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Cochlear implants: Indications, Investigation , Surgery

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Prasanna Datta

Cochlear implants: Indications, Investigation , Surgery

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Susan B. Waltzman j. Thomas Roland jr. Third Edition �Thiemehttp://medical.dentalebooks.com
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Cochlear Implants Third Edition Susan B. Waltzman, PhD Marica F. Vilcek Professor of Otolaryngology Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York J. Thomas Roland Jr., MD Professor of Otolaryngology and Neurosurgery Mendik Foundation Professor and Chairman Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York Thieme New York • Stuttgart • Delhi • Rio http://medical.dentalebooks.com
Thieme Medical Publishers, Inc. 333 Seventh Ave. New York, NY 1 0001 Executive Editor: Timothy Hiscock Managing Editors: j. Owen Zurhellen IV and Barbara A. Chernow Editorial Assistant: Heather Allen SeniorVice President, Editorialand ElectronicProductDevelopment: Cornelia Schulze Production Editor: Sean Woznicki International Production Director: Andreas Schabert Senior Vice President and Chief Operating Officer: Sarah Vanderbilt President: Brian D. Scanlan Printer: Sheridan Books Library of Congress Cataloging-in-Publication Data Cochlear implants (Waltzman) Cochlear implants f (edited by] Susan B. Waltzman, J. Thomas Roland. - Third edition. p. : em. Includes bibliographical references and index. ISBN 978-1 -60406-903-7 (hardback) - ISBN 978-1-60406-906- 8 (elSBN) I. Waltzman, Susan B., editorofcompilation. II. Roland,]. Thomas]r. editor of compilation. Ill. Title. [DNLM: 1. CochlearImplants. 2. Hearing Disorders-surgery. WV 274] RF305 617.8'8220592-dc23 2013024770 Copyright ©2014 by Thieme Medical Publishers, Inc. Thieme Publishers New York 333 Seventh Avenue, New York, NY 10001 USA, 1 -800-782-3488, customerservice@thieme.com Thieme Publishers Stuttgart Riidigerstrasse 14, 70469 Stuttgart, Germany, +49 (0]711 8931 421 , customerservice@thieme.de Thieme Publishers Delhi A-12, Second Floor, Sector-2, NOIDA-201301 , Uttar Pradesh, India +91 120 45 566 00, customerservice@thieme.in Thieme Publishers Rio, Thieme Publicac,:6es Ltda. Argentina Building 16th floor, Ala A, 228 Praia do Botafogo Rio de janeiro 22250-040 Brazil, +55 21 3736-3631 Printed in the United States. 5 4 3 2 1 ISBN 978-1-60406-903-7 Also available as an e-book: elSBN 978-1 -60406-906-8 Important note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may be required. The authors and editors ofthematerial hereinhaveconsultedsourcesbelievedto be reliable in their efforts to provide information that is complete and in accord with the standards accepted at the time of publication. However, in view ofthe possibility of human error by the authors, editors, or publisher of the work herein or changes in medical knowledge, neither the authors, editors, nor publisher, nor any other party who has been involved in the preparation ofthis work, warrants that the information contained herein is in every respect accurateorcomplete, and they are not responsible for any errors or omissions or forthe results obtained from use ofsuch information. Readers are encouraged to confirm the information contained herein with other sources. For example, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the informa­ tion contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindica­ tions for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain. J;jFSC wwwJsc.org MIX Paper from responsible sources FSC"' C021256 This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation without the publisher's consent is illegal and liable to prosecution. This applies in partic­ ular to photostatreproduction, copying,mimeographing or dupli­ cation of any kind, translating, preparation of microfilms, and electronic data processing and storage. http://medical.dentalebooks.com
Contents Preface .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Contributors .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii 1 History of the Cochlear Implant... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Marc D. Eisen 2 Genetics of Hearing Loss and Predictors of Cochlear Implant Outcome .............. Robert W. Eppsteiner, Richard K. Gurgel, and Richardj.H. Smith 3 Consequences of Deafness and Electrical Stimulation on the Peripheral and Central 10 Auditory System.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 james B. Fallon, David K. Ryuga, and Robert K. Shepherd 4 Auditory Neuroplasticity .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Robert C. Froemke, Selena E. Heman-Ackah, and Susan B. Waltzman 5 Mimicking Normal Auditory Functions with Cochlear Implant Sound Processing: Past, Present, and Future .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Ward R. Drennan, Mario A. Svirsky, Matthew B. Fitzgerald, andjay T. Rubinstein 6 Expanding Criteria for the Evaluation of Cochlear Implant Candidates.. . . . . . . . . . . . . . 61 Susan Arndt, Roland Laszig, Antje Aschendorff. and Rainer Beck 7 Principles of Cochlear Implant Imaging .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Andrewj. Fishman and Selena E. Heman-Ackah 8 Intraoperative Monitoring During Cochlear Implantation ... . . . . . . . . . . . . . . . . . . . . . . 100 Mauro K. Cosetti 9 The History of Cochlear Implant Electrode Design... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Maja Svrakic andj. Thomas RolandJr. 10 Cochlear Implant Surgical Technique ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Peter S. Roland andj. Thomas RolandJr. 11 New Horizons in Surgical Technique .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Theodore R. McRackan, Robert F. Labadie, j. Thomas RolandJr., and David S. Haynes 12 A Global View of Device Reliability... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Rolf-Dieter Battmer 13 Revision Cochlear Implantation .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 David R. Friedmann, j. Thomas RolandJr., and Susan B. Waltzman 14 Advancements in Cochlear Implant Programming............................... 148 William H. Shapiro v http://medical.dentalebooks.com
vi 15 Auditory and Linguistic Outcomes in Pediatric Cochlear Implantation .. . . . . . . . . . . . . . 158 Gerard M. O'Donoghue and David B. Pisani 16 Auditory Outcomes in the Adult Population Oliver F. Adunka, Margaret T. Dillon, and Craig A. Buchman 167 17 Therapeutic Approaches Following Cochlear Implantation .. . . . . . . . . . . . . . . . . . . . . . . 182 Warren Estabrooks, K. Todd Houston, and Karen Maclver-Lux 18 Acoustic and Electric Speech Processing .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Bruce}. Gantz, Sarah E. Mowry, Rick F. Nelson, Sean 0. McMenomey, Chris}. james, and Bernard Fraysse 19 Music Perception .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Alexis Roy and Charles}. Limb 20 Auditory Brainstem Implants .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Shoun D. Rodgers, john G. Golfinos, and}. Thomas RolandJr. 21 Applying Cochlear Implant Technology to Tinnitus and Vestibular Interventions... . . . . 221 justin S. Golub, james 0. Phillips, andjay T. Rubinstein 22 The Impact of Cochlear Implantation on the Recipient's Health-Related Quality of Life... . 235 Selena E. Heman-Ackah 23 Future Technology .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Susan B. Waltzman and}. Thomas RolandJr. Index...................................................................... 249 http://medical.dentalebooks.com
Preface This fully updated third edition of Cochlear Implants repre­ sents the superb efforts of many individuals who have contributed significantly to the field. We have built on the previous edition by adding new chapters relating to genet­ ics, neuroplasticity, expanding criteria for implantation, the application of implant technology to tinnitus and vestibular issues, music perception, intraoperative monitoring, device reliability and reimplantation, and the use of quality-of-life and outcome measures-areas that occupy the forefront of cochlear implantation. Other chapters have been revised to reflect current research and clinical applications and pro­ vide the most recent information related to the clinical and translational sciences that continue to advance this exciting technology and its implementation. Patient outcomes, can­ didacy criteria, technical design, surgical technique, and programming and processing concepts are constantly pro­ gressing, and increasing numbers of individuals are gaining significant benefit. Our goal was to create a book that will provide both experienced and new and budding otolaryngol­ ogists-head and neck surgeons, neurotologists, audiologists, neuroscientists, neurophysiologists, speech pathologists, tea­ chers of the deaf, psychologists, and others interested in cochlear implants with an extraordinary resource for years to come. Thanks to the contributors and their hard work, dedication, and attention to detail, we feel that this goal has been exceeded, and we are most grateful to all involved. vii http://medical.dentalebooks.com
viii Contributors Oliver F. Adunka, MD, FACS Associate Professor OtologyfNeurotology/Skull Base Surgery Department of Otolaryngology-Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Susan Arndt, MD Department of Otorhinolaryngology Implant Center Freiburg University of Freiburg Freiburg, Germany Antje Aschendorff, MD Associate Professor Department of Otorhinolaryngology Head of Implant Center Freiburg University of Freiburg Freiburg, Germany Rolf-Dieter Battmer, PhD Professor and Director Center for Clinical Technology Research Trauma Hospital Berlin, Germany Rainer Beck, MD Department of Otorhinolaryngology Implant Center Freiburg University of Freiburg Freiburg, Germany Craig A. Buchman, MD, FACS Professor and Vice Chairman for Clinical Affairs Chief OtologyfNeurotology/Skull Base Surgery Department of Otolaryngology-Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Maura K. Cosetti, MD Assistant Professor and Co-Director of Otology/Neurotology Departments of Otolaryngology-Head and Neck Surgery and Neurosurgery Louisiana State University Health Sciences Center Shreveport, Louisiana Margaret T. Dillon, AuD, CCC-A, F-AAA Assistant Professor Department of Otolaryngology-Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Ward R. Drennan, PhD Virginia Merrill Bloedel Hearing Research Center Department of Otolaryngology-Head and Neck Surgery University of Washington Seattle, Washington Marc D. Eisen, MD, PhD Adjunct Clinical Assistant Professor Department of Otorhinolaryngology-Head and Neck Surgery University of Pennsylvania Philadelphia, Pennsylvania Robert W. Eppsteiner, MD Otolaryngology Resident T32 Research Fellow Department of Otolaryngology-Head and Neck Surgery University of Iowa Hospitals and Clinics Iowa City, Iowa Warren Estabrooks, M.Ed., Dip.Ed.Deaf, LSLS Cert. AVT President and CEO WE Listen International Inc. Toronto, Ontario, Canada james B. Fallon, PhD Bionics Institute Melbourne, Australia and Department of Medical Bionics University of Melbourne Melbourne, Australia AndrewJ. Fishman, MD Director of Neurotology & Cranial Base Surgery Director, Cochlear Implant Program Cadence Neuroscience Institute Winfield, Illinois and International Visiting Professor of Otolaryngology-Head & Neck Surgery NATO Military Hospital, Bydgoszcz, Poland Professor of Pediatric Otolaryngology Children's Hospital of Bydgoszcz Bydgoszcz, Poland Matthew B. Fitzgerald, PhD, CCC-A Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York. New York http://medical.dentalebooks.com
Professor Bernard Fraysse Chairman of the ENT Department H6pital Purpan Toulouse, France David R. Friedmann, MD Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Robert C. Froemke, PhD Assistant Professor of Neuroscience and Otolaryngology Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Bruce j. Gantz, MD, FACS Professor and Head, Department of Otolaryngology-Head and Neck Surgery Brian F. McCabe Distinguished Chair in Otolaryngology­ Head and Neck Surgery Professor, Department of Neurosurgery University of Iowa Carver College of Medicine Iowa City, Iowa john G. Golfinos, MD Chairman, Department of Neurosurgery Associate Professor of Neurosurgery and Otolaryngology New York University School of Medicine NYU Langone Medical Center New York, New York justin S. Golub, MD OtologyfNeurotologyfLateral Skull Base Surgery Fellow Department of Otolaryngology-Head and Neck Surgery University of Cincinnati Cincinnati Children's Hospital Medical Center Cincinnati, Ohio Richard K. Gurgel, MD Assistant Professor Division of Otolaryngology-Head and Neck Surgery University of Utah Salt Lake City, Utah David S. Haynes, MD, FACS Otology Group of Vanderbilt Vanderbilt University Medical Center Nashville, Tennessee Selena E. Heman-Ackah, MD, MBA Otology, Neurotology and Skull Base Surgery Medical Director of Otology, Neurotology, and Audiology Division of Otolaryngology-Head and Neck Surgery Department of Surgery Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts K. Todd Houston, PhD, CCC-SLP, LSLS Cert. AVT School of Speech-Language Pathology and Audiology University of Akron Akron, Ohio Chris j. james, PhD CHU Toulouse-Purpan and Cochlear France SAS Toulouse, France Robert F. Labadie, MD, PhD Professor and Director of Research Department of Otolaryngology-Head and Neck Surgery Professor, Department of Biomedical Engineering Vanderbilt University Nashville, Tennessee Roland Laszig, MD Head, Department of Otorhinolaryngology Implant Center Freiburg University of Freiburg Freiburg, Germany Charlesj. Limb, MD Associate Professor Department of Otolaryngology-Head and Neck Surgery johns Hopkins Hospital johns Hopkins University School of Medicine Peabody Conservatory of Music Baltimore, Maryland Karen Maclver-Lux, MA, Aud(C), LSLS Cert. AVT Director Maclver-Lux Auditory Learning Services King City, Ontario, Canada Sean 0. McMenomey, MD Professor of Otolaryngology and Neurosurgery Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York ix http://medical.dentalebooks.com
X Theodore R. McRackan, MD Department of Otolaryngology-Head and Neck Surgery Vanderbilt University Nashville, Tennessee Sarah E. Mowry, MD Department of Otolaryngology Georgia Regents University Augusta, Georgia Rick F. Nelson, MD, PhD Department of Otolaryngology-Head and Neck Surgery University of Iowa Hospitals and Clinics Iowa City, Iowa Gerard M. O'Donoghue, MD Consultant Neuro-Otologist Nottingham University Hospitals NHS Trust Queens Medical Centre Honorary Professor of Otology and Neurotology University of Nottingham Co-founder, Nottingham Hearing Biomedical Research Unit Nottingham, United Kingdom james 0. Phillips, PhD Research Associate Professor Department of Otolaryngology-Head and Neck Surgery University of Washington Seattle, Washington David B. Pisoni, PhD Distinguished Professor of Psychological and Brain Sciences Chancellor's Professor of Cognitive Science Department of Psychological and Brain Sciences Indiana University Bloomington, Indiana Shaun D. Rodgers, MD Department of Neurosurgery New York University School of Medicine NYU Langone Medical Center New York, New York ]. Thomas RolandJr., MD Professor of Otolaryngology and Neurosurgery Mendik Foundation Professor and Chairman Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York Peter S. Roland, MD Professor and Chairman Department of Otolaryngology-Head & Neck Surgery Professor of Neurological Surgery University of Texas Southwestern Medical Center Dallas, Texas Alexis Roy, MSc Harvard Medical School Boston, Massachusetts jay T. Rubinstein, MD, PhD Virginia Merrill Bloedel Professor and Director Virginia Merrill Bloedel Hearing Research Center Professor of Otolaryngology and Bioengineering University of Washington Seattle, Washington David K. Ryugo, PhD Curran Foundation Professor Garvan Institute of Medical Research Darlinghurst, New South Wales and Conjoint Professor School of Medical Sciences University of New South Wales Kensington, New South Wales Australia William H. Shapiro, AuD, CCC-A Clinical Associate Professor Supervising Audiologist NYU Cochlear Implant Center New York University School of Medicine New York, New York Robert K. Shepherd, PhD Bionics Institute Melbourne, Australia and Department of Medical Bionics University of Melbourne Melbourne, Australia RichardJ.H. Smith, MD Sterba Hearing Research Professor Director, Molecular Otolaryngology and Renal Research Laboratories Vice Chair, Department of Otolaryngology Professor of Otolaryngology, Molecular Physiology & Bio­ physics, Pediatrics and Internal Medicine (Division of Nephrology) University of Iowa Hospitals and Clinics Iowa City, Iowa http://medical.dentalebooks.com
Mario A. Svirsky, PhD Noel L. Cohen Professor of Hearing Science and Vice­ Chairman of Research Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Maja Svrakic, MD Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Susan B. Waltzman, PhD Marica F. Vilcek Professor of Otolaryngology Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York xi http://medical.dentalebooks.com
xii Acknowledgments We thank all the contributors to this third edition. In addition, we are indebted to J. Owen Zurhellen, Timothy Hiscock, and Chris Malone at Thieme Publishers for their commitment, guidance, and patience during the writing of this book; we could not have done it without their profes­ sionalism and support. http://medical.dentalebooks.com
1 History of the Cochlear Implant Marc D. Eisen • Introduction The cochlear implant has created a paradigm shift in the treat­ ment of sensorineural hearing loss. The impact that the implant has had is far greater than one would expect considering the brief time over which its development occurred. In less than four decades, the cochlear implant progressed from the first attempts to elicit hearing via direct electrical stimulation of the auditory nerve to a commercially available device that has restoredvarying degrees of hearing to tens of thousands ofdeaf patients. Several themes that can be discerned in the implant's history are widely applicable to the development of other neu­ ral prostheses. For one, the implant's development was truly an interdisciplinary effort. Significant contributions came from professionals in fields as diverse as engineering, otology, audiol­ ogy, auditory neurophysiology, psychoacoustics, and industry. The interaction among these players was not always harmoni­ ous, but the strife yielded synthesis and progress. Another theme is the courage of a few clinicians to risk their reputations and eschew scientific dogma in the hope of helping the patients that sought their care. A third theme is the willing­ ness of patients to take substantial risks in serving as research subjects, sometimes without any promise of individual gain. This chapter cannot mention each and every contribution that was made to the implant's early development, but rather cites selected events and characters that, with the aid of the "retro­ spectroscope," exemplify these themes and demonstrate the progression of events leading toward a device that enables the patient who has lost all hearing to regain the ability to converse on the telephone and enables the deaf child to develop near­ normal speech production and understanding. The implant's development occurred in several phases. The first phase of pioneering and experimentation began in 1957 and continued throughout the 1960s. The second phase, which entailed feasibility studies, occurred in the 1970s. These studies were conducted to determine whether the implant safely stim­ ulated the auditory pathway and elicited useful hearing. A third phase entailed the subsequent development of a commercially viable multielectrode cochlear prosthesis. • Precursors Several discoveries made during the first half of the twentieth century were not directly related to electrical stimulation of the cochlear nerve, but were influential on the early development of the cochlear implant and therefore warrant mention. These include Homer Dudley's work on the synthesis of speech and his "vocoder," Glenn Wever and his discovery of the cochlear microphonic, and S.S. Stevens and coworkers' description of electrophonic hearing. The Vocoder Homer Dudley was a researcher at the Bell Telephone Laborato­ ries in New York. He described and demonstrated in 1939 a real-time voice synthesizer that produced intelligible speech using circuitry designed to extract the fundamental frequency of speech, the intensity of its spectral components, and its over­ all power. The spectral components were extracted with a series of ten band-pass filters covering the frequency range of speech.l He named the synthesizer the "vocoder," a compressed version of "coding the voice." The operating principles of the vocoder for condensing speech into its principal components formed the basis of early speech processing schemes for multi­ channel cochlear implants. The Cochlear Microphonic In 1930, Wever and Bray2 recorded and described the electrical potentials in the cochlea that faithfully reproduced the sound stimulus. This phenomenon became known as the "Wever-Bray effect." The source of these measured potentials was initially incorrectly assumed to represent auditory nerve discharges. This theory ofthe origin ofthese potentials would be equivalent to the "telephone" theory of hearing, referring to the analogue representation of the voice carried along the "cable" of the auditory nerve as it would along the wires of a telephone line. In truth, what Wever and Bray were recording was not a response of the cochlear nerve, but the cochlear microphonic produced by the outer hair cells in the cochlea. Regardless of the ultimate dismissal of the telephone theory of hearing, it inspired several of the earliest pioneers of the cochlear implant. Electrophonic Hearing S.S. Stevens and his colleagues classically described in the 1930s the mechanism by which the cochlear elements respond to elec­ trical stimulation to produce hearing.3 This mechanism was coined "electrophonic hearing." We now know that electrophonic hearing results from the mechanical oscillation of the basilar membrane in response to voltage changes. The primary tenet of their description was the requirement that the cochlea be intact. Prior to 1957, efforts to stimulate hearing electrically were per­ formed on subjects with at least partially functioning cochleas. These subjects' responses could be accounted for by electrophonic hearing rather than by direct nerve stimulation. Furthermore, the developers of the earliest cochlear implant efforts had the burden of proving that the implants were directly stimulating the cochlear nerve rather than eliciting electrophonic hearing. • Pioneers: 1957-1973 Andre Djourno and Charles Eyries Although numerous attempts to treat deafness with electricity have been reported over the past several centuries,4 the first reported direct stimulation of the cochlear nerve for the purpose of generating hearing appeared as recently as 1957 with the work of Andre Djourno and Charles Eyries. Despite the revolu­ tionary impact that the cochlear implant has had on all auditory disciplines, these beginnings in Paris received little attention. http://medical.dentalebooks.com
2 . . Andre Djourno (1904-1996) received degrees in both science and medicine, yet he devoted his career to science. His early endeavors were studying the electrophysiology of frog periph­ eral nerve.5·6 He then ventured into more medical applications of electricity. Several of Djourno's earlier innovations reflected his inventiveness: a device to measure the pulse continuously,? high-frequency electrical stimulation to remove metal frag­ ments from bones,8 and the use of electroencephalography (EEG) to study narcolepsy.9 Perhaps the most prescient devel­ opment from this period was artificial respiration utilizing direct phrenic nerve stimulation.10 Although this innovation did not reach widespread clinical implementation, it demon­ strated Djourno's interest in neural prostheses. Djourno focused the next phase of his career on fabricating and testing implantable induction coils to be used for "telesti­ mulation," or stimulation through inductive coupling without wires. Djourno assembled these induction coils himself and called them "microbobinages," as the coils wound with wire resembled small spools of thread (� Fig. 1.1). Fig. 1 .1 Example of implantable induction coils ("microbobinages") assembled by Djourno in his laboratory. Induction coils like the ones shown here were used in various applications, including the stimulation of the auditory pathway. The hand holding the coils provides perspective on the implant's size. (Courtesy of the john Q. Adams Center.) Both the active coil and the ground electrode were implanted under the skin of an animal, and stimulation was trans­ cutaneous (rather than percutaneous). The implantable coils were first used to stimulate the sciatic nerve and thus trigger a jump behavior in rabbits. Djourno studied numerous aspects of telestimulation, including electrode biocompatibility (he described using one of the first bioresistant resins, araldite, for example, to coat the electrodes).11 He addressed the effect of stimulus frequency on muscle contraction, and he found that with higher frequency stimuli, muscles would not contract, whereas with lower frequency stimuli muscle contraction was painful. Djourno found the "right" stimulus frequency between 400 and 500 Hz. Since this frequency was within the speech range, he began to use the analogue signal of his own voice as the telestimulating stimulus.12 Triggering a nerve with his voice may well have contributed to the idea of stimulating the cochlear nerve to restore hearing. Djourno also addressed the safety of repetitive stimulation on tissue, demonstrating that the sciatic nerve from an implanted rabbit, when examined histologically and grossly, showed no changes after 2 years of repetitive stimulation.B Throughout this time Djourno revealed little interest in hear­ ing. He recognized, however, the potential of using the micro­ bobinages to stimulate the auditory system, as he noted in a 1954 publication the possibility of "treating deafness" as a potential application.12 Charles Eyries (1908-1996) completed his training in oto­ laryngology in Paris in the early 1940s. Clinically, Eyries earned early recognition for his description of a procedure to treat ozena, or atrophic rhinitis, by placing implants underneath the nasal mucosa to decrease the caliber of the nasal passages.14 This procedure became known in the French literature as the "Eyries operation." Eyries was named chief of otorhinolaryngo­ logy and head and neck surgery at I.:Institut Prophylactique in 1953, which has since been renamed I.:Institut Arthur Vernes. Although primarily a clinician, he had research interests in neuroanatomy and embryology of the facial nerve, and he wrote about surgical facial nerve repairs.15 Eyries had shown little interest in hearing at this point in his career and had never worked with Djourno, although he knew of Djourno because both he and Djourno had laboratories in the medical school associated with the hospital. As the local expert on facial nerve repairs, Eyries was asked in February 1957 to provide a consultation for an unfortunate patient, a 57-year-old man who suffered from large bilateral cholesteatomas. A right-sided temporal bone resection was performed 5 days prior to the consultation and an extensive left temporal bone resection was per­ formed several years earlier. Both procedures involved abla­ tion of the labyrinth and facial nerve sectioning. As a result, the patient was left with bilateral deafness and bilateral facial nerve paralysis. Eyries was consulted to consider a facial nerve graft for reanimation.16 On examination, Eyries found that the caliber of the patient's remaining nerve was too small to support a local nerve transfer. Eyries therefore embarked on a search for appropriate graft material. He went to the medical school seeking cadaverous material, where he met Djourno, who offered to help and suggested stimulating hearing at the same time. Although Eyries was primarily interested in http://medical.dentalebooks.com
his patient's facial reanimation, he agreed to implant an electrode into the patient at the time of surgery. Eyries's justification for agreeing to the implantation was that the cavity was already exposed and the patient had nothing to lose in having the extra procedure.16 From Djourno's standpoint, the patient was deaf and begging to escape from the silence that haunted him, and he was fascinated by the opportunity to telestimulate the auditory system.17 The procedure took place on February 25, 1 957. Eyries performed the right-sided facial nerve graft using fetal sci­ atic nerve as the graft material, which purportedly proved to be successful. At the time of surgery, the proximal cochlear nerve stump was found to be significantly shred­ ded. Djourno and Eyries chose to seat the active electrode into the remaining stump and place the induction coil into the temporalis muscle. A postoperative lateral skull film con­ firmed its placement (� Fig. 1 .2). Some testing was done intraoperatively. The stimulus waveforms included bursts of a 1 00-Hz impulse signal administered 15 to 20 times per minute, low-frequency alternating current, and the analogue signal of words spoken into a microphone. The patient described detecting auditory sensations. Several qualitative observations were made: the patient's discrimination of intensity was good; frequency discrimination was poor; no speech recognition was evident. The patient underwent an extensive post­ operative rehabilitation with the implant under the guid­ ance of the speech therapist. Over the ensuing months more complex stimuli were administered, and the patient was able to differentiate between higher frequency (described as "silk ripping") and lower frequency (described as "burlap tearing") stimulation. He appreciated environmental noises Fig. 1 .2 Lateral skull film of Djourno and Eyries's first implant following surgery. The coil has been embedded in the temporalis muscle, whereas the electrodes were placed near the remaining stump of the cochlear nerve. (Courtesy of the john Q. Adams Center.) and several words, but could not understand speech. The publication that resulted from this work is the seminal citation for direct cochlear nerve stimulation.18 Several months later, during testing, the electrode suddenly ceased to function. Djourno and Eyries went to the operating room to investigate. They found that a solder joint connecting the wires to the ground electrode embedded into the tempora­ lis muscle had broken, and the implant was replaced. The sec­ ond implant, however, suffered the same fate. Eyries held Djourno responsible for the broken electrodes and refused to perform a third implantation.19 The falling out between the two men over this problem was the end of Eyries's involvement in the project. After this event, he and Djourno rarely conversed for the rest of their lives. This was not quite the end of the story for Djourno, however. He went on to address several aspects of hearing applicable to electrical stimulation. For one, he examined the oscillographic representation of spoken words in an effort to give deaf patients a visual representation of speech that they could use for biofeedback when learning to speak.2o After the first implant effort, a colleague approached Djourno to enter into a business venture to develop the implant. The colleague proposed that in exchange for an exclusive arrangement on the project, he would provide Djourno with the financial and engineering support of industry_17 Djourno was always an academic ide­ alist, and he did not believe in profiting from his discoveries. Furthermore, he detested industry and would have no part in granting exclusivity. As a matter of principle, Djourno chose to do another implant with a different oto­ laryngologist, Roger Maspetiol_l7 This second patient, deaf­ ened from streptomycin ototoxicity, was implanted with an electrode near the promontory, rather than within the tem­ poral bone. The patient showed little enthusiasm for her device, and she was lost to follow-up only a few months after it was implanted. Djourno subsequently lost funding for further implant work.21 This signaled the end of Djour­ no's participation in developing an auditory prosthesis. The legacy of the Djourno and Eyries's work was sustained despite the abrupt departure of the two men. Claude-Henri Chouard, who was a student in Eyries's laboratory working on the facial nerve, resumed work on the cochlear implant several years later. Chouard was instrumental in developing one of the first functional multichannel implants, and he credits Charles Eyries as his major source of inspiration.22 Although Djourno and Eyries's implantation on February 25, 1957 is typically credited as the first cochlear implant, a closer evaluation of the patient's anatomy raises the ques­ tion of whether the cochlear nerve or the auditory brain­ stem were stimulated by the implanted electrodes, as wallerian degeneration may have destroyed the cochlear ganglion cells.23 Whether Djourno and Eyries stimulated the cochlear nerve or the cochlear nucleus should not over­ shadow the significance of their work. Electrical methods to treat deafness had been described by numerous practition­ ers for almost two centuries prior to 1 957, beginning with the classic work of Alessandro Volta in the late 18th cen­ tury.4 These previous efforts, however, either were aimed at treating deafness with therapeutic electrical stimulation or were examples of electrophonic hearing. 3 http://medical.dentalebooks.com
4 . . • Early Developments in the Western Hemisphere Dissemination of the work of Djourno and Eyries was at first slow in the Western Hemisphere. This is likely attributable to the fact that their publication appeared only in the French-language medical literature. Additionally, of the pair, the more likely to present his work among clinicians was Eyries, as he was an otolaryngologist. Eyries demonstrated little enthusiasm for the project, however, and his interest was short-lived. Djourno was a physiologist rather than a clinician, making interaction between him and American otolaryngologists less likely despite his continued interest. Word of their work reached William F. House in California serendipitously sometime around 1959, when a patient of his handed him a summary in English of the Djourno and Eyries work.24 The summary was optimistic regarding elec­ trical stimulation to replace hearing, and House was inspired. los Angeles William F. House was a dentist-turned-otologist who began working with his brother Howard P. House at the Otologic Medical Group in Los Angeles upon completion of his residency in 1956. Early in his career he had already made significant con­ tributions to otology and neurotology, including the facial recess approach. He was working at the time on the middle fossa approach to the internal auditory canal in collaboration with john Doyle, a neurosurgeon who also practiced at St. Vincent's Hospital in Los Angeles.2s House and Doyle first sought to record the cochlear nerve response to sound when the nerve was exposed during the middle fossa approach for vestibular neurectomy as a treatment for Meniere's disease. Specifically, they sought to record the nerve output associated with tinnitus.26 They relied on Doyle's brother, james Doyle. an electrical engineer, to address the technical challenge of record­ ing such signals intraoperatively. The nerve output was recorded, but no tinnitus was observed. Successful recordings of sound-induced potentials from the cochlear nerve, however, inspired stimulating the nerve with similar waveforms in order to restore hearing. House and Doyle first attempted electrical stimulation to elicit hearing during stapes surgery by placing a needle elec­ trode on the promontory or into the open oval window. An ear speculum inserted into the external auditory canal served as a ground lead. With square wave stimuli, patients reported hear­ ing the stimulus without discomfort, dizziness. or facial nerve stimulation. These responses were sufficient to encourage House and Doyle to implant a patient with a hard-wire device. The first willing subject was a 40-year-old man with severe oto­ sclerosis and deafness. Promontory stimulation of the right ear on january 5, 1961 revealed consistent responses. On january 9, therefore. a gold-wire electrode was inserted under local anes­ thesia through a postauricular approach into the round win­ dow. The wire was brought out through the postauricular skin.27 The patient reported hearing the electrical stimuli, but he had poor loudness tolerance. Several weeks later the wire was removed. A second patient was also implanted in january 1961. The woman had deafness, tinnitus, and vertigo associated with con­ genital syphilis, and she was brought to the operating room for a vestibular neurectomy through the middle fossa approach. During the procedure, a single gold-wire electrode was placed through the middle fossa approach into scala tympani at the basal part of the cochlea. The wire was brought out through a skin incision. The patient described hearing the square wave stimulation upon waking from anesthesia. Over the ensuing days, the current intensity required to elicit a response increased. For fear of infection or edema, the wire was removed. With the first patient's encouraging responses, and with the hope of producing discrimination of higher frequencies, House and Doyle decided to reimplant him with a five-wire electrode array inserted through the mastoid facial recess and round win­ dow. The electrode array was attached to a more permanent electrode induction system seated in the skull. Over a several­ week testing period, the patient's intensity requirement increased and his postauricular skin began to swell. This device was also removed for risk of infection. Worries of bio­ compatibility of materials ensued. The theoretical basis for the multiple-electrode design was to spread high-frequency stimuli among spatially separated electrodes. By stimulating different subpopulations of audi­ tory nerve fibers at rates slower than their refractory period, they thought, summation among the subpopulations would purportedly yield an overall high-frequency response along the whole nerve. This implant design and its theoretical basis became the foundation for an early cochlear implant patent application submitted by james Doyle and Earle Bal­ lantyne in 1 961 . The patent was not granted until 1969.28 Despite being founded on what has since been shown to be an erroneous theory of electrical stimulation, the patent was ironically prescient in its statement that a 1 6-channel unit would be necessary for implant patients to be able to con­ verse on the telephone. Word of the two implanted patients reached the lay press. The brief articles were overly optimistic in their descriptions of an "artificial ear," going so far as to announce that "surgical implantation of a transistorized device designed to restore hearing of deaf persons is scheduled within 30 days."29 These reports prompted readers who were deaf to call House and Doyle seeking a cure for their deafness, and aroused the interest of investors seeking to cash in on emerging medical technology. House recognized the danger in such publicity, and publicizing the implant work became an issue of considerable conflict between the Doyles and House. Disagreement over how aggressive to proceed with the implant, given the initial bio­ incompatibility problems, opened an irreparable rift between House and the Doyles that brought an end to their collabora­ tion. House had a very busy otologic practice, and implant development took a low priority for several years to follow. The Doyles, on the other hand, continued to experiment, implanting numerous subjects. They collaborated with the Los Angeles otolaryngologist Frederick Turnbull, whose office was used for most of the testing. They reported their results in locaJ3° and nationaJ31 forums, reporting optimistically that electrical stimu­ lation could yield speech perception, but not offering system­ atic testing or analysis. The Doyles ceased their investigations in 1968 due to a lack of research funding.26 http://medical.dentalebooks.com
Stanford University F. Blair Simmons had worked as a research associate in the laboratory of S.S. Stevens at Harvard as a medical student and then with Robert Galambos at the Walter Reed Institute prior to his residency in otolaryngology at Stanford University in Stanford, California. Simmons was an assistant professor in Stanford's Division of Otolaryngology in 1962 for less than a month before he was presented with an unexpected opportu­ nity to stimulate the cochlear nerve intraoperatively. The patient was an 18-year-old man who had developed a recur­ rence of a cerebellar ependymoma that manifested itself as mild hearing loss. Exploratory craniotomy under local anesthesia was planned, and the cochlear nerve would be exposed during the procedure. Prior to surgery, Simmons discussed stimulating the patient's cochlear nerve electrically. The patient agreed to the intraoperative testing and to a preoperative auditory training session. During the awake craniotomy, the patient was asked to describe what he heard when a bipolar electrode was used to stimulate the exposed cochlear nerve with 100- microsecond square wave pulses. The patient described auditory sensations and was able to discriminate stimulation frequencies up to 1 kHz.32 Simmons's first implanted device was then placed 2 years later, in 1964. This second subject was a 60-year-old man who had been unilaterally deaf for several years, and whose better hearing ear then became deaf. He also suffered from retinitis pigmentosum and had associated severe sight disability. Despite being made fully aware that implantation would likely fail and very likely yield no useful hearing, the subject agreed to undergo the implantation. Local anesthesia was used, and the promontory exposed through a postauricular transmeatal approach and elevation of a tympanomeatal flap. A 2-mm coch­ leostomy and then subsequent 0.1 -mm drill hole into the modiolus were performed. A partial mastoidectomy was also performed and the middle ear entered anterior to the facial nerve by removing the incus. A six-electrode array was placed through the mastoid opening into the epitympanum and then through both the cochleostomy and the modiolar opening to a depth of 3 to 4 mm. The electrodes were attached to a plug that was then secured to the mastoid cortex. Psychoacoustic testing was carried out both at Stanford and at Bell Laboratories in New jersey.33 Unfortunately, the subject's combination of disabilities made psychophysical testing very challenging. Based on these unfavorable experiences, Simmons became pessimistic about the future of implantation. He estimated the likelihood that electrical stimulation of the auditory nerve could ever provide a clinically useful means of communication to be "considerably less than 5%."34 Human implantation at Stanford was postponed until further animal testing could prove its utility. House Resumes His Work With the advancements in pacemakers and ventriculoperito­ neal shunts in the late 1960s, House's interest in cochlear implantation was reawakened with more confidence in the safety and efficacy of indwelling devices (.,. Fig. 1.3). House was working with a talented engineer named jack Urban, a collabo­ ration best known for several influential developments in neu­ rotologic instruments. House and Urban aggressively pursued History of the Cochlear Implant Fig. 1 .3 William F. House (left) and Robin Michelson (right) collaborating in the early 1 970s. (Courtesy of the john Q. Adams Center.) implanting their single-channel device in human patients. As much as any other parameter, the durability and safety of the device was on House's mind with this group of patients. Of several patients implanted in 1969, one required having his implant removed due to tissue rejection, and another was lost to follow-up. However, a third patient, Charles Graser, became a long-term experimental subject. In Graser, House found stimu­ lation levels and results that remained stable over the course of years. This gave credence to the safety of electrical stimulation. Charles Graser was deaf for 10 years because of ototoxicity. Postimplantation, he worked intensely as a research subject, and continued to do so enthusiastically for many years. Many of the observations and modifications that House and Urban reported in the 1960s were based on the testing of only subject-Graser. For instance, one of the surprising findings from the work with Graser was that a 1 6,000-Hz carrier fre­ quency signal helped him appreciate higher frequencies, and amplitude-modulating the carrier with the acoustic signal generally sounded the best. This signal processor strategy became standard on the House/3M cochlear implant. Reporting of these early results was primarily by testimonial experiences of the individual subjects rather than systematic study. Another important outcome of these early studies was abandoning the multiple electrode systems for the single-wire electrode.Js San Francisco Robin Michelson (.,. Fig. 1 .3) was an otolaryngologist in private practice in the 1960s in Redwood City, California. He was the grandson of the Nobel Prize-winning physicist Albert Michelson. Robin Michelson's inspiration for cochlear implanta­ tion came from seeing a patient, T.l. Moseley, who had severe tinnitus and otosclerosis. Michelson had sought to monitor the cochlear microphonic during a stapedectomy as a means of immediate feedback, since he performed the procedure under local anesthesia. Moseley, an engineer, agreed to build him a high-gain amplifier with an earpiece that Michelson could use in the operating room. Michelson placed an electrode against 5 http://medical.dentalebooks.com
6 . . the round window. Feedback from the amplifier elicited the sensation of sound for the patient that Michelson was subse­ quently able to pitch match.36 Michelson, like House, originally subscribed to the telephone theory of hearing-that the cochlea presented the auditory nerve with the analogue electrical signal of the auditory stimu­ lus, and that all that was required to restore hearing was to stimulate the auditory nerve with a similar signal. In an attempt to demonstrate that electrical stimulation of the auditory nerve elicited auditory responses, he implanted an electrode into the cat cochlea and measured the cochlear microphonic in the opposite ear. He found that electrical stimulation suppressed the contralateral cochlear microphonic similarly to acoustic stimuli. He concluded, therefore, that electrical stimulation was carried along auditory pathways.37 Although Michelson was likely demonstrating electrophonic hearing rather than direct auditory nerve electrical stimulation, this result inspired him to implant a human volunteer with hearing loss. Michelson's first implant was a single-channel device implanted into a congenitally deaf woman. Testing after implantation revealed that she obtained auditory sensations from stimulation, and that pitch perception was possible for stimulus frequencies less than about 600 Hz. More interesting to Michelson, however, was that the subject could differentiate a square-wave stimulus from a sine-wave stimulus.36 Michelson interpreted this to indicate that the fine structure of the electrical stimulus could be conveyed along auditory pathways. The gold-wire electrode hardened several days after the operation, broke from the rest of the implant, and needed to be removed. Several additional patients received fully implantable single-channel devices, and this preliminary work was presented to the American Academy of Ophthalmology and Otolaryngology in October 1970; a follow-up study was pre­ sented at the 1971 meeting of the American Otological Society. The patients had pitch perception based on stimulus frequency and could recognize speech stimuli but had no word under­ standing. All implanted patients lost whatever residual hearing they had prior to implantation.38 It was around this time that Francis Sooy visited Michelson in Redwood City and saw his work in progress with implantation. Sooy was the chairman of the nascent Department of Oto­ laryngology at the University of California at San Francisco, and this interaction with Michelson confirmed his belief in the potential of cochlear implantation. He persuaded Michelson to join the faculty at UCSF and bring his implant investigations to the University. Sooy also believed that the successful devel­ opment of the cochlear implant required a university-based scientific foundation. After recruiting Michelson, Sooy then recruited Michael Merzenich from the University of Wisconsin. Merzenich was a young neurophysiologist whose interest was mapping the inferior colliculus. He joined the UCSF faculty and began working on recordings from the inferior colliculus for several months before meeting with Michelson about the cochlear implant. Merzenich was initially quite skeptical about the merits of the implants and showed little interest in joining the development effort. After seeing a few patients on a docu­ mentary film created by the otolaryngology resident C. Robert Pettit, however, Merzenich became convinced of its potentiaJ.39 The collaboration between Michelson, a clinical pioneer, and Merzenich, a talented basic scientist with a solid foundation in neurophysiology, was masterminded by Sooy and was an indis­ pensable element in the development of the UCSF cochlear implant program. One of the first studies Merzenich performed was recording the response properties of single units in the cat inferior colli­ culus in response to both sound stimulation from one ear and electrical stimulation from the other ear in implanted cats. He showed that the inferior colliculus neurons responded similarly to electrical and sound stimuli, but that the tuning curves for electrical stimulation were very flat and showed little tuning. Additionally, the responses from animals with ototoxin-induced hair cell destruction showed the same responses to electrical stimuli as untreated cochlea. This was the first definitive dem­ onstration that auditory sensation with implants arose from direct stimulation of the auditory nerve rather than electro­ phonic effects. Responses in the cat were then compared to psychoacoustic measures in the human implanted subjects using the same electrical stimuli in both groups. The conclu­ sions from this work were that with single-electrode devices, periodicity pitch up to about 600 Hz is possible, but no place coding of frequency is possible. Thus in order to convey com­ plex sounds such as speech, multiple-electrode arrays would be necessary.40 This work was presented to the American Otologi­ cal Society at the 1973 annual meeting in St. Louis, and it marked the beginning of the race toward the development of a multichannel cochlear implant. • Controversies and Doubts The year 1973 represents a crossroads in the cochlear implant's development. Until this time, cochlear implantation would have been considered, at best, an idea with potential to help some deaf people sometime in the future, and at worst as a danger­ ous experimental procedure promising nothing better than vibrotactile information. Simmons had downplayed the poten­ tial of implants and abandoned human implantation. The only clinicians performing human implants, House and Michelson, were surgeons far from the mainstream and whose funding was from private sources. In order for the implant development to proceed, implants would need to be granted legitimacy as a valid research pursuit with National Institutes of Health (NIH) funding and demonstrate broad-based clinical application. This section highlights events in the 1970s that accomplished both. National Institutes of Health The NIH itself was partly responsible for giving scientific legiti­ macy to the cochlear implant. In 1970 the Neural Prosthesis Program was established within the National Institute of Neu­ rological Diseases aimed at promoting extramural research on neural prostheses primarily by capitalizing on the contract mechanism of the NIH.41 Initially the program did not focus on an auditory prothesis, but rather on developing a visual pros­ thesis for the blind, and the first contracts focused on this goal. In addition to awarding contracts, the Neural Prosthesis Pro­ gram under the guidance of F. Terry Hambrecht initiated and maintained the annual Neural Prosthesis Workshop. The work­ shop brought together a multidisciplinary group of contractors and consultants to the NIH campus to discuss research findings, delineate important problems, and develop strategies for the http://medical.dentalebooks.com
development of neural prostheses. At the third workshop in january 1973, auditory prostheses first commanded a signifi­ cant part of the agenda. Participants included Michelson, Merzenich, and Simmons. Both Merzenich and Simmons also obtained extramural NIH funding for their implant-related research by this time.41 Early Cochlear Implant Meetings Several meetings over the next several years pitted the implant pioneers against the otology/hearing science establishment. These symposia began to bring cochlear implantation into the limelight, often resulting in considerable controversy. Between 1971 and 1973, significant work removed doubts that the audi­ tory nerve could be stimulated directly with the implant. Con­ cerns that the prominent oro-scientists expressed toward the implant therefore shifted and coalesced during meetings in 1973 and 1974 of the Otological Society, the First International Conference on Electrical Stimulation in San Francisco, and the Third Workshop of the Neural Prosthesis Program. These con­ cerns and their rationales are as follows: • Concern: The remaining nerve fiber population in deafness is not sufficient to support tonotopic stimulation ofthe nerve. This was based on the finding of Hal Schuknecht and coworkers that only a minority of temporal bones examined demonstrated more than two thirds of the normal population ofcochlear ganglion cells.42 Additionally, Nelson Y.S. Kiang, a neurophysiologist at the Massachusetts Institute of Technology who had defined how single auditory nerve units respond to sound in cat, led a vehement opposition to human cochlear implantation. His point ofview was that cochlear implants with the current design could never produce speech understanding or "useful hearing" because electrical stimuli could not convey the complex auditory stimuli that the cochlea provided.43 Implanting humans with devices that offered little more than improved lip reading, he thought, could not be considered prudent. • Concern: Electrical stimulation could convey sounds out ofthe speechfrequency range. Cochlear damage in deafness is typically in its basal half, where high-frequency stimuli are transduced. The electrodes described at the time extended only into the proximal basal part of the cochlea. Therefore, if the place principle were utilized, electrical stimulation would yield only sound frequencies higher than the speech range.44 • Concern: The dynamic range of loudness with electrical stimulation would be too narrow to convey useful sound information. Although loudness grows with sound intensity in the cochlea over a range of nearly 100 dB, the intensity range with electrical stimulation is only about 6 dB, which would severely limit loudness discrimination. The dynamic range of the firing of cochlear nerve fibers of the cat in response to both electrical and acoustic stimulation revealed a similar finding-that the dynamic range in response to sound is 20 to 40 dB, and to electrical stimuli 4 dB.43 • Concern: lntracochlear manipulation that would occur with cochlear implantation would result in significant damage to the cochlea; anything that disturbs scala media would cause degeneration ofthe remaining sensoryfibers. This concern arose from studies of Schuknecht showing that one aspect of cochlear pathology was auditory nerve fiber degeneration.45 Why, then, perform an invasive procedure like the cochlear implant when an externally worn device such as a vibrotactile stimulator could be used to the same end? The above concerns did not dissuade the core group of implant developers from proceeding onward, yet a strong aura of doubt surrounded the cochlear implant. At the forefront of cochlear implant support, however, was Francis Sooy, who was responsi­ ble for assembling the implant devotees in October 1974 with the support of the NIH in order to evaluate the progress and define the research goals for the implant, and to establish guidelines for patient selection and implantation protocols. Two important decisions were made at this meeting. First, criteria for implantation were delimited: full informed consent that the procedure is experimental; no useful hearing in either ear; only those patients able and willing to participate in psychophysical testing; otherwise healthy patients; and, finally, adults only. Second, a consensus decision was made to stop implanting all single-channel devices until an objective evaluation of the patients already implanted could be performed.46 The NIH took the lead in this objective evaluation with a call for applications for a formal objective evaluation of the single-channel recipi­ ents. The future of implant development rested on this objec­ tive evaluation, as a finding that the implant had limited utility may have curtailed allocation of further resources from the Neural Prosthesis Program. The contract to perform the objective assessment was awarded in june 1975 to a team at the University of Pittsburgh led by Robert Bilger. The Bilger Report Thirteen adult single-channel implant subjects, 1 1 implanted by House and two by Michelson, were flown to Pittsburgh for a week-long testing session to take part in the study. The subjects underwent extensive audiological, psychoacoustic, and vestibu­ lar testing. Several of the results were not surprising: Subjects could not understand speech with the implant alone, but the implant helped the patients' lipreading scores. Also not surpris­ ing was the finding that the subjects' quality of life was aided by the implant. A surprising finding, however, was that the subjects' speech production was significantly aided by their implants. The investigators concluded from the study that single-channel implants helped deaf patients. While this conclusion may not seem profound, it was the first objective, scientific assessment of implant performance, concluding that the subjects received benefit from the implant with minimal risk.47 From this, the cochlear prosthesis gained the legitimacy needed to justify funded research efforts toward a multichannel device. Furthermore, while the world waited for the multi­ channel implant, the single-channel device was viable. • Development of a Multichannel Device With the Bilger study confirming the utility of a single-channel device, House moved forward with refinement of his implant. He and jack Urban joined forces with the 3M Company. The House/3M single channel device (.,.. Fig. 1 .4) was implanted into 7 http://medical.dentalebooks.com
8 . . Fig. 1 .4 An early version of the House/3 M single-channel device. Shown is the implanted receiver/stimulator and wire electrodes. (Courtesy of the john Q. Adams Center.) several thousand patients by the early 1980s, and in 1984 the Food and Drug Administration (FDA) granted approval for the device. Other centers, however, concentrated their efforts on researching and developing a multichannel device. At the forefront of this competition were Merzenich, Michelson, Robert Schindler, and colleagues at UCSF (� Fig. 1.5), and Graham Clark at the University of Melbourne in Australia. Clark, a clinically trained otolaryngologist, began investigat­ ing the cochlear implant as a graduate student in the 1960s. Fig. 1 .5 Early eight-channel electrode and epoxy-coated receiver designed by Robin Michelson and assembled by Mel Bartz. The intracochlear portion of the electrode array was formed from Silastic to fill scala tympani. (Courtesy of Stephen Rebscher, University of California at San Francisco.) He realized as early as his graduate thesis in 1969 that the single-channel device had limited utility,48 and he sought to use a systematic scientific approach to developing a multielectrode device. The approach had several fronts: developing speech processing strategies, optimizing the electrode array, and devel­ oping a safe, reliable implantable receiver-stimulator. The efforts toward what would become the Cochlear Corporation's Nucleus multichannel implant was primarily an Australian ven­ ture, as funding came from Australian national telethons and government-associated engineering firms, and partly through government grants.49 Clark and his colleagues reported several important findings, two of which were that inserting the elec­ trode array in an anterograde direction through a single cochle­ ostomy at the round window niche into scala tympani was less traumatic to the cochlear structures than either retrograde insertion or multiple cochleostomies,so.sJ and dissolution of platinum electrodes with biphasic pulsatile stimuli was minimal, implying safe long-term stimulation.s2 Clark first implanted a human subject in 1978, and by 1981 he showed that subjects were able to understand some open-set speech with their implants and without the aid of lipreading.s3 The FDA approval for the Nucleus multichannel implant (Cochlear, Melbourne, Australia) was granted for adult patients in 1985 and children as young as 2 years in 1990. As several technical challenges were overcome in the 1980s, multichannel cochlear implants became a safe option for pro­ foundly deaf adults and children. Patients with the implant were expected to have a quality-of-life improvement and some open-set speech recognition. Another development was required, however, to dramatically improve the speech recognition provided by the implant, and this was the develop­ ment of high-rate interleaved stimulation. Multiple electrode stimulation relies on the place principle of coding auditory stimuli along the cochlea. For separate electrodes to be effective in eliciting different frequency responses, the spatial extent of their stimuli must be different. Several studies in the late 1970s and early 1980s demonstrated that significant interference (known as "interaction") resulted from simultaneous stimula­ tion of multiple electrodes.s4.ss It was found that electrode interaction could be minimized by stimulating the electrodes in a staggered, nonsimultaneous pattern.54 Another discovery was that nonsimultaneous stimulation at pulse rates greater than 1 kHz was especially effective at improving an implant subject's speech understanding. A collaboration between UCSF and the Research Triangle Institute (Research Triangle, NC) resulted in the implementation and testing of a speech processing scheme that utilized this concept. The concept was patented and became known as continuous interleaved sampling (CIS). The implementation of CIS provided a tremendous improvement in implant recipients' performance with speech recognition.56 Since that time there have been numerous noteworthy tech­ nological developments in both device design and coding, and the future promises even greater advances to further enhance performance in the implanted hearing-impaired population. • Conclusion The development of the cochlear implant began in 1957 with the first attempts to restore hearing with direct electrical stimulation of the auditory nerve. In the years that followed, http://medical.dentalebooks.com
the primary proponents of implants were a few otologists try­ ing to help their patients with single-channel devices, despite considerable opposition from leaders in the field. If it were not for these pioneers. cochlear implants may well have been delayed by many years. Following the Bilger study, cochlear implant research gained mainstream support, and efforts toward a marketable multichannel device were underway. Improvements are ongoing and offer a bright future to the hear­ ing-impaired population. • References [ 1 ] Dudley H. Remaking speech. ] Acoust Soc Am 1939; 1 1 ; 169-177 (2] Wever EG, Bray CW. The nature of the acoustic response: the relation between sound frequency of impulses in the auditory nerve. j Exp Psycho! 1 930; 13: 373-387 (3] Stevens SS. On hearing by electrical stimulation. j Acoust Soc Am 1937; 8: 191-195 (4] Shah SB, Chung JH, jackler RK. Lodestones, quackery, and science: electrical stimulation ofthe earbefore cochlear implants. Amj Otol 1997; 18: 665-670 [5] Djourno A. Strohl A. Modifications du courant de peau de grenouille pendant !'excitation electrique. CR Soc Bioi (Paris) 1 937; 125: 625 (6] Djourno A. Variation de l'excitabilite du sciatique de grenouille suivant l'ecart des electrodes. CR Soc Bioi (Paris) 1946; 140: 1 83 (7] Djourno A. Sur Ia mesure instantanee de Ia frequence du pauls. Paris Med (Paris) 1938; 37: 83 (8] Djourno A. Masmonteil, Roucayrol jC. Une application de Ia haute frequence a !'extraction de protheses metalliques. Soc Electrother Radial. 1948; 29: 637-638 (9] Djoumo A, Delayj, Verdeaux G Un cas de narcolepsie avecetude eiectroence­ phalographique. Congres d'Electro-encephalographie de Langue fran�aise, Paris 1949 [10] Djourno A. La respiration eiectrophrenique. Presse Med 1952; 60: 1532- 1533 [ 1 1 ] Djourno A. Excitation eiectrique localisee a distance. C R Acad Sciences. 1953; 236: 2337-2338 (12] Djourno A. Kayser D. La methode des excitations induites a distance. ] Radial 1 954; 36: 1 1 7-118 (13] Djourno A, Kayser D, Guyon L Sur Ia tolerance par le nerf d'appareils eiectri­ ques d'excitation indus a demeure. CR Soc Bioi (Paris) 1955; 149: 1 882-1883 [14] Eyries C. Traitement de l'ozene par un nouveau precede de prothese chirurgi­ cale. Ann Otolaryng. 1946; 13: 581-586 [ 15] Olivier G. Eyries C. Reperes chirurgicaux et aspects du nerf facial extra petreux. Med trap. 1953; 13: 720-723 (16] Eyries C. Experience personelle. Cahiers d'Oto-Rhino-Laryngologie. 1979; 14: 679-681 [ 17] Djourno A. Interview with Phillip Seitz. january 12. 1 994. john Q, Adams Center Archives [18] Djourno A, Eyries C, Vallancien B. De !'excitation eiectrique du nerf cochleaire chez l'homme. par induction a distance, a !'aide d'un micro-bobinage indus a demeure. CR Soc Bioi (Paris) 1957; 1 5 1 : 423-425 [19] Eyries C. Interview with Phillip Seitz, january 10, 1994. john Q, Adams Center Archives (20] Djourno A. Analyse oscillographique instantanee de Ia voix par!ee. CR Soc Bioi (Paris) 1959; 153: 197-198 (21 ] Djourno A. A propos de prothese sensorielle totale. Bull Acad Nat! Med 1977; 161 : 282-283 [22] Chouard CH. Entendre sans Oreilles. Paris: Robert Laffont. 1973 (23] Eisen MD. Djourno, Eyries, and the first implanted electrical neural stimula­ tor to restorehearing. Otol Neurotol 2003; 24: 500-506 [24] House WF A personal perspective on cochlear implants. In: Schindler RA, Merzenich MM. eds. Cochlear Implants. New York: Raven Press 198513- 1 98516 (25] House WF. Cochlear Implants: My Perspective. Newport Beach, CA: AllHear, 1 995 (26] DoylejB. Interview with Philip Seitz, August 22, 1993. john Q, Adams Center Archives [27] House WF. Cochlear implants: beginnings (1957-1961 ). Ann Otol Rhinal Lar­ yngol 1976; 85: 3-6 (28] Doyle JB, Ballantyne EW, inventors Artificial sense organ, U.S. Patent 3,449,768,june 17, 1969 [29] Anonymous . California electronics firm readies "artificial ear" implant. Space Age News. 1961 ; 3: 1 (30] Doyle JB, Doyle JH, Turnbull FM, Abbey j, House L Electrical stimulation in eighth nerve deafness. Bull Los Angel Neuro Soc 1963; 28: 148-150 (31 ] Doyle JH, Doyle JB, Turnbull FM. Electrical stimulation of the eighth cranial nerve. Arch Otolaryngol 1 964; 80: 388-391 (32] Simmons FB. Mongeon Cj. Lewis WR. Huntington DA. Electrical stimulation of acoustical nerve and inferior colliculus; results in man. Arch Otolaryngol 1 964; 79: 559-568 (33] Simmons FB, Epley jM, Lummis RC et al. Auditory nerve: electrical stimula­ tion in man. Science 1965; 148: 104-106 (34] Simmons FB. Electrical stimulation of the auditory nerve in man. Arch Otolar­ yngol 1966; 84: 2-54 (35] House WF, Urban j. Long term results of electrode implantation and elec­ tronic stimulation of the cochlea in man. Ann Otol Rhinal Laryngol 1 973; 82: 504-51 7 (36] Michelson R P. Interview with Phillip Seitz, November 7 , 1995. john Q. Adams CenterArchives (37] Michelson RP. The crossed cochlea effect. Trans Am Acad Ophthal Otolaryngol 1 968 (38] Michelson RP. Electrical stimulation of the human cochlea. A preliminary report. Arch Otolaryngol 1971 ; 93: 31 7-323 (39] Merzenich MM Interview with Marc Eisen, March 26. 2004 (40] Merzenich MM. Michelson RP, Pettit CR. Schindler RA, Reid M. Neural encod­ ing of sound sensation evoked by electrical stimulation of the acoustic nerve. Ann Otol Rhinal Laryngol 1973; 82: 486-503 [41 ] Hannaway C. Contributions of the National Institutes of Health to the Devel­ opment of Cochlear Prostheses. Bethesda, MD: National Institutes of Health, 1 996 [42] Kerr A. Schuknecht HF. The spiral ganglion in profound deafness. Acta Otolar­ yngol 1968; 65: 586-598 (43] Kiang NYS, Moxon EC. Physiological considerations in artificial stimulation of the inner ear. Ann Otol Rhinal Laryngol 1 972; 8 1 : 714-730 (44] Lawrence M, johnsson L-G. The role of the organ of Corti in auditory nerve stimulation. Ann Otol Rhinal Laryngol 1973; 82: 464-472 (45] Schuknecht HF. Lesions ofthe organ of Corti. Trans Am Acad Ophthalmol Oto­ laryngol 1 953; 57: 366-383 (46] Merzenich MM. Sooy FAReport on a workshop on cochlear implants, Univer­ sity ofCalifornia at San Francisco, October 23-25 1 974 (47] Bilger RC. Evaluation of subjects presently fitted with implanted auditory prostheses. Ann Otol Rhinal Laryngol 1977; 86 Suppl 38: 1-176 (48] Clark G. Middle Ear and Neural Mechanisms in Hearing and in the Manage­ ment of Deafness [Doctor of Philosophy Thesis]. Sydney: University ofSydney, 1 969 (49] Clark G. Sounds from Silence. Adelaide: Allen & Unwin, 2000 [50] Clark GM, Hallworth Rj. Zdanius K. A cochlear implant electrode. J Laryngol Otol 1 975; 89: 787-792 (51 ] Clark GM. An evaluation of per-scalar cochlear electrode implantation tech­ niques. An histopathological study in cats. j Laryngol Otol 1977; 91: 185-199 (52] Black FO. Wall C, O'LearyDP, Bilger RC. WolfRV. Galvanic disruption of vesti­ bulospinal postural control by cochlear implant devices. ] Otolaryngol 1978; 7: 519-527 [53] Clark GM, Tong YC, Martin LF. A multiple-channel cochlear implant: an evalu­ ation using open-set CID sentences. Laryngoscope 1981 ; 91 : 628-634 [54] Eddington OK, Dobelle WH, Brackmann DE, Mladejovsky MG. ParkinjL Audi­ tory prostheses research with multiple channel intracochlear stimulation in man. Ann Otol Rhinal Laryngol 1978; 87: 1-39 [55] White M. Design Considerations of a Prosthesis for the Profoundly Deaf. Berkeley, CA: University of California. Berkeley, 1978 (56] Wilson BS, Finley CC, Lawson DT, Wolford RD. Eddington OK, Rabinowitz WM. Better speech recognition with cochlear implants. Nature 1991; 352: 236-238 9 http://medical.dentalebooks.com
1 0 I I 2 Genetics of Hearing Loss and Predictors of Cochlear Implant Outcome Robert W. Eppsteiner, Richard K. Gurgel, and Richard}.H. Smith • Introduction Cochlear implantation is the standard treatment for hearing restoration in patients with bilateral, profound sensorineural hearing loss (SNHL). Although cochlear implant candidates all share the diagnosis of SNHL, the divergent causes of hearing loss create a heterogeneous patient population. This heteroge­ neity in etiology likely contributes to the spectrum of cochlear implant performance. If we better understood the causation of SNHL in deaf patients, we would likely better predict their hearing outcome after implantation. Deafness results from the interplay of environmental and genetic factors affecting the auditory pathway. With the advent of new technologies for genomic enrichment and high-throughput sequencing, the field of genetics has begun a renaissance. Sequencing the entire human genome, which took over a decade for the Human Genome Project, can now be done in a matter ofdays. This new accessibility ofgenetic information is revolutionizing both the molecular study of disease and its management. Among the changes is a paradigm shift in the evaluation of the deaf/hard-of-hearing person, especially if the family history suggests that the hearing loss is inherited. The cornerstone of the evaluation of hearing loss remains the medical history and physical examination, comple­ mented by a thorough audiological assessment, but the next test that should be ordered is a comprehensive genetic assessment. This algorithm underscores the importance of a person's unique genetic traits in the medical decision­ making process.1 This chapter reviews the genetic basis of hearing loss, novel technologies used for comprehensive genetic testing, and the impact of genetics on cochlear implant (CI) performance. • Genetic Basis of Hearing Loss In developed nations, hearing loss is diagnosed in approxi­ mately 1 of every 500 newborns, making it the most common congenital sensory defect.2 It is three times more prevalent than both Down syndrome and cystic fibrosis.3.4 The causes of congenital SNHL may be environmental (for example, congenital cytomegalovirus and antibiotic-induced ototoxicity) or genetic.3 In 70% of cases, hearing loss is nonsyndromic (NSHL), implying that hearing loss is the only recognized phenotypic abnormality. In the remaining 30% of cases, however. other physical findings, such as heterochro­ mia iridis or preauricular pits, co-segregate with the auditory deficit. Collectively, these types of hearing loss are called syndromic (SHL). Most forms of SHL can be recognized from birth, but there are two important exceptions, notable because they are both recessive and relatively common. Usher syndrome, of which there are three types, presents with congenital hearing loss and later-onset retinitis pigmentosa, and Pendred syndrome, which can present with congenital or postlingual hearing loss and later-onset goiter, both appear as NSHL at birth, and thus we refer to these types of SHL as the NSHL mimics. Without genetic testing the NSHL mimics cannot be distin­ guished from true NSHL. The scope of the challenge lies in the fact that NSHL is extremely heterogeneous. Over 67 NSHL-causing genes have been identified; however, the total number is likely double based on data assigning genomic positions to 130 NSHL loci (a locus is a genomic position that harbors a NSHL-causing gene).s Most congenital NSHL (80%) is autosomal recessive (ARNSHL), and, quite unexpectedly, mutations in one gene account for 50% of congenital severe-to-profound ARNSHL in many different world populations.3 G]B2, encodes a protein called Connexin 26, which makes hexameric gap junctions to link cells as a functional syncytium. The relative contribu­ tions made by other genes to severe-to-profound ARNSHL, and to other degrees of congenital hearing loss, have not been determined primarily because until recently the exper­ imental design was prohibitively complex, expensive, and labor intensive. Of the 67 genes implicated in NSHL, 38 cause ARNSHL and 25 cause autosomal dominant NSHL. There are two X-linked causes of NSHL and, in addition, mitochondrial- and microRNA­ associated NSHL occurs.6·7 These genes encode a wide variety of proteins that are expressed in the cochlea and auditory neural pathway and have a diverse spectrum of functions. Structural proteins include actins (ACTG1 ), actin-associated proteins (TRIOBP, RDX) and myosins (MY07A, MY01 5A, MY06, MY01A, MYH9, MYH14); cellular junction/adhesion proteins include otoancorin (OTOA), claudin-14 (CLDN14), and the gap junctions (GJB2, GJB6); extracellular linkage molecules include cadherin 23 (CDH23) and protocadherin 15 (PCDH15); and transporters and channels include pendrin (SLC26A4) and potassium channels (KCNQ4) ("" Table 2.1 ). • Advanced Sequencing Technology for Genetic Testing for Deafness In 1977, Frederick Sanger, the only two-time Nobel laureate in chemistry, developed Sanger sequencing, the gold standard for genetic testing.8 Sanger sequencing utilizes chain-terminating dideoxynucleotide inhibitors to determine nucleotide sequence, and until recently was the only method used for full-gene sequencing. Over the past few years, however, several advanced genomic technologies that parallelize the sequencing process (therefore they are often collectively called massively parallel sequencing [MPS] technologies) have been developed. These technologies produce millions of sequences at once that are bio­ informatically aligned to the parent human genome and queried for nucleotide differences. For an in-depth review of these technologies as applied to hearing loss, the reader is referred to Shearer et al.9 http://medical.dentalebooks.com
. . . . . Table 2.1 List ofGenes Included on the OtoSCOPE Platform with Corresponding Protein Name, Function, and Cochlear Implant Performance Information' Gene Protein Function Cl Perfonnance Reference Membranous labY!ith Genes CDH23 cadherin-related 23 structural (cell adhesion) + 1 8,1 9 CLDN14 Claudin 1 4 structural (tight junction) unknown COLJ JA2 collagen, type XI, alpha 2 structural (extracellular matrix) unknown ESPN espin structural (cytoskeleton of hair bundle) unknown GJB2 gap junction protein, beta 2 ion homeostasis + 22,28-33 GJB6 gap junction protein, beta 6 ion homeostasis + 62 ILDR1 lg-like domain-containing receptor 1 unknown unknown LOXHD1 lipoxygenase homology domain-containing 1 stereociliary protein + MY03A myosin lilA motor protein (hair bundle) unknown MY06 myosin VI motor protein (hair bundle) unknown MY07A myosin VIlA motor protein (hair bundle) + MYOJSA myosin XVA motor protein (hair bundle) unknown OTOA otoancorin structural (extracellular matrix) unknown OTOF otoferlin synaptic transmission (exocytosis at auditory + ribbon synapse) PTPRQ protein-tyrosine phosphatase receptor structural (hair cell shaft connectors) unknown RDX radixin structural (cytoskeleton of hair bundle) unknown SLC26A5 solute carrier family 26, member 5 motor protein (OHC} unknown STRC stereocilin structural (extracellular matrix) unknown TECTA tectorin alpha structural (extracellular matrix) unknown TMC1 transmembrane channel-like 1 unknown + 63 TMIE transmembrane inner ear unknown unknown TRIOBP TRIO and F-actin binding protein structural (cytoskeleton of hair bundle) unknown USH1C Usher syndrome 1C homolog structural (scaffolding protein hair bundle) unknown WHRN whirlin structural (scaffolding protein hair bundle) unknown MYH14 myosin, heavy chain 1 4, nonmuscle unknown unknown POU4F3 pou class 4 homeobox 3 transcription factor unknown T}P2 tight junction protein 2 structural (tight junction) unknown POU3F4 pou-domain class 3 transcription factor 4 transcription factor + 64,65,66 SLC26A4 solute carrier family 26, member 4 ion homeostasis + 36-40 AUGJ actin, gamma 1 structural (cytoskeleton of hair bundle) unknown COCH coagulation factor C homologue, cochlin structural (extracellular matrix) + CRYM crystallin, mu ion homeostasis unknown DFNAS deafness, autosomal dominant 5 unknown unknown SERPINB6 SERPINB6 protease inhibitor (hair cells) unknown Spiral Ganglion Genes ESRRB estrogen-related receptor beta transcription factor unknown CCDCSO coiled-coil domain containing 50 structural (cytoskeleton of hair bundle) unknown G/PC3 GAIP (-terminus interacting protein 3 proposed role in signal acquisition and unknown propagation in cochlear hair cells GJB3 gap junction protein, beta 3 ion homeostasis unknown PCDH15 protocadherin-related 1 5 structural (cell adhesion i n hair bundle) unknown PJVK pejvakin auditory pathway signaling (hair cell and unknown neuronal) TMPRSS3 transmembrane protease, serine 3 unknown variable KCNQ4 potassium voltage-gated channel ion homeostasis unknown MYH9 myosin, heavy chain 9, nonmuscle motor protein (hair cell) + WFS1 Wolfram syndrome 1 (wolframin) ion homeostasis unknown 1 1 http://medical.dentalebooks.com
1 2 Table 2.1 continued I Gene Protein Function Cl Perfonnance Reference I Minimal Data Genes GPSM2 g-protein signaling modulator 2 G-protein coupled receptor signaling pathway unknown - GRXCR1 glutaredoxin cysteine-rich 1 unknown unknown - HGF hepatocyte growth factor mitogen, motogen, and neurotrophic factor unknown - LHFPLS lipoma HMGIC fusion partner-like 5 may function in hair bundle morphogenesis unknown - LRTOMT leucine-rich transmembrane OMT auditory receptor cell development unknown - MARVELD2 MARVEL domain containing 2 epithelial barrier formation unknown - TPRN taperin unknown unknown - PRPS1 phosphoribosylpyrophosphate synthetase 1 nervous system development and nucleotide unknown - synthesis GRHL2 grainyhead-like 2 transcription factor unknown - MY01A myosin lA movement of organelles along actin unknown - filaments SLC1 7A3 solute carrier family 1 7. member 3 ionic and neurotransmitter transmembrane unknown - transport DIAPH1 diaphanous homologue 1 structural (cytoskeleton of hair bundle) unknown - DSPP dentin sialophosphoprotein biomineral tissue development unknown - EYA4 eyes absent homologue 4 transcription factor unknown - CLRN1 clarin 1 may modulate neurotransmission at hair unknown - cell-spiral ganglion cell synapse GPR98 g-protein-coupled receptor 98 may have role in the development of the unknown - central nervous system USH1G SANS (aka Usher syndrome type-1 G protein) structural (hair cell bundles) unknown - USH2A usherin 2A structural (cell adhesion) unknown - MSRB3 methionine-R-sulfoxide reductase B3 protein repair unknown - DIABLO diablo homologue, mitochondrial promotes apoptosis by activating unknown - caspases CEACAM16 carcinoembryonic antigen-related cell adhesion possible structural protein (between unknown - molecule 1 6 tectorial membrane and stereocilia) EYA 1 EVA1 protein unknown unknown II - FOX/1 forkhead box protein 11 transcription factor unknown II - KCNJ10 adenosine triphosphate (ATP)-sensitive inward ion homeostasis unknown 11- Irectifier potassium channel 1 0 Abbreviations: + represents good cochlear implant performance. 0Genes have been divided based on their location ofprimary expression. Genes listed as expressed in the spiral ganglion in certain cases may also be expressed in the membranous labyrinth but are listed as spiral ganglion expressed genes. Multigene Panels Using Microarrays One of the first advanced genomic strategies applied to heredi­ tary hearing loss was the single nucleotide extension microar­ ray (HHL APEX).10 These mutation detection arrays incorporate bound primers to which genomic DNA is hybridized. Fluores­ cent nucleotides are added, and their binding to overhanging primer bases is detected by imaging. HHL APEX does not inter­ rogate entire genes but rather only 198 bases in eight genes where pathogenic variants have been described. Another microarray-based platform is OtoCHIP. It offers an important advantage in that it uses resequencing microarrays to screen specific genes for any nucleotide changes. Biotinylated genomic DNA is hybridized to its complementary probe on the array, which is imaged repeatedly to determine the nucleotide at each genomic position. The current version of OtoCHIP inter­ rogates 19 genes (70,000 bases).11 Multigene Panels Using Targeted Genomic Enrichment An alternative to array-based hybridization is solution-based hybridization, one example of which is targeted genomic enrichment (TGE). In TGE, sheared genomic DNA is hybrid­ ized to biotin-tagged probes (also known as baits) that are complementary to specific sequences of interest. Hybridization occurs in solution (solid-phase hybridization is also possible), and then the genomic DNA-bait complexes are captured using streptavidin beads. Noncapture genomic DNA is washed away, leaving a library enriched for a specific region of interest. There are currently two comprehensive panels for hearing loss that employ TGE: OtoSCOPE and a panel designed by Otogenetics Corporation (Atlanta, GA).12·13 http://medical.dentalebooks.com
Personalized Genomic Medicine In addition to the targeted deafness panels described above, it is possible to sequence a person's entire exome (coding genetic sequence) or even a person's entire genome using next-genera­ tion sequencing. It is no longer far-fetched to consider clinicians having access to a patient's entire genomic sequence to aid in disease diagnosis and treatment. For a variety of technical and bioinformatic reasons, however, it is currently more efficient to use multigene panels than more comprehensive alternatives. • Role of Genetic Testing in Patient Management The role of genetic testing in the management of the deaf/ hard-of-hearing patient is rapidly evolving. With platforms . . . . . .. like OtoSCOPE, all known genetic causes of NSHL can be screened simultaneously, moving the role for genetic testing in patient management to the forefront. Genetic Testing for Cochlear Implant Candidates Currently, when a child or adult with severe-to-profound deafness presents for a CI evaluation, genetic testing is not part of the standard evaluation. We propose an evaluation paradigm in which genetic testing is part of the preoperative evaluation for all CI candidates with suspected NSHL (11> Fig. 2.1 ). Preoperative genetic testing can decrease the number of screening tests ordered, change surgical manage­ ment, and improve patient selection for implantation, thereby decreasing healthcare costs. - Genetic Testing Paradigm for Cochlear Implant Candidates � � ..( Apparent Genetic Hearlng Loss • Medical History Family History Physical Exam Audiogram, ABA, ASSR t t 1.( Apparent Non-Syndromlc ) II.( Syndromlc Hearing Loss )Hearing Loss • • (Comprehensive Genetic Testing with Multlgene Panel ( Phenotype-Based Individual Gene Testing J • • ' Genetic Counaellng ( Pathogenic Mutation In J No Pathogenic Mutation ln 0 J Appropriate Testing: Known Hearing Loss Gene Known Hearing Loss Gene Ophthalmology referral, EKG, Temporal Bone Imaging, etc. • • t ( )..( Non-Syndromlc J (Non-syndromlc Hearing J R-ch-Baeed Testing Hearing Loss Loss Mimic ' ' (( Genetic CounHIIng )) Genetic CounHIIng Appropriate Testing: Ophthalmology referral, EKG, Temporal Bone Imaging, etc. - Fig. 2.1 Proposed genetic testing paradigm for Clcandidates. In cases where inherited deafness does not have syndromic features we recommend comprehensive genetic testing. This will determine if individuals have true nonsyndromic hearing loss or hearing loss caused by a nonsyndromic hearing loss mimic gene such as in Usher or Pendred syndrome. When a mutation in a nonsyndromic mimic gene is identified, referral for appropriate further clinical evaluation should be pursued. Individuals for whom a genetic diagnosis is not reached are excellent candidates for research-based testing and novel gene discovery. Abbreviations: ABR, auditory brainstem response; ASSR: auditory steady-state response; EKG, electrocardiogram. 1 3 http://medical.dentalebooks.com
1 4 I I Genetic Screening in Cochlear Implant Candidates with Usher Syndrome Usher syndrome, an autosomal recessive type of SNL that falls under the rubric of NSHL mimics, is the leading genetic cause of deafness and blindness and illustrates the utility of genetic testing prior to cochlear implantation. Second to mutations in G]B2, mutations in the Usher syndrome genes are the most com­ mon cause of hearing loss in the congenitally deaf Cl population (20% of cases).14 Because the deafness is congenital but the visual impairment is delayed, without genetic testing it can be very difficult to differentiate the Usher syndrome neonate from a neo­ nate with another form of congenital severe-to-profound hearing loss.1s But differentiation is important for many reasons. First, when the diagnosis of Usher syndrome is made early, precau­ tions such as wearing ultraviolet ray (UV)-canceling sunglasses can be taken to delay the onset of vision loss. Second, in patients with Usher syndrome, simultaneous bilateral implants are advo­ cated, because sound localization is improved.16 Because patients with USH1 eventually develop blindness, early bilateral cochlear implantation ensures that hearing outcomes are optimized before vision is lostP Third, preoperative genetic testing provides valu­ able prognostic information, as Usher syndrome patients have excellent hearing outcomes after cochlear implantation.18·19 Improved Patient Selection for Cochlear Implantation with Genetic Testing It is estimated that 3 to 7% of CJ recipients do not benefit from implantation; however, these patients cannot be identified prior to implantation.20·21 Because most CJ recipients with NSHL have very similar audioprofiles, audiological testing cannot be used to prognosticate CI outcomes. It is possible, however, that CI performance may be related to the genetic cause of hearing loss. For example, studies of CJ performance in persons with G]B2-related deafness have shown that outcomes are typically excellent, whereas implantation in persons with DDP1/TIMM8a-related deafness are not advisa­ ble.22,23 The availability of multigene deafness panels like OtoSCOPE make comprehensive studies of this relationship possible. Preliminary data suggest that if the hearing loss is secondary to a gene expressed in the membranous labyrinth (G]B2, CDH23, MY07A), the CI outcome is likely to be a good; in contrast, if the hearing loss is due to a gene expressed in the spiral ganglion (DDP1/TIMM8a), CJ performance may be poor (see below). Decreased Need for Screening Tests The evaluation of a deaf/hard-of-hearing patient with appar­ ent NSHL is not standardized. After an audiogram, temporal bone imaging is often reflexively ordered, often with one or more screening tests including electrocardiogram, renal ultrasound, urinalysis, and ophthalmological evaluation.24 Occasionally genetic testing, typically for G]B2 only, is consid­ ered. This type of evaluation paradigm is not evidence-based and neither is it logical or cost-effective. As an alternative, we propose that after an audiogram, every patient with suspected NSHL should have comprehensive genetic testing. If a diagnosis is established, a large number of exploratory screening tests can be avoided and a directed evaluation can be completed. If SHL is suspected, appropriate screening tests can be ordered as required (.,. Fig. 2.1 ). • Impact of Genetic Mutation on Cochlear Implant Performance Despite more than 60 reports studying genetic mutation and CI outcome, there are few firmly established genotype-phenotype CI performance correlations (Table 2.1 ). Intuitively, the site of pathology along the auditory pathway should be a useful framework for predicting the impact of a genetic lesion on Cl performance. For example, mutations in genes expressed in the membranous labyrinth should portend a good CI outcome because the implant would bypass the lesion and directly stim­ ulate spiral ganglion neurons. In contrast, mutations in spiral ganglion-expressed genes should portend poorer performance because of dysfunction at the site of electrical stimulation. Prior studies suggest that these suppositions are correct (.,. Fig. 2.2).25,26 Membranous Labyrinth Expressed Genes The vast majority of established genotype-phenotype correla­ tions have been published for genes that encode membranous labyrinth proteins including G]B2, SLC26A4, OTOF, LOXHD1, KCNQ1, MYH9, CDH23, MY07A, TMC1, COCH, POU3F4, and the mitochondrial expressed genes. As a CJ bypasses the membra­ nous labyrinth, persons with these genetic types of hearing loss should be among the group of good CI performers, and indeed this is almost always the case. GJB2 G]B2 is the best studied hearing loss gene and has firmly estab­ lished genotype-phenotype correlations. The encoded protein, connexin 26, is expressed in the supporting cells, spiral limbus and spiral ligament of the membranous labyrinth, and may be important in K+ ion recycling in the supporting cells and stria vascularis.27 There are over 25 reports (including over 420 individuals) of G]B2 genotype-phenotype CJ performance corre­ lations, with the general consensus being that G]B2-related deafness is associated with good performance. In fact, some studies have found that patients with G]B2-related deafness perform better than patients with other causes of deafness when congenitally deaf Cl patients are divided into two groups based on G]B2 status.22·2B-33 There is only one report ofa patient with G]B2-related deafness performing poorly; however, the implant was not performed until age 36.34 Consistent with this poor outcome, prolonged profound deafness prior to implantation is associated with higher rates of spiral ganglion cell degeneration, which is an important determinant of CI performance.25·26 http://medical.dentalebooks.com
. . . . . . . Membranous Expressed Genes GJB2, SLC26A4, OTOF, LOXHD I, KCNO I, CDH23, MY07A, POU3F4, MYH9, TMCI, COCH, Mitochondrial Fig. 2.2 Genes with established genotype-phenotype correlations and their location of expression. (Adapted from the Hereditary Hearing Loss Homepage (hereditaryhearingloss.org) with permission from G. Van Camp and R.J.H. Smith.) SLC26A4 SLC26A4 encodes the protein pendrin, a sodium-independent chloride/iodide symporter, and is implicated in Pendred syndrome (SNHL, enlarged vestibular aqueduct, thyroid abnor­ malities). There have been five reports of 49 patients with SLC26A4-related hearing loss correlating Cl performance with SLC26A4 mutations. The majority of these patients had both SNHL and enlarged vestibular aqueduct. The pathophysiological basis of SLC26A4 hearing loss appears to be secondary to mem­ branous labyrinth dysfunction, and, as such, we would expect these Cl recipients to perform well.35 All reports confirm that this is indeed the case.36-4o OTOF There have been four reports (1 2 patients) of Cl performance in patients with otoferlin (OTOF) mutations, all of whom benefited from implantation.41-44 The encoded trans­ membrane protein controls calcium binding and vesicle release at the interface of the inner and outer hair cells and the auditory nerve.45 Hence, otoferlin mutations cause a unique phenotype, which mimics auditory neuropathy or dyssynchrony. The hearing loss is congenital; however, patients often pass newborn hearing screens based on otoa­ coustic emission (OAE) testing but demonstrate profound deafness on auditory brainstem response testing. These results reflect the expression pattern of otoferlin in both outer and inner hair cells. In the presence of OTOF mutations, the inner hair cells are affected first (hence the poor ABR) followed by progressive degeneration of the outer hair cells (the OAEs are ultimately lost).46 Because Cis directly stimulate the spiral ganglion neurons, the causative lesion is bypassed in OTOF-related deafness. Mitochondrial Deafness There have been over 14 reports (23 cases) of Cl performance in mitochondrial deafness. Mitochondrial deafness is usually postlin­ gual, progressive, and in many cases, syndromic. Virtually all cells, including those in the inner ear, depend on mitochondria for adenosine triphosphate (ATP) production via oxidative phospho­ rylation. Typically, when a phenotype manifests in mitochondrial­ associated disease, it does so in cells with high energy require­ ments. Because there are many such cells in many different organ systems, the result is often a multisystem syndromic phenotype. In the cochlea, the cells with the highest energy demands are hair cells and intermediate cells in the stria vascularis. Consequently, mitochondrial deafness results in damage to hair cells and the stria vascularis, and, as would be expected, patients with mito­ chondrial deafness are good Cl performers.47-49 Spiral Ganglion Expressed Genes Cochlear implants stimulate spiral ganglion cells. Therefore, in persons with extensive degeneration of these cells, Cl perform­ ance will be poor. Although there are very few reports of geno­ type-phenotype correlations in genes with robust expression in the spiral ganglia, in the few cases that are available, it does appear that Cl outcomes are more variable. TMPRSS3 TMPRSS3 is robustly expressed in the spiral ganglion, stria vascularis, and cochlear supporting cells and encodes a trans­ membrane serine protease, which is critical to spiral ganglion function.so Although the function of TMPRSS3 has not been completely elucidated, it may be involved in cleavage of neurotrophins in spiral ganglion cells, and, when defective, 1 5 http://medical.dentalebooks.com
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Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery
Cochlear implants: Indications, Investigation , Surgery

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Cochlear implants: Indications, Investigation , Surgery

  • 1. Susan B. Waltzman j. Thomas Roland jr. Third Edition �Thiemehttp://medical.dentalebooks.com
  • 5. Cochlear Implants Third Edition Susan B. Waltzman, PhD Marica F. Vilcek Professor of Otolaryngology Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York J. Thomas Roland Jr., MD Professor of Otolaryngology and Neurosurgery Mendik Foundation Professor and Chairman Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York Thieme New York • Stuttgart • Delhi • Rio http://medical.dentalebooks.com
  • 6. Thieme Medical Publishers, Inc. 333 Seventh Ave. New York, NY 1 0001 Executive Editor: Timothy Hiscock Managing Editors: j. Owen Zurhellen IV and Barbara A. Chernow Editorial Assistant: Heather Allen SeniorVice President, Editorialand ElectronicProductDevelopment: Cornelia Schulze Production Editor: Sean Woznicki International Production Director: Andreas Schabert Senior Vice President and Chief Operating Officer: Sarah Vanderbilt President: Brian D. Scanlan Printer: Sheridan Books Library of Congress Cataloging-in-Publication Data Cochlear implants (Waltzman) Cochlear implants f (edited by] Susan B. Waltzman, J. Thomas Roland. - Third edition. p. : em. Includes bibliographical references and index. ISBN 978-1 -60406-903-7 (hardback) - ISBN 978-1-60406-906- 8 (elSBN) I. Waltzman, Susan B., editorofcompilation. II. Roland,]. Thomas]r. editor of compilation. Ill. Title. [DNLM: 1. CochlearImplants. 2. Hearing Disorders-surgery. WV 274] RF305 617.8'8220592-dc23 2013024770 Copyright ©2014 by Thieme Medical Publishers, Inc. Thieme Publishers New York 333 Seventh Avenue, New York, NY 10001 USA, 1 -800-782-3488, customerservice@thieme.com Thieme Publishers Stuttgart Riidigerstrasse 14, 70469 Stuttgart, Germany, +49 (0]711 8931 421 , customerservice@thieme.de Thieme Publishers Delhi A-12, Second Floor, Sector-2, NOIDA-201301 , Uttar Pradesh, India +91 120 45 566 00, customerservice@thieme.in Thieme Publishers Rio, Thieme Publicac,:6es Ltda. Argentina Building 16th floor, Ala A, 228 Praia do Botafogo Rio de janeiro 22250-040 Brazil, +55 21 3736-3631 Printed in the United States. 5 4 3 2 1 ISBN 978-1-60406-903-7 Also available as an e-book: elSBN 978-1 -60406-906-8 Important note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may be required. The authors and editors ofthematerial hereinhaveconsultedsourcesbelievedto be reliable in their efforts to provide information that is complete and in accord with the standards accepted at the time of publication. However, in view ofthe possibility of human error by the authors, editors, or publisher of the work herein or changes in medical knowledge, neither the authors, editors, nor publisher, nor any other party who has been involved in the preparation ofthis work, warrants that the information contained herein is in every respect accurateorcomplete, and they are not responsible for any errors or omissions or forthe results obtained from use ofsuch information. Readers are encouraged to confirm the information contained herein with other sources. For example, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the informa­ tion contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindica­ tions for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain. J;jFSC wwwJsc.org MIX Paper from responsible sources FSC"' C021256 This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation without the publisher's consent is illegal and liable to prosecution. This applies in partic­ ular to photostatreproduction, copying,mimeographing or dupli­ cation of any kind, translating, preparation of microfilms, and electronic data processing and storage. http://medical.dentalebooks.com
  • 7. Contents Preface .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Contributors .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii 1 History of the Cochlear Implant... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Marc D. Eisen 2 Genetics of Hearing Loss and Predictors of Cochlear Implant Outcome .............. Robert W. Eppsteiner, Richard K. Gurgel, and Richardj.H. Smith 3 Consequences of Deafness and Electrical Stimulation on the Peripheral and Central 10 Auditory System.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 james B. Fallon, David K. Ryuga, and Robert K. Shepherd 4 Auditory Neuroplasticity .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Robert C. Froemke, Selena E. Heman-Ackah, and Susan B. Waltzman 5 Mimicking Normal Auditory Functions with Cochlear Implant Sound Processing: Past, Present, and Future .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Ward R. Drennan, Mario A. Svirsky, Matthew B. Fitzgerald, andjay T. Rubinstein 6 Expanding Criteria for the Evaluation of Cochlear Implant Candidates.. . . . . . . . . . . . . . 61 Susan Arndt, Roland Laszig, Antje Aschendorff. and Rainer Beck 7 Principles of Cochlear Implant Imaging .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Andrewj. Fishman and Selena E. Heman-Ackah 8 Intraoperative Monitoring During Cochlear Implantation ... . . . . . . . . . . . . . . . . . . . . . . 100 Mauro K. Cosetti 9 The History of Cochlear Implant Electrode Design... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Maja Svrakic andj. Thomas RolandJr. 10 Cochlear Implant Surgical Technique ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Peter S. Roland andj. Thomas RolandJr. 11 New Horizons in Surgical Technique .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Theodore R. McRackan, Robert F. Labadie, j. Thomas RolandJr., and David S. Haynes 12 A Global View of Device Reliability... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Rolf-Dieter Battmer 13 Revision Cochlear Implantation .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 David R. Friedmann, j. Thomas RolandJr., and Susan B. Waltzman 14 Advancements in Cochlear Implant Programming............................... 148 William H. Shapiro v http://medical.dentalebooks.com
  • 8. vi 15 Auditory and Linguistic Outcomes in Pediatric Cochlear Implantation .. . . . . . . . . . . . . . 158 Gerard M. O'Donoghue and David B. Pisani 16 Auditory Outcomes in the Adult Population Oliver F. Adunka, Margaret T. Dillon, and Craig A. Buchman 167 17 Therapeutic Approaches Following Cochlear Implantation .. . . . . . . . . . . . . . . . . . . . . . . 182 Warren Estabrooks, K. Todd Houston, and Karen Maclver-Lux 18 Acoustic and Electric Speech Processing .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Bruce}. Gantz, Sarah E. Mowry, Rick F. Nelson, Sean 0. McMenomey, Chris}. james, and Bernard Fraysse 19 Music Perception .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Alexis Roy and Charles}. Limb 20 Auditory Brainstem Implants .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Shoun D. Rodgers, john G. Golfinos, and}. Thomas RolandJr. 21 Applying Cochlear Implant Technology to Tinnitus and Vestibular Interventions... . . . . 221 justin S. Golub, james 0. Phillips, andjay T. Rubinstein 22 The Impact of Cochlear Implantation on the Recipient's Health-Related Quality of Life... . 235 Selena E. Heman-Ackah 23 Future Technology .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Susan B. Waltzman and}. Thomas RolandJr. Index...................................................................... 249 http://medical.dentalebooks.com
  • 9. Preface This fully updated third edition of Cochlear Implants repre­ sents the superb efforts of many individuals who have contributed significantly to the field. We have built on the previous edition by adding new chapters relating to genet­ ics, neuroplasticity, expanding criteria for implantation, the application of implant technology to tinnitus and vestibular issues, music perception, intraoperative monitoring, device reliability and reimplantation, and the use of quality-of-life and outcome measures-areas that occupy the forefront of cochlear implantation. Other chapters have been revised to reflect current research and clinical applications and pro­ vide the most recent information related to the clinical and translational sciences that continue to advance this exciting technology and its implementation. Patient outcomes, can­ didacy criteria, technical design, surgical technique, and programming and processing concepts are constantly pro­ gressing, and increasing numbers of individuals are gaining significant benefit. Our goal was to create a book that will provide both experienced and new and budding otolaryngol­ ogists-head and neck surgeons, neurotologists, audiologists, neuroscientists, neurophysiologists, speech pathologists, tea­ chers of the deaf, psychologists, and others interested in cochlear implants with an extraordinary resource for years to come. Thanks to the contributors and their hard work, dedication, and attention to detail, we feel that this goal has been exceeded, and we are most grateful to all involved. vii http://medical.dentalebooks.com
  • 10. viii Contributors Oliver F. Adunka, MD, FACS Associate Professor OtologyfNeurotology/Skull Base Surgery Department of Otolaryngology-Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Susan Arndt, MD Department of Otorhinolaryngology Implant Center Freiburg University of Freiburg Freiburg, Germany Antje Aschendorff, MD Associate Professor Department of Otorhinolaryngology Head of Implant Center Freiburg University of Freiburg Freiburg, Germany Rolf-Dieter Battmer, PhD Professor and Director Center for Clinical Technology Research Trauma Hospital Berlin, Germany Rainer Beck, MD Department of Otorhinolaryngology Implant Center Freiburg University of Freiburg Freiburg, Germany Craig A. Buchman, MD, FACS Professor and Vice Chairman for Clinical Affairs Chief OtologyfNeurotology/Skull Base Surgery Department of Otolaryngology-Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Maura K. Cosetti, MD Assistant Professor and Co-Director of Otology/Neurotology Departments of Otolaryngology-Head and Neck Surgery and Neurosurgery Louisiana State University Health Sciences Center Shreveport, Louisiana Margaret T. Dillon, AuD, CCC-A, F-AAA Assistant Professor Department of Otolaryngology-Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill, North Carolina Ward R. Drennan, PhD Virginia Merrill Bloedel Hearing Research Center Department of Otolaryngology-Head and Neck Surgery University of Washington Seattle, Washington Marc D. Eisen, MD, PhD Adjunct Clinical Assistant Professor Department of Otorhinolaryngology-Head and Neck Surgery University of Pennsylvania Philadelphia, Pennsylvania Robert W. Eppsteiner, MD Otolaryngology Resident T32 Research Fellow Department of Otolaryngology-Head and Neck Surgery University of Iowa Hospitals and Clinics Iowa City, Iowa Warren Estabrooks, M.Ed., Dip.Ed.Deaf, LSLS Cert. AVT President and CEO WE Listen International Inc. Toronto, Ontario, Canada james B. Fallon, PhD Bionics Institute Melbourne, Australia and Department of Medical Bionics University of Melbourne Melbourne, Australia AndrewJ. Fishman, MD Director of Neurotology & Cranial Base Surgery Director, Cochlear Implant Program Cadence Neuroscience Institute Winfield, Illinois and International Visiting Professor of Otolaryngology-Head & Neck Surgery NATO Military Hospital, Bydgoszcz, Poland Professor of Pediatric Otolaryngology Children's Hospital of Bydgoszcz Bydgoszcz, Poland Matthew B. Fitzgerald, PhD, CCC-A Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York. New York http://medical.dentalebooks.com
  • 11. Professor Bernard Fraysse Chairman of the ENT Department H6pital Purpan Toulouse, France David R. Friedmann, MD Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Robert C. Froemke, PhD Assistant Professor of Neuroscience and Otolaryngology Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Bruce j. Gantz, MD, FACS Professor and Head, Department of Otolaryngology-Head and Neck Surgery Brian F. McCabe Distinguished Chair in Otolaryngology­ Head and Neck Surgery Professor, Department of Neurosurgery University of Iowa Carver College of Medicine Iowa City, Iowa john G. Golfinos, MD Chairman, Department of Neurosurgery Associate Professor of Neurosurgery and Otolaryngology New York University School of Medicine NYU Langone Medical Center New York, New York justin S. Golub, MD OtologyfNeurotologyfLateral Skull Base Surgery Fellow Department of Otolaryngology-Head and Neck Surgery University of Cincinnati Cincinnati Children's Hospital Medical Center Cincinnati, Ohio Richard K. Gurgel, MD Assistant Professor Division of Otolaryngology-Head and Neck Surgery University of Utah Salt Lake City, Utah David S. Haynes, MD, FACS Otology Group of Vanderbilt Vanderbilt University Medical Center Nashville, Tennessee Selena E. Heman-Ackah, MD, MBA Otology, Neurotology and Skull Base Surgery Medical Director of Otology, Neurotology, and Audiology Division of Otolaryngology-Head and Neck Surgery Department of Surgery Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts K. Todd Houston, PhD, CCC-SLP, LSLS Cert. AVT School of Speech-Language Pathology and Audiology University of Akron Akron, Ohio Chris j. james, PhD CHU Toulouse-Purpan and Cochlear France SAS Toulouse, France Robert F. Labadie, MD, PhD Professor and Director of Research Department of Otolaryngology-Head and Neck Surgery Professor, Department of Biomedical Engineering Vanderbilt University Nashville, Tennessee Roland Laszig, MD Head, Department of Otorhinolaryngology Implant Center Freiburg University of Freiburg Freiburg, Germany Charlesj. Limb, MD Associate Professor Department of Otolaryngology-Head and Neck Surgery johns Hopkins Hospital johns Hopkins University School of Medicine Peabody Conservatory of Music Baltimore, Maryland Karen Maclver-Lux, MA, Aud(C), LSLS Cert. AVT Director Maclver-Lux Auditory Learning Services King City, Ontario, Canada Sean 0. McMenomey, MD Professor of Otolaryngology and Neurosurgery Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York ix http://medical.dentalebooks.com
  • 12. X Theodore R. McRackan, MD Department of Otolaryngology-Head and Neck Surgery Vanderbilt University Nashville, Tennessee Sarah E. Mowry, MD Department of Otolaryngology Georgia Regents University Augusta, Georgia Rick F. Nelson, MD, PhD Department of Otolaryngology-Head and Neck Surgery University of Iowa Hospitals and Clinics Iowa City, Iowa Gerard M. O'Donoghue, MD Consultant Neuro-Otologist Nottingham University Hospitals NHS Trust Queens Medical Centre Honorary Professor of Otology and Neurotology University of Nottingham Co-founder, Nottingham Hearing Biomedical Research Unit Nottingham, United Kingdom james 0. Phillips, PhD Research Associate Professor Department of Otolaryngology-Head and Neck Surgery University of Washington Seattle, Washington David B. Pisoni, PhD Distinguished Professor of Psychological and Brain Sciences Chancellor's Professor of Cognitive Science Department of Psychological and Brain Sciences Indiana University Bloomington, Indiana Shaun D. Rodgers, MD Department of Neurosurgery New York University School of Medicine NYU Langone Medical Center New York, New York ]. Thomas RolandJr., MD Professor of Otolaryngology and Neurosurgery Mendik Foundation Professor and Chairman Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York Peter S. Roland, MD Professor and Chairman Department of Otolaryngology-Head & Neck Surgery Professor of Neurological Surgery University of Texas Southwestern Medical Center Dallas, Texas Alexis Roy, MSc Harvard Medical School Boston, Massachusetts jay T. Rubinstein, MD, PhD Virginia Merrill Bloedel Professor and Director Virginia Merrill Bloedel Hearing Research Center Professor of Otolaryngology and Bioengineering University of Washington Seattle, Washington David K. Ryugo, PhD Curran Foundation Professor Garvan Institute of Medical Research Darlinghurst, New South Wales and Conjoint Professor School of Medical Sciences University of New South Wales Kensington, New South Wales Australia William H. Shapiro, AuD, CCC-A Clinical Associate Professor Supervising Audiologist NYU Cochlear Implant Center New York University School of Medicine New York, New York Robert K. Shepherd, PhD Bionics Institute Melbourne, Australia and Department of Medical Bionics University of Melbourne Melbourne, Australia RichardJ.H. Smith, MD Sterba Hearing Research Professor Director, Molecular Otolaryngology and Renal Research Laboratories Vice Chair, Department of Otolaryngology Professor of Otolaryngology, Molecular Physiology & Bio­ physics, Pediatrics and Internal Medicine (Division of Nephrology) University of Iowa Hospitals and Clinics Iowa City, Iowa http://medical.dentalebooks.com
  • 13. Mario A. Svirsky, PhD Noel L. Cohen Professor of Hearing Science and Vice­ Chairman of Research Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Maja Svrakic, MD Department of Otolaryngology-Head and Neck Surgery New York University School of Medicine NYU Langone Medical Center New York, New York Susan B. Waltzman, PhD Marica F. Vilcek Professor of Otolaryngology Department of Otolaryngology-Head and Neck Surgery Co-Director, NYU Cochlear Implant Center New York University School of Medicine NYU Langone Medical Center New York, New York xi http://medical.dentalebooks.com
  • 14. xii Acknowledgments We thank all the contributors to this third edition. In addition, we are indebted to J. Owen Zurhellen, Timothy Hiscock, and Chris Malone at Thieme Publishers for their commitment, guidance, and patience during the writing of this book; we could not have done it without their profes­ sionalism and support. http://medical.dentalebooks.com
  • 15. 1 History of the Cochlear Implant Marc D. Eisen • Introduction The cochlear implant has created a paradigm shift in the treat­ ment of sensorineural hearing loss. The impact that the implant has had is far greater than one would expect considering the brief time over which its development occurred. In less than four decades, the cochlear implant progressed from the first attempts to elicit hearing via direct electrical stimulation of the auditory nerve to a commercially available device that has restoredvarying degrees of hearing to tens of thousands ofdeaf patients. Several themes that can be discerned in the implant's history are widely applicable to the development of other neu­ ral prostheses. For one, the implant's development was truly an interdisciplinary effort. Significant contributions came from professionals in fields as diverse as engineering, otology, audiol­ ogy, auditory neurophysiology, psychoacoustics, and industry. The interaction among these players was not always harmoni­ ous, but the strife yielded synthesis and progress. Another theme is the courage of a few clinicians to risk their reputations and eschew scientific dogma in the hope of helping the patients that sought their care. A third theme is the willing­ ness of patients to take substantial risks in serving as research subjects, sometimes without any promise of individual gain. This chapter cannot mention each and every contribution that was made to the implant's early development, but rather cites selected events and characters that, with the aid of the "retro­ spectroscope," exemplify these themes and demonstrate the progression of events leading toward a device that enables the patient who has lost all hearing to regain the ability to converse on the telephone and enables the deaf child to develop near­ normal speech production and understanding. The implant's development occurred in several phases. The first phase of pioneering and experimentation began in 1957 and continued throughout the 1960s. The second phase, which entailed feasibility studies, occurred in the 1970s. These studies were conducted to determine whether the implant safely stim­ ulated the auditory pathway and elicited useful hearing. A third phase entailed the subsequent development of a commercially viable multielectrode cochlear prosthesis. • Precursors Several discoveries made during the first half of the twentieth century were not directly related to electrical stimulation of the cochlear nerve, but were influential on the early development of the cochlear implant and therefore warrant mention. These include Homer Dudley's work on the synthesis of speech and his "vocoder," Glenn Wever and his discovery of the cochlear microphonic, and S.S. Stevens and coworkers' description of electrophonic hearing. The Vocoder Homer Dudley was a researcher at the Bell Telephone Laborato­ ries in New York. He described and demonstrated in 1939 a real-time voice synthesizer that produced intelligible speech using circuitry designed to extract the fundamental frequency of speech, the intensity of its spectral components, and its over­ all power. The spectral components were extracted with a series of ten band-pass filters covering the frequency range of speech.l He named the synthesizer the "vocoder," a compressed version of "coding the voice." The operating principles of the vocoder for condensing speech into its principal components formed the basis of early speech processing schemes for multi­ channel cochlear implants. The Cochlear Microphonic In 1930, Wever and Bray2 recorded and described the electrical potentials in the cochlea that faithfully reproduced the sound stimulus. This phenomenon became known as the "Wever-Bray effect." The source of these measured potentials was initially incorrectly assumed to represent auditory nerve discharges. This theory ofthe origin ofthese potentials would be equivalent to the "telephone" theory of hearing, referring to the analogue representation of the voice carried along the "cable" of the auditory nerve as it would along the wires of a telephone line. In truth, what Wever and Bray were recording was not a response of the cochlear nerve, but the cochlear microphonic produced by the outer hair cells in the cochlea. Regardless of the ultimate dismissal of the telephone theory of hearing, it inspired several of the earliest pioneers of the cochlear implant. Electrophonic Hearing S.S. Stevens and his colleagues classically described in the 1930s the mechanism by which the cochlear elements respond to elec­ trical stimulation to produce hearing.3 This mechanism was coined "electrophonic hearing." We now know that electrophonic hearing results from the mechanical oscillation of the basilar membrane in response to voltage changes. The primary tenet of their description was the requirement that the cochlea be intact. Prior to 1957, efforts to stimulate hearing electrically were per­ formed on subjects with at least partially functioning cochleas. These subjects' responses could be accounted for by electrophonic hearing rather than by direct nerve stimulation. Furthermore, the developers of the earliest cochlear implant efforts had the burden of proving that the implants were directly stimulating the cochlear nerve rather than eliciting electrophonic hearing. • Pioneers: 1957-1973 Andre Djourno and Charles Eyries Although numerous attempts to treat deafness with electricity have been reported over the past several centuries,4 the first reported direct stimulation of the cochlear nerve for the purpose of generating hearing appeared as recently as 1957 with the work of Andre Djourno and Charles Eyries. Despite the revolu­ tionary impact that the cochlear implant has had on all auditory disciplines, these beginnings in Paris received little attention. http://medical.dentalebooks.com
  • 16. 2 . . Andre Djourno (1904-1996) received degrees in both science and medicine, yet he devoted his career to science. His early endeavors were studying the electrophysiology of frog periph­ eral nerve.5·6 He then ventured into more medical applications of electricity. Several of Djourno's earlier innovations reflected his inventiveness: a device to measure the pulse continuously,? high-frequency electrical stimulation to remove metal frag­ ments from bones,8 and the use of electroencephalography (EEG) to study narcolepsy.9 Perhaps the most prescient devel­ opment from this period was artificial respiration utilizing direct phrenic nerve stimulation.10 Although this innovation did not reach widespread clinical implementation, it demon­ strated Djourno's interest in neural prostheses. Djourno focused the next phase of his career on fabricating and testing implantable induction coils to be used for "telesti­ mulation," or stimulation through inductive coupling without wires. Djourno assembled these induction coils himself and called them "microbobinages," as the coils wound with wire resembled small spools of thread (� Fig. 1.1). Fig. 1 .1 Example of implantable induction coils ("microbobinages") assembled by Djourno in his laboratory. Induction coils like the ones shown here were used in various applications, including the stimulation of the auditory pathway. The hand holding the coils provides perspective on the implant's size. (Courtesy of the john Q. Adams Center.) Both the active coil and the ground electrode were implanted under the skin of an animal, and stimulation was trans­ cutaneous (rather than percutaneous). The implantable coils were first used to stimulate the sciatic nerve and thus trigger a jump behavior in rabbits. Djourno studied numerous aspects of telestimulation, including electrode biocompatibility (he described using one of the first bioresistant resins, araldite, for example, to coat the electrodes).11 He addressed the effect of stimulus frequency on muscle contraction, and he found that with higher frequency stimuli, muscles would not contract, whereas with lower frequency stimuli muscle contraction was painful. Djourno found the "right" stimulus frequency between 400 and 500 Hz. Since this frequency was within the speech range, he began to use the analogue signal of his own voice as the telestimulating stimulus.12 Triggering a nerve with his voice may well have contributed to the idea of stimulating the cochlear nerve to restore hearing. Djourno also addressed the safety of repetitive stimulation on tissue, demonstrating that the sciatic nerve from an implanted rabbit, when examined histologically and grossly, showed no changes after 2 years of repetitive stimulation.B Throughout this time Djourno revealed little interest in hear­ ing. He recognized, however, the potential of using the micro­ bobinages to stimulate the auditory system, as he noted in a 1954 publication the possibility of "treating deafness" as a potential application.12 Charles Eyries (1908-1996) completed his training in oto­ laryngology in Paris in the early 1940s. Clinically, Eyries earned early recognition for his description of a procedure to treat ozena, or atrophic rhinitis, by placing implants underneath the nasal mucosa to decrease the caliber of the nasal passages.14 This procedure became known in the French literature as the "Eyries operation." Eyries was named chief of otorhinolaryngo­ logy and head and neck surgery at I.:Institut Prophylactique in 1953, which has since been renamed I.:Institut Arthur Vernes. Although primarily a clinician, he had research interests in neuroanatomy and embryology of the facial nerve, and he wrote about surgical facial nerve repairs.15 Eyries had shown little interest in hearing at this point in his career and had never worked with Djourno, although he knew of Djourno because both he and Djourno had laboratories in the medical school associated with the hospital. As the local expert on facial nerve repairs, Eyries was asked in February 1957 to provide a consultation for an unfortunate patient, a 57-year-old man who suffered from large bilateral cholesteatomas. A right-sided temporal bone resection was performed 5 days prior to the consultation and an extensive left temporal bone resection was per­ formed several years earlier. Both procedures involved abla­ tion of the labyrinth and facial nerve sectioning. As a result, the patient was left with bilateral deafness and bilateral facial nerve paralysis. Eyries was consulted to consider a facial nerve graft for reanimation.16 On examination, Eyries found that the caliber of the patient's remaining nerve was too small to support a local nerve transfer. Eyries therefore embarked on a search for appropriate graft material. He went to the medical school seeking cadaverous material, where he met Djourno, who offered to help and suggested stimulating hearing at the same time. Although Eyries was primarily interested in http://medical.dentalebooks.com
  • 17. his patient's facial reanimation, he agreed to implant an electrode into the patient at the time of surgery. Eyries's justification for agreeing to the implantation was that the cavity was already exposed and the patient had nothing to lose in having the extra procedure.16 From Djourno's standpoint, the patient was deaf and begging to escape from the silence that haunted him, and he was fascinated by the opportunity to telestimulate the auditory system.17 The procedure took place on February 25, 1 957. Eyries performed the right-sided facial nerve graft using fetal sci­ atic nerve as the graft material, which purportedly proved to be successful. At the time of surgery, the proximal cochlear nerve stump was found to be significantly shred­ ded. Djourno and Eyries chose to seat the active electrode into the remaining stump and place the induction coil into the temporalis muscle. A postoperative lateral skull film con­ firmed its placement (� Fig. 1 .2). Some testing was done intraoperatively. The stimulus waveforms included bursts of a 1 00-Hz impulse signal administered 15 to 20 times per minute, low-frequency alternating current, and the analogue signal of words spoken into a microphone. The patient described detecting auditory sensations. Several qualitative observations were made: the patient's discrimination of intensity was good; frequency discrimination was poor; no speech recognition was evident. The patient underwent an extensive post­ operative rehabilitation with the implant under the guid­ ance of the speech therapist. Over the ensuing months more complex stimuli were administered, and the patient was able to differentiate between higher frequency (described as "silk ripping") and lower frequency (described as "burlap tearing") stimulation. He appreciated environmental noises Fig. 1 .2 Lateral skull film of Djourno and Eyries's first implant following surgery. The coil has been embedded in the temporalis muscle, whereas the electrodes were placed near the remaining stump of the cochlear nerve. (Courtesy of the john Q. Adams Center.) and several words, but could not understand speech. The publication that resulted from this work is the seminal citation for direct cochlear nerve stimulation.18 Several months later, during testing, the electrode suddenly ceased to function. Djourno and Eyries went to the operating room to investigate. They found that a solder joint connecting the wires to the ground electrode embedded into the tempora­ lis muscle had broken, and the implant was replaced. The sec­ ond implant, however, suffered the same fate. Eyries held Djourno responsible for the broken electrodes and refused to perform a third implantation.19 The falling out between the two men over this problem was the end of Eyries's involvement in the project. After this event, he and Djourno rarely conversed for the rest of their lives. This was not quite the end of the story for Djourno, however. He went on to address several aspects of hearing applicable to electrical stimulation. For one, he examined the oscillographic representation of spoken words in an effort to give deaf patients a visual representation of speech that they could use for biofeedback when learning to speak.2o After the first implant effort, a colleague approached Djourno to enter into a business venture to develop the implant. The colleague proposed that in exchange for an exclusive arrangement on the project, he would provide Djourno with the financial and engineering support of industry_17 Djourno was always an academic ide­ alist, and he did not believe in profiting from his discoveries. Furthermore, he detested industry and would have no part in granting exclusivity. As a matter of principle, Djourno chose to do another implant with a different oto­ laryngologist, Roger Maspetiol_l7 This second patient, deaf­ ened from streptomycin ototoxicity, was implanted with an electrode near the promontory, rather than within the tem­ poral bone. The patient showed little enthusiasm for her device, and she was lost to follow-up only a few months after it was implanted. Djourno subsequently lost funding for further implant work.21 This signaled the end of Djour­ no's participation in developing an auditory prosthesis. The legacy of the Djourno and Eyries's work was sustained despite the abrupt departure of the two men. Claude-Henri Chouard, who was a student in Eyries's laboratory working on the facial nerve, resumed work on the cochlear implant several years later. Chouard was instrumental in developing one of the first functional multichannel implants, and he credits Charles Eyries as his major source of inspiration.22 Although Djourno and Eyries's implantation on February 25, 1957 is typically credited as the first cochlear implant, a closer evaluation of the patient's anatomy raises the ques­ tion of whether the cochlear nerve or the auditory brain­ stem were stimulated by the implanted electrodes, as wallerian degeneration may have destroyed the cochlear ganglion cells.23 Whether Djourno and Eyries stimulated the cochlear nerve or the cochlear nucleus should not over­ shadow the significance of their work. Electrical methods to treat deafness had been described by numerous practition­ ers for almost two centuries prior to 1 957, beginning with the classic work of Alessandro Volta in the late 18th cen­ tury.4 These previous efforts, however, either were aimed at treating deafness with therapeutic electrical stimulation or were examples of electrophonic hearing. 3 http://medical.dentalebooks.com
  • 18. 4 . . • Early Developments in the Western Hemisphere Dissemination of the work of Djourno and Eyries was at first slow in the Western Hemisphere. This is likely attributable to the fact that their publication appeared only in the French-language medical literature. Additionally, of the pair, the more likely to present his work among clinicians was Eyries, as he was an otolaryngologist. Eyries demonstrated little enthusiasm for the project, however, and his interest was short-lived. Djourno was a physiologist rather than a clinician, making interaction between him and American otolaryngologists less likely despite his continued interest. Word of their work reached William F. House in California serendipitously sometime around 1959, when a patient of his handed him a summary in English of the Djourno and Eyries work.24 The summary was optimistic regarding elec­ trical stimulation to replace hearing, and House was inspired. los Angeles William F. House was a dentist-turned-otologist who began working with his brother Howard P. House at the Otologic Medical Group in Los Angeles upon completion of his residency in 1956. Early in his career he had already made significant con­ tributions to otology and neurotology, including the facial recess approach. He was working at the time on the middle fossa approach to the internal auditory canal in collaboration with john Doyle, a neurosurgeon who also practiced at St. Vincent's Hospital in Los Angeles.2s House and Doyle first sought to record the cochlear nerve response to sound when the nerve was exposed during the middle fossa approach for vestibular neurectomy as a treatment for Meniere's disease. Specifically, they sought to record the nerve output associated with tinnitus.26 They relied on Doyle's brother, james Doyle. an electrical engineer, to address the technical challenge of record­ ing such signals intraoperatively. The nerve output was recorded, but no tinnitus was observed. Successful recordings of sound-induced potentials from the cochlear nerve, however, inspired stimulating the nerve with similar waveforms in order to restore hearing. House and Doyle first attempted electrical stimulation to elicit hearing during stapes surgery by placing a needle elec­ trode on the promontory or into the open oval window. An ear speculum inserted into the external auditory canal served as a ground lead. With square wave stimuli, patients reported hear­ ing the stimulus without discomfort, dizziness. or facial nerve stimulation. These responses were sufficient to encourage House and Doyle to implant a patient with a hard-wire device. The first willing subject was a 40-year-old man with severe oto­ sclerosis and deafness. Promontory stimulation of the right ear on january 5, 1961 revealed consistent responses. On january 9, therefore. a gold-wire electrode was inserted under local anes­ thesia through a postauricular approach into the round win­ dow. The wire was brought out through the postauricular skin.27 The patient reported hearing the electrical stimuli, but he had poor loudness tolerance. Several weeks later the wire was removed. A second patient was also implanted in january 1961. The woman had deafness, tinnitus, and vertigo associated with con­ genital syphilis, and she was brought to the operating room for a vestibular neurectomy through the middle fossa approach. During the procedure, a single gold-wire electrode was placed through the middle fossa approach into scala tympani at the basal part of the cochlea. The wire was brought out through a skin incision. The patient described hearing the square wave stimulation upon waking from anesthesia. Over the ensuing days, the current intensity required to elicit a response increased. For fear of infection or edema, the wire was removed. With the first patient's encouraging responses, and with the hope of producing discrimination of higher frequencies, House and Doyle decided to reimplant him with a five-wire electrode array inserted through the mastoid facial recess and round win­ dow. The electrode array was attached to a more permanent electrode induction system seated in the skull. Over a several­ week testing period, the patient's intensity requirement increased and his postauricular skin began to swell. This device was also removed for risk of infection. Worries of bio­ compatibility of materials ensued. The theoretical basis for the multiple-electrode design was to spread high-frequency stimuli among spatially separated electrodes. By stimulating different subpopulations of audi­ tory nerve fibers at rates slower than their refractory period, they thought, summation among the subpopulations would purportedly yield an overall high-frequency response along the whole nerve. This implant design and its theoretical basis became the foundation for an early cochlear implant patent application submitted by james Doyle and Earle Bal­ lantyne in 1 961 . The patent was not granted until 1969.28 Despite being founded on what has since been shown to be an erroneous theory of electrical stimulation, the patent was ironically prescient in its statement that a 1 6-channel unit would be necessary for implant patients to be able to con­ verse on the telephone. Word of the two implanted patients reached the lay press. The brief articles were overly optimistic in their descriptions of an "artificial ear," going so far as to announce that "surgical implantation of a transistorized device designed to restore hearing of deaf persons is scheduled within 30 days."29 These reports prompted readers who were deaf to call House and Doyle seeking a cure for their deafness, and aroused the interest of investors seeking to cash in on emerging medical technology. House recognized the danger in such publicity, and publicizing the implant work became an issue of considerable conflict between the Doyles and House. Disagreement over how aggressive to proceed with the implant, given the initial bio­ incompatibility problems, opened an irreparable rift between House and the Doyles that brought an end to their collabora­ tion. House had a very busy otologic practice, and implant development took a low priority for several years to follow. The Doyles, on the other hand, continued to experiment, implanting numerous subjects. They collaborated with the Los Angeles otolaryngologist Frederick Turnbull, whose office was used for most of the testing. They reported their results in locaJ3° and nationaJ31 forums, reporting optimistically that electrical stimu­ lation could yield speech perception, but not offering system­ atic testing or analysis. The Doyles ceased their investigations in 1968 due to a lack of research funding.26 http://medical.dentalebooks.com
  • 19. Stanford University F. Blair Simmons had worked as a research associate in the laboratory of S.S. Stevens at Harvard as a medical student and then with Robert Galambos at the Walter Reed Institute prior to his residency in otolaryngology at Stanford University in Stanford, California. Simmons was an assistant professor in Stanford's Division of Otolaryngology in 1962 for less than a month before he was presented with an unexpected opportu­ nity to stimulate the cochlear nerve intraoperatively. The patient was an 18-year-old man who had developed a recur­ rence of a cerebellar ependymoma that manifested itself as mild hearing loss. Exploratory craniotomy under local anesthesia was planned, and the cochlear nerve would be exposed during the procedure. Prior to surgery, Simmons discussed stimulating the patient's cochlear nerve electrically. The patient agreed to the intraoperative testing and to a preoperative auditory training session. During the awake craniotomy, the patient was asked to describe what he heard when a bipolar electrode was used to stimulate the exposed cochlear nerve with 100- microsecond square wave pulses. The patient described auditory sensations and was able to discriminate stimulation frequencies up to 1 kHz.32 Simmons's first implanted device was then placed 2 years later, in 1964. This second subject was a 60-year-old man who had been unilaterally deaf for several years, and whose better hearing ear then became deaf. He also suffered from retinitis pigmentosum and had associated severe sight disability. Despite being made fully aware that implantation would likely fail and very likely yield no useful hearing, the subject agreed to undergo the implantation. Local anesthesia was used, and the promontory exposed through a postauricular transmeatal approach and elevation of a tympanomeatal flap. A 2-mm coch­ leostomy and then subsequent 0.1 -mm drill hole into the modiolus were performed. A partial mastoidectomy was also performed and the middle ear entered anterior to the facial nerve by removing the incus. A six-electrode array was placed through the mastoid opening into the epitympanum and then through both the cochleostomy and the modiolar opening to a depth of 3 to 4 mm. The electrodes were attached to a plug that was then secured to the mastoid cortex. Psychoacoustic testing was carried out both at Stanford and at Bell Laboratories in New jersey.33 Unfortunately, the subject's combination of disabilities made psychophysical testing very challenging. Based on these unfavorable experiences, Simmons became pessimistic about the future of implantation. He estimated the likelihood that electrical stimulation of the auditory nerve could ever provide a clinically useful means of communication to be "considerably less than 5%."34 Human implantation at Stanford was postponed until further animal testing could prove its utility. House Resumes His Work With the advancements in pacemakers and ventriculoperito­ neal shunts in the late 1960s, House's interest in cochlear implantation was reawakened with more confidence in the safety and efficacy of indwelling devices (.,. Fig. 1.3). House was working with a talented engineer named jack Urban, a collabo­ ration best known for several influential developments in neu­ rotologic instruments. House and Urban aggressively pursued History of the Cochlear Implant Fig. 1 .3 William F. House (left) and Robin Michelson (right) collaborating in the early 1 970s. (Courtesy of the john Q. Adams Center.) implanting their single-channel device in human patients. As much as any other parameter, the durability and safety of the device was on House's mind with this group of patients. Of several patients implanted in 1969, one required having his implant removed due to tissue rejection, and another was lost to follow-up. However, a third patient, Charles Graser, became a long-term experimental subject. In Graser, House found stimu­ lation levels and results that remained stable over the course of years. This gave credence to the safety of electrical stimulation. Charles Graser was deaf for 10 years because of ototoxicity. Postimplantation, he worked intensely as a research subject, and continued to do so enthusiastically for many years. Many of the observations and modifications that House and Urban reported in the 1960s were based on the testing of only subject-Graser. For instance, one of the surprising findings from the work with Graser was that a 1 6,000-Hz carrier fre­ quency signal helped him appreciate higher frequencies, and amplitude-modulating the carrier with the acoustic signal generally sounded the best. This signal processor strategy became standard on the House/3M cochlear implant. Reporting of these early results was primarily by testimonial experiences of the individual subjects rather than systematic study. Another important outcome of these early studies was abandoning the multiple electrode systems for the single-wire electrode.Js San Francisco Robin Michelson (.,. Fig. 1 .3) was an otolaryngologist in private practice in the 1960s in Redwood City, California. He was the grandson of the Nobel Prize-winning physicist Albert Michelson. Robin Michelson's inspiration for cochlear implanta­ tion came from seeing a patient, T.l. Moseley, who had severe tinnitus and otosclerosis. Michelson had sought to monitor the cochlear microphonic during a stapedectomy as a means of immediate feedback, since he performed the procedure under local anesthesia. Moseley, an engineer, agreed to build him a high-gain amplifier with an earpiece that Michelson could use in the operating room. Michelson placed an electrode against 5 http://medical.dentalebooks.com
  • 20. 6 . . the round window. Feedback from the amplifier elicited the sensation of sound for the patient that Michelson was subse­ quently able to pitch match.36 Michelson, like House, originally subscribed to the telephone theory of hearing-that the cochlea presented the auditory nerve with the analogue electrical signal of the auditory stimu­ lus, and that all that was required to restore hearing was to stimulate the auditory nerve with a similar signal. In an attempt to demonstrate that electrical stimulation of the auditory nerve elicited auditory responses, he implanted an electrode into the cat cochlea and measured the cochlear microphonic in the opposite ear. He found that electrical stimulation suppressed the contralateral cochlear microphonic similarly to acoustic stimuli. He concluded, therefore, that electrical stimulation was carried along auditory pathways.37 Although Michelson was likely demonstrating electrophonic hearing rather than direct auditory nerve electrical stimulation, this result inspired him to implant a human volunteer with hearing loss. Michelson's first implant was a single-channel device implanted into a congenitally deaf woman. Testing after implantation revealed that she obtained auditory sensations from stimulation, and that pitch perception was possible for stimulus frequencies less than about 600 Hz. More interesting to Michelson, however, was that the subject could differentiate a square-wave stimulus from a sine-wave stimulus.36 Michelson interpreted this to indicate that the fine structure of the electrical stimulus could be conveyed along auditory pathways. The gold-wire electrode hardened several days after the operation, broke from the rest of the implant, and needed to be removed. Several additional patients received fully implantable single-channel devices, and this preliminary work was presented to the American Academy of Ophthalmology and Otolaryngology in October 1970; a follow-up study was pre­ sented at the 1971 meeting of the American Otological Society. The patients had pitch perception based on stimulus frequency and could recognize speech stimuli but had no word under­ standing. All implanted patients lost whatever residual hearing they had prior to implantation.38 It was around this time that Francis Sooy visited Michelson in Redwood City and saw his work in progress with implantation. Sooy was the chairman of the nascent Department of Oto­ laryngology at the University of California at San Francisco, and this interaction with Michelson confirmed his belief in the potential of cochlear implantation. He persuaded Michelson to join the faculty at UCSF and bring his implant investigations to the University. Sooy also believed that the successful devel­ opment of the cochlear implant required a university-based scientific foundation. After recruiting Michelson, Sooy then recruited Michael Merzenich from the University of Wisconsin. Merzenich was a young neurophysiologist whose interest was mapping the inferior colliculus. He joined the UCSF faculty and began working on recordings from the inferior colliculus for several months before meeting with Michelson about the cochlear implant. Merzenich was initially quite skeptical about the merits of the implants and showed little interest in joining the development effort. After seeing a few patients on a docu­ mentary film created by the otolaryngology resident C. Robert Pettit, however, Merzenich became convinced of its potentiaJ.39 The collaboration between Michelson, a clinical pioneer, and Merzenich, a talented basic scientist with a solid foundation in neurophysiology, was masterminded by Sooy and was an indis­ pensable element in the development of the UCSF cochlear implant program. One of the first studies Merzenich performed was recording the response properties of single units in the cat inferior colli­ culus in response to both sound stimulation from one ear and electrical stimulation from the other ear in implanted cats. He showed that the inferior colliculus neurons responded similarly to electrical and sound stimuli, but that the tuning curves for electrical stimulation were very flat and showed little tuning. Additionally, the responses from animals with ototoxin-induced hair cell destruction showed the same responses to electrical stimuli as untreated cochlea. This was the first definitive dem­ onstration that auditory sensation with implants arose from direct stimulation of the auditory nerve rather than electro­ phonic effects. Responses in the cat were then compared to psychoacoustic measures in the human implanted subjects using the same electrical stimuli in both groups. The conclu­ sions from this work were that with single-electrode devices, periodicity pitch up to about 600 Hz is possible, but no place coding of frequency is possible. Thus in order to convey com­ plex sounds such as speech, multiple-electrode arrays would be necessary.40 This work was presented to the American Otologi­ cal Society at the 1973 annual meeting in St. Louis, and it marked the beginning of the race toward the development of a multichannel cochlear implant. • Controversies and Doubts The year 1973 represents a crossroads in the cochlear implant's development. Until this time, cochlear implantation would have been considered, at best, an idea with potential to help some deaf people sometime in the future, and at worst as a danger­ ous experimental procedure promising nothing better than vibrotactile information. Simmons had downplayed the poten­ tial of implants and abandoned human implantation. The only clinicians performing human implants, House and Michelson, were surgeons far from the mainstream and whose funding was from private sources. In order for the implant development to proceed, implants would need to be granted legitimacy as a valid research pursuit with National Institutes of Health (NIH) funding and demonstrate broad-based clinical application. This section highlights events in the 1970s that accomplished both. National Institutes of Health The NIH itself was partly responsible for giving scientific legiti­ macy to the cochlear implant. In 1970 the Neural Prosthesis Program was established within the National Institute of Neu­ rological Diseases aimed at promoting extramural research on neural prostheses primarily by capitalizing on the contract mechanism of the NIH.41 Initially the program did not focus on an auditory prothesis, but rather on developing a visual pros­ thesis for the blind, and the first contracts focused on this goal. In addition to awarding contracts, the Neural Prosthesis Pro­ gram under the guidance of F. Terry Hambrecht initiated and maintained the annual Neural Prosthesis Workshop. The work­ shop brought together a multidisciplinary group of contractors and consultants to the NIH campus to discuss research findings, delineate important problems, and develop strategies for the http://medical.dentalebooks.com
  • 21. development of neural prostheses. At the third workshop in january 1973, auditory prostheses first commanded a signifi­ cant part of the agenda. Participants included Michelson, Merzenich, and Simmons. Both Merzenich and Simmons also obtained extramural NIH funding for their implant-related research by this time.41 Early Cochlear Implant Meetings Several meetings over the next several years pitted the implant pioneers against the otology/hearing science establishment. These symposia began to bring cochlear implantation into the limelight, often resulting in considerable controversy. Between 1971 and 1973, significant work removed doubts that the audi­ tory nerve could be stimulated directly with the implant. Con­ cerns that the prominent oro-scientists expressed toward the implant therefore shifted and coalesced during meetings in 1973 and 1974 of the Otological Society, the First International Conference on Electrical Stimulation in San Francisco, and the Third Workshop of the Neural Prosthesis Program. These con­ cerns and their rationales are as follows: • Concern: The remaining nerve fiber population in deafness is not sufficient to support tonotopic stimulation ofthe nerve. This was based on the finding of Hal Schuknecht and coworkers that only a minority of temporal bones examined demonstrated more than two thirds of the normal population ofcochlear ganglion cells.42 Additionally, Nelson Y.S. Kiang, a neurophysiologist at the Massachusetts Institute of Technology who had defined how single auditory nerve units respond to sound in cat, led a vehement opposition to human cochlear implantation. His point ofview was that cochlear implants with the current design could never produce speech understanding or "useful hearing" because electrical stimuli could not convey the complex auditory stimuli that the cochlea provided.43 Implanting humans with devices that offered little more than improved lip reading, he thought, could not be considered prudent. • Concern: Electrical stimulation could convey sounds out ofthe speechfrequency range. Cochlear damage in deafness is typically in its basal half, where high-frequency stimuli are transduced. The electrodes described at the time extended only into the proximal basal part of the cochlea. Therefore, if the place principle were utilized, electrical stimulation would yield only sound frequencies higher than the speech range.44 • Concern: The dynamic range of loudness with electrical stimulation would be too narrow to convey useful sound information. Although loudness grows with sound intensity in the cochlea over a range of nearly 100 dB, the intensity range with electrical stimulation is only about 6 dB, which would severely limit loudness discrimination. The dynamic range of the firing of cochlear nerve fibers of the cat in response to both electrical and acoustic stimulation revealed a similar finding-that the dynamic range in response to sound is 20 to 40 dB, and to electrical stimuli 4 dB.43 • Concern: lntracochlear manipulation that would occur with cochlear implantation would result in significant damage to the cochlea; anything that disturbs scala media would cause degeneration ofthe remaining sensoryfibers. This concern arose from studies of Schuknecht showing that one aspect of cochlear pathology was auditory nerve fiber degeneration.45 Why, then, perform an invasive procedure like the cochlear implant when an externally worn device such as a vibrotactile stimulator could be used to the same end? The above concerns did not dissuade the core group of implant developers from proceeding onward, yet a strong aura of doubt surrounded the cochlear implant. At the forefront of cochlear implant support, however, was Francis Sooy, who was responsi­ ble for assembling the implant devotees in October 1974 with the support of the NIH in order to evaluate the progress and define the research goals for the implant, and to establish guidelines for patient selection and implantation protocols. Two important decisions were made at this meeting. First, criteria for implantation were delimited: full informed consent that the procedure is experimental; no useful hearing in either ear; only those patients able and willing to participate in psychophysical testing; otherwise healthy patients; and, finally, adults only. Second, a consensus decision was made to stop implanting all single-channel devices until an objective evaluation of the patients already implanted could be performed.46 The NIH took the lead in this objective evaluation with a call for applications for a formal objective evaluation of the single-channel recipi­ ents. The future of implant development rested on this objec­ tive evaluation, as a finding that the implant had limited utility may have curtailed allocation of further resources from the Neural Prosthesis Program. The contract to perform the objective assessment was awarded in june 1975 to a team at the University of Pittsburgh led by Robert Bilger. The Bilger Report Thirteen adult single-channel implant subjects, 1 1 implanted by House and two by Michelson, were flown to Pittsburgh for a week-long testing session to take part in the study. The subjects underwent extensive audiological, psychoacoustic, and vestibu­ lar testing. Several of the results were not surprising: Subjects could not understand speech with the implant alone, but the implant helped the patients' lipreading scores. Also not surpris­ ing was the finding that the subjects' quality of life was aided by the implant. A surprising finding, however, was that the subjects' speech production was significantly aided by their implants. The investigators concluded from the study that single-channel implants helped deaf patients. While this conclusion may not seem profound, it was the first objective, scientific assessment of implant performance, concluding that the subjects received benefit from the implant with minimal risk.47 From this, the cochlear prosthesis gained the legitimacy needed to justify funded research efforts toward a multichannel device. Furthermore, while the world waited for the multi­ channel implant, the single-channel device was viable. • Development of a Multichannel Device With the Bilger study confirming the utility of a single-channel device, House moved forward with refinement of his implant. He and jack Urban joined forces with the 3M Company. The House/3M single channel device (.,.. Fig. 1 .4) was implanted into 7 http://medical.dentalebooks.com
  • 22. 8 . . Fig. 1 .4 An early version of the House/3 M single-channel device. Shown is the implanted receiver/stimulator and wire electrodes. (Courtesy of the john Q. Adams Center.) several thousand patients by the early 1980s, and in 1984 the Food and Drug Administration (FDA) granted approval for the device. Other centers, however, concentrated their efforts on researching and developing a multichannel device. At the forefront of this competition were Merzenich, Michelson, Robert Schindler, and colleagues at UCSF (� Fig. 1.5), and Graham Clark at the University of Melbourne in Australia. Clark, a clinically trained otolaryngologist, began investigat­ ing the cochlear implant as a graduate student in the 1960s. Fig. 1 .5 Early eight-channel electrode and epoxy-coated receiver designed by Robin Michelson and assembled by Mel Bartz. The intracochlear portion of the electrode array was formed from Silastic to fill scala tympani. (Courtesy of Stephen Rebscher, University of California at San Francisco.) He realized as early as his graduate thesis in 1969 that the single-channel device had limited utility,48 and he sought to use a systematic scientific approach to developing a multielectrode device. The approach had several fronts: developing speech processing strategies, optimizing the electrode array, and devel­ oping a safe, reliable implantable receiver-stimulator. The efforts toward what would become the Cochlear Corporation's Nucleus multichannel implant was primarily an Australian ven­ ture, as funding came from Australian national telethons and government-associated engineering firms, and partly through government grants.49 Clark and his colleagues reported several important findings, two of which were that inserting the elec­ trode array in an anterograde direction through a single cochle­ ostomy at the round window niche into scala tympani was less traumatic to the cochlear structures than either retrograde insertion or multiple cochleostomies,so.sJ and dissolution of platinum electrodes with biphasic pulsatile stimuli was minimal, implying safe long-term stimulation.s2 Clark first implanted a human subject in 1978, and by 1981 he showed that subjects were able to understand some open-set speech with their implants and without the aid of lipreading.s3 The FDA approval for the Nucleus multichannel implant (Cochlear, Melbourne, Australia) was granted for adult patients in 1985 and children as young as 2 years in 1990. As several technical challenges were overcome in the 1980s, multichannel cochlear implants became a safe option for pro­ foundly deaf adults and children. Patients with the implant were expected to have a quality-of-life improvement and some open-set speech recognition. Another development was required, however, to dramatically improve the speech recognition provided by the implant, and this was the develop­ ment of high-rate interleaved stimulation. Multiple electrode stimulation relies on the place principle of coding auditory stimuli along the cochlea. For separate electrodes to be effective in eliciting different frequency responses, the spatial extent of their stimuli must be different. Several studies in the late 1970s and early 1980s demonstrated that significant interference (known as "interaction") resulted from simultaneous stimula­ tion of multiple electrodes.s4.ss It was found that electrode interaction could be minimized by stimulating the electrodes in a staggered, nonsimultaneous pattern.54 Another discovery was that nonsimultaneous stimulation at pulse rates greater than 1 kHz was especially effective at improving an implant subject's speech understanding. A collaboration between UCSF and the Research Triangle Institute (Research Triangle, NC) resulted in the implementation and testing of a speech processing scheme that utilized this concept. The concept was patented and became known as continuous interleaved sampling (CIS). The implementation of CIS provided a tremendous improvement in implant recipients' performance with speech recognition.56 Since that time there have been numerous noteworthy tech­ nological developments in both device design and coding, and the future promises even greater advances to further enhance performance in the implanted hearing-impaired population. • Conclusion The development of the cochlear implant began in 1957 with the first attempts to restore hearing with direct electrical stimulation of the auditory nerve. In the years that followed, http://medical.dentalebooks.com
  • 23. the primary proponents of implants were a few otologists try­ ing to help their patients with single-channel devices, despite considerable opposition from leaders in the field. If it were not for these pioneers. cochlear implants may well have been delayed by many years. Following the Bilger study, cochlear implant research gained mainstream support, and efforts toward a marketable multichannel device were underway. Improvements are ongoing and offer a bright future to the hear­ ing-impaired population. • References [ 1 ] Dudley H. Remaking speech. ] Acoust Soc Am 1939; 1 1 ; 169-177 (2] Wever EG, Bray CW. The nature of the acoustic response: the relation between sound frequency of impulses in the auditory nerve. j Exp Psycho! 1 930; 13: 373-387 (3] Stevens SS. On hearing by electrical stimulation. j Acoust Soc Am 1937; 8: 191-195 (4] Shah SB, Chung JH, jackler RK. Lodestones, quackery, and science: electrical stimulation ofthe earbefore cochlear implants. Amj Otol 1997; 18: 665-670 [5] Djourno A. Strohl A. Modifications du courant de peau de grenouille pendant !'excitation electrique. CR Soc Bioi (Paris) 1 937; 125: 625 (6] Djourno A. Variation de l'excitabilite du sciatique de grenouille suivant l'ecart des electrodes. CR Soc Bioi (Paris) 1946; 140: 1 83 (7] Djourno A. Sur Ia mesure instantanee de Ia frequence du pauls. Paris Med (Paris) 1938; 37: 83 (8] Djourno A. Masmonteil, Roucayrol jC. Une application de Ia haute frequence a !'extraction de protheses metalliques. Soc Electrother Radial. 1948; 29: 637-638 (9] Djoumo A, Delayj, Verdeaux G Un cas de narcolepsie avecetude eiectroence­ phalographique. Congres d'Electro-encephalographie de Langue fran�aise, Paris 1949 [10] Djourno A. La respiration eiectrophrenique. Presse Med 1952; 60: 1532- 1533 [ 1 1 ] Djourno A. Excitation eiectrique localisee a distance. C R Acad Sciences. 1953; 236: 2337-2338 (12] Djourno A. Kayser D. La methode des excitations induites a distance. ] Radial 1 954; 36: 1 1 7-118 (13] Djourno A, Kayser D, Guyon L Sur Ia tolerance par le nerf d'appareils eiectri­ ques d'excitation indus a demeure. CR Soc Bioi (Paris) 1955; 149: 1 882-1883 [14] Eyries C. Traitement de l'ozene par un nouveau precede de prothese chirurgi­ cale. Ann Otolaryng. 1946; 13: 581-586 [ 15] Olivier G. Eyries C. Reperes chirurgicaux et aspects du nerf facial extra petreux. Med trap. 1953; 13: 720-723 (16] Eyries C. Experience personelle. Cahiers d'Oto-Rhino-Laryngologie. 1979; 14: 679-681 [ 17] Djourno A. Interview with Phillip Seitz. january 12. 1 994. john Q, Adams Center Archives [18] Djourno A, Eyries C, Vallancien B. De !'excitation eiectrique du nerf cochleaire chez l'homme. par induction a distance, a !'aide d'un micro-bobinage indus a demeure. CR Soc Bioi (Paris) 1957; 1 5 1 : 423-425 [19] Eyries C. Interview with Phillip Seitz, january 10, 1994. john Q, Adams Center Archives (20] Djourno A. Analyse oscillographique instantanee de Ia voix par!ee. CR Soc Bioi (Paris) 1959; 153: 197-198 (21 ] Djourno A. A propos de prothese sensorielle totale. Bull Acad Nat! Med 1977; 161 : 282-283 [22] Chouard CH. Entendre sans Oreilles. Paris: Robert Laffont. 1973 (23] Eisen MD. Djourno, Eyries, and the first implanted electrical neural stimula­ tor to restorehearing. Otol Neurotol 2003; 24: 500-506 [24] House WF A personal perspective on cochlear implants. In: Schindler RA, Merzenich MM. eds. Cochlear Implants. New York: Raven Press 198513- 1 98516 (25] House WF. Cochlear Implants: My Perspective. Newport Beach, CA: AllHear, 1 995 (26] DoylejB. Interview with Philip Seitz, August 22, 1993. john Q, Adams Center Archives [27] House WF. Cochlear implants: beginnings (1957-1961 ). Ann Otol Rhinal Lar­ yngol 1976; 85: 3-6 (28] Doyle JB, Ballantyne EW, inventors Artificial sense organ, U.S. Patent 3,449,768,june 17, 1969 [29] Anonymous . California electronics firm readies "artificial ear" implant. Space Age News. 1961 ; 3: 1 (30] Doyle JB, Doyle JH, Turnbull FM, Abbey j, House L Electrical stimulation in eighth nerve deafness. Bull Los Angel Neuro Soc 1963; 28: 148-150 (31 ] Doyle JH, Doyle JB, Turnbull FM. Electrical stimulation of the eighth cranial nerve. Arch Otolaryngol 1 964; 80: 388-391 (32] Simmons FB. Mongeon Cj. Lewis WR. Huntington DA. Electrical stimulation of acoustical nerve and inferior colliculus; results in man. Arch Otolaryngol 1 964; 79: 559-568 (33] Simmons FB, Epley jM, Lummis RC et al. Auditory nerve: electrical stimula­ tion in man. Science 1965; 148: 104-106 (34] Simmons FB. Electrical stimulation of the auditory nerve in man. Arch Otolar­ yngol 1966; 84: 2-54 (35] House WF, Urban j. Long term results of electrode implantation and elec­ tronic stimulation of the cochlea in man. Ann Otol Rhinal Laryngol 1 973; 82: 504-51 7 (36] Michelson R P. Interview with Phillip Seitz, November 7 , 1995. john Q. Adams CenterArchives (37] Michelson RP. The crossed cochlea effect. Trans Am Acad Ophthal Otolaryngol 1 968 (38] Michelson RP. Electrical stimulation of the human cochlea. A preliminary report. Arch Otolaryngol 1971 ; 93: 31 7-323 (39] Merzenich MM Interview with Marc Eisen, March 26. 2004 (40] Merzenich MM. Michelson RP, Pettit CR. Schindler RA, Reid M. Neural encod­ ing of sound sensation evoked by electrical stimulation of the acoustic nerve. Ann Otol Rhinal Laryngol 1973; 82: 486-503 [41 ] Hannaway C. Contributions of the National Institutes of Health to the Devel­ opment of Cochlear Prostheses. Bethesda, MD: National Institutes of Health, 1 996 [42] Kerr A. Schuknecht HF. The spiral ganglion in profound deafness. Acta Otolar­ yngol 1968; 65: 586-598 (43] Kiang NYS, Moxon EC. Physiological considerations in artificial stimulation of the inner ear. Ann Otol Rhinal Laryngol 1 972; 8 1 : 714-730 (44] Lawrence M, johnsson L-G. The role of the organ of Corti in auditory nerve stimulation. Ann Otol Rhinal Laryngol 1973; 82: 464-472 (45] Schuknecht HF. Lesions ofthe organ of Corti. Trans Am Acad Ophthalmol Oto­ laryngol 1 953; 57: 366-383 (46] Merzenich MM. Sooy FAReport on a workshop on cochlear implants, Univer­ sity ofCalifornia at San Francisco, October 23-25 1 974 (47] Bilger RC. Evaluation of subjects presently fitted with implanted auditory prostheses. Ann Otol Rhinal Laryngol 1977; 86 Suppl 38: 1-176 (48] Clark G. Middle Ear and Neural Mechanisms in Hearing and in the Manage­ ment of Deafness [Doctor of Philosophy Thesis]. Sydney: University ofSydney, 1 969 (49] Clark G. Sounds from Silence. Adelaide: Allen & Unwin, 2000 [50] Clark GM, Hallworth Rj. Zdanius K. A cochlear implant electrode. J Laryngol Otol 1 975; 89: 787-792 (51 ] Clark GM. An evaluation of per-scalar cochlear electrode implantation tech­ niques. An histopathological study in cats. j Laryngol Otol 1977; 91: 185-199 (52] Black FO. Wall C, O'LearyDP, Bilger RC. WolfRV. Galvanic disruption of vesti­ bulospinal postural control by cochlear implant devices. ] Otolaryngol 1978; 7: 519-527 [53] Clark GM, Tong YC, Martin LF. A multiple-channel cochlear implant: an evalu­ ation using open-set CID sentences. Laryngoscope 1981 ; 91 : 628-634 [54] Eddington OK, Dobelle WH, Brackmann DE, Mladejovsky MG. ParkinjL Audi­ tory prostheses research with multiple channel intracochlear stimulation in man. Ann Otol Rhinal Laryngol 1978; 87: 1-39 [55] White M. Design Considerations of a Prosthesis for the Profoundly Deaf. Berkeley, CA: University of California. Berkeley, 1978 (56] Wilson BS, Finley CC, Lawson DT, Wolford RD. Eddington OK, Rabinowitz WM. Better speech recognition with cochlear implants. Nature 1991; 352: 236-238 9 http://medical.dentalebooks.com
  • 24. 1 0 I I 2 Genetics of Hearing Loss and Predictors of Cochlear Implant Outcome Robert W. Eppsteiner, Richard K. Gurgel, and Richard}.H. Smith • Introduction Cochlear implantation is the standard treatment for hearing restoration in patients with bilateral, profound sensorineural hearing loss (SNHL). Although cochlear implant candidates all share the diagnosis of SNHL, the divergent causes of hearing loss create a heterogeneous patient population. This heteroge­ neity in etiology likely contributes to the spectrum of cochlear implant performance. If we better understood the causation of SNHL in deaf patients, we would likely better predict their hearing outcome after implantation. Deafness results from the interplay of environmental and genetic factors affecting the auditory pathway. With the advent of new technologies for genomic enrichment and high-throughput sequencing, the field of genetics has begun a renaissance. Sequencing the entire human genome, which took over a decade for the Human Genome Project, can now be done in a matter ofdays. This new accessibility ofgenetic information is revolutionizing both the molecular study of disease and its management. Among the changes is a paradigm shift in the evaluation of the deaf/hard-of-hearing person, especially if the family history suggests that the hearing loss is inherited. The cornerstone of the evaluation of hearing loss remains the medical history and physical examination, comple­ mented by a thorough audiological assessment, but the next test that should be ordered is a comprehensive genetic assessment. This algorithm underscores the importance of a person's unique genetic traits in the medical decision­ making process.1 This chapter reviews the genetic basis of hearing loss, novel technologies used for comprehensive genetic testing, and the impact of genetics on cochlear implant (CI) performance. • Genetic Basis of Hearing Loss In developed nations, hearing loss is diagnosed in approxi­ mately 1 of every 500 newborns, making it the most common congenital sensory defect.2 It is three times more prevalent than both Down syndrome and cystic fibrosis.3.4 The causes of congenital SNHL may be environmental (for example, congenital cytomegalovirus and antibiotic-induced ototoxicity) or genetic.3 In 70% of cases, hearing loss is nonsyndromic (NSHL), implying that hearing loss is the only recognized phenotypic abnormality. In the remaining 30% of cases, however. other physical findings, such as heterochro­ mia iridis or preauricular pits, co-segregate with the auditory deficit. Collectively, these types of hearing loss are called syndromic (SHL). Most forms of SHL can be recognized from birth, but there are two important exceptions, notable because they are both recessive and relatively common. Usher syndrome, of which there are three types, presents with congenital hearing loss and later-onset retinitis pigmentosa, and Pendred syndrome, which can present with congenital or postlingual hearing loss and later-onset goiter, both appear as NSHL at birth, and thus we refer to these types of SHL as the NSHL mimics. Without genetic testing the NSHL mimics cannot be distin­ guished from true NSHL. The scope of the challenge lies in the fact that NSHL is extremely heterogeneous. Over 67 NSHL-causing genes have been identified; however, the total number is likely double based on data assigning genomic positions to 130 NSHL loci (a locus is a genomic position that harbors a NSHL-causing gene).s Most congenital NSHL (80%) is autosomal recessive (ARNSHL), and, quite unexpectedly, mutations in one gene account for 50% of congenital severe-to-profound ARNSHL in many different world populations.3 G]B2, encodes a protein called Connexin 26, which makes hexameric gap junctions to link cells as a functional syncytium. The relative contribu­ tions made by other genes to severe-to-profound ARNSHL, and to other degrees of congenital hearing loss, have not been determined primarily because until recently the exper­ imental design was prohibitively complex, expensive, and labor intensive. Of the 67 genes implicated in NSHL, 38 cause ARNSHL and 25 cause autosomal dominant NSHL. There are two X-linked causes of NSHL and, in addition, mitochondrial- and microRNA­ associated NSHL occurs.6·7 These genes encode a wide variety of proteins that are expressed in the cochlea and auditory neural pathway and have a diverse spectrum of functions. Structural proteins include actins (ACTG1 ), actin-associated proteins (TRIOBP, RDX) and myosins (MY07A, MY01 5A, MY06, MY01A, MYH9, MYH14); cellular junction/adhesion proteins include otoancorin (OTOA), claudin-14 (CLDN14), and the gap junctions (GJB2, GJB6); extracellular linkage molecules include cadherin 23 (CDH23) and protocadherin 15 (PCDH15); and transporters and channels include pendrin (SLC26A4) and potassium channels (KCNQ4) ("" Table 2.1 ). • Advanced Sequencing Technology for Genetic Testing for Deafness In 1977, Frederick Sanger, the only two-time Nobel laureate in chemistry, developed Sanger sequencing, the gold standard for genetic testing.8 Sanger sequencing utilizes chain-terminating dideoxynucleotide inhibitors to determine nucleotide sequence, and until recently was the only method used for full-gene sequencing. Over the past few years, however, several advanced genomic technologies that parallelize the sequencing process (therefore they are often collectively called massively parallel sequencing [MPS] technologies) have been developed. These technologies produce millions of sequences at once that are bio­ informatically aligned to the parent human genome and queried for nucleotide differences. For an in-depth review of these technologies as applied to hearing loss, the reader is referred to Shearer et al.9 http://medical.dentalebooks.com
  • 25. . . . . . Table 2.1 List ofGenes Included on the OtoSCOPE Platform with Corresponding Protein Name, Function, and Cochlear Implant Performance Information' Gene Protein Function Cl Perfonnance Reference Membranous labY!ith Genes CDH23 cadherin-related 23 structural (cell adhesion) + 1 8,1 9 CLDN14 Claudin 1 4 structural (tight junction) unknown COLJ JA2 collagen, type XI, alpha 2 structural (extracellular matrix) unknown ESPN espin structural (cytoskeleton of hair bundle) unknown GJB2 gap junction protein, beta 2 ion homeostasis + 22,28-33 GJB6 gap junction protein, beta 6 ion homeostasis + 62 ILDR1 lg-like domain-containing receptor 1 unknown unknown LOXHD1 lipoxygenase homology domain-containing 1 stereociliary protein + MY03A myosin lilA motor protein (hair bundle) unknown MY06 myosin VI motor protein (hair bundle) unknown MY07A myosin VIlA motor protein (hair bundle) + MYOJSA myosin XVA motor protein (hair bundle) unknown OTOA otoancorin structural (extracellular matrix) unknown OTOF otoferlin synaptic transmission (exocytosis at auditory + ribbon synapse) PTPRQ protein-tyrosine phosphatase receptor structural (hair cell shaft connectors) unknown RDX radixin structural (cytoskeleton of hair bundle) unknown SLC26A5 solute carrier family 26, member 5 motor protein (OHC} unknown STRC stereocilin structural (extracellular matrix) unknown TECTA tectorin alpha structural (extracellular matrix) unknown TMC1 transmembrane channel-like 1 unknown + 63 TMIE transmembrane inner ear unknown unknown TRIOBP TRIO and F-actin binding protein structural (cytoskeleton of hair bundle) unknown USH1C Usher syndrome 1C homolog structural (scaffolding protein hair bundle) unknown WHRN whirlin structural (scaffolding protein hair bundle) unknown MYH14 myosin, heavy chain 1 4, nonmuscle unknown unknown POU4F3 pou class 4 homeobox 3 transcription factor unknown T}P2 tight junction protein 2 structural (tight junction) unknown POU3F4 pou-domain class 3 transcription factor 4 transcription factor + 64,65,66 SLC26A4 solute carrier family 26, member 4 ion homeostasis + 36-40 AUGJ actin, gamma 1 structural (cytoskeleton of hair bundle) unknown COCH coagulation factor C homologue, cochlin structural (extracellular matrix) + CRYM crystallin, mu ion homeostasis unknown DFNAS deafness, autosomal dominant 5 unknown unknown SERPINB6 SERPINB6 protease inhibitor (hair cells) unknown Spiral Ganglion Genes ESRRB estrogen-related receptor beta transcription factor unknown CCDCSO coiled-coil domain containing 50 structural (cytoskeleton of hair bundle) unknown G/PC3 GAIP (-terminus interacting protein 3 proposed role in signal acquisition and unknown propagation in cochlear hair cells GJB3 gap junction protein, beta 3 ion homeostasis unknown PCDH15 protocadherin-related 1 5 structural (cell adhesion i n hair bundle) unknown PJVK pejvakin auditory pathway signaling (hair cell and unknown neuronal) TMPRSS3 transmembrane protease, serine 3 unknown variable KCNQ4 potassium voltage-gated channel ion homeostasis unknown MYH9 myosin, heavy chain 9, nonmuscle motor protein (hair cell) + WFS1 Wolfram syndrome 1 (wolframin) ion homeostasis unknown 1 1 http://medical.dentalebooks.com
  • 26. 1 2 Table 2.1 continued I Gene Protein Function Cl Perfonnance Reference I Minimal Data Genes GPSM2 g-protein signaling modulator 2 G-protein coupled receptor signaling pathway unknown - GRXCR1 glutaredoxin cysteine-rich 1 unknown unknown - HGF hepatocyte growth factor mitogen, motogen, and neurotrophic factor unknown - LHFPLS lipoma HMGIC fusion partner-like 5 may function in hair bundle morphogenesis unknown - LRTOMT leucine-rich transmembrane OMT auditory receptor cell development unknown - MARVELD2 MARVEL domain containing 2 epithelial barrier formation unknown - TPRN taperin unknown unknown - PRPS1 phosphoribosylpyrophosphate synthetase 1 nervous system development and nucleotide unknown - synthesis GRHL2 grainyhead-like 2 transcription factor unknown - MY01A myosin lA movement of organelles along actin unknown - filaments SLC1 7A3 solute carrier family 1 7. member 3 ionic and neurotransmitter transmembrane unknown - transport DIAPH1 diaphanous homologue 1 structural (cytoskeleton of hair bundle) unknown - DSPP dentin sialophosphoprotein biomineral tissue development unknown - EYA4 eyes absent homologue 4 transcription factor unknown - CLRN1 clarin 1 may modulate neurotransmission at hair unknown - cell-spiral ganglion cell synapse GPR98 g-protein-coupled receptor 98 may have role in the development of the unknown - central nervous system USH1G SANS (aka Usher syndrome type-1 G protein) structural (hair cell bundles) unknown - USH2A usherin 2A structural (cell adhesion) unknown - MSRB3 methionine-R-sulfoxide reductase B3 protein repair unknown - DIABLO diablo homologue, mitochondrial promotes apoptosis by activating unknown - caspases CEACAM16 carcinoembryonic antigen-related cell adhesion possible structural protein (between unknown - molecule 1 6 tectorial membrane and stereocilia) EYA 1 EVA1 protein unknown unknown II - FOX/1 forkhead box protein 11 transcription factor unknown II - KCNJ10 adenosine triphosphate (ATP)-sensitive inward ion homeostasis unknown 11- Irectifier potassium channel 1 0 Abbreviations: + represents good cochlear implant performance. 0Genes have been divided based on their location ofprimary expression. Genes listed as expressed in the spiral ganglion in certain cases may also be expressed in the membranous labyrinth but are listed as spiral ganglion expressed genes. Multigene Panels Using Microarrays One of the first advanced genomic strategies applied to heredi­ tary hearing loss was the single nucleotide extension microar­ ray (HHL APEX).10 These mutation detection arrays incorporate bound primers to which genomic DNA is hybridized. Fluores­ cent nucleotides are added, and their binding to overhanging primer bases is detected by imaging. HHL APEX does not inter­ rogate entire genes but rather only 198 bases in eight genes where pathogenic variants have been described. Another microarray-based platform is OtoCHIP. It offers an important advantage in that it uses resequencing microarrays to screen specific genes for any nucleotide changes. Biotinylated genomic DNA is hybridized to its complementary probe on the array, which is imaged repeatedly to determine the nucleotide at each genomic position. The current version of OtoCHIP inter­ rogates 19 genes (70,000 bases).11 Multigene Panels Using Targeted Genomic Enrichment An alternative to array-based hybridization is solution-based hybridization, one example of which is targeted genomic enrichment (TGE). In TGE, sheared genomic DNA is hybrid­ ized to biotin-tagged probes (also known as baits) that are complementary to specific sequences of interest. Hybridization occurs in solution (solid-phase hybridization is also possible), and then the genomic DNA-bait complexes are captured using streptavidin beads. Noncapture genomic DNA is washed away, leaving a library enriched for a specific region of interest. There are currently two comprehensive panels for hearing loss that employ TGE: OtoSCOPE and a panel designed by Otogenetics Corporation (Atlanta, GA).12·13 http://medical.dentalebooks.com
  • 27. Personalized Genomic Medicine In addition to the targeted deafness panels described above, it is possible to sequence a person's entire exome (coding genetic sequence) or even a person's entire genome using next-genera­ tion sequencing. It is no longer far-fetched to consider clinicians having access to a patient's entire genomic sequence to aid in disease diagnosis and treatment. For a variety of technical and bioinformatic reasons, however, it is currently more efficient to use multigene panels than more comprehensive alternatives. • Role of Genetic Testing in Patient Management The role of genetic testing in the management of the deaf/ hard-of-hearing patient is rapidly evolving. With platforms . . . . . .. like OtoSCOPE, all known genetic causes of NSHL can be screened simultaneously, moving the role for genetic testing in patient management to the forefront. Genetic Testing for Cochlear Implant Candidates Currently, when a child or adult with severe-to-profound deafness presents for a CI evaluation, genetic testing is not part of the standard evaluation. We propose an evaluation paradigm in which genetic testing is part of the preoperative evaluation for all CI candidates with suspected NSHL (11> Fig. 2.1 ). Preoperative genetic testing can decrease the number of screening tests ordered, change surgical manage­ ment, and improve patient selection for implantation, thereby decreasing healthcare costs. - Genetic Testing Paradigm for Cochlear Implant Candidates � � ..( Apparent Genetic Hearlng Loss • Medical History Family History Physical Exam Audiogram, ABA, ASSR t t 1.( Apparent Non-Syndromlc ) II.( Syndromlc Hearing Loss )Hearing Loss • • (Comprehensive Genetic Testing with Multlgene Panel ( Phenotype-Based Individual Gene Testing J • • ' Genetic Counaellng ( Pathogenic Mutation In J No Pathogenic Mutation ln 0 J Appropriate Testing: Known Hearing Loss Gene Known Hearing Loss Gene Ophthalmology referral, EKG, Temporal Bone Imaging, etc. • • t ( )..( Non-Syndromlc J (Non-syndromlc Hearing J R-ch-Baeed Testing Hearing Loss Loss Mimic ' ' (( Genetic CounHIIng )) Genetic CounHIIng Appropriate Testing: Ophthalmology referral, EKG, Temporal Bone Imaging, etc. - Fig. 2.1 Proposed genetic testing paradigm for Clcandidates. In cases where inherited deafness does not have syndromic features we recommend comprehensive genetic testing. This will determine if individuals have true nonsyndromic hearing loss or hearing loss caused by a nonsyndromic hearing loss mimic gene such as in Usher or Pendred syndrome. When a mutation in a nonsyndromic mimic gene is identified, referral for appropriate further clinical evaluation should be pursued. Individuals for whom a genetic diagnosis is not reached are excellent candidates for research-based testing and novel gene discovery. Abbreviations: ABR, auditory brainstem response; ASSR: auditory steady-state response; EKG, electrocardiogram. 1 3 http://medical.dentalebooks.com
  • 28. 1 4 I I Genetic Screening in Cochlear Implant Candidates with Usher Syndrome Usher syndrome, an autosomal recessive type of SNL that falls under the rubric of NSHL mimics, is the leading genetic cause of deafness and blindness and illustrates the utility of genetic testing prior to cochlear implantation. Second to mutations in G]B2, mutations in the Usher syndrome genes are the most com­ mon cause of hearing loss in the congenitally deaf Cl population (20% of cases).14 Because the deafness is congenital but the visual impairment is delayed, without genetic testing it can be very difficult to differentiate the Usher syndrome neonate from a neo­ nate with another form of congenital severe-to-profound hearing loss.1s But differentiation is important for many reasons. First, when the diagnosis of Usher syndrome is made early, precau­ tions such as wearing ultraviolet ray (UV)-canceling sunglasses can be taken to delay the onset of vision loss. Second, in patients with Usher syndrome, simultaneous bilateral implants are advo­ cated, because sound localization is improved.16 Because patients with USH1 eventually develop blindness, early bilateral cochlear implantation ensures that hearing outcomes are optimized before vision is lostP Third, preoperative genetic testing provides valu­ able prognostic information, as Usher syndrome patients have excellent hearing outcomes after cochlear implantation.18·19 Improved Patient Selection for Cochlear Implantation with Genetic Testing It is estimated that 3 to 7% of CJ recipients do not benefit from implantation; however, these patients cannot be identified prior to implantation.20·21 Because most CJ recipients with NSHL have very similar audioprofiles, audiological testing cannot be used to prognosticate CI outcomes. It is possible, however, that CI performance may be related to the genetic cause of hearing loss. For example, studies of CJ performance in persons with G]B2-related deafness have shown that outcomes are typically excellent, whereas implantation in persons with DDP1/TIMM8a-related deafness are not advisa­ ble.22,23 The availability of multigene deafness panels like OtoSCOPE make comprehensive studies of this relationship possible. Preliminary data suggest that if the hearing loss is secondary to a gene expressed in the membranous labyrinth (G]B2, CDH23, MY07A), the CI outcome is likely to be a good; in contrast, if the hearing loss is due to a gene expressed in the spiral ganglion (DDP1/TIMM8a), CJ performance may be poor (see below). Decreased Need for Screening Tests The evaluation of a deaf/hard-of-hearing patient with appar­ ent NSHL is not standardized. After an audiogram, temporal bone imaging is often reflexively ordered, often with one or more screening tests including electrocardiogram, renal ultrasound, urinalysis, and ophthalmological evaluation.24 Occasionally genetic testing, typically for G]B2 only, is consid­ ered. This type of evaluation paradigm is not evidence-based and neither is it logical or cost-effective. As an alternative, we propose that after an audiogram, every patient with suspected NSHL should have comprehensive genetic testing. If a diagnosis is established, a large number of exploratory screening tests can be avoided and a directed evaluation can be completed. If SHL is suspected, appropriate screening tests can be ordered as required (.,. Fig. 2.1 ). • Impact of Genetic Mutation on Cochlear Implant Performance Despite more than 60 reports studying genetic mutation and CI outcome, there are few firmly established genotype-phenotype CI performance correlations (Table 2.1 ). Intuitively, the site of pathology along the auditory pathway should be a useful framework for predicting the impact of a genetic lesion on Cl performance. For example, mutations in genes expressed in the membranous labyrinth should portend a good CI outcome because the implant would bypass the lesion and directly stim­ ulate spiral ganglion neurons. In contrast, mutations in spiral ganglion-expressed genes should portend poorer performance because of dysfunction at the site of electrical stimulation. Prior studies suggest that these suppositions are correct (.,. Fig. 2.2).25,26 Membranous Labyrinth Expressed Genes The vast majority of established genotype-phenotype correla­ tions have been published for genes that encode membranous labyrinth proteins including G]B2, SLC26A4, OTOF, LOXHD1, KCNQ1, MYH9, CDH23, MY07A, TMC1, COCH, POU3F4, and the mitochondrial expressed genes. As a CJ bypasses the membra­ nous labyrinth, persons with these genetic types of hearing loss should be among the group of good CI performers, and indeed this is almost always the case. GJB2 G]B2 is the best studied hearing loss gene and has firmly estab­ lished genotype-phenotype correlations. The encoded protein, connexin 26, is expressed in the supporting cells, spiral limbus and spiral ligament of the membranous labyrinth, and may be important in K+ ion recycling in the supporting cells and stria vascularis.27 There are over 25 reports (including over 420 individuals) of G]B2 genotype-phenotype CJ performance corre­ lations, with the general consensus being that G]B2-related deafness is associated with good performance. In fact, some studies have found that patients with G]B2-related deafness perform better than patients with other causes of deafness when congenitally deaf Cl patients are divided into two groups based on G]B2 status.22·2B-33 There is only one report ofa patient with G]B2-related deafness performing poorly; however, the implant was not performed until age 36.34 Consistent with this poor outcome, prolonged profound deafness prior to implantation is associated with higher rates of spiral ganglion cell degeneration, which is an important determinant of CI performance.25·26 http://medical.dentalebooks.com
  • 29. . . . . . . . Membranous Expressed Genes GJB2, SLC26A4, OTOF, LOXHD I, KCNO I, CDH23, MY07A, POU3F4, MYH9, TMCI, COCH, Mitochondrial Fig. 2.2 Genes with established genotype-phenotype correlations and their location of expression. (Adapted from the Hereditary Hearing Loss Homepage (hereditaryhearingloss.org) with permission from G. Van Camp and R.J.H. Smith.) SLC26A4 SLC26A4 encodes the protein pendrin, a sodium-independent chloride/iodide symporter, and is implicated in Pendred syndrome (SNHL, enlarged vestibular aqueduct, thyroid abnor­ malities). There have been five reports of 49 patients with SLC26A4-related hearing loss correlating Cl performance with SLC26A4 mutations. The majority of these patients had both SNHL and enlarged vestibular aqueduct. The pathophysiological basis of SLC26A4 hearing loss appears to be secondary to mem­ branous labyrinth dysfunction, and, as such, we would expect these Cl recipients to perform well.35 All reports confirm that this is indeed the case.36-4o OTOF There have been four reports (1 2 patients) of Cl performance in patients with otoferlin (OTOF) mutations, all of whom benefited from implantation.41-44 The encoded trans­ membrane protein controls calcium binding and vesicle release at the interface of the inner and outer hair cells and the auditory nerve.45 Hence, otoferlin mutations cause a unique phenotype, which mimics auditory neuropathy or dyssynchrony. The hearing loss is congenital; however, patients often pass newborn hearing screens based on otoa­ coustic emission (OAE) testing but demonstrate profound deafness on auditory brainstem response testing. These results reflect the expression pattern of otoferlin in both outer and inner hair cells. In the presence of OTOF mutations, the inner hair cells are affected first (hence the poor ABR) followed by progressive degeneration of the outer hair cells (the OAEs are ultimately lost).46 Because Cis directly stimulate the spiral ganglion neurons, the causative lesion is bypassed in OTOF-related deafness. Mitochondrial Deafness There have been over 14 reports (23 cases) of Cl performance in mitochondrial deafness. Mitochondrial deafness is usually postlin­ gual, progressive, and in many cases, syndromic. Virtually all cells, including those in the inner ear, depend on mitochondria for adenosine triphosphate (ATP) production via oxidative phospho­ rylation. Typically, when a phenotype manifests in mitochondrial­ associated disease, it does so in cells with high energy require­ ments. Because there are many such cells in many different organ systems, the result is often a multisystem syndromic phenotype. In the cochlea, the cells with the highest energy demands are hair cells and intermediate cells in the stria vascularis. Consequently, mitochondrial deafness results in damage to hair cells and the stria vascularis, and, as would be expected, patients with mito­ chondrial deafness are good Cl performers.47-49 Spiral Ganglion Expressed Genes Cochlear implants stimulate spiral ganglion cells. Therefore, in persons with extensive degeneration of these cells, Cl perform­ ance will be poor. Although there are very few reports of geno­ type-phenotype correlations in genes with robust expression in the spiral ganglia, in the few cases that are available, it does appear that Cl outcomes are more variable. TMPRSS3 TMPRSS3 is robustly expressed in the spiral ganglion, stria vascularis, and cochlear supporting cells and encodes a trans­ membrane serine protease, which is critical to spiral ganglion function.so Although the function of TMPRSS3 has not been completely elucidated, it may be involved in cleavage of neurotrophins in spiral ganglion cells, and, when defective, 1 5 http://medical.dentalebooks.com