Manual of Botulinum Toxin Therapy [3 ed.] 1009098667, 9781009098663, 9781009105033

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Manual of Botulinum Toxin Therapy Third Edition

Published online by Cambridge University Press

Published online by Cambridge University Press

Manual of Botulinum Toxin Therapy Third Edition

Edited by

Daniel Truong University of California, Riverside The Truong Neurosciences Institute, Fountain Valley, CA, USA

Dirk Dressler Hannover Medical School, Germany

Mark Hallett National Institutes of Health (NIH), USA

Christopher Zachary University of California, Irvine, USA

Mayank Pathak The Truong Neuroscience Institute

Medical Illustrator:

Mayank Pathak

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Shaftesbury Road, Cambridge CB2 8EA, United Kingdom One Liberty Plaza, 20th Floor, New York, NY 10006, USA 477 Williamstown Road, Port Melbourne, VIC 3207, Australia 314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre, New Delhi – 110025, India 103 Penang Road, #05-06/07, Visioncrest Commercial, Singapore 238467 Cambridge University Press is part of Cambridge University Press & Assessment, a department of the University of Cambridge. We share the University’s mission to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. www.cambridge.org Information on this title: www.cambridge.org/9781009098663 DOI: 10.1017/9781009105033 © Cambridge University Press & Assessment 2024 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press & Assessment. First Edition 2009 Second Edition 2013 Third Edition 2024 Printed in the United Kingdom by TJ Books Limited, Padstow Cornwall A catalogue record for this publication is available from the British Library. Library of Congress Cataloging-in-Publication Data Names: Truong, Daniel, editor. | Dressler, Dirk, editor. | Hallett, Mark, 1943– editor. | Zachary, Christopher B., editor. Title: Manual of botulinum toxin therapy / edited by Daniel Truong, University of California, Riverside, Dirk Dressler, Hannover Medical School, Mark Hallett, National Institutes of Health (NIH), Christopher Zachary, University of California, Irvine. Description: Third edition. | Cambridge, United Kingdom ; New York, NY, USA : Cambridge University Press, [2023] | Includes bibliographical references and index. Identifiers: LCCN 2023001833 (print) | LCCN 2023001834 (ebook) | ISBN 9781009098663 (hardback) | ISBN 9781009105033 (epub) Subjects: MESH: Botulinum Toxins–therapeutic use. | Neuromuscular Agents–therapeutic use. | Botulinum Toxins–pharmacology. | Movement Disorders–drug therapy. | Neuromuscular Diseases–drug therapy. Classification: LCC RL120.B66 M36 2023 (print) | LCC RL120.B66 (ebook) | DDC 615.7/78–dc23/eng/20230420 LC record available at https://lccn.loc.gov/2023001833 LC ebook record available at https://lccn.loc.gov/2023001834 ISBN 978-1-009-09866-3 Hardback Cambridge University Press & Assessment has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. [Medical disclaimer:] Every effort has been made in preparing this book to provide accurate and upto-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

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In memory of Diane Truong, a loving wife, who was devoted to improving the lives of patients

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Contents List of Contributors ix Preface for the Third Edition

xv 13 Treatment of Hemifacial Spasm with Botulinum Toxin 100 Karen Frei

1

The Pretherapeutic History of Botulinum Neurotoxin 1 Frank J. Erbguth

2

Botulinum Neurotoxin: History of Clinical Development 9 Daniel Truong, Deepmala Nandanwar and Mark Hallett

3

Pharmacology of Botulinum Toxin Therapy Daniel Truong, Frank Xing and Mark Hallett

4

Immunological Properties of Botulinum Neurotoxins 18 Hans Bigalke, Dirk Dressler and Jürgen Frevert

16 The Role of Ultrasound for Botulinum Neurotoxin Injection in Childhood Spasticity 120 Bettina Westhoff

5

Examination and Treatment of Complex Cervical Dystonia 23 Deepmala Nandanwar, Gerhard Reichel and Daniel Truong

17 The Use of Botulinum Neurotoxin in Spastic Infantile Cerebral Palsy 125 Ann H. Tilton

6

Visualization of Ultrasound-Guided Intramuscular Injections in Muscles Relevant for Cervical Dystonia 34 Stefan Meng and Paata Pruidze

18 The Use of Botulinum Neurotoxin in Spasticity Using Ultrasound Guidance 133 Andrea Santamato, Alessio Baricih and Alessandro Picelli

7

Ultrasound Guidance for Botulinum Neurotoxin Therapy: Cervical Dystonia 48 Panagiotis Kassavetis, Michael E. Farrell and Katharine E. Alter

13

14 Botulinum Toxin in Treatment of Tics Joseph Jankovic

107

15 The Use of Botulinum Toxin in Tremors 113 Shivam Om Mittal and Joseph Jankovic

19 The Use of Botulinum Toxin in Spasticity Mayank S. Pathak and Allison Brashear

163

20 Treatment of Stiff-Person Syndrome with Botulinum Toxin 174 Delaram Safarpour and Bahman Jabbari

8

Treatment of Cervical Dystonia 58 Deepmala Nandanwar, Mayank S. Pathak, Karen Frei and Daniel Truong

21 Botulinum Toxin in Ophthalmology Bettina Wabbels

9

Treatment of Blepharospasm 69 Luca Marsili, Matteo Bologna and Carlo Colosimo

22 Cosmetic Uses of Botulinum Neurotoxins for the Upper Face 188 Katherine Glaser and Dee Anna Glaser

180

10 Botulinum Neurotoxin in Oromandibular Dystonia 73 Roongroj Bhidayasiri, Suppata Maytharakcheep and Daniel Truong

23 Botulinum Toxin for the Lower Face 197 Francisco Pérez-Atamoros, Carolina Hernández, Vivian Laquer and Joshua Spanogle

11 Botulinum Neurotoxin Therapy of Laryngeal Muscle Hyperactivity Syndromes 82 Daniel Truong, Arno Olthoff and Rainer Laskawi

24 Botulinum Toxin in the Treatment of Gummy Smile 207 Rosemarie Mazzuco and Doris Hexsel

12 The Use of Botulinum Neurotoxin in Otorhinolaryngology 89 Rainer Laskawi, Arno Olthoff and Oleg Olegovich Ivanov

25 Botulinum Toxin for the Breast 214 Francisco Pérez-Atamoros, Carolina Hernández, Allen Gabriel and Paige Dekker

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Contents

26 Treatment of Depression with Botulinum Toxin 218 M. Axel Wollmer, Michelle Magid, Tillmann H. C. Kruger and Eric Finzi 27 Hyperhidrosis 223 Berthold Rzany and Markus K. Naumann 28 Botulinum Toxin in the Treatment for Ischemic Digits and Chronic Pain 230 Alexis Ruffolo, Kelli Webb and Michael W. Neumeister 29 Botulinum Toxin in Wound Healing Holger G. Gassner

237

30 Use of Botulinum Neurotoxin in Neuropathic Pain 245 Szu-Kuan Yang, Chen-Chih Jean Chung and Chaur-Jong Hu 31 The Use of Botulinum Toxin in the Management of Headache Disorders 252 Hsiangkuo Yuan and Stephen D. Silberstein 32 Use of Botulinum Toxin in Musculoskeletal Pain and Arthritis 260 Jasvinder A. Singh 33 Treatment of Plantar Fasciitis/Plantar Fasciopathy with Botulinum Neurotoxins 269 Delaram Safarpour, Shivam Om Mittal and Bahman Jabbari

viii Published online by Cambridge University Press

34 Use of Botulinum Toxin in the Treatment of Low Back Pain 275 José De Andrés, Gustavo Fabregat, Ruben Rubio-Haro and Carmen De Andrés-Serrano 35 Use of Botulinum Neurotoxin in the Treatment of Piriformis Syndrome 290 Loren M. Fishman 36 Ultrasound-Guided Botulinum Toxin Injections for Thoracic Outlet Syndrome 299 Michael E. Farrell and Katharine E. Alter 37 Botulinum Neurotoxin in the Gastrointestinal Tract 311 Vito Annese, Alessandro Borrello and Daniele Gui 38 Botulinum Neurotoxin Applications in Urological Disorders 323 Brigitte Schurch and Stefano Carda 39 Treatment of Focal Hand Dystonia 332 Barbara Illowsky Karp, Chandi Prasad Das, Daniel Truong and Mark Hallett

Index

348

Contributors

Katharine E. Alter, MD Senior Research Clinician, Clinical Center Medical Director, Neurorehabilitation and Biomechanics Research Section National Institutes of Health Bethesda, MD, USA José De Andrés, MD Department of Anesthesia, Critical Care and Multidisciplinary Pain Management University General Hospital of Valencia Medical School, University of Valencia Valencia, Spain Carmen De Andrés-Serrano, MD Multidisciplinary Pain Clinic Vithas Virgen del Consuelo Hospital Valencia, Spain Vito Annese, MD Consultant Gastroenterologist Director of Academic Affair Fakeeh University Hospital Dubai, UAE Alessio Baricich, MD Associate Professor of Physical Medicine and Rehabilitation University of Eastern Piedmont Novara, Italy Head of Physical and Rehabilitation Medicine Division “Maggiore della Carità” Hospital Novara, Italy Roongroj Bhidayasiri, MD Chulalongkorn Centre of Excellence for Parkinson’s Disease & Related Disorders, Department of Medicine, Faculty of Medicine

Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok 10330, Thailand The Academy of Science, The Royal Society of Thailan Bangkok 10330, Thailand. Hans Bigalke, MD Institute of Toxicology Medical School of Hannover Hannover, Germany Matteo Bologna, MD Department of Human Neurosciences Sapienza University of Rome, Rome, Italy IRCCS Neuromed Pozzilli (IS), Italy Alessandro Borrello, MD Emergency Surgery Policlinico Gemelli Catholic University of Sacred Heart Rome, Italy Allison Brashear, MD Jacobs School of Medicine and Biomedical Sciences University at Buffalo, New York, USA Stefano Carda, MD Department of Neuroscience University Hospital Lausanne. CHUV. Lausanne, Switzerland Chen-Chih Jean Chung, MD PhD The Department of Neurology, Shuang Ho Hospital, Taipei University The Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan

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List of Contributors

Carlo Colosimo, MD Department of Neurology Santa Maria University Hospital Terni, Italy

Karen Frei, MD Associate Professor of Neurology Loma Linda University School of Medicine Loma Linda, CA, USA

Chandi Prasad Das, MD, FRACP, DM (Neurology) Senior Staff Specialist Neurology Canberra Hospital, ACT, Australia

Jürgen Frevert, PhD Merz Pharmaceuticals GmbH Frankfurt, Germany

Paige Dekker, MD Department of Plastic Surgery University of Southern California Los Angeles, CA, USA

Allen Gabriel, MD Department of Plastic Surgery Loma Linda University Medical Center Loma Linda, CA, USA

Dirk Dressler, MD Movement Disorders Section Department of Neurology Hannover Medical School Hannover, Germany Frank J. Erbguth, MD, PhD Paracelsus Medical University Campus Nuremberg, Dept. of Neurology Nuremberg, Germany Gustavo Fabregat, MD Department of Anesthesia, Critical Care and Multidisciplinary Pain Management University General Hospital of Valencia Valencia, Spain Michael E. Farrell, MD Pain Management Physician, ECMC Center for Interventional Spine & Pain, Erie County Medical Center, Buffalo, NY, USA Assistant Clinical Professor, University of Pittsburgh Medical Center Department of Anesthesiology and Perioperative Medicine Pittsburgh, PA, USA

Holger G. Gassner, MD Finesse Center for Facial Plastic and Reconstructive Surgery University of Regensburg, Faculty of Medicine Regensburg, Germany Dee Anna Glaser, MD Saint Louis University School of Medicine St Louis, MO, USA Katherine Glaser, MD First Capitol Surgical Dermatology St Charles, MO, USA Daniele Gui, MD Emergency Surgery Policlinico Gemelli Catholic University of Sacred Heart Rome, Italy Mark Hallett, MD National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD, USA

Eric Finzi, MD Department of Psychiatry & Behavioral Sciences George Washington School of Medicine Washington, DC, USA

Carolina Hernández, MD Centro Dermatólogico Tennyson CDMX Mexico City, México

Loren M. Fishman, MD Department of Rehabilitative and Regenerative Medicine Columbia University Medical School New York, NY, USA

Doris Maria Hexsel, MD Dermatologist and Principal Investigator Hexsel Dermatologic Clinics Rio de Janeiro and Porto Alegre, Brazil

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List of Contributors

Chaur-Jong Hu, MD The Department of Neurology, Shuang Ho Hospital, Taipei Medical University The Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan

Michelle Magid, MD, MBA President, Austin PsychCare, Austin, TX, USA Associate Professor, Department of Psychiatry, University of Texas at Austin, Dell Medical School, Austin, TX, USA Adjunct Associate Professor, Department of Psychiatry, Texas A&M Health Science Center, Round Rock TX, USA

Oleg Olegovich Ivanov, MD, PhD Clinic of Phlebology Ltd Novokuznetsk, Russia

Rosemarie Mazzuco, MD Rosemarie Mazzuco Dermatology Clinic, Brazil.

Bahman Jabbari, MD Department of Neurology Yale University School of Medicine New Haven, CT, USA

Luca Marsili, MD Gardner Family Center for Parkinson’s Disease and Movement Disorders Department of Neurology University of Cincinnati, Cincinnati, OH, USA

Joseph Jankovic, MD Distinguished Chair in Movement Disorders Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology, Baylor College of Medicine, TX, USA Barbara Illowsky Karp, MD Office of the Clinical Director National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD, USA Panagiotis Kassavetis, MD, PhD Movement Disorders Division Department of Neurology University of Utah Salt Lake City, UT, USA Tillmann H. C. Kruger, MD Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School Hannover, Germany Vivian Laquer, MD Department of Dermatology University of California Irvine, CA, USA First OC Dermatology research Fountain Valley, CA, USA Rainer Laskawi, MD Department of Otolaryngology, Head and Neck Surgery University of Göttingen Göttingen, Germany

Suppata Maytharakcheep, MD Chulalongkorn Centre of Excellence for Parkinson’s Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok 10330, Thailand Stefan Meng, MD Radiology, Hanusch Hospital Vienna, Austria Center for Anatomy and Cell Biology, Medical University Vienna Vienna, Austria Shivam Om Mittal, MD Head of Parkinson’s Disease and Movement Disorders division Consultant Neurologist, Neurological Institute Cleveland Clinic Abu Dhabi, UAE Deepmala Nandanwar, MD The Truong Neuroscience Institute Fountain Valley, CA, USA Markus K. Naumann, MD Head and Chair of the Department of Neurology and Clinical Neurophysiology University of Augsburg Augsburg, Germany Michael W. Neumeister, MD Department of Surgery Elvin G. Zook Endowed Chair Chief Institute for Plastic Surgery Southern Illinois University School of Medicine Springfield, IL, USA

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List of Contributors

Arno Olthoff, PhD University Medical Center Göttingen Phoniatrics and Pedaudiology Department of Otorhinolaryngology Göttingen, Germany

Mayank S. Pathak, M.D. The Truong Neurosciences Institute Fountain Valley, CA, USA

Francisco Pérez-Atamoros, MD Centros Dermatológicos Tennyson Mexico Alessandro Picelli, MD Associate Professor of Physical Medicine and Rehabilitation University of Verona Italy Paata Pruidze, MD Center for Anatomy and Cell Biology, Medical University Vienna Vienna, Austria Gerhard Reichel, MD Center for Movement Disorders, Clinic Paracelsus Zwickau, Germany Ruben Rubio-Haro, MD Multidisciplinary Pain Clinic Vithas Virgen del Consuelo Hospital Valencia, Spain Alexis Ruffolo, MD Department of Plastic Surgery Southern Illinois University School of Medicine Springfield, IL, USA Berthold Rzany, ScM Medizin am Hauptbahnhof Wahlarztzentrum für Dermatologie & Venerologie Vienna, Austria Delaram Safarpour, MD, MSCE, FAAN Oregon Health and Science University Portland, Oregon, USA Andrea Santamato, MD Full Professor of Physical Medicine and Rehabilitation University of Foggia

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Head of Neurorehabilitation Service of Policlinico Foggia, Italy Brigitte Schurch MD Department of Neuroscience University Hospital Lausanne. CHUV. Lausanne, Switzerland Stephen D. Silberstein, MD Jefferson Headache Center Department of Neurology Thomas Jefferson Universit Philadelphia, PA, USA Jasvinder Singh, MD, MPH Endowed Professor, Musculoskeletal Outcomes Research, Division of Clinical Immunology and Rheumatology Professor of Medicine and Epidemiology, University of Alabama at Birmingham Director, Gout Clinic, University of Alabama Health Sciences Foundation Staff Physician, Birmingham Veterans Affairs Medical Center Birmingham, AL, USA Joshua P. Spanogle MD HK Dermatology San Juan Capistrano, CA, USA Ann H. Tilton, MD, FAAN, FANA Professor of Neurology and Pediatrics Section Head of Child Neurology Louisiana State University Health Sciences Center New Orleans Director of the Rehabilitation Center Children’s Hospital New Orleans, LA, USA Daniel Truong, MD The Truong Neuroscience Institute Fountain Valley, CA, USA Department of Neurosciences UC Riverside, Riverside, CA, USA Bettina Wabbels, MD University Hospital Bonn Department of Ophthalmology Bonn, Germany Kelli Webb, MD Plastic and Reconstructive Surgery Department of Surgery Southern Illinois Healthcare Carbondale, IL, USA

List of Contributors

Bettina Westhoff Leitende Ärztin Kinder- und Neuroorthopädie Klinik für Orthopädie und Unfallchirurgie Universitätsklinikum Düsseldorf Düsseldorf, Germany M. Axel Wollmer, MD Department of Gerontopsychiatry Asklepios Klinik Nord-Ochsenzoll Hamburg, Germany Frank Xing, MD The Truong Neuroscience Institute Fountain Valley, CA, USA

Szu-Kuan Yang M.D Xindian Liu-shun clinic, New Taipei City, Taiwan. Department of Neurology, Feng Rong Hospital, New Taipei City, Taiwan. Department of Neurology, Shuang Ho Hospital, Taipei Medical University New Taipei City, Taiwan. Hsiangkuo Yuan, MD Jefferson Headache Center Department of Neurology Thomas Jefferson University Philadelphia, PA, USA

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Preface for the Third Edition

Now in its fifth decade of clinical usage, botulinum neurotoxin accumulates an ever-increasing number of therapeutic applications in a wide range of medical disciplines. From its narrow niche of treating strabismus in 1977, its physiological action of long-term neuromuscular blockade quickly prompted its adoption for treating almost any medical condition associated with involuntary muscle contraction, including blepharospasm, cervical dystonia and other focal dystonias, spasticity, neurogenic bladder and even abnormal motility in the gastrointestinal tract. Its ability to reduce exocrine gland secretions prompted treatment of lacrimation, sialorrhea and hyperhidrosis. Its analgesic properties are being used to ameliorate neurogenic pain, joint pain and migraine. Additionally, the number and variants of botulinum neurotoxin formulations continues to increase. It is this expanding clinical scope, far beyond the popularly recognized cosmetic use for remediation of facial wrinkles, that has impelled us after a hiatus of ten years to produce this third edition of the Manual of Botulinum Toxin Therapy.

We have again recruited chapter submissions from a variety of clinicians from across the globe, all leaders in their field, to present historical, theoretical and practical instruction on application of botulinum neurotoxin in their respective disciplines, encompassing neurology, rehabilitation medicine, ophthalmology, otorhinolaryngology, gastroenterology, urology, dermatology, pediatrics and psychiatry. As in previous editions, the emphasis is on technique. Instructions are facilitated by clear illustrations that guide toxin placement and targeting using a “clinician’s eye” viewpoint wherever possible. Refinements in guidance techniques such as ultrasound, electromyography and fluoroscopy are discussed. Dosing aides for the commonly used toxin preparations are provided. We hope that this book will serve as a teaching aid for the beginner and a practical resource for the advanced practitioner. We are grateful to the contributing authors of this book and to our hardworking publication managers at Cambridge University Press. We express special gratitude to our families and friends for their support and understanding during the preparation of this book.

xv https://doi.org/10.1017/9781009105033.001 Published online by Cambridge University Press

https://doi.org/10.1017/9781009105033.001 Published online by Cambridge University Press

Chapter

1

The Pretherapeutic History of Botulinum Neurotoxin Frank J. Erbguth

Unintended intoxication with botulinum neurotoxin (botulism) occurs only rarely, but its high fatality rate makes it a great concern for the general public and the medical community. In the USA, an average of 110 cases of botulism are reported each year. Of these, approximately 25% are food borne, 72% are infant botulism and the rest are wound botulism. Outbreaks of food-borne botulism involving two or more persons occur most years and are usually caused by eating contaminated home-canned foods.

Botulism in Ancient Times Botulinum neurotoxin poisoning probably has afflicted humankind through the mists of time. As long as humans have preserved and stored food, some of the chosen conditions would be optimal for the presence and growth of the toxinproducing pathogen Clostridium botulinum: for example, the storage of ham in barrels of brine, poorly dried and stored herring, trout packed to ferment in willow baskets, sturgeon roe not yet salted and piled in heaps on old horsehides, lightly smoked fish or ham in poorly heated smoking chambers and insufficiently boiled blood sausages. However, in ancient times there was no general knowledge about the causal relationship between the consumption of spoiled food and a subsequent fatal paralytic disease, nowadays recognized as botulism. Only some historical sources reflect a potential understanding of the life-threatening effects of consuming food intoxicated with botulinum neurotoxin. Louis Smith, for example, reported in his textbook on botulism a dietary edict announced in the tenth century by Emperor Leo VI of Byzantium (886–911), in which manufacturing of blood sausages was forbidden (Smith, 1977). This edict may have its origin in the recognition of some circumstances connected with cases of food poisoning. Also, some ancient formulae suggested by shamans to Indian maharajas for the killing of personal enemies give hint of an intended lethal application of botulinum neurotoxin: a tasteless powder extracted from blood sausages dried under anaerobic conditions should be added to the enemies’ food at an invited banquet. Because the consumer’s death occurred after he or she had left the murderer’s place, with a latency of some days, the host was probably not suspected (Erbguth, 2008).

Botulism Outbreaks in Germany in the Eighteenth and Nineteenth Centuries Accurate descriptions of botulism emerge in the German literature from two centuries ago when the consumption of improperly preserved or stored meat and blood sausages gave rise to many deaths throughout the kingdom of Württemberg in southwestern Germany. This area near the city of Stuttgart developed as the regional focus of botulinum toxin investigations in the eighteenth and nineteenth centuries. In 1793, 13 people were involved in the first well-recorded outbreak of botulism in the small southwest German village of Wildbad; six died. Based on the observed mydriasis in all affected victims, the first official medical speculation was that the outbreak was caused by an atropine (Atropa belladonna) intoxication. However, in the controversial scientific discussion, the term “sausage poison” was introduced by the exponents of the opinion that the fatal disease in Wildbad was caused by the consumption of “Blunzen,” a popular local food from cooked pork stomach filled with blood and spices. The number of cases of suspected sausage poisoning in southwestern Germany increased rapidly at the end of the eighteenth century. Poverty followed the devastating Napoleonic Wars (1795–1813) and led to the neglect of sanitary measures in rural food production (Grüsser, 1986). In July 1802, the Royal Government of Württemberg in Stuttgart issued a public warning about the “harmful consumption of smoked blood-sausages.” In August 1811, the medical section of the Department of Internal Affairs of the Kingdom of Württemberg, on Stuttgart again, addressed the problem of “sausage poisoning,” considering it to be caused by hydrocyanic acid, known at that time as “prussic acid.” However, the members of the nearby Medical Faculty of the University of Tübingen disputed that prussic acid could be the toxic agent in sausages, suspecting a biological poison. One of the important medical professors of the University of Tübingen, Johann Heinrich Ferdinand Autenrieth (1772–1835), asked the government to collect the reports of general practitioners and health officers on cases of food poisoning for systematic scientific analyses. After Autenrieth had studied these reports, he issued a list of symptoms of the so-called sausage poisoning and added a comment, in which he blamed the housewives for

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Erbguth

the poisoning because they did not dunk the sausages long enough in boiling water while trying to prevent the sausages from bursting (Grüsser, 1998). The list of symptoms was distributed by a public announcement and contained characteristic features of food-borne botulism such as gastrointestinal problems, double vision, mydriasis and muscle paralysis. In 1815, a health officer in the village of Herrenberg, J. G. Steinbuch (1770–1818), sent the case reports of seven intoxicated patients who had eaten liver sausage and peas to Professor Autenrieth. Three of the patients had died and the autopsies had been carried out by Steinbuch himself (Steinbuch, 1817).

Justinus Kerner’s Observations and Publications on Botulinum Toxin 1817–1822 Contemporaneously with Steinbuch, the 29-year-old physician and Romantic poet Justinus Kerner (1786–1862) (Fig. 1.1), then medical officer in a small village, also reported a lethal food poisoning. Autenrieth considered the two reports from Steinbuch and Kerner as accurate and important observations and decided to publish them both in 1817 in the Tübinger

Fig. 1.1 Justinus Kerner, 1855.

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Blätter für Naturwissenschaften und Arzneykunde [Tübinger Papers for Natural Sciences and Pharmacology] (Kerner, 1817; Steinbuch, 1817). Kerner again disputed that an inorganic agent such as hydrocyanic acid could be the toxic agent in the sausages, suspecting a biological poison instead. After he had observed further cases, Kerner published a first monograph in 1820 on “sausage poisoning” in which he summarized the case histories of 76 patients and gave a complete clinical description of what we now recognize as botulism. The monograph was entitled “Neue Beobachtungen über die in Württemberg so häufig vorfallenden tödlichen Vergiftungen durch den Genuss geräucherter Würste [New Observations on the Lethal Poisoning That Occurs so Frequently in Württemberg Owing to the Consumption of Smoked Sausages] (Kerner, 1820). Kerner compared the various recipes and ingredients of all sausages that had produced intoxication and found that among the ingredients of blood, liver, meat, brain, fat, salt, pepper, coriander, pimento, ginger and bread the only common ones were fat and salt. Because salt was probably known to be “innocent,” Kerner concluded that the toxic change in the sausage must take place in the fat and, therefore, called the suspected substance “sausage poison,” “fat poison” or “fatty acid.” Later, Kerner speculated about the similarity of the “fat poison” to other known poisons, such as atropine, scopolamine, nicotine and snake venom, which led him to the conclusion that the fat poison was probably a biological poison (Erbguth, 2004). In 1822, Kerner published 155 case reports including autopsy studies of patients with botulism and developed hypotheses on the “sausage poison” in a second monograph Das Fettgift oder die Fettsäure und ihre Wirkungen auf den thierischen Organismus, ein Beytrag zur Untersuchung des in verdorbenen Würsten giftig wirkenden Stoffes [The Fat Poison or the Fatty Acid and Its Effects on the Animal Body System, a Contribution to the Examination of the Substance Responsible for the Toxicity of Bad Sausages] (Kerner, 1822) (Fig. 1.2). The monograph contained an accurate description of all muscle symptoms and clinical details of the entire range of autonomic disturbances occurring in botulism, such as mydriasis, decrease of lacrimation and secretion from the salivary glands, and gastrointestinal and bladder paralysis. Kerner also experimented on various animals (birds, cats, rabbits, frogs, flies, locusts, snails) by feeding them with extracts from bad sausages and finally carried out high-risk experiments on himself. After he had tasted some drops of a sausage extract he reported: “. . . some drops of the acid brought onto the tongue cause great drying out of the palate and the pharynx” (Erbguth and Naumann, 1999). Kerner deduced from the clinical symptoms and his experimental observations that the toxin acts by interrupting the motor and autonomic nervous signal transmission (Erbguth, 1996). He concluded: “The nerve conduction is brought by the toxin into a condition in which its influence on the chemical process of life is interrupted. The capacity of nerve conduction

The Pretherapeutic history of Botulinum Neurotoxin Fig. 1.2 Title of Justinus Kerner’s second monograph on sausage poisoning, 1822.

is interrupted by the toxin in the same way as in an electrical conductor by rust” (Kerner, 1820). Finally, Kerner tried in vain to produce an artificial “sausage poison.” In summary, Kerner’s hypotheses concerning “sausage poison” were that (1) the toxin developed in bad sausages under anaerobic conditions, (2) the toxin acts on the motor nerves and the autonomic nervous system and (3) the toxin is

strong and lethal even in small doses (Erbguth and Naumann, 1999). In Chapter 8 of the 1822 monograph, Kerner speculated about using the “toxic fatty acid” botulinum toxin for therapeutic purposes. He concluded that small doses would be beneficial in conditions with pathological hyperexcitability of the nervous system (Erbguth, 2004). Kerner wrote: “The fatty

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Erbguth

acid or zoonic acid administered in such doses, that its action could be restricted to the sphere of the sympathetic nervous system only, could be of benefit in the many diseases which originate from hyperexcitation of this system” and “by analogy it can be expected that in outbreaks of sweat, perhaps also in mucous hypersecretion, the fatty acid will be of therapeutic value.” The term “sympathetic nervous system” as used during the Romantic period, encompassed nervous functions in general. “Sympathetic overactivity” then was thought to be the cause of many internal, neurological and psychiatric diseases. Kerner favored the “Veitstanz” (St. Vitus dance – probably identical with chorea minor) with its “overexcited nervous ganglia” to be a promising indication for the therapeutic use of the toxic fatty acid. Likewise, he considered other diseases with assumed nervous overactivity to be potential candidates for the toxin treatment: hypersecretion of body fluids, sweat or mucus; ulcers from malignant diseases; skin alterations after burning; delusions; rabies; plague; consumption from lung tuberculosis; and yellow fever. However, Kerner conceded self-critically that all the possible indications mentioned were only hypothetical and wrote: “What is said here about the fatty acid as a therapeutic drug belongs to the realm of hypothesis and may be confirmed or disproved by observations in the future” (Erbguth, 1998). Justinus Kerner also advanced the idea of a gastric tube, suggested by the Scottish physician Alexander Monro in 1811, and adapted it for the nutrition of patients with botulism; he wrote: “if dysphagia occurs, softly prepared food and fluids should be brought into the stomach by a flexible tube made from resin.” He considered all characteristics of modern nasogastric tube application: the use of a guide wire with a cork at the tip and the lubrication of the tube with oil.

sausage-like shape of the causative bacillus discovered later (Torrens, 1998).

TheDiscoveryof“Bacillusbotulinus”inBelgium The next and most important scientific step was the identification of Clostridium botulinum in 1895–1896 by the Belgian microbiologist Emile Pierre Marie van Ermengem of the University of Ghent (Fig. 1.3). On December 14, 1895, an extraordinary outbreak of botulism occurred amongst the 4000 inhabitants of the small Belgian village of Ellezelles. The musicians of the local brass band “Fanfare Les Amis Réunis” played at the funeral of the 87-year-old Antoine Creteur and as it was the custom gathered to eat in the inn “Le Rustic” (Devriese, 1999). Thirty-four people were together and ate pickled and smoked ham. After the meal, the musicians noticed symptoms such as mydriasis, diplopia, dysphagia and dysarthria, followed by increasing muscle paralysis. Three of them died and ten nearly died. A detailed examination of the ham and an autopsy were ordered and conducted by van Ermengem, who had been appointed Professor of Microbiology at the University of Ghent in 1888 after he had worked in the laboratory of Robert Koch in Berlin in 1883. Van Ermengem isolated the bacterium in the ham and in the corpses of the victims (Fig. 1.4), grew it, used it for animal experiments,

Botulism Research after Kerner After his publications on food-borne botulism, Kerner was well known to the German public and amongst his contemporaries as an expert on sausage poisoning, as well as for his melancholy poetry. Many of his poems were set to music by the great German Romantic composer Robert Schumann (1810–1856), who had to quit his piano career because of the development of a pianist’s focal finger dystonia. Kerner’s poem The Wanderer in the Sawmill was the favorite poem of the twentieth-century poet Franz Kafka (in full in Appendix 1.1). The nickname “Sausage Kerner” was commonly used, and “sausage poisoning” was known as “Kerner’s disease.” Further publications in the nineteenth century by various authors (e.g., Müller, 1869) increased the number of reported cases of “sausage poisoning,” describing the fact that the food poisoning occurred after the consumption not only of meat but also of fish. However, these reports added nothing substantial to Kerner’s early observations. The term “botulism” (from the Latin botulus, “sausage”) appeared at first in Müller’s reports and was subsequently used. Therefore, “botulism” refers to poisoning caused by sausages and not to the

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Fig. 1.3 Emile Pierre Marie van Ermengem 1851–1922.

The Pretherapeutic history of Botulinum Neurotoxin

Fig. 1.4 Microscopy of the histological section of the suspect ham at the Ellezelles botulism outbreak. (a) Numerous spores among the muscle fibers (Ziehl 1000). (b) Culture (gelatine and glucose) of mature rod-shaped forms of “Bacillus botulinus” from the ham on the eighth day (1000). (From van Ermengem, 1897.)

characterized its culture requirements, described its toxin, called it “Bacillus botulinus,” and published his observations in the German microbiological journal Zeitschrift für Hygiene und Infektionskrankheiten [Journal of Hygiene and Infectious Diseases] in 1897 (an English translation was published in 1979) (van Ermengem, 1897). The pathogen was later renamed Clostridium botulinum. Van Ermengem was the first to correlate “sausage poisoning” with the newly discovered anaerobic microorganism and concluded that “it is highly probable that the poison in the ham was produced by an anaerobic growth of specific micro-organisms during the salting process.” Van Ermengem’s milestone investigation yielded all the major clinical facts about botulism and botulinum neurotoxin: (1) botulism is an intoxication, not an infection; (2) the toxin is produced in food by a bacterium; (3) the toxin is not produced if the salt concentration in the food is high; (4) after ingestion, the toxin is not inactivated by the normal digestive process; (5) the toxin is susceptible to inactivation by heat; and (6) not all species of animals are equally susceptible.

Botulinum Neurotoxin Research in the Early Twentieth Century In 1904, when an outbreak of botulism in the city of Darmstadt, Germany, was caused by canned white beans, the opinion that the only botulinogenic foods were meat or fish had to be revised. The bacteria isolated from the beans by Landmann (1904) and from the Ellezelles ham were compared by Leuchs (Leuchs, 1910) at the Royal Institute of Infectious Diseases in Berlin. He found that the strains differed, and the toxins were serologically distinct. The two types of Bacillus

botulinus did not receive their present letter designations of serological subtypes until Georgina Burke, who worked at Stanford University, designated them as types A and B (Burke, 1919). Over the next decades, increases in food canning and food-borne botulism went hand in hand (Cherington, 2004). The first documented outbreak of foodborne botulism in the USA was caused by commercially conserved pork and beans and dates from 1906 (Drachmann, 1971; Smith, 1977). Techniques for killing the spores during the canning process were subsequently developed. The correct pH (18 MHz) may be useful when scanning very superficial muscles or structures. A small footprint transducer such as a “hockey stick” is valuable for irregular surfaces, small spaces or smaller patients.

Ultrasound-Guided Botulinum Neurotoxin Therapy: Cervical Dystonia

Ultrasound Basics for Tissues With B-mode US imaging, structures are described based on their echotexture. During B-mode US imaging, structures with a higher water content appear hypoechoic or dark when few US waves are reflected back to the transducer. Structures that are more highly reflective of ultrasound waves (i.e., those with a lower water content) will appear hyperechoic or bright because more of the US waves are reflected back to the transducer. Muscle is made of a mixture of tissue types and therefore has a mixed echotexture appearance, with the contractile element fibers appearing hypoechoic and the intramuscular connective tissue or surrounding fascia appearing relatively hyperechoic. Tendons are hyperechoic, highly anisotropic and fibrillar in appearance. Nerves are less hyperechoic or fibrillar than tendons and have a fascicular appearance, particularly in short axis. Vessels are anechoic (black). Bone is mirror-like and highly reflective of US waves. Therefore, the cortex of bone will appear hyperechoic, and since no US waves penetrate the cortex, acoustic shadowing (hypoechoic/dark) will be observed underneath (Smith and Finnoff, 2009a; Alter, 2010; Alter et al., 2012).

Imaging Techniques An important technical pearl is that the width of the US beam created by a transducer is much narrower than the width/ footprint of the transducer. As a result, if the transducer is placed in contact with the skin and held in a static position, only a thin slice of the region directly under the US beam is visualized. To completely image a structure or target requires the operator to “scan,” or move the transducer up/down, back/ forth to fully image the entire region of interest. This “scout” scan is required prior to any procedure, as it provides the clinician with useful information about structures of interest, the depth/location of the target, the best/safe path to the target, structures to be avoided (nerves, vessels) and the presence of anatomical variations or masses (Smith and Finnoff, 2009a, 2009b; Alter 2010; Alter et al., 2012) When scanning with US, muscles/structures can be imaged either in the transverse (short axis, Fig. 7.1a) or in the longitudinal (long-axis) plane (Fig. 7.1b). The contour lines of muscles and their neighboring structures are best identified in short axis, as long-axis views only reveal a thin imaging slice of the region under the beam (Fig. 7.1b). However, it is recommended to scan in both planes to determine which provides the best view of the target, the surrounding structures and a clear path to the target of injection. When used for procedural guidance, B-mode US provides real-time, continuous visualization of a structure and the location of the needle throughout the procedure, but only if the needle is kept within the beam produced by the transducer. Needle visualization can often be improved using machinespecific software such as beam steering or a needle enhancement preset (Alter and Karp, 2017) . Sometimes needle visualization can also be improved with color Doppler during needle movement/jiggling (Hamper et al., 1991). However, color

Fig. 7.1 (a) Short-axis (cross-sectional) ultrasound scan, anterior cervical region. (b) Long-axis (longitudinal) B-mode ultrasound scan, sternocleidomastoid muscle, anterior cervical region.

Doppler causes decrease of the image quality; therefore, it should be used only intermittently and not throughout the whole procedure. When using an in-plane approach (Fig. 7.2a–c), the needle is inserted along the length of the transducer. When this technique is performed optimally (Fig. 7.2c), the entire needle, including the tip, will be visualized at the same time. Due to anisotropy, needle visualization is optimized by inserting the needle perpendicular to the ultrasound beam, which requires a flat (Fig. 7.2a,c), rather than steep (Fig. 7.2b), angle of insertion relative to the transducer. In the out-of-plane approach, the needle is inserted through the short axis of the transducer (Fig. 7.3a–c). When using an out-of-plane technique, the needle is viewed in short axis and, therefore, appears as a hyperechoic dot. When using the out-of-plane technique, a “walk-down” technique is used to ensure that the tip of the needle is in the target structure (Smith and Finnoff, 2009b; Alter, 2010; Alter et al., 2012). When using a walk-down technique, the clinician jiggles or vibrates the needle during insertion and at the same time fans or slides the transducer to maintain the needle tip

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Fig. 7.2 (a) In-plane technique with flat angle of needle insertion. (b) In-plane technique with shallow angle of needle insertion. (c) In-plane view of needle, sternocleidomastoid muscle, long-axis ultrasound scan.

within the US beam, as the needle approaches the target. If the needle–transducer insertion angle is steep (Fig. 7.3a) (~10 degrees), rather than shallow (Fig. 7.3b), then this helps to keep the tip of the needle under the transducer/within the US

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beam and decreases the amount of transducer repositioning/ fanning/sliding. When a needle is inserted at a shallow angle, the tip can easily pass beyond the US beam and therefore may be in an untargeted muscle or structure. With experience, the

Ultrasound-Guided Botulinum Neurotoxin Therapy: Cervical Dystonia

sonographer should be able to easily calculate or predict the trajectory of the tip of the needle and follow it accurately with the US beam during out-of-plane technique. The two techniques each have advantages and disadvantages, and clinicians are advised to be skilled in both in-plane and out-of-plane approaches. While the in-plane technique is theoretically preferred (the entire needle is visualized), this technique can be technically challenging and difficult to perform when targeting superficial muscles. Depending on the training of the sonographer, the out-of-plane technique can also be accurate in most muscles (Alter et al., 2012; Walter et al., 2018). In addition to providing direct assessment about the depth/ location of the target and the needle, US also provides information about the volume of injectate and resulting distention of the muscle as the injection is performed. This added information can guide the clinician during the procedure to avoid injection of excess volume at one injection site.

Muscle Selection A careful clinical examination with active and passive range of motion (sometimes under anesthesia) is essential for determining the target muscles. Particular attention should be paid in patterns that can easily be confused, such as neck (-collis) versus head (-caput) postures. A range of potential doses for each muscle is sufficient and the final determination can be made based on EMG activity (if EMG is used concurrently with the US) and based on the sonographic appearance of the muscle (taking into account bulk, atrophy, abnormal echogenicity due to fibrosis or other reasons and injectate volume). Groups of adjacent muscles that can be targeted with the same insertion along the path of the needle are: 1. Trapezius and levator scapulae (Fig. 7.4a), 2. Longus colli and longus capitis (Fig. 7.4b) 3. Splenius capitis, semispinalis capitis and OCI (Fig. 7.4c).

Positioning of the Transducer

Fig. 7.3 (a) Out-of-plane technique with steep angle of needle insertion. (b) Out-of-plane technique with shallow angle of needle insertion. (c) Out-of-plane view of needle.

Target muscles can be visualized in the long or short axis. For identification of muscles and adjacent structures, the short axis is preferable, as it reveals the contour lines of the various structures and allows simultaneous visualization of multiple adjacent structures (Figs. 7.1a, 7.4b. 7.4c). However, the long axis is particularly useful when targeting specific muscles such as the levator scapulae (Fig. 7.4a). Another consideration regarding the positioning of the transducer is the orientation relative to the US machine display. Each transducer has a mark or notch that orients to screen left of the US display. Consistency in orienting the transducer/positioning of the notch is essential to facilitate identification of the structures and avoid errors. The authors prefer to use the following conventions: in longitudinal scans the transducer is oriented on the patient so that screen left is rostral and screen right is caudal. In cross-sectional scans, the transducer is oriented on the patient so that left of the display screen represents medial (or anterior) and screen right is lateral (or posterior). In this convention, images obtained on the right or left side of the

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body will appear the same. Other authors or sonographers may prefer to position the transducer–patient–display so that the ultrasound image is a direct reflection of the way the patient is positioned relative to the sonographer. In these conventions the images obtained from the right and left side of the body will be mirror images. These mirror images may be confusing for some novice sonographers who are unfamiliar with muscle pattern recognition.

Commonly Targeted Muscles Anterior Neck Muscles Sternocleidomastoid The superficially located sternocleidomastoid can be imaged either in long-axis/longitudinal (Figs. 7.1b, 7.2c) or in shortaxis/transverse plane (Figs. 7.1a, 7.4b). The transverse plane typically provides a better assessment of the contour lines of the various muscles, fascial planes between muscles, as well as the location of adjacent neurovascular structures (Figs. 7.1a, 7.4b). Scanning in both planes is recommended, a short-axis/transverse-plane scout scan should always be performed first and is then followed by a long-axis/longitudinal scan. The clinician can then choose a scanning plane that provides the best view of the sternocleidomastoid, its depth, thickness and also structures to be avoided including the carotid and jugular vessels (Fig. 7.5). The sternocleidomastoid can be approached with either an in-plane or out-of-plane needle insertion. Injections are most often performed in the upper one-third or proximal portion of the muscle to reduce the risk of dysphagia (Truong et al., 1989).

Longus Colli and Capitis These muscles are located deep in the anterior cervical region (Figs 7.4b, 7.6a, 7.6b). With US guidance, Doppler imaging should be employed for visualization of the carotid and internal and external jugular veins (Fig. 7.6b). A novel lateral approach with contralateral head rotation can sometimes provide a better window between the neurovascular bundle anteriorly and the vertebral transverse processes posteriorly (Farrell et al., 2020). Depending on the dose, a single or multiple injections may be required. Because of their anatomical orientation and proximity, both muscles can be targeted/injected with one needle insertion, which is typically performed between levels C4 and C6. Selection of the level of injection directly in front of the anterior tubercle is preferable, as the boney structure (the tubercle) can stop the needle from damaging more posterior structures such as the nerve root or the vertebral artery.

Anterolateral Neck Muscles Scalene Complex Fig. 7.4 (a) B-mode ultrasound image of levator scapulae (long axis), trapezius (short axis).(b) Short-axis B-mode ultrasound image of longus colli and capitis at C5 level. (c) Short-axis B-mode ultrasound image, posterior neck muscles.

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The scalene muscles (anterior, middle, posterior) are located in the antero-lateral cervical region within the interscalene triangle, posterior and deep to the adjacent sternocleidomastoid Figs. 7.5, 7.7. When performing US-guided scalene injections,

Ultrasound-Guided Botulinum Neurotoxin Therapy: Cervical Dystonia

Fig. 7.5 Anatomical illustration of the sternocleidomastoid muscle and scalene muscles with US transducer position and orientation.

a short-axis/transverse view of the muscle provides the best view of the contour lines of these muscles, the fascial planes between the sternocleidomastoid, scalene muscles, vessels and nerves (Fig. 7.7). In the transverse view, the roots/trunks of the brachial plexus are easily distinguished as they descend through the neck, running between the anterior and middle scalene muscles (Fig. 7.7). Color Doppler imaging will confirm that these circular hypoechoic structures have no flow and are therefore nerves, not vessels (Fig. 7.7b). The phrenic nerve lies within the fascial plane between the sternocleidomastoid muscle (SCM) and the anterior scalene (Fig. 7.7c). US allows injectors to avoid “spearing” the phrenic neve during needle insertions into the anterior scalene.

Posterior Neck Muscles Levator Scapulae The levator scapulae can be approached either from an anterior location where it lies deep to the trapezius (Fig. 7.4a) or,

Fig. 7.6 (a) Anatomical illustration longus capitis and colli muscles. (b) Shortaxis, color Doppler US image, longus capitis and colli muscles at C6 level. AT: anterior tubercle, PT: posterior tubercle, SCM: sternocleidomastoid.

alternately, from the posterior region at its insertion on the scapula, where it again lies deep to the trapezius muscle (Figs. 7.8, 7.9a, 7.9b). It is often best to perform a preliminary scan using both an anterior and posterior approach to determine which technique provides the best view of and approach to the muscle. The authors typically use the anterior approach, especially for patients complaining of muscle pain in this region. Muscle atrophy, which may occur after repeated injections in any muscle, may make visualization of the levator scapulae

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Fig. 7.8 Anatomical illustration posterior cervical muscles. One transducer over the splenius capitis/cervices. Two transducers over the levator scapulae in long and short axes.

therefore, both muscles can be injected during the same needle insertion. When injecting the levator scapulae, it is preferable to identify a portion of the muscle that lies over a rib. This reduces the risk of inadvertent advancement of the needle through intercostal space and into the pleura and lung.

Splenius Capitis When using US guidance, the splenius capitis can be approached from the proximal anterolateral region at the level of the mastoid, just distal to its origin from the ligamentum flavum. At this level (i.e., the mastoid), the splenius capitis lies deep to and posterior to the sternocleidomastoid and deep to and anterior to the trapezius (Fig. 7.10). The splenius capitis/ cervices can also be approached posteriorly where it lies deep to the trapezius (Fig. 7.4c).

Trapezius Fig. 7.7 (a) Short-axis B-mode US image, interscalene triangle. (b) Short-axis color Doppler Image, interscalene triangle. (c) Short-axis B-mode image demonstrating relationship between phrenic nerve, SCM, and anterior scalene. AS: anterior scalene, BP: brachial plexus, UT: upper trunk, MT: middle trunk, LT: lower trunk, MS: middle scalene, SCM: sternocleidomastoid.

difficult, but the injections using the anterior approach may be less problematic due to the clearly defined fascial planes between the levator and overlying trapezius. The levator scapulae is adjacent/deep to the trapezius muscle using either an anterior or posterior approach (Figs. 7.4a, 7.9a, 7.9b);

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The trapezius is divided into descending (formally upper), transverse (formally middle) and ascending (formally lower) sections. For patients with CD, injections are generally directed to the descending and transverse regions. The trapezius is the most superficial muscle in the posterior upper back/neck and generally easy to target. The descending/upper cervical section of the trapezius is approached from either a longitudinal or a transverse direction (Fig. 7.4a,c). Lying deep to the trapezius in this region are the splenius capitis/cervices, semispinalis capitis and oblique capitis inferioris (Fig. 7.4c). The transverse or middle portion of the trapezius is often targeted, along with the levator scapulae (Fig. 7.4a) for patients with shoulder

Ultrasound-Guided Botulinum Neurotoxin Therapy: Cervical Dystonia

Fig. 7.9 (a) Short-axis B-mode US image, posterior approach levator scapulae. (b) Long-axis B-mode US image levator scapulae, posterior approach.

elevation or subjective reports of pain in this region of the muscle.

Splenius Capitis/Semispinalis Capitis/Obliquus Capitis Inferior As described above, the splenius capitis can be approached either at the level of the mastoid (Fig. 7.10a) or from a posterior direction, where it lies deep to the trapezius (Figs. 7.4c, 7.8, 7.10b). If approached at the C2 level, the splenius capitis, semispinalis capitis and obliquus capitis inferior can all be visualized with US imaging and can be injected using an outof-plane approach where the needle is inserted through the skin and into the three levels of muscles to be injected (Fig. 7.4c ).

Longissimus Capitis This muscle can be visualized by moving the transducer slightly lateral from the location described above for the

Fig. 7.10 (a) Short-axis B-mode image, splenius capitis at level of mastoid. (b) Short-axis B-mode image, posterior cervical approach splenius semispinalis muscles.

posterior approach to the splenius/semispinalis muscles. In the transverse axis, it appears oval or round and well defined in-between the lateral edge of the semispinalis and the splenius capitis (Fig. 7.11). It is a relatively thin muscle, and repeated injections can cause atrophy, making identification of the muscle more challenging.

Summary The use of US guidance has a number of advantages over other techniques, including increasing evidence that supports a higher accuracy for most US-guided procedures (Lee et al., 2009; Henzel et al., 2010: Hong et al., 2012). Additional studies are needed to evaluate whether this increased accuracy leads to improved treatment efficacy and reduced risk. US guidance

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Kassavetis, Farrell, Alter Fig. 7.11 Short-axis B-mode image, longissimus capitis, longissimus cervicis.

seems to be the way forward for guided BoNT injections. The time spent and the effort required to acquire this skill is offset by potential benefits to patients. Hands-on training at live courses, time spent with an experienced colleague and the use of reference materials can all help physicians to acquire the skills required for US-guided

References Alter KE (2010). High-frequency ultrasound guidance for neurotoxin injections. Phys Med Rehabil Clin N Am, 21, 607–30. Alter KE, Hallett M, Karp B (eds.) (2012). Ultrasound-Guided Chemodenervation Procedures: Text and Atlas. New York: Demos Medical, pp. 84–107. Alter KE, Karp BI (2017). Ultrasound guidance for botulinum neurotoxin chemodenervation procedures. Toxins (Basel), 10, 18. https://doi.org/10.3390/ toxins10010018 Comella CL, Jankovic J, Truong DD, Hanschmann A, Grafe S (2011). US. XEOMIN Cervical Dystonia Study Group. Efficacy and safety of incobotulinumtoxinA (NT 201, XEOMINVR, botulinum neurotoxin type A, without accessory proteins) in patients with cervical dystonia. J Neurol Sci, 308, 103–9. Costa J, Espírito-Santo C, Borges A et al. (2005). Botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev, 1, CD004315. Davidson J, Jayaraman S (2011). Guided interventions in musculoskeletal

BoNT procedures. The authors recommend that physicians begin to use US as an “add-on” technique to whatever guidance technique is currently used. This strategy allows the physician to achieve the repeated hands-on practice to acquire the skills needed for US imaging and procedural guidance.

ultrasound: what’s the evidence? Clin Radiol, 66, 140–52.

injections in cervical dystonia. Muscle Nerve, 46, 535–9.

Farrell M, Karp BI, Kassavetis P et al. (2020). Management of anterocapitis and anterocollis: a novel ultrasound guided approach combined with electromyography for botulinum toxin injection of longus colli and longus capitis. Toxins (Basel), 12(10), 626. https://doi.org/10.3390/ toxins12100626

Lee IH, Yoon YC, Sung DH, Kwon JW, Jung JY (2009). Initial experience with imaging-guided intramuscular botulinum toxin injection in patients with idiopathic cervical dystonia. AJR Am J Roentgenol, 192, 996–1001.

Glass GA, Ku S, Ostrema JL et al. (2009). Fluoroscopic, EMG-guided injection of botulinum toxin into the longus colli for the treatment of anterocollis. Parkinsonism Relat Disord, 15, 610–13. Hamper UM, Savader BL, Sheth S (1991). Improved needle-tip visualization by color Doppler sonography. AJR Am J Roentgenol, 156, 401–2. https://doi.org/ 10.2214/ajr.156.2.1898823 Henzel KM, Munin MC, Kiyonkuru C et al. (2010). Comparison of surface and ultrasound localization to identify forearm flexor muscles for botulinum toxin therapy. PM R, 2, 642–6. Hong JS, Sathe GG, Niyonkuru C et al. (2012). Elimination of dysphagia using ultrasound guidance for botulinum toxin

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Rodrigues FB, Duarte GS, Castelão M et al. (2021). Botulinum toxin type A versus anticholinergics for cervical dystonia. Cochrane Database Syst Rev, 4, CD004312. https://doi.org/10.1002/ 14651858.CD004312.pub3 Simpson DM, Blitzer A, Brashear A et al. (2008). Assessment: botulinum neurotoxin for the treatment of movement disorders (an evidencebased review). Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 70, 1699–706. Smith J, Finnoff JT (2009a). Diagnostic and interventional musculoskeletal ultrasound: part 1. Fundamentals. PM R, 1, 64–75. Smith J, Finnoff JT (2009b). Diagnostic and interventional musculoskeletal

Ultrasound-Guided Botulinum Neurotoxin Therapy: Cervical Dystonia ultrasound: part 2. Clinical applications. PM R, 1, 162–77. Truong D, Brodsky M, Lew M et al. (2010). Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia. Parkinsonism Relat Disord, 16, 316–23.

Truong D, Lewitt P, Cullis P (1989). Effects of different injection techniques in the treatment of torticollis with botulinum toxin. Neurology, 39(Suppl), 294. Walter U, Dudesek A, Fietzek UM (2018). A simplified

ultrasonography-guided approach for neurotoxin injection into the obliquus capitis inferior muscle in spasmodic torticollis. J Neural Transm (Vienna), 125, 1037–42. https://doi.org/10.1007/ s00702-018-1866-4

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Chapter

8

Treatment of Cervical Dystonia Deepmala Nandanwar, Mayank S. Pathak, Karen Frei and Daniel Truong

Introduction Cervical dystonia (CD) is an idiopathic focal dystonia characterized by abnormal head and neck posture caused by tonic involuntary contractions in a set of cervical muscles. First described by Foltz in 1959, the original term for the disorder, “spasmodic torticollis,” is now considered to be one of the four subtypes of CD. These four subtypes, based on the principal direction of posture, consist of: - Torticollis: Rotation of the head left or right in the transverse plane (Fig. 8.1a). - Lateralcollis: Head tilt toward left or right shoulder, in the coronal plane (Fig. 8.1b). - Anterocollis: Head tilt forward, with neck flexion in the sagittal plane (Fig. 8.1c). - Retrocollis: Head tilt backward, with neck extension, in the sagittal plane (Fig. 8.1d). In recent years, a more detailed analysis of head position relative to the neck has been promulgated, with more precise identification of the muscles involved in particular patterns of CD (Jost and Tatu, 2015). See Chapter 5 of this book for more detail. Cervical dystonia may start at any age, with a peak around 40 years, and is slightly more common in females, with a ratio of 1.7:1. The overall prevalence of CD varies widely among worldwide studies, ranging from 20–4100 cases/million (Defazio et al., 2013). Onset is usually insidious, progressing over 5 years, then stabilizing into a lifelong condition. Occasionally, onset is sudden. Remissions are uncommon, and symptoms often return after a period. Cervical dystonia may also spread to contiguous body parts such as the face or the arms, in which case it is considered a segmental dystonia. If involving noncontiguous parts, that is, neck and foot, it is termed “multifocal.” If involving a majority of the body, it is termed “generalized dystonia.” Characteristic traits of CD include transient relief of symptoms with a sensory trick, or “geste antagoniste,” such as placing the hand lightly on the cheek, or reclining against a headrest while driving, or a pillow while watching TV, thus inducing muscular relaxation and normalization of head posture. Dystonia symptoms may temporarily remit after waking from a night’s sleep, a phenomenon referred to as the “honeymoon” effect (Truong et al., 1989). Stress can exacerbate symptoms. Neck pain is present in about 70–80% of patients. The entire syndrome can cause disability.

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In the first half of the twentieth century, CD was thought to be of psychogenic origin; today, an organic basis for CD is well accepted. Heritable forms are known, such as the DYT7 locus on chromosome 18, which is autosomal dominant with incomplete penetration, and have variable and multifocal manifestations in different individuals. Other than primary idiopathic CD, the disorder may be a secondary condition, caused by neuroleptic medications, certain neurodegenerative diseases, or by trauma. Post-traumatic CD may occur following a relatively mild trauma, may begin within days of the event, often lacks response to a geste antagoniste, and tends to be resistant to treatment with botulinum neurotoxin (BoNT) (Frei et al., 2004). The clinical spectrum of CD is extremely variable: the 54 muscles involved in head and neck posture may show complex mixtures of involvement, unilateral or bilateral, with contractions of tonic, tremulous or myoclonic character. These contractions and movements can induce secondary tissue changes such as muscle hypertrophy, connective tissue fibrosis, contractures and facet joint or bone degeneration. Degenerative disk disease is accelerated in CD, further aggravating pain, causing radiculopathy or even myelopathy. Treatment of CD can consist of oral medications such as benztropine, trihexyphenidyl or benzodiazepines such as diazepam. All have limited utility due to side effects and modest efficacy, but may still be useful as adjunctive treatment in selected cases. Surgical treatment can consist of myectomy or selective peripheral denervation of principally involved muscles; however, adjacent muscles, or the remnants of treated muscles, may “take over” and continue to produce symptoms. Deep brain stimulation, with electrodes placed in the globus pallidus interna, is an efficacious treatment for generalized dystonia, and has been increasingly applied to cervical dystonia, with refinements in electrode placement and device programming. Currently, the most effective, and now first-line treatment of CD, has become intramuscular injection of botulinum toxin (Box 8.1).

Botulinum Neurotoxin Treatment of Cervical Dystonia Use of BoNT therapy is indicated in all forms of CD. Treatment with BoNT should be initiated as early as possible, since secondary changes to the muscles involved

Treatment of Cervical Dystonia

Fig. 8.1 Illustration of postural abnormalities in pure forms of cervical dystonia: (a) torticollis, (b) lateralcollis, (c) anterocollis, (d) retrocollis.

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Nandanwar, Pathak, Frei, Truong

Box 8.1 Management of Cervical Dystonia

Oral medications

Anticholinergics: Trihexyphenydyl, Benztropine GABAergics::Lorazepam, diazepam, baclofen

Cemodenervation

Level A: Rimabotulinum toxin Abobotulinum toxin

Surgery

Deep Brain Stimulation: GPi STN

VMAT2 inhibitors: Tetrabenazine, dutetrabenazine, velbenazine Others: Carbidopa-levodopa, gabapentine, levateraceitam, muscle relaxants (tizanidine,cyclobenzapril etc)

Level B: Onabotulinum toxin Incobotulinum toxin

(contractures) and of connective tissues, bones, joints and cervical discs may occur with long-standing CD. Both botulinum neurotoxin serotype A (BoNT-A, composed of the products onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA) and botulinum neurotoxin serotype B (BoNT-B, composed of rimabotulinumtoxinB), are used. In 1986, Tsui and colleagues published a double-blind, placebocontrolled trial with 21 patients (Tsui et al., 1986). Since then, several controlled trials have confirmed the efficacy of BoNT in CD.

OnabotulinumtoxinA (OnaBoNT-A) The positive results of OnaBoNT-A for the treatment of CD were evident as early as in the 1980s–1990s. The long-term data concerning OnaBONT-A are available with a recently published retrospective study from Germany. The study looked at 135 patients (2592 treatment sessions) treated with OnaBoNT-A for an observation period of up to 17 years. The mean total dose per treatment session was 138±51 mouse units (MU) with a mean increase dose of 124±54 MU, and the mean duration of effect was 10.4±8.7 weeks (Jochim et al., 2019).

AbobotulinumtoxinA (AboBoNT-A)

The first US double-blind, randomized, placebo-controlled, multicenter clinical trial was performed in 2005, reporting significant improvement (10-point vs. 3.8-point reduction in total score, respectively, at week 4) on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), with median duration of response being 18.4 weeks (Truong et al., 2005). Jochim et al. (2019) from Germany looked at the long-term safety and efficacy of AboBoNT-A along with OnaBoNT-A. They observed 209 patients (6660 treatment sessions) treated with AboBoNT-A for a period of up to 27 years. The mean total dose per treatment session was 663±249 MU with a mean

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Selective peripheral denervation (Bertrand procedure) Myectomy

increase dose 585±254 MU and the mean duration of effect was 10.6±9.6 weeks (Jochim et al., 2019).

IncobotulinumtoxinA (IncoBoNT-A) A double-blind, randomized, placebo-controlled, multicenter clinical trial in 2011 showed improvement (placebo = –2.2; IncoBoNT-A 120 U = –9.9; IncoBoNT-A 240 U = –10.9) from baseline to week 4 in TWSTRS total score in 233 patients (Comella et al., 2011).

RimabotulinumtoxinB (RimaBoNT-B) RimaBoNT-B is one of the earliest approved toxins for the treatment of CD by the US Food and Drug Administration (FDA), along with OnaBoNT-A. A 16-week, double-blind, placebo-controlled trial assessed the efficacy of RimaBoNT-B in type A-resistant patients of CD, and reported improvement in the TWSTRS total score at week 4, 8 and 12 (Brin et al., 1999). A 2016 review on RimaBoNT-B in treatment of CD included double-blind, parallel, randomized, placebocontrolled trials from 1977 to 2015 and found improvement in the TWSTRS total score of 6.8 points (Marques et al., 2016). Another post-marketing observational study from Japan included 122 patients who were previously treated with BoNT-A (patients who showed resistance to BoNT-A and patients who did not) and reported improvement on the TWSTRS scale by 5.6 points at 4 weeks (Kaji et al., 2021). All the above BoNT preparations are FDA approved for the treatment of CD. DoxybotulinumtoxinA is a longer-acting botulinum toxin preparation. FDA has accepted its application for treating cervical dystonia, but Doxibotulinumtoxin is not yet FDA-approved for the treatment of cervical dystonia in the US. Limited data are available to compare the head-to-head efficacy of FDA approved BoNT formulation with another. So far, there is no evidence to support the superiority of any one

Treatment of Cervical Dystonia

brand of BoNT (Botox, Xeomin, Dysport and Myobloc). A comparative study of BoNT-A and BoNT-B published in 2005 enrolled 139 patients (74 with BoNT-A and 65 with BoNT-B) and reported similar improvement in the TWSTRS score in both groups (Comella et al., 2005). A similar result was also reported by a randomized, double-blind, multicenter, non-inferiority, two-period crossover study, which was done for 18 months comparing AboBoNT-A and OnaBoNT-A (dosing 2.5:1). This study reported that AboBoNT-A was non-inferior to OnaBoNT-A on the Tusi Scale (4.0±3.9 points for the AboBoNT-A vs. 4.8±4.1 points for OnaBoNT-A; P = 0.091) (Yun et al., 2015).

Neck Muscles and Their Functions Figures 8.2 to 8.5 show the location of the muscles, which are described below.

Posterior Neck Muscles Superficial Group Splenius capitis. The splenius capitis originates in the spinal process of the body of C7 and the bodies of T1 to T3. It inserts into the mastoid process. This muscle turns and tilts the head ipsilaterally. Together, the two splenius capitis muscles extend the head backward (Fig. 8.2). Semispinalis capitis. The semispinalis capitis originates in the transverse processes of the T6 and C7, as well as the articular processes of C4–C6. It inserts between the superior and inferior nuchal lines of the occipital bone. The semispinalis capitis is often a cause of neck pain. Even through its main action is extension, restriction in this muscle can cause pain on rotation at the end of the range. It also rotates the head to the opposite side (Fig. 8.2).

Splenius cervicis. This muscle arises from the spinosus processes of T3–T6. It is inserted, by tendinous fasciculi, into the posterior tubercles of the transverse processes of C1 to C3. This muscle turns the head ipsilaterally. When both splenius cervicis are activated, they extend the head backward (Fig. 8.2). Trapezius. The trapezius originates from the occipital protuberance, the ligamentum nuchae and the processes spinosus and inserts into the lateral third of the clavicle. The trapezius turns the head and neck contralaterally. It also elevates the shoulder (Figs. 8.2, 8.5).

Deep Group Iliocostalis cervicis. The iliocostalis cervicis arises from the angles of the third, fourth, fifth and sixth ribs, and is inserted into the posterior tubercles of the transverse processes of C4–C6. The iliocostalis flexes the head laterally. When both iliocostalis cervicis are activated bilaterally, they extend the neck dorsally (Fig. 8.3). Interspinalis cervicis. These muscles lie between the spinosus processes of the cervical vertebrae. They assist in dorsal extension (Fig. 8.3). Multifidi. The multifidus muscle fills up the groove on each side of the spinous processes of the vertebrae. It arises, in the cervical region, from the articular processes of the lower four vertebrae and inserts into the spinous process of one of the vertebrae above. It rotates the neck contralaterally. When both multifidus are activated, they extend the neck (Fig. 8.3). Obliquus capitis inferior. This muscle arises from the spinous process of the axis and inserts into the inferior and dorsal part of the transverse process of the atlas. It rotates the head and the first cervical vertebra ipsilaterally (Fig. 8.3). Fig. 8.2 The posterior neck muscles, superficial and intermediate groups, often involved in retrocollis.

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Nandanwar, Pathak, Frei, Truong Fig. 8.3 The posterior neck muscles, deep group, involved in retrocollis, best injected using guidance techniques such as ultrasound or electromyography (EMG).

Obliquus capitis superior. The oblique capitis superior originates in the atlas mass, inserting into the lateral half of the inferior nuchal line of the occipital bone. At the atlantooccipital joint, it extends and flexes the head ipsilaterally (Fig. 8.3). Rectus capitis posterior major. This muscle arises from the spinous process of the axis, ascending into the lateral part of the inferior nuchal line of the occipital bone. As the two muscles of the two rectus capitis posterior major pass upward and laterally, they create a triangular space occupied by the recti capitis posteriores minores. The rectus capitis posterior major extends the head and rotates it to the same side (Fig. 8.3). Rectus capitis posterior minor. This is a muscle of triangular form arising from the posterior arch of the atlas and

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inserting into the medial part of the occipital bone at, and below, the nuchal line. It extends the head (Fig. 8.3). Rotatores cervicis. The rotatores cervicis arises from the transverse spinosus process and inserts into the above vertebrae, extending the neck and assisting in contralateral rotation (Fig. 8.3). Semispinalis cervicis. This muscle arises from the transverse processes of the upper five or six thoracic vertebræ. It inserts into the spinous processes of C2–C5. The semispinalis tilts the head to the same side and rotates the head to the contralateral side. Working together, the two semispinalis cervicis extend the head backward. The semispinalis capitis and cervicis and longissimus capitis are commonly overused because of their role in supporting the head when leaning forward. They are often involved in headache pain (Fig. 8.3).

Treatment of Cervical Dystonia Fig. 8.4 The anterior juxta-vertebral muscles of the neck. The longus colli muscle is sometimes injected in anterocollis. Guidance techniques such as ultrasound or EMG recommended.

Levator scapulae. The levator scapulae arises from the transverse processes of C1–C4 and inserts into the medial border of the scapula. This muscle elevates the medial border of the scapula while rotating the lateral angle downward. Together with the rhomboid and trapezius muscles, it pulls the scapula upward and medially, as well as tilts the neck ipsilaterally (Figs. 8.2, 8.5). Longissimus cervicis. The longissimus cervicis is located laterally to the semispinalis. It is the longest subdivision of the sacrospinalis and extends forward into the transverse processes of the posterior cervical vertebrae. Arising from long, thin tendons at the transverse processes of the upper four or five thoracic vertebræ, it is inserted into the posterior tubercles of the transverse processes of the C2–C6. It tilts the head ipsilaterally. When the longissimus cervicis muscles are activated bilaterally, they extend the neck dorsally (Fig. 8.3). Longissimus capitis. Longissimus capitis arises from the posterior surface of the transverse process of T1–T5 and the

articular tubercle of C4–C7 and inserted in posterior margin of mastoid and temporal bone. It extends the head and neck with bilateral contraction and causes lateral flexion and rotation of neck with unilateral contraction.

Anterior Neck Muscles Longus capitis. The longus capitis arises by four tendinous slips from the anterior tubercles of the transverse processes of C3–C6 and ascends, converging toward its fellow of the opposite side, to be inserted into the inferior surface of the basilar part of the occipital bone (Fig. 8.4). Longus colli. The longus colli originates from the lower anterior vertebral bodies and transverse processes and inserts into the anterior vertebral bodies and transverse processes several segments above, flexing the head (Fig. 8.4). Rectus capitis anterior. The rectus capitis anterior is a small muscle originating in the anterior base of the transverse

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Nandanwar, Pathak, Frei, Truong Fig. 8.5 Lateral neck muscles, involved in lateralcollis and torticollis.

process of the atlas and inserting into the occipital bone anterior to the foramen magnum, flexing the head. Furthermore, the rectus capitis anterior stabilizes the atlanto-occipital joint (Fig. 8.4). Rectus capitis lateralis. The rectus capitis lateralis originates in the transverse process of the atlas and inserts into the jugular process of the occipital bone. It tilts the head laterally (Fig. 8.4).

Lateral Neck Muscles Scalene anterior. The scalene muscles are lateral vertebral muscles that begin at the first and second ribs and pass up into the sides of the neck. There are three of these muscles. The anterior scalene originates in the anterior tubercles of

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the transverse processes of C3–C6 and inserts into the first rib. It elevates the ribs for respiration and weakly rotates the head to the opposite side. When both anterior scalene muscles contract, they flex the head forward (Fig. 8.5). Scalene medius. The middle scalene arises from the transverse processes of all cervical vertebrae and inserts into the first rib (behind the anterior scalene). It bends the neck to the same side and also can flex the neck as it lies anterior to the axis (Fig. 8.5). Scalene posterior. This muscle arises from the posterior tubercles of the transverse processes of C5 and C6 cervical vertebrae and inserts into the second and/or third rib. The action of the posterior scalene is to elevate the second rib and tilt the neck to the same side (Fig. 8.5).

Treatment of Cervical Dystonia Table 8.1 Muscles anatomically involved and muscles commonly injected in torticollisa

Table 8.2 Muscles anatomically involved and muscles commonly injected in laterocollis

Muscle name

Ipsilateral

Treated muscles

Muscle name

Ipsilateral

Splenius capitis and cervicis

X

X

Sternocleidomastoid

X

X

Trapezius

X

X

Levator scapulae

X

X

X

X

X

Scalene medius and posterior

X

Longissimus capitis and cervicis

Splenius capitis and cervicis

X

X

Longissimus cervicis and capitis

X

X

Multifidi

X

Intertransversarii cervicis

X

Contralateral

Multifidi

X

Rotatores cervicis

X

Sternocleidomastoid

X

X

Trapezius (horizontal part)

X

X

Semispinalis capitis and cervicis

X

a

X

The cervicis turns the head contralaterally; the semispinalis has weak effect on turning the head contralaterally and only in the upper part (C1–C3).

Sternocleidomastoid. This muscle originates on the mastoid processes and inserts in two areas, one on the sternum and the other on the clavicle, hence the name “sternocleidomastoid.” It turns the head to the opposite side and the chin upward to the opposite side. It also tilts the head to the same side (Fig. 8.5). Intertransversarii cervicis. These muscles are arranged in pairs, passing between the anterior and the posterior tubercles, respectively, to the transverse processes of two contiguous vertebrae. The anterior primary division of the cervical nerve separates the intertransversarii anteriores cervicis muscle from the posterior intertransversarii. They assist in the lateral and the dorsal flexion of the neck (Fig. 8.5).

Muscles Involved in Different Subtypes of Cervical Dystonia Based on the presentation of the head position (Fig. 8.1a,b,c,d), different muscles are involved. The anatomical location, however, limits the muscles that can be treated. Tables 8.1 to 8.4 list the muscles that are anatomically involved and that are actually injected in torticollis (Table 8.1), laterocollis (Table 8.2), anterocollis (Table 8.3) and retrocollis (Table 8.4).

Botulinum Neurotoxin Injection Techniques

The first step in injection is identification of the principal set of muscles responsible for the head and neck deviation, using observation, palpation, a knowledge of the anatomy and vector of each muscle’s contribution, and ancillary tests such as multichannel electromyography (EMG) and/or ultrasound (US). During examination, patients should be instructed not to fight the torticollis, but allow the head to deviate, avoid using sensory tricks (geste antagoniste), and report pain severity. They should perform slow head movements in all common directions

Contralateral

Treated muscles

Table 8.3 Muscles anatomically involved and muscles commonly injected in antecollis

Muscle name

Ipsilateral

Contralateral

Treated muscles

Sternocleidomastoid

X

X

X

Scalene anterior and medius

X

X

X

Longus colli

X

X

X

Longus capitis

X

X

Infrahyoidal muscle

X

X

Rectus capitis anterior

X

X

to look for the null point. Patients may report ease of rotating the head and neck toward the pull of dystonic muscles. Head posture should be evaluated with the patient standing, walking slowly and lying down. In a seated position, the patient should be asked to demonstrate their favorite sensory trick (e.g., touching the chin with the hand). Patients should be asked to hold their head in a neutral position, using compensatory antagonist muscles, for as long as possible. Finally, palpation of the hypertrophied dystonic muscles helps identify them. Testing agonist–antagonist pairs of muscles with multichannel EMG, especially if they produce a reciprocating pattern of EMG bursts, can be used to map active target muscles and formulate an injection plan for at least the first treatment, and can help modify the plan for subsequent treatments. Recommended total doses for the four products on the US market are given in Table 8.5. The total dose is divided into various portions, which are injected into individual dystonic muscles. Table 8.6 summarizes established dose ranges for the most important head and neck muscles. There is no accepted

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Nandanwar, Pathak, Frei, Truong Table 8.4 Muscles anatomically involved and muscles commonly injected in retrocollis

Muscle name

Ipsilateral

Contralateral

Treated muscles

Levator scapulae

X

X

X

Splenius capitis and cervicis

X

X

X

Longissimus capitis and cervicis

X

X

X

Semispinalis capitis and cervicis

X

X

X

Iliocostalis cervicis

X

X

Spinalis capitis and cervicis

X

X

Rectus capitis posterior major and minor

X

X

Rotatores cervicis

X

X

Interspinalis cervicis

X

X

Intertransversarii cervicis

X

X

standard ratio among the four BoNT products, although some clinicians have used the following approximate ratios: (Botox:Xeomin:Dysport:MyoBloc/NeuroBloc as 1:1:3:50). In general, lower doses are used for the initial round of injections, when the individual’s sensitivity and response to BoNT are not yet established. Based on effects and side effects, adjustments in target muscles and dosing are then made for subsequent rounds of injection. Typically, the dose of BoNT for individual muscle depends on the muscle mass, so patients with small necks usually require smaller doses and patients with larger necks or an athletic physique may require higher doses. Doses should be reduced if the same muscle is being injected bilaterally, to avoid side effects such as dysphagia with anterior muscles and neck weakness and head droop with posterior muscles. The number of injection sites within a muscle ranges from one site in smaller muscles to eight sites in larger muscles. Multiple injection sites with smaller doses might also limit diffusion and reduce side effects. This is particularly relevant in the anterior and lateral neck, where excessive spread results in dysphagia. It is important to document the injected muscles as well as the dosage given. The official recommendation from the manufacturers is to reconstitute 100 U OnaBoNT-A or 500 U AboBoNT-A in 1 ml

Table 8.5 Recommendations for total doses (units) in pure torticollis, laterocollis or combined form based on cervical dystonia severity measured by the Tsui Score

Score

OnabotulinumtoxinA

IncobotulinumtoxinA

AbobotulinumtoxinA

RimabotulinumtoxinB

12–15

200–300

200–300

700–1000

10 000

9–12

150–200

150–200

500–700

7500–10 000

6–9

100–150

100–150

300–500

5000–7500

3–6

80–120

80–120

320–400

4000–6000

Table 8.6 Recommended doses for individual muscles involved in cervical dystoniaa

Muscle

OnabotulinumtoxinA (U)

IncobotulinumtoxinA (U)

AbobotulinumtoxinA (U)

RimabotulinumtoxinB (U)

Sternocleidomastoid

20–50

20–50

100–200

1000–2500

Infrahyoid muscles

10–15

10–15

40–60

750–1000

Scalenus anterior

10–20

10–20

40–80

1000–1500

Scalenus medius

10–20

10–20

40–80

1000–1500

Scalenus posterior

10–50

10–50

40–80

1000–2500

Levator scapulae

10–50

10–50

40–100

1250–2500

Trapezius (upper portion)

50–75

50–75

80–200

2500–4000

Splenius capitis

50–100

50–100

200–300

2500–5000

Semispinalis capitis

15–30

15–30

60–120

1000–1500

a

In bilateral injections of some muscles, dose reduction is necessary (see text).

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Treatment of Cervical Dystonia

or 2.5 ml unpreserved NaCl solution, respectively. IncoBoNTA 100 U is usually dissolved in 1 ml NaCl solution. RimaBoNT-B does not require reconstitution and is already in a solution of 5000 U/ml. Systematic studies dealing with any differences in effectiveness at various concentrations of OnaBoNT-A and AboBoNT-A are not available for treatment of CD; however, it is the experience of the authors that use of solutions of 400 U/ml AboBoNT-A and 100 U/ml OnaBoNTA may decrease the prevalence of side effects. This observation may reflect less pronounced diffusion of the BoNT injected at lower volumes, particularly for injections into the sternocleidomastoid muscle. Injections are normally carried out with a 3–5 ml syringe and a 27-gauge hypodermic needle. Guidance techniques should be employed for all muscles if the injector is inexperienced, and for smaller or deeper muscles in all cases. Single-channel EMG, with the BoNT delivered via a cannulized Teflon-coated monopolar hypodermic needle attached to an EMG machine, is an excellent guidance technique and can be easily enhanced by asking the patient to activate the target muscle during needle insertion. Ultrasound helps identify target muscles during injections, particularly deeper muscles, and helps avoid adjacent vital neurovascular structures. The limitations of US are that it usually requires assistance to hold the probe while injecting, and it is difficult to ascertain the involved muscles unless contracting or hypertrophied. Ultrasound guidance for CD is discussed in detail in Chapter 7.

Practical Considerations for Treatment of Cervical Dystonia with Botulinum Neurotoxin The physiological effect of BoNT begins 3 to 12 days after an injection and is sustained for approximately 3 months. Patients should be reexamined periodically over the course of repeated treatments. Muscle hypertrophy and involved muscle patterns may change over time, necessitating the alteration of injection sites or doses. EMG or US can assist in modifying injection pattern when this occurs. To reduce the risk of developing toxin resistance, a 3month or longer interval between injections is recommended. This is thought to reduce the formation of antibodies to BoNT. At follow-up, clinical rating should be repeated, and the actual scores compared with those prior to and 4 weeks after the last injection. Some patients will return prior to the wearing off of the BoNT, making it difficult to localize the muscles for reinjection because they are still denervated. If possible, these patients should be discouraged from receiving a repeat injection at that time and be rescheduled for injection 2–4 weeks later when symptoms begin to appear.

References Brin MF, Lew MF, Adler CH et al. (1999). Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology, 53, 1431–8. https://doi.org/10.1212/wnl.53.7.1431

Video recording is recommended for documentation and for comparison after treatment. Common CD rating scales include the TWSTRS and the Tsui Scale. Such rating scales are recommended not only for clinical trials but also for routine evaluation of CD and of BoNT treatment. Failure of treatment or worsening of CD while being treated with BoNT could reflect resistance to BoNT or an actual increase in severity – but often, the wrong muscles have been injected. Prior to sternocleidomastoid muscle injections, the patient should be asked to tonically activate the muscle by rotating their head against a hand placed at the opposite side of the chin, making the muscle bulge prominently. The accuracy of injection sites can be improved by the physician’s firmly gripping around and behind the muscle with their fingers, particularly in patients with obese necks. Limiting injections to two sites, both in the upper third of the sternocleidomastoid reduces the incidence of dysphagia (Truong et al., 1989). Injections into the lateral neck muscles are best performed when the head is in a straight, neutral position. Trapezius injections can be facilitated by having the patient elevate their shoulders. During injections into the hyoid muscles, the head is extended backward. Side effects of BoNT include hypersensitivity reactions, injection site infections, injection site bleeding or bruising, dry mouth, dysphagia, upper respiratory infection, neck pain and headache. With bilateral posterior neck injections, neck weakness may occur, manifested by a feeling of instability when leaning forward or backward, and is often associated with pain. Dysphagia is associated with injections into the sternocleidomastoid and infrahyoidal muscles, especially with bilateral injections, and is likely caused by local diffusion of the BoNT, inducing weakness of adjacent muscles. Thus, dose per muscle should be cut by 50–60%, at least for first-time treatment, if the same set of muscles is being injected bilaterally. Although BoNT is the first line of treatment for CD, usually one-third of patients discontinue the therapy. A review published in 2017, which summarized longitudinal CD studies, reported the most common reason for patients to stop the BoNT treatment is lack of response, the other reasons being high cost, the need for repeated injections, side effects and others (Jinnah et al., 2018). Thus, it is important to counsel the patient that modifications to the injection plan on subsequent treatment sessions can maximize benefits and reduce side effects. Efforts are also being made to address the issue of frequent reinjection. In this line, a recent phase II, open-label, doseescalation study of daxibotulinumtoxinA evaluated the median duration response (defined as 20% improvement in the TWSTRS total score) was 25.3 weeks (Jankovic et al., 2018). DaxibotulinumtoxinA is currently under phase III study.

Comella CL, Jankovic J, Shannon KM et al. (2005). Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology, 65, 1423–9. https://doi.org/10.1212/01.wnl .0000183055.81056.5c

Comella, CL, Jankovic J, Truong DD, Hanschmann A, Grafe, S (2011). Efficacy and safety of incobotulinumtoxinA (NT 201, XEOMIN®, botulinum neurotoxin type A, without accessory proteins) in patients with cervical dystonia. J Neurol

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Nandanwar, Pathak, Frei, Truong .org/https://doi.org/10.1016/j.toxicon .2017.09.004

Rev, 5, CD0043155. https://doi.org/10 .1002/14651858.CD004315.pub3

Defazio G, Jankovic J, Giel JL, Papapetropoulos S (2013). Descriptive epidemiology of cervical dystonia. Tremor Other Hyperkinet Mov (N Y), 3, tre-03-193-4374-2. https://doi.org/10 .7916/D80C4TGJ

Jochim A, Meindl T, Mantel T et al. (2019). Treatment of cervical dystonia with aboand onabotulinumtoxinA: long-term safety and efficacy in daily clinical practice. J Neurol, 266, 1879–86. https:// doi.org/10.1007/s00415–019-09349-2

Frei KP, Pathak M, Jenkins S, Truong DD (2004). Natural history of posttraumatic cervical dystonia. Mov Disord, 19, 1492–8. https://doi.org/10.1002/mds .20239

Jost WH, Tatu L (2015). Selection of muscles for botulinum toxin injections in cervical dystonia. Mov Disord Clini Pract, 2, 224–6. https://doi.org/10.1002/mdc3.12172

Truong D, Duane DD, Jankovic J et al. (2005). Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, double-blind, placebocontrolled study. Mov Disord, 20, 783–91. https://doi.org/10.1002/mds.20403

Sci, 308, 103–9. https://doi.org/https://doi .org/10.1016/j.jns.2011.05.041

Jankovic J, Truong D, Patel AT et al. (2018). Injectable daxibotulinumtoxinA in cervical dystonia: a phase 2 doseescalation multicenter study. Mov Disord Clin Pract, 5, 273–82. https://doi.org/10 .1002/mdc3.12613 Jinnah, HA, Comella CL, Perlmutter J, Lungu C, Hallett M (2018). Longitudinal studies of botulinum toxin in cervical dystonia: why do patients discontinue therapy? Toxicon, 147, 89–95. https://doi

Kaji R, Endo A, Sugawara M, Ishii M (2021). Efficacy of botulinum toxin type B (rimabotulinumtoxinB) in patients with cervical dystonia previously treated with botulinum toxin type A: a postmarketing observational study in Japan. E Neurological Sci, 100374. https://doi .org/https://doi.org/10.1016/j.ensci.2021 .100374 Marques RE, Duarte GS, Rodrigues FB et al. (2016). Botulinum toxin type B for cervical dystonia. Cochrane Database Syst

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Truong D, Lewitt P, Cullis P (1989). Effects of different injection techniques in the treatment of torticollis with botulinum toxin. Neurology, 39(Suppl), 294. Tsui JK, Eisen A, Stoessl AJ, Calne S, Calne DB (1986). Double-blind study of botulinum toxin in spasmodic torticollis. Lancet, 2, 245–7. https://doi.org/10.1016/ s0140–6736(86)92070-2 Yun JY, Kim JW, Kim H-T et al. (2015). Dysport and Botox at a ratio of 2.5:1 units in cervical dystonia: a double-blind, randomized study. Mov Disord, 30, 206–13. https://doi.org/10.1002/mds .26085

Chapter

9

Treatment of Blepharospasm Luca Marsili, Matteo Bologna and Carlo Colosimo

Main Clinical and Pathophysiological Features Blepharospasm is the most frequent cranial dystonia and consists of involuntary, symmetric, tonic or clonic bilateral contractions of the orbicularis oculi muscle (Hallett, 2002). Blepharospasm can be primary (idiopathic), secondary or psychogenic. A genetic component can be assumed for primary blepharospasm, given that a family history of dystonia is not infrequently found. However, to date, no specific genes have been found in association with isolated primary blepharospasm. However, several genetic variants have been described within the context of more complex phenotypes (Defazio et al., 2017). Primary blepharospasm is an adult-onset focal dystonia, manifesting with forceful eyelid closures. Rarely, blepharospasm is secondary to structural brain lesions, drug-induced or other neurodegenerative conditions like atypical parkinsonism. Contractions of the orbicularis oculi muscle may be accompanied by contractions of the procerus and corrugator supercilii muscles and lower facial and masticatory muscles. The combination of blepharospasm and oromandibular dystonia may be called Meige syndrome (Owecki et al., 2017). Contractions of the orbicularis oculi muscle may also be accompanied by an inhibition of the levator palpebrae muscle, a phenomenon called apraxia of eyelid opening. Blepharospasm’s severity may range from increased blinking frequency (only causing minor discomfort) to a persistent and forceful eyelid closure, leading to functional blindness (Fig. 9.1).

Neurophysiological and neuroimaging studies have contributed to a better understanding of blepharospasm’s pathophysiology. In particular, the loss of inhibition at the cortical and brainstem level together with the abnormalities of sensory processing seem the most important dysfunctions in blepharospasm (Defazio et al., 2017; Mascia et al., 2020). Traditionally, all these findings have been related to a primary basal ganglia disorder. More recently, blepharospasm – as other forms of dystonia – was interpreted as a more complex network disorder (Mascia et al., 2020).

Topographical Anatomy and Function of Periocular Muscles The orbicularis oculi muscle is the most frequently involved muscle in blepharospasm, due to its function of closing the eyelids. The orbicularis oculi arises from the nasal part of the frontal bone, from the frontal process of the maxilla in front of the lacrimal sulcus and from the anterior surface and borders of the medial palpebral ligament. It consists of three components: the orbital, the preseptal and the pretarsal (Fig. 9.2). The orbital component originates in the orbit (medial orbital part) and goes around the eye through the upper eye cover fold and lid, thus reaching the lower eyelid to the palpebral ligament. The preseptal or palpebral component originates in the palpebral ligament and routes above and below the eye inserting in its lateral angle. The orbital and the preseptal muscles form

Fig. 9.1 Severe blepharospasm causing persistent and forceful eyelid closure, thus leading to functional blindness.

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Marsili, Bologna, Colosimo Fig. 9.2 Schematic representation of the three components of the orbicularis oculi muscle.

concentric rings around the eye. The pretarsal component lies on the palpebral margin. Other muscles involved in blepharospasm are the corrugator supercilii, the procerus and the frontalis muscles (Marur et al., 2014) (Fig. 9.2). The corrugator supercilii muscle pulls the eyebrows and the skin from the midpoint of each eyebrow to its internal corner medially and downward (eyebrows adduction). It arises from the orbit (inner part, near the root of the nose) and inserts into the skin of the forehead beyond the centre of each eyebrow. The procerus muscle pulls down the skin of the center of the forehead, forming horizontal wrinkles in the glabella and bridge of the nose regions, usually acting in conjunction with the corrugator supercilii or orbicularis oculi or both. Its function is to assist in flaring the

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nostrils. It originates in the nasal fascia and upper nasal cartilage, running through the root of the nose, and spreads upward to insert in the skin in the middle part of the forehead between the two eyebrows. The frontalis muscle elevates the eyebrows. It is a thin quadrangular muscle adhering to the superficial fascia. This muscle passes through and inserts into the orbicularis oculi’s bundles on the superior border of the eyebrow and the medial parts of the upper eyelid. Finally, the frontalis muscle joins the orbicularis oculi muscle (Marur et al., 2014).

Treatment with Botulinum Neurotoxin Botulinum neurotoxin (BoNT) is considered the first-line treatment for blepharospasm and has been used for more than

Treatment of Blepharospasm

30 years. Several large safety studies and systematic reviews of the literature have shown efficacy and no noteworthy longterm side effects of BoNT (Marsili et al., 2021). The two main available BoNT serotypes are BoNT type A (BoNT-A) and type B (BoNT-B). As per the American Academy of Neurology guidelines, levels of evidence of BoNT for blepharospasm are the following: onabotulinumtoxinA (ONA) and incobotulinumtoxinA (INCO): Level B (probably effective), abobotulinumtoxinA (ABO): Level C (possibly effective), rimabotulinumtoxinB (RIMA): Level U (insufficient evidence) (Simpson et al., 2016). Missing Level A (intervention should be offered) is only caused by lack of Class I studies (Simpson et al., 2016). Before proceeding with BoNT treatment, some important aspects need to be taken into account, namely, the assessment and quantification of the severity of eyelid muscles spasms and increased blinking, the presence of sensory tricks or of apraxia of eyelid opening and the topographical distribution of muscle spasms (Colosimo et al., 2015). Other causes of eyelid closure different from blepharospasm should be ruled out (e.g., hemifacial spasm, tics, facial chorea, eyelid ptosis due to muscle weakness) (Colosimo et al., 2015). Treatment of blepharospasm with BoNT is usually straightforward. Typically, four injections are administered in the orbital or preseptal portion of the orbicularis oculi muscle, but the number of injections can be increased to include the lateral canthus too (Fig. 9.3a). Alternately, BoNT can be injected into the pretarsal component of the orbicularis oculi (Fig. 9.3b). It is believed that pretarsal BoNT-A injections achieve an increased response rate and a longer-lasting response. The injections into the pretarsal component are generally more painful but have the advantage of causing fewer side effects. BoNT injections into the pretarsal component of the orbicularis oculi are considered the most effective strategy for treating involuntary

eyelid closure caused by the muscle contraction as well as for treating apraxia of eyelid opening. As already mentioned, BoNT-A is more effective than BoNT-B in the treatment of blepharospasm. Different brands of BoNT-A produce identical results. Approximate dose ratios are 1:4 for ONA and ABO and 1:1 for ONA and INCO. In general, the total dose (both eyes) of BoNT-A injected per each session ranges from 25 to 50 mouse units (MU) of ONA or INCO or from 100 to 240 MU of ABO. In selected patients with insufficient response to standard treatment, ONA doses may be raised 100 MU (or equivalent doses of other compounds). BoNT injections consist of a chronic cyclic therapy. The mean interval between treatments is 3 to 4 months with less variability than in other dystonia manifestations. The corrugator supercilii, procerus and frontalis muscles may additionally be injected. Recommended doses are 2.5 to 5 MU of ONA/INCO or to 15 MU of ABO for the corrugator supercilii muscle, 2.5 to 5 MU of ONA/INCO or 5 to 7.5 MU ABO for the procerus muscle and 15 MU of ONA/INCO or 40 MU ABO for the frontalis muscle (Table 9.1). See Fig. 9.2 for locations of these muscles. One hundred mouse units of ONA or INCO are diluted with 2–4 ml of normal saline, resulting in a concentration of 25–50 MU/ml. Five hundred mouse units of ABO are diluted with 1.5–2.5 ml of normal saline, producing a concentration of 200–333 MU/ml. The concentration can be adapted, if needed. To date, only a few studies have explored in depth the utilization of BoNT-A for the treatment of blepharospasm (Ramirez-Castaneda and Jankovic, 2013). Results from open-label studies advocate that BoNT-A is highly effective and safe, providing improvement in up to 90–95% of blepharospasm cases with only limited side effects (RamirezCastaneda and Jankovic, 2013). No sufficient data are available on BoNT-B and on other less common BoNT serotypes

Fig. 9.3 Injection sites for the orbicularis oculi muscle. (a) The preseptal portion of the orbicularis oculi muscle is typically injected at four sites, but an additional site can include the lateral canthus. (b) Alternately, BoNT can be injected into the pretarsal component of the orbicularis oculi (Fig. 9.3b).

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Marsili, Bologna, Colosimo Table 9.1 Suggested botulinum neurotoxin doses for cranial muscles in blepharospasm and outcome level of evidence

Muscle

Action

ONA dose (MU)

ABO dose (MU)

INCO dose (MU)

Orbicularis oculi

Closes eyelids

25–50

100–240

25–50

Corrugator supercilii

Adduction of eyebrows

2.5–5

10–15

2.5–5

Procerus

Nasal root folds and wrinkles

2.5–5

5–7.5

2.5–5

Frontalis

Elevates eyebrows

15

40

15

Level of Evidence

-

B

C

B

MU = mouse units; B = Probably effective; C = Possibly effective; ONA = onabotulinumtoxinA; ABO = abobotulinumtoxinA; INCO = incobotulinumtoxinA.

Table 9.2 Botulinum neurotoxin–related main adverse events in blepharospasm

Type of adverse event

Related frequency (% range, according to different studies)

Dry eye

70%

Ptosis

22–70%

Strabismus

Less than 20%

Hematoma

Less than 20%

Diplopia

Less than 20%

Data mainly refer to onabotulinumtoxinA and abobotulinumtoxinA. Other, less common adverse events are not listed in the table. For further details, see the text.

(B, C and F) on treatment of blepharospasm. Side effects of BoNT include dry eyes, diplopia, ptosis, strabismus,

References Colosimo C, Bologna M, Berardelli, A (2015). How do I examine blepharospasm? Mov Disord Clin Pract, 2, 449. Colosimo C, Tiple D, Berardelli A (2012). Efficacy and safety of long-term botulinum toxin treatment in craniocervical dystonia: a systematic review. Neurotox Res, 22, 265–73. Defazio G, Hallett M, Jinnah HA, Conte A, Berardelli A (2017). Blepharospasm 40 years later. Mov Disord, 32, 498–509. Duarte GS, Rodrigues FB, Marques RE et al. (2020). Botulinum toxin type A therapy

hematoma, watering eyes, lid edema, keratitis, entropion/ ectropion, pain and facial weakness (Table 9.2). A recent Cochrane meta-analysis examined the results of all double blind, parallel, randomized, placebo-controlled trials (RCTs) of BoNT-A versus placebo in blepharospasm and concluded that a single BoNT-A treatment results in a significant improvement of blepharospasm-related symptoms, reducing its severity and disability, with less evidence on its tolerability when compared with placebo (Duarte et al., 2020). Unlike cervical dystonia, the effectiveness and safety of long-term treatments of BoNT-A injections in blepharospasm have not been investigated in detail (Marsili et al., 2021). Hence, it is not possible to draw clear and definitive conclusions on the recommended intervals and doses or on their related impact on patients’ everyday life. BoNT-A efficacy and safety profile remains largely unchanged in systematic review of the literature after several years of use (Colosimo et al., 2012).

for blepharospasm. Cochrane Database Syst Rev, 11, CD004900. Hallett M (2002). Blepharospasm: recent advances. Neurology, 59, 1306–12. Marsili L, Bologna M, Jankovic J, Colosimo C (2021). Long-term efficacy and safety of botulinum toxin treatment for cervical dystonia: a critical reappraisal. Expert Opin Drug Saf, 20, 695–705. Marur T, Tuna Y, Demirci S (2014). Facial anatomy. Clin Dermatol, 32, 14–23. Mascia MM, Dagostino S, Defazio G (2020). Does the network model fits neurophysiological abnormalities in blepharospasm? Neurol Sci, 4, 2067–79.

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Owecki, MK, Bogusz H, Magowska A (2017). Henri Meige (1866–1940). J Neurol, 264, 2348–50. Ramirez-Castaneda J, Jankovic J (2013). Long-term efficacy and safety of botulinum toxin injections in dystonia. Toxins (Basel), 5, 249–66. Simpson DM, Hallett M, Ashman EJ et al. (2016). Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 86, 1818–26.

Chapter

10

Botulinum Neurotoxin in Oromandibular Dystonia Roongroj Bhidayasiri, Suppata Maytharakcheep and Daniel Truong

Introduction Oromandibular dystonia (OMD) is a form of focal dystonia that involves the masticatory, lower facial, labial, and lingual musculature affected by the trigeminal, facial, and hypoglossal cranial nerves. The term “cranial dystonia” is used when OMD occurs in association with blepharospasm, and is often referred as Meige’s syndrome (Bhidayasiri et al., 2006).

Epidemiology, Clinical Features and Etiologies There is a wide variability in the prevalence estimates of OMD, influenced by race and ethnicity, but overall, OMD is estimated to affect approximately 70 per million people, frequently affecting women more than men (2:1) (Bhidayasiri et al., 2006). Age appears to be an independent risk factor for OMD, with the mean age at onset between 50 and 60 years. OMD can be classified into various subtypes, which include jaw-opening, jaw-closing, jaw-deviating, lingual, perioral and/ or pharyngeal dystonia, to delineate muscle involvement for botulinum toxin (BoNT) injection therapy. Jaw-closing and jaw-opening OMD are among the two most frequent subtypes, with a mixed pattern identified in one-third of patients; jaw deviation is probably the least prevalent (Gonzalez-Alegre et al., 2014). Common symptoms experienced by OMD patients result from abnormal contractions of these muscles, resulting in involuntary biting of the tongue, cheek, or lips and difficulty with speaking and chewing. Its appearance is often socially embarrassing and disfiguring, and may be triggered by mandibular activities such as talking, yawning, chewing or swallowing. In patients with jaw-closing OMD, dystonic spasms of the temporalis and masseter muscles may result in clenching, or trismus, and grinding of the teeth, or bruxism. On the other hand, the lateral pterygoids, anterior belly of the digastric muscle, and other submental muscles are commonly involved in jaw-opening dystonia, and contractions of these muscles may lead to some degree of anterocollis. OMD, especially the primary form, may be alleviated by introducing different proprioceptive sensory inputs (“sensory tricks”), such as touching the lips or chin, chewing gum or biting on a toothpick, with these strategies being most effective in jaw-opening dystonia compared to other forms (Lo et al., 2007).

As with most forms of dystonia, the majority patients with OMD belong to the idiopathic category, accounting for 60–80% of the reported cases (Tan and Jankovic, 1999; Scorr et al., 2021). Tardive dystonia represents the most common cause of secondary OMD, frequently associated with lingual dystonia and the presence of akathisia, stereotypic movements in the limbs or respiratory dyskinesias (Tan and Jankovic, 2000; Scorr et al., 2021). Less commonly, OMD can occur as an accompanying manifestation of neurodegenerative disorders, post-anoxic states and focal brain or brainstem lesions.

Treatment Options of Oromandibular Dystonia Among the different classes of oral medications, clonazepam and the anticholinergic benzhexol seem to be the most effective, with both typical and atypical antipsychotics, dopamine depleters, levodopa and baclofen also utilized. However, none of these agents has been tested in rigorously controlled clinical trials. Other options include tetrabenazine, sodium valproate and zolpidem, but benefits are only demonstrated in a few single studies (Ma et al., 2021). Evidence is also emerging for the use of deep brain stimulation of the globus pallidus interna and subthalamic nucleus, with a recent meta-analysis demonstrating efficacy in patients with refractory Meige’s syndrome (Hassell and Charles, 2020). Despite a lack of well-controlled clinical trials, recent systematic reviews, evidence-based reviews and clinical experience strongly regard BoNT as the first-line treatment for OMD, regardless of its clinical presentation (Bhidayasiri et al., 2006; Comella, 2018; Dadgardoust et al., 2019; Hassell and Charles, 2020; Ma et al., 2021). When the evidence was classified by the American Academy of Neurology on its quality for the treatment of OMD, abobotulinumtoxinA (AboBoNT) and onabotulinumtoxinA (Ona-BoNT) were given a level C recommendation (possibly effective in the specified population) while incobotulinumtoxinA (Inco-BoNT) and rimabotulinumtoxinB (Rima-BoNT) had a level U recommendation (data are inadequate and treatment is unproven) (Table 10.1) (Hallett et al., 2013). As a result, BoNT dosages provided in this chapter are limited to OnaBoNT and Abo-BoNT, with additional recommendations, where available, from consensus guidelines (Dressler et al., 2021) and the authors own clinical experience. However, these

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Bhidayasiri, Maytharakcheep, Truong Table 10.1 Levels of evidence for the treatment of oromandibular dystonia with botulinum toxin according to the American Academy of Neurology classification of evidence

Botulinum toxin (strain)

Level of evidence

Ona-BoNT

C

Abo-BoNT

C

Inco-BoNT

U

Rima-BoNT

U

• C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. Requires at least one Class II study or two consistent Class III studies. • U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. Assigned in cases of only one Class III study, only Class IV studies, or evidence that is conflicting and cannot be reconciled.

tables do not take into account the published literature suggesting dose equivalence of Ona-BoNT (Botox) and AboBoNT (Dysport), which is reported to vary between 1:2.5 and 1:6 (Bhidayasiri et al., 2006) and 1:1 for Ona-BoNT (Botox) and Inco-BoNT (Xeomin) (Benecke et al., 2009). Dosages for Rima-BoNT were only included when the specific references were available. Table 10.2 provides details of studies with BoNT in patients with OMD (Brin et al., 1987; Jankovic and Orman, 1987; Blitzer et al., 1989; Hermanowicz and Truong, 1991; Van den Bergh et al., 1995; Tan and Jankovic, 1999; Sinclair et al., 2013; Gonzalez-Alegre et al., 2014; Nastasi et al., 2016). In the largest prospective long-term study, a mean total duration of response of Ona-BoNT was demonstrated to last up to 16.4±7.1 weeks with the best response obtained in patients with jaw-closing OMD (Tan and Jankovic, 1999).

Patient Selection for Botulinum Toxin and Examination Techniques Patients with OMD require careful examination to determine the patterns of muscle contractions to enable classification into various subtypes (Table 10.3). The examination should include both patient at rest with eyes open and eyes closed, and when patients are performing different actions to determine the effects of speaking, chewing and any exacerbating activities. The tongue should be examined while at rest on the floor of the mouth as well as in protrusion, when moving side to side and during speech. The effects of sensory tricks in alleviating dystonic activities should also be noted. In addition, patients’ self-reported observations should not be neglected, as certain abnormalities may not be evident during clinical examination. In most OMD patients, substantial benefits can be achieved by limiting injections to the most affected muscles (Table 10.4). Although no controlled trials were available on which OMD subtype responds best to BoNT, most literature advocates those with jaw-closing OMD as better responders than those with jaw-opening OMD (Tan and Jankovic, 1999; Bhidayasiri et al., 2006; Comella, 2018). BoNT therapy for lingual dystonia is more challenging due to the complexity of injecting the

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delicate underlying muscle fibers and their propensity for dysphagia and dysarthria (Comella, 2018). Additional injections may be needed for accompanying blepharospasm and cervical dystonia, details of which are available in separate chapters. Table 10.4 has been modified from the original publication to provide lists of muscles involved in different subtypes of OMD, their respective function, and the corresponding dosages of Ona-BoNT and Abo-BoNT (Bhidayasiri et al., 2006).

Injection Techniques Electromyography (EMG) and ultrasonography were utilized in most reported BoNT studies in OMD, but are not an absolute requirement (Dadgardoust et al., 2019). The following discussion is subdivided according to main clinical types, primarily based on the clinical experience of the authors, and supplemented by literature review.

Jaw-Closing Oromandibular Dystonia For jaw-closing OMD, the masseter is often the initial muscle selected for denervation. If the response is not adequate, other muscles can be considered, including the temporalis and medial pterygoid muscles. Injection is individualized for each patient and EMG guidance is left as a resort to identify deep muscles that are not available to manual palpation (Bhidayasiri et al., 2006). The masseter is a thick quadrilateral muscle consisting of three parts – superficial, intermediate and deep – which arise from the zygomatic arch and insert into the angle and the lateral surface of the ramus of the mandible (Clemente, 1984) (Fig. 10.1). It is easily palpable by instructing the patient to clench their teeth. The masseter can be approached by using a Teflon-coated needle connected to an EMG machine at 1 cm anterior to the posterior border of the ramus. The muscle discharge, when the patient clenches their teeth, also helps to localize the insertion and avoid the parotid gland, which extends from the ear to the masseter and partially covers the posterior part of this muscle. A good starting dose is 30 units of Ona-BoNT (Botox) or 100 units of Abo-BoNT (Dyport). The recommended dosage from the consensus guidelines is between 20 and 60 units of Ona-BoNT (Botox) on each side. Dosage recommendations with Rima-BoNT (Myobloc) are only available from two non-English journals, suggesting 2500 units of Rima-BoNT for each masseter muscle (Bhidayasiri et al., 2006; Dressler et al., 2021). The medial pterygoid occupies the inner aspect of the ramus of the mandible opposite that of the masseter. It arises from the lateral pterygoid plate and the pyramical process of the palatine bone and inserts into the lower and back part of the medial surface of the ramus and angle of the mandible (Clemente, 1984) (Fig. 10.2). The medial pterygoid can be very active in jaw-closing OMD as a result of the so-called whack-a-mole phenomenon after repeated BoNT injections into the masseter and temporalis muscles. Due to its deep location, its injection

Botulinum Neurotoxin in Oromandibular Dystonia Table 10.2 Clinical trials of botulinum toxin in oromandibular dystonia

Reference

No. patients (diagnosis)

Neurotoxin products and injection techniques

Reported outcomes

Duration of benefit

3 (OMD)

Ona-BoNT No guidance technique

20% improvement on blinded examiner rating and videotape scoring. 6.7% improvement om subjective self-assessment rating The duration of efficacy lasted 5.6 weeks.

12.5 weeks (5–28)

Brin et al. (1987)

5 (4 Jaw-closing and 1 lingual OMD)

Ona-BoNT Direct laryngoscopy and Laryngeal electromyography

3 out of 4 patients with jaw-closing OMD and one patient with lingual OMD reported motor improvement on a qualitative scale (0–3).

2.5–3 months

Blitzer et al. (1989)

20 (OMD)

Ona-BoNT Laryngeal EMG

19 patients reported benefit with an average 47% improvement by patient self-assessment.

Not available

Hermanowicz and Truong (1991)

5 (4 jaw-closing OMD, 1 lingual OMD)

Ona-BoNT EMG guidance

All patients reported mild-to-marked clinical improvement on a four-point scale.

Not available

Van den Bergh et al. (1995)

12 (5 OMD, 7 Meige’s syndrome)

Abo-BoNT EMG guidance

6 out of 12 patients showed marked improvement on a subjective rating scale (0–5).

27.0±4.5 weeks

Randomized controlled trials Jankovic and Orman (1987)

Open-label trials

Prospective, observational studies Tan and Jankovic (1999)

162 (jaw-opening, jaw-closing OMD)

Ona-BoNT No guidance technique

67.9% of patients reported definite functional improvement as shown by Global Rating Scale.

16.4±7.1

Nastasi et al. (2016)

50 (jaw opening, jaw closing, jaw deviation, lingual)

Ona-BoNT or Abo-BoNT EMG guidance

Significant improvement in the OMDQ-25 at 1 and 2 months.

5.9±4.3

Retrospective studies Gonzalez-Alegre et al. (2014)

23 (12 jaw-opening, 11 jaw-closing)

Ona-BoNT No guidance technique

All patient with jaw-closing OMD and 71% of patient with jaw-opening OMD demonstrated improvement in global impression scale.

Not given

Sinclair et al. (2013)

59 (Jaw-opening, jaw-closing, jaw deviation)

Ona-BoNT EMG guidance

66% of patients continued treatment.

Not available

OMD = Oromandibular dystonia; Ona-BONT = OnabotulinumtoxinA, Abo-BoNT = AbobotulinumtoxinA; EMG = Electromyography; OMDQ-25 = Oromandibular Dystonia Questionnaire-25

often requires EMG guidance to avoid the risk of complications, such as hematoma or arterial bleeding. The medial pterygoid can be approached either intraorally or from below. When approached from below, the needle is inserted about 0.5–1 cm anterior to the angle of the mandible along the interior aspect of the mandible and angled perpendicularly to the mandible until it can be verified by EMG with the patient clenching their teeth. Care should be taken to avoid the facial artery, which lies anteriorly. A good starting dose (per side) is 20 units of OnaBoNT (Botox) or 30 units of Abo-BoNT (Dyport) or 1000 units of Rima-BoNT (Myobloc) (Bhidayasiri et al., 2006).

The third muscle involved the jaw-closing OMD is the temporalis muscle (Fig. 10.1). This broad, radiating muscle arises from the temporal fossa. Its tendon inserts into the medial surface, apex and anterior border of the coronoid process and the anterior border of the ramus of the mandible (Clemente, 1984). The temporalis closes the jaw, and its posterior fibers retract the mandible. The temporalis is approached perpendicular to its plane and as high as possible in the temporal fossa as the lower part of the temporalis is mostly tendon where injection can be painful. Due to its wide radiation pattern, three to four injections should be given.

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Bhidayasiri, Maytharakcheep, Truong Table 10.3 Muscles in the oromandibular region and their respective functions

Table 10.4 Oromandibular dystonia subtypes, identification of primary muscles and botulinum toxin applications

Muscle name

Function

Subtypes

Temporalis

Close the jaw Posterior fibers retract the mandible Move jaw to the same side

Masseter

Close the jaw by elevating the mandible Retraction of the jaw

Medial pterygoid

Close the jaw Protrude the jaw Moving the jaw to the opposite side

Lateral pterygoid

Digastric Mylohyoid

Open the mouth Protrude the jaw Move the jaw to the opposite side Open the jaw Elevate the hyoid bone Open the jaw Raise the floor of the mouth

Geniohyoid

Open the jaw Elevate and draw hyoid bone forward

Stylopharyngeus muscle

Pulls the nasopharyngeal wall dorsally

Salpingopharyngeus muscle

Raise the pharynx and larynx during swallowing Laterally draws the pharynx walls up

Palatopharyngeus muscle

Elevates pharynx superiorly, anteriorly and medially during swallowing

Muscles involved

Dosage per side (units) Ona-BoNT Abo-BoNT

Jaw closing Temporalis Masseter Medial pterygoid

20–30 30 20

100 100 30

Jaw opening

20–40

60

20

90

Contralateral lateral pterygoid Ipsilateral temporalis

20–40

60

Lingual dystonia

Genioglossus

20 (10 for each site)

30

Perioral dystonia

Orbicularis oris Zygomaticus Mentalis Risorius Levator anguli oris Depressor anguli oris Platysma

20

90

20

60

5–10

30

Jaw deviation

Pharyngeal dystonia

Lateral pterygoid Mylohyoid Digastric muscle Geniohyoid

Stylopharyngeus muscle Salpingopharyngeus muscle Palatopharyngeus muscle

40

Ona-BoNT = OnabotulinumtoxinA; Abo-BoNT = AbobotulinumtoxinA

The recommended dosage (per side) by the consensus guideline is between 20 and 80 units of Ona-BoNT (Botox) (Dressler et al., 2021). The authors, however, opt for around 20 to 30 units of Ona-BoNT (Botox) per side. Starting dose for Abo-BoNT (Dysport) is about 100 units per side and adjusted according to patient’s response (Van den Bergh et al., 1995).

Jaw-Opening Oromandibular Dystonia The muscles involved in jaw-opening include the lateral pterygoid, mylohyoid, digastric, geniohyoid and platysma (Clemente, 1984). Opening of the jaws is performed primarily by the lateral pterygoid muscle. However, at the start of opening, it receives assistance from the submentalis complex, which includes the mylohyoid, digastric and geniohyoid (Clemente, 1984). The platysma may also play a minor role in the opening of the jaw. Most investigators reported injections of the lateral pterygoid in jaw-opening OMD, although others claim success with injection of the submentalis complexes only (Bhidayasiri et al., 2006). The lateral pterygoid is a short conical muscle that arises by two heads, a superior from the great wing of the sphenoid

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bone and an inferior from the lateral surface of the pterygoid plate of the sphenoid (Clemente, 1984) (Fig. 10.2). The lateral pterygoid muscle can be approached intraorally or laterally through the mandibular incisure. However, the intraoral approach can be difficult in patients with high-frequency movement or widely displacing movements of the mandible. The entry point is about 35 mm from the external auditory canal and 10 mm from the inferior margin of the zygomatic arch. Using EMG guidance, the needle is angled upward about 15 degrees to reach the inferior head of the lateral pterygoid. In close vicinity, but more rostral, is the pterygoid branch of the maxillary artery. The amount of toxin reported to be effective in the literature ranges from 20 units to 40 units of Ona-BoNT (Botox) per side (Blitzer et al., 1989). There are limited experiences reported with Abo-BoNT (Dysport), and we recommend a starting dose of about 60 units per side, which can be titrated up if needed. The digastric muscle is part of the submentalis complex. It arises from the mastoid notch of the temporal bone and attaches to digastric fossa of the mandible (Fig. 10.3). It is divided into the anterior and posterior belly by the middle

Botulinum Neurotoxin in Oromandibular Dystonia

Fig. 10.1 The masster and temporalis muscles.

tendon, which is attached to the hyoid bone (Clemente, 1984). Besides elevating the hyoid bone, the digastric pulls the chin backward and downward during opening of the mouth in conjunction with the lateral pterygoid. In contrast to the posterior belly, which is crowded with many nerves, sympathetic trunks, arteries and veins, the anterior belly is open to intervention. The geniohyoid arises from the hyoid bone and inserts into the inferior genial tubercle of the mandible. It elevates the hyoid bone and base of the tongue. With the hyoid bone fixed, it depresses the mandible and opens the mouth. The mylohyoid arises from the hyoid bone as well and attaches to the mylohyoid line on the mandible (Fig. 10.3). It raises the floor of the mouth during swallowing.

The mylohyoid elevates the hyoid bone, thereby pushing the tongue upward or causing protrusion of the tongue (Clemente, 1984). It also assists in opening of the mouth. Muscles of the submentalis complex may be fused together, rendering them difficult to be separated from one another (Clemente, 1984). This muscle group can be palpated when the patient opens their mouth. It is approached about 1 cm from the mandible tip and injected slightly lateral from the midline (Fig. 10.3). A good starting dose of Ona-BoNT (Botox) is 20 units per side. These units are divided and injected into two locations on each side. Higher doses of up to 200 units for the submentalis complex have been reported, but the risk of severe dysphagia is considerable (Tan and

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Bhidayasiri, Maytharakcheep, Truong

Fig. 10.2 The medial and lateral petrygoid muscles.

Jankovic, 1999). For Abo-BoNT (Dysport), 90 units per side is a good starting dose and for Rima-BoNT (Myobloc) about 500 units. In some patients, injection of the platysma can give additional improvement. This muscle depresses the mandible and soft tissues of the lower face as well as tensing the skin of the neck. The platysma fascicles can be easily identified with visual inspection. Often, each platysma is injected with 20 units of Ona-BoNT (Botox), 60 units of Abo-BoNT (Dysport) or 1000 units of Rima-BoNT (Myobloc). The recommended

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dosage from the consensus guidelines is between 20 and 40 units of Ona-BoNT per side (Dressler et al., 2021).

Jaw-Deviating Oromandibular Dystonia The contralateral lateral pterygoid works in conjunction with the medial pterygoid of the same side to deviate the mouth from one side to the other. The temporalis pulls the jaw to the same side. The injections follow the above-mentioned techniques.

Botulinum Neurotoxin in Oromandibular Dystonia

Fig. 10.3 The digastric, geniohyoid and mylohyoid muscles.

Lingual Oromandibular Dystonia In a large series of 172 patients with lingual OMD, four subtypes were identified based on patterns of involuntary movements, including protrusion (thrusting, 68.6%), retraction (16.9%), curling (rolling, 7.6%) and laterotrusion (7.0%) (Yoshida, 2019). Movements of the tongue are delicate, requiring the coordinated function of various extrinsic muscles of the tongue, consisting of the genioglossus, hyoglossus, chondroglossus, styloglossus and palatoglossusy, so careful examination of the tongue is essential for a successful BoNT treatment. Tongue thrusting, one of the

movements often encountered in oromandibular dystonia, is due to the action of the posterior fibers of the genioglossus, whereas the anterior fibers draw the tongue back into the mouth (Clemente, 1984). The genioglossus can be accessed via the submandibular route. Under EMG guidance, the genioglossus can be identified through the digastric muscle at 2 cm in depth. Suggested initial doses, per side, are 10 units of Ona-BoNT (Botox) or 30 units of Abo-BoNT (Dysport), respectively (Bhidayasiri et al., 2006). There is no known experience of Rima-BoNT (Myobloc) with this muscle. Experiences vary on what subtype was the most responsive

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Bhidayasiri, Maytharakcheep, Truong

to BoNT injections. One note of caution when injecting lingual muscles is that the therapeutic window is quite narrow, meaning that doses slightly above the therapeutic level can induce disabling weakness associated with severe dysphagia.

Perioral Oromandibular Dystonia There is no standardized approach for BoNT injections in perioral dystonia. The muscle involved, the orbicularis oris, is an intricate facial expression muscle that consists of fibers from various facial muscles including buccinator, superior levator labii, inferior depressor labii, zygomaticus major, mentalis and inferior incisivus labii. As these muscles are superficial and attached to the skin, a subcutaneous approach should be used similar to the standard procedure for blepharospasm. Only limited evidence is available from two small studies employing different BoNT techniques and injection sites that demonstrated significant reduction of the symptoms.

Pharyngeal Oromandibular Dystonia The pharyngeal muscles consist of the three constrictor muscles and the stylo-, salpingo- and palatopharyngeus. The three constrictors are superior, middle and inferior constrictors. They exercise general sphincteric and peristaltic actions in swallowing. Pharyngeal OMD often involves the constrictor pharynges, with patients often complaining of choking and swallowing difficulties. In addition, pharyngeal OMD often occurs with spasmodic dysphonia. We have noted that sometimes, after treatment of spasmodic dysphonia, there is also unexpected improvement of pharyngeal dystonia. As treatments of constrictor pharynges are almost invariably associated with dysphagia, injections of these muscles are seldom performed. Dosage used per side is 5 to 10 units of Ona-BoNT (Botox) or 30 units of Abo-BoNT (Dysport).

Adverse Events In a recent meta-analysis, adverse events were identified in 27% of patients with dysphagia as the most common attributed to BoNT spread to contiguous muscles involved in swallowing (Dadgardoust et al., 2019). Other commonly reported adverse events were chewing weakness, dysarthria (especially with tongue injections), pain, lip numbness and dry mouth, caused by diffusion into salivary glands (Dadgardoust et al., 2019; Hassell and Charles, 2020). When muscle selection is done carefully and dosing made conservatively, excessive weakness can be minimized. As BoNT labeling of all formulations includes a box warning on potential spreading of toxin effect, remote side effects are always possible, but observed to be very rare, and include generalized weakness, allergic reactions, flulike symptoms or even documentation of EMG abnormalities

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distant to the site of toxin injection. To reduce the risk of xerostomia, good knowledge of anatomy is essential to avoid unintended injections to the parotid glands that overlie the posterior border of masseter muscles. Another adverse event that is probably not frequently mentioned in the literature, but probably occurs more frequently in authors’ experience, is lower facial asymmetry and an asymmetric smile, which occur when BoNT diffuses to risorius and levator anguli oris muscles. Therefore, injections should be targeted at sites that are far from the anterior borders of these muscles.

Summary The development of botulinum toxin has markedly altered the treatment of OMD in recent years, with proposed classification of subtyping, clinical evaluations, muscle-targeting techniques and evidence-based literature published. Even though BoNT is still not officially approved by the US Food and Drug Administration for OMD, it is recommended as the first-line therapy by most experts and evidence-based literature. However, this chapter highlights the need for further controlled studies of various BoNT formulations in OMD to establish robust efficacy and to document potential adverse events associated with such injections. Treating physicians should be diligent when evaluating patients with OMD, performing careful clinical observation and examination as well as evaluating functional interferences (e.g., chewing, speaking) affected by dystonic movements. Once a patient’s candidacy for BoNT is established, careful stepwise planning should begin by selecting the muscles that are primarily responsible and employing a conservative approach to dosing titration. As muscles involved in OMD are small, delicate and situated near each other, adverse events due to BoNT spreading may occur and close follow-up visits are advisable, especially for the first few injection cycles. Patients should be involved in outcome selections and priority should be given to outcomes that are directly related to disturbed daily functions. Future studies in OMD should aim to harmonize candidate selections, injection protocols and outcome assessments to deliver robust efficacy to gain therapeutic approval for this disorder.

Acknowledgment Roongroj Bhidayasiri is supported by Senior Research Scholar Grant (RTA6280016) of the Thailand Science Research and Innovation (TSRI), International Research Network Grant of the Thailand Research Fund (IRN59W0005), Chulalongkorn Academic Advancement Fund into Its 2nd Century Project of Chulalongkorn University, and Centre of Excellence grant of Chulalongkorn University (GCE 6100930004-1), Bangkok, Thailand.

Botulinum Neurotoxin in Oromandibular Dystonia

References Benecke R, Frei K, Comella CL (2009). Treatment of cervical dystonia. In Truong D, Dressler D, Hallett M (eds.) Manual of Botulinum Toxin Therapy. Cambridge: Cambridge University Press, pp. 29–42. Blitzer A, Brin MF, Greene P E, Fahn, S (1989). Botulinum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol, 98, 93–7. www .ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&dopt= Citation&list_uids=2916831 Bhidayasiri R, Cardoso F, Truong DD (2006). Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations. Eur J Neurol, 13 (Suppl. 1) 21–9. www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list_uids= 16417594 Brin MF, Fahn S, Moskowitz C et al. (1987). Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord, 2, 237–54. Clemente C (1984). Muscles and fasciae. In Clemente C (ed.) Gray’s Anatomy, 13th ed. Philadelphia: Lea & Feabiger, pp. 429–605. Comella CL (2018). Systematic review of botulinum toxin treatment for oromandibular dystonia. Toxicon, 147, 96–9. https://doi.org/10.1016/j.toxicon .2018.02.006 Dadgardoust PD, Rosales RL, Asuncion RM, Dressler D (2019). Botulinum neurotoxin a therapy efficacy and safety for oromandibular dystonia: a meta-analysis. J Neural Transm (Vienna), 126, 141–8. https://doi.org/10.1007/s00702–0181960-7 Dressler D, Altavista MC, Altenmueller E et al. (2021). Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity. J Neural Transm (Vienna), 12, 321–35. https://doi.org/10.1007/ s00702–021-02312-4

Gonzalez-Alegre P, Schneider R L, Hoffman H (2014). Clinical, etiological, and therapeutic features of jaw-opening and jaw-closing oromandibular dystonias: a decade of experience at a single treatment center. Tremor Other Hyperkinet Mov (N Y), 4, 231. https://doi.org/10.7916/ D8TH8JSM

update. Front Neurol, 12, 630221. https:// doi.org/10.3389/fneur.2021.630221 Nastasi L, Mostile, G, Nicoletti A et al. (2016). Effect of botulinum toxin treatment on quality of life in patients with isolated lingual dystonia and oromandibular dystonia affecting the tongue. J Neurol, 263(9), 1702–8. https:// doi.org/10.1007/s00415–016-8185-1

Hallett M, Albanese A, Dressler D et al. (2013). Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders. Toxicon, 67, 94–114. https://doi.org/10 .1016/j.toxicon.2012.12.004

Scorr LM, Factor SA, Parra SP, et al. (2021). Oromandibular dystonia: a clinical examination of 2,020 cases. Front Neurol, 12, 700714. https://doi.org/10.3389/fneur .2021.700714

Hassell TJW, Charles D (2020). Treatment of blepharospasm and oromandibular dystonia with botulinum toxins. Toxins, 12. https://doi.org/10.3390/ toxins12040269

Sinclair CF, Gurey LE, Blitzer A (2013). Oromandibular dystonia: long-term management with botulinum toxin. Laryngoscope, 12, 3078–83. https://doi .org/10.1002/lary.23265

Hermanowicz N, Truong DD (1991). Treatment of oromandibular dystonia with botulinum toxin. Laryngoscope, 101, 1216–18. www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=PubMed& dopt=Citation&list_uids=1943423

Tan EK, Jankovic J (1999). Botulinum toxin A in patients with oromandibular dystonia: long-term follow-up. Neurology, 53, 2102–7. www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list_uids= 10599789

Jankovic J, Orman J (1987). Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology, 37(4), 616–23. www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&dopt= Citation&list_uids=3504553 Kamburoglu K, Sonmez G, Nalcaci R, Yurttutan E, Tuzunel, AO (2019). Ultrasonographic evaluation of the masseter muscle before and after botulinum toxin injection in patients with bruxism. Oral Surg Oral MedOral Pathol Oral Radiol, 128, e174. https://doi.org/ https://doi.org/10.1016/j.oooo.2019.01 .059 Lo SE, Gelb M, Frucht SJ (2007). Geste antagonistes in idiopathic lower cranial dystonia. Mov Disord, 22, 1012–17. https://doi.org/10.1002/mds.21149 Ma H, Qu J, Ye, L, Shu Y, Qu Q (2021). Blepharospasm, oromandibular dystonia, and Meige syndrome: clinical and genetic

Tan EK, Jankovic J (2000). Tardive and idiopathic oromandibular dystonia: a clinical comparison. J Neurol Neurosurg Psychiatry, 68, 186–90. www.ncbi.nlm.nih .gov/entrez/query.fcgi?cmd=Retrieve& db=PubMed&dopt=Citation&list_uids= 10644785 Van den Bergh P, Francart J, Mourin S, Kollmann P, Laterre EC (1995). Five-year experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve, 18, 720–9. www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=PubMed& dopt=Citation&list_uids=7783762 Yoshida K (2019). Botulinum neurotoxin therapy for lingual dystonia using an individualized injection method based on clinical features. Toxins, 11. https://doi .org/10.3390/toxins11010051

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Chapter

11

Botulinum Neurotoxin Therapy of Laryngeal Muscle Hyperactivity Syndromes Daniel Truong, Arno Olthoff and Rainer Laskawi

Introduction Spasmodic dysphonia is a focal dystonia characterized by taskspecific, action-induced spasm of the vocal cords. It adversely affects a patient’s ability to communicate. It can occur independently, as part of cranial dystonia (Meige’s syndrome), or in other disorders such as in tardive dyskinesia.

Clinical Features There are three types of spasmodic dysphonia: the adductor type, the abductor type and the mixed type: * adductor spasmodic dysphonia (ADSD) is characterized by a strained-strangled voice quality and intermittent voice stoppage or breaks, resulting in a staccato-like voice, caused by overadduction of the vocal folds * abductor spasmodic dysphonia (ABSD) is characterized by intermittent breathy breaks and associated with prolonged abduction folds during voiceless consonants in speech * patients with the mixed type have presentations of both. Symptoms of spasmodic dysphonia begin gradually over several months to years. The condition typically affects patients in their mid-40s and is more common in women (Adler et al., 1997; Schweinfurth et al., 2002). Spasmodic dysphonia may coexist with vocal tremor. Patients with ADSD show evidence of phona-tory breaks during vocalization. The vocal breaks typ ically occur during phonation associated with voiced speech sounds (Sapienza et al., 2000). Stress commonly exacerbates speech symptoms, whereas they are absent during laughing, throat clearing, coughing, whispering, humming and falsetto speech productions (Aronson et al., 1968). The voice tends to improve when the patient is emotional.

Botulinum Neurotoxin Treatment for Adductor Spasmodic Dysphonia The efficacy of botulinum neurotoxin (BoNT) in the treatment of spasmodic dysphonia has been proven in a double-blind study (Truong et al., 1991). On average, patients treated for ADSD with BoNT experience a 97% improvement in voice. Side effect included breathiness, choking and mild swallowing

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difficulty (Truong et al., 1991). The duration of benefit averages about 3–4 months depending on the dose used.

Muscles Injected with Botulinum Neurotoxin Treatment of ADSD involves mostly injection of BoNT into the thyroarytenoid muscles. A study using fine-wire electromyography (EMG) (Klotz et al., 2004) indicated that: * both the thyroarytenoid and the lateral cricoarytenoid muscle may be affected in ADSD, although the involvement of thyroarytenoid is more predominant * the thyroarytenoid and lateral cricoarytenoid muscles are equally involved in tremorous spasmodic dysphonia * interarytenoid muscle may be involved in some patients in both ADSD and in tremorous spasmodic dysphonia. Successful injections of BoNT into the ventricular folds indicated the involvement of the ventricular muscles in ADSD (Schönweiler et al., 1998). Injection of BoNT can be made into the thyroaryte noid muscle, either unilaterally or bilaterally. Unilateral injection may result in fewer adverse events such as breathiness, hoarseness, swallowing difficulty after the injection (Bielamowicz et al., 2002), but the strong voice intervals are also reduced. The patient may experience breathiness for up to 2 weeks, followed by the development of a strong voice. After an effective period of a few months, the spasmodic symptoms slowly return as the clinical effect of BoNT wears off. The duration of effect is dose related.

Injection Techniques The BoNT is injected intramuscularly. Different techniques of injection have been proposed, including the percutaneous approach (Miller et al., 1987), the transoral approach (Ford et al., 1990), the transnasal approach (Rhew et al., 1994) and point touch injections (Green et al., 1992).

Percutaneous Technique A Teflon-coated needle connected to an electromyography (EMG) machine is inserted through the space between the cricoid and thyroid cartilages and pointing toward the thyroartenoid muscle (Fig. 11.1). The localization of the needle is verified by high-frequency muscle discharges on the EMG

Botulinum Neurotoxin Therapy of Laryngeal Muscle Hyperactivity Syndromes

Fig. 11.1 Anatomy of the laryngeal muscles relevant for botulinum neurotoxin injections. (a) Saggital view showing the laryngeal structure. The arrows denote the direction for injection into the thyroarytenoid muscle for adductor spasmodic dysphonia and into the interarytenoid muscle for the tremorous spasmodic dysphonia. (b) Superior view showing the laryngeal structure and these technical aspects looking from superior angle.

underneath into the airway. The resulting cough would anesthetize the undersurface area of the vocal cord as well as the endotracheal structures, enabling the patients to tolerate the gag reflex (Truong et al., 1991).

Transoral Technique In the transoral approach, the vocal folds are indirectly visualized and the injections are performed using a device originally designed for collagen injection. Indirect laryngoscopy is used to direct the needle in an attempt to cover a broad area of motor end plates (Figs. 11.3 and 11.4) (Ford et al., 1990). A large wastage of the BoNT because of the large dead volume of the long needle is a drawback of this technique. In patients who cannot tolerate the gag reflex, a direct laryngoscopic injection can be performed under short total anesthesia (Fig. 11.5). Fig. 11.2 Transcutaneous injection technique. The injection should be done using electromyography control.

when the patient performs a long “/i/” (Miller et al., 1987). The BoNT is then injected (Fig. 11.2). For patients with excessive gag reflex, 0.2 ml 1% lidocaine can be injected either through the cricothy roid membrane or

Transnasal Technique In the transnasal approach, BoNT is injected though a channel running parallel to the laryngoscope with a flexible catheter needle. This technique requires prior topical anesthesia with lidocaine spray (Rhew et al., 1994). The location of the injection is lateral to the true vocal fold to avoid damaging the vocal fold mucosa.

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Point Touch Injections In the point touch technique, the needle is inserted through the surface of the thyroid cartilage halfway between the thyroid notch and inferior edge of the thyroid cartilage. The BoNT is given once the needle is passed into the thyroarytenoid muscle (Green et al., 1992).

Fig. 11.3 The transoral approach using a 90° video-endoscope.

For injections into the ventricular folds, a transoral or transnasal approach is required (Fig. 11.4). Because EMG signals cannot be received from the ventricular muscle, a percutaneous technique is not recommended.

Botulinum Neurotoxin Doses Doses of BoNT used for the treatment of spasmodic dysphonia vary depending on the particular brand of BoNT used (Table 11.1). In general, although there are correlations between the doses, the appropriate dose for a given BoNT product is dictated by the possible side effects of the BoNT on the adjacent organs or muscles. The approximate dose relation between onabotulinumtoxinA, incobotulinumtoxinA, abobotulinumtoxinA and rimabotulinumtoxinB is 1:1:3.5:50. This dose relationship should not be used a guideline as the diffusion rates of these BoNTs differ and the proximity of the muscle involved in swallowing should be the defining factor for the dose chosen. In the early literature, the doses of BoNT (onabotulinumtoxinA) used for ADSD ranged from 3.75 to 7.5 U for bilateral injections (Brin et al., 1988a, 1988b; Brin et al., 1989; Truong et al., 1991) to 15 U for unilateral injections (Miller et al., 1987; Ludlow et al., 1988). Later literature and common practice have recommended the use of lower doses (Blitzer and Sulica, 2001). We recommend starting with 0.5 U onabotulinumtoxinA/incobotulinumtoxinA, 1.5 U abobotulinumtoxinA or 200 U rimabotulinumtoxinB when injected bilaterally and to adjust the dose as needed. Our estimated average dose is 0.5 U onabotulinumtoxinA/ incobotulinumtoxinA, 2–3 U abobotulinumtoxinA or 300 U rimabotulinumtoxinB. Beneficial effects last about 3–4

Fig. 11.4 Endoscopic view during transoral botulinum neurotoxin application (see Fig. 11.3). (a) Injection into the left vocal fold. (b) Injection into the right ventricular muscle (ventricular fold).

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Botulinum Neurotoxin Therapy of Laryngeal Muscle Hyperactivity Syndromes Table 11.1 Doses of various botulinum neurotoxin products

Diagnosis and treatment technique

OnabotulinumtoxinA (U)

IncobotulinumtoxinA (U)

AbobotulinumtoxinA (U)

RimabotulinumtoxinB (U)

ADSD, unilateral injections

5–15

5–15

15–45

250–500

ADSD, bilateral injections

0.5–3

0.5–3

1.5–9

100–250

ABSD, unilateral injections

15

15

45

Not known

ABSD, bilateral injections

1.25–1.75

1.25–1.75

4.5–6

Not known

Vocal tremor

2

2

7.5

100–250

Laryngeal spasmodic dyspnea

2.5U

2.5

7.5

100–250

ADSD = adductor spasmodic dysphonia; ABSD = abductor spasmodic dysphonia. Source: Modified from Truong and Bhidayasiri (2006).

Fig. 11.5 Injection during microlaryngoscopy with a short general anesthestic. (a) The procedure, which normally does not use a tracheal tube and the injection is made during a short period of apnea. (b) Microscopical view of the larynx during microlaryngoscopy, the dots mark the typical injection points.

months in our patients treated with onabotulinumtoxinA, incobotulinumtoxinA or abobotulinumtoxinA. They last about 8 weeks with rimabotulinumtoxinB (Adler et al., 2004a) but may be longer with higher doses (GuntinasLichius, 2003). In patients who received BoNT serotype B after type A fail ure, the duration was only about 2 months despite higher doses up to 1000 U per cord.

Botulinum Neurotoxin Treatment for Abductor Spasmodic Dysphonia Injection Technique and Muscles Injected With the thyroid lamina rotated forward, the needle is inserted behind the posterior edge and directed toward the posterior

cricoarytenoid muscle. Location is veri fied by maximal muscle discharge when patients per form a sniff (Figs. 11.6 and 11.7) (Blitzer et al., 1992). The average onset of effect is 4 days and duration of benefit is 10.5 weeks. Adverse effects included exertional wheezing and dysphagia. In another approach, the needle is directed along the superior border of the posterior cricoid lamina and between the arytenoid cartilages. For anatomical rea sons, the BoNT is injected at a high location and allowed to diffuse down into the muscle for therapeutic effects (Fig. 11.8). A refined technique with the needle penetrating through the posterior cricoid lamina into the posterior cricoarytenoid muscle seems to be simpler and has the advantage of direct injection into the muscle (Meleca et al., 1997).

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Truong, Olthoff, Laskawi Fig. 11.6 Anterolateral view of the larynx and posterior cricoarytenoid muscle with the thyroid lamina rotated forward and to the other side.

Between 2 and 4 U onabotulinumtoxinA/ incobotulinumtoxinA or 12 U abobotulinumtoxinA on one side and 1 U onabotulinumtoxinA/3 U abobotulinumtoxinA on the opposite side are used. If a higher dose is required for each side, the injection of the opposite side should be delayed for about 2 weeks to avoid compromising the airway.

Spasmodic Laryngeal Dyspnea Spasmodic laryngeal dystonia results in laryngopharyngeal spasm primarily during respiration. Patients’ breathing problems are even improved with speaking (Zwirner et al., 1997). Dyspnea is caused by an intermittent glottic and supraglottic airway obstruction from both laryngeal and supralaryngeal/ pharyngeal muscle spasms. Treatment includes injections with BoNT into the thyroarytenoid and ventricular folds (Zwirner et al., 1997). These improvements last from 9 weeks to 6 months.

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Vocal Tremors Patients with essential tremor also demonstrate trem ors of the voice. The intrinsic laryngeal muscles are tremulous during respiration and speech, with the thyroarytenoid muscles most often involved (Koda and Ludlow, 1992). Patients reported subjective reduction in vocal effort and improvement in voice tremors following injection with BoNT into the vocal cord (Adler et al., 2004b). Improvement may also occur with treatment of the lateral cricoarytenoid and interarytenoid muscles (Klotz et al., 2004). For the treatment of vocal tremors, the thyroary tenoid muscles are often injected using a technique similar to that used for ADSD. Many patients who started with voice tremors will later develop spasmodic dysphonia over the long term. The average doses used are about 2 U onabotulinumtoxinA/ incobotulinumtoxinA or 8 U abobotulinumtoxinA. For rimabotulinumtoxinB, about 200 U would be needed.

Botulinum Neurotoxin Therapy of Laryngeal Muscle Hyperactivity Syndromes Fig. 11.7 Injection into the posterior cricoarytenoid muscle in a patient using a lateral approach.

Fig. 11.8 Dorsolateral view showing the anatomy of posterior cricoarytenoid, oblique arytenoids and transverse arytenoid muscles.

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References Adler CH, Edwards BW, Bansberg SF (1997). Female predominance in spasmodic dysphonia. J Neurol Neurosurg Psychiatry, 63, 688. Adler CH, Bansberg SF, Hentz JG et al. (2004a). Botulinum toxin type A for treating voice tremor. Arch Neurol, 61, 1416–20. Adler CH, Bansberg SF, Krein-Jones K, Hentz JG (2004b). Safety and efficacy of botulinum toxin type B (Myobloc) in adductor spasmodic dysphonia. Mov Disord, 19, 1075–9. Aronson AE, Brown JR, Litin EM, Pearson JS (1968). Spastic dysphonia. II. Comparison with essential (voice) tremor and other neurologic and psychogenic dysphonias. J Speech Hear Disord, 33, 219–31. Bielamowicz S, Stager SV, Badillo A, Godlewski A (2002). Unilateral versus bilateral injections of botulinum toxin in patients with adductor spasmodic dysphonia. J Voice, 16, 117–23. Blitzer A, Brin MF, Stewart C, Aviv JE, Fahn S (1992). Abductor laryngeal dystonia: a series treated with botulinum toxin. Laryngoscope, 102, 163–7.

dysphonia): observations of 901 patients and treatment with botulinum toxin. Adv Neurol, 78, 237–52.

botulinum toxin injection for abductory spasmodic dysphonia. Otolaryngol Head Neck Surg, 117, 487–92.

Brin MF, Blitzer A, Fahn S, Gould W, Lovelace RE (1989). Adductor laryngeal dystonia (spastic dysphonia): treatment with local injections of botulinum toxin (Botox). Mov Disord, 4, 287–96.

Miller RH, Woodson GE, Jankovic J (1987). Botulinum toxin injection of the vocal fold for spasmodic dysphonia. A preliminary report. Arch Otolaryngol Head Neck Surg, 113, 603–5.

Ford CN, Bless DM, Lowery JD (1990). Indirect laryngoscopic approach for injection of botulinum toxin in spasmodic dysphonia. Otolaryngol Head Neck Surg, 103, 752–8.

Rhew K, Fiedler DA, Ludlow CL (1994). Technique for injection of botulinum toxin through the flexible nasolaryngoscope. Otolaryngol Head Neck Surg, 111, 787–94.

Green DC, Berke GS, Ward PH, Gerratt BR (1992). Point-touch technique of botulinum toxin injection for the treatment of spasmodic dysphonia. Ann Otol Rhinol Laryngol, 101, 883–7.

Sapienza CM, Walton S, Murry T (2000). Adductor spasmodic dysphonia and muscular tension dysphonia: acoustic analysis of sustained phonation and reading. J Voice, 14, 502–20.

Guntinas-Lichius O (2003). Injection of botulinum toxin type B for the treatment of otolaryngology patients with secondary treatment failure of botulinum toxin type A. Laryngoscope, 113, 743–5.

Schonweiler R, Wohlfarth K, Dengler R, Ptok M (1998). Supraglottal injection of botulinum toxin type A in adductor type spasmodic dysphonia with both intrinsic and extrinsic hyperfunction. Laryngoscope, 108, 55–63.

Klotz DA, Maronian NC, Waugh PF et al. (2004). Findings of multiple muscle involvement in a study of 214 patients with laryngeal dystonia using fine-wire electromyography. Ann Otol Rhinol Laryngol, 113, 602–12.

Blitzer A, Sulica L (2001). Botulinum toxin basic science and clinical uses in otolaryngology. Laryngoscope 111, 218–26.

Koda J, Ludlow CL (1992). An evaluation of laryngeal muscle activation in patients with voice tremor. Otolaryngol Head Neck Surg, 107, 684–96.

Brin MF, Fahn S, Moskowitz C et al. (1988a). Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Adv Neurol, 50, 599–608.

Ludlow CL, Naunton RF, Sedory SE, Schulz GM, Hallett M (1988). Effects of botulinum toxin injections on speech in adductor spasmodic dysphonia. Neurology, 38, 1220–5.

Brin MF, Blitzer A, Stewart C (1988b). Laryngeal dystonia (spasmodic

Meleca RJ, Hogikyan ND, Bastian RW (1997). A comparison of methods of

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Schweinfurth JM, Billante M, Courey MS (2002). Risk factors and demographics in patients with spasmodic dysphonia. Laryngoscope, 112, 220–23. Truong D, Bhidayasiri R. Botulinum toxin in laryngeal dystonia (2006). Eur J Neurl, 13 (Suppl 1), 36–41. Truong DD, Rontal M, Rolnick M, Aronson AE, Mistura K (1991). Double-blind controlled study of botulinum toxin in adductor spasmodic dysphonia. Laryngoscope, 101, 630–4. Zwirner P, Dressler D, Kruse E (1997). Spasmodic laryngeal dyspnea: a rare manifestation of laryngeal dystonia. Eur Arch Otorhinolaryngol, 254, 242–5.

Chapter

12

The Use of Botulinum Neurotoxin in Otorhinolaryngology Rainer Laskawi, Arno Olthoff and Oleg Olegovich Ivanov

Introduction Various disorders affecting the ears, nose and throat (ENT) are suited for treatment with botulinum neurotoxin (BoNT). They can be divided into two general groups: * disorders concerning head and neck muscles (movement disorders) * disorders caused by a pathological secretion of glands located in the head and neck region. Table 12.1 summarizes the diseases relevant to otolaryngology. The focus in this chapter lies on indications that are not reviewed in other chapters; therefore, laryngeal dystonia, hemifacial spasm, blepharospasm and synkinesis following defective healing of the facial nerve will not be covered here.

Dysphagia and Speech Problems Following Laryngectomy Some patients are unable to achieve an adequate speech level for optimal communication after laryngectomy. One of the causes is spasms of the cricopharyngeal muscle. In this condition, BoNT can reduce the muscle activity and improve the

quality of speech (Chao et al., 2004). Swallowing disorders in neurological patients can result from a disturbed coordination of the relaxation of the upper esophageal sphincter and can lead to pulmonary aspiration. The cricopharyngeal muscle is a sphincter between the inferior constrictor muscle and the cervical esophagus and is primarily innervated by the vagus nerve. The following procedure can be used as a test prior to a planned myectomy or as a single therapeutic option that has to be repeated. Botulinum neurotoxin was injection into the cricopharyngeal muscle at three injection sites under general anesthesia, using 10–20 U onabotulinumtoxinA/ incobotulinumtoxinA (or 50–100 U abobotulinumtoxinA or 500–1000 U rimabotulinumtoxinB [BoNT B]) (Fig. 12.1). In dysphagia caused by spasms or insufficient relaxation of the upper oesophageal sphincter, injection of BoNT as described can improve the patients’ complaints (Fig. 12.2). Patient should be evaluated for symptoms of concomitant gastroesophageal reflux to avoid side effects such as “refluxlaryngitis.” If there is gastroesophageal reflux, the etiology and treatment should be clarified prior to initiation of BoNT therapy.

Table 12.1 Diseases treated with botulinum neurotoxin type A in otorhinolaryngology

Movement disorders

Disorders of the autonomous nerve system

Facial nerve paralysis

Gustatory sweating, Frey’s syndrome

Hemifacial spasm

Hypersalivation, sialorrhea

Blepharospasm, Meige’s syndrome

Intrinsic rhinitis

Synkinesis following defective healing of the facial nerve

Hyperlacrimation, tearing

Oromandibular dystonia Laryngeal dystonia Palatal tremor Dysphagia

Fig. 12.1 The cricopharyngeal muscle. Intraoperative aspect prior to injection of botulinum neurotoxin into the cricopharyngeal muscle. The dots mark the injection sites (20 U onabotulinumtoxinA at each point).

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Fig. 12.2 Patient with severe swallowing disorder caused by irregular function of the upper esophageal sphincter. (a) Aspiration during swallowing. (b) Following three injections of botulinum neurotoxin (20 U onabotulinumtoxinA), the pharyngo-esophageal passage is normalized.

Palatal Tremor Repetitive contractions of the muscles of the soft palate (palatoglossus, palatopharyngeus, salpingopharyngeus, tensor and levator veli palatini muscles) lead to a rhythmic elevation of the soft palate. This disorder has two forms, symptomatic palatal tremor and essential palatal tremor. Symptomatic palatal tremor can cause speech and also swallowing disorders through velopharyngeal insufficiency. Most patients suffering from essential palatal tremor complain of “ear clicking.” This rhythmic tinnitus is caused by a repetitive opening and closure of the orifice of the eustachian tube. A particular sequel of pathological activity of soft palate muscles is the syndrome of a patulous eustachian tube. These patients suffer from “autophonia” caused by an open eustachian tube due to the increased muscle tension of the paratubal muscles (salpingopharyngeus, tensor and levator veli palatini muscles) (Olthoff et al., 2007). For the first treatment session, the injection of in total 5 U onabotulinumtoxinA/incobotulinumtoxinA (uni- or bilaterally)

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(25 U abobotulinumtoxinA; 250 U rimabotulinumtoxinB) into the soft palate (Figs. 12.3 and 12.4) is adequate in most patients. If necessary, this can be increased to 15 U onabotulinumtoxinA/ incobotulinumtoxinA (75 U abobotulinumtoxinA; 750 U rimabotulinumtoxinB) on each side. The application is normally performed transorally (transpalatinal or via postrhinoscopy) under endoscopic control. The insertion of the tensor veli palatini muscle is used as landmark for the treatment of palatal tremor and the salpingopharyngeal fold as landmark for the treatment of a patulous eustachian tube (Figs. 12.3 and 12.4). To optimize detection of the target muscle, injection under electromyographic control is recommended. Landmarks are given to avoid vascular injections and to indicate the most “responsible” muscle. The synergistic function of targeted soft palate and paratubal muscles (salpingopharyngeus, tensor and levator veli palatini) often interferes with clinical and therapeutical separation. To avoid side effects such as iatrogenic velopharyngeal

Use of Botulinum Neurotoxin in Otorhinolaryngology Fig. 12.3 Dorsal view of the nasopharynx and soft palate (modified after Tillmann, 2005). The arrows mark the possible sites of onabotulinumtoxinA injections. The salpingopharyngeal fold is used as a landmark.

insufficiency, treatment should be started with low doses, as described above.

Hypersalivation (Sialorrhea) Hypersalivation can be caused by various conditions such as tumour surgery, neurological and pediatric disorders and disturbances of wound healing following ENT surgery. Hypersalivation also is of relevance for a number of reasons in patients suffering from head and neck cancers. Some of these patients are unable to swallow their saliva because of a stenosis of the upper esophageal sphincter caused by scar formation after tumor resection. In other patients, there are disturbances of the sensory control of the “entrance” of the supraglottic tissues of the larynx, allowing saliva to pass into the larynx. In patients with Parkinson’s disease, decreased swallowing also leads to hypersalivation as it interferes with saliva clearance. This may lead to continuous aspiration and aspiration pneumonia. In a third group of patients, complications of impaired wound healing after extended surgery can occur, such as fistula formation following laryngectomy. Saliva is a very aggressive agent and can inhibit the normal healing process. Both the parotid and submandibular glands are of interest in this context. The parotid gland is the largest of the salivary glands. It is located in the so-called parotid compartment in

the pre- and subauricular region, with a large compartment lying on the masseter muscle. The gland also has contact with the sternocleidomastoid muscle (Fig. 12.5). The submandibular gland (Figs. 12.6 and 12.7) lies between the two bellies of the digastric muscle and the inferior margin of the mandible, which form the submandibular triangle. The gland is divided into two parts – the superficial lobe and the deep lobe – by the mylohyoid muscle (Fig. 12.6c). In the first period of our treatment series we injected according to the Ellies protocol (Ellies et al. 2014). To reduce saliva flow, we follow the SIAXI study (Jost et al., 2019). We inject 30 units incobotulinumtoxinA into each parotid gland (Figs. 12.8 and 12.9) and 20 units incobotulinumtoxinA into each submandibular gland at one or two sites (Fig. 12.10). Injection of botulinum neurotoxin type A (BoNT-A) has been shown to be effective in reducing saliva flow (Fig. 12.11). Side effects such as local pain, diarrhea, luxation of the mandible and a “dry mouth” are rare.

Gustatory Sweating (Frey’s Syndrome) Gustatory sweating is a common sequel of parotid gland surgery (Laskawi and Rohrbach, 2002). The clinical picture is characterized by extensive production of sweat in the lateral region of the face. The sweating can be intense and become a

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Fig. 12.4 Transoral view of injection sites in patients with palatal tremor. The insertion of the tensor veli palatini muscle is used as landmark.

cause of a serious social stigma. Injection with BoNT has become the first-line treatment (Laskawi and Rohrbach, 2002). For an optimal outcome, the affected area should be marked with Minor’s test (Fig. 12.12). First, the face is divided into regional “boxes” using a waterproof pen (Fig. 12.12b). The affected skin is covered with iodine solution before starch powder is applied. The sweat produced by masticating an apple induces a reaction between the iodine solution and the starch powder, resulting in an apparent deep blue color (Laskawi and Rohrbach, 2002). Intracutaneous injections of BoNT (for 4 cm2, approximately 2.5 U onabotulinumtoxinA/ incobotulinumtoxinA,

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12.5 U abobotulinumtoxinA, 125 U rimabotulinumtoxinB) (Fig. 12.12c). Side effects are rare and with none of the possible sequelae, such as dryness of the skin or eczema, in some patients. The total dose required depends on the extent of the affected area, and up to 100 U onabotulinumtoxinA/ incobotulinumtoxinA (500 U abobotulinumtoxinA, 5000 U rimabotulinumtoxinB) can be necessary. The duration of improvement persists longer than that seen in patients with movement disorders (Laskawi and Rohrbach, 2002), and some patients have a symptom-free interval of several years.

Use of Botulinum Neurotoxin in Otorhinolaryngology

Fig. 12.5 The parotid gland under ultrasound. The presentation depends on the position of the probe. (a,b). Probe in the vertical position (a) to give a longitudinal view of the parotid (b). (c,d) Probe in the horizontal position (c) to give a transverse view of the parotid (d).

Rhinorrhea, Intrinsic Rhinitis

Hyperlacrimation

In the past few years, BoNT-A has been used in intrinsic or allergic rhinitis (Özcan et al., 2006). The main symptom in these disorders is extensive rhinorrhea with secretions dripping from the nose. There are two approaches for applying BoNT-A in these patients: it can either be injected into the middle and lower nasal turbinates or applied with soaked on a sponge (Fig. 12.13). For the injection approach, 10 U onabotulinumtoxinA/ incobotulinumtoxinA (50 U abobotulinumtoxinA, 500 U rimabotulinumtoxinB) is injected into each middle or lower turbinate. For the sponge technique, a sponge is soaked with a solution containing 40 U onabotulinumtoxinA and a sponge is applied into each nostril. The effect of the injections has been demonstrated in placebo-controlled studies (Özcan et al., 2006). Nasal secretion is reduced for about 12 weeks (Fig. 12.14). Side effects such as epistaxis or nasal crusting are uncommon.

Hyperlacrimation can be caused by stenoses of the lacrimal duct, misdirected secretory fibers following a degenerative paresis of the facial nerve (crocodile tears) or mechanical irritation of the cornea (in patients with lagophthalmus). The application of BoNT is useful in reducing pathological tearing in these patients (Whittaker et al., 2003; Meyer, 2004). The lacrimal gland is located in the lacrimal fossa in the lateral part of the upper orbit and is divided into two sections (Fig. 12.15). Usually 5–7.5 U onabotulinumtoxinA/incobotulinumtoxinA (25–37.5 U abobotulinumtoxinA, 250–375 U rimabotulinumtoxinB) is injected into the pars palpebralis of the lacrimal gland, which is accessible under the lateral upper lid (Fig. 12.16). Medial injection may result in ptosis as a possible side effect. The reduction of tear production lasts about 12 weeks (Fig. 12.17) (Meyer, 2004).

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Fig. 12.6 Submandibular gland. (a) Probe in longitudinal position. (b) Longitudinal ultrasound showing the submandibular gland and other structures. Note the localization of the internal and external carotid artery and the external jugular vein. (c) The submandibular gland (GL.SUBMAND.; borders of the gland clearly marked by the four crosses) and the surrounding structures (mylohyoid muscle [M.MYLO.] and digastric muscle [M.DIG]. (d) Probe in transverse position. (e) Transverse ultrasound probe showing the submandibular gland and other structures. Note the localization of the internal and external carotid artery and the external jugular vein position.

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Use of Botulinum Neurotoxin in Otorhinolaryngology

Fig. 12.7 Intraoperative injection of 15 U onabotulinumtoxinA into the submandibular gland during laryngectomy showing the anatomical position of the gland in the submandibular fossa.

Fig. 12.8 Injection of botulinum neurotoxin type A into the parotid and submandibular glands (same technique used for both). We prefer to inject both glands, with 7.5 U onabotulinumtoxinA into each of the three points of each parotid gland and with 15 U onabotulinumtoxinA into each submandibular gland. Ultrasound-guided injection is recommended.

Fig. 12.9 Frontolateral view of the left parotid gland with typical injections sites for botulinum neurotoxin.

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Laskawi, Olthoff, Ivanov Fig. 12.10 Laterocaudal view of the left submandibular gland with typical injections sites for botulinum neurotoxin.

Fig. 12.11 The effect of botulinum neurotoxin injection on saliva flow in patients with hypersalivation. Pretreatment status returns after 12 weeks (Ellies et al., 2004).

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Use of Botulinum Neurotoxin in Otorhinolaryngology

Fig. 12.12 Treatment of gustatory sweating (Frey’s syndrome) with botulinum neurotoxin. (a) Patient with extensive gustatory sweating following total parotidectomy. The affected area is marked by Minor’s test, showing a deep blue color. (b) The affected area is marked with a waterproof pen and divided into “boxes” to guarantee that the whole plane is treated. (c) Intracutaneous injections of onabotulinumtoxinA are performed. The white color of the skin can be seen during the intracutaneous application of onabotulinumtoxinA. (d) Patient eating an apple 2 weeks after treatment. The marked area that was sweating prior to treatment is now completely dry.

Fig. 12.13 Botulinum neurotoxin is injected into the middle and lower turbinates to treat rhinorrhea or applied with a sponge soaked with a solution of botulinum neurotoxin.

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Laskawi, Olthoff, Ivanov Fig. 12.14 Example of a patient with extensive intrinsic rhinitis. Botulinum neurotoxin type A has been applied with sponges. The consumption of paper handkerchiefs (number shown on vertical axis) is reduced dramatically for a long period after the application (horizontal axis).

Fig. 12.15 The localization of the lacrimal gland and the upper lid/orbit.

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Fig. 12.16 Injection into the pars palpebralis of the lacrimal gland. With the patient looking strongly in the medial direction; the upper lid is lifted, and a little “lacrimal prominence” becomes evident. Entering here in a lateral direction, the gland tissue can be approached easily.

Fig. 12.17 Patient with extensive tearing caused by a stenosis of the lacrimal duct after resection of a malignant tumor of the right maxilla. (a) Pretreatment; (b) post-treatment.

References Chao SS, Graham SM, Hoffman HT (2004). Management of pharyngoesophageal spasm with Botox. Otolaryngol Clin North Am, 37, 559–66. Ellies M, Gottstein U, Rohrbach-Volland S, Arglebe C, Laskawi R (2004). Reduction of salivary flow with botulinum toxin: extended report on 33 patients with drooling, salivary fistulas, and sialadenitis. Laryngoscope, 114, 1856–60. Jost WH, Friedman A, Michel O, et al. (2019). SIAXI: placebo-controlled, randomized, double-blind study of

incobotulinumtoxA for sialorrhea. Neurology, 92, e1982–e91. Laskawi R, Rohrbach S (2002). Frey’s syndrome: treatment with botulinum toxin. In Kreyden OP, Böni R, Burg G (eds.) Hyperhidrosis and Botulinum Toxin in Dermatology. Basel: Karger, pp. 170–7. Meyer M (2004). Störungen der Tränendrüsen. In Laskawi R, Roggenkämper P (eds.) Botulinumtoxintherapie im Kopf-HalsBereich. Munich: Urban & Vogel. Özcan C, Vayisoglu Y, Dogu O, Gorur K (2006). The effect of intranasal injection

of botulinum toxin A on the symptoms of vasomotor rhinitis. Am J Otolaryngol, 27, 314–18. Olthoff A, Laskawi R, Kruse E (2007). Successful treatment of autophonia with botulinum toxin: case report. Ann Otol Rhinol Laryngol, 116, 594–8. Tillmann B (2005). Atlas der Anatomie des Menschen. Berlin: Springer-Verlag, p. 180. Whittaker KW, Matthews BN, Fitt AW, Sandramouli S (2003). The use of botulinum toxin A in the treatment of functional epiphora. Orbit, 22, 193–8.

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Chapter

13

Treatment of Hemifacial Spasm with Botulinum Toxin Karen Frei

Introduction

Pathophysiology

Hemifacial spasm (HFS) is characterized as involuntary irregular clonic or tonic movements of the facial muscles innervated by cranial nerve VII on one side of the face and is most often a result of vascular compression of the facial nerve at the root exit/entry zone (Wang and Jankovic, 1998). Facial muscle twitches usually begin in the periocular region and can progress to involve the cheek, perioral and platysma muscles. Hemifacial spasm is almost always unilateral. Bilateral HFS occurs rarely, starting out unilaterally with symptoms beginning in the unaffected side after several months to years. In bilateral HFS, the facial twitching of the two sides is asynchronous. Atypical HFS cases initiate in the orbicularis oris and buccinator muscles and gradually spread upward to involve the orbicularis oculi (Ryu et al., 1998). Muscles involved in HFS include the orbicularis oculi, orbicularis oris and zygomaticus predominantly, with frontalis, corrugator, nasalis, buccinators, risorius, depressor angularis oris, mentalis and platysma less commonly (Fig. 13.1). Clinical presentation is variable, with different muscles involved in different patients. The prevalence of HFS worldwide is unknown but has been estimated to be 10 per 100,000 (Ozzello and Giacometti, 2018). HFS is more prevalent in females, with a 2:1 ratio. HFS has been found to be familial in a few families, but no gene has been identified as causative (Miwa et al., 2002). HFS commonly begins in the fifth decade with an average age of onset being 55 years. It tends to have a fluctuating course. HFS is a chronic condition with rare remissions. Symptoms often continue during sleep and can provoke insomnia. Emotion and stress tend to exacerbate facial twitching. Ear clicks can occur, attributed to contracture of the tensor tympani or stapedius muscles, which resolve with treatment (Rudzinska et al., 2010). Although benign, HFS can be disabling due to social embarrassment and excessive closure of the affected eye, interfering with vision. Symptoms tend to progress over time, and facial weakness may develop independent of botulinum toxin (BoNT) therapy. Hypertension is thought to be associated with HFS; however, this is not consistent. HFS can occur along with other cranial nerve syndromes, namely trigeminal neuralgia which is known as tic convulsive and CN VIII.

Imaging studies have confirmed that the most frequent cause of HFS is vascular compression of the facial nerve at the root exit/entry zone. The root exit/entry zone represents the transition between central and peripheral nerve myelin and is mechanically vulnerable. The severity of compression correlates with the severity of HFS symptoms. Vascular compression generally involves the anterior inferior cerebellar artery in 45.9% of cases, the posterior inferior cerebellar artery in 47.2% and the vertebral basilar artery in 17.5%. Other arteries have been found in 11.7% cases and veins can be seen in 4.9% (Mercier and Sindou, 2018). There can be multiple compressive vessels. The offending vessel is ipsilateral to the facial nerve and side of the HFS. Hypertension and HFS tend to occur with ventrolateral medullary compression. There are two theories behind the development of HFS: either direct contact with mechanical irritation of the nerve, resulting in ephaptic transmission of impulses between adjacent neurons leading to abnormal firing or hyperexitability of the facial motor nucleus due to irritative feedback from peripheral lesions. Nonvascular origins of HFS occur less commonly and include facial nerve injury or Bell’s palsy, demyelination presumed to involve the facial nucleus and various tumors and space-occupying lesions in the cerebellopontine angle. More sustained facial muscle contractions tend to occur in brainstem tumors.

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Differential Diagnosis HFS must be distinguished from other conditions involving the facial musculature, including blepharospasm, facial myokymia, oromandibular dystonia, facial tic, hemimasticatory spasm, post–Bell’s palsy synkinesis, focal seizures and functional or psychogenic. Blepharospasm, a form of dystonia causing involuntary closure of the eyes, usually occurs bilaterally and concerns only the eyelids (with the exception of Meige’s syndrome, where it can occur along with other facial muscle dystonia). Bright light can exacerbate the condition, which subsides during sleep. Facial myokymia, a fine rippling movement of the facial muscles, is associated with an abnormality of the brainstem

Treatment of Hemifacial Spasm with Botulinum Toxin

Fig. 13.1 Facial musculature involved in hemifacial spasm with proposed injection sites.

such as that seen in multiple sclerosis. Oromandibular dystonia, another form of dystonia, involves only the lower facial muscles, mouth and jaw. Facial tics tend to be multifocal and not unilateral, have more complex movements and are usually associated with premonitory sensations and mild voluntary suppression. Hemimasticatory spasm affects jaw closure, with painful muscle contractions. Facial synkinesiae, often occurring following Bell’s palsy, are caused by misdirected axonal sprouting after facial nerve lesions. Periocular muscle activation can be associated with perioral movements and vice versa. They may be mistaken for HFS and can be treated similar to HFS with BoNT injections (Roggenkamper et al., 1994). Focal seizures, including epilepsia partialis continua, may be erroneously diagnosed as HFS (Wang and Jankovic,

1998). Finally, psychogenic cases tend to have acute onset of symptoms with inconsistent and incongruous features; tend to be associated with somatizations; improve with distraction, placebo, suggestion or psychotherapy; can have spontaneous remission and have normal neuroimaging (Yalto and Jankovic, 2011).

Diagnosis Clinically, the Babinski 2 or other Babinski sign, in which there is paroxysmal synkinesis when the orbicularis oculi contracts the internal part of the frontalis contracts resulting in eyebrow raise during eye closure, can confirm the diagnosis of HFS (Yalto and Jankovic, 2011). Diagnostic tests for HFS include

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Frei Table 13.1 Muscles involved in hemifacial spasm

Muscle name

Mechanism of action

Depth of muscle

Injection Tips

Orbicularis oculi – preseptal/ pretarsal Orbicularis oculi – orbitalis

Close the eye lids Squeeze eyes shut

Superficial

Pretarsal just above the lashes in the lateral and medial upper lid. Orbitalis just under the lateral eyebrow just inside the orbital ridge

Orbicularis oris

Closes, protrudes and compresses lips

Superficial

Avoid injections

Zygomaticus major

Pulls angle of mouth superolaterally

Superficial

Diagonal from lateral corner of mouth to below lateral orbital ridge. Inject below lateral orbital ridge.

Zygomaticus minor

Elevates the upper lip

Superficial

Frontalis

Elevates the eyebrows and wrinkles forehead skin

Superficial

Above the eyebrows

Corrugator

Brings eyebrows together medially and inferiorly

Slightly deeper

Hold the corner of the medial eyebrow to inject

Procerus

Depresses the medial part of the eyebrow

Slightly deeper

In between the eyebrows

Nasalis

Narrows and widens the nostrils

Superficial

Along the side of the nose

Levator labii superioris

Elevates upper lip exposing maxillary teeth

Deep to zygomaticus

Buccinator

Compresses cheek against teeth

Deep to zygomaticus and risorius

Risorius

Pulls angle of mouth laterally and superiorly

Superficial

Lateral to corner of mouth

Depressor labii inferioris

Pulls lip inferiorly and medially

Superficial

Avoid

Depressor angularis oris

Pulls angle of mouth laterally and inferiorly

Deep to depressor labii inferioris

Diagonal from corner of mouth to edge of mandible. Follow frown line for injection

Mentalis

Depresses and everts lower lip and wrinkles chin

Deep to depressor labii inferioris

Tip of chin

Platysma

Depressing lower lip and corner of mouth and depresses mandible opening mouth

Superficial

Just underneath edge of mandible

high-resolution brain magnetic resonance imaging (MRI) with attention to the cerebellopontine angle, with and without contrast, which will detect any space-occupying lesion requiring neurosurgical intervention. Magnetic resonance angiography of the intracranial vessels may help to define the site of vascular compression. Electromyography (EMG) can help with the differential diagnosis in difficult cases, and electroencephalography may be able to detect epileptiform discharges characteristic of a focal seizure.

Treatment Treatment of HFS has included medications, microvascular decompression and BoNT injections. Medications such as

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baclofen, clonazepam, carbamazepine and phenytoin may provide mild improvement at the expense of side effects. Microvascular decompression (Janetta’s operation) involves placing surgical gauze in between the facial nerve and the compressing blood vessel. Success rates from microvascular decompression vary from 75 to 95%, with delayed relief of symptoms up to 1 year following surgery occurring in 30% and recurrence in 2–4%. Surgical complications include hearing loss in 2–3% and facial palsy in 1–2%, in addition to the accepted surgical risk of intracranial hemorrhage, stroke and even death (Sindou and Mercier, 2018). Brainstem auditory evoked potential (BAEP) monitoring may be helpful in the prevention of hearing loss during surgery.

Treatment of Hemifacial Spasm with Botulinum Toxin Fig. 13.2 The orbicularis oculi and its parts.

Injections of BoNT are the preferred treatment of HFS. They are successful in over 90% of patients. Patients with HFS tend to require a lower dose, with a longer duration of effect compared with blepharospasm (Cannon et al., 2010). Injections of BoNT provide relief from symptoms for a period of approximately 12 weeks, and repeated injections have been found to be effective for many years. They can provide relief from symptoms without the adverse effects of neurosurgery. Serotype A BoNT, in the forms of onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA, and serotype B (rimabotulinumtoxinB) have all been used in the treatment

of HFS. Use of EMG guidance during injection is not necessary. Side effects of BoNT injections tend to be those associated with other facial injections: erythema and ecchymosis of the region injected, dry eyes, mouth droop, ptosis, lid edema and facial muscle weakness (Elston, 1986; Yoshimura et al., 1992). Ptosis could be caused by local diffusion of the BoNT to affect the levator palpabrea. Improvement in symptoms can be expected to occur within 3 to 14 days, with a peak effect at approximately 2–3 weeks. Effects from BoNT injections are transient, with a mean

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Table 13.2 Dosages of neurotoxin and muscles commonly injected

Toxin

Frontalis

Corrugator

Procerus

Orbicularis oculi

Dose (U) Zygomaticus minor

Buccinator

Depressor angularis oris

Depressor labii oris

Platysma

OnabotulinumtoxinA/ incobotulinumtoxinA

10

2.5–4

2–3

20

1–1.5

2

1–1.5

1–1.5

15

AbobotulinumtoxinA

30

7.5–10

5–7.5

60–120

2.5

5–7.5

2.5–5

2.5–5

50

RimabotulinumtoxinB

500

50–75

50–75

1000

50

100

50

50

500

Source: Modified from Frei et al. (2006).

Treatment of Hemifacial Spasm with Botulinum Toxin Fig. 13.3 Orbicularis oculi anatomy with proposed initial botulinum toxin injection sites and doses.

duration of approximately 2.8 months. Duration of the beneficial effect among patients is highly variable. The sites of injection should be decided with the patient’s goals in mind. Prior to receiving the injections, the patient must be evaluated to identify the muscular involvement in HFS. A knowledge of facial anatomy is imperative to develop an effective plan for injections. (See Fig. 13.1.) Because HFS can progress over time, patients should be evaluated prior to each set of injections. Injections should be directed to the muscle belly with the depth of injections dependent upon the anatomy. For example, the orbicularis oculi is more superficial, requiring less depth compared with a deeper muscle such as the corrugator. Table 13.1 lists the facial muscles involved in HFS and their relative depth. The musculature around the eye deserves special attention. The orbicularis oculi is composed of two parts: the pars palpebralis, which ordinarily closes the eyelid, and the pars orbitalis, which squeezes the eye shut with stronger contractions. The pars palpebralis has two parts: a preseptal and a pretarsal region (Fig. 13.2). Injections in the orbicularis oculi can be given in the pretarsal, preseptal and orbital parts of the muscle. Typically, injections are in the upper lid in the lateral and medial pretarsal portion and in the lateral orbital portion. Avoiding the arch of the eyebrow in the orbitalis and preseptal region of the upper lid can prevent ptosis by inadvertent spread to the levator palpebrae. Orbital injections avoiding the arch of the eyebrow will provide similar results as pretarsal injections but with fewer side effects (Colakoglu et al, 2011). Orbital injections for lower lid symptoms are given in the lateral and at the level of the pupil. Medial lower lid injections can be associated with diplopia with spread to the inferior oblique muscle.

The orbicularis oris is avoided to prevent paralysis of the mouth. Injection into the lower facial muscles tends to be beneficial in those with more severe HFS. In rare cases, the platysma may need to be injected as well. When injecting facial muscles, there needs to be some concern about cosmetic outcome. For example, weakening the zygomaticus muscle leads to a reduction in the elevation of the corner of the mouth when smiling. On some occasions, consideration might be given to injections on the unaffected side of the face in the interests of maintaining facial symmetry. Total doses of BoNT used per hemifacial spasm treatment have been reported from 10 to 34 U onabotulinumtoxinA (Mezaki et al, 1999). Total doses of abobotulinumtoxinA used per treatment range from 53 to 160 U (Elston, 1992; Yu et al., 1992) and for rimabotulinumtoxinB doses range from 1250 to 4000 U, with a mean effective dose of 2039 U (Tousi et al., 2004). Table 13.2 lists the dosages of each BoNT and the muscles commonly injected (Frei et al, 2006). In practice, the 100 U vial of onabotulinumtoxinA or incobotulinumtoxinA could be diluted with 4 or 5 ml of normal saline. This results in a dilution to 2.5 U/0.1 ml or 2.0 U/0.1 ml, respectively. Dysport comes in 300 U and 500 U vials, which when diluted in 1.5 or 2.5 ml, respectively, give a dilution of 200 U/ ml. For the injection, 0.5 ml of the solution is drawn and diluted inside the syringe with another 0.5 ml of normal saline. The final concentration then would be 10 U in 0.1 ml. This solution is then used for injection into different sites (Fig. 13.3). To minimize side effects, initial injections with a lower dose of BoNT are recommended. Orbicularis oculi injections in the lateral orbital rim, just below the level of the eyebrow and below the eye at the lateral and middle (not medial) orbital regions, are recommended. Lower medial injections can be

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Frei

associated with diplopia. The zygomaticus muscle is a common muscle involved in HFS, and injections directed diagonally from the corner of the mouth should avoid lip involvement. Additional facial muscles can be injected as appropriate. The patient should be reevaluated approximately 1 month later to assess the effects of the initial injections. At that time, further modification of the injections, either

References Cannon PS, MacKenzie KR, Cook AE, Leatherbarrow B (2010). Difference in response to botulinum toxin type A treatment between patients with benign essential blepharospasm and hemifacial spasm. Clin Exp Ophthalmol, 38, 688–91. Colakoglu BD, Cakmur R, Uzunel F (2011). Is it always necessary to apply botulinum toxin into the lower facial muscles in hemifacial spasm? A randomized, single-blind, crossover trial. Eur Neurol, 65, 286–90. Elston JS (1986). Botulinum toxin treatment of hemifacial spasm. J Neurol Neurosurg Psychiatry, 49, 827–9. Elston JS (1992). The management of blepharospasm and hemifacial spasm. J Neurol, 239, 5–8. Frei K, Truong DD, Dressler D (2006). Botulinum toxin therapy of hemifacial spasm: comparing different therapeutic preparations. Eur J Neurol, 13(Suppl 1), 30–5. Linder JS, Edmonson BC, Laquis SJ, Drewry RD, Jr., Fleming JC (2002). Skin cooling before periocular botulinum toxin A injection. Ophthal Plast Reconstr Surg, 18, 441–2. Mercier, P, Sindou, M (2018). The conflicting vessels in hemifacial spasm:

increasing dose or additional injection sites, can be determined for the next set. Injection pain can be reduced either with skin cooling using ice or with EMLA cream (lidocaine 2.5% and prilocaine 2.5%) (Lindner et al., 2002). Treatment with BoNT appears to remain effective over long-term use, ranging from 4 to 20 years. Many patients will require adjustment of BoNT dose requiring higher doses over time.

Literature review and anatomical-surgical implications. Neurochirurgie, 64, 94–100. Mezaki T, Kaji R, Kimura J, Ogawa N (1999). Treatment of hemifacial spasm with type A botulinum toxin (AGN 191622): a dose finding study and the evaluation of clinical effect with electromyography. No To Shinkei, 51, 427–32. Miwa H, Mizuno Y, Kondo T (2002). Familial hemifacial spasm: report of cases and review of the literature. J Neurol Sci, 193, 97–102. Ozzello, DJ, Giacometti, JN (2018). Botulinum toxins for treating essential blepharospasm and hemifacial spasm. Int Ophthalmol Clin, 58, 49–61. Price J, Farish S, Taylor H, O’Day J (1997). Blepharospasm and hemifacial spasm. Randomized trial to determine the most appropriate location for botulinum toxin injections. Ophthalmology, 104, 865–8. Roggenkamper P, Laskawi R, Damens W, Schroeder M, Nuessgens Z (1994). Orbicular synkinesis after facial paralysis: treatment with botulinum toxin. Doc Ophthalmol, 86, 395–402. Rudzinska M, Wojcik M, Szczudilik A (2010). Hemifacial spasm non-motor and motor-related symptoms and their

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response to botulinum toxin therapy. J Neural Transm, 117, 765–72. Ryu H, Yamamoto S, Miyamoto T (1998). Atypical hemifacial spasm. Acta Neurochir (Wien), 140, 1173–6. Sindou M, Mercier P (2018). Microvascular decompression for hemifacial spasm: Outcome on spasm and complications: a review. Neurochirurgie, 64, 106–16. Tousi B, Perumal JS, Ahuja K, Ahmed A, Subramanian T (2004). Effects of botulinum toxin-B (BTX-B) injections for hemifacial spasm. Parkinsonism Relat Disord, 10, 455–6. Wang A, Jankovic J (1998). Hemifacial spasm: clinical findings and treatment. Muscle Nerve, 21, 1740–7. Yalto, TC, Jankovic J (2011). The many faces of hemifacial spasm: differential diagnosis of unilateral facial spasms. Mov Disord, 26, 1582–92. Yoshimura DM, Aminoff MJ, Tami TA, Scott AB (1992). Treatment of hemifacial spasm with botulinum toxin. Muscle Nerve, 15, 1045–9. Yu YL, Fong KY, Chang CM (1992). Treatment of idiopathic hemifacial spasm with botulinum toxin. Acta Neurol Scand, 85, 55–7.

Chapter

14

Botulinum Toxin in Treatment of Tics Joseph Jankovic

Introduction Tics are brief, sudden, movements (motor tics) or sounds (phonic tics) that are intermittent but may be repetitive and stereotypic (Jankovic et al., 2022). Although tics often spontaneously improve after childhood, they may persist into adulthood and become associated with a variety of comorbid disorders such as attention deficit disorder and obsessivecompulsive disorder. Tourette’s syndrome (TS), considered a genetic and neurodevelopmental disorder, is the most common cause of chronic tics. There are many other causes of tics, referred to as “tourettism” or secondary tics, including insults to the brain and basal ganglia (infection, stroke, head trauma, drugs and neurodegenerative disorders) (Jankovic and Mejia, 2006). The currently used criteria for the diagnosis of definite TS, published by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (American Psychiatric Association, 2013) are as follows: 1. Both multiple motor and one or more vocal tics are present at some time during the illness, although not necessarily concurrently. 2. The tics occur many times a day (usually in bouts) nearly every day or intermittently throughout a period of more than 1 year without a tic-free period of more than 3 consecutive months. 3. The onset is before age 18 years. 4. The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington’s disease or postviral encephalitis).

Clinical Features Motor and phonic tics consist of either simple or complex movements that may be seemingly goal directed. Motor tics may be rapid (clonic) or more prolonged (Jankovic et al., 2021). Many patients exhibit suggestibility and may have a compulsive component, sometimes perceived as an “urge” or a need to perform the movement or sound repetitively until it feels “just right” (Leckman et al., 1994). Some patients repeat other’s gestures (echopraxia) or sounds (echolalia). Many tics are semi-voluntary and are preceded by a premonitory sensation or urge (e.g., crescendo feeling of “tension” before a shoulder shrug, compulsive touching) and may be suppressible (Jankovic et al., 2022). Such premonitory phenomena may

consist of a generalized urge or sensation in the local area of the tic (Kwak et al., 2003).

Treatment Options The most effective anti-tic medications act by blocking dopamine receptors or by blocking vesicular membrane transporter type 2 (VMAT2) and thus depleting presynaptic dopamine (Pringsheim et al., 2019a, 2019b; Billnitzer and Jankovic, 2020). The dopamine -blocking drugs may have a variety of side effects including drowsiness, weight gain, school phobia, parkinsonism and tardive dyskinesia. Tardive dyskinesia, however, has not been reported with dopamine-depleting drugs, such as tetrabenazine, deutetrabenazine or valbenazine (Jankovic, 2016). Although these drugs have been found useful in the treatment of chorea associated with Huntington’s disease and tardive dyskinesia, they have not been approved by the US Food and Drug Administration for the treatment of tics. While shown effective in open label trials, it has been difficult to demonstrate their efficacy in double-bind, placebo-controlled trials (Jankovic et al., 2021). Although considered by many a treatment of choice in patients with moderate to severe tics, the VMAT2 inhibitors may be potentially associated with parkinsonism, depression, drowsiness, insomnia and akathisia. There are many other medical and surgical treatments available for patients with TS but comprehensive discussion of these therapeutics is beyond the scope of this chapter (Pringsheim et al., 2019a, 2019b; Jankovic, 2020; Moretti, 2020)

Use of Botulinum Toxin When oral medications fail to provide satisfactory relief of tics, local chemodenervation with botulinum toxin (BoNT) offers the possibility of relaxing the muscles involved in focal tics without causing undesirable systemic side effects (Anandan and Jankovic, 2021). Focal tics that are repetitively performed are more effectively treated with BoNT than more generalized tics manifested by complex movements that would require injections in multiple muscles. This is especially true if the motor and phonic tics are dystonic (Baizabal-Carvalo et al, 2022a). Two studies demonstrated that onabotulinumtoxinA

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Jankovic

injections markedly reduced in the frequency and intensity of dystonic tics in patients with TS (Jankovic, 1994). The effect lasted a mean of 14.4 weeks. The mean dose per session was 57.4 U in the upper face, 79.3 U in the lower face, 149.6 U in the cervical muscles and 121.7 U in other muscles of the shoulder, forearm and scalp. Four patients received 17.8 U in the vocal cords. In the 25 patients of the study with premonitory sensory symptoms, 21 (84%) had notable reduction in these symptoms. Another open label study involving 30 patients with phonic tics treated with 2.5 U onabotulinumtoxinA in both vocal cords (Porta et al., 2004). Phonic tics improved after treatment in 93% patients, with 50% being tic free. Patients reported improvement in their social life reduced from 50% to 13% post-injection and those with tics causing severe effects on work or school activities. In the 16 subjects (53%) experiencing premonitory symptoms, only 6 (20%) continued to have these sensations after injection. Hypophonia, which was mild, was the only side effect of note in 80% of patients. These results are similar to our initial experience with vocal cord injections in patients with severe simple and complex phonic tics, including coprolalia (Scott et al., 1996). An important observation made in these initial and subsequent trials was that premonitory sensory symptoms and urges were markedly reduced or even eliminated by the local BoNT injection (Bellows and Jankovic, 2019; Kwak et al., 2000; Moretti, 2020). Complications of BoNT were usually transient and consisted of focal weakness of the injected muscles. Only one controlled trial of BoNT in tics has been reported (Marras et al., 2001). This randomized, placebo-controlled, double-blind, crossover study of onabotulinumtoxinA was conducted on 18 patients with tics associated with TS (Marras et al., 2001). There was a 37% reduction in the number of tics per minute within 2 weeks compared to vehicle. The premonitory urge was reduced with an average change in urge scores of –0.46 in the treatment phase and +0.49 in the placebo phase (score range 0 to 4, which was none to severe). Although 50% of patients noted motor weakness in the injected muscles, the weakness was not functionally disabling. Problems with the study included insufficient power to demonstrate significant differences in measured variables such as severity, global impression and pain. In addition, the patients were only assessed at 2 weeks postinjection and the full effect of the treatment may not have been realized. Finally, the patients did not rate their tics as significantly compromising at baseline, indicating that their TS was rather mild. Although tics are often considered relatively benign, many patients with TS have severe, disabling and potentially lifethreatening tics, so-called malignant TS (Cheung et al., 2007). These complicated tics may result from intense, forceful contractions associated with some tics or from compulsive, self-injurious behavior (Baizabal-Carvallo et al., 2022b). In one recent study that included 6791 individuals with TS and 67910 unaffected individuals, TS patients had a 39% increased

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risk of having any cervical spine disorder, probably as a results of repeated head jerking (Isung et al., 2021). In 1996, we described two patients with TS who had compressive cervical myelopathy as a result of severe motor tics involving the neck (so-called whiplash tics) (Krauss and Jankovic, 1996). Subsequently, another TS patient was reported with violent dystonic tics, resulting in cervical myelopathy and quadriparesis, who had not responded to high doses of neuroleptic drugs. The tics improved in all three patients. These reports draw attention to the possibility that some tics can produce disabling compressive myelopathy and, therefore, need to be treated early and aggressively (Cheung et al., 2007; Aguirregomozcorta et al., 2008; Isung et al., 2021). Because of lack of controlled trials, the Cochrane Review concluded that it is uncertain about BoNT effects in the treatment of focal motor and phonic tics as the quality of the evidence is very low (Moretti, 2020). However, long-term experience with a large number of patients has confirmed the beneficial effects of BoNT injections in the treatment of tics, particularly focal dystonic and phonic tics (Vincent, 2008; Jankovic, 2020) (Table 14.1).

Our Experience Our long-term experience with BoNT in well over 1000 patients with tics provides further evidence that this is a safe and effective treatment modality, particularly in patients with focal tics, such as blinking, facial grimacing, jaw clenching, neck extensions (“whiplash tics”) and shoulder shrugging.

Dosages and Muscles Injected The exact muscles and location of injections are determined by considering which movements are of particular concern by the patient, by observing the predominant movement (including severity) of the tic being performed and by determining whether there is a significant localized premonitory sensation or urge associated with the tic. Dosing varies depending on the intensity of the premonitory sensation, force of the contraction, and size of the muscle, but the average starting dose is 25–50 units of onabotulinumtoxinA or incobotulinumtoxinA, 75–150 units of abobotulinumtoxinA, and 1500–2500 units of rimabotulinumtoxinB into the splenius muscle. The dosages of BoNT injected into vocal folds for phonic tics are, of course, substantially smaller, about 1–2 units of onabotulinumtoxinA and 3–5 units of abobotulinumtoxinA on each side. Rarely, as patients experience improvement of their BoNT tic they may have a worsening of tics in other areas or develop new tics. A common tic seen in TS patients is to have sudden retrocollic jerking of the neck, which can lead to pain and cervical spine injury (Kwak et al., 2000). This tic can be effectively treated when the splenius capitis muscles are injected, as indicated in Fig. 14.1. The injection is most efficacious if the patients frequently have a premonitory sensation or urge in the posterior neck just prior to performing the tic.

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Table 14.1 Selected studies of botulinum toxin injection for tics

Reference Design

Size

Treatment (technique, dose)

Brand

Jankovic, 1994

10 (Ages 13–53)

30–300 U

OnabotulinumtoxinA Up to 72 weeks

Kwak et al., Open label, 2000 case series with unblinded assessments

35

Marras Double et al., 2001 blinded, crossover, placebo controlled

20 randomized18 completed (2 lost to followup)

Variable doses based on clinical judgment.

Open-label, case series

Follow-up

109

Outcome

Adverse Events

Comments

Pilot study, tic response rated on 0–4 scale and premonitory urge response rated on 0–3 scale.

Transient ptosis (1), neck weakness (1)

All 10 patients noted moderate to marked improvement in tics and premonitory urges.

Clinical effect on 457.4 U, 79.3 U in the OnabotulinumtoxinA Mean duration of follow-up was 21.2 point self-rating lower face, 149.6 scale months (range, 1. U in the cervical 5–84 months); muscles, and 121.7 mean peak effect of U in other muscles 115 sessions was 2.8 of the shoulder, weeks (range, 0–4); forearm and scalp. the mean duration Four patients of benefit was 14.4 received 17.8 U in weeks (maximum, the vocal cord. 45 weeks); mean latency to onset of benefit was 3.8 days (maximum, 10 days).

Mild and transient, including neck weakness (4), dysphagia (2), ptosis (2), nausea (1), hypophonia (1), fatigue (1), and generalized weakness (1).

Variable protocol based on location of tic involvement Twenty-one (84%) of 25 patients with premonitory sensations derived marked relief of these symptoms (mean benefit, 70.6%).

Primary measure: number of treated tics per minute on a videotape segment. Secondary measures: number of untreated tics per minute, the Shapiro Tourette Syndrome Severity Scale score, a numerical assessment of the urge to perform the treated tic (0 to 4), the premonitory sensation associated with the treated tic (0 to 4), and the patient’s global impression of change.

50% of patients noted weakness not functionally disabling of the injected muscles. 2 patients noted a significant motor restlessness during the active treatment. 2 patients felt the inability to perform the treated tic led to a new tic to replace it.

Observed no pattern to suggest that certain tics respond better than others to botulinum toxin treatment.

OnabotulinumtoxinA All outcomes compared week 2 with baseline measurement. Patients reassessed weeks 6, 12, and every 4 weeks until patient and examiners agreed tic disorder had reached baseline and then the patient crossed over to the second phase of the trial.

110

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Table 14.1 (cont.)

Reference Design

Size

Treatment (technique, dose)

Porta et al., Open label 2004 case series with unblinded assessments

30

Rath et al., 2010

15 (Ages 18–84)

Observational study

Brand

Follow-up

Outcome

Adverse Events

Comments

2.5 IU in both vocal OnabotulinumtoxinA Assessed after 15 days and then cords; mean 4 times over a 12number injections month period. were 1.9 per patient with a mean interval 4.2 months apart.

Phenomenology of tics, global impression of changes by physician and patient, number of BONT-A injections given, interval between injections.

Mild hypophonia was the only side effect of note (80% of patients).

Premonitory experiences dropped from 53% to 20%.

OnabotulinumtoxinA Duration of treatment 1–10 years; mean duration of efficacy was 8.6 weeks.

16 of 18 tics (89%) short-term efficacy was reported successful. Premonitory urges lessened or disappeared.

1 patient each developed transient muscle weakness and flu-like symptoms

3 patients reported permanent remission, but 1 patient later developed a new tic; the best possible outcome was achieved in 5 of 6 (83%) eye tics, 5 of 7 (71%) cervical tics.

Botulinum Toxin in Treatment of Tics Fig. 14.1 Suggested injection sites for “whiplash tic.”

References Aguirregomozcorta M, Pagonabarraga J, Diaz-Manera J et al. (2008). Efficacy of botulinum toxin in severe Tourette syndrome with dystonic tics involving the neck. Parkinsonism Relat Disord,14, 443–5. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.) (DSM-5). Arlington, VA: American Psychiatric Publishing. Anandan C, Jankovic J (2021). Botulinum toxin in movement disorders: an update. Toxins (Basel). 13, 42. Baizabal-Carvallo JF, Alonso-Juarez M, Jankovic J (2022a). Dystonic motor and phonic tics in Tourette syndrome. J Neurol, 269(10), 5312–18. Baizabal-Carvallo JF, Alonso-Juarez M, Jankovic J (2022b). Self-injurious behavior in Tourette syndrome. J Neurol, 269(5), 2453–9. Bellows S, Jankovic J (2019). Treatment of dystonia and tics. Clin Park Relat Disord, 2, 12–19.

Billnitzer A, Jankovic J (2020). Current management of tics and tourette syndrome: behavioral, pharmacologic, and surgical treatments. Neurotherapeutics, 17,1681–93.

deutetrabenazine in children and adolescents with Tourette Syndrome: A randomized clinical trial. JAMA Netw Open, 4, e2128204.

Cheung MY, Shahed J, Jankovic J (2007). Malignant Tourette syndrome. Mov Disord, 22, 1743–50.

Jankovic J, Hallett M, Okun M, Comella C, Fahn S (2022). Principles and Practice of Movement Disorders, 3rd ed. Philadelphia: Elsevier, pp. 418–50.

Isung J, Isomura K, Larsson H et al. (2021). Association of Tourette Syndrome and Chronic Tic Disorder with Cervical Spine Disorders and Related Neurological Complications JAMA Neurol, 78(10), 1205–11.

Jankovic J, Mejia NI (2006). Tics associated with other disorders. In Walkup J, Mink J, Hollenbeck P (eds.), Advances in Neurology, Vol. 99, Tourette Syndrome. Philadelphia: Lippincott Williams & Wilkins, pp. 61–8.

Jankovic J (1994). Botulinum toxin in the treatment of dystonic tics. Mov Disord, 9, 347–9.

Kendall KA, Leonard RJ (2011). Interarytenoid muscle botox injection for treatment of adductor spasmodic dysphonia with vocal tremor. J Voice, 25, 114–19.

Jankovic J (2016). Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin Pharmacother, 17, 2461–70. Jankovic J (2020). Treatment of tics associated with Tourette syndrome. J Neural Transm (Vienna). 127, 843–50. Jankovic J, Coffey B, Claassen DO et al. (2021). Safety and efficacy of flexible-dose

Krauss JK, Jankovic J Severe motor tics causing cervical myelopathy in Tourette’s syndrome (1996). Mov Disord, 11, 563–6. Kwak C, Vuong KD, Jankovic J (2003). Premonitory sensory phenomenon in Tourette’s syndrome. Mov Disord, 18, 1530–3.

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Jankovic Kwak, CH, Hanna PA, Jankovic J (2000). Botulinum toxin in the treatment of tics. Arch Neurol, 57, 1190–3. Leckman JF, Walker DE, Goodman WK, Pauls DL, Cohen DJ (1994). “Just right” perceptions associated with compulsive behavior in Tourette’s syndrome. Am J Psychiatry, 151, 675–80. Marras C, Andrews D, Sime E, Lang AE (2001). Botulinum toxin for simple motor tics: A randomized, double-blind, controlled clinical trial. Neurology, 56, 605–10. Moretti A (2020). Is botulinum toxin effective and safe for motor and phonic tics in patients affected by Tourette syndrome? A Cochrane Review summary with commentary. Dev Med Child Neurol, 62, 274–6.

Pandey S, Srivanitchapoom P, Kirubakaran R, Berman BD (2018). Botulinum toxin for motor and phonic tics in Tourette’s syndrome. Cochrane Database Syst Rev, 1, CD012285. Porta M, Maggioni G, Ottaviani F, Schindler A (2004). Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci, 24, 420–3. Pringsheim T, Holler-Managan Y, Okun MS et al. (2019a). Comprehensive systematic review summary: treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology, 92, 907–15. Pringsheim T, Okun MS, Müller-Vahl K et al. (2019b). Practice guideline recommendations summary: treatment of tics in people with Tourette syndrome

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and chronic tic disorders. Neurology, 92, 896–906. Rath JJ, Tavy DL, Wertenbroek AA et al. (2010). Botulinum toxin type A in simple motor tics: short-term and long-term treatment-effects. Parkinsonism Relat Disord, 16, 478–81. Scott BL, Jankovic J, Donovan DT (1996). Botulinum toxin into vocal cord in the treatment of malignant coprolalia associated with Tourette’s syndrome. Mov Disord, 11, 431–3. Singer HS (2005). Tourette’s syndrome: from behaviour to biology. Lancet Neurol, 3,149–59. Vincent DA Jr (2008). Botulinum toxin in the management of laryngeal tics. J Voice, 22, 251–6.

Chapter

15

The Use of Botulinum Toxin in Tremors Shivam Om Mittal and Joseph Jankovic

Introduction Tremor is one of the common movement disorders encountered by neurologists in clinical practice. Based on the history and phenomenology, the tremor can be classified commonly as Parkinson’s disease (PD) tremor, essential tremor (ET), essential tremor plus, dystonic tremor, task-specific tremor and other tremor syndromes (Lenka and Jankovic, 2021). This chapter describes the role of botulinum neurotoxin (BoNT) in several tremor conditions and provides some practical clinical pearls related to BoNT injection techniques.

Essential Tremor Essential tremor (ET) usually presents with 4 to 10 Hz of bilateral upper limb action tremor (Lenka and Jankovic, 2021). According to the Task Force on Tremor (now called the Tremor Study Group) of the International Parkinson and Movement Disorder Society, there are currently two types of essential tremor, which includes ET and ET plus. In ET, there should be isolated tremor syndrome identified by bilateral upper limb action tremor, a duration of at least 3 years, “absence of other neurological signs, such as dystonia, ataxia, or parkinsonism” and it may or may not be accompanied by “tremor in other locations (e.g., head, voice, or lower limbs)” (Bhatia et al., 2017). ET with additional neurological soft signs is now labeled as ET plus, as per the new tremor classification (Bhatia et al., 2017; Lenka and Jankovic, 2021). ET patients can also have accompanying head and vocal cord tremor. Isolated focal tremor involving the head or vocal cord is also described (Bhatia et al., 2017). Patients with cervical dystonia commonly have dystonic head tremor, which needs to be clinically differentiated from ET head tremor or isolated head tremor (Bhatia et al., 2017). The heterogeneity of associated features suggests that there may be subtypes of ET with different and unique pathogenic mechanisms.

Treatment for ET As per the American Academy of Neurology recommendations, medications such as propranolol and primidone are the first-line treatment options (Zesiewicz et al., 2011). Other medications such as topiramate and pregabalin may also be

helpful. Overall, the medications can improve the tremor by 50 to 60%. For medical refractory tremor, patients can be considered for surgical options such as deep brain stimulation or thalamotomy by MRI-guided, focused ultrasound procedure (Fasano and Deuschl, 2015). For the patients who have medication refractory tremor and are not candidates for surgical treatment options, BoNT injection is a clinically helpful tool in the armamentarium for treating ET (Mittal et al., 2019).

Parkinson’s Disease Tremor Tremor, present in about 75% of patients with PD, is typically a 4–6 Hz resting tremor, usually asymmetric, involving hand (classical “pill-rolling tremor”) but it may also involve legs, lips and jaw, but almost never involves the neck and head. The resting hand tremor is often exacerbated during walking or while performing physical or mental tasks, and it abates with volitional activity. Patients with PD also often exhibit a reemergent tremor, which is a form of resting tremor that reemerges after a latency of a few seconds when hands and arms are held in an anti-gravity, horizontal posture (Jankovic, 2016). This reemergent tremor is usually more disabling than the typical resting tremor, as it often interferes with ability to hold objects against gravity.

Treatment for PD Tremor Treatment options for PD tremor includes levodopa medications, dopamine agonists and anticholinergic medications. Unlike the other cardinal motor features of PD such as bradykinesia and rigidity, tremor may be refractory to pharmacological treatment or may require the use of high doses of levodopa. Anticholinergic medications (e.g., trihexyphenidyl) can help some patients with refractory PD tremor, but their clinical use is limited in the elderly population. Surgical treatment such as deep brain stimulation of subthalamic nucleus or globus pallidus interna or MRI-guided, focused ultrasound treatment is effective against refractory PD tremor, but each surgical intervention has its own limitations such as strict eligibility criteria, surgical risks, availability of specialized center and the affordability by the patient.

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Mittal, Jankovic

Botulinum Toxin in Tremor Conditions Botulinum Toxin in ET There are several open-label (OL) studies and four randomized controlled studies (RCT) published on BoNT in ET hand tremor (Mittal et al., 2019). Initial studies used a fixed-dose, fixed-muscle design where every patient received the same dose of BoNT in the same forearm muscles. In the past few years, a customized injection approach or individualized treatment for BoNT injections has been proposed with more favorable results and with fewer adverse effects, such as hand weakness. In the first RCT study (Jankovic et al., 1996), 25 patients were injected in both the wrist flexors (flexor carpi radialis [FCR] and flexor carpi ulnaris [FCU]) and the extensors (extensor carpi radialis [ECR] and extensor carpi ulnaris [ECU]) with 50 U of onabotulinumtoxinA (OnaA) and with an additional 100 U after 4 weeks if they failed to show any clinical improvement. Resting, postural and kinetic tremors were evaluated at intervals of 2 to 4 weeks for 16 weeks using tremor severity rating scales, accelerometry and assessments of tremor improvement and functional disability (Jankovic et al., 1996). Postural accelerometry measurements showed a 30% reduction in amplitude in 9 of 12 OnaA-treated subjects and in 1 of 9 placebo-treated subjects. There were no significant improvements in the functional rating scales. All patients treated with OnaA reported mild, transient degree of finger extensor weakness. In a multicenter, double-blinded, placebo-controlled (DBPC) study (Brin et al., 2001), 133 patients with ET were randomized to treatment with either low-dose (50 U) or high-dose (100 U) OnaA or placebo. Both the wrist flexors (FCU, FCR) and extensors (ECU, ECR) were injected. The results of treatment on assessment using functional rating scales indicated that low-dose OnaA significantly (p