Botulinum Toxin: Procedures in Cosmetic Dermatology [3rd Edition] 1455727814, 9781455737765

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3rd

PROCEDURES IN COSMETIC DERMATOLOGY

Edition

Botulinum Toxin Edited by

Alastair Carruthers MA, BM, BCh, FRCPC, FRCP(Lon) Clinical Professor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Jean Carruthers MD, FRCSC, FRC (OPHTH), FASOPRS Clinical Professor, Department of Ophthalmology and Visual Science, University of British Columbia, Vancouver, BC, Canada Series Editor

Jeffrey S. Dover MD, FRCPC, FRCP Associate Professor of Clinical Dermatology, Yale University School of Medicine, New Haven, CT; Adjunct Professor of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH; Adjunct Associate Professor of Dermatology, Brown Medical School, Providence, RI; Director, SkinCare Physicians, Chestnut Hill, MA, USA Associate Editor

Murad Alam MD Professor of Dermatology, Otolaryngology, and Surgery; Chief, Section of Cutaneous and Aesthetic Surgery, Northwestern University, Chicago, IL, USA

For additional online content visit expertconsult.com

London  New York  Oxford  St Louis  Sydney  Toronto  2013

SAUNDERS is an imprint of Elsevier Inc. © 2013, Elsevier Inc. All rights reserved. First edition 2005 Second edition 2008 Third edition 2013 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www. elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-1-4557-2781-0 Ebook ISBN: 978-1-4557-3776-5

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DEDICATION

We dedicate this volume to our children and their families. Our sons were young when the botulinum toxin story began and they have regarded the efforts of their parents to cope with this accidental discovery with tolerance and increasing pride over the years. We have appreciated the support and encouragement they have given us (rather than the other way round). The love they have given us means we are indeed fortunate! Alastair and Jean Carruthers To the women in my life: my grandmothers, Bertha and Lillian, my mother, Nina, my daughters, Sophie and Isabel and especially to my wife, Tania. For their never-ending encouragement, patience, support, love, and friendship To my father, Mark – a great teacher and role model; my mentor, Kenneth A. Arndt for his generosity, kindness, sense of humor, joie de vivre, and above all else curiosity and enthusiasm Jeffrey S. Dover

Elsevier’s dedicated editorial staff has made possible the continuing success of this ambitious project. The new team led by Belinda Kuhn, Martin Mellor and the production staff have refined the concept for the second edition while maintaining the series’ reputation for quality and cutting-edge relevance. In this, they have been ably supported by the graphics shop, which has created the signature high quality illustrations and layouts that are the backbone of each book. We are also deeply grateful to the volume editors, who have generously found time in their schedules, cheerfully accepted our guidelines, and recruited the most knowledgeable chapter authors. And we especially thank the chapter contributors, without whose work there would be no books at all. Finally, I would also like to convey my debt to my teachers, Kenneth Arndt, Jeffrey Dover, Michael Kaminer, Leonard Goldberg, and David Bickers, and my parents, Rahat and Rehana Alam. Murad Alam

CONTRIBUTORS

Murad Alam MD Professor of Dermatology, Otolaryngology, and Surgery; Chief, Section of Cutaneous and Aesthetic Surgery, Northwestern University, Chicago, IL, USA

Timothy C. Flynn MD Clinical Professor, Department of Dermatology, University of North Carolina, Chapel Hill, NC; Medical Director, Cary Skin Center, Cary, NC, USA

Andrew F. Alexis MD MPH Director, Skin of Color Center, Saint Luke’s Roosevelt Hospital; Assistant Clinical Professor, Columbia University College of Physicians & Surgeons, New York, NY, USA

Jürgen Frevert PhD Head of Botulinum Toxin Research, Merz Pharmaceuticals GmbH, Potsdam, Germany

Annelyse C. Ballin MD Clinical Research, Dermatology Research Institute, Coral Gables, FL, USA Andrew Blitzer MD DDS Professor of Clinical Otolaryngology, College of Physicians and Surgeons, Columbia University; Director, New York Center for Voice and Swallowing Disorders; Medical Director, New York Center for Clinical Research, New York, NY, USA Fredric S. Brandt MD Private Practice, Coral Gables, FL and New York; Dermatology Research Institute, Coral Gables, FL, USA Mitchell F. Brin MD Senior Vice President, Global Drug Development, Chief Scientific Officer, BOTOX®, Allergan, Inc., Irvine, CA; Professor of Neurology, University of California, Irvine, CA, USA Letícia Cardoso Secco MD Volunteer Dermatologist, Hospital do Servidor Público Municipal de São Paulo, Brazil Alex Cazzaniga BS, MBA Director of Clinical Research, Dermatology Research Institute, Coral Gables, FL, USA Chung-Yin Stanley Chan MD Procedural Dermatology Fellow, SkinCare Physicians, Chestnut Hill, MA, USA Joel L. Cohen MD Director, AboutSkn Dermatology and DermSurgery, Englewood; Associate Clinical Professor, Department of Dermatology, University of Colorado, Denver, CO, USA Jeffrey S. Dover MD, FRCPC, FRCP Associate Professor of Clinical Dermatology, Yale University School of Medicine, New Haven, CT; Adjunct Professor of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH; Adjunct Associate Professor of Dermatology, Brown Medical School, Providence, RI; Director, SkinCare Physicians, Chestnut Hill, MA, USA Steven Fagien MD, FACS Private Practice, Aesthetic Eyelid Plastic Surgery, Boca Raton, FL, USA

Conor J. Gallagher PhD Director, Global Neurotoxin Science, Medical Affairs, Allergan Inc., Irvine, CA, USA Dee Anna Glaser MD Professor and Vice Chairman; Director Cosmetic and Laser Surgery, Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, MO, USA Richard G. Glogau MD Clinical Professor of Dermatology, University of California Medical Center, San Francisco, CA, USA Greg J. Goodman MBBS, FACD, MD Associate Professor, Monash University; Chief of Surgery, Skin and Cancer Foundation Inc, Carlton, VIC, Australia Jeremy B. Green MD Private Practice, Dr. Brandt Dermatology Associates, Coral Gables, FL; Voluntary Assistant Professor, University of Miami Department of Dermatology & Cutaneous Surgery, Miami, FL, USA Pearl E. Grimes MD Director, Vitiligo and Pigmentation Institute of Southern California; Clinical Professor, Division of Dermatology, David Geffan School of Medicine, University of California, Los Angeles, CA, USA Shannon Humphrey MD, FRCPC, FAAD Clinical Instructor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada Derek H. Jones MD Associate Clinical Professor, Dermatology, David Geffan School of Medicine, University of California, Los Angeles, CA, USA Joely Kaufman MD Private Practice, Coral Gables, FL; Voluntary Assistant Professor of Clinical Dermatology, University of Miami Miller School of Medicine; Co-Director of Cosmetic Medicine, University of Miami, Miami, FL, USA Kathryn Kent MD Resident, Department of Dermatology, Boston University, Boston, MA, USA Nils Krueger PhD Clinical Research Scientist, Sadick Research Group, New York, NY, USA

Contributors

Wooshun Lee MD Medical Director, Medytox Inc, Seoul, Korea Phillip M. Levy BA, MD, FMHDerm Aesthetic Dermatologist, Private Practice, Geneva, Switzerland; Lecturer, Faculty of Medicine and Pharmacology, University of Franche-Comté, Besançon, France Austin Liu MD Chief Resident, Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA Ian A. Maher MD, FAAD Assistant Professor, Mohs Surgeon, Department of Dermatology, Virginia Commonwealth University, Richmond, VA, USA Kavita Mariwalla MD Assistant Clinical Professor, Department of Dermatology, Columbia University, New York, NY, USA Adam R. Mattox DO, MS Physician Research Fellow, Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, MO, USA Gary D. Monheit MD, FAAD, FACS Private Practice, Total Skin and Beauty Dermatology Center, PC; Associate Clinical Professor, Departments of Dermatology and Ophthalmology, University of Alabama at Birmingham, Birmingham, AL, USA

Gerhard Sattler MD Fellow of Dermatology; Clinical Director of Rosenparkklinik, Darmstadt, Germany Kyle Koo-II Seo MD, PhD Clinical Associate Professor, Dermatology, Seoul National University College of Medicine; Director, Dermatology, Modelo Clinic, Seoul, Korea Massimo Signorini MD Chief of Surgery, Istituto Dermatologico Europeo, Milan, Italy Jason Sneath BSc, CPH, MD Resident, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada Nowell Solish MD, FRCPC Assistant Professor of Dermatology, University of Toronto, ON, Canada Ada R. Trindade de Almeida MD Dermatologist, Dermatologic Clinic, Hospital do Servidor Público Municipal de São Paulo and private office, São Paulo, Brazil

David M. Ozog MD, FAAD Director of Cosmetic Dermatology; Vice-Chair of Operations, Division of Mohs and Dermatological Surgery, Henry Ford Hospital, Detroit, MI, USA

Melanie Warycha MD Procedural Dermatology Fellow, Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Andrew Pickett BSc, PhD Director and Founder, Toxin Research Limited, Wrexham, UK; Adjunct Professor, Botulinum Research Center, UMASS Dartmouth, MA, USA

Jacob M. Waugh MD Chief Scientific Officer and Medical Director, Revance Therapeutics, Newark, CA, USA

Thomas E. Rohrer MD Clinical Associate Professor of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI; Director of Mohs Fellowship, SkinCare Physicians, Chestnut Hill, MA, USA

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Neil S. Sadick MD, FAAD, FAACS, FACP, FACPh Clinical Professor, Weill Cornell Medical College, Cornell University; Sadick Dermatology and Research Group, New York, NY, USA

Naissan O. Wesley MD Dermatologist and Dermatologic Surgeon, Skin Care and Laser Physicians of Beverly Hills, Los Angeles, CA, USA

PREFACE

Our authors join us in hoping that you find this volume both instructive and entertaining. This is the third edition of Botulinum Toxin in the Procedures in Cosmetic Dermatology series, but do not think that this is the same old material polished and updated! The topic has been completely rethought and reorganized and new authors selected for almost all the chapters. We hope you appreciate this new look and find it both more accessible and a fresher presentation of all the material that has been generated since the last edition in 2008. One of the important innovations relates to the different commercially available neurotoxins. This is an area where opinion may well be influenced by those commercial interests and it is hard to make sure that all the contributions are unbiased. We have therefore gone in the other direction and have asked each of the companies to produce a chapter about their approved product, avoiding comparisons as much as possible. We hope that we have achieved our aim of producing, overall, a result that balances the need to give accurate information with the essential that it be fairly representative. We are delighted to include historic chapters by the pioneers of the therapeutic use of botulinum toxin, Drs

Blitzer and Brin, as well as a forward-looking chapter on the topical use of the toxin by Drs Glogau and Waugh. In general the book is divided between the background information in the front half and the clinical, cosmetic use in the second half. This clinical section looks at the cosmetic use from a very current perspective and it is fascinating to see how usage, even in the brow, has changed in recent years. In particular, the clinical use of the toxin in some of the smaller facial muscles and in the lower face and neck, is much better understood and an important part of facial cosmetic treatment. We have concluded with a section on the treatment of excessive sweating, which continues to be an important part of clinical toxin use. This volume and the attached video demonstrations should give you an intensive view of leading experts in the field worldwide about the cosmetic use of botulinum toxin. We believe that we have covered the field broadly, fairly, and accurately, and we hope that you will agree. Alastair and Jean Carruthers Vancouver, BC, Canada April 2012

SERIES PREFACE TO THE THIRD EDITION

Seven years ago we embarked on an effort to produce Procedures in Cosmetic Dermatology, a series of high quality, practical, up-to-date, illustrated manuals. Our plan was to provide dermatologists, dermatologic surgeons, and others dedicated to the pursuit of functional knowledge with detailed portable books accompanied by high quality “how to” DVD’s containing all the information they needed to master most, if not all, of the leading edge cosmetic techniques. Thanks to the efforts of world class volume editors, master chapter authors, and the tireless and extraordinary publishing staff at Elsevier, the series has been more successful than any of us could have imagined. Over the past seven years, 15 distinct volumes have been introduced, and have been purchased by thousands of physicians all over the world. Originally published in English, many of the texts have been translated into different languages including Italian, French, Spanish, Chinese, Polish, Korean, Portuguese, and Russian.

Our commitment has always been to ensure that the practical, easy to use information conveyed in the series is also extremely up-to-date, incorporating all the latest methods and materials. To that end, given the rapidly changing nature of our subspecialty, the time has now come to inaugurate the third edition. During the next few years, refined, enlarged, and improved texts will be released in a sequential manner. The most time-sensitive books will be revised first, and others will follow. This series is an ever evolving project. So in addition to third editions of current books, we will be introducing entirely new books to cover novel procedures that may not have existed when the series began. Enjoy and keep learning. Jeffrey S. Dover MD FRCPC and Murad Alam MD, MSCI

Procedures in Cosmetic Dermatology Series Editor; Jeffrey S. Dover MD, FRCPC, FRCP Associate Editor: Murad Alam MD Chemical Peels Second edition Rebecca C. Tung, MD and Mark G. Rubin MD ISBN 978-1-4377-1924-6

Lasers and Lights Third edition George Hruza MD and Mathew Avram MD ISBN 978-1-4557-2783-4

Treatment of Leg Veins Second edition Murad Alam, MD and Sirunya Silapunt, MD ISBN 978-1-4377-0739-7

Photodynamic Therapy Second edition Mitchel P. Goldman MD ISBN 978-1-4160-4211-2

Body Contouring Bruse E Katz MD and Neil S Sadick MD FAAD FAACS FACP FACPh ISBN 978-1-4377-0739-7

Liposuction C. William Hanke MD MPH FACP and Gerhard Sattler MD ISBN 978-1-4160-2208-4

Non Surgical Skin Tightening and Lifting Murad Alam MD MSCI and Jeffrey S Dover MD RCPC FRCP ISBN 978-1-4160-5960-8

Scar Revision Kenneth A Arndt MD ISBN 978-1-4160-3131-4

Botulinum Toxin Third Edition Alastair Carruthers MA BM BCh FRCPC FRCP(Lon) and Jean Carruthers MD FRCSC FRC(Ophth) FASOPRS ISBN 978-1-4557-2781-0

Hair Transplantation Robert S. Haber MD and Dowling B Stough MD ISBN 978-1-4160-3104-8

Soft Tissue Augmentation Third edition Jean Carruthers MD FRCSC FRC(Ophth) FASOPRS and Alastair Carruthers MA BM BCh FRCPC FRCP(Lon) ISBN 978-1-4557-2782-7 Cosmeceuticals Second edition Zoe-Diana Draelos MD ISBN 978-1-4160-5553-2

Blepharoplasty Ronald L. Moy MD and Edgar F Fincher MD ISBN 978-1-4160-2996-0 Advanced Face Lifting Ronald L. Moy MD and Edgar F Fincher MD ISBN 978-1-4160-2997-7

For Elsevier Content Strategist: Belinda Kuhn Content Development Specialist: Martin Mellor Publishing Services Ltd Project Manager: Sruthi Viswam Design: Miles Hitchen Illustration Manager: Jennifer Rose Marketing Manager: Carla Holloway

SERIES PREFACE FIRST EDITION

While dermatologists have been procedurally inclined since the beginning of the specialty, particularly rapid change has occurred in the past quarter century. The advent of frozen section technique and the golden age of Mohs skin cancer surgery have led to the formal incorporation of surgery within the dermatology curriculum. More recently technological breakthroughs in minimally invasive procedural dermatology have offered an aging population new options for improving the appearance of damaged skin. Procedures for rejuvenating the skin and adjacent regions are actively sought by our patients. Significantly, dermatologists have pioneered devices, technologies, and medications, which have continued to evolve at a startling pace. Numerous major advances including virtually all cutaneous lasers and light-source-based procedures, botulinum exotoxin, soft tissue augmentation, dilute anesthesia liposuction, leg vein treatments, chemical peels, and hair transplants have been invented, or developed and enhanced, by dermatologists. Dermatologists understand procedures and we have special insight into the structure, function, and working of skin. Cosmetic dermatologists have made rejuvenation accessible to risk-averse patients by emphasizing safety and reducing operative trauma. No specialty is better positioned than dermatology to lead the field of cutaneous surgery while meeting patient needs. As dermatology grows as a specialty, an ever-increasing proportion of dermatologists will become proficient in the delivery of different procedures. Not all dermatologists will perform all procedures, and some will perform very few, but even the less procedurally directed amongst us must be well versed in the details to be able to guide and educate our patients. Whether you are a skilled dermatologic surgeon interested in further expanding your surgical repertoire, a complete surgical novice wishing to learn a few simple procedures, or somewhere in between, this book and this series are for you. The volume you are holding is one of a series entitled ‘Procedures in Cosmetic Dermatology’. The purpose of each book is to serve as a practical primer on a major topic area in procedural dermatology.

If you want to make sure you find the right book for your needs, you may wish to know what this book is and what it is not. It is not a comprehensive text grounded in theoretical underpinnings. It is not exhaustively referenced. It is not designed to be a completely unbiased review of the world’s literature on the subject. At the same time, it is not an overview of cosmetic procedures that describes these in generalities without providing enough specific information to actually permit someone to perform the procedures. And, importantly, it is not so heavy that it can serve as a doorstop or a shelf filler. What this book and this series offer is a step-by-step, practical guide to performing cutaneous surgical procedures. Each volume in the series has been edited by a known authority in that subfield. Each editor has recruited other equally practical-minded, technically skilled, hands-on clinicians to write the constituent chapters. Most chapters have two authors to ensure that different approaches and a broad range of opinions are incorporated. On the other hand, the two authors and the editors also collectively provide a consistency of tone. A uniform template has been used within each chapter so that the reader will be easily able to navigate all the books in the series. Within every chapter, the authors succinctly tell it like they do it. The emphasis is on therapeutic technique; treatment methods are discussed with an eye to appropriate indications, adverse events, and unusual cases. Finally, this book is short and can be read in its entirety on a long plane ride. We believe that brevity paradoxically results in greater information transfer because cover-to-cover mastery is practicable. We hope you enjoy this book and the rest of the books in the series and that you benefit from the many hours of clinical wisdom that have been distilled to produce it. Please keep it nearby, where you can reach for it when you need it. Jeffrey S. Dover MD FRCPC and Murad Alam MD

ACKNOWLEDGMENTS

Looking back over the past 30 years of our involvement in the clinical use of botulinum toxin there are very many people who have supported and encouraged us. The first to be mentioned, of course, is Alan Scott, MD, who has been consistently generous with his educational efforts, his clinical information, his research results and, with his wife Ruth, hospitality. Sitting on their deck above Mill Valley looking towards the Golden Gate Bridge we have learned more about botulinum toxin than in any lecture hall. From the early days of oculinum and then botox we have had fascinating and enlightening discussions with Mitchell Brin, MD and Andrew Blitzer, MD both from Columbia. The early group of us who formed a core set of advisers for Allergan (our advice was not always well received and usually was ahead of its time) consisted of Andrew Blitzer, MD, Richard Glogau, MD, Nicholas Lowe, MD, Arnold Klein, MD and the two of us. These sessions and teleconferences set the stage for the future education and development of the cosmetic use of botulinum toxin and were a major learning experience for us all. The basic science which Roger Aoki, PhD, of Allergan Inc., provided to us gave a solid basis for our understanding of how the toxin works and the meaning of both basic and clinical studies. In more recent years we have had valuable assistance from many individuals, many of whom are coauthors in

this book. We have greatly appreciated the contributions of many of our international colleagues such as Ada Trindade de Almeida, MD, Francisco Perez Atamoros, MD and Koenraad de Boulle, MD. To all of the authors of this text, we salute you! We are so grateful for the hard work you have put into this volume and the tolerance you have shown when faced with yet more unreasonable editorial demands. The proof of your labours and dedication is easily seen between the covers of this book. Any list of acknowledgments would not be complete without recognizing the people who actually do the work to make it all work: our staff and our patients. Our patients have been so very tolerant, especially in the beginning when we did not fully understand the potential benefits as well as the pitfalls of the cosmetic use of botulinum toxin. Our staff have been consistently supportive and helpful (finding photographs from the vaguest descriptions, following up results good and bad, keeping things running smoothly so we could go off and deliver another lecture). We could not have done it without you! Finally, our friends and family have accepted the fact that we might or might not be in a given place at a given time, that we spend more time thinking about them in airports than actually talking to them, that our crazy idea has generated a crazy life. Many thanks to you all! Alastair and Jean Carruthers

Therapeutic uses of the botulinum toxins Andrew Blitzer

Summary and Key Features • Botulinum toxins exzymatically affect the SNARE proteins in neural endings • Botulinum toxins will reduce and prevent the release of substances exocytosed by SNARE proteins • Reduction of SNARE function may have therapeutic implications for autonomic, sensory and motor parts of the nervous system • Reduction of acetyl choline neurotransmitter can reduce the hyperfunction of muscles in various dystonias • Reduction of acetyl choline neurotransmitter can reduce autonomic nervous system hyperfunction such as hyperhidrosis and sialorrhea • Reduction of SNARE function can also reduce the release of inflammatory mediators such as substance P, CGRP, glutamate and others • Reduction of inflammatory mediators can have an affect on pain syndromes • Pain syndromes such as post-herpetic neuralgia, migraine headaches, TMD can be improved with botulinum toxin • Inflammatory conditions such as rheumatoid arthritis may be improved with intra-articular injections of botulinum toxin • Bioengineered toxins may allow precise localization and decrease of exocytosed proteins such as hormones

Introduction Since the 1970s, when Alan Scott introduced botulinum neurotoxin A as a therapeutic agent, the number of different uses for this drug has increased exponentially. In the 1950s, Arnold Burgen and Vernon Brooks, at McGill, discovered that botulinum toxin presynaptically blocked the release of acetylcholine from motor nerve terminals,

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thus weakening muscle strength by chemical denervation. Brooks also reported the fact that botulinum toxin could possibly be used therapeutically. The observation that tetanus and botulinum toxins blocked the exocytosis of acetylcholine was further refined with the discovery that these toxins enzymatically degraded different portions of the soluble N-ethyl maleimide-sensitive factor attachment protein receptor (SNARE) proteins. Alan Scott’s original work using botulinum toxin to weaken muscle for the correction of strabismus, and then blepharospasm, led others to begin to investigate the toxins for use with other dystonias and hyperfunctional muscular disorders. The original observations of Kerner that patients with botulism had dry mouth and eyes suggested that the toxin might be used to control hypersecretory states. With the knowledge that the autonomic nervous system also depended on acetylcholine as the neurotransmitter, it seemed even more likely that botulinum toxin could be used to control disorders of this system. Clinical trials have shown efficacy in autonomic disorders such as hyperhidrosis, sialorrhea, and Frey syndrome. A number of trials for hyperfunctional muscular disorders such as cervical dystonia and spasticity showed a dramatic reduction of pain, even greater than the reduction of muscle function. Our trials of toxin use for cosmetic indications revealed a number of individuals whose migraine headaches disappeared. These and other studies revealed a pattern that seemed to indicate that the toxin had a role in pain syndromes. Other studies then showed that, even in cases of post-herpetic neuralgia, pain could be decreased or eliminated. This clinical information led to the discovery that inflammatory mediators such as calcitonin gene-related peptide (CGRP), substance P, glutamate and others are also released by SNARE proteins. The toxin will reduce or eliminate the release locally of inflammatory mediators that have the effect of lowering central nervous system pain thresholds and thereby causing central sensitization. Botulinum toxin was found to reverse this effect. Many pain studies are in progress. Toxin treatment of chronic migraine headaches was recently EU and FDA approved after extensive clinical trials. The newest change to potential toxin treatment has been the ability to change the molecule. The binding site of the molecule has been altered chemically to add specific ligands. This allows a toxin to be created that has an affinity for sensory, but not motor neurons, autonomic

Botulinum toxin

neurons, and even certain excretory glands. Keith Foster, of Syntaxin, recently described making a specific ligand for growth hormone secretory cells in the pituitary gland. Growth hormone is also secreted with a SNARE-related exocytosis, and therefore can be modulated with targeted specific botulinum toxin. This treatment could be used for patients with acromegaly. Other glandular secretions should be studied in this new paradigm for hypersecretory control. The following material will in greater depth describe the use of botulinum toxins for the management of disorders of efferent nerves and muscular hyperfunction; afferent nerves, pain disorders, and inflammatory conditions; autonomic nervous system disorders; and glandular hypersecretion. (See Box 1.1.) Hyperfunctional muscular uses

Cervical dystonia (spasmodic torticollis) Dystonia is a group of neurological disorders characterized by muscular hyperfunction with abnormal movements and / or postures often accompanied by pain. Cervical dystonia, the most common of the dystonias (most often lateral colli, but also retrocollis and anterocollis) comprises disorders with abnormal neck postures and pain. Results of injecting the hyperfunctioning and painful muscles with botulinum toxin in several randomized, placebo-controlled or open-label studies have shown that 50–90% of patients receive benefit (improved function and / or reduced pain).The results may vary with dose and choice of muscles to be injected. The dosage range for CD is 200–400 units of Botox®. Xeomin®, botulinum toxin A (Merz Pharm.) has also been approved by the FDA for CD. Myobloc®, botulinum toxin B (Solstice) has been FDA approved for CD, particularly in patients who have a resistance to type A toxin. Blepharospasm is a focal dystonia affecting the orbicularis oculi muscle producing excessive blinking or eye closure. This was one of Alan Scott’s original studies, and led to toxin use in other dystonias. Using botulinum toxin A for management of blepharospasm has been shown in several studies to produce significant improvement in 70–100% of patients. Toxin injections have become the treatment of choice for this disorder. Scott’s original work comprised studies of toxin use for eye muscle balancing in cases of strabismus, and later esotropia, exotropia, and nystagmus. Scott extended the use of toxin to patients with hemifacial spasm. This is a condition in which the anterior inferior cerebellar artery beats on and compresses the facial nerve (VII), causing irritability and facial twitching. The treatment can be a neurosurgical decompression of the nerve, or injections of botulinum toxin into orbicularis oculi, and may include the zygomaticus and levator labii muscles to diminish the twitching and hyperfunctional activity. The same approach may be used for patients with post-traumatic or post-Bell’s palsy facial synkinesis. Aside

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Box 1.1 

Therapeutic uses of botulinum toxins I. Hyperfunctional muscular use: 1. Dystonia a. Cervical dystonia b. Blepharospasm c. Oromandibular dystonia d. Spasmodic dysphonia e. Occupational writer’s cramp f. Foot dystonia g. Musician’s dystonia h. Facial dystonia i. Meige syndrome j. Tic disorders and stuttering 2. Hyperfunctional facial lines (cosmetic) 3. Hemifacial spasm / facial synkinesis 4. Strabismus 5. Esotropia / exotropia 6. Nystagmus 7. Post-stroke and cerebral palsy spasticity 8. Tremor disorders: limb, neck, vocal 9. Myoclonus 10. Other laryngeal disorders: puberophonia, vocalis process granulomas II. Autonomic nervous system use 1. Hyperhidrosis: axillary, palmar, plantar, and facial 2. Benign prostatic hypertrophy 3. Sialorrhea / sialocele / drooling 4. Rhinitis 5. UES / LES achalasia 6. Neurogenic hyperactive bladder 7. Frey syndrome 8. Anal fissures 9. Vaginismus / anismus III. Afferent nervous system / pain syndromes / anti-inflammatory: 1. Tension headaches 2. Migraine headaches 3. Temporomandibular disorders / bruxism 4. Myofascial pain 5. Post-herpetic neuralgia 6. Arthritis 7. Trigeminal neuralgia 8. Low back pain IV. Glandular and secretory cell modulation 1. Growth hormone / acromegaly

from treating the synkinetic side of the face, often toxin is given to the contralateral face to balance the weakness for symmetry. These facial studies led to a number of investigators realizing the cosmetic benefit for functional facial lines and opened the door for injections of toxin for cosmesis. Pearl 1  Botulinum toxins may be used for management of lines and wrinkles of the face that are related to pleating of the skin overlying the facial muscles of expression.

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Therapeutic uses of the botulinum toxins

Pearl 2  Botulinum toxin may be used to control hyperfunctional muscular conditions such as dystonia, tremor, spasticity, and synkinesis.

Oromandibular dystonia is a focal dystonia affecting the muscles of the jaw and may present most commonly with closing spasms, making opening of the mouth for eating and chewing very difficult. It may also present with opening spasms, making closing of the mouth difficult, or with lateral or protrusive spasms of the jaw. Some patients may have writhing movements of the jaw making speaking and eating difficult. In a number of cases the tongue is also involved, producing not only a jaw opening but also uncontrolled tongue protrusion. When this is combined with other cranial dystonias (usually blepharospasm) it has been termed ‘Meige syndrome’. Our group successfully treated the first oromandibular dystonia (OMD) with botulinum toxin in 1983. We reported our series in a publication in 1989. Treatment of the tongue with toxin is often ill advised in many of these patients, since the production of a hypofunctional tongue causes dysarthria and significant dysphagia. The successful treatment of OMD led to the management of other hyperfunctional disorders of the jaw including temporomandibular disorders (TMD) and bruxism. The usual muscles injected are the masseter, temporalis, and external pterygoids. Spasmodic dysphonia is a focal dystonia of the larynx. Most patients have the adductor or closing type producing a strain-strangled voice type. We performed the first injection of botulinum toxin injections of the larynx for this condition in 1984. The other types are the abductor or opening type that produces a whispering voice or voice with breathy breaks. There are also patients with adductor respiratory spasms and a singer’s dystonia. All of these can be managed with botulinum toxin injections, and this has become the standard treatment for these disorders. Laryngeal injections were extended to include management of vocal tremor, vocalis process granulomas, puberophonia, stuttering with glottal block, and other hyperfunctional vocal disorders. Occupational writer’s cramp (focal dystonia of the hand) was also found to be a disorder in which toxin can reduce spasm and return normal function. These injections are usually given with EMG guidance into the muscle causing the abnormal postures or contractures. This treatment also is for other functionally specific hand dystonias including stenographer’s dystonia and musician’s dystonia. This treatment was extended to include dystonias of the feet. In cases of more generalized dystonia, the abnormal limb postures can also be reduced and function increased with toxin injections of the affected muscles. Treatment has also been extended to patients with post-stroke spasticity and cerebral palsy spasticity. Toxin treatment has reduced the contractures and pain.

Extending the concept of reducing hyperfunctional muscle activity with toxin injections, patients with tremor disorders and myoclonus have been successfully treated. This includes treatment of the limbs, neck, palate, and vocal cords. Although the toxin doesn’t prevent the tremulous activity it can decrease it, thereby decreasing the patient’s symptoms. Autonomic nervous system use Based on observations of patients with botulism, many have autonomic symptoms such as dry eyes and dry mouth. Since the sweat glands are cholinergic, it became obvious that toxin injections should be able to decrease their function. Numerous studies have shown this and led to FDA approval for axillary hyperhidrosis. Studies have also shown efficacy on palmar, facial, and plantar hyperhidrosis. The effects on these glands last longer than in muscle perhaps owing to glandular atrophy. Frey syndrome or gustatory sweating is from aberrant regeneration of the autonomic nerve supply of the salivary glands to the sweat glands of the skin after trauma. Injecting the facial skin with toxin can prevent the gustatory sweating for 6–24 months. The salivary glands themselves can be injected to decrease salivary production in patients who have drooling, sialorrhea, and sialoceles. Recent studies are extending the use of botulinum toxin to treat rhinitis with rhinorrhea (also cholinergically induced).

Pearl 3  Acetylcholine release is also the neurotransmitter for the parasympathetic nervous system, and blockade can therapeutically improve conditions such as hyperhidrosis, sialorrhea, sphincter spasms, and rhinitis.

Other autonomic indication began to evolve with the success found with hyperhidrosis and salivary conditions. Upper and lower esophageal sphincter achalasia or hyperactivity and gastroparesis can be diminished with intramuscular injections of botulinum toxin. These are usually performed endoscopically. Recently, the FDA has approved Botox® for neurogenic hyperactive bladder function. There are also several trials for the use of botulinum toxin for benign prostatic hypertrophy. The initial data has shown gland reduction for about 6 months with apoptosis and sphincter weakness. Patients with painful, non-healing anal fissures had been treated with surgical sphincterotomy. Not all of the patients had healing with this procedure and some had permanent fecal incontinence. With toxin injection, there is a temporary chemical sphincterotomy, improved blood flow with near-100% healing of the fissures, and dramatic pain reduction. Anismus and vaginismus management with toxin have also been reported.

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Botulinum toxin

Afferent nervous system / pain syndromes / anti-inflammatory A number of hyperfunctional muscular conditions had pain associated with them, and it was thought that pain reduction was related only to the reduced muscle contracture. Our group’s work with cosmetic injections led Bill Binder to observe that several patients with a migraine headache history ceased to have headaches. Patients with post-herpetic neuralgia also could be injected with toxin and have resolution of pain. These clinical observations led basic scientists to discover that SNARE proteins also release inflammatory mediators from afferent nerves. The toxin can bind to C fibers and A-delta fibers, and reduce or prevent release of the inflammatory mediators, thereby reducing pain and allowing central thresholds to rise. The management of chronic migraine headaches with Botox® has recently been FDA approved. Numbers of other studies of toxin in pain disorders have included trigeminal neuralgia, myofascial pain, tension headaches, temporomandibular disorders with pain, and low back pain. The anti-inflammatory effects have also been studied in a small series of patients with rheumatoid arthritis.

Pearl 4  It has been found that botulinum toxin can bind and blockade to the unmyelinated C-fibers and partially myelinated A-delta fibers of the sensory nervous system.

Pearl 5  Botulinum toxin has been found to also block the release of inflammatory mediators such as CGRP, substance P, glutamate, and others from its effect on SNARE proteins.

Pearl 6  Pain syndromes such as chronic migraine, post-herpetic neuralgia, temporomandibular disorders and others can be treated with botulinum toxins.

Glandular and secretory cell modulation Foster and his group have shown that SNARE proteins are also responsible for the exocytosis and release of many hormones. Therefore, if ligands can be made to allow selective binding of the toxin to specific glandular cell proteins, toxin can be released in these cells to cleave the SNARE proteins and therefore prevent exocytosis of the hormone. Foster reported reduction of growth hormone with a bioengineered toxin in animals. Much more work needs to be done in this arena, but this exciting development opens up brand new ways of managing many disorders.

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Further reading Aoki KR 2003 Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 43(suppl 1): S9–S15 Arad-Cohen A, Blitzer A 2000 Botulinum toxin treatment for symptomatic Frey’s syndrome. Otolaryngology, Head and Neck Surgery 122:237–240 Binder WJ, Brin MF, Blitzer A, et al 2000 Botulinum toxin type A (Botox) for the treatment of migraine headaches; an open-label study. Otolaryngology, Head and Neck Surgery 123:669–676 Blasi J, Chapman ER, Link E, et al 1993 Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365:160–163 Blitzer A, Brin MF 1997 Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngology, Head and Neck Surgery 116:328–330 Blitzer A, Brin MF, Greene PE, et al 1989 Botulinum toxin injections for the treatment of oromandibular dystonia. Annals of Otolaryngology, Rhinology and Laryngology 98:(2)93–97 Blitzer A, Brin MF, Stewart C 1998 Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12 year experience in more than 900 patients. Laryngoscope 108:1435–1441 Blitzer A, Zalvan C, Gonzales-Yanes O, et al 2002 Botulinum toxin injections for the management of the hyperfunctional larynx. In: Brin MF, Jankovic J, Hallett M (eds) Scientific and therapeutic aspects of botulinum toxin. Lippincott Williams & Wilkins, Philadelphia, p 207–217 Carruthers JDA 1995 The treatment of congenital nystagmus with Botox. Journal of Pediatric Ophthalmology and Strabismus 32:306–308 DeFazio G, Abbruzzese G, Girlanda P, et al 2002 Botulinum toxin A treatment for primary hemifacial spasm: a 10 year multicenter study. Archives of Neurology 59:418–420 Diener HC, Dodick DW, Aurora SK, et al 2010 PREEMPT 2 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 30(7):804–814; Epub 17 Mar Freund B, Schwartz M, Symington JM 2000 Botulinum toxin: new treatment for temporomandibular disorders. British Journal of Oral and Maxillofacial Surgery 38:466–471 Frucht SJ 2004 Focal task-specific dystonia in musicians. Advances in Neurology 94:225–230 Gless R, Nauman M, Werner B, et al 2000 Injections of botulinum toxin A into the salivary glands improve sialorrhea in amytropic lateral sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry 69:121–123 Glogau RG 1998 Botulinum A neurotoxin for axillary hyperhidrosis. Dermatologic Surgery 24:817–819 Gui D, Cassetta E, Anastasio G, et al 1994 Botulinum toxin for chronic anal fissure. The Lancet 344(8930):1127–1128 Laskawi R, Damanez W, Roggenkamper P 1994 Botulinum toxin treatment in patients with facial synkinesis. Archives of Otolaryngology 4:S195–S199 Liu HT, Tsai SK, Kao MC, et al 2006 Botulinum toxin A relieved neuropathic pain in a case of post-herpetic neuralgia. Pain Medicine 7(1):89–91 Maria G, Brisinda G, Civello IM, et al 2003 Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology 62:259–264 Meng J, Wang J, Lawrence G, et al 2007 Synatorbrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by Botulinum toxin reflects their anti-nociceptive potential. Journal of Cell Science 120:2864–2874

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Therapeutic uses of the botulinum toxins

Pasricha P, Ravich W, Kalloo A 1993 Botulinum toxin for achalasia. The Lancet 341:244–245 Phelan MW, Franks M, Somogyi GT, et al 2001 Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. Journal of Urology 165:1107–1010 Scott AB 1981 Botulinum toxin injection of the eye muscles to correct strabismus. Transactions of the American Ophthalmologic Society 79:734–770

Shaari CM, Sanders I, Wu BL, et al 1995 Rhinorrhea is decreased in dogs after nasal application of botulinum toxin. Otolaryngology, Head and Neck Surgery 112:566–571 Smith SJ, Ellis E, White S, et al 2000 A double-blind, placebo controlled study of botulinum toxin in upper limb spasticity after stroke or head injury. Clinical Rehabilitation 14:5–13

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2 

History of onabotulinumtoxinA therapeutic Mitchell F. Brin, Andrew Blitzer

Summary and Key Features • Botulinum toxin has become a valuable therapy for treating selected neurological and urological disorders and managing the appearance of glabellar facial lines • After identification of a muscle-relaxing substance present in sausages, scientists attributed these effects to a bacterium that became known as Clostridium botulinum. They isolated and characterized the neurotoxin, and described its mechanism of action on nerve terminals • Dr Alan Scott, an ophthalmologist in San Francisco, began studying botulinum toxin type A (‘Oculinum’) in the 1960s and 1970s as a possible treatment for patients with strabismus • Following Alan Scott’s successful studies in strabismus patients, he and others, including our group at Columbia University working under a research protocol, examined botulinum toxin type A in several neurological conditions, including blepharospasm, cervical dystonia, and also hyperfunctional facial lines, marked by the overactivity of facial or neck muscles • Oculinum was approved for the treatment of strabismus and blepharospasm by the United Stated Food and Drug Administration in 1989 • Alan Scott’s first manufactured research therapeutic, Oculinum, was later acquired by Allergan and renamed Botox® • Other botulinum toxin products have subsequently been licensed, each having its own clinical profile and dosing strategy; today these products have unique non-proprietary names • As of 2011, onabotulinumtoxinA (Botox® / Botox® Cosmetic) is approved for multiple indications worldwide, including eight indications in the United States • In providing a treatment option for several rare neurological conditions, the clinical development of onabotulinumtoxinA may have contributed to an enhanced understanding of these disorders

Introduction The development of botulinum toxin for therapeutic use is marked by its cross-disciplinary use for varied medical conditions. In particular, botulinum toxin has become a valuable therapy for selected disorders, treated by multiple specialists, whereby symptoms were inadequately managed with existing treatments. In this chapter, we provide an overview of development events, interspersed with personal observations of historical and human interest. Due to the structure and format of this book, this chapter is not fully referenced. For full reference citations to the events described here, the reader is referred to the additional reading list at the end of this document and the references therein and is encouraged to seek supplementary sources. Currently unapproved uses are mentioned for historical purposes, and health care providers should ascertain product licensure information regarding locally approved indications. In describing the formally developed uses of botulinum toxin, we confine ourselves to those for which Botox® (onabotulinumtoxinA) has been approved by regulatory agencies in the United States or Europe. Identification, isolation, and characterization The first well-described cases of medical illness after oral ingestion of an apparent foodstuff that may have contained some botulinum toxin were reported between 1817 and 1822 by the German physician Justinus Kerner. Kerner noted that the active substance interrupted signals from the motor nerves to muscles, but spared sensory nerves and cognitive abilities. He also theorized that the substance could possibly be used as therapy for medical conditions when ingested orally. The bacterial etiology of botulism was first noted by the microbiologist Emile Pierre van Ermengen who documented his findings in 1897, identifying and naming the responsible bacteria as Bacillus botulinus, which later became Clostridium botulinum. In 1905, Tchitchikine found that C. botulinum produced a substance that affected neurotransmitter function. In 1919, Professor Burke of Stanford University described an alphabetical classification for the different serotypes of botulinum toxin based on his toxin–antitoxin experiments.

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History of onabotulinumtoxinA therapeutic

Purification and crystallization of botulinum neurotoxin followed in the ensuing decades, eventually enabling mechanism of action studies. Dr Carl Lamanna and colleagues observed dissociation between the hemagglutinating activity of botulinum toxin type A and its toxicity, leading to further studies that identified both toxic and non-toxic proteins in the crystalline toxin complex. Lamanna also observed the extreme potency of botulinum toxin, which would later be recognized as a major advantage for a local, injectable therapy. In the late 1940s and early 1950s, Arnold Burgen and Vernon Brooks at McGill University discovered that botulinum toxin acted presynaptically to block the release of acetylcholine from motor nerve terminals. Brooks mentioned to a colleague, Edward Schantz, that the toxin might be useful for weakening hyperactive muscles. Edward Schantz had worked in the Chemical Corps at Fort Detrick purifying botulinum toxin using the method established by Lamanna and Duff. Schantz then relocated to the University of Wisconsin where he perfected the purification and crystallization of botulinum toxin. In 1971, Daniel Drachman, with toxin purified and supplied by Edward Schantz, showed that injecting minute amounts of botulinum toxin type A in the hindlimbs of chicks caused local denervation. In 1979, Lance Simpson described the key elements of the mechanism of action: binding, internalization, translocation, and interruption of neurotransmitter release. Pamphlett clarified that there is neither cell death nor axonal degeneration and the affected nerve terminals do not degenerate. Although traditionally called a neurotoxin because of its potential to cause generalized muscle weakness at exceedingly high doses, in 2004 our group reported that botulinum toxin type A is not cytotoxic.

conditions. He found that injecting minute amounts into extraocular muscles of monkeys with electromyographic (EMG) guidance produced long-lasting effects for the correction of strabismus and, at the doses used, without any systemic effects. Scott published these preclinical results in 1973, performed additional preclinical toxicology studies to evaluate doses that produced systemic effects in primates and obtained an Investigational New Drug (IND) designation from the US Food and Drug Administration (FDA) to conduct the first clinical trial for humans with strabismus in 1977 by injecting minute amounts locally into the extraocular muscles. He called his formulation ‘Oculinum’ (Fig. 2.1). This clinical trial led to the 1980 publication of the first 19 patients, where efficacy in treating strabismus was reported. In the early 1980s, at the Columbia University Neurological Institute, we were funded by the Dystonia Medical Research Foundation with the primary goal of identifying effective treatments for dystonia, in addition to exploring the disease’s genetic underpinnings. Stanley Fahn was the principal investigator of the Center, Mitchell Brin was a Movement Disorders Fellow and Center’s Program Coordinator, and Andrew Blitzer was acting Chairman of the Department of Otolaryngology. Dr Fahn learned directly from Dr Scott when he attended a workshop in which Dr Scott described his use of Oculinum. He submitted a protocol to the Columbia University Institutional Review Board and also obtained an IND from the FDA to evaluate the potential therapeutic use of Oculinum. The

Exploration of clinical potential In the 1960s and 1970s, Alan Scott, an ophthalmologist in San Francisco, was seeking an alternative to surgery for the correction of strabismus. Scott has described the events that led to his clinical studies with botulinum toxin type A in several articles, and readers are encouraged to read his accounts. Scott and his colleague Carter Collins were studying the forces and actions of eye muscles, and they considered whether a long-acting muscle-weakening agent could be used for treatment of strabismus. Based on Daniel Drachman’s work, Scott thought that botulinum toxin might be an option. Drachman directed Scott to Edward Schantz, who provided him with botulinum toxin for testing. It was noted that, historically, outbreaks of type A botulism produced predominantly motor weakness, whereas type B caused a predominance of autonomic symptoms and thus type A was selected by Scott. Schantz provided the crystallized botulinum toxin type A by regular mail in a metal tube placed in another metal tube. Scott took the crystalline toxin into his laboratory and diluted it into small aliquots, buffered it with albumin instead of gelatin, and developed testing and storage

Figure 2.1  Oculinum 100 units research vial.

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Botulinum toxin

clinical protocol’s inclusion criteria enabled our broad research program. During our first year of study, we examined the potential use of Oculinum in treating patients with primary and symptomatic inappropriate contractions, including those of the facial muscles (e.g. blepharospasm, hemifacial spasm, jaw (oromandibular dystonia, temporomandibular joint dysfunction), facial synkinesis, palatal myoclonus, tongue), neck (e.g. cervical dystonia), vocal cords (e.g. spasmodic dysphonia), limbs (e.g. arm dystonia, writer’s cramp, occupational / stenographer’s cramp, legs), various tremors, etc. and reported our initial findings in 1985. Many of our treatments were the first-described therapeutic assessments of Dr Scott’s botulinum toxin type A, and these were further elaborated upon in subsequent publications. Furthermore, the research contributed to the establishment of new areas for investigation. In addition, we were interested in possible systemic effects. In our initial studies, we tested vital capacity with a hand-held spirometer and did not find an adverse effect on pulmonary function. We also initiated single-fiber electromyography studies, identified subclinical distant muscle effects, and reported our findings.

Nomenclature Alan Scott called his manufactured research therapeutic ‘Oculinum’. The name Oculinum reflected the strabismus use and was a combination of linking the ‘ocul’ for eyes, with ‘lining’-up-the-eye and the Latinate ending ‘um’ added to legitimate drugs (personal communication, Alan Scott). At Columbia University, we coined and published the term ‘Botox’, which was the same product (Oculinum) manufactured by Dr Scott. This original formulation, Oculinum, was licensed to Allergan with the first approval for strabismus and blepharospasm in December 1989. Allergan subsequently acquired the product in 1991 as ‘Oculinum Injectable’, and then changed the trade name to ‘Botox®; this name was accepted by the FDA in 1992. Although the finished, marketed botulinum neurotoxin products do not have the same properties, publications have discussed the neurotoxins without referring to brand names. Historically, basic science colleagues used the abbreviations BoNT, Botx, and BoTX and BoTx for the research, raw material botulinum toxin, with BoNT/A referring to serotype A. ‘BTX’ had also been used for more than two decades to refer to finished products, with BTX-A referring to serotype A. This nomenclature should not be confused with Batrachotoxin (‘poison dart frog’ poison), which has also been abbreviated as BTX. In the early 2000s, ‘BTXA’ was used for the product manufactured by the Lanzhou Institute of Biological Products (LIBP) of the People’s Republic of China (PRC). Consequently, most authors discontinued the use of BTXA or BTX-A when referring generally to type A botulinum toxin, and adopted the BoNTA or BoNT-A terminology. However, in 2009, the FDA applied the

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United States Adopted Names Council terminology to botulinum toxins, with onabotulinumtoxinA referring to Botox®, abobotulinumtoxinA to Dysport® and rimabotulinumtoxinB referring to Myobloc®, and subsequently, incobotulinumtoxinA for Xeomin®, Merz’s formulation of BoNTA. When discussing different botulinum neurotoxin products, it is important to note their differences in clinical dosing. Botulinum toxin doses are expressed in units of biological activity, which differ for each product. For instance, the units of onabotulinumtoxinA and abobotulinumtoxinA are different and in 1993 we published the statement that ‘these products are distinct, and dosing is significantly different so that if one administers the same number of Dysport® units as when delivering Botox®, serious side effects may occur.’ Regulatory agencies worldwide have issued language stating that units are neither interchangeable nor convertible between different botulinum products. Thus, unit doses of one product cannot be used to generate doses of another. Developed indications for onabotulinumtoxinA OnabotulinumtoxinA is approved for eight different indications in the United States, which are described in Table 2.1 along with their year of approval and the US FDA indication. Table 2.1 also lists the approval years for these indications in the European Union (EU).

Strabismus As noted previously, the therapeutic use of botulinum toxin type A began with strabismus, in 1978 when Alan Scott used the toxin to treat the disorder in children after successful experiments in monkeys. The rationale for treating strabismus was that the toxin would create weakness in the injected ocular muscles, causing them to relax over time. This would enable the antagonist muscles contract more effectively, achieving the desired result. Scott noted in 1980 that, along with its efficacy in strabismus correction, botulinum toxin type A was an appropriate therapeutic agent because it had no known effects other than muscle paralysis, had no antigenic effects at small doses and, based on his experience at the time, did not diffuse to muscles adjacent to those injected, produced dose-dependent effects that could last for several weeks, and, in the treatment of strabismus, did not show systemic effects. Scott’s work, including a combination of double-blind and open-label studies under his original IND, led to the initial FDA approval for botulinum toxin type A as Oculinum in 1989 for the treatment of strabismus.

Blepharospasm After his initial success with onabotulinumtoxinA for the treatment of strabismus, Scott postulated that the

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History of onabotulinumtoxinA therapeutic

Table 2.1  Approved indications for onabotulinumtoxinA in the United States and Europe Year of FDA approval

Description

Indication statement approved by US FDA

Year of EU approval*

1989

Strabismus Deviation of the alignment of one eye in relation to the other.

N/A

1989

Blepharospasm A dystonic condition characterized by involuntary, repetitive eyelid closure caused by spasmodic or sustained contraction of the orbicularis oculi muscles

Treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII disorders in patients ≥12 years of age and above

2000

Cervical dystonia A focal dystonia characterized by involuntary contractions of the neck and shoulder muscles consisting of any combination of head tilting, torsion, neck extension or flexion; frequently accompanied by moderate to severe pain

Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain

1995

2002**

Glabellar lines Vertical lines between the eyebrows caused by contraction of the corrugator and procerus muscles

For the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and / or procerus muscle activity in adult patients ≤65 years of age

2003***

2004

Primary axillary hyperhidrosis A condition of localized, excessive sweating of the axillae

Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients

2001

2010

Focal upper limb spasticity A velocity-dependent increase in muscle tone of the upper limbs with exaggerated tendon jerks resulting from hyperexcitability of the stretch reflex; occurs as one component of the upper motoneuron syndrome

Treatment of upper limb spasticity in adult patients, to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris) and finger flexors (flexor digitorum profundus and flexor digitorum sublimis)

2001

2010

Chronic migraine At least 15 headache dyas per month for >3 months, of which >8 headache days per month are migraine and/or are treated and relieved by triptan/ergot

Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer)

2010

2011

Detrusor overactivity associated with a neurological condition Overactivity of the detrusor muscle (a smooth muscle in the urinary bladder) caused by a neurological condition that can result in urinary incontinence

Treatment of urinary incontinence due to detrusor overactivity associated with a neurological condition [e.g. spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication

2011

N/A

Juvenile cerebral palsy dynamic equinus foot deformity A neurological disorder that appears in infancy or early childhood and permanently affects body movement and muscle coordination but generally does not worsen over time; equinus foot deformity results from dynamic overactivity or spasticity of the gastrocnemius–soleus muscle complex alone, or in combination with other ankle muscles, or from fixed muscle contractures

N/A

1997

1994

EU = European Union, FDA = Food and Drug Administration, N/A = not applicable. *First EU approval in United Kingdom or Ireland (Reference Member State of the Mutual Recognition Process). Specific indications often vary from those licensed in the United States. **As Botox® Cosmetic. ***Approved as VISTABEL® in France (Reference Member State of the Mutual Recognition Process).

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Botulinum toxin

toxin could also be used to treat blepharospasm by weakening the orbicularis oculi muscles. He proved his theory correct when he injected 39 cases and observed improvement in all of them. Several case series, open-label and double-blind placebo-controlled (DBPC) studies, including our own, confirmed the efficacy of onabotulinumtoxinA for blepharospasm. OnabotulinumtoxinA was approved by the FDA in 1989, along with strabismus, for the treatment of blepharospasm associated with dystonia in patients at least 12 years of age.

axillary hyperhidrosis. Two global pivotal studies were conducted, with additional long-term follow-up extensions. Whereas the benefit typically experienced by patients treated with skeletal muscle disorders is approximately 3–4 months, the average duration of effect in axillary hyperhidrosis is 6–7 months, with 28% of patients experiencing benefit exceeding 1 year in one study. These studies led to global registration of onabotulinumtoxinA for the treatment of severe axillary hyperhidrosis, with approval by the FDA in 2004.

Cervical dystonia

Adult post-stroke spasticity

Alan Scott treated the first three cervical dystonia patients with his product in 1983. Joseph Tsui et al at the University of British Columbia then extended this work and published a pilot study in which 12 patients received onabotulinumtoxinA injections into relevant neck muscles for the treatment of spasmodic torticollis (cervical dystonia). In both their pilot study and a follow-up DBPC study, they observed that onabotulinumtoxinA not only decreased abnormal movement but provided pain relief as well; our studies demonstrated similar results. Shortly after beginning our research with onabotulinumtoxinA, we were funded by the FDA’s Office of Orphan Product Development to conduct a doubleblind study examining the efficacy of onabotulinumtoxinA in the treatment of cervical dystonia, the results of which were reported by Greene et  al in 1990. Later, based on an Allergan-sponsored, pivotal Phase III study, onabotulinumtoxinA was approved by the FDA in 2000 for the treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain.

In 2009 Alan Scott reported treating the first patients with thigh adductor spasms, ‘Rather large doses of 300 units in two patients with thigh adductor spasms showed systemic safety…’. Many years after his initial treatments, reports of possible systemic effects were described in other patients. In 1989, Das & Park of the Southend District Stroke Unit of Rochford Hospital in Essex, United Kingdom reported on the use of botulinum toxin type A to treat eight post-stroke patients refractory to conventional therapy and observed improvement in spasticity with an acceptable side effect profile. Many open-label and several double-blind trials followed and have confirmed these findings. Allergan initiated a global registration program focused on treating patients with upper-limb post-stroke spasticity. Approved in Europe in 2001, US approval was granted in 2010.

Glabellar lines The use of onabotulinumtoxinA for cosmetic purposes dates back to the 1980s and the history of these investigations is described in another chapter. Allergan initiated a development program for the treatment of glabellar lines that ultimately led to worldwide approvals of this indication. OnabotulinumtoxinA was approved in several countries in South America by 2000, as Botox® Cosmetic in Canada in April 2001 and in the USA on 12 April 2002 for the treatment of moderate to severe glabellar lines.

Primary focal hyperhidrosis In the 1950s, Ambache reported on animal studies that explored the potential blocking effect of botulinum toxin on sweat glands. Human data were not available until 1994, when Bushara & Park reported areas of anhidrosis around botulinum toxin type A injection sites in hemifacial spasm patients. Allergan initiated a series of registration clinical trials examining onabotulinumtoxinA for the treatment of

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Juvenile cerebral palsy Most neurotoxin development programs of botulinum toxin type A in children with cerebral palsy have focused on equinus gait deformity, a common motor manifestation of prolonged focal muscle spasticity in this population. Approved for equinus gait deformity due to spasticity in Europe in 1997 and currently in most of the world, onabotulinumtoxinA is not approved for this indication in the United States, and development continues.

Chronic migraine The migraine history, similar to that of cosmetic, was serendipitous. Drs Blitzer and William Binder were residents at the Mount Sinai Hospital and together they published their first manuscripts in 1978. In the early 1990s, Dr Blitzer trained Dr Binder on the cosmetic treatment approach, and he collaborated on our research and co-authored our initial hyperfunctional facial lines manuscripts. Also in the 1990s, Dr Binder observed that, when treating patients with onabotulinumtoxinA for cosmetic enhancement, some of his patients with a history of migraine headaches reported a reduction or elimination of the number or intensity of their headaches concurrently with the cosmetic effect. Having later contacted us, we

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History of onabotulinumtoxinA therapeutic

pooled our observations and reported our findings in 1998, with a full manuscript published in 2000. Allergan initiated a headache development program and explored dose, treatment paradigm, and patient selection in multiple studies. Two large Phase III studies were conducted and onabotulinumtoxinA was approved for chronic migraine in the UK and US in 2010.

Neurogenic detrusor overactivity Schurch first reported the use of onabotulinumtoxinA to treat detrusor overactivity in spinal cord-injured patients in 2000. Allergan initiated a development program examining the effects of onabotulinumtoxinA treatment for detrusor overactivity in patients with spinal cord injury and multiple sclerosis. This program resulted in the issuance of licenses for onabotulinumtoxinA for neurogenic detrusor overactivity in North America, Europe and other regions in 2011.

Cell-based potency assay The mouse LD50 potency assay is required by global regulatory agencies for testing final commercial neurotoxin product prior to release. This assay has been the standard for potency and stability testing for all botulinum neurotoxins, and involves determining the median lethal dose of botulinum neurotoxin in mice at 72 hours following intraperitoneal injection. The ‘3R’ principles of refinement, reduction and eventual replacement of laboratory animals in manufacturing have been an objective of many pharmaceutical companies. Allergan addressed these principals for onabotulinumtoxinA manufacturing, recognizing the hurdle to overcome the technical challenges of establishing a non-animal assay that: (1) reflected the four distinct mechanisms of neurotoxin action (binding, internalization, translocation, cleavage of SNAP-25); (2) established an appropriate level of assay sensitivity; and (3) met quality standards for commercial use and hurdles that regulatory agencies established for approval of changes to product-related procedures. In 2011, a cell-based potency assay (CBPA) for onabotulinumtoxinA was approved by the FDA, and subsequently additional regulatory agencies. The CBPA is used, where approved, for stability and potency testing with the goal of reducing the use of animal-based assay testing. Commentary The seminal work of Dr Alan Scott has opened doors to numerous patients and scientists, and botulinum toxin therapy joins other biopharmaceuticals that have impacted medical care by safely and effectively relieving a spectrum of chronic and previously often ineffectively treated human disorders. In the field of aesthetics, onabotulinumtoxinA has advanced the science of facial rejuvenation. In addition to the direct medical benefits for patients,

botulinum toxin therapy has elevated the general awareness of many conditions, particularly uncommon ones where patients were enrolled into clinical research studies, and also those approved by regulatory agencies for treatment. This increased awareness afforded the medical research community the opportunity to further characterize and study these disorders, often with remarkable results. Historically, at the authors’ original Columbia University Center, the availability of onabotulinumtoxinA as a research therapy brought patients into the clinic where descriptive, genetic, pathophysiology, and other studies were conducted. It seems possible that the increased number of patient consultations, coupled with funding from governmental, patient, and other organizations, helped advance the original mission of the Dystonia Medical Research Foundation and those of other organizations, and accelerated scientific progress. None of this work could have been performed without the broad contributions of so many patients, investigators, scientists and clinicians. Acknowledgments The authors gratefully acknowledge the editorial assistance of Mary Ann Chapman, PhD. Further reading Ambache N 1951 A further survey of the action of Clostridium Botulinum toxin upon different types of autonomic nerve fibre. Journal of Physiology (Lond) 113:1–17 Brin MF, Aoki KR, Dressler D 2004 Pharmacology of botulinum toxin therapy. In: Brin MF, Comella C, Jankovic J (eds) Dystonia: etiology, clinical features, and treatment. Lippincott, Williams & Wilkins, Philadelphia, p 93–112 Brin MF, Blitzer A 1993 Botulinum toxin: dangerous terminology errors [letter] [see comments]. Journal of the Royal Society of Medicine 86:493–494 Brin MF, Fahn S, Moskowitz C, et al 1987 Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Movement Disorders 2:237–254 Brooks VB 2001 Vernon Brooks. In: Squire LR (ed) The history of neuroscience in autobiography. Academic Press, New York, p 76–117 Burgen AS, Dickens F, Zatman LJ 1949 The action of botulinum toxin on the neuro-muscular junction. Journal of Physiology (Lond) 109:10–24 Burke GS 1919 Notes on Bacillus botulinus. Journal of Bacteriology 4:555–570 Bushara KO, Park DM 1994 Botulinum toxin and sweating. Journal of Neurology, Neurosurgery and Psychiatry 57:1437–1438 Das TK, Park DM 1989 Effect of treatment with botulinum toxin on spasticity. Postgraduate Medical Journal 65:208–210 Fahn S, List T, Moskowitz CB, et al 1985 Double-blind controlled study of botulinum toxin for blepharospasm. Neurology 35(Suppl1):271 Greene P, Kang U, Fahn S, et al 1990 Double-blind, placebocontrolled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 40:1213–1218 Kerner J 1822 Das Fettgift und die Fettsaure und ihre Wirkungen auf den thierischen Organismus. Ein Beytrag zur Untersuchung des in verdorbenen Wursten giftig wirkenden Stoffes. CottaVerlag, Stuttgart, Tubingen

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Scott A 2009 Development of botulinum toxin (Foreword). In: Jankovic J, Albanese A, Atassi MZ, et al (eds) Botulinum toxin – therapeutic clinical practice and science. Saunders, Philadelphia Scott AB 1980 Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Journal of Pediatric Ophthalmology and Strabismus 17:21–25 Scott AB 1994 Preface. In: Jankovic J, Hallett M (eds) Therapy with botulinum toxin. Marcel Dekker, New York, p vii–ix

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Scott AB 2004 Development of botulinum toxin therapy. Dermatologic Clinics 22:131–133, v Simpson LL 1981 The origin, structure, and pharmacological activity of botulinum toxin. Pharmacological Reviews 33:155–188 Snipe PT, Sommer H 1928 Studies on botulinus toxin. 3. Acid precipitation of botulinus toxin. Journal of Infectious Diseases 43:152–160

History of cosmetic botulinum toxin Alastair Carruthers, Jean Carruthers

Summary and Key Features • In the mid-eighties, Dr Jean Carruthers noticed a concomitant improvement in glabellar rhytides in a patient treated with botulinum toxin (BoNT) for blepharospasm • First trial involved 18 patients and was published in 1992 • By 2002, open-label studies of more than 800 patients confirmed the efficacy and safety of BoNT in the treatment of hyperfunctional wrinkles • In April 2002, the Food and Drug Administration (FDA) approved BoNT for the non-surgical reduction of glabellar rhytides • Cosmetic BoNT is now used for hyperkinetic lines in the face, neck, and chest, for facial sculpting, and as an adjunct to other rejuvenating modalities • The original formulation of BoNT has since gone on to receive approval for 20 indications in more than 75 countries

Introduction The discovery of ‘sausage poison’ and subsequent identification of Clostridium botulinum as the bacterium responsible has had an enormous and lasting impact on the field of cosmetic dermatology. As is often the case in medicine, a series of serendipitous discoveries – coupled with astute clinical observations – unlocked the potential of botulinum toxin (BoNT) and led to significant medical gains (Tables 3.1 and 3.2). Once hailed as a promising breakthrough for a handful of muscular disorders, BoNT has since become a veritable mainstay of the cosmetic practitioner, its popularity growing exponentially to become one of the most requested procedures in facial rejuvenation. Serendipitous discovery By the late 1980s, nearly 10 000 patients had received injections of BoNT type A (BoNT-A; then called ‘Oculinum’ and distributed to qualified injectors by Dr Alan

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Scott of the Smith Kettlewell Institute of Visual Sciences, San Francisco, CA) for the treatment of strabismus, benign essential blepharospasm, and hemifacial spasm (Smith Kettlewell 1990.) Many of these patients had received multiple injections with no evidence of antibody formation or systemic complications over 6 years of continued use. In Vancouver, British Columbia, ophthalmologist Dr Jean Carruthers noticed a remarkable and unexpected effect in the brow of a patient treated for blepharospasm: a noticeable reduction in the appearance of glabellar furrows, giving her a more serene, untroubled expression. Dr Carruthers discussed the observation with her dermatologist spouse, Dr Alastair Carruthers, who was attempting to soften the forehead wrinkles of his patients using soft-tissue-augmenting agents available in the eighties. CASE STUDY 1  Mrs. LW, 50-years-old, had suffered for 20 years from severe bilateral spasms and twitches of her eyelids on both sides. Despite her normal visual acuities, she was unable to drive her car and apprehensive about crossing the street. Her clerical job had become increasingly difficult to perform; her eyelids would spasm and close without warning, worsening toward the end of the working day. Treatment with 30 units of onabotulinumtoxinA (Botox®) on each side resulted in almost complete symptom relief for approximately 3 months. In addition, she noticed that her brow and face appeared more relaxed, and her friends commented about how ‘fresh’ and attractive she looked. The deep frown lines between her brows appeared to efface, and her husband thought she looked less intense and angry. At her next appointment, Mrs. LW expressed concern when her doctor (JC) did not treat the medial ends of her eyebrows. When her doctor explained that she had not observed any spasm in those areas, Mrs. LW said: ‘Every time you treat me there, I get this beautiful, untroubled expression.’ It was the birth of the realization that onabotulinumtoxinA could be helpful in other patients with similar glabellar folds and medial brow ptosis.

Pearl 1  Listen carefully to your patients – they often have valuable insights to share!

Botulinum toxin

Table 3.1  Timeline of clinical discovery

Pearl 2 

Late 1700s

Outbreaks of deadly illness from contaminated foods sweeps across Europe

1793

Biggest outbreak in Wildebrad, Southern Germany

Keep an open mind about new treatments and indications for old treatments. For example, long eyelashes were reported as adverse events after treatment with bimatoprost. Now, bimatoprost is an FDA-approved treatment to thicken, darken, and lengthen eyelashes.

1811

‘Prussic acid’ named as culprit in sausage poisoning

1822

Dr Justinus Kerner publishes monograph of ‘sausage poison’ and accurately describes botulism

1895

Professor Emile Pierre Van Ermengem identifies Clostridium botulinum as causative agent of botulism

1895–1915

Seven serotypes of toxins are recognized

1928

Dr Herman Sommer isolates most potent serotype: BoNT-A

1946

Carl Lamanna and James Duff develop concentration and crystallization techniques subsequently used by Dr Edward J. Schantz at Fort Detrick, Maryland, for possible biological weapon

1972

Dr Schantz takes his research to the University of Wisconsin, where he produces the large batch of BoNT-A that remained in clinical use until December 1997

Current options for the aging face at the time included surgery and soft-tissue augmentation, which either did not address the underlying facial musculature contributing to the emergence of hyperfunctional rhytides or were associated with considerable risk, questionable efficacy, and inconvenience. Surgical procedures, such as rhytidectomy, liposuction, brow lift, dermabrasion, and chemical peels, constituted major procedures that were sometimes associated with significant side effects (including scarring and abnormal facial movements) and long recovery periods. Available soft-tissue augmenting agents included collagen, silicone, or autologous fat, which have been reported to produce embolic necrosis of the retina and blindness if accidentally injected into the retinal circulation. Bovine collagen was associated with allergic reactions, and concerns about adjuvant disease were raised with the use of silicone. The timing for a non-invasive and easy injectable treatment that carried little risk of complication could not have been more perfect, nor the aging population more willing and eager. Patient zero and the first clinical trials

Table 3.2  Timeline of therapeutic development and use

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Late 1960s–early 1970s

Dr Alan Scott begins animal experimentation with BoNT-A supplied by Dr Schantz

1973

Dr Scott publishes the first report of BoNT-A in primates

1978

FDA grants approval to begin testing small amounts of the toxin (Oculinum) in human volunteers

1980

Landmark paper demonstrating that BoNT-A corrects gaze misalignment in humans

1988

Allergan Inc. acquires rights to distribute Dr Scott’s Oculinum in the United States

1989–

FDA approves BoNT-A for the nonsurgical correction of strabismus, blepharospasm, hemifacial spasm, and Meige syndrome in adults Clinical use expands to include treatment of cervical dystonia and spasmodic torticollis Allergan purchases Dr Scott’s company and renames the toxin Botox®

Intrigued by the possibilities, the Carruthers injected a small amount of Scott’s BoNT-A between the brows of their assistant, Cathy Bickerton Swann – known as ‘patient zero’ – and awaited the results (Figure 3.1A–D). Seventeen more patients followed, aged 34 to 51, who would become part of the first report on the efficacy of BoNT-A, published in 1992. Subjects received injections directly into the glabellar furrow (10–12.5 U/furrow), as well as one or more subsequent injections into the corrugator muscles (10–20 U/furrow or per corrugator) 3 to 4 months following previous injections. One patient did not respond at all to injection, and one was lost to follow-up. The remaining patients experienced varying degrees of brow improvement, from complete line effacement (six of seventeen) (Fig. 3.2) to discernible brow creases that simply lessened in depth (eight subjects). The effects of the toxin lasted from 4 to 11 months, depending on the number of repeated injections and length of exposure. In general, subjects who received treatment over a longer period of time experienced a treatment persistence of 7–11 months. Side effects included one case each of brow and lid ptosis that resolved within 14 days, two cases of transient headache, and one subject who experienced transient numbness at the injection site. Although the authors conclude by saying that BoNT-A is safe and effective, ‘We do not believe at present that it is the treatment of choice’ except

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History of cosmetic botulinum toxin

A

B

C

D

Figure 3.1  ‘Patient zero’ before (A, B) and after (C, D) injection of BoNT into the glabella: (A, C) resting, (B, D) frowning. From Carruthers JDA, Carruthers JA 1992 Treatment of glabellar frown lines with C. botulinum-A exotoxin. Journal of Dermatologic Surgery and Oncology 18:17-21. Reprinted with permission of Dermatologic Surgery.

A

B

Figure 3.2  The first clinical trial of BoNT in the glabellar furrow and corrugator muscles demonstrated varying degrees of improvement to the appearance of the brow. (A) Pre-treatment. (B) Here, treatment led to complete line effacement.

for ‘those who are collagen-allergic or who are disinclined to undergo surgery.’ The publication of their findings drew a flurry of interest among other clinicians, some of whom had already begun their own off-label experiments. Clark & Berris

restored symmetry in a post-surgical patient with unilateral frontal nerve paralysis and one-sided frown lines and brow elevation on animation by injecting BoNT-A into the opposite functioning frontalis muscle. Blitzer and colleagues had used BoNT-A to treat focal dystonia since

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Botulinum toxin

1984. By the late eighties, they had noticed a loss of hyperfunctional lines in subjects treated with the toxin for a number of disorders, including blepharospasm, Meige’s syndrome, hemifacial spasm, and post-Bell’s palsy facial synkinesis. In order to study the phenomenon further, 26 patients aged 3–84 years with hyperfunctional lines and dystonia received aliquots of 1.2–10 U BoNT-A via electromyography (EMG) guidance into the frontalis and corrugators muscles, nasolabial fold, lateral canthus, or platysma. The effect of the BoNT-A occurred within the first 24–72 hours, peaked at 2–3 weeks, when follow-up injections were performed, if necessary, and lasted from 3 to 6 months. Minimal adverse effects included ptosis of the eyelid and, in the case of nasolabial fold injections, droop of the upper lip. All patients experienced substantial benefit from treatment. Recognizing the need for trials of longer duration, Keen and colleagues devised the first double-blind, placebocontrolled study to assess the efficacy and safety of BoNT-A for the treatment of facial rhytides in a group of twelve healthy subjects (one of whom was lost to follow-up) aged from 32 to 62 years. Nine patients with hyperfunctional forehead rhytides and two patients with prominent crow’s feet received injections of either 0.2 mL normal saline or BoNT-A (eight injection sites with 10 U in the forehead, two sites with 5 U in the periorbital wrinkles) on both sides of the face via EMG guidance. Before and after photographs documented the treatment effect (determined by blind self-assessment and investigator grading) 2 and 6 weeks after injection, and patients were followed for a minimum of 1 year. BoNT-A treatment led to a significant (p