The desire for cosmetic intervention from the mildest to the most dramatic is motivated by the subjective experience of how one feels about oneself. One may feel young but perceive oneself to look old. Such individuals seek treatment to recapture a feeling they once had. They have the sense that they are still vibrant, energetic, and sexy inside but that their outsides no longer seem to reflect this. At a more subtle level they may even have the experience that how they look is beginning to reflect how they feel instead of the other way around. Thus, they seek cosmetic treatment in the hope that, if they make the wrinkles disappear, so too will the feeling of getting older. Some will express these hopes in more magical ways. The middle-aged woman who believes that cosmetic treatment is the only way to keep her husband from leaving her is quite likely to be disappointed in the outcome. Yet for others, cosmetic treatment is part of a coordinated effort to ‘do something’ in their lives. Data support the idea that some who seek cosmetic treatment are ‘doers’17,18. These are people who take action in their lives. Thus, cosmetic treatment may be integrated into a characterologic approach towards life which results in not just a new face but also meaningful and long-lasting changes. Prologue 5The psychological profile of cosmetic patients The existing data have focused almost exclusively on surgical procedures. Thus, there is reason to wonder whether the results can be applied to non-surgical procedures such as BOTOX®. It seems that psychological and social pressures previously described are present in all patients who seek to improve their looks. Core motivations remain constant even as the way these motivations are expressed may vary. In addition, researchers have not found differences between individuals based on the types of procedures performed. As such, if there is no difference between groups of patients who get face lifts as compared to those who get nose jobs, perhaps there is little difference between these surgical patients and those who get BOTOX®. Finally, there are also overwhelming data to support the high rates of psychiatric symptomatology in dermatology patients as compared to the general population or other medical specialties. Therefore, we can reasonably assume that many cosmetic patients will present with some type of psychological symptomatology. While we must await empirical confirmation for our contention that there is more uniformity than not amongst cosmetic patients when it comes to BOTOX®, there is still much to be learned from examining the psychological studies that do exist. Many of these studies have been reviewed elsewhere in more detail18, so highlights of a few of the major findings from some of the more empirically rigorous studies will be discussed. Edgerton et al, in one of the first such studies conducted in 196019, found that almost 70 per cent of his sample were psychiatrically impaired, with many suffering from depression and personality disorders. Thirty years later he conducted a second study20 and found similar rates of psychiatric disturbance. Meyer et al21 found 70 per cent of the face lift patients he interviewed suffered from some type of personality disorder, while Napoleon22 found that according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), 70 per cent of his sample met the criteria for personalityfeet downward over the surface of the mid and lateral cheeks (Figure 4.15). In most Botulinum toxin in clinical dermatology 172individuals the zygomaticus major helps to elevate the corner of the mouth and move it laterally with smiling, but, in so doing, it can mobilize lateral cheek skin downward and medially, extending the lower crow’s feet down the face, especially in individuals who have inelastic, loose, redundant skin. Figure 4.15 Lower crow’s feet and lateral cheek rhytides The zygomaticus major originates on the zygomatic bone, just anterior to the zygomaticotemporal suture line, and then continues downward toward the angle of the mouth and joins other muscle fibers of the modiolus before its fibers reach the oral commissure, where they interdigitate with the fibers of the levator anguli oris and superficial and deep fibers of the orbicularis oris. The zygomaticus minor, on the other hand, originates more medially on the zygoma than the zygomaticus major just behind the zygomaticomaxillary suture line. Its fibers move downward to insert more medially and directly into the upper lip, interdigitating with fibers of the levator labii superioris. The zygomaticus minor helps elevate the center of the upper lip, exposing the maxillary teeth. Both muscles of the zygomatic 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 (see Appendix 4). Cosmetic uses of botulinum toxin 173 Figure 4.16 The levator labii superioris alaeque nasi is divided into two separate bundles of muscles distally; one that inserts over the ala and skin of the nose, the other that inserts in the upper lip, skin, and mucosa The levator labii superioris alaeque nasi originates from the superior part of the frontal process of the maxilla close to the side of the nose (Figure 4.16). It travels obliquely downward and laterally, dividing itself into two separate muscle bundles. The one smaller bundle inserts medially into the greater alar cartilage and skin of the nose. The other larger bundle continues downward toward the lateral aspect of the upper lip and crosses over the front of the levator labii superioris, merging with fibers of the levator labii superioris and orbicularis oris. It inserts along the floor of the dermis into the overlying skin of the ipsilateral aspect of the upper lip near the upper part of the nasolabial furrow and fold. The lateral labial muscle bundle raises and everts the upper lip and increases the curvature of the upper part of the nasolabial sulcus. The medial nasal muscle bundle Botulinum toxin in clinical dermatology 174dilates the nostrils and displaces the circumalar facial sulcus laterally, elevating the nasolabial fold (see Appendix 4). The levator labii superioris originates from the maxilla at the lower margin of the orbit, just above the infraorbital foramen, deep to the orbicularis oculi (Figure 4.17). Coursing downward between the lateral bundle of the levator labii superioris alaeque, 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 Figure 4.17 The levator labii superioris is a deeper muscle originating under the orbicularis oculi Cosmetic uses of botulinum toxin 175 Figure 4.18 The levator anguli oris lies deep to the muscles of the mid face conjunction with other muscles, it moves and deepens the nasolabial sulcus, especially during expressions of seriousness and sadness (see Appendix 4). The levator anguli oris originates more deeply in the canine fossa of the maxilla, just below the infraorbital foramen (Figure 4.18). It lies beneath and deep to 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 into the lower portion of the nasolabial sulcus. It raises the lateral aspect of the upper lip, and the lateral corners of the mouth when smiling or laughing. It also deepens and shifts the contour of the nasolabial sulcus (see Appendix 4). The previous group of four muscles was formerly 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. (See Appendix 4). Dilution Botulinum toxin in clinical dermatology 176Injecting minimal volumes of BOTOX® in this area is of paramount importance so as not to have unintended diffusion of the BOTOX® affect the surrounding muscles of the mid face. Therefore, a 100 U vial of BOTOX® should be reconstituted with only 1 ml of normal saline (see Appendix 1). Dosing: how to correct the problem (what to do and what not to do) Injecting 1 and not more than 2 U of BOTOX® into the mid nasofacial angle just lateral to the upper border of the ala nasi will weaken the upper nasal fibers of the levator labii superioris alaeque nasi and flatten the upper and medial aspect of the nasolabial fold (Figures 4.19 and 4.20a). Depending on the depth of the nasolabial sulcus and the height of the nasolabial fold, another technique is to inject 1 and not more than 2 U of BOTOX® lateral and slightly inferior to this point to weaken the lower fibers of the levator labii superioris and zygomaticus minor (Figure 4.20a, b). These injection techniques should be performed only by the very experienced physician whose patient produces innumerable wrinkles of the mid cheek with smiling or squinting or both, and whose nasolabial folds are exaggerated with a simple upward movement of the upper lip, as in sniffing and smiling. Proper patient selection is of paramount importance, because untoward sequelae can occur very easily and be devasting to the patient. The use of electromyographic guidance when treating this area is of inestimable value. An injection of 1–2 U and not more than 3 U of BOTOX® near the origins of the zygomatic complex along the zygomatic arch at the inferior border of the orbicularis oculi of the lower eyelid (Figure 4.21) can achieve an additive effect of diminishing lower lateral canthal rhytides along with effacing nasolabial folds. Depending on the idiosyncratic anatomy of a particular individual, the shape of the face, and the strength of the muscles, it might be necessary to administer one or two injections of BOTOX®, each over the mid to lateral malar prominence, to obtain the consistent results desired (Figure 4.21) (see Appendix 2). Figure 4.19 ‘×’ marks the point where 1 U of BOTOX® was injected into this 53-year-old to diminish the depth of the nasolabial sulcus. Note the elongation of the upper lip, flattening Cosmetic uses of botulinum toxin 177of the philtrum, and thinning of the vermillion in this patient at rest Figure 4.20a ● marks the point where 1–2 U of BOTOX® can be injected to weaken the nasal fibers of the levator labii superioris alaeque nasi to diminish the nasolabial fold Outcomes (results) There have been a few attempts to establish a fail-safetechnique in which some of the upper lip levators could be treated with BOTOX® to reduce a deep nasolabial sulcus and fold without subsequent adverse effects. If one considers the levator labii superioris alaeque nasi the principal muscle that creates the nasolabial fold, and the other central and lateral lip levators (the levator labii superioris, zygomaticus complex, and levator anguli oris) and risorius responsible for Botulinum toxin in clinical dermatology 178deepening the nasolabial sulcus when they contract, then precisely placed low-volume injections of BOTOX® 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 BOTOX® can unwittingly produce secondary changes that interfere with the primary function of these muscles, i.e. elevating the upper lip and laterally abducting the corners of the mouth, which are Figure 4.20b ● marks the point where 1–2 U of BOTOX® can be injected to weaken the levator labii superioris and zygomatic minor to diminish the nasolabial fold necessary movements when one speaks, smiles, laughs, yawns, or forcibly breathes by mouth (see Appendix 3). Cosmetic uses of botulinum toxin 179Complications (adverse sequlae) (see Appendix 5) Just 1 to 3 U of BOTOX® into each lip levator complex in the lower nasofacial sulcus will collapse the upper extent of the nasolabial fold and also elongate the upper lip, with fairly long lasting results1. However, injecting this area can result in a flat mid face with elongation of the upper lip, effacement of the philtrum, and narrowing and diminishing the fullness of the upper vermillion, an appearance that is not well accepted by most individuals, especially those who already have a naturally longer upper lip (Figure 4.19). Overzealous treatment of this area can result in an asymmetric smile and a ptotic upper lip, causing drooling and fluid incontinence when drinking from a glass or cup. In most patients, these nasolabial lines are best treated with implants and fillers, and not with BOTOX®. Overinjecting BOTOX® 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 Figure 4.21 Injection of 1–3 U of BOTOX® at the lateral zygomatic arch near the origin of the Zygomaticus complex can diminish lower crow’s feet and help efface the upper and mid Botulinum toxin in clinical dermatology 180nasolabial 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 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 seeking a reduction in the fullness of their nasolabial folds (see p. 148). Usually, injecting only 1–2 U of BOTOX® away from the mouth, and near the origins of the zygomaticus major et minor and levator labii superioris, can help reduce both the nasolabial fold and the lower lateral canthal wrinkles and lower lateral cheek rhytides, usually with minimal effect to the strength of the upper lip sphincter competence and smile symmetry3,17. It is extremely important, however, that minimal volume BOTOX® is injected precisely into the fibers of the targeted muscles. The objective is to inject minimal amounts of BOTOX® to lightly weaken and not paralyze these muscles. 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 complication2,18 (Figure 4.19). In older patients who have a large amount of excessive fat deposition 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 nasolabial folds might even be enhanced if the lateral upper lip levators are 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 unexpected sequelae, e.g. upper lip ptosis, asymmetry, and even oral sphincter incompetence. For example, weakening the zygomatic muscles also can soften the nasolabial folds, but the smile may be changed, reducing the extent of its upward and lateral expansion. However, for those patients with an exaggerated gingival smile, weakening of the central upper lip levators may actually function in a positive fashion, reducing the full upward movement of the upper lip, thereby not allowing overexposure of the crown and gums of the anterior upper teeth to occur when smiling or laughing (see p. 148). Injecting BOTOX® in the mid face in an attempt to diminish the nasolabial folds and to eliminate the random wrinkling of the center of the cheeks produced by squinting or smiling should only be attempted by the most experienced physician injector. Selecting the right patient can be more important, at times, than any other aspect of a BOTOX® injection. Understanding how certain facial and cheek wrinkles and folds are produced, Cosmetic uses of botulinum toxin 181and how to palpate and identify the offending muscles for injection, is the key to success or failure. Attempting to reduce mid cheek wrinkling and nasolabial folds with injections of BOTOX® can result in not only a flattening of the nasolabial fold, but also an overall flattening of the cheek and an elongation of Treatment implications when injecting nasolabial folds 1. Nasolabial folds are best reduced by injections of soft tissue fillers and implants rather than with injections of BOTOX®. 2. The levator labii superioris alaeque nasi is the muscle primarily responsible for the creation of the nasolabial sulcus and fold. 3. Injections of 1–2 U of BOTOX® should be given in the lower nasofacial or upper alar facial sulcus in an attempt to flatten the nasolabial fold. 4. Injections of BOTOX® 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. 5. Injections of BOTOX® too lateral to the nasofacial angle will produce an overall flattening of the mid cheek and a drop in the soft tissue support of the malar fat pad. 6. In the properly selected patient, a combination of injections of BOTOX® and soft tissue fillers and implants will produce longer lasting results than if the nasolabial folds were treated solely with either alone. 7. Successful treatment of the nasolabial fold is absolutely dependent upon proper patient assessment of what actually is causing and increasing the fold and sulcus. the upper lip, an eklabion or lip ptosis as well as lip asymmetry and lack of oral sphincter control. For these reasons, it is probably most advisable not to treat this area of the mid face with BOTOX® unless the patient is willing to endure unconditionally the expected untoward sequelae. Injecting the melolabial sulcus with a soft tissue filler and resurfacing the cheeks by chemical peeling, dermabrasion, or laser abrasionis probably a more dependable way to address these problems and produce the best consistent results most of the time. Exaggerated upper gum 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 concealing 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 the 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 gum mucosa. Consequently, they attempt only to smile partially Botulinum toxin in clinical dermatology 182when being photographed or during social interactions, which creates a certain amount of anxiety for those affected and who are more self-conscious. These individuals commonly tend to have sharply defined nasolabial folds with deep furrows (Figure 4.22). 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. 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 of these changes. 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 (Figure 4.23). Many of these individuals have a long history of smoking tobacco. Functional anatomy The ideal tooth exposure when smiling has been calculated to be three-quarters of the dental crown height of the upper incisors and no more exposure than 1–2 mm of upper gum mucosa. Figure 4.22 Individuals with a gummy smile commonly will have deep nasolabial folds and furrows as seen in this 23 year old Cosmetic uses of botulinum toxin 183 Figure 4.23 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-cigarette smoker with extensive photodamage. Note the minimal gummy smile and the slight nasal tip depression with smiling Generally, men show less gum and interlabial excursion than women19,20. There are many reasons for this ‘gingival smile/ which is the result of an increase in the interlabial space combined with an excessive contraction of the upper lip levators, producing an excessive amount of exposure of the gums upon smiling or laughing19,20. Additional causes of this exaggerated upper gum 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. Functionally, according to Rubin, there are three patterns of smiles by which an individual is identified21,22. The first and most commonly encountered type of smile (67 per cent 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 per cent of the incisors (Figure 4.24). This type of smile is produced predominantly by the pull of the zygomaticus major. The canine smile is the second most commonly identified smile pattern (35 per cent of the patients studied) and is characterized by a high elevation of the center of the upper lip, exposing Botulinum toxin in clinical dermatology 184 Figure 4.24 The most common type of smile is produced primarily by the pull of the zygomaticus major Figure 4.25 The canine smile exposes the canine teeth before the rest of the upper lip is elevated the canine teeth first before the rest of the upper lip is elevated (Figure 4.25). The canine smile can produce anywhere from a partial central dental reveal to an exaggerated full denture show with a certain amount of gingival exposure (Figure 4.22). This pattern of smile is produced predominantly by a 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. Cosmetic uses of botulinum toxin 185The third and least commonly seen smile pattern is the full denture smile, which was seen in about 2 per cent 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 contraction of all the upper lip levators and lower lip depressors around the mouth at the same time (Figure 4.26). 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 (Figure 4.22). These two conditions usually are found together, because contraction of the levator labii superioris alaeque nasi creates a steep medial nasolabial fold while lifting the central upper lip a few extra millimeters, which also can expose gingiva. With such hyperkinetic upper lip levators, asymmetric smiles usually are not uncommon (Figures 4.27 and 4.28). (See Appendix 4) Figure 4.26 The full denture smile is characterized by the simultaneous partial or full exposure of both upper and lower dentures Dilution Injecting minimal amounts of low-volume BOTOX® In the central face is of paramount importance. The least amount of unintended diffusion of BOTOX® in this area of stratified tiers of different muscle bundles can be disastrous to the overall therapeutic success and cosmetic appearance of the patient and the tenure of reputation of a physician injector. Therefore, most qualified physicians treating this area of the face will reconstitute a 100 U vial of BOTOX® with only 1ml of normal saline (see Appendix 1). Botulinum toxin in clinical dermatology 186 Figure 4.27 Hyperkinetic upper lip levators create a slight gummy smile, that is asymmetrically higher on the upper right side in this 20-year-old. Note the deep nasolabial folds Figure 4.28 Hyperkinetic upper lip levators create a slight gummy smile in this 47-year-old who also has an asymmetric smile caused by her left depressor labii inferioris. Note the deep nasolabial folds Cosmetic uses of botulinum toxin 187Dosing: how to correct the problem (what to do and what not to do) To non-surgically elongate the upper lip, especially during a smile, the central upper lip levators need to be gently relaxed (not paralyzed) with injections of BOTOX®. With the patient in a sitting or semireclined position, injections of 1–2 U of BOTOX® applied perpendicularly to the surface of the skin and deeply into the nasofacial groove can be administered (Figures 4.19 and 4.20). This can be accomplished by palpating 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 Figure 4.29 Place the needle perpendicular to the skin surface and inject 1–2 U of BOTOX® deeply into the belly of the muscle at the nasomaxillary groove while the patient smiles excessively Botulinum toxin in clinical dermatology 188 Figure 4.30 The central lip levators (i.e.direct retractors): levator labii superioris alaeque nasi and levator labii superioris and the indirect retractor, depressor septi nasi 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 finger in this position, contraction of the levator labii superioris alaeque nasi can be felt. At the point of maximum thickness of the muscle, 1–2 U of BOTOX® can be injected deeply intramuscularly and just above the periosteum (Figure 4.29). Remember to reserve this injection technique only for those patients who have an exaggerated gingival smile, and in whom the levator labii superioris alaeque nasi can be palpated. Also, remember that injecting BOTOX® 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 (Figure 4.30). The more laterally located muscles, i.e. zygomaticus major and minor, Cosmetic uses of botulinum toxin 189levator anguli oris, and risorius, are to be avoided; otherwise, either an adynamic or asymmetric smile can result. If migration of BOTOX® extends into the superficial fibers of the orbicularis oris an inability to fully pucker the lips also will occur. Another technique is to inject 1–2 U of BOTOX® intraorally into the bellies of the two central upper lip levators19 (Figure 4.31) by passing the needle through the gingivo-labial sulcus above the alveolar ridge at the same point in the nasofacial groove as described above. A minimum dose of low-volume BOTOX® should just barely relax the central upper lip levators so that the upper lip cannot fully retract upward (Figure 4.32) (see Appendix 2). If the excessive gummy show is at its highest in the center of the upper lip, then 1 U of BOTOX® may need to be injected into the distal half of the depressor septi nasi (Figure 4.30). Outcomes (results) Because of the anatomy of the different co-dependent muscles and their attachments in the area of the upper lip skin and orbicularis oris, the risk-benefit ratio of treating a patient with a gingival smile is high and the potential co-morbidity is significant. 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 BOTOX® 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 (Figure 4.19). In addition, it is Figure 4.31 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 Botulinum toxin in clinical dermatology 190 Figure 4.32 The central lip levators (i.e. direct retractors): levator labii superioris alaeque nasi and levator labii superioris possible to diminish the appearance of an idiosyncratic horizontal rhytid when and if it is present across the transverse aspect of the upper lip. An additional 1–2 U of BOTOX® at the base of the columella into the depressor septi nasi by the technique described above (p. 134) may be necessary to further eliminate the central aspect of this horizontal upper lip rhytid (Figure 4.23). Remember to avoid injecting and affecting the deep fibers of the Orbicularis oris, otherwise lip incompetence and asymmetry will occur. No more than 2 U of BOTOX® at each injection site should be attempted, especially during the initial treatment session. In patients with extremely thin and atrophic lips, the transverse lip rhytides may not be amenable to treatments of BOTOX®, because atrophic 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 I-III), have spent a Cosmetic uses of botulinum toxin 191lot of time outdoors, and may or may not have a history of smoking tobacco (Figure 4.23) (see Appendix 3). Complications (adverse sequelae) (see Appendix 5) Assistance with an electromyograph (EMG) might ensure a more accurate needle placement and avoid untoward results when attempting to treat an exaggerated upper gum smile with injections of BOTOX®. Inaccurate needle placement or overzealous dosing in this area is subject to upper lip ptosis, 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, because the upper lip levators (i.e. levator labii superioris alaeque, levator labii superioris, the zygomaticus complex, risorius, levator anguli oris, and orbicularis oris) (Figure 4.33) can easily be affected by the least amount of diffusion of the BOTOX®. Buccal sphincter incompetence can result in an embarrassing incontinence of liquid or solids. Figure 4.33 The levator labii superioris alaeque nasi, zygomaticus major and minor, levator labii superioris, levator Botulinum toxin in clinical dermatology 192anguli oris, risorius and obicularis oris participate in buccal sphincter competence Treatment implications when injecting a gummy smile 1. Injecting the levator labii superioris alaeque nasi can reduce exaggerated gingival show by elongating the upper lip. It also will efface the nasolabial sulcus and fold and flatten the philtrum and vermillion. 2. Only inject the levator labii superioris alaeque nasi when it can be palpated, otherwise, non-targeted muscles will be affected, and lip competence and symmetry will be compromised. 3. Prior to any treatment with BOTOX®, inform the patient of the risk to benefit ratio, potential co-morbidities, and inherent topographical and cosmetic changes expected when perioral mimetic muscles are weakened. 4. Patients with either a zygomatic (‘Mona Lisa’) smile, a full denture or a canine smile without exaggerated gingival exposure should not be treated with BOTOX® injections to reduce the nasolabial folds (see previous section). Asymmetric smile Introduction: problem assessment and patient selection Many men and women are born with an asymmetric smile (idiopathic asymmetry) (Figure 4.27, 4.28, and 4.34 to 4.36). This also can be manifested as a familial trait, which is especially disconcerting for women who display this type of smile (Figure 4.37). 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, but not as frequently, they are reticent to openly show their smile in public, and seek ways to hide their mouths when laughing or smiling with others. Those who have a prominent position in the workplace are especially selfconscious of an obviously ‘crooked smile’, and prefer not to smile when being photographed. Functional anatomy No matter what type of smile one has (zygomatic, canine, or full denture) if it is asymmetrical or ‘crooked’ it is always a source of anxiety and self-consciousness for the bearer, whether male or Cosmetic uses of botulinum toxin 193 Figure 4.34 In this 55-year-old female an asymmetric smile is caused by hyperkinetic lateral levators of the left side of the upper lip Figure 4.35 In this 62-year-old male an asymmetric smile is caused by hyperkinetic central levators of the right side of the upper lip Botulinum toxin in clinical dermatology 194 Figure 4.36 In this 46-year-old female an asymmetric smile iscaused by weakened elevators of the left lateral upper lip and angle of the mouth (zygomaticus, levator anguli oris, risorius). Note the down turned commissure on the left Figure 4.37 Father (55 years old) and daughter (20 years old) manifesting the same type of idiosyncratic, asymmetric smile caused by a hyperkinetic right depressor labii inferioris. The daughter also has a mild gummy smile with deep nasolabial grooves and folds female. Aside from a segmental weakening of the upper lip levators or the orbicularis oris, an asymmetric smile can be created by the unilateral malfunctioning of a lower lip Cosmetic uses of botulinum toxin 195depressor that is usually weaker or stronger than its contralateral paired muscle. This commonly occurs with either the depressor anguli oris or the depressor labii inferiors, or both, and also with isolated, portions of muscle fibers of the upper or lower orbicularis oris. The depressor labii inferioris is a quadrilateral muscle that originates from the oblique line of the mandible between the symphysis menti and the mental foramen (Figure 4.38). Its fibers travel upward and medially to insert into the skin and mucosa of the lower lip, decussating with fibers of its paired muscle from the opposite side along with some muscle fibers of the orbicularis oris. Inferiorly and laterally it is continuous with the platysma (pars labialis) (Figure 4.39). The function of the depressor labii inferioris is to pull the lower lip downward and slightly laterally when a person is chewing, smiling, laughing, or speaking, and it can help evert the lower lip when necessary. It should act in unison with its paired counterpart on the opposite side of the chin, and therefore in a symmetric fashion, 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. (See Appendix 4). Figure 4.38 Depressor labii inferioris is a square, deeply situated muscle on the chin Botulinum toxin in clinical dermatology 196 Figure 4.39 Depressor labii inferioris and platysma can interlace their fibers in some individuals Dilution Because of the widespread interlacing of muscle fibers in the perioral area, the success of treating a particular muscle in the lower face is predicated upon not having the BOTOX® diffuse beyond the area of injection. Consequently, minimal amounts of low-volume, highly concentrated BOTOX® should be used when targeting a perioral muscle for treatment. Therefore, experienced physicians will reconstitute a 100 U vial of BOTOX® with only 1 ml of normal saline (see Appendix 1). Dosing: how to correct the problem (what to do and what not to do) Depending on the particular situation, the type of asymmetry to be corrected and the location and strength of the muscle to be weakened it is usually advisable for the injector Cosmetic uses of botulinum toxin 197to determine the appropriate dose of BOTOX® necessary for injection at the time of treatment. Ordinarily, the Figure 4.40 This 47-year-old with an idiosyncratic asymmetric smile is shown before and 3 weeks after 3 U of BOTOX® were injected into her left depressor labii inferioris stronger side of the face is weakened with injections of BOTOX® to correct an asymmetry (Figure 4.40). Each patient’s problem should be evaluated individually and a solution determined according to the patient’s idiosyncratic anatomy. Prior to injection the patient should be in the sitting position and contracting the muscle to be treated. The needle should pass perpendicular to the skin’s surface and enter directly into the belly (thickest part) of the muscle (see Appendix 2). Outcomes (results) When the problem has been correctly assessed, and the proper conservative dose of BOTOX® determined, weakening the hyperkinetic muscle on the side of the face producing the asymmetry with injections of BOTOX® will correct the asymmetry (Figures 4.40 and 4.41). The Figure 4.41 This 20-year-old with an idiosyncratic asymmetric smile is Botulinum toxin in clinical dermatology 198shown before and 1 month after 1 U of BOTOX® was injected into her right depressor labii inferioris effect of the treatment should last at least 3 months, if not longer. It is best to attempt to correct an asymmetry with a lower dose, which can be increased by a touch-up treatment 2–3 weeks later when the patient returns for his or her obligatory post-treatment evaluation. It is better to correct a problem conservatively, albeit insufficiently, so that the appropriateness of the corrective action can be confirmed. Subsequently, additional units of BOTOX® can then be injected with confidence to adequately treat the problem to the satisfaction of the patient and physician (see Appendix 3). Complications (adverse sequelae) (see Appendix 5) A fallacious assessment and conclusion to a problem can produce incomplete and even improper results which can become an intolerable annoyance to the patient. Therefore, a thorough knowledge of the anatomy and function of the muscles of the face and area of the body to be treated is absolutely necessary when one is attempting to treat a patient with BOTOX®, whether or not the problem is a recognized commonly occurring complaint with wellestablished and approved techniques of treatment (i.e. glabellar frown lines) or an idiosyncratic or iatrogenic asymmetry. Overzealous treatment of any problem can only lead to adverse sequelae which are all dependent on the location and the particular muscle or muscles in which the problem resides. In the case of an asymmetric smile, the same complications of an adynamic smile and incompetent buccal sphincter causing difficulty with eating, drinking, swallowing, and speech articulation can occur. Treatment implications when injecting an asymmetric smile 1. Know the anatomy and function of the muscle(s) to be treated. 2. Inject low-volume, minimal doses of BOTOX® directly into the muscle(s) in question. 3. First treatments should be conservative with low doses of BOTOX® to confirm the appropriateness of the treatment. 4. All first-time and repeatedly treated patients must be re-evaluated 2–3 weeks after a BOTOX® treatment session 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. 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 Cosmetic uses of botulinum toxin 1993. 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 4. Manaloto RM, Alster TS. Periorbital rejuvenation: a review of dermatologic treatments. Dermatol Surg 1999; 25:1–9 5. Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 1996; 34:788–97 6. Carruthers J, Carruthers A. Botulinum toxin (BOTOX®) chemodenervation for facial rejuvenation. Facial Plast Surg 2001; 9:197–204 7. Carruthers J, Carruthers A. Practical cosmetic BOTOX® techniques. J Cutaneous Med Surg 1999; 3 (Suppl 4):55–9 8. 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 9. Matarasso SL. Complications of botulinum A exotoxin for hyperfunctional lines. Derm Surg 1998; 24:1249–54 10. 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-22S11. Tamura BM, Odo MY, Changi B et al. Treatment of nasal wrinkles with botulinum toxin. Derm Surg 2005; 3:271–5 12. LeLouran C. Botulinum toxin A and facial lines: the variable concentration. Aesthet Plast Surg 2001; 25:73–84 13. Almeida AT de Nose. In: Excel D, Almeida AT de (eds). Cosmetic use of Botulinum Toxin. Porto Allergre, Brazil: AGE Editora, 2002:158–63 14. Atamoros, PF. Botulinum toxin in the lower one-third of the face. Clin Derm 2003; 21:505–12 15. Pessa JE, Brown F. Independent effect of various facial mimetic muscles on the nasolabial fold. Aesth Plast Surg 1992; 16:167–71 16. Hoefflin SM. Anatomy of the platysma and lip depressor muscles. A simplified mnemonic approach. Dermatol Surg 1998; 24:1225–31 17. Rohrich RJ, James JE, Fagien S et al. The cosmetic use of botulinum toxin. Plast Reconstr Surg 2003; 112(Suppl):177S 18. 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 19. 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 20. 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 21. Rubin LR. The anatomy of a smile: its importance in the treatment of facial paralysis. Plast Reconstr Surg 1974; 53:384–7 22. Rubin LR. The anatomy of the nasolabial fold: the keystone of the smiling mechanism. Plast Reconstr Surg 1999; 103:687–91 Botulinum toxin in clinical dermatology 2005 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 purpose encompasses the perioral region and chin, which is the area that includes the remainder of the superficial muscles of facial expression. The orbicularis oris provides motor function to the upper and lower lips, and the corners of the mouth. The remaining facial muscles consist mostly of the upper lip levators and the depressors of the lower lip, which are not necessarily antagonistic to each other, but act more synergistically with one another, opening and closing the mouth and performing essential buccal functions in unison with the orbicularis oris, such as maintaining sphincter control and lip competence with or without a mouth filled with solid material, liquid, or air. Other vital functions of the orbicularis oris together with its levators and depressors include the ability to make sounds and articulate them into speech, 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 another. In addition, by contracting the orbicularis oris along with its levators and depressors in a particularly idiosyncratic manner, a person consciously or unconsciously can express various and sundry emotions. In the lower face some, if not all of the upper lip levators and the lower lip depressors interdigitate with the fibers of the orbicularis oris, which also can function as an antagonistic muscle to them and perform the opposite movement of either the levators and the depressors after they have moved in unison to separate or approximate the lips when opening or closing the mouth, as one does when blowing air or liquid out of the mouth. After the completion of a particular function by the labial levators and depressors, the orbicularis oris can move in the opposite direction to open or shut the mouth by pursing or puckering the lips. This subtle but functional difference in the way the various perioral muscles operate plays a significant role in how to devise a treatment plan with BOTOX®. One cannot just identify a levator or a depressor in the lower face and weaken it like in the upper face with injections of BOTOX® without potential consequences of lip asymmetry, sphincter incompetence affecting mastication or deglutition, and a disturbance in sound production and word pronunciation. Because of these functional differences and the complex muscle interactions in the lower face, only the experienced physician should attempt to reduce various rhytides of the lower face or correct anatomic variations and asymmetries of this area with injections of BOTOX®. 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 individual to express deep felt emotions and personal sentiment, the mouth also is the center of focus for the mid and lower face. A full lip with a smooth and distinct border of the vermillion delineating it from the rest of the 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 person’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 tobacco smoking. Frequent and chronic cigarette smoking also can augment perioral dynamic wrinkles, probably because of the persistent lip puckering and pursing needed to hold a cigarette in the mouth while inhaling and exhaling tobacco smoke (Figure 5.1). Dynamic perioral wrinkles are found in those who are genetically predisposed and frequently pout and repetitively purse their lips, whether voluntarily 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 (Figure 5.2). Other activities, such as cigarette smoking, sipping liquids from a straw, and playing certain musical wind instruments, provide a supplemental role in the Botulinum toxin in clinical dermatology 202 Figure 5.1 Note the perioral wrinkles that are produced when this 56 year old inhales on a cigaretteCosmetic uses of botulinum 203 Figure 5.2 Note the perioral wrinkles in this 57-year-old woman expressing her displeasure and exasperation by pursing her lips formation of dynamic perioral rhytides. Repeated purse-string-like movements of the orbicularis oris exaggerate and intensify the dynamic perioral lines on a daily basis. Men usually are not in the habit of pursing or puckering their lips as is commonly done by women. Consequently, men are less afflicted than women with perioral wrinkling, nor are they bothered by peribuccal rhytides 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. 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 wrinkling can be the result of identifiable causes, like age 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 functions on a daily basis. Much of the static wrinkling of the perioral area can be reduced by invasive surgical procedures such as facial skin resurfacing,either by laser, mechanical dermabrasion or chemical peeling, and other different types of surgical procedures like rhytidectomy, and various surgical plasties, implants, and excisions. It also can be reduced by non-invasive procedures such as injections of various soft tissue fillers. It is important to distinguish the dynamic wrinkles of the lips from those that are static, which are intrinsically produced because of photodamage and chronologic aging. Static wrinkling usually is not affected by treatment with BOTOX®. Static wrinkles can be easily distinguished from dynamic wrinkles by asking a person to purse their lips. If Botulinum toxin in clinical dermatology 204there are rhytides present in the lips prior to pursing the lips and there is minimal change or intensification of these wrinkles with movement, especially in someone over the age of 60–65 years or in a younger person who possesses extensive solar elastosis of their exposed skin, then their perioral rhytides are primarily static and probably unamenable to treatment with BOTOX® (Figure 5.3). If the wrinkles intensify 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 BOTOX® (Figure 5.4a, b). Functional anatomy The shape of the mouth and the position of the lips are controlled by a complex threedimensional arrangement of interlacing and decussating bundles of different facial muscles. Figure 5.3 This 72-year-old has deep peribuccal rhytides and moderate solar elastosis of the face and lips at rest. Her peribuccal rhytides barely intensified with puckering. Note the presence of most of the peribuccal rhytides that persist 1 month after a treatment of BOTOX®, because the bulk of her wrinkles were age related and of the static type. Note also the eversion and fullness of the upper lip, that were intensified by puckering, seen 1 month after a treatment with BOTOX® These include various levators (retractors and evertors) of the upper lip (i.e. levator labii superioris alaeque nasi, levator labii superioris, zygomaticus major et minor, levator anguli oris, and risorius), various depressors, retractors, and evertors of the lower lip Cosmetic uses of botulinum 205(depressor labii inferioris, depressor anguli oris, and mentalis), a multilamellar, compound sphincter (the orbicularis oris), and the buccinator1. The orbicularis oris is not a simple sphincter like the orbicularis oculi. It is comprised of multiple lamellae of muscular fibers traversing in different directions around the orifice of the mouth. It is composed partly of muscle fibers from other facial muscles 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 consist of four independent quadrants (right, left, upper, and lower) of striated muscle, each containing a pars peripheralis and a pars marginalis. These two right and left anatomic parts (right and left partes peripheralis and 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. The smaller pars marginalis corresponds to the vermillion of the lip and the larger pars peripheralis corresponds to the remainder of the free unattached portion of the lip that is encompassed by glabrous skin. 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 (Figure 5.5). Most of the muscle fibers in the pars peripheralis are thought to originate within the modiolus, as a direct continuation of the many modiolar muscles. A considerable number of these muscle fibers also originate from the buccinator, an accessory muscle of mastication, which reinforces 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 that arise from the maxilla pass inferiorly around the angle of the mouth and insert into the lower lip. Those fibers that arise from the Figure 5.4a This 53-year-old with deep peribuccal rhytides and severe solar elastosis of the face and lips is shown at rest and with puckering before a treatment with BOTOX®. Note that rhytides intensify with puckering Botulinum toxin in clinical dermatology 206 Figure 5.4b Same patient at rest and 3 weeks after her first treatment of BOTOX®. Note the rhytides at this early posttreatment time have only partially effaced. Note also the fullness and eversion of the vermillion after BOTOX® 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 pursestring fashion without decussating (Figure 5.6). Superficial to those deep intrinsic muscle fibers 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 depressor and levator 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 in the upper lip, inserting into the skin at the Figure 5.5 The Orbicularis oris. Courtesy of Gray’s Anatomy Cosmetic uses of botulinum 207 Figure 5.6 Orbicularis oculi—the buccinator helps form the intrinsic muscle fibers of the Orbicularis oris midline. Reinforcing these superficial transverse fibers of the upper and lower lips are interdigitating oblique muscle fibers from the levator labii superioris, the zygomaticus major, and the depressor labii inferioris. In addition, there are the intrinsic 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 (see Appendix 4). Botulinum toxin in clinical dermatology 208The function of the orbicularis oris is to close the mouth by approximating the lips. By contracting the deep fibers and the superficial oblique ones, the orbicularis oris can apply the lips closely to the alveolar 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 andthe 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 considered, in part, an antagonist to the lip levators and depressors. Direct labial retractors are those levators and depressors that enter directly into the tissue of the lips without passing through and interlacing with the modiolus (Figure 5.5). For the most part, when these muscles contract, they exert a vertical pull at right angles on the buccal aperture. 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 (Figure 5.6). The direct lip retractors 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 (Figure 5.5). 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, occupying any vacant space between them (Figure 5.7). In both the upper and lower lips the direct retractors interlace their fibers into a continuous sheet of muscle superficial to the intrinsic fibers of the pars peripheralis and pars marginalis of the orbicularis oris as they travel through the substance of the free lip and sequentially attach to the undersurface of the dermis and mucous membrane. The buccinator, on the other hand, is not a typical facial muscle. 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. It originates from the posterior portion of the alveolar process of the maxilla, from the upper medial surface 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 Cosmetic uses of botulinum 209 Figure 5.7 The depressor labii inferioris, depressor anguli oris, and the platysma modiolus near the angle of the mouth to become continuous with the intrinsic fibers of the orbicularis oris. The upper fibers of the buccinator 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 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, holding food between the teeth and preventing it from becoming lodged between the teeth and cheek. It also assists the tongue in directing and maintaining the food between the teeth while chewing. As the mouth closes, the teeth glide over the buccolabial mucosa, which must be continuously and progressively retracted away from the opposing surface of the teeth, otherwise a person would inadvertently bite down on the inner surface of the buccal mucosa consistently. Contraction of the buccinator also prevents the cheeks from becoming overly distended by positive air pressure when air fills the oral cavity. The buccinator also assists in gradually expelling from inbetween the lips accumulated air within the oral Botulinum toxin in clinical dermatology 210cavity, as when 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 location where they interlace their muscle fibers to form a dense, compact, mobile fibromuscular mass called the modiolus (Figure 5.8). As many as seven facial muscles, divided in different bundles within various anatomic planes, converge in a spiraling 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 configuration of a blunt kidney-shaped cone (Figure 5.5). 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 dermis, 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 (Figure 5.5). The subtle, three-dimensional movements of a 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 activites of biting, chewing, drinking, sucking, swallowing, and controlling changes in oral vestibular contents and pressure. The innumerable subtle variations in movement involved in speech, the generation and modulation of sounds and musical tones or the harsh sounds used in shouting, screaming, crying, and all the permutations of facial expression, ranging from mere hints to exaggerated distortions, be they symmetric or asymmetric, are enabled by the intricately synergistic and subtle displacements of the modiolus. Many of the major 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 modiolar muscles include the zygomaticus major, levator anguli oris, depressor anguli oris, platysma pars modiolus, risorius, and the main functional sphincteric effectors, the buccinator and orbicularis oris (Figure 5.8). As the interlabial and interdental 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 buccolabial sulci (marionette lines) are less deep and curved. With the lips in contact and the teeth in tight approximation, the modiolus can move only a few millimeters in all directions. The mobility of the modiolus is maximized when the upper and lower teeth are separated by 2–3 mm, similar to its position when speaking. The muscular modiolar activities are enhanced by the partial separation of the jaws, integrating buccal functional movements with the direct labial retractors (levators of the upper lip and depressors of the lower lip). All of the delicate but complex movements of the lips and mouth can be consciously and many times involuntarily set into motion from Cosmetic uses of botulinum 211moment to moment by subtle and intricate contractions of the multifariously complex mimetic muscles of the perioral area. (See Appendix 4). Figure 5.8 The modiolus and its principal muscles Dilution When injecting BOTOX® into the orbicularis oris, minimal dosage must be used2. Because there may be a multitude of vertical lines across the lips, concentrated BOTOX® will not spread readily across the expanse of the surface of the superficial fibersof the orbicularis oris. In order to have the BOTOX® spread evenly and extensively over the superficial fibers of the orbicularis oris, one can reconstitute a 100 U vial of BOTOX® with anywhere from 1 to 4 ml of normal saline. In this way, dilute, large volumes of BOTOX® can be allowed to spread across the expanse of the superficial fibers of the orbicularis oris when only 1 or 2 U are injected in each quadrant of the pars peripherals of the upper and lower lips. Applying BOTOX® superficially and in low dosages will avoid any compromise in the sphincteric function of the deeper muscle fibers of the orbicularis oris3,4 (see Appendix 1). Botulinum toxin in clinical dermatology 212Dosing: how to correct the problem (what to do and what not to do) Because of the complex nature of the orbicularis oris and the way it functions, injections of BOTOX® 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. BOTOX® or any botulinum toxin should be injected into an area of maximal muscle contraction. This is particularly 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, because they are dependent upon the particular strength of the various superficial fibers of the orbicularis oris at that location along the lip, which are different in every patient. In properly selected patients in the upright sitting or semirecumbent position, 1–2 U of BOTOX® can be injected into each pars peripheralis of the upper and lower lips at the level of the lower dermis and no deeper than the dermo-subcutaneous junction. At this level the superficial fibers of the orbicularis oris can be found. Injection points can be either into the border between the pars peripheralis and pars marginalis (Figure 5.9), or 3 and no more than 5 mm superior to the vermillion border into the pars peripheralis of the orbicularis oris (Figure 5.10). It is recommended that, at the initial treatment session, quadrants of the pars peripheralis of both the upper and lower lips be treated with no more than 2 U of BOTOX® injected into each site, applied symmetrically. BOTOX® should not be injected directly into the center of the philtrum, for risk of flattening its lateral edges. If the lower lip does not possess very deep rhytides, then it should be treated with only minimal amounts of BOTOX®, i.e. no more than 1 unit in each quadrant, especially at the initial treatment session, for risk of weakening the overall sphincteric action of the lips. It is best to treat the lips symmetrically, injecting the four quadrants of the pars peripheralis so as to weaken the orbicularis oris in a relatively proportional and symmetric manner, but 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 1–2 U of BOTOX®, injected subdermally, will suffice to produce the desired effect2–4. In patients who have had repeated treatments of BOTOX® over many years and, therefore, are well known to the physician injector, slightly higher doses, but not more than 3–4 U of BOTOX®, can be injected into each lip quadrant (Figure 5.11a–e). 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 Cosmetic uses of botulinum 213 Figure 5.9 Injections of BOTOX® at the junction of the upper pars marginalis and pars peripheralis of the orbicularis oris in this 59-year-old patient were painful Figure 5.10 Injections of BOTOX® placed 3 to 5 mm above the vermillion border within the center of the pars Botulinum toxin in clinical dermatology 214peripheralis of the orbicularis oris were less painful for this 53-year-old patient contraction4 (Figure 5.12). It is important that the patient return 2 to 3 weeks after a treatment session with BOTOX® so that the physician can assess the patient for any asymmetry or aberration in lip function4. For those patients who also have their lips injected with soft tissue fillers, it has been found that injections of BOTOX® 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 BOTOX®5. When other cosmetic procedures are performed during the same treatment session in which BOTOX® needs to be injected, the BOTOX® treatment should be given last. The total dose for BOTOX® injected into the upper lip should not exceed 6 U, and that for the lower lip should not exceed 4 U, unless the physician knows the patient very well and has Figure 5.11a This 47-year-old is shown at rest before and 2 weeks after her third BOTOX® treatment of perioral vertical rhytides. Note the subtle fullness of the vermillion and eversion of its border Cosmetic uses of botulinum 215Figure 5.11b This patient is shown at rest before and 3 weeks after a treatment of perioral vertical rhytides. Note the subtle fullness of the vermillion and eversion of its border Figure 5.11c This 56-year-old is shown puckering before and 3 weeks after a treatment of perioral vertical rhytides Figure 5.11d This 39-year-old is shown at rest before and 2 weeks after a treatment of perioral vertical rhytides. Note the subtle fullness of the vermillion and eversion of its border treated the patient successfully without complications in the past with higher doses of BOTOX® (Figure 5.11a) (see Appendix 2). Botulinum toxin in clinical dermatology 216Outcomes (results) 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 BOTOX®. Even so, the perioral area is high on the treatment list when patients request cosmetic rejuvenation of the face. When BOTOX® 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 Figure 5.12 Point (×) should only be injected in extreme cases of excessively deep rhytides in the center of the lip (philtrum). Adapted from Smychyshyn N, Sengelmann R. Botulinum toxin A treatment of Cosmetic uses of botulinum 217perioral rhytides. Dermatol Surg 2003; 29:490–5 appearance and emotional status of the patient. In addition to relaxing the superficial fibers of the Orbicularis oris and producing a smoothening of the cutaneous surface of the lip, there also can be a widening of the philtrum and a slight eversion of the vermillion, producing an attractive ‘pseudo’ augmentation of the lips 3,4,6 (Figure 5.11). Many feel that this pseudoaugmentation and eversion of the lips are best realized when BOTOX® is injected directly into the cutaneovermillion border (Figure 5.9), but similar lip fullness and eversion can be seen when BOTOX® is injected a few millimeters above the vermillion line (Figures 5.10 and 5.11a–d). Only dynamic perioral wrinkles can be attenuated by BOTOX®, not the static rhytides that result from photodamage and age (Figure 5.3). For correction of static wrinkles and solar elastosis, various soft tissue fillers and different resurfacing procedures with adjunctive treatments of BOTOX® when appropriate will give the best results. Because low doses are used to efface perioral rhytides, the usual duration of effect from injections of BOTOX® in the lips is sometimes 2 and generally no more than 3 months (see Appendix 3). Complications (adverse sequelae) (see Appendix 5)The perioral area of the face is probably the most difficult to treat with BOTOX® 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 (frontalis) and a few co-depressor muscles (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 BOTOX® to diffuse readily into an adjacent interdigitating muscle or group of muscles that produce a different set of facial movements. Consequently, adverse sequelae or, at the very least, annoying side effects are bound to occur. Using a higher dosing range (≥ 5–6 U per upper lip and ≥ 3–4 U per lower lip) of BOTOX® will subject the patient to difficulties with lip puckering when attempting to whistle or kiss. A slightly asymmetric smile is relatively common in the general population (see Chapter 4). It also can be created or accentuated by unequal dosing and asymmetric injections of BOTOX®. 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 various 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, kiss or there can be a concomitant inability to approximate the lips tightly which can lead to fluid or even food incontinence, causing one to drool or actively dribble liquid out of the mouth while drinking from a glass or cup, or sipping from a straw, or eating from a spoon7–9. The inability to purse or pucker the lips can last up to one month or even longer after a treatment of BOTOX®. One should not be tempted to inject higher doses of BOTOX® into the lips similar to the way one can increase the injection dose in the Botulinum toxin in clinical dermatology 218periorbital area. Doing so will definitely lead to any number of the 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 BOTOX®. If 2 U of BOTOX® can be injected effectively and safely into a patient’s lip, as Treatment implications when injecting perioral rhytides 1. Only dynamic wrinkles in the lips are reducible by BOTOX® treatments. Accurate patient assessment is the key to a successful outcome. 2. Treating hyperkinetic superficial fibers of the orbicularis oris with BOTOX® will relax surface rhytides, evert the vermillion, and create the appearance of fullness in the lips. 3. Inject low doses of high-volume BOTOX® superficially in the lips, and see the patient 2–3 weeks after each treatment. 4. Treat the lips with symmetrically placed injections of BOTOX®. Each individual injection site can be dosed differently. 5. Inject the lower lip conservatively and with a lower dose of BOTOX® than in the upper lip to avoid functional aberrations. 6. Avoid injecting BOTOX® into the base of the philtrum. 7. Avoid treating close to the corners of the mouth, for risk of creating incompetent commissures, eklabion, an asymmetric smile, drooling, and even dribbling. Figure 5.13b Same patient puckering 5 weeks after a BOTOX® treatment. Note the subtle fullness of the lips and the eversion of the vermillion border Cosmetic uses of botulinum 219 Figure 5.13a This 59-year-old is accentuating her dynamic perioral rhytides by puckering. She has had at least four BOTOX® treatments in the past little as 3 or 4 U of BOTOX® in that same individual may result in some or all of the adverse sequelae of an asymmetric smile and lack of sphincter control, causing food and liquid incontinence, and difficulty with speech and sound articulation as described above. So the temptation to inject even 1 U more in an upper or lower lip to improve the results or extend the duration of BOTOX® treatment must be overcome, unless visible ineffectiveness of a particular dosage of a BOTOX® treatment already has been experienced by the patient. Then a gradual increase in dose and number of injection sites can be attempted with each subsequent BOTOX® treatment session. Melomental folds Introduction Patients who have a chronic downward projection of the corners of the mouth commonly also will possess pronounced melomental folds. These superfluous folds of skin are created by deep furrows in the skin emanating away and generally downward from the oral commissures and are identified as inferior melolabial sulci, ‘drool grooves’, or ‘marionette lines’. When these lines are present, they usually impart to others the negative expressions of sadness, disapproval, unpleasantness, and melancholia. When these ‘marionette lines’ extend downward along lateral sides of the mentum they Botulinum toxin in clinical dermatology 220reinforce 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. Marionette lines can be a source of frustration and embarrassment, particularly for women during social interactions, or for those who maintain a prominent position in the work force. Until recently the only way to efface these lines was either by invasive surgical procedures such as rhytidectomies and resurfacing, or injections of soft tissue fillers which would produce results that were mediocre and temporary at best. Injections of BOTOX® have enhanced these results, bringing them a little closer to a more satisfactory outcome. Functional anatomy 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 (Figure 5.14). 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 (Figure 5.15). The muscle fibers of the depressor anguli oris narrow as they travel upward and converge onto the angle of the mouth, where some muscle fibers insert directly into the undersurface of the skin while other fibers insert into the modiolus and interdigitate with muscle fibers of the risorius and orbicularis oris in the area of the upper lip. 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. There are still some other deeper muscle fibers of the depressor anguli oris that interdigitate with muscle fibers of the levator anguli oris. In some individuals the depressor labii Cosmetic uses of botulinum 221 Figure 5.14 Depressor anguli oris pulls the corners of the mouth downward Botulinum toxin in clinical dermatology 222 Figure 5.15 Depressor labii inferioris depresses the lateral aspect of the lower lip inferioris will traverse the midline inferior to the mental tubercle and decussate with fibers of its paired muscle of the opposite side, creating the transversus menti or the ‘mental sling’. 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 and zygomaticus major, displacing the corners of the mouth downward and slightlydisorder and 19.5 per cent had a major psychiatric diagnosis. Some of these studies have been criticized because they relied on interviews and there was a perception that the researchers were biased towards the presence of psychopathology. It has been argued that a slightly different picture emerges if one looks at the results from studies that have relied on ‘paper and pencil’ or psychometric measures. Several of these studies have not found such severe levels of psychopathology in patients seeking cosmetic surgery. Goin conducted two studies23,24. In one, he found no significant levels of psychopathology as measured by the MMPI in 50 face lift patients . In the other, 121 rhinoplasty patients scored in the normal range according to the Brief Symptom Inventory. However, similar psychometric studies have supported the notion that cosmetic patients suffer from underlying psychopathology. Micheli-Pelligrini and Manfrida25 found ‘marked psychopathology in 65 rhinoplasty patients according to scores on the MMPI and the Rorschach while, Kisley et al26 found patients presenting for cosmetic treatment were nine times more likely to have high scores on measures of body concerns and psychiatric morbidity than a matched control group. In an especially rigorous study that employed both types of assessment procedures and was conducted in several sites, Meningaud et al27 evaluated 103 patients scheduled to receive a variety of different cosmetic procedures. These included blepharoplasty, face lifts, liposuction, rhinoplasty, baldness surgery, and otoplasty. Patients were assessed Botulinum toxin in clinical dermatology 6using both structured interviews and psychometric scales. The subjects were assessed on their level of depression, and the degree of social phobia and social anxiety and were given a generic test that measured quality of life. The study employed three control groups. The first was based on normative scores in a larger study of European populations; the second, a group of patients scheduled for noncosmetic surgical procedures of similar severity or intensity; and the third, individuals randomly chosen from the phone book. The structured interviews indicated that 50 per cent of the patients had taken psychotropic medication, of which 27 per cent was antidepressants. The study population was significantly more depressed (platerally when it contracts in an expression of grief, sorrow, and sadness. Upon opening the mouth, the mentolabial sulcus becomes more horizontal and deeper in its center (see Appendix 4). Dilution When treating the depressor anguli oris and the perioral area, BOTOX® should not be allowed to diffuse beyond the targeted muscle, otherwise, cosmetic aberrations such as an asymmetric smile, and functional disturbances such as drooling, dribbling, or even dysarthria are sure to follow. Therefore, the highest volume of diluent that should be used to reconstitute a 100 U vial of BOTOX® is 1 ml of normal saline. Any volume of diluent higher than 1 ml is sure to invite adverse sequelae (see Appendix 1). Cosmetic uses of botulinum 223Dosing: how to correct problem (what to do and what not to do) The downward angling of the ‘marionette lines’ can be improved by injecting 2–5 U of BOTOX® intramuscularly at the border of the mandible at a point that is most inferior to an imaginary vertical line that passes through the nasolabial sulcus (Figure 5.16). 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 contracting the corners of the mouth downward while they are pronouncing the letter ‘e’ in an exaggerated fashion9,10. 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 (Figure 5.17). In the majority of individuals, the depressor anguli oris lies approximately 1–2 mm anterior to the masseter. After the patient clenches their teeth and the anterior border of the masseter is identified, have them exaggerate the pronunciation of the letter ‘e’. The location of a hypertrophic depressor anguli oris should be easily palpated along the anterior border of the masseter along the body of the mandible. At times the depressor anguli oris can be detected more easily by palpating it intraorally along the inferior alveololabial sulcus. At the point at which the enlarged belly of the depressor anguli oris can be felt, 3–5 U of BOTOX® can be injected with the patient in the upright sitting or semirecumbent position (Figure 5.18). If the depressor anguli oris cannot be palpated, then it should not be treated. Be precise and accurate when injecting BOTOX® into the depressor anguli oris, since the orbicularis oris and depressor labii inferioris are immediately 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 (Figures 5.16 and 5.17). If the depressor anguli oris is palpated over this bony groove, lift the skin and muscle with the nondominant hand before injecting BOTOX®. With this technique BOTOX® can be injected directly Figure 5.16 The correct point of injection for the depressor anguli oris is not at the inferior extent of the melomental crease, but slightly more Botulinum toxin in clinical dermatology 224posteriorly at the most inferior point of an imaginary line that passes through the nasolabial sulcus Figure 5.17 The masseter can be easily palpated when the patient clenches their teethCosmetic uses of botulinum 225 Figure 5.18 Injecting the depressor anguli oris at the most inferior point of the nasolabial sulcus at the lower border of the body of the mandible, approximately 1 cm lateral and 1 cm inferior to the corner of the mouth. During the injection the patient pronounces the letter ‘e’ in an exaggerated manner into the fibers of the depressor anguli oris, while avoiding injecting the neurovascular structures of that area11–13 (See Appendix 2). Outcomes (results) Injections of BOTOX® will relax the depressor anguli oris and allow 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 and minor. When the corners of the mouth are relaxed and elevated with BOTOX® a person appears younger and naturally relaxed and pleasant (Figure 5.19 and 5.20a, b). Depending on the intensity of the marionette lines present, this area is best treated in combination with soft tissue fillers and some form of resurfacing. BOTOX® then will usually prolong the beneficial effect of such rejuvenation procedures. The beneficial effects from injections of BOTOX® can last from 4 to 6 months (see Appendix 3). 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, BOTOX® can diffuse focally into the muscle fibers of the orbicularis oris and produce a localized area of inadequate sphincteric closure of the oral cavity and a segmental inability to pucker the lips, Botulinum toxin in clinical dermatology 226resulting in a localized area of eklabion, 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 inability to purse or even pucker the lips, contain fluid in the mouth or drink from a glass, sip from a straw, or eat from a spoon. Pronunciation of certain sounds can be hampered and the articulation of words will be difficult. Also, an annoying adynamic smile, with only the upper lip moving, is likely to occur. Overzealous injections with doses over 6–8 U of BOTOX® will also place patients at risk for developing the adverse sequelae as described above. Even when the appropriate dose is precisely injected, intense massaging of Figure 5.19 This 47-year-old possesses a deep labiomental furrow and downward projecting corners of the mouth before injection of BOTOX®. the area after the injection can displace the BOTOX® and cause similar adverse events as described. For the first-time patient, treatment in this area can produce similar but transient side effects that may be disconcerting to the uninformed and unprepared patient so pretreatment warning of these potential side effects is advisable.Cosmetic uses of botulinum 227 Figure 5.20a This 52-year-old is shown at rest before and 3 weeks after a BOTOX® treatment of her depressor anguli oris Figure 5.20b Same patient frowning before and 3 weeks after a BOTOX® treatment of her depressor anguli oris. Note the slightly asymmetric smile with forced frowning, which lasted approximately 2–3 weeks after the initial BOTOX® treatment, and was of no concern to the patient. No other adverse sequelae were experienced by the patient Botulinum toxin in clinical dermatology 228Treatment implications when injecting marionette lines 1. Inject BOTOX® only when the depressor anguli oris can be precisely palpated and securely identified. 2. The depressor anguli oris usually can be identified at the inferior end of the nasolabial sulcus and anterior to the masseter. 3. Avoid injecting BOTOX® into the marginal mandibular nerve and facial artery and vein by lifting the soft tissue before injecting. 4. Avoid injecting BOTOX® into the depressor labii inferioris and orbicularis oris by remaining at least 1 cm lateral and 1–1.5 cm inferior to the lateral oral commissure and injecting minimal volumes. 5. Always inject minimal volumes of highly concentrated BOTOX® in the perioral area. Deep mental crease andwas nothing whatsoever noticeable and our physical exam confirmed this. In fact, Frank’s hair was rather long and carefully combed, with no evidence of thinning or loss. Frank quickly admitted that he could not go out and was unable to work because of his hair. He spoke about how going bald made him feel ugly and unattractive to woman and unable to go on interviews for jobs. ‘Who would ever hire me looking like this’ he exclaimed. He went on to say that he felt just like Samson, weak and ‘just not a man’. After a bit more history he admitted that he had been saving the hairs in a jar by the side of his bed and was convinced something dreadfully serious must be wrong with him. We reassured him that we did not think this was the case. We offered to do some tests, which despite numerous consultations had not been Botulinum toxin in clinical dermatology 8conducted, and to try to help him solve this dilemma. We also took photos to document his status since he said he lost ‘tons of hair each day’. Over the next several weeks we saw him regularly and continued to work with him on understanding his experience of the problem. We reported that the tests and our close monitoring of his scalp indicated there was nothing wrong with him and gently suggested that, as the photos documented, it appeared that he was not actually losing much hair. I explained that people frequently attributed emotional worries such as depression, anxiety, and low self esteem to physical complaints and offered some medication that might improve his mood and decrease his constant worry that he was gravely ill. Although unconvinced that he was not rapidly balding, he was now sufficiently comfortable with us to accept our recommendation, especially when we assured him we would continue to work together. The prevalence of BDD is thought to be 1–2 per cent in the general population32. However, this is considered to underestimate the actual occurrence as many patients report they are too embarrassed to tell their doctor about their concerns37. Surprisingly, studies have shown that BDD occurs equally in men and women38. The illness often begins in adolescence with the appearance of puberty and the increase in bodily concerns and anxieties about sexuality. BDD frequently occurs co-morbidly with other psychiatric disorders such as depression, obsessive compulsive disorders, social phobias, substance abuse, personality disorders, and other somatic illness such as hypochondria and eating disorders. Several studies have documented that the prevalence in dermatology practices is far higher, with rates varying between 6 per cent and 15 per cent32. Thus, this is not a minor problem for the cosmetic practitioner. It is of particular concern because several studies32,39 indicate that cosmetic treatment is of either no help or actually makes the patients worse. When Jenny, a 20-year-old secretary, walked into the office Dr S’s first thought was that she was a model. He was stunned when she began to cry that she was too ugly to ever get a date. When she indicated the virtually non-existent mole on her upper forearm as the culprit for her despair he was incredulous. Despite his reassurances that ‘it was nothing’ she kept crying and saying that it made her feel terrible. She was afraid she would die alone and went on to say that her job was in jeopardy because of ‘how she looked’. Dr S tried to talk her out of the procedure, adding that the risks from the laser might outweigh the benefits. However, he finally relented, hoping that treatment would make her feel better, only to have her become enraged and depressed at the hyperpigmented mark that was left after the procedure. This type of reaction makes intuitive sense. For these patients, the cosmetic concern is thought to mask more intense feelings of self loathing or other unconscious conflicts that are not able to be expressed in words but have been displaced on to the skin. It has been my experience that self destructive impulses related to the need for self punishment and problems in self soothing and the ability to manage intense affective states are easily observed. As McDougall has noted40, these patients are often extremely regressed and have suffered significant trauma that has affected their body integrity at a very early age. This has interfered with their psychological development and their ability to reflect on their own experiences and to form meaningful attachments with others. Because of the level of distress and impaired thinking, BDD patients often engage in a variety of compulsive behaviors related to their bodily concern. These can include hours of time checking themselves in the mirror, applying camouflage make up, and excessive Prologue 9grooming. These compulsive behaviors can sometimes become destructive, frequently worsening a mild or non-existent condition. In addition to skin picking and excessive scratching, several authors,35–37 also describe patients who remove their own moles, scour their skin with harsh household chemicals, and perform other ‘do it yourself procedures with catastrophic results. Clearly these behaviors can move beyond the realm of self destructive into the frankly suicidal and there are some data41 to suggest that these patients have high rates of suicidality. BDD is thought to be present in many, if not all, patients who seek multiple cosmetic procedures. The patients who have multiple treatments are often recognizable simply by how they look. There do seem to be some natural limitations to what cosmetic treatments can accomplish. Many magazine covers offer excellent examples of people who have sought multiple treatments. Michael Jackson and the Bride of Wildenstien are two of the more famous examples. It seems quite clear that cosmetic treatment with this group is unlikely to turn out well. Thus, for these patients, the seeking of cosmetic treatment really is an example of surgical treatment for a psychological problem that is bound to fail. These are people who end up looking worse despite their efforts to look better. Their need to stay young and their fears of aging and death drive them to make physical changes that are no longer effective. Ironically, in some of the more dramatic cases the intense fear of looking older results in one looking more like a corpse than less so. Treating these patients can be quite difficult as they often have little insight and frequently refuse a psychiatric referral. Their image of themselves is distorted by powerful unconscious forces and they are convinced that changing their outsides will address the sense of disatisfaction or self loathing that they feel inside. Before concluding this section a brief word should be made about those situations in which a patient in the acute phase of a psychiatric illness comes for cosmetic treatment. Joan, a 35-year-old grade school teacher, appeared for her appointment dressed in old sweatpants. Dr James, who had known her for several years, noticed that she was also not wearing make up and had not even combed her hair. She told the doctor that she had been feeling tired lately. She was hoping that by smoothing out the laugh lines she hated so much, along with a week’s vacation in Florida during the school break where she could work on her tan, things would get better. A few quick questions by Dr James revealed that she had felt too depressed to go to work the last two days and had not been sleeping or eating in a couple of weeks. After ruling out the flu or other organic cause for her behavior, Dr James asked whether she was feeling depressed. She immediately began to cry and admitted that yes, she was. Dr James gently said that fixing her face right now seemed unlikely to help her feel better and instead suggested she might want to call a colleague to make sure that her depression did not get any worse. When she started to balk that she was really fine, Dr Jamesmore firmly stated that this was just a precaution but in his professional opinion it was really something she needed to do for herself. Once she was feeling a bit better he promised he would fit her into his schedule and complete the work she requested. The issue is not that when these patients are no longer depressed they might not want cosmetic treatment. It is that since their desire for treatment is being driven by their depression and a sense of self distorted by this change in mood state, the surface change is almost certainly going to be ineffective and perpetuate a denial of a potentially more serious medical condition. These are patients whose psychological state renders them Botulinum toxin in clinical dermatology 10momentarily unable to make good decisions for themselves. They need their doctor to recognize this and act accordingly by getting the treatment they need and delaying any other decisions until their mood and judgment have improved. What to do The good news is that it is possible to recognize these patients and there are several ways to get them the psychiatric help they need. While self report measures are available that have been shown to reliably detect the presence of BDD41, more useful are good, basic interview skills and the development of a good doctor-patient relationship. Preprocedure interviews should begin with basic questions as to what concerns the patient has about their appearance. Patients should be able to clearly articulate what they do not like about their appearance and what they hope BOTOX® or the cosmetic procedure will accomplish. Their goals should be realistic and within the scope of what the doctor’s work can accomplish. Patients who report they are devastated by their problem and have been unable to work or see friends because of the physical defect should immediately alert the physician of the need to explore the appropriateness of cosmetic treatment in more detail. In addition, those who describe spending hours in front of the mirror examining or grooming themselves are describing behavior which may indicate the presence of a more severe psychiatric disorder. It is also wise to always question whether the patient has sought cosmetic treatments before and what their reactions to the procedures have been. As illustrated in the previous example, when a patient is describing being depressed or anxious about their appearance, further inquiry about the presence of these psychiatric symptoms is warranted. Patients who balk at this type of inquiry are, by their reaction, indicating a greater emotional investment and psychological sensitivity to their appearance and the request for cosmetic treatment. As a rule, overly intense emotional reactions or defensiveness often suggest that an issue is highly charged psychologically. An extreme reaction to a relatively neutral and standard question about a patient’s medical history may indicate that other thoughts or feelings are fueling the response. If, after a thorough exploration of the patient’s motives, goals, and expectations, the dermatologist is still concerned s/he may wish to seek a consultation. To this end it is useful for cosmetic practitioners to develop a relationship with a psychologist or psychiatrist who is well versed in these issues and with whom they can establish a good, collaborative working relationship. At the point in which a referral becomes indicated it is essential to approach this like any other referral. Explain to the patient that because cosmetic treatment changes the way one looks it almost always impacts on how they feel. In fact, a change in mood or self esteem is usually the motivation for treatment in the first place. The consultation is being sought to assess whether this is the right decision for the patient at this moment in time. Take solace in the thought that sensible patients with whom you can work collaboratively and who want to take the best care of themselves will likely see the wisdom of this. Those who get angry and storm out of the office are likely illustrating that they are not good candidates for cosmetic treatment. For those who can be referred, or who can be treated within the confines of a dermatologic visit, a number of treatment options do exist. The literature has shown that a Prologue 11variety of psychocutaneous disorders respond well to psychological intervention. Depending on the types of illness and symptoms displayed, individual and group psychotherapy, medication, hypnosis, psychoeducational counseling, and psychoanalysis have all been shown to be extremely useful. Outcomes In those patients for whom cosmetic treatment is assessed to be appropriate, outcome studies clearly show that it is effective. Post-procedure interviews and psychometric measures reveal that patients are generally pleased with the results of their cosmetic procedure. Edgerton et al42 found 86 per cent of his ‘aging face’ patients reported an improved sense of wellbeing. Marcus43 found 25 patients who underwent rhinoplasty were pleased with the results, felt more confident in social situations, and were better able to enjoy life. Rankin et al44 found that depression is lifted and quality of life improves after cosmetic surgery. Meningaud et al45 also found that social anxiety lessens after surgery and 87 per cent of his sample described positive changes resulting from the procedure. Certainly the anecdotal reports from the dermatologists that I have spoken with about BOTOX® confirm these empirical findings. All report that their patients are almost universally pleased with the results. The only outcome study that assesses patient satisfaction with the use of BOTOX® to treat facial lines also indicates a high level of satisfaction46. We can surmise that these satisfied patients did not expect treatment to change their lives but only wanted to look and feel a little bit better about themselves. These do not seem to be people who are pathologically focused on their bodies, or have distorted body image. In fact, studies have shown (see Sawyer et al28 for review) that while individuals who seek cosmetic treatments may be more dissatisfied with their appearance, they tend to be specifically unhappy with the part of their body they are coming to have changed, not with their appearance as a whole. That is, they do not generally come in saying ‘I hate my body’, but rather, ‘I don’t like these wrinkles’ or ‘my nose is ugly’. They have specific aspects of themselves that they do not like and they wish to have changed. These types of specific complaints may be even more typical of patients requesting BOTOX®. Since this is exactly what cosmetic treatments such as BOTOX® can do, these are the patients who are happy and satisfied with the treatment they receive. Summary So far the data seem to suggest that a number of patients seeking cosmetic surgery do have some type of co-morbid psychiatric diagnosis or psychological symptom and that the rates seem to be higher than that of the general population. In addition, there is a smaller group who appear to have the type of severe psychiatric illness that would preclude them from having cosmetic treatment. For this smaller sample the psychological motivation and their goals for cosmetic treatment are likely to be more intense and pervade their whole sense of being. Cosmetic treatment is not experienced as relatively unconflicted but is frequently seen as something that ‘will change my life’. For many of Botulinum toxin in clinical dermatology 12these patients, more complex issues of dissatisfaction and conflict have been displaced onto a single physical characteristic and the fantasy is that remedying this physical flaw will alter what is unconsciously a much more profound sense of distress and unhappiness. However, for large numbers of patients the presence of psychiatric symptoms or conflict does not preclude cosmetictreatments such as BOTOX®. For these people, their wish for cosmetic treatment is not necessarily a consequence of psychiatric disorder and thus pathologic. The uniquely individual choice to have a cosmetic procedure has been integrated into a sense of self that is functionally adaptive. These are people for whom cosmetic treatment represents a decision about their lives and their bodies, not a life-altering or magical experience. For most of these patients, many of the cultural and psychological pressures described earlier are present but not all-consuming. They are influencing but not driving the person to live in a certain way. For these people, cosmetic treatments are not only justified and medically sound but can be very effective. In closing, I hope that the cosmetic practitioner, especially one who plans to use BOTOX®, has a greater appreciation for the complexity of the work in which s/he is engaged. While it may seem as if the average BOTOX® patient is requesting a simple procedure with little psychological meaning, a more thorough analysis clearly shows that this is not necessarily the case. The choice to change one’s body is complex and multidetermined. It is influenced by the culture we live in and the way we feel about ourselves, our bodies, and our sexuality. It clearly involves subtle shifts in how we think about aging as well. The fact that there is more psychological meaning in this choice does not mean that cosmetic procedures are pathologic or morally wrong. Moreover, by listening to our patients and even engaging them in thinking about their decisions more deeply, dermatologists need not fear talking their patients out of something they have already decided to do. However, physicians may learn when the procedure would be dangerous and what steps a patient might take so that they could go forward at a later date. In establishing a thoughtful and collaborative relationship with patients, physicians are in a better position to advise them and have them take their advice. I am not suggesting that every dermatologist or cosmetic surgeon become a psychologist. That is not who you are, what you are trained in, or what your patients come to you for. At the same time, taking a psychological approach to your work, listening to your patients, and learning a little bit about what makes them tick is an invaluable tool of every good doctor. It is bound to make you better able to assess your patients and determine who needs the treatment you are offering and who does not. It is also certain to aid in the establishment of a good doctor-patient relationship and may even make your work more interesting and rewarding. References 1. Cordwell JM. Ancient beginnings and modern diversity of the use of cosmetics. In: JA Graham, Kligman AM, eds. The Psychology of Cosmetic Treatments 1985:37–44 2. Simon BE. Body image and plastic surgery. In: Graham JA, Kligman AM, eds. The Psychology of Cosmetic Treatments 1985:238–46 3. Kligman JA. Overview of psychology of cosmetics. In: Graham JA, Kligman AM, eds. The Psychology of Cosmetic Treatments 1985:26–36 Prologue 134. Grossbart TA, Sarwer DB. Psychosocial issues and their relevance to the cosmetic surgery patient. Semin Cutan Med Surg 2003; 22:136–47 5. Sullivan HAS. The Interpersonal Theory of Psychiatry. New York: WW Norton and Co, 1953 6. American Society for Aesthetic Plastic Surgery. Cosmetic survey national data bank, 2002 statistics 7. Pruzinsky T, Edgerton MT. Body image change in cosmetic plastic surgery. In; Cash, TF, Pruzinsky T, eds. Body Images: Development, Deviance, and Change New York: Guilford Press, 1990:217–36 8. Stirn A. Body piercing: medical consequences and psychological motivations. Lancet 2003; 361:1205–15 9. Cash TF, Gillen B, Burns DS. Sexism and ‘Beautyism’ in personnel consultant decision making. J Appl Psychol 1977; 62:301–10 10. Dipboye RL, Fromkin HL, Wiback K. Relative importance of applicant sex, attractiveness, and scholastic standing in evaluation of job applicant resumes. J Appl Psychol 1975; 60:39–43 11. Frieze I, Olsen J, Russell J. Attractiveness and income for men and women in management. J Appl Soc Psychol 1991; 21(3): 1039–57 12. Dipboye RL, Arvey RD, Terpstra DE. Sex and physical attractiveness of raters and applicants as determinants of resume evaluations. J Appl Psychol 1977; 62:228–94 13. Hamermesh DS, Biddle JE. Beauty and the labor market. Am Econ Rev 1994; 84:1174–94 14. Graham JA. Overview of the psychology of cosmetics. In: Graham JA, Kligman AM, eds. The Psychology of Cosmetic Treatments 1985:26–36 15. Johnson DF. Appearance and the elderly. In: The Psychology of Cosmetic Treatments Overview of Psychology of Cosmetics, New York: Praeger Publishers, 1985:152–60 16. Ringel EW. The morality of cosmetic surgery for aging. Arch Dermatol 1998; 134:427–31 17. Sawyer DB, Wadden TA, Pertschuk MJ, Whitaker LA. The psychology of cosmetic surgery: a review and reconceptualization. Clin Psychol Rev 1998; 18:1–22 18. Goin DIM, Goin MK. Psychological understanding and management of the plastic surgery patient. In: Georgiade NG, Georgiade GS, Riefkohl R, Barwick WJ, eds. Essential of Plastic, Maxillofacial, and Reconstructive Surgery, Baltimore, MD: Williams & Wilkens, 1987:1127–43 19. Edgerton MT, Jacobson WE, Meyer E. Surgical-psychiatric study of patients seeking plastic (cosmetic) surgery: ninety-eight consecutive patients with minimal deformity. Br J Plastic Surg 1960; 13:136–45 20. Edgerton MT, Langman MW, Pruzinsky T. Plastic surgery and psychotherapy in the treatment of 100 psychologically disturbed patients. Plast Reconstr Surg 1991; 88:594–608 21. Meyer E, Jacobson WE, Edgerton MT, Canter A. Motivational patterns in patients seeking elective plastic surgery. Psychosom Med 1960; 22:193–202 22. Napoleon A. The presentation of personalities in plastic surgery. Ann Plast Surg 1993;31:193–208 23. Goin MK, Rees TD. A prospective study of patients’ psychological reactions to rhinoplasty. Ann Plast Surq 1991; 27:210–15 24. Goin MK, Burgoyne RW, Goin JM, Staples FR. A prospective psychological study of 50 female face-lift patients. Plast Reconstr Surg 1980; 65:436–42 25. Micheli-Pellegrini V, Manfrida GM. Rhinoplasty and its psychological implications: applied psychology observations in aesthetic surgery. Aesthet Plast Surg 1979; 3:299–319 26. Kisley S, Morkell D, Allbrook B, Briggs P, Jovanovic J. Factors associated with dysmorphic concern and psychiatric morbidity in plastic surgery outpatients. Aust NZ J Psychiatry 2002; 36:121–6 27. Meningaud JP, Benabida L, Servant JM et al. Depression, anxiety and quality of life among scheduled cosmetic surgery patients: multicentre prospective study. J Cranio-Max Surg 2001; 29:177–80 Botulinum toxin in clinical dermatology 1428. Sawyer DB, Crerand MA. Psychosocial issues in patient outcomes. Facial Plast Surg 2002; 18:125–33 29. Rohrich RJ. The who, what, when, and why of cosmetic surgery: do our patients need a preoperative psychiatric evaluation? Plast Reconstr Surg 2000; 106:1605–7 30. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: APA Press, 1994 31. Grossbart TA, Sawyer DB. Psychosocial issues and their relevance to the cosmetic surgery patient. Semin Cutan Med Surg 2003; 22:136–47 32. Phillips KA, Dufresne RG. Body dysmorphic disorder: a guide for dermatologists and cosmetic surgeons. Am J Dermatol 2000; 1:235–43 33. Cotterill JA. Body dysmorphic disorder. Dermatol Clin 1996; 14:457–63 34. Koblenzer CS. The broken mirror: dysmorphic syndrome in the dermatologist’s practice. Fitz J Clin Dermatol 1994; March/April:14–9 35. Phillips KA. The Broken Mirror: Understanding and Treating Body Dysmorphic Disorder. New York: Oxford University Press, 1996 36. Philips KA, McElroy SL. Insight, overvalued ideation, and delusional thinking in body dysmorphic disorder:theorectical and treatment implications. J Nerv Ment Dis 1993; 181(11):699–702 37. Veale D. Outcome of cosmetic surgery and ‘DIY’ surgery in patients with body dysmorphic disorder. Psychiatr Bull 2000; 24:218–21 38. Phillips KA, Diaz SF. Gender differences in body dysmorhic disorder. J Nerv Ment Dis 1997; 185:570–7 39. Castle DJ, Honigman RJ, Phillips KA. Does cosmetic surgery improve psychosocial wellbeing? MJA 2002; 176:601–4 40. McDougal J. Theaters of the Body. New York: W.W. Norton & Co., 1989 41. Dufresne Jr RG, Phillips KA, Vittirio CC, Wilkel CS. A screening questionnaire for body dysmorphic disorder in a cosmetic dermatologic surgery practice. Dermatol Surg 2001; 27:457–62 42. Edgerton MT, Webb WL, Slaughter R et al. Surgical results and psychosocial changes following rhytidectomy. Plast Resconstr Surg 1963; 33:503–21 43. Marcus P. Psychological aspects of cosmetic rhinoplasty. Br J Plast Surg 1984; 37:313–18 44. Rankin M, Borah GL, Perry AW, Wey PD. Quality of life outcomes after cosmetic surgery. Plast Reconstr Surg 1998; 102:2139–47 45. Meningaud JP, Benadiba L, Servant JM et al. Depression, anxiety and quality of life: outcome 9 months after facial cosmetic surgery. J Cranio-Max Surg 2003; 31:46–50 46. Cox SE, Finn JC, Stetler L, Mackowiak J, Kowalski JW. Development of the facial lines treatment satisfaction questionnaire and initial results for botulinum toxin type-A treated patients. Dermatol Surg 2003; 29:444–9 Prologue 151 PHARMACOLOGY, IMMUNOLOGY AND CURRENT DEVELOPMENTS K Roger Aoki History Botulinum toxin type A stands alongside digitalis, atropine, and paclitaxel 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 botulism when ingested. In the early 1800s, the German physician Kerner provided one of the earliest descriptions of food poisoning caused by botulism that followed ingestion of smoked sausages1. In the late 1800s, Professor van Ermengem, a Belgian microbiologist, identified 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 (Figure 1.1), and colleagues at Fort Detrick, Maryland, where botulinum toxin type A was purified, obtained in crystalline form, and synthesized in sufficient quantities for research1. 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 animals1 (Figure 1.2). 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 Figure 1.1 Professor Ed Schantz in his laboratory contacted Professor Schantz to ask whether he had a substance that might be used to produce such chemical denervation. Schantz suggested botulinum toxin type A and Scott soon reported that this protein was able to correct strabismus in an experimental model1. 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, focusing on purification, high potency, and preservation. Because no protein drugs of this type had ever been developed, 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 humans2. The batch of botulinum toxin type A developed by Schantz was eventually approved for human use (Figure 1.2) under the name Oculinum™. Oculinum™ 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 important adjunctive treatment worldwide for adult spasticity and juvenile cerebral palsy. Although initial studies focused on the effects of botulinum toxin type A in conditions of skeletal muscle hyperactivity, it has become clear that its action extends to other classes of disorders. Botulinum toxin type A is being actively investigated for the treatment of many smooth muscle conditions such as achalasia, anal fissure, and overactive bladder and is an Pharmacology, immunology and current developments 17 Figure 1.2 History of botulinum neurotoxin development Figure 1.3 From left to right: Drs Alan Scott, Alastair Carruthers, Mrs Ruth Scott and Dr Jean Carruthers at one of their catch-up sessions accepted treatment for some autonomic disorders such as primary hyperhidrosis. It has also demonstrated utility in migraine and certain other painful conditions, leading to the exploration of possible additional mechanisms of action outside of its inhibition of acetylcholine release. Botulinum toxin A was approved for temporary improvement of moderate to severe glabellar (frown) lines associated with corrugator and/or procerus Botulinum toxin in clinical dermatology 18muscle activity in adult patients aged 65 years or less by the United States FDA in 2002 (BOTOX® Cosmetic) and subsequently in other countries (Vistabel® or Vistabex®). This first approval for an aesthetic indication was due to the early observation by Dr. Jean Carruthers while she worked with Dr Alan Scott during the early clinical evaluation of Oculinum (Figure 1.3). The majority of clinical studies on botulinum neurotoxin have been conducted with the type A preparation produced from the Hall strain of C. botulinum (BOTOX®). This was the original preparation used clinically and continues as the most widely studied and used botulinum neurotoxin therapeutic in the world today. In 2000, a botulinum neurotoxin preparation based on the B serotype was introduced into clinical use in the United States and Europe for the treatment of cervical dystonia. Additional preparations based on the A serotype (based on a different strain than the US product) are also available in Europe and other countries outside of the United States. As biologic products, doses of botulinum neurotoxins are given in units of biological activity as opposed to weight in milligrams as is commonly used for chemically synthesized drugs. However, unlike most other medicinal biological products, units of botulinum neurotoxins are not standardized, and thus doses of one product do not apply to any of the others. Manufacture of botulinum neurotoxins for clinical use Botulinum neurotoxins are complex biologic products that must be manufactured according to strict regulatory requirements in order to be approved for clinical use in the United States and other countries. The method of manufacture determines not only the purity of the final product but