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NEUROTOLOGY ISBN: 0-323-01830-0

Second Edition
Copyright © 2005 by Mosby, Inc. All rights reserved.

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NOTICE

Otolaryngology is an ever-changing field. Standard safety precautions must be followed, but as new
research and clinical experience broaden our knowledge, changes in treatment and drug therapy may
become necessary or appropriate. Readers are advised to check the most current product information
provided by the manufacturer of each drug to be administered to verify the recommended dose, the
method and duration of administration, and contraindications. It is the responsibility of the licensed
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Previous edition copyrighted 1994.

Library of Congress Cataloging-in-Publication Data

Neurotology/[edited by] Robert K. Jackler, Derald E. Brackmann.—2nd ed.

p. ; cm.
ISBN 0-323-01830-0
1. Vestibular apparatus—Diseases. 2. Vestibular apparatus—Surgery. 3. Auditory
pathways—Diseases. 4. Auditory pathways—Surgery. I. Jackler, Robert K. II. Brackmann,
Derald E
[DNLM: 1. Vestibular Nerve. 2. Vestibulocochlear Nerve Diseases. 3. Skull Base
Neoplasms. WL 330 N497 2004]
RF260.T49 2004
617.8′82—dc22
2003066638

Acquisitions Editor: Rebecca Schmidt Gaertner

Developmental Editor: Anne Snyder
Publishing Services Manager: Joan Sinclair
Project Manager: Mary Stermel

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 Dedication

To Laurie and Charlotte

v
 Preface

In the early 1990s, the first edition of this text helped to of the ear and auditory nervous system. Among the numer-
define the body of knowledge encompassed by neurotol- ous fruits of this investment are over 60,000 cochlear
ogy, which was then a relatively new field. Over the past implant devices placed worldwide and the continued
decade, major strides have been realized on a number of refinement of the auditory brainstem implant. Programs
fronts. In terms of specialty organizations, the American have been initiated in the development of a vestibular pros-
Neurotology Society has grown to over 500 members. thesis. In genetics, over 100 genes for hereditary hearing
Across the Atlantic, neurotology has been organized through impairment have been localized, a significant portion of
the European Academy of Otology and Neurotology, an which have been cloned. In neurotologic tumors, great
active group of some 300 members. strides have been made in understanding the molecular
Perhaps no aspect of neurotology has undergone a greater genetic basis for acoustic neuroma, NF-2, paragangliomas,
degree of maturation than training. In the United States, two- and papillary adenocarcinomas of the endolymphatic sac.
year post-residency fellowships are now formally accredited Functional imaging, in which the chemical processes
by the American Council of Graduate Medical Education. within the brain and other tissues are mapped, also has a
As of early 2004, approximately 20 fellowship programs promising future. Looking forward a few decades, it seems
are active, 10 of which have completed the accreditation probable that the first human sense to be directly coupled
process. In a major milestone, neurotology has become the with implanted digital devices on a routine basis will be the
first subspecialty of Otolaryngology–Head and Neck Surgery ear. It can be envisioned that man-machine interaction
to achieve board certification by the American Board of with computers and communication devices will revolu-
Otolaryngology. tionize how the ear is used.
In the clinical realm, a sizable and ever increasing num- The companion surgical atlas to this text, promised in
ber of practitioners are focusing their professional efforts the preface of the first edition, was published in full color
in neurotology. In the operating room, microsurgical tech- in 1996 (Jackler RK: Atlas of Neurotology and Skull Base
nology continues to evolve with improved microscope and Surgery. St. Louis, Mosby, 1996). A second edition is being
drill systems, image guidance, and more capable neuro- contemplated at present. With the digital publishing revo-
physiologic equipment to mention just a few advances. In lution currently in full force, it can be envisioned that
tumor surgery, the emphasis continues to be on develop- future editions of these works will appear primarily on the
ment of minimally invasive techniques that maximize internet.
tumor control while optimizing neural preservation. Over the last few decades, neurotology has achieved
Innovative radiotherapy methods, particularly stereotactic critical mass as a field, both through the number of scientists
techniques, have developed a role in selected neurotologic and clinicians engaged in it as well as through the steady
tumors. In the vestibular field, numerous new therapies accumulation of new knowledge and clinical capabilities.
have been devised for BPPV and entire new diagnoses, The editors hope that this comprehensive resource, as the
such as superior semicircular canal dehiscence, have been primary textbook in the field, will serve to foster excellence
introduced. and stimulate innovation in neurotology.
Research in the field is robust. The National Institute of
Deafness and Other Communication Disorders budget
has risen from $166.8 million in 1995 to $380.4 million in Robert K. Jackler, MD
2004—a large fraction of which is dedicated to investigation Derald E. Brackmann, MD

vii
 Contributors

Kedar K. Adour, MD Derald E. Brackmann, MD, FACS

Director of Research, Senior Consultant, Kaiser-Permanente Clinical Professor of Otolaryngology–Head and Neck Surgery
Medical Center, Oakland, California; Emeritus President and Clinical Professor of Neurosurgery, University of Southern
and Founder, Sir Charles Bell Society, San Francisco, California California School of Medicine; President, House Ear Clinic;
Board of Directors, House Ear Institute; Los Angeles, California
Sumit K. Agrawal, BSc, MD
Resident, Department of Otolaryngology, University of Sujana S. Chandrasekhar, MD
Western Ontario; Resident, London Health Sciences Centre; Associate Professor of Otolaryngology, Mount Sinai School
London, Ontario, Canada of Medicine; Director of Otology/Neurology and Director,
Cochlear Implant Program, Mount Sinai Medical Center;
Stephanie Moody Antonio, MD New York, New York
Assistant Professor, University of Maryland School of Medicine,
Baltimore, Maryland Wileen Chang, MS
Audiologist, University of California-San Francisco,
John R. Arrington, MD San Francisco, California
Professor of Radiology, University of South Florida College
of Medicine; Attending Neuroradiologist, HL Moffitt Cancer Douglas A. Chen, MD
and Research Center; Tampa, Florida Clinical Associate Professor, University of Pittsburgh;
Co-Director, Hearing and Balance Center, Allegheny General
Yasmine A. Ashram, MD, D ABNM Hospital; Pittsburgh, PA
Lecturer, Neurophysiology Division, Department
of Physiology, University of Alexandria, Alexandria, Egypt Steven W. Cheung, MD
Associate Professor-in-Residence, Otology, Neurotology
Robert J. Backer, MD and Skull Base Surgery, Department of Otolaryngology–Head
Division Chief, Neurological Surgery, St. John’s Mercy Medical and Neck Surgery, University of California-San Francisco,
Center, St. Louis, Missouri San Francisco, California

Thomas J. Balkany, MD Sung J. Chung, MD

Hodgkiss Professor and Chairman, Department Private Practice, ENT Surgical Consultants, Ltd, Joliet, Illinois
of Otolaryngology; Professor, Department of Pediatrics;
Professor, Department of Neurosurgery; Chief, Department Harold V. Clumeck, PhD
of Neurotology; University of Miami School of Medicine; Chief Lecturer, Department of Communication Sciences and
of Service, ENT, Jackson Memorial Hospital; Miami, Florida Disorders, California State University, Hayward, California;
Section Chief, Speech Pathology, VA Medical Center,
Loren J. Bartels, MD, FACS San Francisco, California
Clinical Professor, Department of Otolaryngology, University
of South Florida College of Medicine; Immediate Past Chief Newton J. Coker, MD
of the Medical Staff, Tampa General Hospital; Tampa, Florida Professor, Bobby R. Alford Department
of Otorhinolaryngology and Communicative Sciences,
Nikolas H. Blevins, MD Baylor College of Medicine; Attending Physician,
Assistant Professor, Department of Otolaryngology–Head & Otorhinolaryngology, The Methodist Hospital; Attending
Neck Surgery, Stanford University of Medicine, Palo Alto, Physician, Otorhinolaryngology, Michael E. DeBakey Veterans
California Affairs Medical Center; Attending Physician,
Otorhinolaryngology, Harris County Hospital District
Dennis I. Bojrab, MD (Ben Taub); Attending Physician, Otorhinolaryngology,
Michigan Ear Institute, Farmington Hills, Michigan St. Luke’s Hospital; Houston, Texas
ix
x CONTRIBUTORS

Hugh D. Curtin, MD Adrien A. Eshraghi, MD, MSc

Professor of Radiology, Harvard Medical School; Chief Assistant Professor of Otolaryngology, University of Miami
of Radiology, Massachusetts Eye and Ear Infirmary; Boston, School of Medicine; Attending Physician and Surgeon, Jackson
Massachusetts Memorial Hospital, Miami Veterans Administration Hospital,
and University of Miami Ear Institute; Miami, Florida
Edward J. Damrose, MD
Assistant Professor of Otolaryngology, Stanford University, Grace Fan, MD
Stanford, California Diagnostic Radiology, Kaiser Permanente Oakland Medical
Center, Oakland, California
C. Phillip Daspit, MD, FACS
Clinical Professor of Surgery (Otolaryngology), University Laurel M. Fisher, PhD
of Arizona; Chief, Section Neurotology, Department House Ear Institute, Los Angeles, California
of Neurosurgery, Barrow Neurological Institute; Chairman,
Institute Review Board, St. Joseph’s Hospital; David R. Friedland, MD, PhD
Phoenix, Arizona Assistant Professor, Division of Otology and Neuro-otologic
Skull Base Surgery, Department of Otolaryngology
J. Diaz Day, MD and Communication Sciences, Medical College of Wisconsin;
Associate Professor of Neurosurgery, Drexel University College Attending Physician, Froedtert and Medical College Hospital;
of Medicine, Philadelphia, Pennsylvania; Allegheny General Milwaukee, Wisconsin
Hospital, Pittsburgh, Pennsylvania
Rick Friedman, MD, PhD
Antonio De la Cruz, MD Associate Research Scientist, House Ear Institute, Los Angeles,
Clinical Professor of Otolaryngology/Head and Neck Surgery, California; Active Staff, Chapman Medical Center, Orange,
University of Southern California; Director of Education, California; Active Staff, St. Vincent Medical Center; Cedars-
House Ear Institute; Active Staff, St. Vincent Medical Center; Sinai Medical Center; USC Medical Center; Los Angeles,
Active Staff, LAC/USC Medical Center; Los Angeles, California
California; Active Staff, Torrance Memorial Hospital, Torrance,
California Richard R. Gacek, MD, FACS
Professor of Otolaryngology, Department
Manuel Don, PhD of Otolaryngology–Head and Neck Surgery, University
Head, Electrophysiology Department, House Ear Institute, of Massachusetts Medical Center, Worchester, Massachusetts
Los Angeles, California
Bruce J. Gantz, MD, MS
Christopher F. Dowd, MD Professor and Department Head, University of Iowa,
Clinical Professor of Radiology, Neurological Surgery, Iowa City, Iowa
Neurology and Anesthesia and Preoperative Care;
Interventional Neuroradiology, The Neurovascular Medical Sanjay Ghosh, MD
Group; University of California, San Francisco School Neurosurgeon, Senta Medical Clinic, San Diego, California
of Medicine, San Francisco, California
Gerard Gianoli, BSE, MD
Karen Jo Doyle, MD, PhD Clinical Associate Professor, Departments of Otolaryngology
Associate Professor, Department of Otolaryngology, Head and and Pediatrics, Tulane University Medical School,
Neck Surgery, University of California, Davis Medical Center, New Orleans, Louisiana; North Oaks Hospital, Hammond,
Sacramento, California Louisiana; The Ear and Balance Institute, Baton Rouge,
Louisiana
Colin L. W. Driscoll, MD
Assistant Professor, Mayo Clinic College of Medicine; Joel A. Goebel, MD, FACS
Consultant, Department of Otorhinolaryngology, Mayo Clinic Residency Program Director and Professor
and Mayo Foundation; Rochester, Minnesota and Vice Chairman, Washington University School
of Medicine, St. Louis, Missouri
David R. Edelstein, MD
Clinical Professor of Otorhinolaryngology, Weill Medical Robert A. Goldenberg, MD
College of Cornell University; Chairman, Department of Professor and Chief, Department of Otolaryngology, Wright
Otolaryngology–Head and Neck Surgery, Manhattan Eye, State University School of Medicine, Centerville, Ohio;
Ear and Throat Hospital; New York, New York Associate Clinical Professor, University of Cincinnati School
of Medicine, Cincinnati, Ohio
Bruce M. Edwards, AuD
Senior Audiologist, University of Michigan Health System, John Grant, MB, FRCS(C), FACS
Department of Otolaryngology–Head and Neck Surgery, Associate Professor of Neurosurgery, University
Division of Audiology and Electrophysiology, Ann Arbor, of Missouri-Kansas City; Children’s Mercy Hospital
Michigan and Clinics; Kansas City, Missouri
 Contributors xi

John H. Greinwald Jr, MD William E. Hitselberger, MD

Associate Professor, Department of Otolaryngology, University Neurosurgeon, St. Vincent’s Hospital; House Ear Clinic;
of Cincinnati; Assistant Director, Center for Hearing Los Angeles, California
and Deafness Research, Cincinnati Children’s Hospital Medical
Center; Cincinnati, Ohio Annelle V. Hodges, PhD
Associate Professor of Otolaryngology, University of Miami
A. Julianna Gulya, MD, FACS School of Medicine, Miami, Florida
Clinical Professor of Otolaryngology, George Washington
University, Washington, DC Ronald A. Hoffman, MD
Professor of Clinical Otolaryngology, Albert Einstein College
Van V. Halbach, MD of Medicine, Bronx, New York; Director of Otology, Beth Israel
Clinical Professor of Radiology, Neurological Surgery, Medical Center, New York, New York
Neurology, and Anesthesia and Preoperative Care;
Interventional Neuroradiology, The Neurovascular Medical Karl L. Horn, MD
Group; University of California, San Francisco School Ear Associates, PC; Presbyterian Ear Institute; Albuquerque,
of Medicine, San Francisco, California New Mexico

Courtney D. Hall, PhD Michael M. Hovsepian, MD

Assistant Professor, Department of Rehabilitation Medicine, Staff Radiologist, Fullerton Radiology Medical Group, Inc.,
Emory University, Atlanta, Georgia; Research Health Scientist, Fullerton, California
Rehabilitation Research and Development Center, Atlanta
VAMC, Decatur, Georgia Timothy E. Hullar, MD
Assistant Professor, Department of Otolaryngology–Head
Hal L. Hankinson, MD and Neck Surgery, Washington University School of Medicine,
Neurosurgical Associates, Albuquerque, New Mexico St. Louis, Missouri

Robert K. Jackler, MD
Lee A. Harker, MD
Sewall Professor and Chair, Department of
Deputy Director, Boys Town National Research Hospital;
Otolaryngology–Head and Neck Surgery,
Vice Chairman, Department of Otolaryngology and Human
Professor, Departments of Neurosurgery and Surgery,
Communication, Creighton University School of Medicine;
Stanford University School of Medicine, Stanford, CA
Omaha, Nebraska
Alexis H. Jackman, MD, BA
Richard E. Hayden, MD Resident in Otolaryngology, New York University School
Department of Otolaryngology–Head and Neck Surgery, of Medicine, New York, New York
Mayo Clinic, Scottsdale, Arizona
Michael J. Kaplan, MD
Carl B. Heilman, MD Professor of Otolaryngology, Professor of Head and Neck Surgery,
Associate Professor, Department of Neurosurgery, Tufts Stanford University School of Medicine, Stanford, California
University School of Medicine; Tufts New England Medical
Center; Boston, Massachusetts Collin S. Karmody, MD, FRCSE
Professor of Otolaryngology, Tufts University School of
Susan J. Herdman, PhD Medicine, New England Medical Center, Boston, Massachusetts
Professor, Departments of Rehabilitation Medicine and
Otolaryngology–Head and Neck Surgery, Emory University, Robert W. Keith, PhD
Atlanta, Georgia; Research Health Scientist, Rehabilitation Professor, Departments of Otolaryngology and Communication
Research and Development Center, Atlanta VA Medical Center, Sciences and Disorders, University of Cincinnati; Director,
Decatur, Georgia Division of Audiology, University of Cincinnati Medical
Center; Cincinnati, Ohio
Randall T. Higashida, MD
Clinical Professor of Radiology, Neurological Surgery, Kevin E. Kelly, MD
Neurology, and Anesthesia and Preoperative Care; Family Practice Program, Phoenix Baptist Hospital, Phoenix,
Interventional Neuroradiology, The Neurovascular Medical Arizona
Group; University of California, San Francisco School
of Medicine, San Francisco, California Paul R. Kileny, PhD
Professor and Director, Division of Audiology
Barry E. Hirsch, MD, FACS and Electrophysiology, Department of Otolaryngology,
Professor, Departments of Otolaryngology, Neurological University of Michigan Health System, Ann Arbor, Michigan
Surgery, and Communication Sciences and Disorders; Director,
Division of Otology, Department of Otolaryngology; University Louis J. Kim, MD
of Pittsburgh School of Medicine and School of Physical Resident, Neurological Surgery, Barrow Neurological Institute,
Medicine and Rehabilitation; Pittsburgh, Pennsylvania St. Joseph’s Hospital and Medical Center, Phoenix, Arizona
xii CONTRIBUTORS

Karen Iler Kirk, PhD Larry B. Lundy, MD

Associate Professor and Psi Iota Xi Scholar, Department Assistant Professor of Otolaryngology–Head and Neck Surgery,
of Otolaryngology–Head and Neck Surgery, Indiana University Mayo School of Graduate Medical Education, Jacksonville,
School of Medicine, Indianapolis, Indiana Florida

G. Robert Kletzker, MD, FACS Lawrence R. Lustig, MD

Clinical Assistant Professor, Department Associate Professor, Department of Otolaryngology–Head and
of Otolaryngology–Head and Neck Surgery, Washington Neck Surgery, Johns Hopkins University, Baltimore, Maryland
University School of Medicine; Active Staff, St. John’s Mercy
Medical Center; Barnes Jewish Hospital; Missouri Baptist William M. Luxford, MD
Medical Center; Associate Staff, St. Luke’s Hospital; Clinical Professor, University of Southern California, Keck
St. Louis, Missouri School of Medicine; Associate, House Ear Clinic; Los Angeles,
California
John F. Kveton, MD
Clinical Professor of Otolaryngology/Surgery and Alexander S. Mark, MD
Neurosurgery, Yale University School of Medicine; Attending Associate Clinical Professor of Radiology and Neurosurgery,
Surgeon, Yale New Haven Hospital; New Haven, Connecticut George Washington University Medical Center; Director
of MRI, Washington Hospital Center; Washington, DC
Anil K. Lalwani, MD
Mendik Foundation Professor and Chairman, Department of Angela D. Martin, MD
Otolaryngology and Professor of Physiology and Neuroscience, Chief Resident Associate and Instructor in Otolaryngology,
New York University School of Medicine, New York, New York Mayo Clinic College of Medicine and Mayo Foundation,
Rochester, Minnesota
Paul R. Lambert, MD, FACS
Professor and Chair, Department of Otolaryngology–Head Michael W. McDermott, MD, FRCSC
and Neck Surgery, Medical University of South Carolina, Departments of Neurological Surgery and Radiation Oncology,
Charleston, South Carolina University of California at San Francisco, San Francisco,
California
Michael J. LaRouere, MD
Clinical Assistant Professor, Department John S. McDonald, DDS, MS, FACD
of Otolaryngology–Head and Neck Surgery, Wayne State Volunteer Professor, Department of Anesthesia, and Volunteer
University, Detroit, Michigan; Chairman, Department Associate Professor, Department of Pediatrics, Division
of Otology, Neurotology, and Skull Base Surgery, Providence of Pediatric Dentistry, University of Cincinnati College
Hospital, Southfield, Michigan; Attending Neurotologist, of Medicine, Cincinnati, Ohio
Michigan Ear Institute, Farmington Hills, Michigan
Arnold H. Menezes, MD
John P. Leonetti, MD Professor of Neurosurgery and Vice Chairman, Department
Professor of Otolaryngology–Head and Neck Surgery, Loyola of Neurosurgery, Roy and Lucille Carver College of Medicine,
University, Stritch School of Medicine, Chicago, Illinois; University of Iowa Hospitals and Clinics, Iowa City, Iowa
Director, Loyola Center for Cranial Base Surgery, Loyola
University Medical Center, Maywood, Illinois Ted A. Meyer, MD, PhD
Fellow in Neurotology, University of Iowa, Iowa City, Iowa
Robert E. Levine, MD
Clinical Professor of Ophthalmology, University of Southern Anand N. Mhatre, PhD
California, Keck School of Medicine; Co-Founder Assistant Professor, Department of Otolaryngology, New York
and Co-Director, Center for Facial Nerve Function, University School of Medicine, New York, New York
House Ear Clinic; Los Angeles, California
Dawna Mills, AuD
Charles J. Limb, MD Adult Cochlear Implant Coordinator, House Ear Clinic,
Assistant Professor, Department of Otolaryngology–Head Los Angeles, California
and Neck Surgery, Johns Hopkins University School of
Medicine; Assistant Professor, Otology, Neurotology, and Skull Lloyd B. Minor, MD, FACS
Base Surgery, Johns Hopkins Hospital; Baltimore, Maryland; Andelot Professor and Chairman, Department
Staff Physician, National Institute on Deafness and Other of Otolaryngology–Head and Neck Surgery, The Johns
Communication Disorders, National Institutes of Health, Hopkins University School of Medicine, Baltimore, Maryland
Bethesda, Maryland
Richard T. Miyamoto, MD, MS
William W. M. Lo, MD Arilla Spence DeVault Professor and Chairman, Department
Clinical Professor of Radiology, University of Southern California, of Otolaryngology–Head and Neck Surgery, Indiana University
Keck School of Medicine; Section Chief, Neuroradiology, School of Medicine; Co-Chief, Otolaryngology–Head
St. Vincent Medical Center; Los Angeles, California and Neck Surgery, Clarion; Indianapolis, Indiana
 Contributors xiii

Aage R. Møller, PhD Steven R. Otto, MA

Professor, MF Johnson Endowed Chair, University of Texas Advanced Research Associate, House Ear Institute,
at Dallas, Dallas, Texas Los Angeles, California

Edwin M. Monsell, MD, PhD Dennis Pappas, MD

Professor of Otolaryngology–Head and Neck Surgery, Wayne Pappas Ear Clinic; Director of Neurotology, Healthsouth
State University School of Medicine, Detroit, Michigan Medical Center; Birmingham, Alabama

Jean K. Moore, PhD Lorne S. Parnes, MD, FRCSC

Emeritus Scientist, House Ear Institute, Los Angeles, California Professor and Chair, Department of Otolaryngology,
University of Western Ontario; Chief, Department of
Karsten Munck, MD Otolaryngology, London Health Sciences Centre; London,
Resident, University of California, San Francisco, Ontario, Canada
San Francisco, California
Ian F. Parney, MD, PhD, FRCSC
Haruka Nakahara, MD Neuro-Oncology Service, Department of Neurological Surgery,
Assistant Professor, Department of Otolaryngology–Head and University of California at San Francisco, San Francisco,
Neck Surgery, Tokyo University Medical School, Tokyo, Japan California

J. Gail Neely, MD Myles L. Pensak, MD

Professor and Director, Otology/Neurotology/Base of Skull Professor Otolaryngology–Head & Neck Surgery and
Surgery, Department of Otolaryngology–Head and Neck Surgery, Neurologic Surgery, University of Cincinnati, Cincinnati, Ohio
Washington University School of Medicine, St. Louis, Missouri
Markus H. F. Pfister, MD
Steven A. Newman, MD Visiting Assistant Professor, Department of Otolaryngology–
Professor of Ophthalmology, University of Virginia, Head and Neck Surgery, Stanford University School of
Charlottesville, Virginia Medicine, Stanford, California

Thomas Nikolopoulos, MD, DM, PhD

Lawrence H. Pitts, MD
Assistant Professor, Athens University Medical School,
Professor, Neurosurgery and Otolaryngology, University of
Athens, Greece
California at San Francisco, San Francisco, California
John K. Niparko, MD
George T. Nager Professor, Otolaryngology–Head and Neck
Curtis W. Ponton, PhD
Senior Scientist, Compumedics Neuroscan, El Paso, Texas
Surgery, The Johns Hopkins School of Medicine; Director,
Division of Otology, Neurotology, Johns Hopkins Hospital;
Baltimore, Maryland Steven D. Rauch, MD
Associate Professor, Otology and Laryngology, Harvard
Michael A. Novak, MD Medical School; Surgeon, Department of Otolaryngology,
Clinical Assistant Professor of Surgery, University of Illinois, Otology Service, Massachusetts Eye and Ear Infirmary; Boston,
School of Medicine at Urbana-Champaign; Chairman, Division Massachusetts
of Otolaryngology, Carle Clinic Association; Urbana, Illinois
Miriam I. Redleaf, MD
Gerard M. O’Donoghue, MD, FRCS Assistant Professor of Surgery, University of Illinois Hospitals,
Professor, Department of Surgery, University of Nottingham; University of Illinois, Chicago, Illinois
Professor, Department of Otolaryngology, Queens Medical
Centre, University Hospital; Nottingham, United Kingdom Grayson K. Rodgers, MD
President/Director, Birmingham Hearing and Balance Center,
John S. Oghalai, MD Birmingham, Alabama
Assistant Professor, Department of Otorhinolaryngology
and Communicative Sciences, Baylor College of Medicine, Seth I. Rosenberg, MD, FACS
Houston, Texas Clinical Assistant Professor, Department of
Otorhinolaryngology, University of Pennsylvania, Philadelphia,
Michael J. O’Leary, MD, FACS Pennsylvania; Active Staff, Sarasota Memorial Hospital; Active
Clinical Assistant Professor, Uniformed Services University Staff, Cape Surgery Center; Active Staff, Surgery Center of
of the Health Sciences, Bethesda, Maryland; Chief, Sarasota; Vice President, Silverstein Institute; Vice President,
Neurotology, Skull Base Surgery Division, Senta Medical Ear Research Foundation; Sarasota, Florida
Clinic, San Diego, California
Edwin W Rubel, PhD
Vincent B. Ostrowski, MD Professor, Department of Otolaryngology–Head and Neck
Midwest Ear Institute, Indianapolis, Indiana Surgery, University of Washington, Seattle, Washington
xiv CONTRIBUTORS

Christina L. Runge-Samuelson, PhD Robert W. Sweetow, PhD

Assistant Professor, Division of Otology and Neuro-otologic Clinical Professor of Otolaryngology and Director
Skull Base Surgery, Department of Otolaryngology of Audiology, University of California San Francisco,
and Communication Sciences, Medical College of Wisconsin; San Francisco, California
Children’s Hospital of Wisconsin/Froedtert Hospital;
Milwaukee, Wisconsin Mark J. Syms, MD
Otologist/Neurotologist, Section of Neurotology, Department
Tammy S. Schumacher-Monfre, MSN, APNP of Neurosurgery, Barrow Neurological Institute; Attending
Instructor, Department of Otolaryngology and Communication Otologist/Neurotologist, Phoenix Children’s Hospital;
Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin Phoenix, Arizona
Mitchell K. Schwaber, MD
Clinical Associate in Otolaryngology, Vanderbilt University; Thomas A. Tami, MD, FACS
Medical Director, St. Thomas Neuroscience–Hearing and Professor of Otolaryngology, University of Cincinnati,
Balance Center, St. Thomas Hospital; Nashville, Tennessee Cincinnati, Ohio

Dietrich W. F. Schwarz, MD, PhD Steven A. Telian, MD

Professor, Department of Surgery (Otolaryngology), University John L. Kemink Professor of Neurotology, University
of British Columbia, Vancouver, British Columbia, Canada of Michigan, Ann Arbor, Michigan

Samuel H. Selesnick, MD Fred F. Telischi, MEE, MD

Professor and Vice Chairman, Department
Professor of Otolaryngology, University of Miami School
of Otorhinolaryngology, Weill Medical College of Cornell
of Medicine; Attending Physician and Surgeon, Jackson
University; Attending Otolaryngologist, Weill Cornell Center
Memorial Hospital; Director, University of Miami Ear
of New York Presbyterian Hospital; New York, New York
Institute; Miami, Florida
Robert V. Shannon, PhD
Adjunct Professor, Biomedical Engineering, University of R. David Tomlinson, PhD
Southern California; Head, Department of Auditory Implants Associate Professor, Department of Otolaryngology,
and Perception, House Ear Institute; Los Angeles, California University of Toronto, Toronto, Ontario, Canada

Neil T. Shepard, PhD Debara L. Tucci, MD

School of Medicine, University of Pennsylvania; Director Associate Professor, Duke University Medical Center, Durham,
of Audiology, Speech Pathology, and the Balance Center, North Carolina
University of Pennsylvania Health System, Hospital
of the University of Pennsylvania; Philadelphia, Pennsylvania
P. Ashley Wackym, MD
John C. Koss Professor and Chairman, Department
Herbert Silverstein, MD, FACS
of Otolaryngology and Communication Sciences, Medical
President, Silverstein Institute, Sarasota, Florida
College of Wisconsin; Chief, Otolaryngology–Head and Neck
Ameet Singh, MD Surgery, Froedtert and Medical College Hospital; Chief,
Resident, Department of Otolaryngology, Strong Memorial Pediatric Otology, Children’s Hospital of Wisconsin;
Hospital, University of Rochester Medical Center, Rochester, Milwaukee, Wisconsin
New York
Robert A. Williamson, MD
Aristides Sismanis, MD, FACS Fellow in Otology/Neurotology, The Bobby R. Alford
Professor and Chairman of Otolaryngology–Head and Neck Department of Otorhinolaryngology and Communicative
Surgery, Virginia Commonwealth University Medical Center, Sciences, Baylor College of Medicine, Houston, Texas
Richmond, Virginia
Charles Yingling, PhD, D ABNM
William H. Slattery III, MD Otolaryngology/Head and Neck Surgery, Stanford University,
Clinical Professor, Department of Otolaryngology, University of Stanford, California
Southern California; Director, Clinical Studies Department and
Associate, House Ear Institute and Clinic; Los Angeles, California
Nancy M. Young, MD
Peter G. Smith, MD, PhD Associate Professor, Northwestern University Feinberg School
Clinical and Assistant Professor of Otolaryngology–Head of Medicine; Head, Section of Otology and Neurotology,
and Neck Surgery, Washington University School of Medicine, Children’s Memorial Hospital; Chicago, Illinois
St. Louis, Missouri
Kenneth C. Y. Yu, MD
Eric E. Smouha, MD, FACS Staff Surgeon, Department of Otolaryngology–Head and Neck
Associate Professor of Surgery and Clinical Neurosurgery, State Surgery, United States Air Force Base, Elmendorf Air Force
University of New York at Stony Brook, Stony Brook, New York Base, Alaska
 Foreword

THE NEUROTOLOGY SAGA: internal auditory canal of acoustic tumors. I remember

A PERSONAL PERSPECTIVE going to the library and reading as much as I could find on
acoustic tumors. The recurring theme was that these were
During the past few years, I have heard myself introduced serious, although benign, lesions that should be operated
on occasion as the “Father of Neurotology.” If this is true, on as early as possible.
then it is also true in my case that being this kind of a During the last few months of my residency, a remark-
father is not something that was planned; it just happened. able event occurred that was to change my life. Howard
In looking back, I realize now that it all started during had heard of some interesting work going on in Germany
my third and last year of ear, nose, and throat (ENT) called “tympanoplasty.” He visited Dr. Wullstein in
residency at Los Angeles County Hospital. The year was Wurtsburg and for the first time saw the Zeiss microscope.
1955. I was 31 years old. By then June and I had been He immediately ordered a microscope (I believe for the
married for 10 years, and Karen was 8 and David 7. I had large sum of $2,000) and invited Dr. Wullstein to come to
completed dental school, served 2 years in the Navy as a Los Angeles to demonstrate his techniques. It was my job
dentist, finished medical school, and taken the ENT resi- to chauffeur the doctor to his demonstrations. The film
dency so that I could become a plastic surgeon. June was that he showed of temporal bone surgery through the
helping to hold the household together by working part microscope were astounding to me in terms of what you
time in my brother Howard’s office as an RN. could see of the temporal bone structures over what we
ENT was not a sought-after residency at that time had been seeing with the headlight and loops. He took
because it was widely believed that penicillin was eliminat- these films by working to a point in the tympanoplasty and
ing the sinus, mastoid and tonsil, and adenoid problems then swinging in a microscope with a camera mounted on
that occupied the eye, ear, and nose specialists. In fact, we one eyepiece. While he worked through the other eyepiece,
had so few residents that I was obliged to be on-call at the he filmed the procedure.
hospital every other night. Fortunately, the library was well- When Howard’s microscope arrived he began using it
stocked so I had time to read the latest ENT literature. in the new stapes mobilization procedures, and I would
There was no full-time ENT faculty, but there was usually take the microscope to the morgue at night to explore the
an attending physician to help in the clinics and in surgery wonders of the temporal bone.
several times a week. As I look back, I can now call the resi- On completion of my residency in July 1956, I joined
dency a learning residency instead of a teaching residency. Howard in his office. By then I had become fascinated with
During the last year of my residency much of my learning otology, and—because of Howard’s practice—I was able to
came through Howard, who (being 15 years older than I) had spend all my time in otology. The first few hours of each
finished the 2-year Los Angeles County residency in 1939 day were spent making the rounds of several Los Angeles
and had established a large practice that was 95% otology. hospitals to change the dressings of Howard’s numerous
He was doing seven or eight fenestration operations a fenestration patients. The remainder of the day was spent
week; this included Saturday morning surgery. In addition in the office cleaning fenestration cavities and seeing a
to this, he usually had two or three ENT doctors taking a never-ending stream of otology patients.
1-month course from him in otology. The students would
observe surgery during the day and come to the County
Hospital morgue at night to do fenestrations on cadavers. STARTING PRACTICE
I would often help in the morgue, and Howard encouraged AND DEVELOPMENT OF THE FACIAL
me to do cadaver head and neck dissection and surgical RECESS APPROACH
procedures. On Saturdays, I often observed his surgery.
Howard also introduced me to a very remarkable, older It was an exciting time to be starting an otology practice.
ENT practitioner, Gilbert Roy Owen. He had become Wulstein and Zolner had introduced “tympanoplasty”
very interested in temporal bone and sinus x-ray. As time surgery using a Zeiss microscope a few years earlier, and
permitted I would go to his office, and he would take me Howard was doing a few skin grafts to the middle ear at the
through his remarkable collection of x-ray pathology. One time of mastoid surgery. John Shea (whom I had gotten to
of the things he repeatedly showed me was the enlarged know during my residency because he had spent some time
xix
xx FOREWORD

with Howard learning fenestration surgery) had boldly infection that destroyed the graft. To overcome this prob-
introduced stapedectomy because so many of the stapes lem, many different mastoid obliteration procedures such
mobilization procedures that had been introduced by as swinging in muscle from the temporalis, and various
Rosen a couple of years before were refixing. Howard, plastic and tissue inserts were advocated. I tried all of these
who for years had been doing 10 or 12 fenestrations a procedures and found them all to be wanting.
week, asked John to come to Los Angeles and demonstrate It became obvious to me that the best answer was to
his revolutionary stapes removal operation. As the word avoid creating a cavity. After all, we were no longer simply
spread of the remarkable results these stapedectomy opening things for drainage; we were now after a cure for
patients were getting, the patients came flocking to the infection. But if we left the posterior boney ear canal
Howard’s office. I was immediately busy working up these intact, could we see well enough to remove all the infected
patients and getting them on Howard’s surgery schedule. tissue in the middle ear? The answer was “no,” so it was
It soon became apparent that Howard had no time for back to the dissection lab again. I had seen Wullstein on
anything else except otosclerosis surgery. No one wanted his type I tympanoplasties, that is, those with an intact
the kid brother to do their stapes surgery. Many of the ossicular chain drill a “control hole” and was able to visu-
patients, hoping to get their hearing restored by this new alize through this disease in the middle ear. This was done
miracle surgery, turned out to be chronic ear patients. quite blindly, and it frightened me because I could visual-
After all, antibiotics except for sulfa drugs had only been in ize a good chance of hitting the mastoid part of the facial
widespread use for 10 years. Howard was more than will- nerve. In the dissection lab, I learned how to skeletonize
ing to turn these patients over to me and encouraged them the mastoid part of the facial just inferior to the horizontal
to have me do their mastoid surgery. canal and open the area widely for good visualization of
During my residency, the goal of radical and modified the stapes incus and posterior part of the middle ear. The
radical mastoid surgery was to open the mastoid to allow it chorda tympani nerve and the annulus of the ear drum
to drain rather than back up into a brain abscess. Antibiotics were used as landmarks. I named this the “facial recess
and tympanoplasty procedures using the microscope were approach” because I wanted to emphasize the facial nerve
challenging these concepts that had been the standard of as the basic landmark.
practice for the past 75 years. The microscope made it Fortunately, this approach is now widely used and has
possible to see the facial nerve more clearly and, therefore, become the standard in cochlear implant surgery. However,
allowed much more complete removal of cholesteatoma leaving the canal wall intact led to new problems. Wullstein
and granulation from the middle ear rather than leaving had advocated four types of tympanoplasty. Type 1 would
it wherever the facial nerve might be. Indeed, I remember now be called a myringoplasty because the ossicular chain
my instructors during my residency telling me that if is intact. Type 2 was a graft to the head of the stapes. Type
you so much as touch the facial nerve, it will become 3 was a graft to the promontory to leave the oval window
paralyzed. open if the stapes superstructure was gone. Type 4 was
Tympanoplasty procedures were now advocating graft- fenestration of the horizontal canal if the oval window
ing over the middle ear with skin and, thus, violating the was obliterated. It is obvious that these procedures were
leave open for drainage principle. It was soon found that designed to avoid reconstructing the ossicular chain.
grafting over infected granulation even with vigorous Leaving the canal wall intact made it necessary to recon-
postoperative antibiotics was unsuccessful. It became struct the ossicular chain since the graft was now in the
obvious to me that if all the middle ear granulation and location of the previous ear drum. As intact canal wall pro-
cholesteatoma was to be removed it was necessary to know cedures became more widely used, a number of otologists,
where facial nerve was and treat it as a friendly landmark. including myself, devised a number of prosthetic recon-
The microscope made this possible through identifying struction procedures.
the horizontal canal and lifting the granulation to locate Such reconstruction of the ossicular chain led to another
the facial nerve in the tympanic segment. Visualization was problem. If the middle ear did not become aerated, the
also enhanced by developing continuous irrigation suction hearing result was poor and the graft would adhere to
where the amount of water flow and suction were con- the promontory. There would also be a retraction of the
trolled by rotating the thumb over the suction hole. Until graft into the attic and a new cholesteatoma formation.
then, mastoid surgery had been done by drilling using two I tried a number of procedures to avoid this retraction,
hands on the drill as taught by Lempert; then irrigating including placing wire mesh in the attic to prevent the
and suctioning. This was a slow, tedious process, and retraction. I called the procedure the “iron curtain proce-
I remember taking 3 or 4 hours to do a mastoid in the dure.” Months later, to my horror, if the middle ear did not
laborious way. However, using one hand on the drill and aerate I saw the skin retract through the mesh and, thus,
one hand on the suction was sometimes viewed as reckless become a worse problem than the original cholesteatoma.
surgery. However, Howard let me do it and often came to I learned that aeration, not obliteration, is essential for
my defense in discussions with colleagues. successful chronic ear surgery.
The principle of chronic ear surgery thus changed to I told the story of my experience with the development
remove the disease and cure the infection. The tym- of chronic ear surgery in a book dedicated to neurotology
panoplasty grafts were now much more successful, but to illustrate how temporal bone surgery had developed
there were still problems. Mastoid cavities are subject after the microscope was introduced. The use of amplifi-
to accumulation of debris and recurrent infection. It was cation, continuous suction irrigation, and use of the facial
discouraging to see a nice tympanoplasty result, with some nerve as a landmark allowed us to develop temporal bone
improvement in hearing, be wiped out by a recurrent procedures to move through the temporal bone with
 Foreword xxi

dispatch and, thus, develop the next generation of tempo- Unfortunately, he did not recover any hearing. Some years
ral bone surgery. The retrolabyrinthine, translabyrinthine, later he was to become one of my first cochlear implant
transcochlear, and middle fossa approaches would not patients.
have been possible before today’s chronic ear surgery was
developed.
DEVELOPMENT OF ACOUSTIC
NEUROMA SURGERY
DEVELOPMENT OF THE MIDDLE
FOSSA APPROACH My discouragement because the operation did not recover
any hearing was offset by my realization that the middle
Obviously, otosclerosis has been a big part of my life. To fossa approach had a number of other possibilities, such as
find out more about it, I read a two-volume series of arti- vestibular nerve section and identification of the facial
cles on otosclerosis that had been collected by the nerve during acoustic tumor surgery.
American Otologic Society. One of the articles that caught Early in practice I had seen a very handsome young fire-
my eye was a study that detailed how otosclerosis lesions man with a unilateral hearing loss. I sent him to Dr. Owen
commonly occurred around the cochlea above the internal for x-rays. The report came back that he had an enlarged
auditory canal and compressed the cochlear nerve. This internal auditory canal. I referred him to Dr. Kurze who
was theorized to be a possible cause for the sensorineural concurred with my diagnosis of an acoustic neuroma. He
loss that I was frequently seeing in otosclerotic patients. It told me that he did not want to operate at that time
seemed logical to me that if you could drill away the oto- because the patient would trade a little hearing loss and
sclerosis and relieve the pressure on the eighth nerve, you tinnitus for certain facial paralysis and possibly ataxia.
might reverse some of the hearing loss. Within 2 years he had developed facial numbness and early
I have always been an early riser, and I remember sitting papilledema. I attended the surgery, which was performed
one morning and looking at a dissected skull that my with the patient in the sitting position and took some
father had given me in dental school. There was a yellow hours. Unfortunately, the patient stopped spontaneous
line for the greater superficial petrosal nerve, and it respiration and died several days later. In a later discussion
occurred to me that this might be the key to follow back to with Dr. Kurze, we both agreed that he had done all he
the geniculate ganglion and then on along the labyrinthine could. I will never forget what he said, “You have to real-
part of the facial to the internal auditory canal. ize we were dealing with a large tumor.”
By this time we could afford a babysitter, so June and I realized in the aftermath of the loss of this patient that
I started going to the morgue to see if I could get to the the key to early acoustic tumor surgery was preservation of
internal auditory canal without damaging the hearing or the facial nerve. I remember that I dreaded seeing and
the facial nerve. Because of my experience with diamond evaluating patients with unilateral hearing loss because
burrs and irrigation in dentistry, I had already adapted these I felt that if a diagnosis of acoustic neuroma was established
procedures to my work in chronic ear surgery. June would the patient’s doom was sealed.
set up the microscope and instruments and act as the scrub June and I continued our sessions in the morgue. I was
nurse to facilitate the dissection. Since the approach called trying to work out an approach to the cerebello-pontine
for elevation of the temporal lobe, I recruited the help of a angle through the middle fossa. The concept was to iden-
young neurosurgeon, Ted Kurze, and after a number of dis- tify the facial nerve at the beginning of the procedure and
sections I felt we were ready for our first case. then to dissect the acoustic tumor away from it. I had
For this case, I selected an attorney who had changed never operated on a acoustic tumor, but I teamed up with
careers to become an accountant after he went completely a young neurosurgeon, Jack Doyle, who had just finished
deaf. His medical records clearly showed that he had oto- his residency at the Mayo Clinic. We did our first acoustic
sclerosis. On August 1, 1958, June’s birthday, we did the in January 1960, using the microscope, with the patient in
first middle fossa decompression at St. Vincent Hospital in the sitting position. Drilling out the labyrinth and internal
Los Angeles. I was very honored and not a little scared that auditory canal down to the jugular bulb using a slow
Dr. Carl Rand, the dean of Los Angeles neurosurgery, Jordan Day drill is a long and very tedious procedure. Jack
Cushing’s last resident, and Dr. Kurze’s associate, came to Urban, a fantastic engineer who died some years ago and
watch the surgery. whom I still miss very much, helped me develop a special
As far as I know, this was the first intracranial procedure retractor and a seat with arm rests. It was a partial removal.
in which the operating microscope was used. During the The patient had some facial weakness but recovered well.
procedure, using the old Jordan Day drill with belt-driven During the next 3 years, we were to do another 20 tumors
engine arm and hand-piece, enough static electricity this way. The histories and the results are chronicled in
developed that it caused frequent stimulation of the facial our first monograph.
nerve. I could feel facial contractions through the drapes.
I had experienced this a number of times before during
chronic ear surgery, so it was not an unknown phenomenon DEVELOPMENT OF THE
to me, but I was already so nervous that I came very close TRANSLABYRINTHINE APPROACH
to aborting the procedure.
Fortunately, the patient recovered well, with no facial Operating in the sitting position and removing the
weakness. I remember his wife telling me how sexy she labyrinth through the middle fossa was very onerous to me.
thought he looked with his completely shaved head. My experience with mastoid surgery, with the patient
xxii FOREWORD

prone on the table, seemed to present some interesting television equipment. It seemed like he could do it all, if it
possibilities. So it was back to the dissection lab and to involved engineering.
investigations on how to remove the labyrinth and open Over the next few years, we did a number of acoustic
the internal auditory canal using mastoid procedures. neuroma surgeries using the translabyrinthine approach.
I soon found that the facial nerve could be skeletonized, After 50 cases, we decided it was time to publish our
the labyrinth removed, and the internal auditory canal results. I was very impressed with Cushing’s volume, pub-
opened, without having to retract any brain or drill away lished in 1917. Each patient that he had operated on up to
any bone with the dura open. that time was documented in detail and in sequence. I tried
Fortunately at this time, Bill Hitselberger came into my to emulate this example by publishing each of my cases in
life and, for the first time, I could work with a neurosur- the same way. Fortunately, Dr. George Shambaugh, who
geon who really wanted to learn temporal bone surgery was at that time the editor of the Archives of
and be able to apply the expertise of neurosurgery to the Otolaryngology, suggested that we devote an entire issue
problems of acoustic neuroma surgery. We soon recog- of the journal to these cases. This issue was the first sig-
nized that it was safer and much easier to operate with the nificant recognition of this work, and I shall always be
patient in a supine position and to approach the angle grateful to him. It set forth clearly the value of micro-
through the mastoid and the labyrinth. This eliminated surgery in acoustic tumor surgery. This heralded a very
the constant worry of air embolism and considerably significant change in intracranial surgery and was not met
shortened the dissection down to the angle. with enthusiasm by the neurosurgical community.
By now, I too, had begun teaching in Howard’s courses, It was through television equipment, starting with the
and many students wanted to learn the temporal bone black and white sets, that we were able to teach many
approaches. One of these students was Frank Ellis from students. These students have established neurotology
Sydney, Australia. During each night of dissection, I would programs and greatly advanced neutotologic procedures
emphasize that the key to establishing the exact location of worldwide. I remember Dr. Wullstein saying in one of his
the facial was to identify it at the beginning of the tumor lectures, “If a man develops a procedure that lasts for 3 years
dissection at the point where it entered the fallopian canal unchanged he has done a very outstanding piece of work,
at the lateral end of the internal auditory canal. I would if it is unchanged in 10 years the man was a genius, but if the
say, “Frank you’ve got to see that bar of bone (the vertical work is unchanged for 20 years he is working in a dead
crest) at the end of the canal.” It was Frank who dubbed it field. There is no question that neurotology is not a dead
Bill’s bar, a name that has stuck. It is the key to saving the field. Like any father I am very proud of my many neuro-
facial nerve and making early acoustic neuroma removal tology sons and daughters.”
possible.
Bill Hitselberger and I developed a very close working
relationship and, when faced with a complication of death,
we would carefully explore what we should have done William F. House, M.D.
differently or return to the morgue for a new look at a Staff Otologist
particular part of the surgery. We were backed up by Jack Hoag Memorial Presbyterian Hospital
Urban who often observed surgery and developed instru- Private Practice
mentation, microscope viewing tubes, and camera and Newport Beach, California
 Introduction
The History of Neurotology
and Skull Base Surgery

Outline
Introduction Lawrence R. Lustig, MD
Medical Thought Prior to the European Renaissance
Sixteenth Century—The Vesalian Revolution
Otologic Anatomists of the Renaissance
Seventeenth Century
Duverney’s Influence on Otologic & Neurotologic
Pathophysiology
Eighteenth Century
Elucidation of the Membranous Labyrinth
Surgical Advances in the 17th and 18th Centuries—Mastoid
Trephination
The Nineteenth Century
Sir Charles Bell and Cranial Nerve Physiology
Early 19th-Century Advances in Vestibular Science
Vestibular Semicircular Canal Physiology: Flourens
The State of Otology and the Neurosciences in the Mid-19th
Century
Joseph Toynbee and the Origins of Modern Aural
Pathology
The Vienna Medical School
Adam Politzer—The Father of Otology
Elucidation of the Organ of Corti
Modern Surgery Is Born
Resurrection of the Mastoidectomy
The Pathophysiology of Coalescent Mastoiditis: Friedrich Bezold
Sir William Macewen: The First Skull Base Surgeon?
Victor Horsley and the Birth of Neurosurgery
Sir Charles Ballance: Pioneering Skull Base Surgeon
19th-Century Advances in Facial Nerve Surgery
Scientific Advancement in Vestibular Physiology in the late
19th Century: Prosper Mèniére and the First Description of
Ménière’s Disease
Twentieth Century
A Tumor That Helped Defined a Specialty: Acoustic
Neuroma
Harvey Cushing: The Founder of Modern Neurosurgery
Nylén, Holmgren, and the Birth of the Operating
Microscope
Walter Dandy
Advances in Vestibular Science in the Early 20th Century
Georges Portmann and the Endolymphatic Sac
Reemergence of the Operative Intervention for Ménière’s Disease
in the 1930s and 1940s: Walter Dandy’s Vestibular Nerve
Section
Terence Cawthorne and the Rise of the Transmastoid
Labyrinthectomy
Neurotologic Surgery Advances in the 1930s and 1940s:
Maurice Sourdille, Julius Lempert, and the Fenestration
Operation
Glomus Jugulare Tumors—Harry Rosenwasser

1
2 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Outline—Cont’d
Neurotologic Surgical Advances in the 1950s
William House and the Birth of Modern Neurotology and Skull
Base Surgery
Electrical Stimulation of the Auditory Nerve—The Birth of
Cochlear Implants
The Creation of the American Neurotologic Society
Conclusion

“In my conception of scientific work, history and research are so before the first skull base or neurotology fellow was trained,
indivisibly linked that I cannot even conceive of one without the before the operating microscope came into use, and before
other.” the first vestibular schwannoma resection was performed,
Theodor Billroth (1829-1894), Über das Lehren und Lernen der medicin- the seeds of our specialty were being sewn by visionaries
ishen Wissenbschaften, as translated by Lesky.1
in the anatomic, physiologic, and surgical sciences.

INTRODUCTION MEDICAL THOUGHT PRIOR TO THE

EUROPEAN RENAISSANCE
When did the subspecialty of neurotology and skull base
surgery begin? Was it at the first attempt to operate on the If the underpinnings of neurotology and skull base surgery
facial or hearing nerves in the 19th century? Are its origins are otologic and neuroanatomy and otologic physiology,
dated to the first operation on a vestibular schwannoma in then the origins of the specialty can be considered to
the late 1800s? Was it founded with the introduction of the date back to antiquity. In the age of the Romans, human
operating microscope toward ear surgery in the 1920s? society, including medicine, had advanced to new heights.
Was it when otologists and neurosurgeons first combined Of all the ancient Roman scientific scholars, the most
their expertise to tackle complicated skull base lesions in influential was undeniably Claudius Galen of Pergamum
the 1960s? Or was it at the founding of societies devoted (c. 129–200 AD). For 1500 years the main source of European
to solely neurotology or skull base surgery? The closer one physician’s knowledge about the human body came from
examines the question, the quicker one realizes that there the writings of Galen. As one of the most prolific writers
really is no specific point in time when neurotology and of antiquity, Galen was said to have produced more than
skull base surgery “became” an independent subspecialty. 500 treatises on physiology, rhetoric, grammar, drama, and
Rather, it has slowly emerged out of a confluence of inter- philosophy. Mostly, though, Galen is best known for his
related disciplines and technologies over the past century prolific treatises on anatomy. Since Roman custom forbade
to become the field that we know of today as “neurotology dissection of the human body, Galen performed all his
and skull base surgery.” Its formation required the marriage dissections on monkeys for external anatomy and used pigs
of neurosurgery and otology; the introduction of the oper- for internal anatomy. Predictably, this led Galen to many
ating microscope; and advances in surgical technique, inaccurate conclusions. However, as the Roman empire
anesthesia, and radiology. Along the way, the field also began waned, and Christianity, with its belief in the resurrection
involving specialists within ophthalmology and craniofa- of the human body, subsequently dominated the middle
cial and plastic and reconstructive surgery. Lastly, and ages, Galen’s inaccuracies would remain buried until the
perhaps most importantly, the formation of neurotology Renaissance.2 However, Arabic and Byzantium medicine
and skull base surgery required pioneering surgeons laden flourished, based on the ancient Hellenic and galenic
with confidence, daring, and foresight, who were willing traditions. It was during this time that Aëtius of Amida of
to push the boundaries of their training, sometimes under the Byzantine school wrote a comprehensive description
the ridicule or scorn of the medical establishment. This of ear diseases.3 Unfortunately, due to religious restric-
historical review is a salute to these pioneers’ efforts. tions like those that existed in Europe, anatomic dissection
It is undeniable that the field of neurotology and skull was forbidden, limiting the potential medical advances of
base surgery is in a period of rapid transition, whose his- these great civilizations.
tory is still being written. Thus, rather than wade into the By the 13th century, the potential benefits of human
academic debate on matters of primacy of current tech- cadaveric dissection began to be realized by some enlight-
niques that makes the practice of surgery so enlivening ened leaders throughout Europe. Emperor Frederick II,
(and is the focus of this textbook), this historical overview who founded the universities at Padua and Naples (and
will focus on the origins of the specialty up through the incidentally fought continuously with the Church over the
last quarter century, ignoring the myriad strides and extent of its authority) decreed that all physicians in his
accomplishments made within the past 25 years. Long domain were to learn anatomy by studying the human
 The History of Neurotology and Skull Base Surgery 3

body, and be required to provide proof of such training.4 anatomy was really only a compendium of statements about
With the arrival of the Black Death in 1348, limited animals in general. Vesalius insisted that his students see,
necropsy was allowed by the Church in the hopes of find- feel, and decide for themselves about the inaccuracies of
ing the cause. However, the papacy continued its general Galen’s anatomy. His subsequent anatomic studies culmi-
prohibition against necropsy and only slowly relaxed its nated in perhaps the most influential textbook of anatomy
restrictions over the following 200 years. It was not until ever written. De Humanis Corporis Fabrica5 (The Structure
1537 that Pope Clement VII, following the example of the of the Human Body) was published in 1543, the same year
leading universities at that time, finally endorsed teaching as Copernicus’ De Revolutionibus, and was destined to be as
by anatomic dissection.4 This official sanction paved the equally influential. Amazingly, the treatise was completed
way for a new anatomic revolution. Although Italian artists before Vesalius was 28 years old.
such as Leonardo da Vinci subsequently became known for Vesalius’ revolutionary approach helped bring anatomy
precise and exquisite anatomic drawings during the time, from the realm of guesswork and superstition into the
this new paradigm shift in anatomy came by way of Brussels, domain of science. As the darkness of the Middle Ages
the birthplace of Andreas Vesalius. waned and coalesced into the Renaissance, the necessity of
human dissection became obvious and widely accepted.
Renaissance artists like Leonardo, Raphael, and Titian had
SIXTEENTH CENTURY—THE VESALIAN broadcast a new realism in the palaces and churches of
REVOLUTION Europe, while architects such as Brunelleschi and Alberti
were leading a reexamination and reinterpretation of the
Born in Brussels in 1514 as the son of the apothecary ancient Roman texts and traditions. What Vesalius said was
to the emperor Charles V, Andreas Vesalius (1514–1564) unimportant compared with the path he opened for future
(Fig. I-1) received the best medical education of his time at students to learn about all organs of the body. Vesalius
the University of Paris, where he studied under Professor firmly placed anatomy on the foundations of observed facts
Sylvius, the celebrated champion of Galen’s writings. and demonstration. Within a scant half-century, vesalian
As professor at the University of Padua, in conducting anatomy prevailed in European medical schools, and the
his required “anatomy” (from the Greek anatome, for study of anatomy would never be the same.2,4 By paving
“cutting up”) he departed from the usual custom of staying the way for a generation of otologic and neuroanatomists,
seated high in the professorial cathedra (chair) while a Vesalius was instrumental in establishing a method for under-
barber-surgeon pulled out organs from the cadaver below. standing the anatomy of the ear and skull base, a critical
Instead, Vesalius himself handled the body and dissected step in the formation of the specialty of neurotology and
the organs. While teaching from Galen’s text, Vesalius skull base surgery.
noted many instances where Galen’s description was not
found in the human body. He soon realized that Galen’s Otologic Anatomists
of the Renaissance
As with all great teachers, perhaps Vesalius’ greatest achieve-
ment was in his influence on a generation of scientists and
anatomists. One of his students, Giovanni Ingrassia (1510–
1580) (Fig. I-2), was responsible for significant advances
in the field of otologic anatomy. Initially teaching at
Padua, he eventually ended up as a professor in Palermo.
According to Politzer, his lectures on anatomy and medicine
became so popular that it was impossible to find accom-
modations for all the foreign students and physicians who
had come to Palermo to learn from him.6 Additionally, his
humanitarianism and generosity were renown in Palermo,
primarily related to his duties as sanitary counselor for
the city that resulted in a marked reduction in mortality
during the bubonic plague. Ingrassia was a master anatomist
of his era and particularly known for his advances in bone
anatomy. In the ear, he is credited with the discovery of the
stapes and the description of the tympanic cavity, the oval
and round windows, and the chorda tympani. He accurately
described the mastoid air cell system, the cochlea, and the
semicircular canals. According to Politzer, he may have also
been the earliest to describe the sound conductivity of the
teeth.6
Some physicians, however, were not eager to embrace
the vesalian revolution. Among Vesalius’ contemporaries
was Bartholommeo Eustachio (Fig. I-3), one of the fore-
Figure I-1. Andreas Vesalius (1514–1564). (From Politzer A: A History of most anatomists of his era. Living from approximately
Otology, Part I, 1904.) 1524–1574, Eustachio developed fame not only as an
4 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Figure I-2. Giovanni Ingrassia (1510–1580). (From Politzer A: A History of Figure I-3. Bartholommeo Eustachio (1520–1574). (From Politzer A:
Otology, Part I, 1904.) A History of Otology, Part I, 1904.)

anatomist and physician, but also as a philosopher and a were entrusted to an assistant, but somehow became lost.
linguist. He was a professor at the Sapienza hospital, the They were rediscovered 160 years later in the Vatican Papal
same hospital da Vinci had been denied access to only a few Library by Lancisi, Pope Clement XI’s personal physician.
decades earlier for performing dissections there. As a pro- On the advise of Morgagni, Eustachio’s illustrations were
fessor, Eustachio was a fanatical supporter of Galen’s published with Lancisi’s own notes in 1714.9
anatomic ideas. As a result, he and Vesalius became natural Although he is known for his otologic discoveries,
antagonists. Eustachio vehemently criticized Vesalius’ Eustachio’s findings span the entire field of anatomy. He
description of the organ of hearing, going so far as to say described the tensor tympani and was the first to establish
that Vesalius’ entire work failed to contain a shred of truth.6 that the chorda tympani is intimately associated with the
He was critical of Vesalius’ description of the course and lingual nerve. Eustachio’s writings contain cross sections
ramifications of the facial and acoustic nerves and of his of the petrous portion of the temporal bone, the ossicles,
superficial description of the organ of hearing. Given and the vestibule (Fig. I-4). He described the turns of the
Vesalius’ lack of interest in the anatomy of the ear, and this cochlea, the osseous and membranous spiral lamina, and
being Eustachio’s field of expertise, these charges may have the modiolus. His greatest contribution to otology,
held some truth.7 however, lay in providing a precise description of the shape
Eustachio’s principle work was the Opuscula Anatomica, and course of the tubular structure bearing his name,
written in 1564.8 Its beautiful copper plate illustrations described in Epistola de Auditus Organis (within the

Figure I-4. Eustachio’s illustrations of

the cross section of the temporal bone,
from Tabulae Anatomicae, 1772. (From
Politzer A: A History of Otology, Part I,
1904.)
 The History of Neurotology and Skull Base Surgery 5

Opuscula Anatomica) in 1562.8 It is the first known work

dedicated exclusively to the ear. Though the existence of
the eustachian tube was vaguely known to Aristotle,
Celsus, Vesalius, and Ingrassia, the recognition of its exact
morphology is without doubt credited to Eustachio.
Furthermore, he recognized the physiologic and therapeutic
importance of his discovery, though it was not until the 18th
century that this discovery influenced otologic therapy.
Antonio Valsalva described the structure in greater detail a
little more than 100 years later and is responsible for naming
the tube in Eustachio’s honor.10
Another of the great Italian Renaissance anatomists who
helped provide the anatomic underpinnings of neurotology
and skull base surgery was Gabrielle Fallopio (1523–1562)
(Fig. I-5). Born only 9 years after Vesalius in 1523, Fallopio
lived a brief 40 years. It is said that his brilliance even
surpassed that of his teacher, Vesalius, and is regarded as
the founder of the Italian School of Anatomy, the alma
mater of the most important anatomists of that era. When
Vesalius’ second edition of the Fabrica was published,
Fallopio published a detailed critique, and many of his
corrections were included in subsequent editions. His intel-
ligence, charm, and humility made him one of the most
admired personalities of his generation; it is only with the
reportedly brusque Eustachio that Fallopio is said not to
Figure I-6. Title page from Fallopio’s masterpiece of anatomical description,
have gotten along well.6 Observationes Anatomicae, 1561.
Though Fallopio is perhaps best known for his original
descriptions of the female reproductive system (the fallo-
pian tubes), his otologic advances are significant. Fallopio’s
descriptions of the ear were equaled only by Eustachio’s, Fallopio also described the complete development of the
but his description of the course and ramifications of the ossicles at early stages of development, the communication
acoustic nerve, described in his most influential work, between the mastoid cells and tympanic cavity, the function
Observations Anatomicae11 (Fig. I-6), was far superior. of the tympanic ring, as well as naming the tympanic cavity
“tympanum” based on its similarity to a drum. He described
the ossicles, the two windows, the promontory, and the
chorda tympani and discovered the canalis sive aqueductus
that bears his name—the fallopian canal—containing the
intratemporal portion of the facial nerve.11

SEVENTEENTH CENTURY
It is not surprising that the earliest advances in neurotol-
ogy and skull base surgery were anatomic, since anatomy is
primarily a descriptive science; one simply needs to look at
an anatomic preparation and accurately describe what is
seen. The Renaissance anatomists, armed with a sense of
discovery and a renewed interest in the reinterpretation of
traditional teachings, began a journey that is still being
carried out to this day. Based on the work of these pioneers,
by the start of the 17th century a surprising amount of
otologic anatomy was known, including a complete
description of the course and ramifications of the facial
and acoustic nerves, the ossicles, the turns of the cochlea,
the labyrinth, and the eustachian tube, among others.
Of course the finer details would have to wait for newer
technologic advances such as microscopy. However, con-
tinuing even through the 18th century these remarkable
achievements were principally anatomic, with theories of
function and pathologic states based on ancient, specula-
Figure I-5. Gabrielle Fallopio (1523–1562). (From Politzer A: A History of tive, and largely untested, beliefs. Invasive surgery was of
Otology, Part I, 1904.) course extraordinarily dangerous. Neurosurgery at that
6 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

time simply consisted of draining pus in cases of abscess

through a trephination.12
It was not until our predecessors began applying these
anatomic and physiologic principles toward a rational
approach to the human body, beginning about the 1700s,
that the first significant advances happen in the pathophys-
iology of ear disease. Several fundamental changes had to
occur for this transformation to take place. First, technol-
ogy had to reach a certain level of expertise to enable sci-
entists to perform the adequate investigations. The obvious
example of this was the invention of the light microscope,
by Anton van Leeuwenhoek (1632–1723), which brought
about a renewed interest in otologic anatomic exploration,
which had been waning prior to its introduction. A second
important shift during the 17th century was an intellectual
one; scientific investigation and its application in general
began to be viewed in a new light, though it was not until
the following century that this shift really took a firm hold
in the scientific community. Francis Bacon of Verulam
(1561–1626) started this intellectual revolution by espousing
the experimental method and inductive reasoning derived
from observed facts, put forth in his classic text Novum
Organum in 1620. Bacon, in contrast to those before him,
advocated the belief in science not only as a philosophy or
purely scholarly endeavor, but also as a tool whereby
humanity could exert power and control over nature. He Figure I-7. Traite de l’organe de l’ouie (Treatise on the Organ of Hearing),
was Duverney’s influential otologic masterpiece, and published in 1683.
was, in essence, the first “modern” scientist.13 Shown in this figure is the first English edition, translated from the French
As a result, knowledge regarding otologic and neuro- by John Marshall in 1737. (From Duverney GJ: Traite de I’organe de I’ouie,
anatomy and physiology in the 17th century advanced at contenant la structure, les usages et les maladies de toutes les parties
an incremental pace compared with that of the prior de l’oreile. London, Samuel Baker, 1737.)
century. Despite great advances in all natural sciences
during the 17th century, there was no spectacular progress
concerning the pathology and therapy of diseases of the As one of the first to apply physiologic and pathologic
ear or brain. There was one notable exception to this, how- principles to the study of the ear, Duverney indirectly
ever, brought about by Guichard Duverney. influenced all those who came after him. Though known
for being a superb anatomist, Duverney became convinced
Duverney’s Influence on Otologic that knowledge of anatomy alone was insufficient for under-
standing how we hear, a great departure from many of
and Neurotologic Pathophysiology his predecessors. The problem that Duverney and other
Joseph Guichard Duverney (1648–1730) was one of otologic anatomists faced up to that time was clearly sum-
otology’s great pioneers, and his influence on the patho- marized in the introduction of his text:
physiology of diseases of the ear was so far-reaching that
a brief description of his achievements is merited. The “Of all the Organs assign’d to the Use of Animals, we have the
precocious Duverney was only 19 years old when he was least knowledge of those of the senses; but there is none more
appointed anatomic demonstrator at the Jardin du Roi obscure than that of Hearing: the minuteness and Delicacy of the
Parts which compose it, being enclos’d by other Parts, (which by
in Paris. There, his extraordinary knowledge, legendary reason of their Hardness, are Scarcely penetrable) render the
lectures, and magnanimous personality made him one of Enquiries into them more difficult, and their Structure some-
the most revered European physicians of the century. It thing so intricate, that there is as much Trouble in explaining, as
was for him that the position of the court anatomist was their was in discovering them.”
created in France, a position that lasted until the French (Translation by John Marshall, 1737)14
Revolution. His principal work, Traite de l’organe de l’ouie
(Treatise on the Organ of Hearing)14 (Figs. I-7 and I-8), ini- Duverney proceeded to introduce new and revolutionary
tially published in 1683, was the first comprehensive work methods of investigation, and he presented new theories on
devoted solely to the ear and was instantly hailed within sound perception based on contemporary physical under-
the European scientific community. This monumental standing. He directly addressed pathologic states of the
work is considered a milestone in otology. Duverney didn’t ear, including otalgia, otorrhea, and tinnitus, and classified
have access to the microscopic structure of the organ of causes of ear obstruction and diseases of the tympanic
hearing, and many of his theories were based on old and membrane. He reported on purulent middle ear infections,
incorrect misconceptions of how the ear functioned. Still, challenging the prevailing belief that all aural discharge
his observations on anatomy, physiology, and pathology of was from an intracranial source. By the end of the 17th cen-
the organ of hearing went far beyond anything written tury, Duverney was considered the leading authority of the
before his time. organ of hearing in Europe and is credited with almost
 The History of Neurotology and Skull Base Surgery 7

Figure I-8. Illustrations from

Duverney’s Traite de l’organe de
l’ouie. These plates demonstrate
Duverney’s mastery of otologic
anatomy. (From Duverney GJ: Traite
de I’organe de I’ouie, contenant la
structure, les usages et les maladies
de toutes les parties de l’oreile.
London, Samuel Baker, 1737.)

single-handedly sparking widespread interest in the anatomy after Duverney’s groundbreaking work.16 Valsalva’s thesis
and physiology of the ear in the following century.15 highlighted his dissatisfaction with the scholastic and anti-
Despite Duverney’s advances and admonishments, how- scientific methods of his teachers and, following Malpighi’s
ever, pathologic-anatomic research was declining during advice, began an extensive series of clinical investigations,
the 17th century, and speculative hypotheses bases on the pathologic-anatomic studies, and animal dissections. In
physical and chemical discoveries of this time were promi- 1688 he became surgeon at the Hospital of the Incurables
nent.6 However, the end of the 17th century would see the
birth of a new technology that would again revolutionize
anatomic study: Guided by the discovery of the microscope
by Anton van Leeuwenhoek and the subsequent scientific
advances of Marcello Malpighi (including the confirmation
of the existence of capillaries as the connection between
the arterial and venous system), over the next 200 years
otologic and neuroanatomy would advance considerably.

EIGHTEENTH CENTURY
After Duverney, the 18th century witnessed an explosion
in the understanding of the ear and its inner workings,
brought about in large part by the groundbreaking works
of such eminent physicians as Morgagni, Scarpa, Cotugno,
and Santorini. Rising above all these great scientists, how-
ever, was Antonio Maria Valsalva (1666–1723) (Fig. I-9).
Valsalva was born into an old noble family in Imola, a small
town near Bologna, in northern Italy, in 1666. The son of
a goldsmith and the third of eight children, Valsalva
received his early education from the Jesuits. At 16 he was
sent to the University of Bologna to study the sciences.
The University of Bologna was one of the premier in
Europe at that time and even included a number of women
faculty.16 A student of the great Marcello Malpighi,
Valsalva became his most outstanding student.
Valsalva earned his degree in medicine and philosophy Figure I-9. Antonio Maria Valsalva (1666–1723), one of the first true
in 1687 with a thesis entitled, “On the superiority of the physician scientists who advocated correlating clinical findings with
experimental method,” which was published only 4 years pathologic study.
8 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

where he practiced for 25 years. In 1697, at the age of 31,

he was appointed public dissector of anatomy by the senate
of Bologna, considered to be an extraordinary honor for
someone not born in the city. Eight years later he became
professor and lecturer of anatomy, a rank he held until his
death.
Giovanni Battista Morgagni, Valsalva’s student and first
biographer, described Valsalva as calm and gentle, able to
tolerate many hours of work without impatience or fatigue.
His zeal, courage, endurance, and self-discipline were said
to have surpassed even that of the great Vesalius, since
Valsalva continued to spend days and nights dissecting even
when he was quite old and ill. Valsalva developed new sur-
gical techniques and was an outstanding diagnostician who
based opinions on pathologic-anatomic examinations. He
was a crusader for the mentally ill and was among the first
to organize their humane treatment by advocating the abo-
lition of chains, gags, and beatings. When he died of a stroke
(termed apoplexy in his day), it was noted that Valsalva had
been the first to clearly recognize its anatomic basis.
His principle treatise on the anatomy and physiology of
the ear was the result of 16 years of work and the dissection
of more than 1000 human heads. Published in 1704, it was
termed the Tractatus de Aure Humana (Treatise of the Human
Ear)10 (Figs. I-10 and I-11). The immense value of this work
is demonstrated by the fact that the anatomic sections of all
major otologic treatises up to the 19th century are based
on Valsalva’s work, parts of which remain valid even today.
In this work, he describes for the first time the sebaceous
glands of the auricle (1c. Cap.1, V, p.11), previously unknown Figure I-11. Illustrations from Valsalva’s Tractatus. These include his detailed
external ear muscles (1c. Cap.1, IV, p.11), inconsistent study of the eustachian tube (named by Valsalva), which made possible his
openings in the tegmen that would later become known as now famed “Valsalva” maneuver.

Figure I-10. Title pages from

Valsalva’s monumental Tratactus de
Aure Humana (Treatise of the human
ear), published in 1704. This ground-
breaking treatise is the basis for all
otologic anatomic works up through
the 19th century and represents a
true milestone in otologic anatomy
and medicine.
 The History of Neurotology and Skull Base Surgery 9

Hyrtl’s fissures (1c. Cap.2, V-VII, pp. 21–23). He named

the eustachian tube in Eustachio’s honor (1c. Cap.2, XVI,
pp. 30–32), popularized the term labyrinth for the entire
inner ear, and was the first to observe the presence of a
watery fluid within the labyrinth (1c. Cap.3, XVII, p. 51).
Valsalva was also the first physician to systematically
inspect the tympanic membrane of living subjects. While
inspecting a case in which the superior segment of
the eardrum was full of pus, he observed that pus and air
disappeared in the region of the foramen of Rivinus when
the patient exhaled forcefully with his mouth and nose
closed, which subsequently became known as Valsalva’s
maneuver:

“. . . I exposed the auditory passage to the sun, and stretched open

the same element. I therefore saw the tympanic membrane mois-
tened by a portion of superior liquid, and at a specific locus; from
this place in like manner, I sighted a diseased fluid rushing out
simultaneously along with air, whenever an ailing person held
back breath by force, as I ordered, with nostrils and mouth
closed.”10
(Tractatus, 1c. Cap.2, p. 20) (Translated by Lustig et al.)17

Domenico Cotugno (1736–1822) (Fig. I-12) ushered in

the next great leap in understanding of labyrinthine fluid,
the membranous inner ear, and endolymphatic sac. Born
Figure I-13. Title page to Cotugno’s work, De Aquaeductibus Auris Humanae
in poverty in 1736 in Ruvo, near Naples, diligent study and Internae Anatomica Dissertatio, 1775.
his ingeniousness led to an appointment as full professor
on anatomy and surgery in Naples at the prodigious age
of 30. There he taught for the remainder of his successful
career. His greatest fame came as a result of his first, and completely fills the cavities of the labyrinth, debunking
smallest, work, De Aquaeductibus Auris Humanae Internae an idea that had been around since the time of Galen, that
Anatomica Dissertatio18 (Figs. I-13 and I-14). In this land- air fills the inner ear. Cotugno achieved success where
mark treatise, Cotugno was the first to establish that fluid others had failed by dissecting fresh, as opposed to macer-
ated temporal bones. Using this new technique, he
went on to describe the cochlear and vestibular aqueducts,
the ever-present occurrence of labyrinthine fluid, and the
function of an aqueduct connecting the labyrinth to the
endolymphatic sac. He was also the first to hypothesize
on the physiology of hearing, taking this fluid into
account.9,19,20

Elucidation of the Membranous

Labyrinth
The detailed and painstaking studies of otologic anatomists
up to the late 1700s created a nearly complete understand-
ing of the osseous labyrinth. However, knowledge of the
membranous labyrinth consisted of false ideas most likely
because of poor methods of specimen preparation.
Cotugno’s success demonstrated first hand the need for
fresh, meticulously prepared tissue. Antonio Scarpa (1747–
1832) (Fig. I-15), employing a keen sense of observation
and exquisite attention to detail and tissue preparation,
would subsequently describe the correct anatomy of the
membranous labyrinth, considered one of the most impor-
tant advances in 18th-century otology.
Born in poverty in 1747, Scarpa was educated by his
uncle, a priest, and was first employed as a secretary to the
great anatomist-pathologist Morgagni, at the University
Figure I-12. Domenico Cotugno (1736–1822). (From Politzer A: A History of of Bologna. Gradually, Scarpa became well versed in all
Otology, Part I, 1904.) disciplines of medicine and surgery, becoming Morgagni’s
10 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Figure I-14. Illustration from

Cotugno’s work, demonstrating
his anatomical preparations of the
temporal bone and bony labyrinth.

most revered student. It is said that Morgagni died in window.21 His greatest contribution came in1789 with the
Scarpa’s arms.6 He continued his education by traveling to publication of Disquisitiones Anatomicae de Auditu et Olfactu,
the leading medical centers of Europe. His first book, De where he presented his discovery of the membranous
Structura Fenestrae Rotundae (Fig. I-16), asserted that sound labyrinth and the spiral cochlear duct, filled with fluid later
is transmitted to the labyrinth both by way of the ossicular called Scarpa’s fluid, or endolymph.22 His studies, outlined
chain and by way of air in the middle ear to the round in this treatise, also elucidated much of the anatomy of other
otologic sensory organs and the ganglial system, whereby
the vestibular ganglion subsequently became known as
Scarpa’s ganglion.

Surgical Advances in the 17th

and 18th Centuries—Mastoid
Trephination
Surgery involving the skull in the 17th and 18th centuries
was primarily concerned with trauma and infection. Jean-
Louis Petit (1674–1750), the eminent Paris surgeon,
advised skull trephining in all cases of scalp wounds
with an associated skull fracture.12 In 1736 Petit also
described, for the first time, how he would trephine the
mastoid process to relieve aural suppuration (Fig. I-17).23
According to Petit:

“The pus is situated in bony cavities whose walls cannot collapse;

it lodges there, gives rise to caries of the bone, and this caries
cannot be reached by any topical application. Purulent collec-
tions bring about death by destroying some structure necessary
to life or because the pus, being abundant, and not let out in time,
is reabsorbed into the blood and causes rigors, fever, and other
purulent deposits in certain of the viscera. These abscesses may
persist for a long time before reaching a stage in which they cause
death; but from the very first days of their formation they ought
to be opened.”
(As translated by Sonnenschein) 24

Figure I-15. Antonio Scarpa (1747–1832). (From Politzer A: A History of (It has been speculated that it was not Petit, but the pio-
Otology, Part I, 1904.) neering physician and surgeon Ambrose Paré who originally
 The History of Neurotology and Skull Base Surgery 11

Figure I-16. Title page of Scarpa’s

first book, De Structura Fenestrae
Rotundae Auris et de Tympano
Secondario Anatomicae
Observationes, 1772 (left), and
illustrations of the inner ear from
this monumental work (right).

proposed trephination of the mastoid in 1560, nearly 200 involved fitting the tip of a syringe into the mastoid
years prior to this description, on the King of France, and vigorously irrigating. After his initial success, and
François II. However, though technically capable, Paré in supported by further cadaveric studies, he subsequently
all likelihood did not attempt the surgical procedure.)25 made a small hole in the mastoid cortex with a trocar and
The Prussian military surgeon Jasser also reportedly again successfully cured a patient by repeated irrigations.26
operated on a soldier for coalescent mastoiditis, postauric- Despite the successes of Petit and Jasser, however, mastoid
ular swelling, and aural discharge in 1776. His technique trephination subsequently fell into disrepute. The personal

Figure I-17. Skull trephines (right) used by Jean-Louis Petit (1674–1750) (left), used to treat mastoid suppuration. (From Ballance C: Essays on Surgery of the
Temporal Bone. London, Macmillan, 1919.)
12 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

physician to the King of Denmark, Baron Bergen, having research careers became centralized around the professor,
heard of Petit’s success with the mastoid trephination pro- enabling the gradual introduction of new specialties that
cedure, though perhaps not completely understanding the incorporated the scientific advances occurring simultane-
correct indications for the operation, persuaded a surgeon to ously.32 This academic organization eventually became
operate on his own mastoid to relieve his tinnitus and hear- the model for American universities. (The influential von
ing loss. Bergen’s well-publicized tragic and painful death Tröltsch later credited the “critical German spirit” for the
12 days later literally doomed the procedure for a hundred gradual intellectual shift from England to Germany and
years, until it was again successfully reintroduced by Herman eastern Europe during this time period.30)
Schwartze in the late 1800s.26 There was also emerging a new consensus on surgical
education. Inspired by the famed 18th-century surgeon
John Hunter, who saw anatomy not as a static branch of
THE NINETEENTH CENTURY medicine, but rather as a dynamic science that incorpo-
rated pathology and functionality, anatomic teaching
Despite limited surgical successes in the mastoid and cranial began to be viewed as the foundation of surgical training.
cavity, the progress in otologic knowledge through the 18th With this new emphasis on anatomic and pathologic
century was primarily concerned with anatomic discoveries, education, it is no coincidence that many operations, such
with only a few advances in pathophysiology. At the begin- as the appendectomy and hysterectomy, were successfully
ning of the 19th century, the dissection of cadavers was described for the first time during the late 1800s and early
widely accepted and an integral part of medical education. 1900s.33,34 Furthermore, the numerous European wars of
As a result, in the early 1800s the demand for cadavers the 18th and 19th centuries provided most surgeons ample
increased dramatically. This lead to body shortages, fueling trauma experience, establishing the careers of such notable
illegal body acquisitions, and in some cases murder, to surgeons as John Bell (1763–1820) and his younger
obtain cadavers for dissection!4 However, by the mid-19th brother Charles Bell (1774–1842), John Abernathy
century the study of gross anatomy was legally standardized (1764–1831), and Sir Astley Cooper (1768–1841).
throughout European medical schools and has changed little Additionally, the physics of sound and acoustical science
until the present. was advancing at a rapid pace, thanks to the works of
Yet, despite Valsalva’s emphasis of the importance of Laplace, Jean-Daniel Colladon (1802–1893), and Félix
pathologic correlation with disease states a century before, Savart (1791–1841). All these simultaneous anatomic,
knowledge in this area was still limited, and clinical diagno- physiologic, and surgical developments crystallized the
sis hadn’t changed appreciably during the previous 300 years. understanding of the ear and skull base during the 19th
Ear exams were still performed with available sunlight as century and would lead to the independent creations of
they were before the Renaissance, and surgery of the ear was otology and neurosurgery, the twin pillars of neurotology
limited to a few operations of the external auditory meatus and skull base surgery.
and auricle, despite soaring advances in other surgical areas.
As already mentioned, the early “mastoidectomy” or mastoid Sir Charles Bell and Cranial
trephine was nearly abandoned in the late 1700s, though not Nerve Physiology
completely, being condemned by ear surgeons in the medical
literature as late as 1870.27 Neurosurgery still primarily con- Sir Charles Bell (Fig. I-18) is now most commonly remem-
sisted of operations on the skull itself; trephination for infec- bered for the clinical facial palsy bearing his name.
tions, and the management of head trauma. The two primary Yet Bell’s contributions to medical science were infinitely
clinical otologic advances during the 18th century were greater. In the early part of the 19th century, Bell would
catheterization of the eustachian tube by E. G. Guyot in conduct a series of investigations that would radically change
1724, and paracentesis of the drum, popularized by Sir Astley our understanding of neuroanatomy and neurophysiology.
Cooper in 1800.28,29 Interestingly, Guyot was the postmaster Charles Bell was born in 1774 in Fountainbridge, a
of Versailles who was said by von Tröltsch to have relieved suburb of Edinburgh. It was during his high school years
his own deafness by injecting his eustachian tube using a that the young Charles began to assist his older brother
curved tube introduced through his mouth.30 John, a lecturer at the Anatomy School in Edinburgh,
It is not until the 19th century that a significant under- where Charles also began attending medical lectures.35
standing of otologic disease and advances in neurotology By 1799 at the precocious age of 23, the younger Charles
and neurosurgery finally take place. Great strides in had already displayed a surgical and anatomic skill akin to
histology, pathology, and physiology in the early 1900s led that of his master and older brother. By 1814, while prac-
to the development of the new branch of laboratory ticing in London as the surgeon to the Middlesex
medicine in the second half of the 19th century.31 Though Hospital, Charles Bell had already achieved a formidable
this pathologic-anatomic revolution began in Paris in the reputation, having published A System of Dissections in
early part of the century with Cruveilhier, it was quickly 1798, contributed to his brother John’s Anatomy of the
superseded by advancements in what is now Germany and Human Body, and completed his masterful, Essays on the
Austria.32 Germany was at the forefront of this revolution Anatomy of Expression in 1806. This later, magnificent
because they had developed a large body of full-time sci- four-volume publication revealed Bell not only as an expert
entists, while in the rest of Europe, research and teaching anatomist, but as one contemporary put it, one possessed of
still depended mainly on the work of practicing physicians. the “. . . most exquisite taste and feeling for sculpture and
In German universities, the organization of teaching and painting.”35 John Flaxman (1755–1826), one of the greatest
 The History of Neurotology and Skull Base Surgery 13

It was within this milieu that Bell came to his monu-

mental conclusions regarding the physiology of cranial
and spinal nerves. That it should first occur to Bell that
definite nerves have a definite course from the brain to the
periphery and that different nerves have quite distinct
functions entitles him to everlasting fame. His discovery
that the roots of the spinal nerves have distinct, compart-
mentalized functions was subsequently hailed as epoch-
making as Harvey’s discovery of the circulatory system.
These revolutionary theories that established the functions
of the anterior and posterior spinal roots were put forward
following a series of experiments, which he highlighted in
a letter penned to his brother John in 1810. Charles clearly
realized the import of his work: “I write to tell you that
I really think I am going to establish my Anatomy of the
Brain on facts the most important that have been discov-
ered in the history of science . . .”35
In August 1811, when Bell was 37 years old, 100 copies
of his Idea of a New Anatomy of the Brain38 were published
and sent to personal friends. So revolutionary were the
ideas contained within the manuscript that it has been
referred to some as the “Magna Carta” of modern neurol-
ogy. Unfortunately, the limited distribution of the monu-
mental work would later lead to confusion regarding the
primacy of Bell’s contributions.
Figure I-18. Sir Charles Bell (1774–1842), whose research led to a Ten years later Bell read a series of papers to the Royal
revolutionary conception of the anatomy and physiology of the cranial and
spinal nerves. His discovery that individual nerves have a defined course Society37 in which he proposed a classification of nerves
from the brain to the periphery, that different nerves have quite into two broad groups: those involved in “respiration”
distinct functions, and that the roots of the spinal nerves have distinct, (including the facial, vagus, spinal accessory, phrenic, and
compartmentalized functions has been hailed as epoch-making as Harvey’s long thoracic nerves), and another group that included
discovery of the circulatory system.
all the other “symmetrical” nerves that Bell felt were
necessary for “life and motion.” Bell also made several crit-
of English sculptors, later said that the book had done ical observations in the living donkey that clearly estab-
more for the arts than anyone of the age.36 lished separate roles for the facial nerve (motion) and
These contributions alone would have merited Bell’s trigeminal nerve (sensation). In support of these obser-
inclusion into the pantheon of great physicians. However, vations, Bell quoted several of his clinical cases. Among
Bell would accomplish much more. In the preface to his other findings, these experiments allowed Bell to clearly
now classic work, The Nervous System of the Human Body differentiate a more potentially serious central facial palsy
(Fig. I-19),37 in which his papers originally read to the from a less serious peripheral injury and allowed him
Royal Society through the 1920s were reprinted, Bell to admonish surgeons to be watchful of the facial nerve
summarized the prevailing attitude toward neurology at when operating in this area. Interestingly, nearly all of
the start of his investigations: Bell’s cases of facial palsy that accompanied this pioneering
work resulted from tumors, purulent infection, or iatro-
“In the period immediately preceding the publication of these geny, and not from what we today would consider Bell’s
papers in the Philosophical Transactions, there was a singular palsy.
indifference to the study of the nerves; and an opinion very gen- Based on the innovative work of Bell, François
erally prevailed that as the notions of the ancients had descended
to us uncontroverted and unimproved, the subject was entirely
Magendie (1783–1855) in France was able to subsequently
exhausted. The hypothesis that a nervous fluid was derived from solve the riddle of the ganglion in the spinal cord. While
the brain, and transmitted by nervous tubes, was deemed Bell and Magendie were initially quite friendly, their
consistent with anatomical demonstrations, and there was no relationship turned sour when each claimed primacy in
hope for improvement.” the discovery of the separate function of the nerve roots.
The debate turned rather rancorous at times.35 History
Despite the anatomic knowledge, physiology of the cranial has been kind to both scientists, however, giving neither
and spinal nerves was limited, and the concept that separate sole credit for the discovery. It is now known as the
nerves would transmit sensory and motor information was Bell–Magendie rule, which in medical literature is used to
occasionally speculated about, but never proven. It was indicate the direction of conduction in the spinal nerve
generally accepted that a nervous fluid circulated along the roots. For a long time it also had the double entendre of
nerves, indifferently one way or the other, acting both for signifying a compromise between the points of view of the
motion and sensation. The function of the ganglia of the older type of anatomist who arrived at function by way of
spinal nerves and of the large ganglion related to the poste- inference and the physiologically minded investigator who
rior root of the trigeminal nerve was still a mystery. insists on experimental verification.
14 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Figure I-19. The frontispiece to The

Nervous System of the Human Body
and illustrations from the work. The
book, which was an embodiment of a
series of lectures delivered to the
Royal Society through the 1920s,
outlined Bell’s theories on the
anatomy and physiology of nerves.
As was the case with all his
publications, all the masterful
illustrations were done by Bell
himself. (From Bell C: The Nervous
System of the Human Body: As
Explained in a Series of Papers Read
before the Royal Society of London,
with an Appendix of Cases and
Consultations on Nervous Diseases.
London, Henry Renshaw, 1844.)

Early 19th-Century Advances Darwin, grandfather of Charles Darwin and a famous

physician in his own right, made an association between
in Vestibular Science vertigo and tinnitus in 1794, but owing to the state of
The understanding of disorders of balance would also knowledge of the time, was limited to observation of the
undergo major advances in the 19th century. The nearly phenomena only.39,40 It was well known that the inner ear
universal belief that vertigo was primarily due to a central mediated sound perception, and a variety of competing
pathology persisted well into the 19th century. Erasmus theories sough to explain how hearing actually takes place.
 The History of Neurotology and Skull Base Surgery 15

The semicircular canals were felt to be an extension of the operation, the animals could still hear, and that the direc-
auditory apparatus, also mediating the sensation of sound. tion of the movements was exactly the same as that of
Autenrieth was probably the first to propose that the the canal that had been divided. Interestingly, Flourens
semicircular canals mediated a sensation other than pure concluded from his results that the semicircular canals
hearing, proposing in 1802 that they were used in deter- influenced the directional movements of pigeons, rather
mining the direction from which sound came.41 J. E. Purkyne than being the organ of equilibrium.46 Furthermore,
(1787–1869) described opticokinetic nystagmus in 1820 Flourens did not make the scientific leap separating the
and classified at least five types of vertigo. Yet he believed, vestibular and auditory functions of the inner ear, believ-
as did the other physicians of his time, that the senses of ing still that both mediated sound perception, with the
motion and acceleration were mediated by cutaneous cochlea being the more essential of the two.41
pressure receptors or alterations in blood flow and that all Flourens’ observations only slowly permeated into the
vertiginous disorders were due to cerebral or cerebellar medical community. Yet it provided the first scientific clue
pathology.42,43 These misconceptions would undergo a that vertiginous disorders were not of a central nervous
radical change over the course of the 19th century, spurred origin, spurring others to study this newly emerging topic.
in part by the monumental changes that were occurring In 1836, for example, Nicholas Deleau pointed out that
throughout the medical community. too often diseases of the ear (though he supposed the mid-
dle ear) were mistaken for diseases of the brain, and
Vestibular Semicircular Canal included vertiginous attacks simulating prodromes of
Physiology: Flourens “apoplexy.”47 Over the following 30 years, many other
investigators reproduced and partially confirmed the results
Working within the flourishing European scientific envi- obtained by Flourens, including Harless, Brown-Sequard,
ronment of the early 1800s, Marie-Jean Pierre Flourens and Czermak. However, none of these men provided revo-
(1794–1867) (Fig. I-20) provided the first scientific clues lutionary breakthroughs (though Brown-Sequard did dis-
that the semicircular canals were intimately involved in the cover labyrinthine calorics without realizing the full
regulation of balance. As a professor of comparative significance of his finding).41,46
anatomy in Paris, Flourens published a series of experi-
ments pertaining to the function of the inner ears, first in The State of Otology and the
1824, and again in 1842 and 1861.6,44,45 In these remark- Neurosciences in the Mid-19th
able series of studies, Flourens demonstrated in pigeons Century
that lesions in the horizontal semicircular canals caused
the animal to turn on its vertical axis, while posterior The middle third of the 19th century was a time of great
canal lesions caused the birds to roll over backwards. From scientific advancement, and medicine and surgery were
his experiments, Flourens observed that even after the developing at an increasingly rapid pace. Despite this, in
the mid-1830s, the treatment of ear diseases was still neg-
lected and disdained by most surgeons. Sir Astley Cooper,
inventor of the myringotomy paracentesis, had abandoned
the ear for general surgery in the early 1800s. Von
Tröltsch, as late as 1863 bluntly stated, “There is scarcely
any department of the science of medicine in which there
is, even at this day, so much ignorance of facts, and such a
want of possessiveness of opinion, as in aural medicine and
surgery.”30 Theodor Billroth echoed these sentiments in
1874 when he wrote that, “ . . . the instruction in diseases of
the ear was in a very bad state. I remember well from my
own student days how the poor deaf people were sent from
one clinic to the other; nobody felt inclined to take any
interest in them. With a few obvious exceptions this field
is therapeutically much too barren.”48 Billroth then stated
that otologic surgery called “. . . for a certain amount of
heroism in a man to sacrifice himself to this, therapeuti-
cally the most thankless and limited, phase of surgery.”48
Most physicians of this time felt as Billroth and von
Tröltsch did; that the ear was complicated, inaccessible,
and dangerous, as demonstrated by the disastrous early
attempts at mastoid surgery resulting in deafness or severe
tinnitus. Though the anatomy of the ear was well described
by this time, its physiology was far from completely under-
stood, and a rational approach to pathology was barely
evident, being little more than that advanced by Valsalva
and Duverney 150 years earlier. All this would be radically
Figure I-20. Marie-Jean Pierre Flourens (1794–1867). (From Politzer A: changed by the great English otologic anatomist-patholo-
A History of Otology, Part I, 1904.) gist, Joseph Toynbee.
16 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Joseph Toynbee and the Origins World War II. The summary of his observations were put
of Modern Aural Pathology forth in his textbook, Diseases of the Ear,50 first published in
1860, which until then was the most comprehensive work
Born in 1815, Joseph Toynbee (1815–1866) (Fig. I-21) was of its kind (Figs. I-22 and I-23). Additionally, Toynbee was
the second of 15 children of a wealthy Lincolnshire farmer. the first to describe stapes footplate immobilization from
At 17 years of age he traveled to London to begin an
apprenticeship. Even at an early stage, he had decided on
aural surgery. At only 23, Toynbee was elected to the Royal
College of Surgeons, based on his well-known dissecting
ability, and he was eventually appointed to a post at the
Hunterian Museum. His subsequent work led to his election
as a fellow of the Royal Society, one of the youngest men
ever to receive the honor.49
From the beginning, Toynbee realized that the paucity
of aural pathology was the primary reason for its relega-
tion to medicine’s backwaters. Toynbee wrote in the intro-
duction of his text, “. . . if we carefully survey the history
of the rise and progress of Aural, as a distinct branch of
Scientific Surgery, one main cause of the disrepute into
which it had fallen may be traced to the neglect of the
Pathology of the organ of hearing—a neglect that doubt-
less led also to the ignorance which has prevailed as to the
structure and functions of some of the most important
of its parts.”50 Toynbee thus became determined at an
early stage of his career to study and dissect every ear he
could possibly lay his hands on. Within 20 years he had
amassed a world-famous collection of over 2000 speci-
mens, which attracted scientists from all over the world.
From this collection Toynbee derived most of his observa-
tions. Though presented to the Hunterian Museum on his
death, the collection was completely destroyed during

Figure I-22. Toynbee’s pioneering work, Diseases of the Ear, first published
in 1860.

Figure I-21. Joseph Toynbee (1815–1866), the founder of aural pathology,

and a master of eustachian tube function. Toynbee was one of the first Figure I-23. Illustrations from Toynbee’s Diseases of the Ear. These include
physicians to correlate the clinical ear exam with pathologic findings. the correct use of the Toynbee tube, and a device termed the explorer for
(From Politzer A: A History of Otology, Part I, 1904.) eustachian tube catheterization.
 The History of Neurotology and Skull Base Surgery 17

otosclerosis, and invented an artificial eardrum made of a available to him in Vienna, Rokitansky’s ambition was clear
disc of India-rubber sandwiched between two small silver and comprehensive:
plates.51 This artificial drum was a design standard for
nearly 100 years, until replaced by tympanoplasty by Zöllner “First . . . sorting the facts scientifically on a purely anatomical
and Wullstein in the 1950s. (Toynbee was not, however, basis and thereby creating the subject of general pathological
the first to propose of an artificial tympanic membrane— anatomy which would justify its separate existence as such . . . sec-
this concept dates back at least as early as 1640.)52 ond, demonstrating the applicability of the facts and their utiliza-
tion for diagnosis in live patients . . .”
(Rokitansky, as translated by Lesky)1
The Vienna Medical School
In the second half of the 19th century the Vienna Medical Slowly through the mid-1800s Rokitansky’s work
School (Fig. I-24) was home to the greatest medical minds permeated almost every branch of medicine, helping to
of the day, a concentration of physicians and scientists provide a pathologic-anatomic basis for specialty after spe-
unequaled in the annals of medicine until then. These cialty, including neurology, dermatology, ophthalmology,
included such notable figures as Billroth, Kaposi, Chiari, pediatrics, and obstetrics. Otology was spared until
Rokitansky, Czermak, Hyrtl, Skoda, Politzer, Barany, Toynbee obtained Rokitansky’s text and proceeded to
Alexander, Zuckerkandl, Ludwig, Gruber, and Brauer. model his studies after Rokitansky’s teachings. Until
According to Henry Hun, a neurologist and author of a Toynbee laid these scientific foundations, otology could
guide for American medical students training in Europe at not advance past the back-alley of medicine it inhabited.
that time, “. . . there is, undoubtedly, no place where a stu- According to Anton Friedrich von Tröltsch (1829–1890)
dent can attend so many excellent clinics with so little loss (Figs. I-25 and I-26), “. . . Toynbee contributed most to this
of time, or where he can so well train his eyes and hands in change (in otology) . . . by his numerous sections of the audi-
methods of diagnosis and treatment, as in Vienna.”53 More tory apparatus, as well as by various contributions to our
directly, Lesky stated that during this seminal time period, anatomical and physiological knowledge of aural disease.”30
“Vienna medicine had become world medicine.”1 Thus, by the 1860s, Rokitansky’s teachings were firmly
Much of this reputation and brilliance centered on in place in otologic medicine. “I need not speak to you,
a pathologist named Karl Rokitansky (1804–1878). gentleman, of the importance of pathologic anatomy, for
Rokitansky’s three-volume Handbuch der Pathologischen medical science, any more than I need to tell you that the
Anatomie, first published in 1842, was the most extensive sun illuminates the earth over which it shines. We have
pathologic-anatomic text ever written and was referred to already seen how late it was in the history of aural medicine
by Heyfelder of Erlangen as “. . . one of the noblest prod- and surgery before pathological investigation of the ear was
ucts of medical literature.”1 Virchow, champion of the cel- undertaken, and that the slow and late development of this
lular theory and the father of modern physiology, would part of our science resulted as it necessarily must, from this
later base his life’s work on many of the principles founded neglect of the appearances of the organ on the cadaver,”
by Rokitansky. Utilizing the wealth and variety of material wrote von Tröltsch in 1869.30 After Toynbee’s immense

Figure I-24. The Vienna Medical

School in the late 1800s, home to the
greatest physicians in the world at
that time. (From Lesky E: The Vienna
Medical School of the 19th Century.
Baltimore, The Johns Hopkins
University Press, 1976.)
18 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Figure I-25. Anton Friedrich von Tröltsch (1829–1890), one of the founders
of modern otology. In addition to his influence on most great otologists
of the 19th century, von Tröltsch was also a master otologic anatomist
(remembered for the pouch of von Tröltsch) and introduced the concave
head mirror now used by otolaryngologists the world over.

otologic work, the stage was set for someone to master both Figure I-26. The title page to Anton Friedrich von Tröltsch’s highly influential
the clinical and pathologic-anatomic facets of the burgeon- otology textbook, Krankheiten des Ohres, published in 1862.
ing field of otology and create an independent specialty.

Adam Politzer—The Father of Otology

While Toynbee was laying the foundations for aural pathol-
ogy in England, otology was transforming itself from a
discipline in surgery to a subspecialty in its own right in
Vienna under the direction of one of the most influential
otologists of all time. If anyone can rightly be called the
“father” of otology, it must be Adam Politzer (1835–1920)
(Fig. I-27). Without diminishing the work of such great men
of the time as Schwartze, Gruber, and von Tröltsch, Politzer
was the charismatic leader of this newly emerging specialty.
Adam Politzer was born in Alberti, Hungary, in 1835,
the son of a successful Jewish merchant. Following in
his grandfather’s footsteps, he became a physician after
graduating from the University of Vienna in 1859, spend-
ing time as a special pupil of Skoda, Ludwig, and
Rokitansky.54 Under the influence of Rokitansky’s teach-
ings in Vienna, Politzer realized that the only way to
advance the field of otology was to become a master of
aural morphology. For the next several years Politzer trav-
eled throughout Europe to study under the leaders of the
field. He spent time in Würzburg, the leading center for
microscopic research in the world at that time, under
Kölliker, Müller, and von Tröltsch. Politzer also spent time
in London studying Toynbee’s famous collections of
specimens, and under Ménière and Bernard in France,
where the clinical-anatomic revolution started earlier in Figure I-27. Adam Politzer (1835–1920), the “father” of otology.
 The History of Neurotology and Skull Base Surgery 19

the century by Cruveilhier was still exerting influence.32

This extensive background made Politzer one of the great
masters of specimen preparation technique at that time.
His rapidly expanding collection of temporal bones was soon
almost as large as Toynbee’s and was in demand through-
out Europe.
Politzer’s mission, a direct extension of Rokitansky’s
teachings to establishing a correlation between the find-
ings of his dissections and true clinical findings, had been
partially realized by Toynbee, Wilde in Dublin, and von
Tröltsch in Würzburg. However, none of these men had
access to the tremendous wealth of pathology offered by
the Vienna General Hospital, caring for 3 to 4 thousand
patients at any given time.53 While giving ample credit to
his predecessors and contemporaries, Politzer went on to
define a specialty. He completely characterized a whole
series of diseases previously grouped under the vague
heading “dry middle ear catarrh.” He was the first to
define panotitis, leukemia of the ear, labyrinthine suppura-
tion, and established that a cholesteatoma was related to an
ingrowth of squamous epithelium. His textbook Lehrbuch
der Ohrenheilkunde (Textbook of the Diseases of the Ear
and Adjacent Organs)55 originally published in 1878,
was in its fifth edition by 1908, had been translated into
multiple languages, and was used the world over as the
standard of otologic practice. Politzer, along with his col-
league Joseph Gruber, had made Vienna the premier des-
tination for otologic training in the world at that time and
had established otology as a respectable specialty.
In 1863, together with von Tröltsch and Schwartze,
Politzer started the Archiv für Ohrenheilkunde (Archives
of Otology), the first journal dedicated to disorders of the Figure I-28. The 50th anniversary title page of the Archiv fur Ohrenheilkunde
ear, and later founded the Austrian Otological Society (Archives of Otology), the first journal dedicated to disorders of the ear.
(Fig. I-28). Politzer was a talented artist who spent his The three founders of the journal are depicted: Adam Politzer, Anton Friedrich
von Tröltsch, and Hermann Schwartze.
evenings drawing findings from his immense collections.
His unexcelled knowledge base and superb teaching abili-
ties made him a revered professor. He could teach with
equal fluency in German, English, French, and Italian.
He had a mild manner was said to be unfailingly courteous,
winning him the affection of all who visited him at his clinic.
On Politzer’s retirement from teaching in 1907, he received
a farewell message from his students, which carried the
names of 366 otologists from 21 countries and included
every prominent otologist in the world at that time.54
Politzer was truly one of the finest men to grace the field of
otology and has left a lasting mark which is still felt today.

Elucidation of the Organ of Corti

Marquis Alfonso Corti (1822–1888) (Fig. I-29) was born into
an ancient noble Italian family in the state of Lombardy.
Scarpa, who died when Corti was only 10 years old, was a
family friend and great influence on Corti. Political upheaval
and wars in Italy and France forced Corti to travel abroad
and eventually settle in Würzburg, where most of his inves-
tigations on the anatomy of the inner ear were carried out.
There he developed a close friendship with the great pathol-
ogist Virchow and took part in Virchow’s wedding.9,56
In 1850 Corti described for the first time the sensory
epithelium, the spiral ganglion, the tectorial membrane,
and the stria vascularis of the inner ear. These results were Figure I-29. Marquis Alfonso Corti (1822–1888), for whom the organ of
published in the Zeitschrift für Wissenschaftliche Zoologie in Corti is named.
22 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

involved with helping start the first journal dedicated and Erlangen, graduating in 1866. Although initially an
solely to the ear, Archiv für Ohrenheilkunde, in 1863 along ophthalmologist, training under the great, pioneering eye
with von Tröltsch and Politzer. Schwartze eventually suc- surgeon von Graefe, he subsequently studied pathologic
cumbed to a nervous condition of restlessness, vertigo, and principles under the direction of Virchow. From 1866
delusions, dying of heart failure at the age of 73. onward, he lived and taught in Munich under the tutelage
It was Schwartze’s mentor, von Tröltsch, who was respon- of von Tröltsch where he studied the ear while practicing
sible for urging Schwartze to fully develop a method of ophthalmology.32 Von Tröltsch was so influential to the
treatment for suppurative processes of the temporal bone. young Bezold, that he is repeatedly cited in Bezold’s text.
In 1863, Schwartz published his influential work on the According to Bezold, von Tröltsch’s text was the “codex” of
indications for the mastoid operation and his success otology. “. . . There is hardly a part of our branch which
with the use of specifically designed chisels and gouges (see v. Tröltsch did not enrich with new and fruitful views.”67
Fig. I-33).64 According to Whiting, an American otologist In 1878, Bezold published his findings pertaining to coa-
in 1911, through this publication Schwartze had, lescent mastoiditis leading to an abscess.66 The manuscript
“. . . clearly enunciated the technical and symptomatic itself described in intricate detail the ways in which a
principles upon which are based the steps of the modern coalescent mastoiditis could spread beyond the mastoid.
mastoid operation as performed to-day (sic), and however In the introduction of this manuscript, Bezold outlined the
much we may modify our practice the innovations result in prevailing lack of clinical information on the topic: “It used
a little more or a little less than Schwartze’s operation . . .”65 to be that the diseases of the mastoid were exclusively seen
Later, in 1889 Stacke and subsequently Zaufal in 1890 as in association with diseases of the tympanum. Because of
described the radical mastoid operation.23 this there is little in the otologic literature concerning
the pathology of mastoid disease as a primary process.” He
The Pathophysiology of Coalescent then went on to describe a case of a 6-year-old boy, who
developed a coalescent mastoiditis from a cholesteatoma
Mastoiditis: Friedrich Bezold (which he termed an epidermoid mass) 16 years after his
It was also during this seminal time period that Friedrich original presentation. Additionally, he reviewed the world
Bezold (1842–1908) (Fig. I-34) published his findings per- literature up to that time on disease processes of the mas-
taining to coalescent mastoiditis leading to an abscess.66 toid that spread to contiguous areas. Bezold would later
Bezold was born in Rothenburg an der Tauber (in modern describe the course of mastoid inflammation and infection.
day Bavaria). He studied medicine throughout the However, it was not until 3 years later in 1881 that he
Germanic states, including München (Munich), Würzburg, would publish a paper specifically pertaining to a mastoid
infection leading to a neck abscess, which was translated
in a short review by the American Journal of Otology that
same year.68 In the manuscript, Bezold correctly described
the pathway of extension through the digastric groove.
Bezold arrived at these conclusions by boring through the
mastoid into the digastric groove in cadavers, forcibly
injecting colored gelatin, and studying where it had infil-
trated into the neck. Bezold then recommended treatment
of the disease based on his studies: “. . . perforating the
digastric groove through the mastoid cells, entering the
cells at the lower part of the mastoid process, and extend-
ing the opening into the incisura mastoidea.” He then
presented a case treated in this fashion, which was healed
in 14 days. Years later Bezold acknowledged in his text-
book (as translated by Hollinger in 1908), “They (coalescent
mastoiditis leading to a neck abscess) produce a very distinct
clinical picture . . . and in literature are often called
Bezold’s mastoiditis, because I studied its development
experimentally on the cadaver.”67

Sir William Macewen: The First Skull

Base Surgeon?
If one man can be named the first true skull base surgeon,
then surely Sir William Macewen is he. Once called the
founder of neurosurgery by Harvey Cushing, and “the
unfair surgeon,” by others for his exhaustive work ethic,
leaving little behind for “. . . aftercomers to improve or
amend,” Sir William Macewen (1848–1924) (Fig. I-35) left
Figure I-34. Friedrich Bezold (1842–1908), the German otologist who
behind a legacy still felt today.69,70 Macewen was born on
thoroughly described the complications of suppurative mastoiditis, including the Scottish Island of Bute, the youngest of 12 children. As
the “Bezold’s abscess,” a coalescent mastoiditis with extension into the neck. the son of a master mariner, the young Macewen learned
 The History of Neurotology and Skull Base Surgery 23

“. . . nothing short of extraordinary,”72 and “. . . one of the

most remarkable books ever written on a neurosurgical
subject.”73 Certainly, one can claim that it is also one of
the most remarkable books ever written on a neurotologic
subject. In the monumental work he described 94 cases of
intracranial infections and reported such extraordinary
results as successful evacuation of a brain abscess in 21 out
of 22 cases (Fig. I-36). As later pointed out by Jefferson,
Macewen may deserve the honor of the first clear descrip-
tion of mastoiditis.74 Macewen reported on 54 mastoidec-
tomies for infections confined to the middle ear and
mastoid, and a separate listing of mastoidectomies in which
extension into the cranium occurred. As a surgeon who was
“. . . as familiar and at home operating on the head and
brain, as a clinician educated by past experience to recog-
nize the signs of brain disease, and as an anatomist who had
made a special study of the ear, he was triply armed imme-
diately to follow the clues given him by the state of the
patient or local extensions of the disease.”74 For these
reasons, Macewen must be considered the first true skull
base surgeon, equally versed in operations of the ear and
brain, and pathologic processes affecting both. It is perhaps
because of Macewen’s residence in Glasgow, some distance
from the epicenter of British medicine in London, that
he felt his accomplishments went unrecognized in his
Figure I-35. Sir William Macewen (1848–1924), perhaps one of the first true
skull base surgeons. He pioneered aseptic surgery of the brain and temporal
lifetime.75
bone. In his later years, Macewen became an elder statesman
of surgery. He was president of the British Medical
Association, president of the International Society of
Surgeons, and the surgeon to the king in Scotland. He was
to use tools and to work with his hands at an early age. He invited to become the chair of surgery at the newly estab-
joined the Glasgow Medical Faculty in 1865 and began his lished Johns Hopkins Medical School in 1889, but an
surgical work the same time Joseph Lister carried out his agreement was not reached and Halstead was ultimately
revolutionary antiseptic research. Lister was Macewen’s appointed instead. Macewen died after a severe case of
premier influence as a young faculty member and was pneumonia in 1924 at the age of 76.70,76,77
instrumental in Macewen’s pioneering work in surgical
antisepsis. Victor Horsley and the Birth
In his now classic, Pyogenic Infective Diseases of the Brain
and Spinal Cord, Macewen outlined his technique of treat-
of Neurosurgery
ing otogenic intracranial complications.71 His results were It wasn’t just otology that had defined itself as a unique
so extraordinary for the era, they were unequaled until the subspecialty in the later half of the 19th century.
era of computed tomography and have been deemed, Neurosurgery, the second pillar of neurotology and skull

Figure I-36. Illustrations from

Macewen’s classic medical master-
piece, Pyogenic Infective Diseases
of the Brain and Spinal Cord. The
illustration shows two children with
acute subperiosteal squamomastoid
abscesses. (From Macewan W:
Pyogenic Infective Diseases of the
Brain and Spinal Cord. Glasgow,
Scotland, James Maclehose & Sons,
1893, p 9.)
24 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

base surgery, also saw its nascent beginnings during this London operated on a tumor that had been diagnosed and
time. The National Hospital for Nervous and Mental localized to the right motor cortex by the neurologist
Diseases, located on Queen’s Square in London, is consid- Alexander Bennett.75,80 Although brain tumors had been
ered by most to be the birthplace of neurologic surgery. removed previously, Bennett’s localization of the tumor
Although Macewen was clearly one of the stars of this and Godlee’s first use of antiseptic technique during tumor
emerging field, his practice in distant Glasgow limited his surgery made the case quite extraordinary. Using Bennett’s
influence among his contemporaries. The National knowledge of neuroanatomy and pathophysiology, Godlee
Hospital hosted such luminaries as Charles-Édouard was able to plan his craniotomy directly over the tumor,
Brown-Séquard, John Hughlings Jackson, and Sir William and easily remove the tumor, which turned out to be a
Gowers, making it the center for neurologic studies in glioma. The patient survived the immediate operation, but
the world at that time. However, the most famous surgeon succumbed to purulent cerebritis a month after surgery.
to grace the hospital staff was also credited with the found- The case is noteworthy for overcoming the third most
ing of modern neurologic surgery: Sir Victor Horsley challenging obstacle, following anesthesia and asepsis, that
(1857–1916) (Fig. I-37). A contemporary of Macewen’s faced the development of neurosurgery; tumor localiza-
and also credited with some of neurosurgery’s earliest tion. With this obstacle overcome, employing the help of
successes, it was Horsley’s, “. . . indefatigable physiological neurologists such as Bennett, neurosurgical advances
experimentation in addition to his clinical and pathologi- accelerated. Godlee’s case is noteworthy also from the
cal experiments,” that has led to his inclusion in neuro- standpoint of who attended the operation: the neurologist
surgery’s pantheon.72 Horsley was also the first surgeon Hughlings Jackson, the neurosurgeons Victor Horsley and
ever to devote a majority of his efforts to neurosurgery. His David Ferrier, and Joseph Lister (Godlee’s uncle) were
contributions to neurosurgery included the first laminec- reported to be there.75
tomy for a spinal neoplasm, the first carotid ligation for
aneurysm, the first transcranial approach to the pituitary, Sir Charles Ballance: Pioneering Skull
pioneering intracranial trigeminal nerve sectioning for Base Surgeon
neuralgia, and the use of bone wax to stem bleeding from
bone, to name but a few of his many accomplishments.78 Along with Victor Horsley, Sir Charles Ballance (1857–1936)
According to Cushing, after Horsley was appointed surgeon (Fig. I-38) was another of the pioneering British neuro-
to the, “. . . National Hospital for the Paralyzed and logical surgeons. Neurotology and skull base surgery can
Epileptic, Queen Square, the birth of modern neurologic also claim Ballance as one of its instrumental founders as
surgery may properly be assumed to have taken place.”79 well, based on his landmark surgical advances within the
Victor Horsley was present at what is widely considered temporal bone. Born in Middlesex, England, Ballance
the first modern brain tumor surgery. In 1884, Rickman entered medical school in 1875 at St. Thomas’ Hospital in
Godlee at the Hospital for Epilepsy and Paralysis in London. As one of the stars of his medical school class,

Figure I-38. Sir Charles Ballance, a pioneering neurotologist and skull base
Figure I-37. Sir Victor Horsley (1857–1916), the father of neurologic surgeon. (From Shambaugh GE: Surgery of the Ear. Philadelphia,
surgery. (From Paget S: Sir Victor Horsley. New York, Harcourt, 1920.) WB Saunders, 1967, with permission.)
26 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

be predicted that as the mastoidectomy became popular for the first time the disease that now bears his name. Born in
treating mastoid suppuration after its introduction by the southwest of France, Mèniére completed his medical
Schwartz,64 the number of iatrogenic facial nerve injuries studies at the Hotel-Dieu in Paris, where he was closely
also rose, providing a further spur to facial nerve surgery influenced by Guillaume Dupuytren and later by Itard,
repair. It is no coincidence that the first report of a facial one of the leading otologists in Europe at that time. After
nerve crossover repair was reported by Drobnik in 1879, receiving his doctorate in 1828, he took up a position as
only 6 years after Schwartz’s publication.89 As noted by assistant professor of the Paris Faculty of Medicine, later
Duel in 1933 in his historical retrospective, “. . . unskilled to become a fellow of the university. In 1848, Mèniére
surgery of the temporal bone brought with it an ever began a French translation of a German textbook on hear-
increasing number of cases of accidental paralysis.”90 Sir ing loss by Kramer.92,93 Within this translation, Mèniére
Charles Ballance had tremendous influence on facial nerve added a footnote that mentioned a case of labyrinthine
surgery during this time, with his introduction of a spinal hemorrhage resulting in sudden deafness.94 This was, in
accessory-facial nerve crossover anastomosis in 1895, as fact, the same case report he would describe 13 years later
well as the first reported attempt at rerouting the facial in his now classic description of endolymphatic hydrops.
nerve intratemporally.26,91 Several other surgeons also In 1861, in a series of reports before the Paris Academy
attempted facial nerve crossover operations during this of Medicine, Mèniére described a group of patients with
time, including Faure, Kennedy, and Cushing.89 Over the the symptoms of vertigo, nausea, and vomiting, and
course of the next 25 years, nearly all the lower cranial sought, “. . . to attribute vertigo and falling to lesions dif-
nerves would be used as possible crossover grafts to the ferent from those which have their site exclusively in the
facial nerve, and controversy surrounded whether to per- brain, and as a consequence to institute a rational treat-
form end-to-end versus end-to-side anastomoses, issues ment for these affections, for too long a time confused
which are still debated today. under a single title.”95 In these seminal reports, Mèniére
described a series of patients with neural deafness, with the
hearing loss greater in the low frequencies, and though
Scientific Advancement in Vestibular sometimes bilateral, mostly the occurrence was unilateral.
Physiology in the late 19th Century: He noted that the ear exam was nearly always normal, and
Prosper Mèniére and the First that the symptoms of tinnitus, vertigo, nausea, and vomit-
ing stopped when the hearing was completely lost, typi-
Description of Ménière’s Disease cally after many years. He also reported worsening of the
In one of the first great advances in understanding vestibu- condition with quinine. To illustrate his basic point that
lar physiology in the later portion of the 19th century, vertigo, nausea, and vomiting may be due to an inner ear
Prosper Mèniére (1799–1862) (Fig. I-40) described for disorder, he again presented the case of the young girl
whom he footnoted in his translation of Kramer’s work
13 years previously, but in even greater clinical detail. The
girl had a sudden onset of complete deafness, vertigo, nau-
sea, and vomiting, dying after 5 days of close observation.
After a pathologic exam demonstrated no evidence of a
central nervous system lesion, Mèniére himself examined
the temporal bones. He identified a blood-tinged exudate
within the semicircular canals, but not within the cochlea.
Then, citing Flourens’ work from 33 years earlier,
Mèniére asserted, “. . . that the symptoms which appear in
man and which consist of vertigo, nausea, the syncopal
state, which is accompanied by ear noises, and which has
deafness as its consequence, may depend on an alteration
which has as its site that portion of the labyrinth of which
we have spoken” (translation by Williams).96 Mèniére later
published the remainder of his observations in several
reports, the last on September 21, 1861.26 Though contro-
versy surrounded his report after his death, Ménière’s
principle and noteworthy accomplishment was to establish
that the combination of vertigo, hearing loss, nausea, and
vomiting has as their basis an inner ear pathology.96
Despite Flourens’ earlier observations and Ménière’s
accomplishments however, there was still prevailing
confusion on the precise mechanisms of balance control
within the medical community in the later half of the 19th
century. This reflected, more than anything else, a lack of
understanding of vestibular physiology. Friedrich Leopold
Figure I-40. Prosper Mèniére (1799–1862), the first to establish that the
Goltz (1834–1902) (Fig. I-41), a scientist from Strasbourg,
combination of vertigo, hearing loss, nausea, and vomiting has as their basis took the next large step to change this, ushering in the next
an inner ear pathology. (From Politzer A: A History of Otology, Part I, 1904.) leap in the understanding of the labyrinth. In 1870, Goltz
28 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

reviewed by Jackler, at an international conference of neu- decisions to operate, rather than relying on medical physi-
rosurgeons, mortality for these operations was 78%, and cians or neurologists.107 Cushing made meticulous, ana-
most survivors had serious disability.106 However, these tomically based surgical technique fashionable, rather than
statistics would be radically changed by the most influen- reliance on speed. Of course, this was made possible by his
tial neurosurgeon of the 20th century, Harvey Cushing. improved technical advances such as hemostasis and insis-
tence on superior anesthesia. So pervasive was his instruc-
Harvey Cushing: The Founder tion, that to this day, nearly all American-trained neurologic
surgeons can somehow trace their legacy back to Cushing.
of Modern Neurosurgery Cushing’s advances within the field of skull base surgery
There is perhaps no one in the annals of neurologic sur- are equally monumental, particularly with regard to the
gery about whom more has been written than Harvey treatment of acoustic neuromas. After realizing that the
Cushing (1869–1939) (Fig. I-42), a man whose name is tumors could not be completely removed by current stan-
synonymous with the field. His personality and accom- dards, he advised intracapsular removal of the tumor and
plishments are the stuff of legend. subtotal resection (Fig. I-43).109 Combined with his other
Born the youngest of 10 children in a long line of physi- technical advances, this approach enabled Cushing to reduce
cians, Cushing followed his father, grandfather, great-grand- surgical mortality from near 90% to 20%, as noted in his
father, and great-great-grandfather’s path into medicine. classic monograph, Tumors of the Nervus Acusticus and the
After an undergraduate education at Yale, he studied med- Syndrome of the Cerebello-Pontine Angle, published in 1917.110
icine at Harvard Medical School. He subsequently went to By 1920, Cushing had redefined the specialty of neuro-
Johns Hopkins University to train under the pioneering logic surgery, with its emphasis on a strong foundation
surgeon Halsted, where he was also exposed to the other of neurologic training. According to Greenblatt, “. . . with
medical icon of that era, Sir William Osler. From Johns further demonstration of his successes in training, in ther-
Hopkins and later at Harvard, Cushing would revolution- apeutic results, and in research productivity, the Cushing
ize the field of neurosurgery. He introduced the concept of model became the world model.”108
meticulously documented anesthesia records and the use of
continuous intraoperative blood pressure monitoring. He Nylén, Holmgren, and the Birth
was perhaps the first surgeon to make regular use of the of the Operating Microscope
new technology of x-rays, including making the emulsions
and developing the films himself. He described the While Cushing was laying the foundations for modern
“Cushing response,” the physiologic changes induced by a neurologic surgery in America, two unassuming Swedish
rise in intracranial pressure. He performed pioneering surgeons were developing a technology that would ulti-
work in balanced salt solutions that led to modern intra- mately revolutionize the fields of otology, neurotology,
venous therapy. He pioneered transsphenoidal pituitary skull base surgery, and neurosurgery.
surgery. He revolutionized surgical training by introducing
canine surgery for medical students. He radically improved
intracranial hemostasis with the development of surgical
clips and electrocautery, and with it, drastically improved
surgical morbidity during neurosurgical procedures.75,107,108
In addition to these “technical” advances, Cushing
radically changed the practice of surgery. He insisted that
surgeons take responsibility for their own diagnoses and

Figure I-43. Illustrations from Cushing’s landmark treatise, Tumors of the

Nervus Acusticus and the Syndrome of the Cerebello-Pontine Angle, 1917,
demonstrating his technique of vestibular schwannoma tumor removal,
Figure I-42. The “father” of modern neurological surgery, Harvey Cushing. leaving the tumor capsule intact. (From Cushing H: Tumors of the Nervus
(Courtesy of the Alan Mason Chesney Medical Archives, Johns Hopkins Acusticus and the Syndrome of the Cerebello-Pontine Angle. Philadelphia,
University.) WB Saunders, 1917.)
 The History of Neurotology and Skull Base Surgery 29

The operating microscope evolved out of the optics of meeting of the Swedish Otolaryngologic Society and again
the microscope originally pioneered by Robert Hooke and in Paris in July of that same year.114
Anton van Leeuwenhoek in the mid-1600s. Yet it was the Unfortunately, after his initial contribution of the
inherent constraints of ear surgery that led to development monocular operating microscope, Nylén found himself
of a microscope uniquely suited to the operating room. unable to continue to develop the instrument in the clinic
Otology and neurotology were uniquely poised for this of his chief, Gunnar Holmgren (Fig. I-45), where tradition
transition because of the difficulties imposed by the micro- and custom dictated that the chief alone could carry out
scopic anatomy of the inner ear, limiting what ear surgeons the new, and still experimental otosclerosis surgery, one of
could do by unmagnified eyesight alone. Furthermore, with the primary applications of the new “otomicroscope.”
the development of improved anesthesia at the beginning Holmgren was already known for having introduced the
of the 20th century, the need for more precise surgical operating loupes to ear surgery and thus already had a sub-
technique within otology, as championed by Cushing in stantial appreciation for the need of magnification during
neurosurgery, became paramount. these procedures. After seeing his assistant Nylén use the
Carl-Olaf Nylén (Fig. I-44) was an assistant in the operating microscope, Holmgren immediately recognized
University Otolaryngology Clinic in Stockholm under the the added advantages of the microscope over loupes
chief Gunnar Holmgren in the early 1920s. Prompted by during these cases. However, Holmgren didn’t simply
Maier and Lion’s report of endolymph movements in copy Nylén’s idea—he significantly advanced it and gave
the living pigeon using a low-power microscope,111 Nylén ample credit for the idea to his assistant. In one of his
began work on a higher power microscope that could be publications, he stated, “. . . following a good idea of my 1.
used during ear surgery. Such a device would have direct Assistant surgeon Dr. Nylén I tried a microscope and
relevance to Nylén’s primary clinical interest of study— found the Zeiss binocular microscope a very suitable
labyrinthine fistulas.112 instrument . . .”115 To the Zeiss binocular, ophthalmologic
Nylén’s first monocular microscope was developed by scope, Holmgren added a light source and support suitable
the Brinnell-Leitz factory (see Fig. I-44, right). Nylén later for the operating theater and began using it that same year,
recalled his initial use of the microscope, in 1922 (Fig. I-46).115 Compared with Nylén’s monocular
scope, Holmgren had developed an entirely new and revo-
“The idea of using a larger magnification than had previously lutionary binocular operating microscope.
been employed, occurred to me early in 1921 when I was exper- In his initial description of the uses of the operating
imenting with labyrinthine fistula operations on temporal bone
preparations from human beings and in living animals. . . . In
microscope in the temporal bone, Holmgren enthusiasti-
November 1921 I used the Brinell microscope for observations cally presaged its benefit in ear surgery, stating that the
and operations in two cases of chronic otitis with labyrinthine fis- advantages of using the microscope for radical operations
tulas, and in one case with bilateral pseudo-fistula symptoms.”113 on otitis, “. . . are indeed so obvious that no operator, who
has had experience of the lens will give it up when doing
Nylén later modified the scope with the help of his this operation.”115 Holmgren’s words are prescient indeed,
friend and engineer Persson so it could more easily mount as any current otologic, neurotologic, skull base surgeon
on the patient. These results were reported in 1922 at the or neurosurgeon will attest! Additionally, Holmgren

Figure I-44. Carl-Olaf Nylén (left)

and his first monocular microscope
(right). (From Dohlman GF,
Arch Otolaryngol 90:161–165, with
permission.)
30 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Figure I-45. Gunnar Holmgren, Nylén’s chief at the University Otolaryngology

Clinic in Stockholm, who significantly improved the operating microscope. Figure I-47. Walter Dandy (1886–1946). (Courtesy of the Alan Mason
(From Shambaugh GE: Surgery of the Ear. Philadelphia, WB Saunders, 1967, Chesney Medical Archives, Johns Hopkins University.)
with permission.)

Walter Dandy
employed what he termed, “. . . a little circular cutting file, At approximately the same time Nylén and Holmgren
viz., one driven by a little electro-motor of the type which were introducing the operating microscope to aural sur-
is often used by dentists, armed with the very smallest gery, one of Cushing’s protégé’s was carrying on the trans-
drills obtainable, which are sufficiently small to make it formation of neurosurgery started by his mentor. Walter
possible that even very delicate bone operations can be Dandy (1886–1946) (Fig. I-47), perhaps Cushing’s most
carried out in the utmost safety under the guidance of the accomplished student, is clearly responsible for ushering in
eye.”116 This was perhaps the first application of the drill the next great leap in neurotologic, neurosurgical, and
for aural surgery and has to be regarded as a seminal event skull base surgery.
in the history of neurotology and skull base surgery. Passing up a Rhodes Scholarship to enter Johns
Hopkins Medical School, Dandy would go on to redefine
the specialty of neurosurgery. After graduating medical
school, he was appointed by Halsted to surgery, and spent
his first year in the Hunterian Labs where Cushing was
carrying out his physiologic experiments. There the two
giants developed a contentious relationship almost from
the start. At one point, Dandy accused Cushing (appar-
ently with some justification) of not being, “. . . a real
scientist.”117 It is no surprise, therefore, that when Cushing
left Johns Hopkins to take over the new neurosurgical
department at Brigham Hospital in Boston in 1912, Dandy
was not asked to join the team. Furthermore, the animosity
did not entirely dissolve after Cushing’s departure; accord-
ing to Greenblatt, “. . . Cushing often remained jealously
suspicious of anything that issued . . .” from Dandy’s work
at Hopkins.108
If great minds truly do clash, then the squabbles
between Cushing and Dandy should come as no surprise.
For as much as Cushing transformed the landscape of neu-
Figure I-46. Gunnar Holmgren is shown using binocular operative rologic surgery, Dandy would nearly rival his teacher’s
microscope, from his 1922 monograph, “Operations on the temporal bone
carried out with the help of the lens and the microscope.” (From Holmgren G:
accomplishments while at Johns Hopkins. Perhaps Dandy’s
Operations on the temporal bone carried out with the help of the lens and the greatest accomplishment came while he was still in his
microscope. Acta Otolaryngol 4:383–393, 1922.) training years. In 1918 he reported on ventriculography by
 The History of Neurotology and Skull Base Surgery 31

the injection of air into the cerebral ventricles.118 The century, knowledge of Ménière’s disease had progressed
effect on the field of neurosurgery was enormous, for it little since Ménière’s original description nearly 40 years
allowed the direct localization and size estimation of brain earlier. Many vertiginous disorders were still confusingly
tumors for the first time. According to Horrax, “It brought grouped together, and therapy was based on empiricism
immediately into the operable field at least one third more and anecdotal reports. For example, Crockett in 1903
brain tumors than could be diagnosed and localized previ- attempted to remove the stapes in two patients with
ously by the most refined neurological methods.”72 One Ménière’s disease, which lead to complete deafness. A year
year later he introduced pneumoencephalography. later Lake opened the semicircular canals in a Ménière’s
Dandy’s influence upon neurotology and skull base sur- patient and instilled an antiseptic solution.123,124 This lack
gery was equally profound. In 1917 he reported on the first of a rational approach to Ménière’s disease was in part due
successful total excision of an acoustic neuroma.119,120 to the poor state of vestibular diagnosis. This would be
Whereas Cushing had advocated leaving the capsule intact radically changed by the eminent physician-scientist
to minimize surrounding brain injury, bleeding, and facial Robert Bárány (1876–1936) (Fig. I-49). Barany fundamen-
paralysis, Dandy recommended total excision (Fig. I-48). tally advanced our understanding of vestibular physiology
This departure from his former teacher’s doctrine reportedly during the first part of the century. Bárány initially trained
left Cushing infuriated.117,121 Reports extending into the under Adam Politzer. Working at the University of Vienna,
1940s followed Dandy’s subsequent practice of the suboccip- Barany introduced into the clinical exam caloric testing,
ital approach for complete acoustic neuroma resection.122 rotational testing, galvanic testing, and the air-fistula test.46
Dandy’s influence on neurotology and skull base sur- He correlated various forms of nystagmus with vestibular
gery would not end with his achievements in vestibular pathologies and explored the relationship between the
schwannoma resection. As discussed later on, his influence semicircular canals and the central nervous system. His
on the treatment of Ménière’s disease was equally important. new methods of examination enabled the clinician to
However, to better understand the import of these advances, differentiate between eighth nerve tumors, vestibular
it is necessary to understand the advances that were simul- neuronitis, and other forms of nystagmus. Much of this
taneously occurring in the vestibular sciences in the early work was outlined in his classic work, “Untersuchengen
part of the 20th century. über den vom Vestibularapparat des Ohres reflektorisch
ausgelosten rhythmischen Nystagmus und seine Begleiter-
Advances in Vestibular Science scheinungen,” published in volume 40 of the Monatschrift für
Ohrenheilkund.46,125 For his achievements, Bárány received,
in the Early 20th Century among numerous other international awards, the Nobel
Even with the rapidly accumulating data on the structure Prize in medicine 1915. Tragically, due to professional
and function of the vestibular apparatus, at the turn of the jealousy and religious prejudice, he was accused by his

Figure I-48. Dandy’s technique of

tumor excision, from his monograph,
“Results of removal of acoustic
tumors by the unilateral approach,”
published in 1941. (From Dandy WE:
Results of removal of acoustic
rumors by the unilateral approach.
Arch Surg 42:1026–1033, 1941.)
32 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

Figure I-49. Robert Bárány. (From Pappas DG: Bárány’s History of Vestibular Figure I-50. Georges Portmann, a pioneer in surgery of the endolymphatic
Physiology: Translation and Commentary. Ann Otol Rhinol Laryngol 93:1–16, sac for Ménière’s disease. (From Shambaugh GE: Surgery of the Ear.
1984.) Philadelphia, WB Saunders, 1967, with permission.)

colleagues in Vienna of plagiarism. He was eventually According to Portmann himself, “I was pleased that
inducted into the Austrian army during World War I. He I had dared to carry out the first operation on the inner ear
learned of his award of the Nobel Prize while a Russian to decompress the membranous labyrinth by opening the
prisoner in 1915. The Swedish Red-Cross had to exchange endolymphatic sac in an attempt to relieve vertigo and pre-
him for a high-ranking Russian officer so he could deliver serve, not destroy, hearing.”127 It was considered the first
his Nobel lecture. He thereafter shunned his former successful operation for Ménière’s disease. Although
Viennese colleagues, spending the remainder of his pro- endolymphatic sac decompression would not become
fessional life at the University of Uppsala in Sweden.46 popular in the United States for another 20 years, a new
era in neurotology had begun.
Georges Portmann and the
Endolymphatic Sac
Bárány’s work inspired a generation of vestibular clinicians
and scientists. Among those influenced by Bárány was
Georges Portmann, from Bordeaux, France (Fig. I-50).
Based on earlier work he performed in fish in the early
1920s and the belief that increased pressure within the
endolymphatic sac produced Ménière’s syndrome, Portmann
proposed a new method for treating the disease by opening
the endolymphatic sac.126 He based his operation on: (1)
other’s research in rabbits that demonstrated changes in
endolymphatic sac pressure (including opening the sac)
causing changes in limb tonus; (2) the analogy of Ménière’s
disease with ocular glaucoma, termed aural glaucoma, as
advanced by Knapp in 1871; and (3) Guild’s research 1 year
previously demonstrating the endolymphatic sac as an
organ of endolymphatic fluid filtration. Portmann pro-
posed a transmastoid opening of the endolymphatic sac
with a small knife to relieve the pressure from Ménière’s
syndrome (Fig. I-51). The operation was first attempted
on January 18, 1926, on a patient with Ménière’s disease
and extremely severe vertigo. The patient reportedly Figure I-51. An illustration from Georges Portmann’s endolymphatic sac
had complete resolution of vertiginous symptoms. operation demonstrating his technique.
 The History of Neurotology and Skull Base Surgery 33

Reemergence of the Operative

Intervention for Ménière’s Disease in
the 1930s and 1940s: Walter Dandy’s
Vestibular Nerve Section
Walter Dandy (1886–1946), though he stated that he ini-
tially began sectioning the eighth cranial nerve for patients
with vertigo as early as 1912, started selectively sectioning
the vestibular nerve beginning around 1930.128 By 1940,
he published the results of the operation in over 400
patients with Ménière’s disease. Dandy was not the first to
treat Ménière’s disease by dividing the VIIIth cranial
nerve, as this honor probably belongs to R. H. Parry, who
reported on such a case using a middle fossa approach in
1902.129 Undoubtedly, the primitive state of neurologic
surgery at the time, the outcome of Parry’s reported case
(complete facial nerve paralysis), and the report of two
other deaths from similar attempts at relieving vertigo
dissuaded others from trying this treatment for quite some
time. By the time of Dandy’s report in 1941, however, the
procedure was far safer. As Dandy stated, “Ménière’s dis-
ease can be permanently cured by division of the auditory
nerve. This procedure carries almost no risk to life. Up to
the present time, I have performed 401 operations, with 1
death—the 358th case—due to meningitis.”130
Figure I-52. Sir Terence Cawthorne, a pioneering surgeon who helped
Dandy was a neurosurgeon by training, yet otolaryngol- popularize the transmastoid labyrinthectomy and was instrumental in
ogists and otologists were more and more involved in applying the operating microscope to aural surgery. (From Shambaugh GE:
caring for patients with vertiginous disorders, particularly Surgery of the Ear. Philadelphia, WB Saunders, 1967, with permission.)
after scientific advances pinpointed the essential lesion to
the labyrinth. Though, even at the time of his publication
in 1941, Dandy was not convinced that the semicircular mid-1900s.133 While serving on the staff of the National
canals were the seat of the pathology in Ménière’s disease. Hospital for Nervous Diseases and the Metropolitan
In fact, Dandy pointedly stated that Hallpike and Cairns’ Hospital in England, he began intensively studying
assertion that the pathology of Ménière’s lay in the semi- labyrinthine vertigo. In 1943, Cawthorne introduced a
circular canals was, “. . . by no means secure and I think is transmastoid labyrinthectomy as a means of destroying the
very doubtful.”130 Similarly, as for the dietary (low-salt) labyrinth and curing the symptoms of Ménière’s disease.134
medical cures offered by Furstenberg and others, Dandy The transmastoid labyrinthectomy was certainly not a new
wrote, “I do believe them to be useless.”130 The evidence operation when Cawthorne reintroduced it in the 1940s.
against Dandy’s point of view mounted, however, and The earliest known reports of labyrinthectomy for treating
Dandy’s method of intracranial division of the vestibular balance disorders date to 1904, with reports by both Lake
nerve became supplanted by other, less invasive procedures and Milligan.124,135,136 Following these reports, the
over the following decade. labyrinthectomy became the more popular treatment over
vestibular nerve section for vertigo because it was felt to be
Terence Cawthorne and the Rise of the a safer operation.136 However, the labyrinthectomy failed
Transmastoid Labyrinthectomy to gain widespread acceptance for treatment of vertiginous
disorders among neurosurgeons, who still favored the
One of the principle reasons for the demise of vestibular vestibular nerve section and its potential for hearing
nerve section was that otologists of the 1930s and 1940s preservation. Dandy’s work and widely published results
encountered a number of difficulties when attempting to on vestibular nerve section subsequently dominated the
perform Dandy’s surgery, most obvious being the unfamil- medical community, and Dandy’s technique gradually won
iarity of neurosurgical anatomy.131 As a result, a variety of favor during the 1920s and 1930s.
otologic operations were tried during this time to relieve When Cawthorne’s repopularized the labyrinthectomy
patients of the severe symptoms of Ménière’s disease, in the 1940s, however, the appeal to the otolaryngologic
including injections of alcohol through the horizontal canal community was immediate. The mastoid operation was
or stapes footplate, electrocoagulation of the horizontal one that all otolaryngologists were quite familiar with
canal, or simply opening the labyrinth and suctioning already. As amply noted in this historical review, the mas-
the contents.132 However, it was the British otologist toidectomy had become a widely accepted treatment for
Terence Cawthorne’s (Fig. I-52) method—the transmastoid suppurative diseases of the ear and chronic otitis media
labyrinthectomy—that eventually became the new standard since the 1860s. By the 1940s, all otolaryngology training
for treating Ménière’s disease in the 1940s and 1950s. programs included the mastoidectomy as a basic part of
Sir Terence Cawthorne (1902–1970) was universally resident training, practiced essentially as it is today, with
acknowledged as one of the greatest ear surgeons in the the exception of the types of instruments used. Modifying
34 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

the mastoid operation to include a labyrinthectomy was a Sourdille developed his passion for hearing preservation
simple step, and the transmastoid labyrinthectomy quickly surgery.137 Following World War I, Sourdille traveled to
became the preferred method for treating patients with Sweden where he studied with Holmgren and Bárány. There
Ménière’s disease, surpassing the vestibular nerve section he witnessed firsthand the spectacular, though often short-
championed by Dandy. With the subsequent rise of the lived, labyrinthine fenestration results with the microscope
operating microscope in the 1960s, this debate between that Holmgren was achieving on patients with otosclerosis.
the superiority of the labyrinthectomy versus the vestibu- The high incidence of deafness eventually led Bárány and
lar nerve section would again rage within the surgical Holmgren to abandon the procedure.
community, and in some circles, is still being debated. However, Sourdille recognized that the two principle
drawbacks of Holmgren’s operation were closure of
the fistula and the risk of infection. After experiments in the
Neurotologic Surgery Advances in the cadaver, Sourdille developed a three-stage procedure. He
1930s and 1940s: Maurice Sourdille, decided that the horizontal canal was the most accessible,
Julius Lempert, and the Fenestration and he closed the fistula with a thin cutaneous flap from
Operation the external auditory canal, which came to be known as
“Sourdille’s flap.”137 Not only were his hearing results supe-
Pioneering efforts to restore hearing to patients with oto- rior, but the auditory improvement lasted. After Sourdille
sclerosis has undeniably benefited the development of presented his results in 1929 to the French Academy of
neurotology and skull base surgery. For the operation to Medicine, word quickly spread throughout Europe and the
succeed required improvements in both aural operative Americas, leading both otologists and patients from around
technique and surgical microscopy, advances that were the world to seek out Sourdille. He eventually came to
ultimately incorporated into neurotologic and skull base North America in 1937, lecturing in several cities about his
surgery. During the 1940s, two figures stand prominent in new, improved technique. Ultimately, however, Sourdille’s
the development of an effective surgical treatment for oto- technique would lose favor to one devised by an American
sclerosis: Maurice Sourdille (1885–1961) (Fig. I-53) and sitting in the audience of one of these lectures.
Julius Lempert. As Shambaugh later recollected, Julius Lempert was
Though the lesser known of the two men, Maurice present in the audience at the New York Academy of
Sourdille’s influence on the surgical treatment of otosclerosis Medicine, where Sourdille was speaking at the invitation
is perhaps nearly as important. After studying at the of Edmund Fowler.138 Afterward, Lempert reportedly
University of Paris in 1911, he eventually became a pupil of invited Sourdille to dinner where he obtained further details
Lermoyez, one of the most prominent otolaryngologists in of the new procedure. It would be a meeting that Sourdille
France at that time. It was under Lermoyez’s tutelage that would later regret.
Julius Lempert (1890–1968) (Fig. I-54) was truly one of
the groundbreaking neurotologists of the 20th century and
has been considered by some to be the father of modern
otology.139 According to Terence Cawthorne, Lempert,
“. . . lead the renaissance of otologic surgery and of otol-
ogy as a science, at the very moment that antibiotics began
to remove acute mastoid infections and their dread com-
plications from the surgeon’s scalpel to the family doctor’s
prescription pad.”140 His charm and charisma were
legendary. He developed the endaural approach to ear
surgery141 and popularized the drill in otologic surgery, as
used by Holmgren before him. According to Glasscock,
his exposure of the carotid artery during temporal bone
surgery in 1938 was one of the seminal events of skull base
surgery development.139
However, it was at Sourdille’s lecture in New York that
Lempert would conceive of his legendary method for the
fenestration operation that would make him famous. He
altered Sourdille’s technique into a single-stage procedure,
applied his endaural approach, and used a dental burr to
expose the horizontal semicircular canal. However, in his
subsequent descriptions of the technique, Lempert failed
to cite Sourdille’s prior work.137 This appears not to be the
first time that Lempert failed to cite prior work that may
have influenced him. In Lempert’s original description of
the endaural approach to the mastoid, he failed to cite
Figure I-53. Maurice Sourdille (1885–1961), a pioneering French surgeon for Joachim Heermann, the German physician who had first
otosclerosis. Sourdille developed the three-stage fenestration operation that
would later become the basis for Lempert’s famed fenestration operation. described the procedure.138
(From Shambaugh GE: Surgery of the Ear. Philadelphia, WB Saunders, 1967, Regardless of the controversy surrounding the primacy of
with permission.) the procedure, Lempert’s one-stage fenestration operation
 The History of Neurotology and Skull Base Surgery 35

bear on the classification of glomus tumors, previously

termed a variety of confusing names, such as hemangioen-
dothelioma. Over the years, Dr. Rosenwasser built up an
impressive series of cases of glomus tumors and is widely
considered the father of glomus jugulare surgery while
he was on faculty at Columbia University in New York.
Dr. Rosenwasser was later elected as president of the
American Otological Society in 1966.144
Advances in the understanding and treatment of glomus
jugulare tumors began with Rosenwasser’s report.145 The
classic clinical finding of a glomus tumor of the middle ear,
a reddish blush against the drum, known colloquially as
Brown’s sign, was named after Lester A. Brown in a report
of his findings in six patients in 1953.146 However, it was-
n’t until the 1960s with the introduction of polytomogra-
phy and retrograde jugulography, a rational classification
scheme proposed by Alford and Guilford, and innovative
skull base approaches that were developed during this time
that diagnosis and treatment of glomus jugulare tumors
really began to accelerate.139

Neurotologic Surgical Advances

in the 1950s
Surgical advances in neurotology in the 1950s are princi-
Figure I-54. Julius Lempert, the highly influential surgeon who popularized pally remembered for three advances: the stapedectomy
the fenestration operation for otosclerosis, and performed pioneering
neurotologic and skull base surgery. (From Shambaugh GE: Surgery of the operation, the modern tympanoplasty, and the develop-
Ear. Philadelphia, WB Saunders, 1967, with permission.) ment of a microscope that would revolutionize surgery.
Of the three, the development of the microscope is the
most important, since it directly enabled the other two
rapidly took hold and revolutionized otologic surgery in advances.
the United States. Surgeons and patients from all over After Nylén’s, and subsequently Holmgren’s, descrip-
the world soon flocked to Lempert’s private office in tion of the operating microscope, its adaptation by the
New York, while Sourdille slipped into relative obscurity. general otologic community was slow. George Shambaugh
Sadly, when Lempert’s operation was ultimately sup- Jr. was the first to apply the binocular microscope to
planted by the stapes mobilization procedure, and later the Lempert’s one-stage fenestration operation in the 1940s.
stapedectomy, it would be Lempert who would refuse to With the assistance of the operating microscope, as well as
change, ultimately slipping into obscurity himself. the first use of continuous irrigation to help wash away
bone dust, Shambaugh was able to demonstrate signifi-
Glomus Jugulare Tumors— cantly better surgical results, highlighting the utility of the
microscope during ear surgery.147 During the same period,
Harry Rosenwasser Cawthorne in London was popularizing the microscope
There is no doubt that glomus tumors have played a for transmastoid labyrinthectomy and for operations on
pivotal role in the development of neurotology and skull the facial nerve, Tullio began applying the microscope to
base surgery. The innovative infratemporal fossa skull base mastoid surgery, and Simpson-Hall began using the
approaches that have been developed and refined over the microscope for Sourdille’s earlier fenestration operation in
years have their origins in surgery for glomus tumors. Europe.112
As has been noted by Schuknecht, perhaps the first com- Despite these reports, however, there was still some
plete description of a glomus body tumor was in 1937 in the general resistance to the use of the “otomicroscope” for
Dutch literature by J. Lubbers.142 However, it was in 1941 several reasons. First, there were cost issues; these micro-
when Stacy Guild was credited with the first description of scopes were custom built and quite expensive. Second,
a glomus jugulare tumor in the English literature.143 It was Lempert preferred the loupes for ear surgery along with a
just a year later when Harry Rosenwasser, a surgeon at headlamp, probably because of the microscope’s limita-
The Mount Sinai Hospital in New York City operated on tions, and his technique dictated much of what was done in
a patient with a vascular mass protruding from his ear and operating rooms of the United States during the 1940s.148
extending into the mastoid (though not reported until Last, and perhaps most important, were the microscope’s
1945).144 In this report, Rosenwasser credited Guild with technical limitations—each of the previously mentioned
the first report of a glomus tumor. It was most likely surgeons, and many others, had their own, unique micro-
Rosenwasser and Guild’s lack of access to the Dutch liter- scope design, which were slightly modified and improved
ature that led to the historical confusion on primacy of the versions of the original operating microscopes of
description of glomus tumors. Following these initial Holmgren and Nylén, and which incorporated better
reports, however, a new understanding was brought to working distances, maneuverability, and lighting.113
36 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

operative field through the same objective as the operating

surgeon was viewing. It also incorporated variable magni-
fication from 6× to 40×, an adequate working distance of
≈20 cm using a 200- or 250-mm lens, which was just about
ideal for ear surgery.113
In many ways, the Zeiss-Opton can be considered the
“Model T” of operating microscopes. It wasn’t the first, but
it was adaptable, it was affordable, and it was durable, all of
which led to its enduring success. The microscope was
presented for the first time at the fifth medical congress in
Amsterdam in 1951 and was commercially produced from
1953 onward.149 Today, many of these scopes are still work-
ing as well as they did when they were introduced in the
1950s, and nearly every otologist, neurotologist, neurosur-
geon, and skull base surgeon over the age of 40 can claim at
least part of his or her training to the Zeiss OpMi-1.
Most of the development of Zeiss’s OpMi-1 was done in
collaboration with Hörst Wullstein and Fritz Zöllner during
the development of their revolutionary technique of tym-
panoplasty, or what they termed plastic surgery of the sound
conducting apparatus.150 According to Wullstein, as translated
by Mudry, “In the era of surgical dissection, microsurgery
brought a new dimension into surgery far less reachable by
conventional methods. This can only be compared with the
radical change that occurred in medicine with the introduc-
Figure I-55. The Zeiss OpMi-1 binocular dissecting microscope, also known tion of antisepsis, asepsis and anesthesia.”148
as the Opton microscope. This scope would revolutionize neurotologic and
skull base surgery through its ease of use and widespread availability. With Zöllner and Wullstein’s landmark work on surgery
(From Mudry A: The History of the Microscope for Use in Ear Surgery. Am J for chronic ear disease, the utility of the microscope became
Otol 21(6):877–886, with permission.) obvious and was quickly adapted for nearly every type of
otologic surgery. Rosen developed the stapes mobilization
procedure,151 while Shambaugh, Derlacki, Heermann, and
Then in 1951, the Zeiss company, under the direction of House simultaneously advanced and independently adapted
Hans Littmann, produced the OpMi-1 binocular dissect- it toward stapes surgery, along with specially designed
ing microscope (Fig. I-55), also known as the Zeiss-Opton, instruments for use under the microscope (Fig. I-56).152–154
which simultaneously incorporated many of the advances These instruments are all still routinely used during otologic
that had occurred over the previous decade.113 This device and neurotologic surgery, and homage is paid every time a
would revolutionize microsurgery. Of particular importance, surgeon asks their scrub nurse for an instrument such as the
the microscope included illumination that entered the “Rosen knife.”

Figure I-56. Some of the pioneering aural surgeons of the 1950s. George E. Shambaugh, Jr. (left), was instrumental in applying the operating microscope to
otosclerosis surgery, along with Dr.’s House (right), Rosen, Derlacki, and Heermann. John Shea (center) pioneered the modern stapedectomy operation.
 The History of Neurotology and Skull Base Surgery 37

Perhaps the most important adaptation of the micro-

scope, however, was by John Shea, who used it to develop
the stapedectomy procedure.155 The success of this opera-
tion influenced a generation of ear surgeons and made
them facile with the operating microscope. According to
Glasscock, “. . . it was Shea who made it a practical, every-
day instrument for performing otologic procedures.”139 In
fact, this widespread acceptance of the microscope during
routine otologic surgery, as pioneered by surgeons such as
Shea, Cawthorne, and Shambaughand Rosen, directly lead
to the birth of an independent subspecialty: neurotology
and skull base surgery.

William House and the Birth

of Modern Neurotology and Skull
Base Surgery
Today the operating microscope is the indispensable tool
of the neurosurgical, neurotologic, and skull base surgeon.
However, this was not the case in the late 1950s and early
1960s. While the operating microscope was beginning to
permeate otologic surgery, neurosurgery was still per-
formed by essentially the same techniques championed by
Dandy and Cushing. History has taught us that most scien-
tific paradigm shifts are introduced from outside the estab-
lishment, and often in the face of tremendous resistance.156 Figure I-57. William House, the “father” of modern skull base surgery.
When the operating microscope was first introduced into (From House W: Monograph: Transtemporal bone microsurgical removal of
acoustic neuromas. Arch Otolaryngol 80:597–756, 1964, with permission.)
neurosurgery by an outsider—an otologist—such fierce
antagonism was similarly met. From the moment William
House (Fig. I-57) applied the operating microscope to angle for resection of vestibular schwannomas. House,
acoustic neuroma resection, he faced an uphill battle. That along with William Hitselburger, thus introduced the
his prescience and perseverance led to his ultimate triumph operating microscope and otologic surgical technique to
over the neurosurgical establishment of the day has earned neurosurgery.160 The operative approach was immediately
him a revered spot in the pantheon of great ear surgeons. recognized for its importance within the otolaryngologic
The 1960s were a time of tremendous social change. It community. George Shambaugh Jr. wrote in the foreword
saw the birth of the free-speech movement, a countercul- to House’s highly influential 1964 monograph that his
tural revolution, and an entire generation questioning the work was, “. . . destined to become a second milestone in
values and morays of their parents and society at large. the surgical approaches through the temporal bone made
Otology and neurosurgery were not spared the changes possible and practical by microsurgical temporal bone
happening in the broader social context. It was perhaps the techniques.”161 In fact, the first milestone that Shambaugh
social trends of the day that enabled surgeons such as House was referring to was Cushing’s work nearly 50 years prior.
to openly question and challenge the way surgery was per- Shambaugh also noted in his foreword the not so subtle
formed, particularly by another field such as neurosurgery. manner in which House patterned his monograph exactly
After completion of his residency, William House joined as Cushing laid out his classic work in Tumors of the Nervous
his brother Howard in a private otology practice in the Acusticus in 1917.110
flourishing Los Angeles of the 1950s. William House soon Despite the enthusiastic reception of the work within
developed an interest in the treatment of diseases of the otolaryngology, the opposition that House and Hitselburger
inner ear. It was House’s interest in sensorineural hearing faced from the neurosurgical community, which had
loss from otosclerosis and the possibility of restoring traditionally cared for these tumors, was fierce.139,157 The
hearing by drilling out the internal auditory canal that squabble at House’s own institution would ultimately be
ultimately led him to attempt a middle fossa approach.157 mirrored across the country on numerous other hospital
After a series of experiments on cadavers in his local staffs as similar turf wars would play themselves out
morgue, he attempted the middle fossa approach using the between neurosurgeons and otologists. However, soon the
operative microscope, along with the neurosurgeon Kurze advantages of House and Hitselberger’s microscopic tech-
on a patient with cochlear otosclerosis.158,159 The patient nique became obvious, and the microscope quickly spread
did not regain hearing, nor did the two subsequent to other fields, including neurosurgery itself. Both otology
patients on whom the operation was attempted. According and neurosurgery gradually came to realize that by
to House, when he presented the operative approach at a combining their individual expertise toward the resection
symposium, he was publicly ridiculed not only for the of vestibular schwannomas, the ultimate benefactor was
results, but for the approach itself.157 the patient. Once the acoustic neuroma obstacle had been
It was several years subsequent to this that House revived cleared, collaboration on resection of other skull base
the translabyrinthine approach to the cerebellopontine tumors soon followed. Thus, one can argue convincingly
38 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY

that once the reconciliation between neurosurgery and otol- Djourno and Eyries published their first data on direct
ogy over acoustic neuromas had occurred in the late 1960s stimulation of the cochlear nerve in a totally deaf person in
and early 1970s, the field of skull base surgery was born. 1957. During a reoperation for facial paralysis and deafness
House’s influence on neurotology was profound. He went in a 50-year-old man, an electrode was placed into the
on to develop additional, expanded approaches to the skull region of the cochlear nerve stump and a current was
base, including the extended middle fossa and transcochlear passed. The patient heard sounds like “crickets” or a
approaches. His pioneering work on cochlear implants was “roulette wheel.”170,171 The researchers never followed up
far ahead of its time and again initially met with great oppo- their results, however, and their work remained obscure for
sition from within otology’s own elite establishment.162 a number of years.
Clearly, one of House’s laudatory attributes as a person is his In 1961 William House and James Doyle designed a few
perseverance in the face of misdirected opposition. In each implantable cochlear-stimulating devices based on the work
case, he appears to have won, convincingly. As noted by of the scientists at MIT and in the Soviet Union and tested
Glasscock, “Had William F. House not had such a strong them in human patients. Due to poor construction and the
personality, had he not been so determined, then neuro- toxic nature of the implant material, however, the devices
otology would not exist as we know it today.”139 had to be removed after 3 weeks. Despite this setback and
the use of a nonphysiologic stimulating current, House and
Electrical Stimulation of the Auditory Doyle’s initial results indicated that patients could perceive
Nerve—The Birth of Cochlear Implants the rhythm of speech and music and were aware of a variety
of environmental sounds.172 The technical difficulties they
The 1960s were notable for another milestone in neuro- encountered, however, discouraged them from continuing
tology, the birth of the cochlear implant. As the first true further with cochlear implants for a number of years.
prosthetic device that enables the restoration of a lost The most widely acclaimed implantation in the 1960s
sense, the cochlear implant surely has to be ranked as one occurred under the direction of Blair Simmons at Stanford
of the greatest achievements of medical science. Fittingly, University.173 He placed an implant in the cochlea of a
cochlear implants arose out of uncoordinated international terminally ill, congenitally deaf patient and showed that
efforts, replete with individuals who persisted in their the patient could perceive sound. Ironically, because the
work despite fierce criticism within the academic and med- patient could not understand speech, Simmons concluded
ical communities. in his landmark paper that, “. . . the chances are small indeed
Attempts to electrically stimulate the ear date as early as that electrical stimulation of the auditory nerve can
1790, when Alexander Volta, professor of natural philoso- ever provide a uniquely useful means of communication.”
phy at the University of Pavia, was experimenting with the A colleague of Simmons, Robin Michelson, would ulti-
relatively new phenomenon of electricity. He inserted a mately leave Simmons to begin his own program at the
metal rod into each of his ears, connected a 50-volt battery University of California San Francisco.
between them, and heard a noise similar to the boiling of In 1973 the First International Conference on Cochlear
a viscous liquid.163 In the mid-18th century, two prominent Implants was held at the University of California San
otolaryngologists introduced the idea of electrical stimula- Francisco. By this time, House had preformed a total of
tion to medicine by advocating it for the diagnosis and 22 implants, Michelson and his colleagues had done seven
treatment of many ear diseases. This short-lived field of with some published results, and Simmons had done two.
“electro-otiatrics” was abandoned by the start of the 20th Additional cochlear implant development programs were
century, however, and remained dormant for the following well underway in Melbourne, Australia, and Innsbrück,
30 years.164,165 Austria, each making landmark strides on their own.
The idea that sound could be artificially created through However, Merle Lawrence summed up the prevailing
electrical stimulation of the ear was resurrected by two attitudes of a large segment of the medical and scientific
events in the early 20th century. In 1925 radio engineers community when he implied at the conference assembly
discovered that sound could be produced by stimulating that there is no way, “. . . of the number of channels or
electrodes in the near vicinity of the ear, and in 1930 Weaver electrode points . . .” by means of which one can get tono-
and Bray discovered a phenomenon known as the “cochlear topic or specific frequency stimulation by attempting to
microphonic,” an electrical potential arising from the stimulate first order neuron dendrites in the cochlea, and
cochlea as a result of acoustic stimulation.166 Shortly before all that would be produced would be “noise.”174 Harold
World War II, a group of scientists at MIT, the prominent Schuknecht, another conference participant, was more
psychophysicist S. S. Stevens, and a group of Soviet scien- direct when he flatly stated at the conference’s conclusion,
tists, began independently investigating the concept of elec- “. . . I will admit that we need a new operation in otology
trical stimulation of the eighth nerve.167–169 Each of these but I am afraid this is not it.”174
groups tried to stimulate the cochlea from within the mid- Much of the criticism of the implants at this point
dle ear to create sound. With only primitive electronics such centered on the belief that it was immoral to proceed in
as vacuum tubes, however, this proved to be too great a humans until sufficient animal work had been done,
technical feat. Each group encountered difficulty with the combined with the prevailing belief that the device itself
dynamic range of their devices and couldn’t create sound would simply never work because of the extensive and irre-
without causing pain or stimulating the facial nerve. versible neural damage already present in deaf individuals.
However, their early, rigorous scientific endeavors were Beyond these concerns, extravagant claims surfacing in the
instrumental in setting the stage for successful stimulation public, including testimonials about “. . . hearing the chirp-
of the eighth nerve within the following two decades. ing of mockingbirds once again (and) enjoying symphony
 The History of Neurotology and Skull Base Surgery 39

music . . .” further alienated the scientific community and Eighty years ago, Sir Charles Ballance, the pioneering
made research in cochlear implants a pariah of audiologic skull base surgeon, eloquently acknowledged what each of
research.175 us owes to our teachers and predecessors, and his senti-
However, a pivotal year for the advancement of the ments remain relevant today as we look forward to the next
cochlear implant came in 1977, when the National Institutes millennium:
of Health began an independent, multicenter study of
patients with cochlear implant devices. Led by Dr. Bilger at “Every man is a debtor to his profession. A vast field of our art
the University of Pittsburgh, the study concluded that the and science still remains unmapped and unexplored. I trust that
device was a definite aid in communication.176 Bilger, who succeeding generations of surgeons . . . will devote time to
was skeptical of cochlear implants, was actually converted to research work. Research adds zest and satisfaction to life, and
gives the promise of that thrill of delight which accompanies the
a modest supporter by the results of his own report: “It . . . first perception, the slow unfolding of some new truth or princi-
(the report) . . . put to rest some of the wilder claims about ple. Thus may we surgeons rightly forge new weapons against
the benefits of . . . implants and it substantiated that for some disease and death” (Sir Charles Ballance, 1922).12
individuals there were benefits in lip reading, environmental It is only through such dedication to clinical and surgical
awareness and voice modulation control.”175 What is more advances and basic neurotologic research that tomorrow’s
important, the study provided substantial scientific evidence leaders, as great and revolutionary as those in our historical
for the benefits of cochlear implantation and gave credibility past will emerge, and neurotologic and skull base history
to the emerging technology. will continue to advance.

The Creation of the American

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 Chapter
The Human Brainstem
Auditory System

Outline 1
Brainstem Topography Inferior Colliculus Jean K. Moore, PhD
Generation of Evoked Descending Pathways
Potentials Effects of Hearing Loss
Information Processing in the Conclusions
Brainstem
Cochlear Nuclei
Superior Olivary Complex
Lemniscal Nuclei

T his chapter looks at the human brainstem auditory

system from several standpoints relevant for the
clinician. First, it examines the unique topography of the
nucleus is a very prominent laminar nucleus, while the lat-
eral olivary nucleus is a small compact cell group.
Periolivary cells ring the medial and lateral nuclei and
human central auditory pathway. Next, it considers how form a column of cells extending almost a centimeter
brainstem structures act as generators of evoked auditory rostrally through the brainstem. At the point where the
potentials, information that may be useful in distinguish- pons is no longer covered laterally by the middle cerebel-
ing peripheral and central pathology. It then considers the lar peduncle, the auditory pathway swings laterally to
manner in which information from the cochlea is analyzed become a flattened, superficial band of axons, the lateral
and altered as it passes through brainstem centers. Finally, lemniscus. A few clusters of small cells scattered through-
it reviews what is currently known about the type and out the lemniscus are vestiges of the lower lemniscal nuclei.
degree of central degenerative change that occurs subse- The dorsal lemniscal nucleus is a distinct cell group that
quent to hearing loss. gives rise to the dorsal commissure of the lateral lemniscus.
The lateral lemniscus terminates in the inferior colliculus,
a large and irregularly spherical nucleus that is connected
BRAINSTEM TOPOGRAPHY to the contralateral colliculus through the collicular
commissure.
An overview of the brainstem auditory pathway in lon- Previous comparisons of the human and cat brainstem1
gitudinal section, based on serially sectioned human brain- have shown that their auditory centers are approximately
stems,1 is presented in Figure 1-1. As shown in this figure, the same size, but because of the overall size of the human
the brainstem auditory pathway begins at the pontomed- brainstem, human auditory centers are strung out along a
ullary junction, at the point where the cochlear nerve enters considerably longer pathway. An accurate measurement of
the brainstem and terminates in the cochlear nuclei. The the length of the human brainstem auditory pathway has
cochlear nuclear complex consists of two components, a been obtained from a computer reconstruction based on
dorsal nucleus and a ventral nucleus. The dorsal cochlear a series of digitized histologic sections.2 The reconstruc-
nucleus is a flattened structure that curves around the infe- tion shows that the distance the axon of a neuron in the
rior cerebellar peduncle on the dorsolateral surface of the human ventral cochlear nucleus travels to reach the ipsi-
brainstem. The ventral nucleus is a compact structure that lateral superior olivary complex is approximately 10 mm;
extends laterally along the caudal edge of the middle cere- to reach the contralateral superior olivary complex is about
bellar peduncle. The cochlear nerve enters the center of 25 mm; to reach the upper level of the contralateral lateral
the ventral cochlear nucleus, and its axons radiate to inner- lemniscus is about 40 mm; and to reach the center of the
vate both the dorsal and ventral nuclei. The pathway contralateral inferior colliculus is roughly 45 mm. Thus a
carrying most of the ascending auditory information to response in the human brainstem to a transient stimulus
higher centers originates in the ventral nucleus, and its will consist of waves of action potentials passing along
axons leave the nucleus as the trapezoid body, a broad myelinated axons for a total distance of up to 4.5 cm. In the
pathway that crosses the brainstem. Within the brainstem, cat, by comparison, the total distance from the center of
the superior olivary complex lies a short distance medial the cochlear nuclei to the center of the contralateral infe-
and rostral to the cochlear nuclei. The medial olivary rior colliculus is less than 2 cm.
45
46 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

waves I and II were present but all subsequent waves

were absent.
When intrasurgical recordings were made directly from
the surface of the human brainstem,3,7 they indicated that
waves III, IV, and V are generated by brainstem structures.
A wave coinciding with scalp-recorded wave III was seen
when electrodes were placed over the cochlear nuclei. Both
these recordings and human dipole studies5 concluded that
wave III is generated by a volley of action potentials in
axons emerging from the cochlear nuclei in the trapezoid
body. Similar conclusions have been reached on the basis
of tumors or demyelinating lesions in the lower pons that
affect or eliminate wave III.8
Because they occur later, waves IV and V presumably
reflect activity at a higher brainstem level. This assump-
tion is confirmed by intrasurgical electrodes placed on the
dorsal surface of the pons that recorded potentials corre-
sponding to scalp-recorded waves IV and V.7 In an attempt
to locate the point of generation of these two waves more
precisely, the length of the human brainstem pathway was
correlated with the latencies of waves IV and V to derive
Figure 1-1. Overview of the brainstem auditory pathway as seen in axonal conduction velocity.2 The most reasonable conduc-
longitudinal section. Spatial relationships and dimensions are based on tion velocity, one closely matching the known conduction
reconstructions from serially sectioned human brainstems. Auditory nuclei velocity of eighth nerve axons, was obtained by assuming
(solid outlines) are labeled in the lower half of the figure and tracts that waves IV and V were generated at the level of the
(dotted outlines) are labeled in the upper half. AS, acoustic stria; BIC,
brachium of inferior colliculus; CIC, commissure of inferior colliculus; superior olivary complex contralateral to the stimulated
DCLL, dorsal commissure of lateral lemniscus; DCN, dorsal cochlear ear, presumably by the bend in the axonal pathway occur-
nucleus; DNLL, dorsal nucleus of lateral lemniscus; IC, inferior colliculus; ring at that point (see Fig. 1-1). The idea that waves IV
LSO, lateral superior olivary nucleus; MCP, middle cerebellar peduncle; and V are generated at the level of the olivary complex,
MSO, medial superior olivary nucleus; PO periolivary region; TB, trapezoid
body; VCN, ventral cochlear nucleus; VNLL, ventral nucleus of lateral
rather than higher in the brainstem, is supported by the
lemniscus; VIIIc, cochlear nerve. (Modified from Moore JK: The human fact that both waves are intact after destructive lesions of
auditory brainstem as a generator of auditory evoked potentials. Hear Res the inferior colliculus.9,10
19:33–43, 1987.). The brainstem auditory system is known to consist of
separate pathways running in parallel.11 On the one hand,
many axons leave the cochlear nuclei and run without
interruption to the contralateral inferior colliculus.12 As
GENERATION OF EVOKED POTENTIALS they traverse the trapezoid body and lateral lemniscus,
these axons do not encounter any synaptic junction.
Evoked auditory brainstem responses (EABR) are gener- Alternatively, some pathways to the inferior colliculus
ally regarded as reflecting synchronized discharges in synapse in the intermediate brainstem nuclei, such as the
groups of axons. However, it is difficult to apply the results medial and lateral olivary nuclei and the periolivary cell
of animal investigations when attempting to identify the groups.12 It has been suggested that the closely spaced
generators of potentials evoked from the human brainstem waves IV and V reflect activity in parallel asynaptic and
because the human cochlear nerve and brainstem pathways monosynaptic pathways. Passing though a single synaptic
are much longer than those in other species. More relevant junction would delay the wave of action potentials by
information can be obtained from studies done in human approximately 0.7 msec, which is, in fact, the interval sep-
subjects. In contrast to lower mammals, in which only a arating waves IV and V. Additional support for the idea
single wave is generated by the cochlear nerve, there is evi- that waves IV and V are generated by parallel pathways
dence that the human cochlear nerve generates comes from EABRs recorded during placement of an
the two earliest potentials of the EABR, waves I and II. auditory brainstem implant device on the cochlear nuclei.13
Intrasurgical recordings, made with a wire electrode placed Because tumor removal interrupts the continuity of the
directly on the auditory nerve,3,4 concluded that wave I is eighth nerve, the peripheral generators of the EABR are
generated within the cochlea, presumably by activation missing and the electrical stimulus acts directly on
of the peripheral nerve processes contacting cochlear hair cochlear nucleus neurons. This direct activation of axons
cells. Wave II was localized to the cochlear nerve at the leaving the cochlear nuclei bypasses cochlear mechanics,
level of the internal auditory meatus. Similarly, dipole the synapses at the level of the hair cells, and the synapses
localization studies5 concluded that wave II is generated as in the cochlear nuclei, all of which normally precede
the wave of action potentials following a click stimulus wave III. In these recordings, peaks are recognizable that
crosses the conduction boundary between the temporal correspond in time to waves III, IV, and V of the acousti-
bone and the intradural space. This interpretation is cally evoked ABR. When the stimulus rate is increased
supported by clinical findings in a case of Gaucher’s from 100/sec to 200/sec, the peak corresponding to wave
disease with marked brainstem gliosis,6 in which EABR IV is unaffected, but the peak corresponding to wave
 The Human Brainstem Auditory System 47

V shows rapid attenuation. This implies that the two peaks axons form tightly bundled fascicles penetrating the central
are generated by different pathways, rather than by area of the ventral nucleus. Studies in mouse slice prepara-
sequential structures in a single pathway, and that wave V tions have shown that these dorsal nucleus cells project to
is rate-sensitive because its generator contains a synaptic bands of neurons in the ventral nucleus that are innervated
junction. by the same subset of auditory nerve axons.18 Thus, this
system appears to provide extremely frequency-specific
inhibition with one synaptic delay to neurons in the ventral
INFORMATION PROCESSING nucleus.
IN THE BRAINSTEM The point-to-point nature of these dorsal-to-ventral
nucleus connections stands in contrast to a much more
Cochlear Nuclei widespread projection pattern of commissural axons. The
commissural projection arises from relatively large glycine-
The activity of the cochlea is carried as a single represen- positive cells scattered throughout the cochlear nuclei.
tation in the auditory nerve. Upon entering the nerve root Their large-diameter axons come together to form a dis-
in the center of the ventral cochlear nucleus, its axons tinct bundle, the commissural stria, and form a plexus of
bifurcate to form ascending and descending branches. In axons in the contralateral nuclei.19 Within the contralateral
humans, as in other species, fascicles of ascending cochlear complex, commissural axons branch widely and
branches of the cochlear nerve fill the anterior half of the distribute their inhibitory terminal very broadly.20 This
ventral nucleus, and similar fascicles of descending glycine-positive commissural projection is undoubtedly
branches penetrate the posterior part of the nucleus and responsible for the short-latency crossed inhibition shown
then continue into the dorsal nucleus.14 The ventral in recordings in the cat21 and presumably plays a role in the
nucleus is very densely innervated, but in the dorsal balance of level of activity of the cochlear nuclei on the two
nucleus synaptic terminals are much more sparsely scat- sides of the brainstem.
tered. The tonotopic sequence of axons in the auditory It is apparent that by the time auditory information has
nerve identified in the monkey15 is identical to that of passed through its first central synapse in the cochlear
other mammalian species, with high-frequency informa- nuclei, it has been acted on by modulatory influences.
tion carried by fibers bifurcating in the tip of the nerve First, a recoding of the pattern of activity in the auditory
root, and an orderly sequence of progressively lower fre- nerve occurs during the interaction of the presynaptic
quencies extending down to axons bifurcating at the base axons and the postsynaptic neuron. Second, there is an
of the nerve root. Frequency information should therefore interplay of that excitatory activity with intrinsic inhibitory
be represented in the human ventral cochlear nucleus as systems. These factors combine to ensure that a unique
stacked sheets of eighth nerve axons, with the highest pattern of activity is carried in each of the pathways leaving
frequency input in the most dorsal sheets and lowest fre- the cochlear nuclei.
quency input in the most ventral. In the human dorsal
cochlear nucleus, changes in the cytoarchitecture have
altered the direction of axons such that the cochleotopic
Superior Olivary Complex
planes run parallel to the surface of the nucleus.14 One basis for complexity in brainstem information pro-
Neurons in the cochlear nuclei do not simply relay pitch cessing is the fact that the cochlea, unlike the retina or
information to higher auditory centers. Instead, the nuclei body surface, does not directly encode the spatial locus
are a point of transformation of the pattern of activity of a stimulus. Instead, the spatial dimension of a sound
carried in the auditory nerve. Each individual auditory stimulus must be recreated by the central auditory system.
nerve axon, as it runs through the nuclei, passes through Behavioral studies in cats have implicated the superior
areas of different cell types.1,14 Distinct types of synapses olivary complex in this process. Animals with lesions at or
are formed on each class of neuron, with the synapses vary- above the level of the superior olivary complex are unable
ing from expanded calyces surrounding the cell body to to locate a sound source in the spatial field contralateral to
scattered small boutons located mainly on dendrites.16 As the lesion, while lesions below the level of the olivary com-
a result, the transformation of impulses across the synapse plex cause more diffuse deficits.22 A very similar deficit has
results in a distinctive pattern of activity in each postsyn- been seen in a human subject with an extensive midline
aptic cell group. pontine lesion that eliminated crossed input to the supe-
An additional factor in the transformation of the pattern rior olivary complex on both sides.23 The subject could
of information originally carried by the cochlear nerve is detect frequency and amplitude modulation and had no
the presence of many synaptic terminals containing the general deficit in detection of auditory temporal informa-
inhibitory transmitters γ-aminobutyric acid (GABA) and tion, but was unable to determine, by sound alone, the
glycine. Several types of inhibitory systems have been location and direction of motion of objects in the envi-
described in nonprimate mammals, but two systems are ronment, such as ringing telephones and passing trains.
particularly well developed in the baboon17 and, by analogy, Collectively, these findings imply that the central repre-
in humans. The first system is a very precise, tonotopically sentation of auditory space is first organized at the level of
specific system projecting from the dorsal nucleus to the the superior olivary complex and that the process of orga-
ventral nucleus. The origin of this system is a population nization occurs similarly in humans and other mammals.
of glycine- and GABA-positive cells in the central dorsal Physiologic studies carried out in animals have long
cochlear nucleus that are characterized by dendritic arbors indicated that time and intensity cues to spatial location
flattened in the isofrequency planes of the nucleus. Their are analyzed separately in the superior olivary complex,
48 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

and dipole studies carried out in human subjects24 suggest The medial and lateral olivary nuclei are surrounded by
that the same is true in humans. The human dipole studies a separate component of the olivary complex, the perioli-
involved recordings of the binaural interaction component vary region. Human periolivary cells are roughly grouped
of the EABR, which is obtained by subtracting the into medial, lateral, and dorsal periolivary nuclei. A unique
response to a binaural stimulus from the algebraic sum feature of the human periolivary system is a rostral column
of the right and left ear monaural responses to the same of cells that extends up to 8 to 10 mm through the pons.
stimulus. The reduction in total activity in the binaural Periolivary neurons are a heterogeneous population that
response is presumed to reflect the fact that the binaural forms ascending and descending projections to a number
response involves convergence of activity from the right of diverse targets. The hypertrophied rostral cell group is
and left ears on some subset of brainstem auditory neurons composed of a type of periolivary neuron that, in the cat,
that process information from both ears. When the binau- forms a projection to the inferior colliculus31 and thus may
ral interaction component was determined for a variety of represent the main ascending pathway from the periolivary
interaural time and intensity differences, the dipoles for region to the midbrain. Other periolivary neurons form
interaural time versus intensity differences had slightly dif- descending pathways and are discussed in the section on
ferent locations in the brainstem, suggesting that time and the descending auditory system.
intensity cues are processed by two separate structures.
The system that uses interaural time differences has Lemniscal Nuclei
long been believed to be the medial olivary nucleus. This
nucleus is a laminar structure, with long primary dendrites In most species, the lower part of the lemniscus contains
extending medially and laterally from a central column of two sizable nuclei, the ventral and intermediate lemniscal
cell bodies. The laterally directed dendrites are innervated nuclei. These nuclei are prominent in the cat and are
by the ventral cochlear nucleus on the same side of the extremely large in echolocators such as the porpoise and
brainstem, and the medially directed dendrites are inner- bat, suggesting that they are related to some aspect of
vated by the nucleus on the contralateral side.12 Thus, each high-frequency acoustic processing. In humans, these nuclei
neuron receives frequency-matched input from both ears. are represented only by cell clusters scattered along the
The discharge rate of cells in the medial nucleus is influ- course of the lateral lemniscus.1 Thus the comparative devel-
enced by interaural time differences, including phase opment of the lower lemniscal nuclei across mammals
disparities, and shows phase-locking to both monaural and suggests that their reduction in the human brainstem, like
binaural stimuli.25,26 These response properties allow the that of the lateral olivary nucleus, is related to our com-
neurons to create a map of interaural time differences paratively low-frequency range of hearing.
along the rostrocaudal axis of the nucleus. Because time In contrast, the dorsal lemniscal nucleus is a prominent
disparities are most useful for low-frequency sound, and cell group, very similar in size and morphology to the cor-
phase cues are unambiguous only below 1500 Hz, the responding nucleus in the cat.1 In mammals, afferent input
medial nucleus is biased toward low-frequency information, to the dorsal nucleus comes mainly from the medial and
with most of its neurons having best frequencies of less lateral superior olivary nuclei,32 meaning that its input
than 3 to 4 kHz.27 Given that the human range of audible is related primarily to spatial localization. The dorsal
frequencies is quite low by general mammalian standards, nucleus projects directly to the adjacent inferior colliculus
it is not surprising that the human medial olivary nucleus and through its commissure to the dorsal lemniscal
is twice as large as that of the cat and several times larger nucleus and inferior colliculus on the opposite side.33
than those of most other species.28 Because large head size Because the dorsal nucleus consists mainly of neurons that
increases the range of frequencies that can be used for use GABA as a neurotransmitter,34 this symmetrical and
interaural phase difference cues, both human head size and reciprocal projection is inhibitory and must influence the
low-frequency hearing range may account for the promi- level of activity in the inferior colliculus bilaterally. It is
nence of the medial olivary nucleus in our binaural hear- likely that the dorsal lemniscal nucleus plays a role in the
ing system. balance of ipsilateral and contralateral activity related to
Stimulus intensity cues are generally believed to be spatial mapping in the inferior colliculus.
processed by the lateral olivary nucleus. Single unit record-
ings have shown that lateral nucleus neurons respond to Inferior Colliculus
interaural intensity differences and also to monaural ampli-
tude fluctuations.29,30 Because intensity cues can be used Essentially all the axons in the lateral lemniscus terminate
across a broad range of frequencies, the mammalian lateral in the inferior colliculus, with greatest density in its central
olivary nucleus has an orderly representation of best nucleus. Thus the central nucleus receives overlapping
frequencies spanning the entire audible range.27 The input from the dorsal and ventral cochlear nuclei, the medial
nucleus is large in carnivores that are sensitive to frequen- and lateral olivary nuclei, periolivary cell groups, and the
cies from 20 Hz to 40 kHz and is extremely large in echolo- lemniscal nuclei, particularly the dorsal lemniscal nucleus.
cating species, such as bats and porpoises, whose range The overlap of the ascending projections to the central
extends above 100 kHz.28 Possibly because our range of nucleus does not occur in a random manner, but rather in
usable frequencies is restricted to those at the low end of an organized fashion related to the laminar organization of
the mammalian spectrum, the human lateral nucleus is a the nucleus. As axons enter the central nucleus, they form
relatively small nucleus, much smaller than that of the cat bands running from ventrolateral to dorsomedial. These
and similar in absolute size to the nucleus in rodents and axonal bands run parallel to cellular planes formed by neu-
insectivores.28 rons with flattened, disc-shaped dendritic fields, producing
 The Human Brainstem Auditory System 49

a laminar architecture of alternating bands of axons and nuclei.39 Electrophysiologic studies of the external cortex
flattened cells. Studies of evoked activity and 2-deoxyglu- show that many cells are influenced by both auditory and
cose labeling in primates have shown that the laminae rep- somatosensory stimuli, and most have relatively nonspe-
resent frequency-specific planes of the central nucleus.35,36 cific response fields, reflecting broad frequency ranges and
The tonotopic planes are curved and tipped at about 20 to large areas of the body.40 An organized map of auditory
30 degrees from the horizontal, with a regular progression space has been demonstrated in this region,41 and behav-
of best frequencies from low dorsally to high ventrally. ioral studies have shown that lesions here cause deficits in
Some projections, such as those from the ventral cochlear the ability to orient to sound.22 Neurons in the intercollic-
nucleus and the lateral olivary nucleus, span the entire ular area project to the deep layers of the superior collicu-
tonotopic spectrum, while the medial olivary nucleus is a lus, where the auditory map is aligned with the map of
major source of afferents to the low-frequency region of visual space. In turn, output from the multimodal neurons
the central nucleus. in the deep layers of the superior colliculus plays a major
Tonotopy is not the only organizing principle within the role in control of the motor nuclei for head and eye turn-
inferior colliculus. Recordings in the cat show that neurons ing. Thus the external cortex of the inferior colliculus is
in the central nucleus respond to simulations of natural the beginning of a process of integration of auditory input
combinations of interaural time and intensity differences with visual and somatosensory information, leading to
and to spectral cues indicating location of a sound source.37 creation of a multisensory spatial map and, ultimately,
Most cells are sensitive to stimulus location along the hor- direction of head and eye position by that map.
izontal azimuth, and about half of the neurons tested The caudal half of the pericentral region of the inferior
are sensitive to elevation. This suggests that at the level of colliculus is often called the dorsal cortex because it is
the colliculus, pathways representing spatial localization, a multilayered structure, with neurons segregated into
that is, those from the medial and lateral olivary nuclei several layers and cells becoming progressively larger in
and dorsal lemniscal nucleus, are integrated into a single the deeper layers. This area is a way station for relaying cor-
spatial map. Overall, it seems safe to assume that multiple tical influence to the brainstem. Many of the axons descend-
parameters of auditory stimuli, including frequency spec- ing from cortex bypass the thalamus and travel to the
trum, loudness, time patterning, and spatial location, are inferior colliculus, where they end in the dorsal cortex.42,43
correlated within the central nucleus to produce an inte- Efferent axons from the dorsal cortex project down to the
grated neural representation of the stimulus. level of the superior olivary complex, where they terminate
Information from the central nucleus of the colliculus is exclusively in the periolivary region.44 The periolivary cells
passed on to the forebrain by axons that form the brachium that receive these projections form the olivocochlear path-
of the inferior colliculus. Brachial axons continue forward way that travels in the vestibular nerve to reach the cochlea.
on the surface of the brainstem, lateral to the superior Recent work has provided a clearer picture of the
colliculus, to reach the medial geniculate complex of the human olivocochlear system. Immunostaining for choline
thalamus. This ascending pathway from the inferior col- acetyltransferase (ChAT), the synthesizing enzyme for
liculus is the route for essentially all information ulti- acetylcholine, has been used to identify olivocochlear
mately reaching the thalamic and cortical levels. However, neurons in the human brainstem45 and efferent terminals
the inferior colliculus is also the source of descending on hair cells in the human cochlea.46 In addition, immuno-
auditory pathways, which are discussed in the following staining has made it possible to identify two subdivisions
section. One descending projection ultimately reaches the of the human efferent system. One division, the medial
acousticomotor centers involved in head and eye orienta- olivocochlear system, is known to form synaptic terminals
tion to sound. A second descending system is the purely contacting outer hair cells, and occasionally, their afferent
auditory pathway to lower brainstem auditory centers and, fibers. This subsystem appears as a population of large mul-
through the olivocochlear projection, to the cochlea itself. tipolar cells, scattered throughout the periolivary region,
In sum, it appears that the inferior colliculus is a point of that are immunopositive only for ChAT. The other subdi-
convergence for a series of parallel brainstem pathways, but vision, the lateral olivocochlear system, forms synaptic
also a point of divergence from which integrated auditory terminals contacting afferent fibers from inner hair cells
information is sent up to auditory cortex, back down the and, in some cases, inner hair cell somata. These are pre-
brainstem through feedback pathways, and to centers con- dominantly small oval cells, located in or near the lateral
cerned with motor responses to sound stimuli. olivary nucleus. They colocalize a variety of neuropeptides
with the cholinergic enzymes and can be visualized by
Descending Pathways their reactivity for both ChAT and calcitonin gene-related
peptide (CGRP). The most significant difference between
The central nucleus of the inferior colliculus is surrounded the human olivocochlear system and that of other mam-
by a relatively large pericentral zone. The rostral half of malian species is the relative size of the two subdivisions.
this zone is notable for being an area of multisensory In mammals generally, the lateral efferent component is
convergence. This region has been called the external cor- consistently the largest portion of the olivocochlear system,
tex and is also termed the intercollicular area because it making up approximately 75% of the system in the cat
forms a bridge, anatomically and functionally, between the and monkey, 85% to 90% in rodents, and 90% to 100% in
inferior and superior colliculi. In addition to auditory bats. In contrast, the human lateral olivocochlear system
input from the central nucleus of the colliculus, it receives makes up at most one-third to one-half of the total
visual input via the optic tract38 and somatosensory input number of efferent axons. Despite anatomic differences,
from the spinal trigeminal nucleus and the dorsal column the behavioral influence of the human olivocochlear system
50 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

can be demonstrated in subjects in whom vestibular than one-third of normal. However, there are indications
neurectomy has disrupted the efferent projection to the that ganglion cell survival is not the only factor in central
cochlea. These subjects have no detectable change in hear- neuronal survival, and that causal factors play a prominent
ing in quiet surroundings, but in the presence of noise, role in determining the degree of central degenerative
there is increased subjective loudness and worsened inten- change. On the one hand, excellent preservation of central
sity discrimination in the deafferented ear.47 neurons was seen in a patient with neurofibromatosis type
2, in whom tumor removal 7 and 10 years prior to death
had disrupted the eighth nerves, thus reducing the popula-
EFFECTS OF HEARING LOSS tion of cochlear ganglion cells acting on the brainstem to
effectively zero. In addition, among the subjects with
Prosthetic stimulation, provided at the level of the ear, the reduced populations of ganglion cells, neuronal degenera-
cochlea, or the brainstem, requires some structural foun- tive change was significantly greater in those with deafness
dation in the central auditory system to process the input. due to bacterial meningitis or adult-onset cochleosaccular
Thus one question to be considered is the possibility of degeneration (Scheibe’s degeneration). Additionally, there
degenerative change in brainstem auditory centers subse- was some evidence for a direct effect of genetic mutation
quent to hearing loss. Some insight into this question can on the central nervous system, as one subject with Scheibe’s
be obtained from investigations of changes in the human degeneration showed changes in other eighth nerve-related
brainstem subsequent to adult-onset, bilateral profound brainstem nuclei.50
hearing loss.48,49 The subjects of these investigations were
temporal bone/brainstem donors with well-documented
clinical histories, including cause of deafness, age of onset, CONCLUSIONS
duration of deafness, and hearing assessments. Postmortem
examination of the temporal bones provided histopatho- Information from the ear undergoes significant reorganiza-
logic evaluation and counts of the number of surviving tion as it passes through the brainstem, with an interplay of
cochlear ganglion cells. In the brainstems of these pro- excitation and inhibition, and changing patterns of activity
foundly deaf subjects, neuronal size was measured by in successive populations of neurons. The present protocol
digitizing the cross-sectional area of cells in the cochlear for placement of the auditory brainstem implant adjacent to
nuclei, superior olivary complex, and inferior colliculus. cochlear nuclei takes advantage of the ability of brainstem
A reduction in neuronal size was observed in all of the sub- centers to process and modify the artificial electrical stim-
jects. The change was primarily a reduction in the volume uli. If it becomes technically feasible to implant electrode
of cell cytoplasm, with little change in size of the cell arrays higher in the auditory pathway, consideration will
nucleus, and it was accompanied by marked reduction in have to be given to the issue of sacrificing the brainstem’s
cell staining. Because protein production occurs in the contribution to stimulus resolution and perception. How-
cytoplasmic compartment of cells, smaller size reflects a ever, it is also true that much of the complexity of stimulus
lesser volume of the subcellular machinery needed to sup- processing in the brainstem relates to recreation of the
port this activity. Reduction in stainable cytoplasmic Nissl auditory spatial field, a factor that will not be significant in
substance (rough endoplasmic reticulum, RNA) also use of a central prosthetic device. Thus, at the present time,
reflects lower levels of protein synthetic activity. One con- optimal device placement is still an open question.
sistent observation was that, in any given subject, all of the It is clear that profound deafness ultimately causes
auditory centers were affected equally, that is, the same degenerative changes within the auditory pathway, but
degree of size reduction and pallor was seen in neurons of these changes did not appear to occur immediately after
the cochlear nucleus, which are directly innervated by the hearing loss and complete loss of central neurons was
cochlear nerve, and in the higher brainstem nuclei. This never observed. The pronounced central degeneration in
indicates that the factors that produce cellular degenera- subjects with genetically and meningitis-induced deafness
tion in the central nervous system operate across several suggests that cause of deafness is at least as important as
synaptic levels of the central pathway. severity and duration of hearing loss. Thus etiology may
The size of central auditory neurons in these profoundly provide at least a partial explanation of differences in
deaf subjects varied from near normal to only 50% of nor- performance among those who have suffered hearing loss.
mal, despite the fact that all of the subjects ultimately The fact that profound loss of auditory input over decades
experienced the same degree of hearing loss. One poten- did not appear to cause complete degeneration of the
tial factor in the differential central degeneration appeared central auditory structures gives reason for optimism and
to be duration of deafness. Not surprisingly, the best pre- allows for an expectation that even the most severely
servation of central neurons was seen in a case in which affected cases will maintain a population of neurons poten-
onset was sudden and the duration of deafness was only tially responsive to stimulation from a prosthetic device.
1 year. The excellent survival of central auditory neurons in
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involved in reflexive head orientation to sound. J Neurophysiol 47. Zeng F-G, Martino KM, Linthicum FH, Soli SD: Auditory percep-
541:1183–1202, 1978. tion in vestibular neurectomy subjects. Hear Res 142:102–112,
23. Griffiths TD, Bates D, Rees A, et al: Sound movement detection 2000.
deficit due to a brainstem lesion. J Neurol Neurosurg Psychiatry 48. Moore JK, Niparko JK, Miller MR, Linthicum FH Jr: Effect of
62:522–526, 1997. profound hearing loss on a central auditory nucleus. Am J Otol
24. Pratt H, Polyakov A, Kontorovich L: Evidence for separate pro- 15:588–595, 1994.
cessing in the human brainstem of interaural intensity and temporal 49. Moore JK, Niparko JK, Perazzo LM, et al: Effect of adult-onset
disparities for sound lateralization. Hear Res 108:1–8, 1997. deafness on the human central auditory system. Ann Otol Rhinol
25. Yin TCT, Chan JC: Interaural time sensitivity in medial superior Laryngol 106:385–390, 1997.
olive of cat. J Neurophysiol 645:465–488, 1990. 50. Lalwani AK, Linthicum FH, Wilcox ER, et al: A five-generation
26. Spitzer MW, Semple MN: Neurons sensitive to interaural phase family with late-onset progressive hereditary hearing impairment
disparity in gerbil superior olive: Diverse monaural and temporal due to cochleosaccular degeneration. Audiol Neurootol 2:139–154,
response properties. J Neurophysiol 73:1668–1690, 1995. 1997.
 Chapter
Physiology of the Ear and the
Auditory Nervous System
2 Outline

Aage R. Møller, PhD Introduction Classical Ascending Auditory Higher-Order Processing

The Ear Pathways Parallel Processing and
Sound Conduction to the Cochlear Nucleus Stream Segregation
Cochlea Superior Olivary Complex and Connections to Other
Frequency Analysis in the Binaural Hearing Nonauditory Parts of the Brain
Auditory System Inferior Colliculus Evoked Potentials Generated
The Cochlea as a Frequency Medial Geniculate Body by the Ear and the Auditory
Analyzer Auditory Cortex Nervous System
Representation of Frequency Nonclassical Ascending The Ear
in the Auditory Nerve Pathways Electrocochleographic
Basis for Frequency Efferent System Potentials
Discrimination in the Olivocochlear Bundle Evoked Potentials from the
Auditory System: Temporal Centrifugal Pathways to Auditory Nervous System
or Place Representation? the Cochlear Nucleus and Brainstem Auditory Evoked
The Auditory Nervous Higher Centers Potentials
System Neural Plasticity Acoustic Middle Ear Reflex

INTRODUCTION system. Understanding the role of the nonclassical audi-

tory pathways has progressed over the years, and the
Many of the disorders confronting the neurotologist are importance of connections from the auditory pathways to
related to the auditory nervous system. Therefore, neuro- nonauditory parts of the brain have been explored. Studies
tologists need to comprehend the physiologic processes in animals that have provided important information about
that occur in the ear as well as those arising from the the way the auditory nervous system codes and transforms
auditory nervous system. Initially, understanding of the complex sounds will also be discussed in this chapter.
processing that occurs in the ear and the auditory nervous Current knowledge about the function of the auditory
system was mainly limited to academic interest. Now the nervous system is based primarily on recordings made from
development of cochlear and brainstem implants has made single nerve fibers and cells in animals. Because it is not
understanding of the function of the processing that technically feasible to record from single nerve cells or
occurs in the ear and the auditory nervous system of direct nerve fibers in the human auditory system, it is important
clinical importance. Therefore the function of both the ear to know how results obtained from animal experiments can
and the central auditory system will be covered here. The be applied to understanding the human auditory system.
representation of the frequency of sounds in the auditory Recording of evoked potentials, either from electrodes
nervous system is of particular importance and it is dis- placed on the scalp or from electrodes placed intracranially
cussed separately in this chapter. in patients undergoing neurosurgical operations, has been
The physiologic processes involved in coding and trans- the most common method of studying the physiology of
formation of complex sounds are important because most the human auditory system. Such studies have contributed
natural sounds not only have a broad spectrum but a more to understanding the pathophysiology of disorders that
or less rapidly varying frequency or spectral composition. affect the ear and the auditory nervous system.
The intensity of natural sounds such as speech sounds also Auditory evoked potentials are used in the diagnosis of
varies more or less rapidly. Having an understanding of pathologies of the human ear and auditory nervous system
how sounds such as pure tones are processed by the audi- and also in intraoperative monitoring. Interpretation of
tory system is not sufficient to understanding how complex evoked potential tests such as brainstem auditory evoked
sounds such as speech sounds are processed by the ear and potentials (BAEP, also known as AEP or ABR) requires
the various nuclei of the auditory system. During recent neurotologists to understand how neural activity in the
years much information has been gained about processing auditory nerve and auditory nuclei and fiber tracts is
in more central parts of the auditory system, and the reflected in the BAEP, as well as how changes in function
importance of parallel processing and stream segregation are reflected in these potentials and what those changes
has become evident. It has also become evident that neural mean in terms of pathologic processes. In many applications
plasticity is important for the functioning of the auditory of the BAEP, it is important to know the neural generators
52
 Physiology of the Ear and the Auditory Nervous System 53

of the different components of these potentials. This chap- entrance of the ear canal is different from that measurable
ter describes the generation of sound-evoked electrical without the person being present because the head acts as
activity in the ear, the auditory nerve, and the various audi- an obstacle that disturbs a free sound field. When sound
tory nuclei of the ascending auditory pathway. The trans- reaches an observer from a source that is located in front
formation of these near-field potentials into far-field of the observer, the sound pressure at the entrance of the
potentials that can be recorded from electrodes placed on ear canal is higher than it would be in that place if the
the scalp is also discussed. The neural generators of the person were not present. Together with the effect of the
BAEP are described on the basis of auditory evoked poten- resonance in the ear canal, the total gain is approximately
tials that were recorded from humans. Auditory evoked 15 dB in the frequency range between 2 and 5 kHz.2,3
potentials recorded from animals are different from those The sound pressure at the entrance of the ear canal
recorded from humans because of anatomic differences. depends on the direction to the sound source. Therefore,
The neural generators of the human BAEP can therefore the sound pressure at the two ears is different except when
not be directly deduced from studies of animals. sound reaches the observer from directly in front of or
More recently, magnetoencephalography (magnetic behind the observer. The difference depends on the
evoked potentials, MEP), a measure of the magnetic field frequency of the sounds. There is also a difference in the
that is created by electrical currents in the central nervous arrival time of sounds at the two ears that is a direct func-
system (CNS), has come into use for studies of the response tion of the azimuth. The arrival time difference together
to sensory simulation. Functional imaging methods such as with the difference between the sound pressure at the two
functional MRI (fMRI), positron emission tomography ears are the physical bases for directional hearing.
(PET), and single-photon emission computed tomography Sounds that reach the tympanic membrane set it into
(SPECT) are other means of detecting activation of neural motion, and this motion is conducted to the fluid of
structures due to sound stimulation for research purposes the cochlea by the three ossicles of the middle ear. The
and are beginning to find clinical applications. These meth- middle ear functions as an impedance transformer, which
ods all measure small changes in blood flow and the use improves the transmission of sound to the cochlear fluid.
of such methods are based on the assumption that increased This improvement in transmission is mainly the result
neural activity is associated with increased blood flow. of the large ratio between the area of the tympanic mem-
However, this assumption has been challenged. brane and that of the stapes footplate.2,4 The improvement
This chapter describes the basic functions of the ear and of sound transmission varies with its frequency. The
the auditory nervous system. The role of the cochlea as a increase is between 25 and 30 dB. This also means that the
frequency analyzer and the representation of frequency in middle ear causes a large difference between the amount
the nervous systems are discussed, followed by a discussion of sound that reaches the two windows of the cochlea.
of neural processing of complex sounds. Contemporary This difference between the force at the two windows sets
knowledge and understanding of higher-order processing the fluid in the cochlea into motion. The improvements
in the auditory nervous system is described as assessed of sound transmission to the cochlea by the action of
using different experimental methods in studies of animals the middle ear compared with a situation when an equal
as well as in a few studies in humans. Parallel processing amount of sound reaches both windows is thus much
and stream segregation are described, and their impor- greater than the aforementioned 25 to 30 dB; patients
tance in central processing of auditory information is dis- without the middle ear can experience hearing impairment
cussed. The role of neural plasticity in the normal function on the order of 50 dB.2
of the auditory system and as a cause of symptoms of Various pathologies can affect the function of the mid-
pathologies is discussed. The anatomy and physiology of dle ear.2,4 For example, the sound transmission through
the acoustic middle ear reflex is examined in view of its the middle ear changes (decreases) when the air pressure
importance in neurotologic diagnoses. in the middle ear cavity is different from the ambient
pressure.2,5 Transmission of sound is also decreased when
fluid in the middle ear covers the tympanic membrane or
THE EAR parts of it.2 Tympanometry, which involves measuring the
ear’s acoustic impedance (or admittance or compliance)
The following description of the function of the ear is while the air pressure in the sealed ear canal is varied, can
divided into that of the sound conductive apparatus and determine the pressure in the middle ear cavity noninva-
that of the cochlea. The description of the function of the sively.2,5 Disorders such as otosclerosis impair hearing by
cochlea focuses on its ability to separate sounds according adding stiffness to the middle ear. A perforation of the
to their frequency (frequency analysis). tympanic membrane impairs hearing by allowing sound to
enter into the middle ear cavity and by impairing the func-
tion of the tympanic membrane.2,6
Sound Conduction to the Cochlea Two small muscles that are attached to the ossicles can
The ear canal and the middle ear conduct sound to the affect sound transmission through the middle ear. One, the
cochlea, where the sensory cells are located. The ear canal tensor tympani, is innervated by the trigeminal nerve and
and the acoustic effects of the head as an obstacle in a pulls the tympanic membrane inward when it contracts,
sound field modify the sound that reaches the cochlea. thus causing the tympanic membrane to be stretched and
The ear canal acts as a resonator that is tuned to a fre- thereby attenuating sound transmission for low-frequency
quency of approximately 3 kHz depending on the length sounds. The other muscle, the stapedius muscle, is
of the canal (average 2.8 kHz).1 The sound pressure at the attached to the stapes and pulls the stapes in a direction
54 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

perpendicular to its normal motion in response to sound. decreases until the wave motion becomes extinct. The
The stapedius muscle is innervated by the facial nerve, and distance that the wave travels before it reaches its peak
its contraction also decreases the middle ear’s ability to amplitude is a direct function of the frequency of the
conduct low-frequency sounds. In humans the stapedius sound that has initiated the motion. Thus, the vibration
muscle contracts as an acoustic reflex in response to a amplitude of the basilar membrane in response to low-
strong sound. (See the section on Acoustic Middle Ear frequency sounds is highest near the apex of the cochlea,
Reflex near the end of this chapter.) while high-frequency sounds give rise to maximal vibra-
Contraction of the stapedius and the tensor tympani tion of regions of the basilar membrane at the base of the
muscles increases the ear’s acoustic impedance.2,5,7 The cochlea. Each point of the basilar membrane vibrates
contractions of the stapedius muscle can therefore be with the greatest amplitude for a certain frequency, and
recorded by measuring changes in the ear’s acoustic each point can be regarded as possessing frequency selec-
impedance. This technique is noninvasive. Unlike a con- tivity, that is, being tuned to a certain frequency (Fig. 2-1).
traction of the tensor tympani muscle, which causes the A frequency scale can be laid out along the basilar mem-
tympanic membrane to move inward, a contraction of the brane with respect to the highest vibration amplitude, low
stapedius muscle does not cause any noticeable movement frequencies at the apex and high frequencies at the base of
of the tympanic membrane.2,7 the cochlea. This also means that the basilar membrane
separates sounds according to their spectral contents, and
Frequency Analysis the different spectral components of a complex sound are
separated along the basilar membrane.
in the Auditory System Once technologic advances made it possible to measure
The cochlea separates sounds according to their frequency the vibration amplitude of the basilar membrane in living
(or spectrum*) before the sounds are converted into a neu- animals at sound intensities within or just above that of
ral code by the inner hair cells. The frequency selectivity of normal sounds,10 and later down to threshold values11–13
auditory nerve fibers and cells in the nuclei throughout the (see Fig. 2-1), it became evident that the motion of the
ascending auditory pathways including those of the audi- basilar membrane was nonlinear. Its frequency selectivity
tory cerebral cortex is based on the frequency selectivity of depended on the sound intensity.
the cochlea. However, that frequency selectivity is trans- The vibration of the basilar membrane activates sensory
formed in various ways as the information ascends in the cells (inner and outer hair cells) that are located along the
auditory nervous system. Much of our knowledge about the basilar membrane. The hair cells are therefore activated
function of the frequency analysis in the cochlea has been according to the frequency (spectrum) of sounds. The
achieved by studies of the responses from single auditory outer hair cells are morphologically similar to inner hair
nerve fibers but valuable information has also been cells, but they have a purely mechanical function in that
obtained by recordings from single hair cells and from they act as “motors” that amplify the motion of the basilar
measurements of the vibration of the basilar membrane.

The Cochlea as a Frequency Analyzer

Studies of the frequency selectivity of the ear were pio-
neered by von Békésy between 1928 and 1942 (see von
Békésy 19608), who examined this feature in human
cadaver ears. This work provided the first experimental
evidence that the cochlea performs a frequency analysis on
incoming sounds and that the type of motion of the basi-
lar membrane is a traveling wave. Theoretical studies of
the hydromechanical properties of the cochlea have been
important in providing the basis for experimental studies
and for providing explanations of the findings in animal
studies. (For a review of the frequency selective properties
of the cochlea, see a recent book by Jozef Zwislocki.9)
The basilar membrane is set into motion by the cochlear
fluid. That motion is a traveling wave because of the prop-
erties of the basilar membrane and the interaction between
the basilar membrane and the fluid in the cochlea. The
traveling wave is initiated at the base of the cochlea and
progresses toward the apex. As it travels along the basilar
membrane, its amplitude first increases and then, once the
wave has traveled a certain distance, its amplitude rapidly

*Frequency and spectrum of sounds are sometimes used synonymously

but the word frequency should only be used to describe the properties of Figure 2-1. Basilar membrane vibration amplitude as a function of frequency
simple sounds such as pure tones or trains of impulses, while the proper- for different sound levels in a guinea pig. (Adapted from Johnstone BM,
ties of complex sounds should be described by their spectrum which Patuzzi R, Yates GK: Basilar membrane measurements and the traveling
represents the distribution of energy as a function of the frequency. wave. Hear Res 22:147–153, 1986.)
 Physiology of the Ear and the Auditory Nervous System 55

membrane for sounds of low intensities.14 This amplifica-

tion, which adds approximately 50 dB to the sensitivity of
the ear gradually decreases with increasing sound intensity,
thereby compressing the intensity range of sounds. The
transduction mechanism of the inner hair cells provides
additional amplitude compression. Amplitude compres-
sion is important because of the limited dynamic range of
neural coding in auditory nerve fibers.

Representation of Frequency
in the Auditory Nerve
The frequency (or spectrum) of sounds is represented in two
ways in the auditory nerve. One way, the place representa-
tion, is a result of the frequency selectivity of the basilar
membrane, and the other, the temporal representation, is by
the temporal pattern of the discharges of single auditory
nerve fibers. The basis for the temporal representation of
sounds is that the vibration of the basilar membrane is
reflected in the time pattern of the discharges in auditory
nerve fibers. Thus, a pure tone causes the basilar membrane
to vibrate with a frequency of the tone and this vibration is
reflected in the excitation of inner hair cells and subse-
quently in the temporal pattern of the discharges of auditory
nerve fibers. This phenomenon, known as phase-locking,
has been experimentally confirmed, at least for sounds of Figure 2-2. Frequency response area of a single auditory nerve fiber in a
guinea pig. A continuous tone, the frequency of which was varied, was used
relatively low frequencies. as stimulus. The different rows of nerve impulses are the responses to this
Place Representation of Frequency tone when its intensity was varied in 5-dB steps. (Adapted from Evans EF:
The frequency response and other properties of single fibers in the
in the Auditory Nerve guinea pig cochlear nerve. J Physiol 226:263–287, 1972.)
Individual inner hair cells are activated according to the
frequency of sounds that reach the ear, and therefore nerve
fibers of the auditory nerve that innervate these hair cells amplitude of the basilar membrane in human cadaver ears
also become activated according to the frequency of or in the ears of anesthetized experimental animals used
sounds. Each nerve fiber consequently responds best to a very high sound levels. The need to use high-intensity
certain frequency of a pure tone. The response of an indi- stimuli resulted in selectivity curves that were much
vidual nerve to tones decreases as the frequency of a tone broader than the FTCs of single auditory nerve fibers.
is changed up or down from the frequency to which Thus a discrepancy arose in measurements of tuning acuity
the fiber responds best. Recordings from single auditory of the basilar membrane and single auditory nerve fibers.
nerve fibers by means of microelectrodes in response to This discrepancy gave rise to several hypotheses about what
pure tones have confirmed that assumption. The discharge kind of “spectral sharpening” could be occurring in the
rate of a single auditory nerve fiber increases above its nor- neural transduction process.18
mal spontaneous rate when the stimulus sound’s frequency
and intensity are within a certain range15–17 (Fig. 2-2).
A curve that envelops the area of response shows the
thresholds of a single auditory nerve fiber for tones of differ-
ent frequencies. Such curves are known as tuning curves or
frequency threshold curves (FTCs). The frequency at which
the threshold is lowest is known as the nerve fiber’s best
frequency, or the nerve fiber’s characteristic frequency (CF).
It corresponds to the frequency of the tone that produces the
highest vibration amplitude on the basilar membrane. When
FTCs are obtained from representative samples of auditory
nerve fibers, a family of such tuning curves is obtained, and
the CFs of the individual nerve fibers cover the entire range
of frequencies audible to the particular animal from which
the recordings were obtained15–17 (Fig. 2-3).
The vibration amplitude of the basilar membrane for
sounds at physiologic levels is extremely small, and only
recently has it become possible to study the vibration of
Figure 2-3. Family of frequency tuning curves obtained by recording from a
the basilar membrane down to the threshold of hearing. number of auditory nerve fibers. (Adapted from Kiang NYS, Watanabe T,
Ten to 20 years ago, the techniques for obtaining basilar Thomas EC, Clark L: Discharge Patterns of Single Fibers in the Cat’s Auditory
membrane tuning curves by measuring the vibration Nerve. Cambridge, MA, MIT Press, 1965.)
56 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Studies of the frequency selectivity of auditory nerve fibers

using noise as stimuli in connection with cross-spectral
analysis of the discharge rates of single auditory nerve
fibers in animals showed evidence that the basilar mem-
brane is nonlinear from threshold values of sound intensi-
ties to above physiologic sound levels.19,20 These studies
showing that the frequency selectivity of the auditory
periphery broadened when the intensity of the sound
was increased were confirmed by studies of the motion of
the basilar membrane.11–13 The obtained FTCs19,20 were
narrower near the threshold of hearing, and their width
increased when the sound level increased. In addition,
the frequency to which a certain nerve fiber is tuned
shifts downward when the sound intensity increases2,19,20
(Fig. 2-4). Earlier, it was shown that the location of maxi-
mal generation of cochlear microphonics (CM) along the
basilar membrane shifts with the intensity of the stimulus
sound.21 These results were confirmed when the frequency
selectivity of the cochlea in living animals were studied,
using methods that allowed measurements of the vibration
of the basilar membrane near the threshold of hearing11,13
(see Fig. 2-1). Similar results were obtained in anes-
thetized cats13 and guinea pigs.11,12 It also became evident Figure 2-5. Frequency selectivity of the basilar membrane (Thick line:
that the mechanical tuning curves of the basilar membrane isovelocity; thin line: isodisplacement) determined at sound levels near the
threshold of hearing, compared with a FTC (dashed line) of the auditory
in living animals were nearly identical to the FTCs nerve. Both measurements were done in anesthetized guinea pigs. (Adapted
obtained by measuring the responses from single auditory from Sellick PM, Patuzzi R, Johnstone BM: Modulation of responses of spiral
nerve fibers12,13 (Fig. 2-5). There was no longer a need of ganglion cells in the guinea pig cochlea to low frequency sound. Hear Res
7:199–221, 1982.)

a “second” filter that sharpened the selectivity of the

basilar membrane.
The results of these studies radically changed the view of
the function of the ear as a frequency analyzer. A similar
fundamental change in our understanding of the frequency
analyzing function of the ear was caused by the discovery of
the role of the outer hair cells. The explanation for this
nonlinearity of the basilar membrane response was pro-
vided when it was shown that the outer hair cells act as
“motors” that provide the energy necessary to compensate
for frictional losses of the basilar membrane motion.14 The
action of the outer hair cells is thus responsible for the high
degrees of sensitivity and frequency selectivity of the basi-
lar membrane that is present at low stimulus intensities.
Loss of outer hair cells results in a hearing loss of 50 to
60 dB and a degradation in cochlear frequency selectivity.2
The discovery of the function of the outer hair cells also
explained the results of earlier studies of the responses
from single auditory nerve fibers that showed that the
frequency selectivity of the cochlea is vulnerable and
depends on metabolic activity.18 Evans showed that depriv-
ing the cochlea of oxygen results in a broadening of the
tuning curves18 (Fig. 2-6). At the time these studies were
published the results were interpreted to indicate the exis-
tence of a neural mechanism (“second filter”) that sharp-
ened the frequency selectivity of the basilar membrane.
These studies were performed using simple sounds as
stimuli, mostly pure tones. Other aspects of coding of
Figure 2-4. Tuning properties of a single auditory nerve fiber in a rat sounds in the auditory nerve become apparent when more
estimated from the responses of a single auditory nerve fiber to
pseudorandom noise of different intensities (given in dB SPL). (Adapted
complex sounds are used. The tuning curves shown in
from Møller AR: Frequency selectivity of phase-locking of complex sound in Figures 2-2 and 2-3 were obtained by probing with a single
the auditory nerve of the rat. Hear Res 11:267–284, 1983.) tone, the frequency and intensity of which was changed, to
 Physiology of the Ear and the Auditory Nervous System 57

It has been shown recently that two-tone inhibition is

not mediated through synaptic transmission but rather it is
a result of the nonlinearity in the micromechanics of the
cochlea,23 and is thus another manifestation of cochlear
nonlinearities. This is one reason why many investigators
prefer to call this phenomenon two-tone suppression
rather than two-tone inhibition.
Temporal Representation of Frequency
in the Auditory Nerve
The discharges of single nerve fibers are phase-locked to
the waveforms of sounds within their response areas24
(Fig. 2-8). Such phase-locking can be demonstrated at
least for frequencies below 4 to 5 kHz.19,20,25 This is
assumed to be the basis for the temporal hypothesis for
frequency discrimination in the auditory system, which
was originally known as the volley theory.26 Phase-locking
to the waveform of a sound means that the neural discharges
in single auditory nerve fibers have a higher probability of
appearing at a certain phase of the sound than at other
phases of the sound. Phase-locking was first shown to
Figure 2-6. Effect of anoxia on the frequency threshold curves of a single occur in fibers of the auditory nerve for pure tones,27 but
auditory nerve fiber in a guinea pig. (Adapted from Evans EF: Normal and later it was shown to occur also for more complex sounds
abnormal functioning of the cochlear nerve. Symp Zool Soc Lond
37:133–165, 1975.) such as those that consist of more than one sinusoid28
(Fig. 2-9), including broadband sounds such as vowels29
determine the least intensity necessary to produce a notice- and broadband noise.19,20
able increase in firing rate. When two tones are presented,
one constant tone at the fibers CF and the other a tone
with varying intensity and frequency, it is found that the
discharges evoked by the constant tone decrease when the
variable tone is within a specific intensity and frequency
range. Figure 2-7 shows examples of such interaction in
which the response area, obtained using a single tone, is
shown together with the areas of intensity and frequency
in which a second tone decreased the discharge rate of
the response evoked by the first tone (cross hatched in Figure 2-8. Phase-locking of discharges in a single guinea pig auditory nerve
fiber to a low-frequency tone (300 Hz), near threshold. (Adapted from
Fig. 2-7).22 Note that there are two such inhibitory areas, Arthur RM, Pleiffer RR, Suga N: Properties of “two tone inhibition” in
one on each side of the response area of the fiber depicted primary auditory neurons. J Physiol 212:593–609, 1971.)
in Figure 2-7. This is typical for auditory nerve fibers, and
this two-tone inhibition has been studied extensively.22

Figure 2-9. Period histograms of discharges in a single auditory nerve fiber

Figure 2-7. Inhibitory areas of a typical auditory nerve fiber (cross hatched) of a squirrel monkey to stimulation with two tones of different frequencies
in a cat together with the frequency threshold curve (filled circles). that were locked together with a frequency ratio of 3:4 and an amplitude ratio
The inhibitory areas were determined by presenting a constant tone (CTCF ) of 10 dB. The different histograms represent the responses to this sound
together with a tone, the frequency and intensity of which were varied to when the intensity was varied over a 50-dB range. (Modified from Rose
determine the threshold of a small decrease in the neural activity evoked by JE, Hind JE, Anderson DJ, Brugge JF: Some effects of stimulus intensity on
the constant tone (CTCF ). (Adapted from Sachs MB, Kiang NYS: Two-tone response of auditory fibers in the squirrel monkey. J Neurophysiol
inhibition in auditory nerve fibers. J Acoust Soc Am 43:1120–1128, 1968.) 34:685–699, 1971.)
58 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Basis for Frequency Discrimination in the Auditory the auditory nerve function as spatial averagers that not
System: Temporal or Place Representation? only preserve the precision of temporal coding but in fact
can improve the temporal precision of neural coding.34,35
The frequency of a sound can be determined equally well
Some neurons in the cochlear nucleus respond with
from its spectrum as from its temporal pattern. Therefore,
greater temporal precision than that of auditory nerve
auditory frequency discrimination can either be based on
fibers.36,37 That temporal information is preserved in
the place of maximal vibration along the basilar membrane
synaptic transmission is also evident from the fact that
(place hypothesis), or the coding of the temporal pattern of
directional hearing depends on the detection of very small
sounds in the discharge pattern of auditory nerve
time intervals between the arrival time at the two ears.
fibers (temporal hypothesis), or a combination of both.
That temporal information must be preserved until it can
The question of the importance of place versus temporal
be decoded, presumably in the medial superior olivary
representation for frequency discrimination was of purely
nucleus. Psychoacoustic studies have shown that human
academic interest before cochlear implants were intro-
observers can discriminate azimuths with an accuracy of a
duced. Since then it has become of great practical and
few degrees, corresponding to less than 10 μsec (microsec-
clinical significance for the design and use of cochlear
onds). This means that temporal coding must be preserved
implants.2,30,31
with that level of precision through at least two synapses
The place principle of coding the frequency of a sound
(cochlear nucleus and medial superior olivary nucleus) in
was favored for many years as an explanation for the ability
addition to that of the hair cells.
to discriminate frequency. Recently evidence has accumu-
Other studies have shown that phase-locking in the audi-
lated that indicates temporal coding may play a more
tory nerve can be demonstrated for frequencies of at least
important role in the coding of frequency or spectral com-
up to 5 kHz,19,20 and it probably exists for much higher
ponents of sounds than was believed earlier. The finding
frequencies.38 The great importance of temporal coding of
that the frequency to which a fiber in the auditory nerve
complex sounds also explains the success of cochlear
is tuned changes with the intensity of the sound19,20
implants, which provide excellent timing of sounds but
(see Fig. 2-4) indicates that frequency maps in higher
only coarse place representation of sound spectra.31
centers of the ascending auditory pathway, including the
Another indication of the importance of the temporal
auditory cortex, would change with the intensity of a sound
code for frequency discrimination is the fact that disorders
because such maps are based on cochlear frequency tuning.
of the auditory nerve impair speech discrimination more
This generates doubt that the place principle alone is
than does a hearing loss of cochlear origin with the same
responsible for the neural coding that is the basis for
threshold shift. Disorders of the auditory nerve are likely to
discrimination of the frequency of a pure tone or for dis-
cause desynchronization of neural activity, thus impairing
crimination of complex sounds such as speech sounds on
the temporal code of frequency. Recently, the term auditory
the basis of their frequency.30
neuropathy has been used to describe such disorders.
It has been evident for a long time that the selectivity of
In summary, it seems that the ability of the cochlea to
the basilar membrane is not sufficiently acute to explain
separate sounds according to their frequency may be less
the power of human frequency discrimination but it was
important for frequency discrimination than was previ-
assumed that some (unknown) neural mechanisms would
ously assumed. Instead the importance of the cochlea’s fre-
sharpen the selectivity so that it would be sufficiently acute
quency selectivity may rather be to separate the sound
to explain the ability to discriminate small differences in
spectrum of complex sounds such as speech sounds into
frequency of sounds. The fact that the frequency to which
narrow “slices” to facilitate temporal coding of sounds.31
a point on the basilar membrane is tuned depends on
the intensity of the sounds demonstrates that basilar
membrane tuning,2,10,11,13,19–21 and thus the place principle, THE AUDITORY NERVOUS SYSTEM
is not sufficiently robust to explain common psychoa-
coustic findings that frequency discrimination depends The ascending auditory nervous system is anatomically
little on sound intensity.32 This is a strong indication that organized so that it can perform hierarchical and parallel
mitigates against the place hypothesis as a basis for audi- processing of auditory information. Two different ascending
tory frequency discrimination. pathways have been identified: the classical pathways (also
Increasing evidence has accumulated during this time known as the lemniscal or the specific pathways) and the
regarding the importance of the temporal code for dis- nonclassical pathway (extralemniscal, or nonspecific path-
crimination of complex sounds such as speech sounds. ways).2,35,39–42 The anatomy and the function of the classical
Frequency discrimination is important for discrimination pathways are better known than that of the nonclassical.
of speech sounds. However, it has been shown that the
temporal representation of vowel sounds in the discharge Classical Ascending
pattern of single auditory nerve fibers is more robust29 Auditory Pathways
than place representation of vowel spectra.33
A major obstacle for the temporal hypothesis has been The classical auditory ascending pathways are more com-
the belief that synaptic transmission involved temporal plex than the ascending pathways of other sensory sys-
uncertainties (synaptic jitter) that would impair the tems.2,35,40 All auditory information is interrupted by
precision of temporal coding of frequency. That obstacle, synaptic transmission in each of the three main relay
however, does not exist because many neurons that receive nuclei: the cochlear nucleus (CN), the central nucleus of
hundreds and indeed thousands of synaptic inputs from the inferior colliculus (ICC), and the ventral portion of the
 Physiology of the Ear and the Auditory Nervous System 59

medial geniculate body (vMGB) (Fig. 2-10). The fiber All these nuclei have complex internal networks of neu-
tract of the lateral lemniscus (LL) crosses the midline rons that process auditory information, although the FTCs
while connecting the CN with the ICC. The brachium of of neurons in the cochlear nucleus, the nuclei of the supe-
the IC (BIC) connects the ICC with the vMGB, which rior olivary complex, and the nucleus of the inferior
projects to the primary (and secondary) auditory cerebral colliculus are rather similar to those of fibers of the auditory
cortices (AI, AAF, PAF). Other nuclei, such as those of the nerve16 (Fig. 2-11). Whereas the representation of the fre-
superior olivary complex (SOC), the dorsal and ventral quencies of simple sounds such as pure tones seems consis-
nuclei of the lateral lemniscus (DNLL and VNLL) inter- tent throughout the ascending auditory nervous system,
rupt some ascending information (see Fig. 2-10). auditory information about complex sounds undergoes

AI Cortex
AAF

AII PAF

Dorsel
thalamus D
Ventral
M OV thalamus

DC
Inferior
ICX calliculus
ICC

B LL

Figure 2-10. Schematic drawing of the

ascending auditory pathways. A, Anatomic
locations and connections from the audi-
tory nerve to the MGB. AN, auditory nerve;
CN, cochlear nucleus; SOC, superior
olivary complex; LL, lateral lemniscus;
NLL, nuclei of the lateral lemniscus; ICC,
central nucleus of the inferior colliculus;
BIC, brachium of the inferior colliculus;
MGB, medial geniculate body. (Adapted
from Møller AR: Sensory Systems:
Anatomy and Physiology. Amsterdam,
Academic Press, 2001). B, Connections
from the central nucleus of the inferior
colliculus (ICC ) to the ventral portion of
the MGB and their connections to auditory
cortical radiations. Most of the connections
have reciprocal descending connections;
only one of which are shown (between AI
and the MGB). AAF, anterior auditory field;
AI, primary auditory cortical area; D dorsal
division; DC, dorsal cortex of the inferior
A colliculus; ICC, central nucleus of the
inferior colliculus; ICX, external nucleus of
the inferior colliculus; M, medial (or mag-
nocellular) division of MGB; OV, ovoid part
of the MGB; PAF, posterior auditory field; V,
ventral division (Adapted from Møller AR:
Sensory Systems: Anatomy and Physiology.
Amsterdam, Academic Press, 2001.)
60 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

in the ascending auditory pathway to tone bursts indicate

that successive transformation of information occurs as it
ascends in the ascending auditory pathways.
Although the ascending auditory pathways are mainly
crossed, there are connections between the CN and the ipsi-
lateral ICC and there are ample connections between nuclei
on the two sides (see Fig. 2-10). The information from the
two ears reaches the same neurons in the nuclei of the SOC
and in the ICC and that is assumed to be the basis for the
ability to discriminate the direction to a sound source and
perception of auditory space43 (directional hearing). The
A superior colliculus (SC), which receives auditory input from
the ICC, is important for perception of auditory space.

Cochlear Nucleus
When the auditory nerve enters the cochlear nucleus each
fiber bifurcates and one branch terminates on neurons in
the anterior ventral cochlear nucleus (AVCN). The other
branch bifurcates again, and one branch terminates on neu-
rons in the posterior ventral cochlear nucleus (PVCN), and
the other branch terminates in the dorsal nucleus of the
cochlear nucleus (DCN). This means that each fiber of the
B auditory nerve innervates each of the three main divisions
of the cochlear nucleus, thus enabling information that is
carried in each of the fibers of the auditory nerve to be
processed (in parallel) in three different populations of neu-
rons. This represents the beginning of parallel processing
that is abundant in the ascending auditory nervous system.
Tonotopic organization is clearly evident in the cochlear
nucleus44 (Fig. 2-12), and each of the three main subdivisions
of the cochlear nucleus has its own frequency map. At first
glance the responses of single nerve cells of all divisions of
the cochlear nucleus possess frequency selectivity similar to
that of single auditory nerve fibers (see Fig. 2-11), but some
C neurons in the CN have tuning curves of different shapes,
and some neurons’ FTCs have more than one peak.2,18,44
Response areas of cells in the cochlear nucleus to a tone,
the frequency of which is changed, become narrower when
the frequency of the tone is changed rapidly, compared
with those obtained in response to tones with slowly varying

D
Figure 2-11. Tuning curves obtained from the auditory nerve (A), dorsal
cochlear nucleus (B), trapezoidal body (C), and inferior colliculus (D). Solid
lines in D show average human hearing threshold. (Adapted from Katsuki Y,
Sumi T, Uchiyama H, Watanabe T: Electric responses of auditory neurons in
cat to sound stimulation. J Neurophysiol 21:569–588, 1958.)

considerable transformation and reorganization as it passes

through the various nuclei of the ascending auditory path-
ways, as can be demonstrated by recording the response to
Figure 2-12. Tonotopical organization in the cat cochlear nucleus. Pv,
complex sounds such as sounds the frequencies or intensi- posterior ventral; Av, anterior ventral; Dc, dorsal cochlear nucleus. (Adapted
ties of which vary at different rates. The response patterns from Rose JE, Galambos R, Hughes JR: Microelectrode studies of the
of the auditory nerve fibers and of cells of the various nuclei cochlear nuclei in the cat. Bull Johns Hopkins Hosp 104:211–251, 1959.)
 Physiology of the Ear and the Auditory Nervous System 61

frequency45 (Fig. 2-13), and more nerve impulses are

delivered when the frequency of the stimulus tone is close
to the cell’s CF. When the frequency of the stimulus tone
is changed above a certain rate, the response again broad-
ens. Similar changes have not been demonstrated in the
responses of auditory nerve fibers, and the above men-
tioned features of cells in the cochlear nucleus therefore
are taken as an indication of some of the transformations
that occurs in the responses of cells in auditory nuclei.
Other signs of processing of information in the cochlear
nucleus are the differences in the response to tone burst
between cells in the cochlear nucleus compared with audi-
tory nerve fibers. Although the shape of post-stimulus
time histograms of the responses of all single auditory
nerve fibers to tone bursts are similar, showing a rapid
increase in discharge after a brief latency and then a slight
gradual decrease in the discharge rate (Fig. 2-14A), the
shape of post-stimulus time histograms of the responses of
different neurons in the cochlear nucleus varies and at least
four different types of response patterns have been identi-
fied2,17,46–49 (Fig. 2-14B).
Post-stimulus time histograms of the response to tone
bursts have been used to classify neurons in the cochlear
nucleus but other differences could be used for classifica-
tion of neurons in the CN. One such feature relates to
the responses to small changes in the amplitude of sounds.
The discharge rate of neurons in the cochlear nucleus in
response to tones, the amplitudes of which are varied sinu-
soidally (sinusoidally amplitude-modulated tones),
becomes modulated with the same frequency as that used
to modulate the stimulus tones,2,25,50 and different neurons
respond to such sounds in distinctly different ways.47,48,51–53
A plot showing the degree of modulation of the discharge
rate as a function of the modulation frequency is known as
the modulation transfer function (MTF).
The discharge rates of neurons in the cochlear nucleus
are modulated to the greatest extent for modulation

Figure 2-14. A, PST histograms of responses to tone bursts of different

intensities recorded from a single auditory nerve fiber in a cat. (Adapted
from Kiang NYS, Watanabe T, Thomas EC, Clark LF: Discharge Patterns
of Single Fibers in the Cat’s Auditory Nerve. Cambridge, MA, MIT Press,
1965.) B, PST histograms of responses of cells in the cochlear nucleus to
tone bursts. Each histogram represents one class of units. (Adapted from
Pfeiffer RR: Classification of response patterns of spike discharges for
units in the cochlear nucleus: Tone-burst stimulation. Exp Brain Res
Figure 2-13. Histograms of the responses recorded from a single nerve cell 1:220–235, 1966.)
in the cochlear nucleus of a rat to tones, the frequencies of which were
changed at two different rates. A, At 10 sec for a complete path. B, At 156
ms for a complete path. C, D, Histograms showing the same data on an
expanded time/frequency scale. The change in the frequency of the stimulus
tones is shown below. (Adapted from Møller AR: Coding of sounds with
rapidly varying spectrum in the cochlear nucleus. J Acoust Soc Am 55:
631–640, 1974.)
62 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

frequencies in the range of 50 to 150 Hz,47,48,54,55 (Fig. 2-15) The SOC is usually regarded as the most peripheral
while MTF of auditory nerve fibers have cut-off frequen- level at which the ascending auditory pathway crosses from
cies of approximately 1 kHz.25 Neurons in the cochlear one side to the other. However, there are also connections
nucleus thus selectively modulate the frequency of a tone between the two cochlear nuclei, as mentioned earlier.
(or noise) as well as the frequency of a tone stimulus. When hearing acuity is nearly equal in both ears, the
At the “best” modulation frequency, the discharges of neu- direction of a sound can be determined with great accuracy
rons in the cochlear nucleus may be modulated nearly 100% and, perhaps more importantly in humans, binaural hearing
when the amplitude of the sound is modulated by only a few helps to discriminate sound on the basis of the location of its
decibels.2,36,49,50,54 The response of cells in the cochlear source in space. When listening to speech in an environ-
nucleus is also different from that of auditory nerve fibers in ment with more than one speaker, or in a noisy environ-
that cells in the CN respond better to the modulation wave- ment, binaural hearing improves the ability to distinguish
form than do auditory nerve fibers.47,48,54,55 one speaker from another. The use of binaural hearing for
Although the vast majority of nerve cells in the cochlear this purpose is known as the “cocktail party phenomenon.”
nucleus receive input from only the ipsilateral ear, some The ability to discriminate from which direction a
neurons respond to contralateral sounds,56–58 either by sound is coming is based on the difference in arrival time
increasing their discharge rate (excitatory) or by decreasing and intensity of the sound that reaches both ears. When a
it (inhibitory). Sound-driven activity from the ipsilateral ear sound is located directly in front of the head, or exactly
can also, in a few nerve cells, be inhibited by delivering behind the head, the sound will arrive at both ears at pre-
sound, in a specific frequency range, to the opposite ear. cisely the same time. When a sound comes from any other
direction, it will arrive at each ear at different times
because of the different distance between each ear and the
Superior Olivary Complex and Binaural Hearing
sound source. The value of this time difference is a direct
The superior olivary complex (SOC) (see Fig. 2-10) con- function of the azimuth to the sound source (and the prop-
sists of a series of nuclei scattered in the brainstem. The agation velocity of the sound), which is constant. Jeffress60
anatomic organization of the SOC in humans versus that presented a hypothesis that describes how interaural time
in small animals is the most different of all the ascending differences can be detected by a neural circuit that consists
auditory nuclei of the brainstem.59 The possible physio- of coincidence detectors and variable delay lines.
logic effects of these differences are difficult to assess, but Experimental evidence has been presented that such a
caution should be exercised when drawing conclusions circuit exists in the medial superior olivary (MSO) nucleus
from the results of studies in animals about the function of of the SOC.61
the various groups of neurons in the SOCs of humans. It has been shown in animal experiments that neurons in
the MSO nucleus act as coincidence detectors and only
respond when excited from both ears simultaneously.
These coincidence detectors receive their input from
cochlear nucleus cells through axons of different lengths.
These axons act as delay lines with different delays, which
enables the coincidence detectors to respond to sounds
that arrive at the two ears with different intervals. A popu-
lation of neurons with such an array of coincidence detec-
tors with their delay lines of different length could cover
the range of interaural delays that correspond to azimuths
of 180 degrees (approximately 0.65 msec).
In addition to the interaural time difference, interaural
intensity differences that are a function of the azimuth are
used as a physical basis for directional hearing. However,
intensity differences between the sound at one ear and that
at the other ear has a more complex relationship to the
azimuth than the interaural time differences and is highly
dependent on the spectrum of the sound. Neurons in the
SOC may be sensitive to interaural intensity differences
but that property of binaural hearing is primarily
processed by neurons in the inferior colliculus.

Inferior Colliculus
The IC is the midbrain nuclei of the ascending auditory
pathways (see Fig. 2-10). On anatomic grounds, the IC can
be divided into the central nucleus (ICC), the external
Figure 2-15. Modulation transfer functions obtained in a single auditory nucleus (ICX), and the dorsal cortex (DC).41,62 The neurons
nerve fiber (thin line) and a cell in the cochlear nucleus (heavy line) of a rat.
(Adapted from Møller AR: Dynamic properties of primary auditory fibers
of the ICC are the midbrain relay nucleus of the classical
compared with cells in the cochlear nucleus. Acta Physiol Scand ascending auditory pathways.63 The cells of the ICC receive
98:157–167, 1976.) auditory input via the lateral lemniscus,64 mainly from the
 Physiology of the Ear and the Auditory Nervous System 63

contralateral ear, but significant input also comes from the Some neurons of the ICC respond with a sustained dis-
ipsilateral ear through the nuclei of the lateral lemniscus. charge when stimulated with continuous sounds or tone
The ICX and DC belong to the nonclassical auditory path- bursts, whereas others respond only to the onset or the off-
ways, and these nuclei receive their auditory input mainly set of tone bursts.41 In this connection, keep in mind that
from neurons in the ICC. the response pattern may be affected by the level and type
It is generally assumed that all auditory information is of anesthesia used. Responses in unanesthetized animals
interrupted by synaptic contacts in neurons of the ICC. tend to have more complex patterns than those from
However, considerable differences may exist among anesthetized animals. This is true also for more peripheral
species, and there are indications that in the chimpanzee levels of the auditory system. Although responses from the
some cochlear nuclear axons may bypass the IC.41 Similar auditory nerve and the ventral portion of the cochlear
findings have been made more recently showing connec- nucleus are generally assumed not to be affected by anes-
tions between neurons in the DCN and the medial division thesia, a noticeable effect of anesthesia on the dorsal
of the MGB.65 cochlear nucleus has also been demonstrated.68
Also, neurons in the central nucleus of the IC are tono- Many neurons in the central nucleus of the IC respond
topically organized,41,66 similar to more peripheral nuclei. in a nonmonotonic fashion, which means that the discharge
Neurons in the central nucleus of the IC exhibit frequency rate first increases when the stimulus level is increased
selectivity similar to that of neurons in the auditory nerve from threshold levels and then, at a certain stimulus inten-
and the cochlear nucleus, but again the variations in the sity, the rate begins to decrease, reaching very low values
widths and shapes of the tuning curves of these neurons at the highest stimulus levels.41
are greater than that of neurons of more caudally located Studies have shown that development of a normal
nuclei41,67 (Fig. 2-16). response pattern of the neurons in the ICC depends on

A C

B D
Figure 2-16. Four different types of tuning curves found in the inferior colliculus. CF, characteristic frequency. (Adapted from Ehret G, Romand R: The Central
Auditory Pathway. New York, Oxford University Press, 1997; after Ehret G, Merzenich MM: Complex sound analysis (frequency resolution, filtering and spectral
integration) by single units of the inferior colliculus in the cat. Brain Res Rev 13:139–163, 1988.)
64 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

prior sound stimulation, especially in young animals.41,69 and posterior auditory fields (AAF and PAF), which
When 2-day-old gerbils underwent ablation of the cochlea receive input from the AI. Neurons in the AI on one side
on one side, responsiveness of the ipsilateral ICC was connect to neurons in similar areas on the other side
greatly enhanced 6 months after birth compared with the through the corpus callosum.81,82 Single nerve cells in the
response in normal animals. Apparently, sound deprivation AI cortical area respond to sounds in a more stereotypical
caused reorganization of the ascending auditory pathways. fashion than do neurons in the more caudally located
Deprivation of sound70 and hearing loss due to auditory nuclei of the ascending auditory pathway, but cortical
overstimulation (in adult cats) have been shown to result in neurons have more complex frequency tuning than that of
a decrease in temporal integration of the IC.71 This change cells in the nuclei at more caudal levels of the ascending
may reflect hypersensitivity of the IC to sound. auditory pathways.83 Nerve cells in the primary auditory
Experimental evidence for involvements of the ICC in cortex usually respond to stimulation of both ears, and
directional hearing have been presented, and neurons in they are distinctly sensitive to the time interval between
the ICC have been shown to specifically respond to differ- stimulation of the two ears.83,84 Responses of the nerve
ences between the ears in the intensity of a sound.72 The cells of the auditory cortex to pure tones indicate that
physical properties of the head provide the interaural these nerve cells are organized according to the frequency
intensity differences that are related to the azimuth of a to which they are tuned. Cells in the AI and the AAF
sound source. The modification of the spectrum of sounds cortex respond well to amplitude-modulated sounds, but
by the physical properties of the head also contribute to the range of modulation frequencies is much lower than
the perception of space (stereophonic sound).43 that of neurons at more peripheral levels.85,86
Almost all neurons in the ICC respond to contralateral Animal experiments in which sounds have been applied
sound stimulation, whereas fewer than 40% of the neurons to both ears have shown that cortical neurons are orga-
are excited by ipsilateral sound stimulation.41 There are sev- nized in bands where neurons respond with excitation
eral anatomic bases for binaural interaction in the auditory from the contralateral and ipsilateral ear (EE). These
midbrain. One is the commissure of the IC, which is a large bands alternate with bands where neurons are excited from
fiber bundle that connects the two ICCs. The lateral lem- the contralateral ear but inhibited from the ipsilateral ear
niscus and the ICC are also connected via the DNLL and (EI).87 Also, recent animal experiments have revealed a
VNLL. The commissure of Probst connects one of the dor- high degree of neural plasticity of cortical neurons caused
sal nuclei of the lateral lemniscus with the corresponding by deprivation88 and prior stimulation with various kinds
nucleus on the other side as well as the contralateral ICC. of sounds.86
Directional information from the auditory system is The auditory cortex in humans is located deep in the
integrated with that from the visual system in the SC to lateral fissure of the temporal lobe, in the superior tempo-
achieve a perception of space.73,74 Some neurons in the SC ral gyrus (Heschel’s gyrus)77,83 (Brodmann’s area 41), and it
thus respond to sound, although this nucleus does not is therefore not easily accessible for studies using physio-
function as a relay nucleus for auditory stimuli.41 logic methods. Only a few studies of the physiology of the
The IC is a reflex center that passes on auditory infor- human auditory cortex have been published.
mation to motor systems, for example, to the spinal cord Penfield and Rasmussen89 showed that electrical stimula-
and to the SC, which activates the extraocular muscles. tion of the primary auditory cortex in their patients who
The IC is not involved in the acoustic middle ear reflex.75 were operated on under local anesthesia evoked a sensation
of simple sounds, such as buzzing. Celesia,90 in recording
evoked potentials from the exposed auditory cortex in
Medial Geniculate Body
patients undergoing neurosurgical operations, has shown
The medial geniculate body (MGB) is the thalamic relay that sounds are represented bilaterally in the human cortex.
nucleus of the auditory pathway. On anatomical grounds, These somewhat contradictory findings call into ques-
the MGB in the cat has been divided into ventral, dorsal, tion the level that should be assigned to the primary audi-
and medial divisions,76 and physiologic studies have shown tory cortex. Is the cortex the end point in the auditory
that the response patterns of neurons in these three divi- system, the point at which we actually perceive and
sions are different. The ventral MGB (vMGB) belongs to interpret natural sounds, such as speech sounds, to which
the classical ascending auditory pathways, and the dorsal we are normally exposed? When viewed in one way, the
and medial portions of the MGB belong to the nonclassical primary auditory cortex may be regarded as just another
pathways. All information from the ICC is conducted to the stage of the ascending auditory pathway where consider-
vMGB through the brachium of the IC (BIC), where all able information processing occurs, as indicated by the
information is interrupted by synaptic connections before it response patterns of single cortical neurons being more
reaches the cerebral cortex. The neurons in the vMGB are complex than that of neurons in the lCC and the vMGB.
sharply tuned, and they project to the primary auditory cor- The primary auditory cortex may thus be just another com-
tex.77 There is a considerable projection from the auditory mon pathway in the ascending auditory pathway leading
cortex to the vMGB78,79 as well. No known connections toward higher brain centers (association cortices) where
exist between the vMGB of the two sides. complex sounds such as speech and music are interpreted.
For the neurotologist, the answer to the questions may
not be very important because lesions rarely occur on the
Auditory Cortex
auditory cortex, and modern imaging techniques, such as
The primary auditory cortex (AI) receives its input from CT and MRI can delineate most lesions that affect the
the vMGB.77,80 Other auditory cortical areas are the anterior auditory cortex. Before these techniques were available,
 Physiology of the Ear and the Auditory Nervous System 65

low-redundancy speech was used in tests designed to iden- that the nonclassical auditory pathways receive input from
tify the location, and perhaps the nature, of lesions in this other sensory systems, most noticeably the somatosensory
part of the auditory nervous system.91,92 system.39,41,63,95–97 For example, some neurons in the
cochlear nucleus receive input from the somatosensory
system (dorsal column nuclei and trigeminal nuclei)95,96,98
Nonclassical Ascending (for a more detailed description of the nonclassical path-
Pathways ways see Chapter 9, and Møller, 2003.35). Some neurons in
the ICX receive input from the somatosensory system
The main anatomic differences between the classical (mainly cutaneous tactile), and approximately 10% of the
and the nonclassical ascending auditory pathways are that neurons in the ICX receive both somatosensory and audi-
the nonclassical pathways are interrupted by synaptic con- tory input.41,63 The main auditory input to the DC and
tacts with neurons in the medial and dorsal part of the ICX is from the ICC, but some evidence indicates that
MGB whereas the classical pathways use the ventral por- auditory input may also arise from the auditory cortex.41
tion of the MGB (Fig. 2-17). Neurons in the dorsal and Animal studies have confirmed that somatosensory
medial MGB project to secondary cortices and association input can interact with the responses to auditory input
cortices,41,93 and those in the ventral part project to pri- from neurons in the ICX and DC41 and evoked responses
mary auditory cortex (AI). There is a direct connection from the surface of the IC.99 Interaction between sensory
from neurons in the dorsal and medial MGB to the lateral modalities has been demonstrated at several levels of
nucleus of the amygdala.94 This connection provides a fast sensory pathways.100
route through which little processed information can The tonotopic organization seems to be less prominent
reach the amygdala. Another important difference in the ICX and DC compared with that in the ICC. These
between the classical and nonclassical auditory systems is neurons are broadly tuned and sometimes difficult to
excite with the simple stimuli that are usually employed in
such experiments.93 The neurons in the ICX and DC are
more sensitive to the effects of anesthesia than neurons in
the ICC, which may explain some of the differences in the
results reported by different investigators. Also, the
anatomic border between the ICC and the ICX and DC is
diffuse, which means that some neurons from which
recordings were made may have been assigned to the
incorrect nucleus.
An expression of interaction between the auditory sys-
tem and the somatosensory system has been demonstrated
in humans by observing the effect of somatosensory stim-
ulation on the loudness of sounds.101,102 Using that tech-
nique, it was found that electrical stimulation of the
median nerve could affect the perception of loudness in
young children but the effect decreased with age and only
a few individuals older than 18 years of age experience
any change in the perception of such sounds as a result
of electrical stimulation of the median nerve102 (see
Chapter 9). Median nerve stimulation can alter the per-
ception of tinnitus in some patients with severe tinnitus,
a fact taken as an indication of an abnormal involvement
of the nonclassical auditory system in these patients.101
Evidence that somatosensory stimulation can alter the
perception of sounds in humans with some forms of severe
tinnitus has been confirmed by other investigators
(see Chapter 9).
On the basis of the diverse functions of the nonclassical
auditory system some investigators distinguish between
two different nonclassical auditory systems: a diffuse sys-
Figure 2-17. Schematic drawing of the ascending nonclassical auditory tem and a polysensory system.103
pathways. Connections from the central nucleus of the inferior colliculus
(ICC) to the external nucleus of the inferior colliculus (ICX ) and the dorsal
cortex of the inferior colliculus (DC) and connections from these nuclei to Efferent System
other structures. Efferent input from the cerebral cortex and connections to
the DC and ICX from the somatosensory system (dorsal column nuclei) The auditory pathways include abundant descending sys-
and from the opposite IC are not shown (for more details see Fig. 9-1). tems. Traditionally, the efferent pathways have been
AAF, anterior auditory field; AI, primary auditory cortex; AII, secondary described as separate systems, and two main efferent sys-
auditory cortex; D, dorsal division; M, medial division; OV, ovoid part of the
MGB; PAF, posterior auditory field; SAG, sagulum; V, ventral division.
tems have been identified: one the olivocochlear bundle
(Adapted from Møller AR: Sensory Systems: Anatomy and Physiology. that terminates in the ear and one that terminates in vari-
Amsterdam, Academic Press, 2003.) ous nuclei of the ascending auditory system. However, it
66 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

may be more appropriate to regard the descending systems descending system from the ICC to neurons in the dorsal
as being reciprocal pathways to the ascending pathways, cochlear nucleus bilaterally.118
because most of the neurons that receive ascending input Generally, little is known about the physiology of the
also send descending fibers to the same nuclei from which descending auditory systems. It has been shown that elec-
they receive ascending input (and often also other nuclei of trical stimulation of the auditory cortex affects sound-
the auditory pathways). activated responses of the cochlear nucleus.119 More
recently it was shown that inactivation of cortical cells
caused a change in the frequency to which neurons in the
Olivocochlear Bundle MGB as well as the ICC were tuned.120
The olivocochlear bundles consist of the crossed olivo-
cochlear bundle (COCB) that originates in the medial Neural Plasticity
superior olivary nucleus (MSO)104,105 and the uncrossed
Neural plasticity is usually regarded as a process that cause
olivocochlear bundle (UOCB) that originates in the lateral
changes in the nervous system in response to altered
superior olivary complex (LSO). The COCB fibers mainly
demands or which shifts function from one region of the
terminate on outer hair cells, whereas the UOCB fibers
CNS to another after injuries. Neural plasticity is assumed
mainly terminate on axons of inner hair cells. The efferent
to involve establishment of new connections or elimina-
fibers have sharp frequency tuning and about the same
tion of connections (synapses and axons or dendrites) or by
sensitivity as auditory nerve fibers.106
changes in synaptic efficacy. Morphological changes can
Early animal experiments have shown that activation of
be altered as a result of the firing pattern of neurons121 and
the COCB results in a decrease of stimulus-driven neural
that is the basis for activity induced plasticity. Recent
activity in fibers of the auditory nerve,107,108 but more
studies have shown that neural plasticity is much more
recently it has become evident that neural activity in these
extensive than earlier assumed and it is not always bene-
fibers can also affect the mechanical properties of the
ficial to the organism. For example, neural plasticity can
cochlea. This effect is mediated by the termination of
cause symptoms and signs of disorders such as pain and
efferent fibers on the cell bodies of outer hair cells and is a
tinnitus.122,123
consequence of the fact that the outer hair cells are an
Studies of the auditory cortex have shown that extensive
integral part of the mechanical system of the cochlea.14
alterations in processing may occur as a result of deprivation
This means the medium that transmits the stimulus to the
of input or exposure to specific kinds of sounds.88,124–127 The
receptors (inner hair cells) is controlled from the
nucleus basalis128 (an acetylcholine pathway) is important
CNS.109,110 Neural activity in the COCB can be elicited by
for many functions such as memory, arousal, and facilitation
(contralateral) sound stimulation. The mechanical proper-
of neural plasticity of the auditory cortex that are caused
ties of the cochlea can therefore be affected by contralat-
by prior sound stimulation.129 The functional changes in
eral sound stimulation, which can be detected by recording
the response of neurons in the AI cortex caused by prior
otoacoustic emissions from the ear.111,112
sound stimulation are facilitated by electrical stimulation
The functional importance of the OCB is not yet under-
of the nucleus basalis as well as by application of acetyl-
stood, but some studies indicate that its stimulation
choline to the cortex.129 These changes involve the tuning
reduces masking in auditory nerve fibers.113 Other behav-
of cortical neurons and of their response to temporal
ioral studies, performed in patients who had undergone
information.86,129
vestibular nerve section in the cerebello pontine angle that
included section of the OCB, show no measurable deficits
as a result of the neurotomy. Several psychoacoustic tests Higher-Order Processing
on such patients have not revealed any specific effects of The primary auditory cortex may be regarded as one of
severing the OCB except a better ability to detect signals the final common pathways to higher CNS centers.
at unexpected frequencies, and that was interpreted as an Connections from the primary auditory cortices (AI) reach
impaired ability to focus attentions in the frequency secondary auditory cortices such as the anterior (AAF) and
domain.114 It has been reported that the OCB offers pro- posterior auditory fields (PAF) and from there, auditory
tection against noise-induced hearing loss.115 It is difficult information can reach larger regions of association
to believe that such an effect should be the primary func- cortices. Neurons in the auditory AI cortex respond only
tion of this system because noise-induced hearing loss was to sound, but some neurons in secondary cortices respond
probably not a factor that influenced an animal’s survival to other sensory modalities. Such multimodal responses
during evolution. are common in neurons in the association cortices,
where information from different sensory modalities is
integrated.
Centrifugal Pathways to the Cochlear Nucleus
and Higher Centers
Parallel Processing and Stream Segregation
The descending systems of the central auditory pathways
are abundant.78,116 The number of fibers that connect Considerable processing of auditory information occurs in
cortical cells with cells in the MGB is several times larger the association cortices, and there is evidence that the
than that of the fibers that ascend from the MGB to the same information is processed in different populations
auditory cortex.117 The cells of the auditory cortex also of neurons (parallel processing) and that different types
send connections to the ICC.78,116 There is also an abundant of information is processed in different populations of
 Physiology of the Ear and the Auditory Nervous System 67

neurons (stream segregation). Although parallel process- The lateral nucleus of the amygdala connects to the baso-
ing is prominent throughout the ascending auditory lateral group of nuclei, which in turn connect to the cen-
pathways beginning in the cochlear nucleus, stream segre- tral nucleus of the amygdala. That nucleus connects to
gation seems to be mainly present in the cerebral cortex. many parts of the brain, such as the hippocampus and var-
Stream segregation has been studied to the greatest extent ious endocrine centers.35,94 It also connects to the nucleus
in the visual system, where it has been demonstrated that basalis, which is important for neural plasticity94 and con-
spatial information (“where”) and object information trolling arousal.
(“what”) is processed in two different regions of associa- The nonclassical pathways that provide input to the
tions cortices (dorsal and ventral regions, respectively).130 amygdala through the low route may not be active in
Although the basis for parallel processing is obvious adults, but there are indications that it is active in young
from the anatomy of the auditory systems, stream segrega- children102 and in some patients with tinnitus101 (see
tion has only been demonstrated in the auditory system Chapter 9). The fast path between the dorsal and medial
relatively recently.131–134 One form of stream segregation in auditory thalamus and the amygdala may explain why
the auditory system is based on projections of two differ- sounds can evoke emotional reactions and why tinnitus can
ent kinds of information from the vMGB to the supertem- evoke fear and phonophobia and cause other affective
poral plane in addition to the more commonly known symptoms such as depression.35,136
projection to the AI area.131 Neurons in another cortical
region, the caudomedial cortical area, receive input indi-
rectly from the vMGB via AI, and many of these neurons EVOKED POTENTIALS GENERATED
respond to the spatial location of a complex sound,
whereas neurons in the lateral surface of the superior BY THE EAR AND THE AUDITORY
temporal gyrus respond best to complex sounds such as NERVOUS SYSTEM
species-specific communication sounds. Auditory stream
segregation has been demonstrated in monkeys,131,133 Evoked potentials from the ear and the auditory nervous
where it has been shown that certain populations of system are important diagnostic tools. They have provided
neurons respond to complex sounds, whereas others some insight in the differences between the human auditory
preferentially respond to pure tones.134 Little is known system and that of the animals commonly used in studies
about stream segregation of auditory information in asso- of the function of the auditory system.
ciation cortices.
The Ear
Connections to Other Nonauditory
Parts of the Brain Several different types of evoked potentials can be
recorded from the cochlea and its vicinity in response to
Similar to other sensory systems, the auditory system has sound. The earliest of such potentials is the cochlear
ample connections to parts of the brain that are not usually microphonic (CM), which, as the name indicates, is a
associated with sensory functions.35 Connections between potential that has the same waveform as the sound. When
the auditory system and motor systems are evident from recorded from the round window membrane, the CM
such phenomena as the startle response and the acoustic potential is assumed to be generated by outer hair cells.137
middle ear reflex. There are also connections to speech Neural activity in the auditory nerve gives rise to evoked
motor centers from the auditory system. potentials (action potentials, APs) that can be recorded
Connections from the auditory system to structures of from the round window.
the limbic system are important under normal conditions When recorded from animals, these potentials are
and in pathologies of the auditory system such as severe known as CM, summating potentials (SP), and AP
tinnitus123 (see Chapter 9). It is especially true of nuclei of (Fig. 2-18), and when recorded from the promontorium of
the amygdala, which are important to the auditory sys- the cochlea in humans they are known as electrocochleo-
tem.35,94 Auditory information can reach the nuclei of the graphic (ECoG) potentials (Fig. 2-19). When recorded
amygdala through mainly two routes. One route involves from the round window in small animals, the AP consists
the primary auditory cerebral cortex, secondary cortices, of two negative peaks, the first generated in the cochlea by
and association cortices, which connect to the lateral neural transduction processes and the second generated by
nucleus of the amygdala.135 That route is known as the the cochlear nucleus138 and conducted to the recording
“high route,”94 and it carries highly processed informa- site by electronic conduction. Whereas the CM can best
tion. The other route known as the “low route,”94 is be visualized in response to continuous pure tones of
shorter and faster and consists of direct connections to the low frequency, the AP is best visualized in response to a
lateral nucleus of the amygdala from the dorsal and transient sound. This potential is a slow potential that
medial parts of the MGB. The low route thus carries follows the envelope of a sound and, like the CM, it is
information from the nonclassical auditory pathway while generated by hair cells.137 The SP is best visualized in
the high route carries information from the classical audi- response to tone bursts. The polarity of the SP can be
tory pathways. This information is likely to be subjected either negative or positive, depending on the condition of
to modulation by other sensory input and intrinsic infor- the cochlea and the way the SP is recorded.139 By choosing
mation from different parts of the CNS. The low route a tone burst stimuli of a not-too-high frequency, all three
carries information that is little processed and less potentials can be visualized in the same recording2
affected by other (intrinsic of extrinsic) neural activity. (see Fig. 2-18).
68 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Evoked Potentials from the Auditory

Nervous System
Auditory evoked potentials that are generated in the audi-
tory nervous systems can be recorded from electrodes
placed on the scalp. Three main types of auditory evoked
potentials have been identified. The most commonly used
type for neurotologic diagnosis is the evoked potentials
that appear during the first 10 msec after a transient sound.
These potentials are known as the brainstem auditory
evoked potentials (BAEP). Potentials that appear in the
time window of 0 to 80 msec (or 10 to 100 msec) after a
stimulus are known as the middle latency responses
(MLR), and those potentials that occur at longer latencies
(50 to 500 msec or 50 to 1000 msec) are known as event-
related potentials (ERP). Other auditory evoked potentials
are the frequency-following response (FFR)143 and various
Figure 2-18. Recording from the round window of a rat showing cochlear kinds of myogenic potentials144 that can be recorded from
microphonic (CM ) and action potentials (AP ) (N1N2). The stimulus was a
5-kHz tone burst. The summating potential (SP ) is represented by the
electrodes placed on the scalp. These potentials, including
baseline shift during the tone burst. The sound is shown at the bottom of the MLR and the ERP, have little importance in neuroto-
the graph. (Adapted from Møller AR: Auditory Physiology. New York, logic diagnosis, and their generators are not known in any
Academic Press, 1983.) detail. We will therefore limit the discussions to the BAEP.

Electrocochleographic Potentials Brainstem Auditory Evoked Potentials

The neural components of the ECoG potentials recorded These potentials are generated by the auditory nerve and
in humans are different from the APs recorded in small the fiber tracts and nuclei of the ascending auditory path-
animals in that the AP consists of two distinct peaks and way of the brainstem. Recorded in the conventional way,
the neural component of the ECoG normally consists of differentially between electrodes that are placed on the
one peak140,141 (see Fig. 2-19). The reason for this differ- vertex (Cz) and on the mastoid (or earlobe) on the side that
ence between the response in humans and that in small is being stimulated, the BAEPs are characterized by five to
animals is that potentials generated in the cochlear nucleus seven vertex-positive peaks.145 The first five peaks of the
in small animals are conducted effectively to the recording BAEP are relatively constant (although peak IV may at
site (the cochlea) due to the small distance between the times be difficult to identify), but the peaks beyond peak V
cochlea and the cochlear nucleus. In humans, potentials are variable. Some investigators prefer to display the
that are generated in the cochlear nucleus are attenuated BAEP with the vertex-positive peaks pointing upward;
because of the much longer distance from the recording others show them pointing downward. The common way
site (the cochlear capsule) to the cochlear nucleus (the of displaying neuroelectric potentials is with the negative
length of the auditory nerve in small animals is 5 to 8 mm, potential of the active electrode giving a downward deflec-
whereas in humans it is 25 mm.142 tion (Fig. 2-20). Only the vertex-positive peaks are labeled
The SP can also be identified in the ECoG recordings. (with Roman numerals), whereas both positive and nega-
ECoG potentials are often elicited by click sounds, which tive peaks of other evoked potentials are usually labeled.
provide distinct AP components but less distinct CM and The spectral filtering used in connection with recording
SP responses. If the purpose of recording ECoG is to BAEP alters its waveform depending on the settings of the
obtain CM and SP responses, it is advantageous to use filters and the kinds of filters. Different investigators use a
tone bursts as stimuli.2 different degree of filtering, which is one reason the wave-
forms of the BAEP shown by different investigators often
differ.
The BAEP is of interest in neurotologic diagnosis
because these potentials reflect the successive activation
of the fiber tracts and nuclei of the ascending auditory
pathway that is located in the brainstem (see Møller,
20002). The BAEP is an effective diagnostic tool for dis-
orders that affect the auditory nerve, such as vestibular
schwanomas.146,147 Together with recordings of the
acoustic middle ear reflex and speech discrimination tests,
these tests are very effective in diagnosing vestibular
schwanomas.147 BAEP is also an effective test of vascular
Figure 2-19. Typical electrocochleographic (ECoG) recording from the irritation of the auditory nerve, such as may occur in
promontorium of an individual with normal hearing in response to click
stimuli (arrow). (Adapted from Eggermont JJ: Electrocochleography. In
patients with tinnitus148 and in patients with a particular
Keidel WD, Neff WD [eds.]: Handbook of Sensory Physiology, vol 3, form of vestibular disorder (disabling positional vertigo,
chap 15, New York, Springer Verlag, 1976.) DPV)149 and inflammatory processes that affect the
 Physiology of the Ear and the Auditory Nervous System 69

cerebellopontine angle in humans compared with animals,

A including nonhuman primates.
Other studies that used intracranial recordings of
evoked potentials from different structures that belong to
the ascending auditory pathway have revealed that peak III
of the BAEP is mainly generated by the cochlear
nucleus.156 However, it must be emphasized that the neural
generators of peaks III, IV, and V are more complex than
B those of peaks I and II. Peaks I and II only have contribu-
tions from the auditory nerve. Although the (ipsilateral)
cochlear nucleus is the main contributor to peak III,
peak III also may have contributions from the auditory
nerve, and possibly from the cochlear nucleus, on the
opposite side.
Little is known about the generator of peak IV, but stud-
ies in patients undergoing neurosurgical operations indi-
cate that the source of peak IV is located near the
C midline157 and that the SOC is most likely an important
contributor to peak IV.152 The anatomy of the SOC is
complex, with nuclei scattered throughout a large region
of the brainstem, and there are many interconnections
between the two sides of the SOC. The fact that the
appearance of peak IV is not as constant as the other peaks
of the BAEP makes it difficult to determine the exact
anatomical location of the generators of this peak.
It was assumed earlier that peak V was generated by the
Figure 2-20. BAEP obtained in an individual with normal hearing. A, Vertex- IC but the results of intracranial recordings in patients
positive peaks shown as upward deflections. B, Vertex-positive peaks shown undergoing neurosurgical operations have indicated
as downward deflections. C, BAEP after filtering.
that the sharp (vertex-positive) portion of the peak is gen-
erated by the lateral lemniscus where it terminates in the
auditory nerve. A prerequisite for the use of BAEPs in IC.157–159 The slow (vertex-negative) deflection that
differential diagnosis in neurotology is a determination of follows the sharp part of peak V (SN10)160 most likely rep-
which neural structures generate the different components resents dendritic potentials from the IC.161 Animal experi-
of these potentials. In the following section, the sources of ments, however, indicate that the IC does not produce any
these potentials are discussed. noticeable far-field potentials,154 despite the fact that a
very clear (slow) response can be obtained by recording
Neural Generators of Brainstem Auditory
directly from the nucleus both in animals154 and in
Evoked Potentials
humans.158,159 The failure of the IC to produce any notice-
Earlier studies of the neural generators of the BAEP used able far-field potentials is assumed to be related to nearly
information from animal research to identify the sources random organization of the dendrites of the cells of the IC,
of BAEP peaks, but the differences between the small which causes the electrical field produced by the nuclei to
animals used in such studies and humans made it difficult decrease rapidly with distance from the nucleus (known as
to draw conclusions about the neural generators of the a closed field).162 However, the SN10 of some individuals is
human BAEP on the basis of animal studies. The animals very large, suggesting a large individual variation of the
commonly used for auditory research only have four anatomy of the IC.
distinct peaks in their BAEP compared with the five in The fact that only vertex-positive peaks of the BAEP are
humans.150 Intracranial recordings from the auditory nerve labeled has diverted the interest from the vertex-negative
in patients undergoing neurosurgical operations revealed peaks. Most studies of the neural generators of the BAEP
that the auditory nerve is the generator of the first two have focused on the vertex-positive peaks despite the fact
peaks (I and II) in humans,151–153 whereas in animals only that the negative peaks may have distinct generators,157 as
peak I is generated by the auditory nerve and peak II is does the vertex-positive peaks, and these vertex-negative
generated by the cochlear nucleus.150,154 The explanation peaks may be of diagnostic value. Figure 2-21 shows a sim-
for these differences is that the human auditory nerve is plified summary of the neural generators of the BAEP in
much longer than that of the animals commonly used in humans.163
studies of the auditory system. The auditory nerve in The generation of evoked potentials from the nervous
humans is approximately 2.5 cm long,142,155 and it is only system is often represented by dipoles. The amplitude of
0.8 cm in the cat. Even the monkey has a much shorter the recorded potentials depends on the orientation of such
auditory nerve than humans.154 This difference in length (fictive) dipoles in relation to a line through the two
of the eighth cranial nerve in humans and the animals used recording electrodes. The greatest amplitude is obtained
in studies of the auditory system is partly the result of when the orientation of the dipoles is parallel to the line
humans having larger heads than these animals and partly between the recording electrodes, and small potentials are
the result of the much larger subarachnoidal space of the recorded when the orientation of a dipole is perpendicular
70 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

ACOUSTIC MIDDLE EAR REFLEX

The acoustic middle ear reflex causes the middle ear mus-
cles to contract in response to a strong sound. Testing of
the acoustic middle ear reflex is of value in neurotologic
diagnosis because its reflex arc involves the ear and parts of
the ascending auditory nervous system up to the nuclei of
the SOC. Also the reflex’s efferent limb involves the facial
motonucleus and the most central portion of the facial
nerve. Disorders of the auditory nerve affect the response
of the acoustic middle ear reflex, and, in particular, the
growth of the reflex response with increasing stimulus
intensity is grossly impaired in many disorders of the audi-
tory nerve, such as vestibular schwannomas and vascular
compression. The contraction of the middle ear muscles
can be recorded noninvasively by recording changes in the
ear’s acoustic impedance.2
Contraction of the stapedius muscle reduces sound
transmission in the middle ear and, therefore, the reflex
acts to keep input to the cochlea nearly constant for sounds
that exceed the threshold of the reflex. The acoustic mid-
dle ear reflex acts to suppress steady-state sounds of slowly
varying intensity, whereas transmission of sounds with fast
changes in intensity are not affected.2,165 An intact middle
ear reflex has been shown to be important in protecting
against hearing damage from noise exposure.166
The neural pathway (reflex arc) of the stapedius reflex
has been studied in detail in the rabbit by lesion tech-
niques.75 The reflex arc for the stapedius muscle involves
the cochlea, the auditory nerve, the ventral cochlear
nucleus, and the trapezoidal body. There are connections
to the ipsilateral and contralateral facial motonuclei via
interneurons in the medial superior olive2 (Fig. 2-22).
Figure 2-21. Neural generators of the human BAEP. DCN, dorsal division of
the cochlear nucleus; LL, lateral lemniscus; MG, medial geniculate body;
Direct connections also exist between the ventral cochlear
SO, superior olivary complex; VCN, ventral division of the cochlear nucleus. nucleus and the facial motonucleus. In addition, numerous
(Adapted from Møller AR, Jannetta PJ: Simultaneous surface and direct indirect pathways exist, but little is known about these.
brainstem recordings of brainstem auditory evoked potentials (BAEP ) in The inferior colliculus does not seem to be involved in the
man. In Cracco RQ, Bodis-Wollner I [eds.]: Evoked Potentials, chap 20, acoustic middle ear reflex.75 The population of neurons in
New York, Alan R Liss, 1986.)
the facial motonucleus involved in the acoustic reflex is
located at the edge of the facial motonucleus anatomically
adjacent to the SOC.167
In humans, activation of the acoustic middle ear reflex
to a line through the recording electrodes. The dipoles of causes contractions of only the stapedius muscle. In the
the generators of peak I and II are nearly horizontal, animals commonly used in auditory research, the tensor
whereas the source of peak V is nearly vertical and the tympani muscle is also involved, although it has a some-
orientation of the dipole of peak III is approximately what higher threshold than the stapedius muscle. The
30 degrees from the horizontal plane.164 This means that reflex arc for the acoustic tensor tympani reflex that is
the conventional electrode placement (between the mas- active in animals involves the cochlea, the auditory nerve,
toid and the vertex) is not ideal for recording peak I, II, the ventral cochlear nucleus, the superior olivary complex,
and V but nearly ideal for recording peak III. This is the and the motonucleus of the fifth cranial nerve.75 In
reason that some investigators have chosen to record humans, the tensor tympani can be made to contract by
BAEP in two channels, with one pair of electrodes placed stimulating the skin around the eye, for instance by an air
at the ear lobe and the other pair placed at the vertex and
the neck. The placement of the earlobe electrodes is ideal
for recording peak I and II and will also record peak III.
The other pair of electrodes are in an ideal position to
record peak V and will also record peak III.
Individual differences in the auditory nervous system are
considerable, which makes the amplitude and the latency
Figure 2-22. Reflex arc of the acoustic stapedius reflex. N VIII, Auditory
of the different components of the BAEP vary among nerve; N VII, facial nerve; VCN, ventral cochlear nucleus; SO, superior olive;
individuals. The effectiveness of different electrode place- n VII, facial motonucleus. (Adapted from Møller AR: Auditory Physiology.
ments also varies from one individual to another. New York, Academic Press, 1983.)
 Physiology of the Ear and the Auditory Nervous System 71

puff.168 This response is not an acoustic reflex, but a response means that the facial nerve is in the process of
trigeminal reflex similar to the blink reflex. regenerating, and although no facial muscle activity is yet
When only one ear is stimulated, the reflex response is present, this return of the reflex is a good indication that
bilateral. In humans, ipsilateral stimulation elicits a stronger facial function will also return. The ipsilateral response
contraction than the same level of contralateral stimulation, returns sooner than the contralateral response and should
and the threshold for ipsilateral activation is slightly lower therefore be used as a test of regeneration of the facial nerve.
than it is for contralateral activation.169 Bilateral stimulation
is about 3 dB more effective than ipsilateral stimulation
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 Chapter
Anatomy of the Central
Vestibular System

Outline 3
Peripheral Anatomy Vestibulocerebellar Other Afferent Projections to Richard R. Gacek, MD, FACS
Vestibular Nerve Connections the Vestibular Nuclei
Vestibular Nuclei Commissural Projections Spinal Vestibular Projections
Central Termination of the Vestibulospinal Projections Vestibulocerebellar Projections
Vestibular Nerve Vestibulo-Ocular Projections Higher Central Vestibular
Efferent Projections of Efferent Vestibular Pathway Centers
Vestibular Nuclei Vestibuloreticular Projections Cortical Vestibular Projection

T he vestibular system is one of the oldest central nervous

system reflex pathways, both phylogenetically and
ontogenetically. It performs a basic stabilizing function in
from the surface of the sense organ to the ampullary roof
and serves as an elastic partition that can be deformed by
endolymph movement created by the stimulus of angular
all species, although in higher animal forms it is especially acceleration or deceleration. This cupular deflection causes
developed to provide orientation for posture and locomotion a deflection of the rigid stereocilia, which protrude from
on land, sea, and air. The reflexes to eye muscles and trunk the sensory cells, resulting in an electrical response in the
and limb muscles are developed to meet the needs of these vestibular nerve fibers. The macula of the utricle or the
animal forms. Although the primary function of the main- saccule is a saucer-shaped arrangement of neurosensory
tenance of body orientation in space is accomplished by cells that lies beneath a mesh-like otoconial membrane
intricate vestibular system reflexes acting on the body, that contains calcium carbonate crystals (otoliths) with a
limb, and extraocular muscles, other modalities interact specific gravity of 2.71. Displacement of the otoconial
with the vestibular system to accomplish equilibrium. blanket by linear acceleration and deceleration or gravity
These are vision, proprioception, and cerebellar function. causes deflection of the hair cell cilia in this sense organ
The discussion here focuses primarily on the vestibular and a subsequent neural discharge.
system because most of the disorders encountered clinically Two types of cell populate the sensory epithelium of the
affect the peripheral and less often the central nervous mammalian vestibular labyrinth.3 These are called type I
portions of the pathway. The neurotologist, however, and type II hair cells4,5 (Fig. 3-1). Type I hair cells are phy-
should be aware of other contributing sensory systems, not logenetically newer, are flask shaped, and are engulfed by a
only because they may occasionally be responsible for large calyx-like terminal, which is supplied by large-caliber
balance disorders but also because of their role in recovery vestibular dendrites. Small vesiculated nerve terminals also
from a vestibular lesion induced by either pathology or make contact with the nerve terminal or the dendrite.6 A
therapy. single large dendrite typically innervates one or two type I
hair cells and rarely may innervate three hair cells. Type II
hair cells are cylindrical and directly contacted by small
PERIPHERAL ANATOMY bouton-type terminals belonging to small-caliber vestibular
dendrites. Vesiculated bouton terminals also contact the cell
Mammals have two types of vestibular sense organ, crista surface of the type II hair cells. Small afferent fibers branch
ampullaris and macula utriculi and sacculi, which are con- and innervate a large number of type II hair cells over a
tained in the endolymph-filled membranous labyrinth sur- larger area of the vestibular sensory epithelium. Therefore,
rounded by perilymph in the bony labyrinth. The different each large nerve fiber receives input from a restricted area
chemical compositions of endolymph and perilymph1 are of the sense organ, but each small fiber is associated with
responsible for vastly different bioelectric potentials that more extensive regions of the neuroepithelium. Both types
are essential for the normal function of these sense organs.2 of hair cell have a characteristic arrangement of cilia pro-
Crista ampullaris is the sense organ of the semicircular truding from the cuticular (superior) plate. Each cell has a
canal and is located in the enlarged portion (ampulla) of single kinocilium located at one edge of a large number (100
the membranous semicircular canal, which is positioned to to 200) of stereocilia (see Fig. 3-1). This special arrange-
represent a plane in space. The crista is a ridge of neurosen- ment of the kinocilium and stereocilia determines the
sory epithelium that is covered by a gelatinous cupula electrical response that occurs from ciliary deflection.7,8
composed of mucopolysaccharides. The cupula extends Deflection of the cilia toward the kinocilium decreases the

75
76 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Location of type I hair cells differs in the two types of sense

organ.10 Type I hair cells are predominant at the top of the
crista and type II cells are more common along the slopes.
Macular type I hair cells seem to be more prevalent near
the striola line, although they may be distributed among the
type II cells in the remaining areas of the macula.11,12

VESTIBULAR NERVE
The vestibular nerve that supplies the five vestibular sense
organs in each labyrinth is composed of bipolar neurons
with myelinated peripheral and central processes.13,14 The
ganglion cells of these bipolar neurons are located in
Scarpa’s ganglion surrounded by cerebrospinal fluid in the
internal auditory canal (Fig. 3-3). The human vestibular
nerve is composed of approximately 18,000 neurons,15 and
the monkey has a similar number. The cat has 12,000 nerve
fibers, the guinea pig and chinchilla, each about 7000.16
In the cat the myelinated fiber composition ranges from
1 to 10 μm with the majority being between 2 and 4 μm.
Richter and Spoendlin17 found that the ganglion cells of
Scarpa’s ganglion in the cat measured from 25 to 47 μm in
diameter. In these mammalian species the sense organs of
Figure 3-1. The two types of mammalian vestibular hair cell and their the semicircular canals and the utricle receive an approxi-
innervation.
mately equal number of nerve fibers, whereas the saccular
nerve contains a lower number. For example, in the monkey
and the human, each of the three ampullary nerves and the
potential difference that exists between endolymph and the utricular nerve has approximately 3500 nerve fibers. The
sensory cell (approximately 120 mmol), causing intracellular saccular nerve has slightly fewer than 3000 nerve fibers.
depolarization and an increase in the frequency of the action These first-order vestibular neurons terminate in all four
potentials in vestibular nerve fibers. Conversely, deflection major vestibular nuclei and in three minor nuclei.
of the cilia away from the kinocilium results in intracellular The dendrites of the neurons supplying the cristae of the
hyperpolarization and a decrease in the vestibular nerve three semicircular canals are located in both the inferior and
action potentials. Since most vestibular neurons have a rest- the superior vestibular divisions but their axons are located
ing neural discharge, an opportunity exists to either increase in the rostral half of the vestibular nerve as it enters the
or decrease the neural activity. brainstem (see Fig. 3-3). The neurons supplying both
Type I and type II hair cell distribution in the vestibular the utricular and saccular maculae occupy the caudal half
sense organs is characteristic for the type of sense organ.9 In of the vestibular nerve before entering the brainstem. The
the crista ampullaris all hair cells are similarly oriented so differential localization of the canal and macular fibers pre-
that the kinocilium is on the same side of the stereocilia. In dicts a different termination within the vestibular nuclei.
the crista of the lateral canal the kinocilium is located closest The canal neurons terminate in the superior and medial
to the utricle, whereas in the vertical canals the kinocilium is vestibular nuclei primarily, although the macular input
located away from the utricular end of the membranous
canal (Fig. 3-2). In the macula of the utricle and saccule the
hair cell orientation is 180 degrees opposite in the two halves
of the macula. In the utricular macula the hair cell polariza-
tion is directed toward a line that more or less bisects the
macula (striola line). In the saccular macula the polarization
of hair cells is away from the striola line. This arrangement
of hair cells in each macula makes it possible for opposite
effects to occur in hair cells of each half of the macula in
response to a given stimulus. In the crista, the movement
of endolymph in a particular canal can produce either a
decrease or an increase in the neural resting potentials.
When angular acceleration occurs in a particular plane, the
coplanar canals from each labyrinth are stimulated in oppo-
site directions, producing excitation in one canal and inhibi-
tion in the other. The two canals are complementary. The
lateral canals of each labyrinth are coplanar; the anterior and
posterior canals of one labyrinth are complementary to the Figure 3-2. Schematic summary of the polarization of hair cell cilia in the
posterior and anterior canals of the contralateral labyrinth. vestibular sense organs.
 Anatomy of the Central Vestibular System 77

Vestibular nerve fibers are spontaneously active so as to

allow bidirectional change depending on the deflection of
hair cell cilia in the periphery. Generally, the discharge rates
range from 10 or fewer spikes per second to more than 100
spikes per second.22 A small but undetermined number of
neural units are silent unless provoked. The mean firing
rates in the nerve supplying the cristae are somewhat higher
than those supplying the maculae (the crista is 90 spikes per
second and the macula is 60 spikes per second).
Although a major input to the vestibular nuclei is from
the labyrinth, several other afferent inputs influence the
activity in these nuclei and their reflex actions via several
efferent projections. A description of the major vestibular
nuclei and several minor cell groups precedes a discussion
of these afferent and efferent projections.

VESTIBULAR NUCLEI
The first-order vestibular neurons terminate in all four
major vestibular nuclei (Fig. 3-4) and in three minor ones.
The main vestibular nuclei are the superior, lateral, medial,
and descending nuclei.23
The superior vestibular nucleus lies in the rostral portion
of the fourth ventricle and is bordered by the brachium
conjunctivum superiorly, the restiform body laterally, the
fourth ventricle medially, and various neural structures
coursing across the brainstem ventrally; these are the facial
Figure 3-3. The peripheral course of first-order vestibular neurons in a right
ear. SG, Scarpa’s ganglion; OCB, efferent cochlear bundle. The darkened area
nerve root, the descending trigeminal root, and the rostral
shows location of large fiber group in the superior vestibular division. end of the lateral vestibular nucleus, which undercuts the
caudal end of the superior nucleus. The superior vestibular
nucleus is comprised of medium-sized neurons, which
concerns the lateral, medial, and descending vestibular tend to have a high concentration in the central portions
nuclei.18,19
Vestibular neurons display a wider spectrum of fiber size
than the cochlear nerve.16 In the cat the vestibular neurons
range from 1 to 10 μm in diameter, and the cochlear nerve
ranges from 1 to 8 μm. Similarly, the monkey vestibular
nerve fiber range is from 1 to 9 μm, whereas the cochlear
nerve is 1 to 8 μm. In the monkey most of the fibers in both
the nerves are from 3 to 4 μm in diameter, whereas in the cat
the cochlear nerve has a majority of fibers in the 3- to 4-μm
range, while the majority of cat vestibular nerve fibers are
2 to 4 μm. In this population of vestibular nerve fibers, one
can differentiate a small population of large neurons and a
larger population of small neurons18 (see Fig. 3-3). These
two types of vestibular neuron are associated with a different
peripheral input, with the large fibers innervating the type I
hair cells and the small fibers the type II hair cells. A group
of intermediate-sized fibers has a dimorphic form of inner-
vation that combines both type I and type II hair cells. The
differential localization of these fibers in the ampullary
nerve, where large fibers predominate in the center and
smaller ones at the periphery, reflects the peripheral
terminus of these fibers. The large fibers have been shown
to have an irregular discharge pattern and the small fibers
a regular discharge pattern,20,21 further strengthening the
concept of differential units within the vestibular nerve
supplying a different hair cell terminus and exhibiting
different activity patterns and probably central terminations.
The significance of these two major types of functional Figure 3-4. Summary of the central termination of the vestibular neurons
units is not known. that supply the cristae ampullares.
78 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Figure 3-6. Transverse section through the dorsal (DL) and ventral (VL)
Figure 3-5. Photomicrograph of a transverse section through the superior divisions of lateral vestibular nucleus and the rostral extension of medial
vestibular nucleus showing the distribution of large, medium, and small nucleus (M). RB, restiform body; DAS, dorsal acoustic stria; V, descending
cells (cresyl violet stain). RB, restiform body; BC, brachium conjunctivum; trigeminal root; VII, facial nerve genu; VI, abducens nucleus.
IV, fourth ventricle; V, vestibular nerve root.

of the nucleus, while small neurons predominate laterally projection of myelinated fibers enters the nucleus from a
and medially (Fig. 3-5). The medium-sized cells are multi- dorsal aspect to supply the dorsal division. These represent
polar or pear shaped. Clusters of larger multipolar cells, cerebellar vestibular afferents. However, collateral
which are dispersed among the medium-sized cells, are branches from the descending rami of canal neurons also
present in the central portion of the nucleus. The dendrites terminate in cells of the ventral division. The dorsal divi-
of the cells in the superior nucleus radiate in different sion of the lateral nucleus receives its primary input from
directions. Some dendrites are directed medially and ventral the cerebellar cortex, particularly from the hemisphere,
laterally. In the peripheral region of the nucleus, dendrites flocculus, and paraflocculus. The primary output of the
are arranged tangential to the nuclear border. By and large large multipolar neurons of the lateral nucleus is in a
the dendritic trees of these neurons remain within the con- descending direction to the anterior horn cells of the spinal
fines of the nucleus, but in the ventral region some dendrites cord. These neurons form the lateral vestibulospinal tract.
may extend into the adjacent reticular formation. The larger The medial vestibular nucleus is the longest rostracau-
neurons in the central portion of the nucleus are strung out dally of the major vestibular nuclei and has a main body
in a ventral lateral to dorsal medial direction and separated that extends from the caudal end of the lateral vestibular
by bundles of nerve fibers representing the incoming nucleus caudal to the facial nerve nucleus, where it tapers
vestibular nerve. The large and medium-sized neurons are to its caudal end. The medial border of the nucleus is
primarily those that represent vestibulo-ocular projections formed by the floor of the fourth ventricle; laterally, it
and vestibulocerebellar projections. The small neurons rep- interfaces with the descending vestibular nucleus. The
resent commissural neurons.24 The peripheral input to the medial vestibular nucleus has a narrow rostral extension
superior vestibular nucleus is entirely from the semicircular that extends medial to the dorsal acoustic stria and blends
canals, while the efferent projections are vestibulo-ocular, in with the caudal portion of the superior vestibular
vestibulocerebellar, and commissural. nucleus (see Figs. 3-6 and 3-7). The cells of the medial
The lateral vestibular nucleus is located immediately
caudal to the superior vestibular nucleus and its rostral end
undercuts the caudal end of the superior vestibular
nucleus. It is bordered laterally by the restiform body,
superiorly by the cerebellar nuclei, medially by the dorsal
acoustic stria, which separates it from the medial vestibu-
lar nucleus, and caudally by the rostral ends of the medial
and descending vestibular nuclei. The lateral vestibular
nucleus is characterized by large, multipolar neurons and
numerous smaller cells, which are concentrated in two
subdivisions, a larger dorsocaudal division and a smaller
rostroventral division (Fig. 3-6). This division represents a
separation of the two groups of large neurons, which
receive different primary inputs. The ventral division of
the lateral vestibular nucleus receives input from the
labyrinth, primarily those fibers inputting from the utric-
ular macula. The primary vestibular fibers enter the nucleus Figure 3-7. Transverse section through the caudal part of the lateral
from a lateral aspect and are seen to radiate in a fanlike nucleus and the midportion of medial (M) nucleus. The group Y nucleus is
pattern within the limits of the nucleus. A prominent also seen at this level.
 Anatomy of the Central Vestibular System 79

densely packed, small, spindle-shaped neurons that are

interspersed between the restiform body and the lateral
vestibular nucleus and capped by the fasciculus angularis26
(see Fig. 3-7). It extends laterally toward the dorsal cochlear
nucleus. A subdivision of this nucleus (infracerebellar) lies
dorsal to the fasciculus angularis and contains large and
medium-sized multipolar and pear-shaped neurons. The
small neurons of the group Y nucleus represent commis-
sural projections to the contralateral group Y and superior
vestibular nuclei24 (Fig. 3-10B). The larger neurons in the
infracerebellar nucleus, which project ipsilaterally to the
oculomotor and trochlear nuclei, represent vestibulo-
ocular neurons (Fig. 3-10A). Because both divisions of the
group Y receive input from the saccular nerve,18 they activate
commissural as well as vestibulo-ocular reflexes initiated
by saccular input.27
The interstitial nucleus of the vestibular nerve (NIV) is a
fusiform nucleus with some strands of cells embedded in the
entering vestibular root fibers as it courses over the descend-
ing trigeminal root (Fig. 3-11). The cells are medium sized
Figure 3-8. High-power photomicrograph of the medial nucleus showing and elongated parallel to the vestibular root fibers.
the large vestibulo-ocular neurons (to abducens nucleus) and smaller
commissural neurons.
Occasionally large cells derived from the lateral nucleus are
found in this nucleus. This nucleus has two divisions, rostral
and caudal, which receive collateral input from the neurons
vestibular nucleus are large, medium, and small with most projecting from the semicircular canals (see Fig. 3-4).
of the small neurons located in the rostral extension The rostral division receives the input from the canals of the
(Fig. 3-8), whereas in the wider caudal section or body of the superior vestibular division (lateral and anterior), while the
medial nucleus, large and medium-sized cells predominate caudal receives those of the posterior canal.18 The efferent
(see Fig. 3-7). The large and medium cells in the body of projection of the NIV is not precisely known, although it
the medial vestibular nucleus represent the primary terminus has been observed to label when horseradish peroxidase
of first-order neurons terminating by way of the descending (HRP) is injected into the contralateral vestibular nuclei,
rami of incoming nerve fibers. These neurons represent which suggests a commissural connection.24
input from the semicircular canals, the utricle, and to a The group L nucleus is a small subset of medium-sized
smaller extent, the saccule. These neurons project contralat- lateral vestibular nucleus multipolar neurons that lies
erally as the vestibulo-ocular pathway, and in a descending between the lateral vestibular nucleus and the restiform
fashion down the medial longitudinal fasciculus as the body (see Figs. 3-6 and 3-7). These cells have abundant
medial vestibulospinal tract. A small number of neurons in branching dendrites, which are oriented parallel to the
the medial vestibular nucleus also project rostrally in the fibers of the restiform body. It is considered part of the
lateral tegmental field as a separate vestibulo-ocular pathway lateral nucleus and sends fibers to spinal cord levels.23
(ascending tract of Deiters), which terminates in the ipsi- Because it is regarded as part of the lateral nucleus, the
lateral portion of the oculomotor nucleus that serves the afferent input to this minor nucleus is from the utricular
medial rectus eye muscle.25 The larger neurons in the ros- nerve.
tral extension of the medial vestibular nucleus represent
vestibulo-ocular neurons projecting to the ipsilateral and
contralateral abducens nuclei (see Fig. 3-8). The small neu-
rons throughout the rostral as well as the body of the medial
vestibular nucleus provide the commissural projections of
this nucleus.
The descending (spinal) vestibular nucleus parallels and
is lateral to the body of the medial vestibular nucleus
extending from the caudal end of the lateral vestibular
nucleus and bordered laterally by the restiform body
(Fig. 3-9). This nucleus contains large and medium neurons,
which are interspersed among longitudinally coursing
fiber bundles representing the descending rami of first-
order vestibular neurons as well as cerebello-vestibular
projections. The primary output of the descending nucleus
is in a descending direction over the medial vestibulospinal
tracts. A commissural component is present comparable to
those of the medial and superior vestibular nuclei.
Several minor cell groups are associated with the Figure 3-9. Transverse section through the caudal portions of the medial (M)
vestibular nuclei.23 The group Y nucleus is comprised of and descending (D) vestibular nuclei.
80 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

and the restiform body. It contains small cells with short

branching dendrites that are confined to the territory of
the group. Although it has been considered part of the
descending vestibular nucleus, lesions of the eighth nerve
do not produce degeneration in this group, although there
is abundant degeneration in the descending nucleus.
Therefore it does not receive primary input from the peri-
phery. However, group X does receive a heavy influx of
spinal afferent ascending fibers as well as a projection from
the contralateral descending vestibular nucleus. These cere-
bellar and spinal projections qualify it as part of the
vestibular nuclear complex.
Group Z is a small collection of cells near the nucleus
gracilis just beneath the dorsal surface of the medulla. It is
dorsal to the caudal end of the descending vestibular
nucleus and group G. It contains medium-sized cells,
which are oval, and it has unbranched dendrites that do not
extend beyond its nuclear borders. This group does not
receive primary vestibular fibers but does receive spinal
afferents. Therefore it is similar to group X in this regard.
Other small-cell groups have been mentioned in the
literature regarding the vestibular nuclear complex, but
A their efferent and afferent projections are unknown and
they do not appear to be important for vestibular function.

Central Termination
of the Vestibular Nerve
The first-order neurons from the cristae bifurcate on
entering the brainstem and then terminate in all regions
of the superior vestibular nucleus by way of an ascend-
ing ramus and the rostral portion of the medial vestibular
nucleus by way of a descending ramus.13,14,18 Collateral
branches are given off both the descending and ascending
branches, providing additional rich termination in the ros-
tral extension of the medial nucleus and ventral division of
the lateral nucleus (see Fig. 3-4). Collaterals also supply
terminal fibers to the medial portion of the superior nucleus.
The incoming axons of the vestibular neurons also terminate
in the interstitial nucleus of the vestibular nerve by way of
short collaterals. The ascending ramus after terminating in
the superior nucleus proceeds through the brachium con-
junctivum to the vestibular portion of the cerebellum (the
nodulus, uvula, flocculus, and paraflocculus). A differential
localization of ascending rami and termination exists for
superior and lateral canal input compared with the poste-
B rior canal input in the superior vestibular nucleus.18,19 The
Figure 3-10. The two components of group Y nucleus are shown by posterior canal input terminates more caudally and cen-
retrograde labeling techniques. A, Infracerebellar division to the trally in the superior nucleus, while the cristae of the supe-
oculomotor nucleus. B, Commissural neurons of group Y.
rior division terminate rostrally and laterally. The superior
and lateral canal afferents terminate by short collaterals in
Group F is a collection of closely packed relatively large the rostral division of the NIV, while the posterior canal
cells near the descending vestibular nucleus. Ventrolaterally, afferents similarly terminate in the caudal division of the
it is related to the spinal trigeminal tract and nucleus, and NIV. Descending vestibular nerve rami of the superior and
the cells have short, richly branched dendrites that do not lateral canal rami are more ventrally located than those
extend far from the cell bodies. This group does not receive belonging to posterior canal fibers. The termination of these
primary vestibular fibers but does send fibers to the cerebel- two groups in the medial nucleus remains ventrodorsal.
lum and therefore is considered a part of the vestibular These canal afferents all converge in the medial vestibular
nucleus complex. The group does receive input from the nucleus with the utricular and saccular macular fibers.
cerebellum by way of the hook bundle. Input from the utricular macula is primarily to the ventral
Group X is another very discrete small-cell group that is division of the lateral vestibular nucleus and to the medial
located lateral to the caudal end of the descending nucleus and descending vestibular nuclei (Fig. 3-12). The input
 Anatomy of the Central Vestibular System 81

Figure 3-11. This section through the

vestibular nerve root shows the
interstitial nucleus of the vestibular
nerve (NIV). S, superior vestibular
nucleus; CN, cochlear nucleus;
V, descending trigeminal root.

from the saccule is also to the ventral division of the lateral up approximately 90% of the active second-order neurons.
vestibular nucleus and the medial nucleus. However, the Type I neurons are those that respond in the same directional
saccule has a unique input to the group Y nucleus, which pattern as first-order afferents. The next most common are
differentiates it from utricular fibers. Neither utricular nor the type II neurons, which exhibit an opposite response pat-
saccular macular fibers terminate primarily in the cerebel- tern to that seen in the first-order neurons providing
lum, but they do project to the vestibular cerebellum by input. Types III and IV are extremely uncommon and show
way of second-order neurons in the medial and descending both increased and decreased activity during rotations in
nucleus and possibly the reticular formation. both directions. The majority of type I and type II second-
Four physiological types of second-order vestibular order neurons are located in the rostral portion of the
neurons have been described in the major vestibular medial vestibular nucleus and the superior nucleus, where
nuclei. Type I neurons are the most numerous; they make the primary input of canals is concentrated.

EFFERENT PROJECTIONS
OF VESTIBULAR NUCLEI
The primary efferent projections of the vestibular nuclei
for purposes of the initiation of vestibular reflexes are
vestibulocerebellar, commissural (vestibulovestibular),
vestibulospinal, vestibulo-ocular, vestibuloreticular, and
the efferent pathway to the end organs (Figs. 3-13, 3-14,
and 3-15). The vestibulocerebellar and commissural neu-
rons are special in that they can be regarded as efferent
projections of the nuclei that in turn modify or influence
the activity of the vestibular nuclei. They do not directly
bring about the activation of a peripheral muscle group,
which stabilizes the body; instead, they modify the activity
in the vestibular nuclei.

Vestibulocerebellar Connections
The vestibulocerebellar connection is a very prominent
projection between the vestibular nuclei and the cerebellum
that emphasizes the relationship between these two centers.
All four major vestibular nuclei, and in particular the
Figure 3-12. Summary of the central termination of the vestibular neurons medial and descending nuclei, contain second-order neurons
that supply the otolith sense organs. that project abundantly to the anterior and posterior lobes
82 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Figure 3-15. Summary of the projections of the saccular macula.

IFC, infracerebellar nucleus; LVST, lateral vestibulospinal tract;
MVST, medial vestibulospinal tract; MLF, medial longitudinal fasciculus.
Figure 3-13. Line drawing summary of the reflex projections of the cristae
ampullares. ND, nucleus of Dankschewitz; INC, interstitial nucleus of Cajal;
VO, vestibulo-ocular; VV, commissural; VS, vestibulospinal; MLF, medial
longitudinal fasciculus.
Primary vestibulocerebellar fibers have been described
in both submammalian and mammalian animal forms to
of the vermis and to the vestibulocerebellum.28 The ves- terminate in the flocculus and nodulus of the cerebellum
tibulocerebellar projections can be primary or secondary. ipsilaterally. This is a heavily ipsilateral pathway, which
Primary vestibulocerebellar fibers represent the continua- includes the paraflocculus and the caudal folia of the uvula.
tion of vestibular nerve axons that terminate in the vestibu- The bundles of primary vestibulocerebellar fibers have
lar nuclei and then continue on to the vestibulocerebellum.29 been grouped into three types: medial, intermediate, and
lateral. The medial group of fibers passes dorsally through
the medial aspect of the superior nucleus through the fasti-
gial nucleus and then curves ventrally to enter the nucleus.
Some fibers emerge at the ventral aspect of the nucleus
and enter the nodulus and uvula. The lateral group of pri-
mary vestibulocerebellar fibers takes a dorsal and lateral
direction to loop around the restiform body from medial
to lateral and merge in the lateral aspect of this structure
to supply the flocculus and paraflocculus. The smallest
intermediate group of fibers passes through the rostral
part of the interpositus cerebellar nucleus, where it termi-
nates in the cortex of the flocculus. Therefore primary
vestibulocerebellar fibers terminate in an extensive region of
the cerebellum consisting of the uvula, ventroparaflocculus,
dorsoparaflocculus, the lateral dentate nucleus, and the
flocculonodular lobe.
Retrograde degeneration studies have indicated that the
origin of secondary vestibulocerebellar fibers is primarily in
the caudal vestibular nuclei (the descending and medial
(MLF) nuclei as well as group X) and that they terminate in regions
similar to that of the primary vestibulocerebellar fibers.30
Since this group of fibers originates primarily from the
caudal vestibular nuclei, it probably is more closely related
to vestibulospinal activity in the cerebellum. The labyrinth,
particularly the semicircular canals, projects directly to the
vestibular part of the cerebellum by way of first-order affer-
Figure 3-14. Summary of the reflex projections of the utricular macula. ents. Second-order neurons in the caudal vestibular nuclei,
MVST, medial vestibulospinal tract; LVST, lateral vestibulospinal tract; especially those receiving input from the maculae, also form
MLF, medial longitudinal fasciculus. projections to the cerebellum. In a reciprocal way, the
 Anatomy of the Central Vestibular System 83

vestibulocerebellar projections terminate in all four major

vestibular nuclei with the major part of this activity repre-
senting Purkinje cells in both the vestibulocerebellar cortex
and the vermis. The effect of this projection is primarily
inhibitory and modifies vestibular nuclear activity. Details of
this projection are presented in a later section.

Commissural Projections
Commissural projections are also quite prominent and
concern primarily the superior and medial vestibular
nuclei with a weaker connection between the descending
nuclei and the projection between the group Y nuclei24
(Fig. 3-16). The superior vestibular nucleus represents a
large part of the commissural pathway and uses the com-
missure of the superior nuclei, which courses beneath the
floor of the fourth ventricle and terminates in the entire
nucleus.31 Some fibers pass around the lateral border of the
superior nucleus to end caudally in the lateral portion of
the lateral nucleus. Some fibers may terminate more caudally
in the descending and medial nuclei. The commissural
projections between the caudal vestibular nuclei in particu-
lar take a much more ventral course through the brainstem
to cross the midline before arching upward to terminate in Figure 3-17. Retrograde label demonstrating the commissural neuron
population of the medial vestibular nucleus. See Figure 3-8.
the medial and descending nuclei of the contralateral side.
The commissural projections are provided by the small
neurons in these nuclei, which are more numerous than
the larger neurons that give rise to vestibulo-ocular pro- are divided into lateral (LVST) and medial vestibular
jections (Fig. 3-17). The effect of commissural activity is spinal tracts (MVST) (see Figs. 3-13, 3-14, and 3-15). The
largely inhibitory and because it involves primarily the LVST is an ipsilateral projection originating from the
superior, descending, and medial vestibular nuclei, this neurons of the lateral vestibular nucleus.32 The fibers of
activity is provoked mainly by input from the semicircular the LVST proceed ventrally and somewhat medially after
canals. It is thought that commissural inhibition initiated leaving the vestibular nuclei and then turn in a caudal
by canal activity may potentiate the inhibition of the con- direction, where they are located dorsal medial to the
tralateral complementary canal, therefore representing an nucleus of the facial nerve and dorsal lateral to the inferior
effective mechanism for differential activity in complemen- olive and lateral to the hypoglossal nerve. On leaving the
tary or coplanar canals. The primary mechanism for this medulla, the fibers continue into the spinal cord where
differential coplanar canal activity is afforded by the oppo- they are found largely in the ventral half of the lateral
site polarization of hair cells in the cristae. Because the funiculus, while other fibers pass in the lateral part of the
maculae have an opposite polarization of the hair cells in ventral funiculus.33 Fibers terminate in the anterior horn
the two halves of the sense organs, commissural projec- cells of the spinal gray matter terminating in lamina VIII
tions may not be necessary to produce a differential effect and lamina VII. A few fibers terminate in lamina IX, which
from activation of this sense organ. contains alpha as well as gamma motoneurons.
Physiologic studies indicate that the vestibulospinal
Vestibulospinal Projections fibers exert a monosynaptic excitatory influence on extensor
motoneurons, but a polysynaptic pathway through inter-
Vestibulospinal reflexes constitute one of the most important nuncial neurons in laminae VII and VIII is also possible.
reflex activities of the vestibular system. These projections Brodal’s studies32,34,35 have shown that the large and
medium cells of the lateral vestibular nucleus giving rise to
the lateral vestibulospinal tract are somatotopically organ-
ized so that the most rostral ventral cells project to the
cervical cord, while those in the most caudal and dorsal
division terminate in the lumbosacral cord.
The origin of the tract to the thoracic cord is located in
the intermediate zone of Deiters nucleus. The dorsal
division of the lateral vestibular nucleus has a close relation
to the cerebellum, where it receives direct Purkinje cell
input. The activity of the LVST is excitatory to the extensor
muscles of the limbs, but it inhibits the flexor muscles by
local neuronal circuits. The lateral vestibular nucleus is also
Figure 3-16. Summary of the commissural projections of the vestibular activated by input from proprioceptive impulses in the
nuclei. somatosensory system (joints, muscle tendons, etc.), which
84 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

arrive by way of the spinovestibular tracts. The peripheral portion of the lateral vestibular nucleus, and in the infrac-
input to the ventral portion of the lateral vestibular nucleus erebellar division of the group Y nucleus. There is evi-
is from all the sense organs, but particularly from the dence that some first-order vestibular neurons projecting
maculae of the utricle and saccule. Therefore, the LVST to from the utricle also connect directly to the ipsilateral
the upper levels of the spinal cord, that is the cervical and abducens nucleus.37 The efferent projection pathways
thoracic levels, are tightly connected to the otolith organs. of these vestibular neurons are the medial longitudi-
The MVST is not as extensive as the LVST and projects nal fasciculus (MLF), the ascending tract of Deiters, retic-
bilaterally over the medial longitudinal fasciculi to the cer- ular formation, and the brachium conjunctivum. The
vical and upper thoracic cord levels36 (see Figs. 3-13, 3-14, vestibulo-ocular projections that are responsible for hori-
and 3-15). The medial vestibulospinal tract course is along zontal eye movement differ from those that elicit vertical
the medium raphe, where it terminates on the anterior or oblique eye movements. The medial and lateral rectus
horn gray matter in laminae VIII and VII. The pathway is muscle groups innervated by the oculomotor and abducens
bilateral and some of the fibers, especially those coming nuclei are responsible for horizontal eye movements
from the medial vestibular nucleus, dichotomize and send (Fig. 3-18), while the superior and inferior recti and
a branch ascending in the medial longitudinal fasciculus as superior and inferior oblique muscles are responsible for
well as a descending ramus, which forms the MVST.32 The oblique and rotatory eye movements. These muscles
MVST originates from the medial, lateral, and descending are innervated by the oculomotor and trochlear nuclei
vestibular nuclei and performs both excitatory and (Fig. 3-19).
inhibitory functions. Its peripheral input is from the canals The cranial nerve nuclei serving the extraocular muscles
and to a lesser extent the utricle. The vestibulospinal tracts are three, four, and six. The third or oculomotor nucleus is
arising from the caudal levels of the vestibular nuclei are the most complex and is located in the floor of the mid-
activated primarily by gravity receptors (utricle, saccule). brain and near the aqueduct of Sylvius. This nucleus serves
However, there is also a pathway for cervical muscle acti- the innervation of four eye muscles, the medial and inferior
vation from canal input by way of connections to the recti, the inferior oblique, and the superior rectus. The
caudal vestibular nuclei. organization of this nucleus, demonstrated by retrograde
axonal tracers, indicates that the nucleus comprises rostra-
Vestibulo-Ocular Projections caudally oriented cell columns, which are contained in two
halves of the nucleus38 (Fig. 20A and B). In the rostral half
In mammals, a very prominent vestibular reflex associated of the nucleus, the main subnuclei are those innervating
with the labyrinth function is the vestibulo-ocular reflex.14 the medial rectus and the inferior rectus, with the medial
The vestibulo-ocular second-order neurons are located rectus being located dorsally while the inferior rectus is
in the superior and medial vestibular nuclei, the ventral immediately ventral. In the caudal division of the oculo-
motor nucleus the subnucleus for the superior rectus is
located medially, while the subnucleus for the inferior
oblique, the smallest of all of the subnuclei, is located just
lateral to that for the superior rectus. All of the subnuclei
except for that supplying the superior rectus provide ipsi-
lateral innervation to the respective eye muscle. The superior

Figure 3-18. Summary of the vestibulo-ocular neuronal network serving Figure 3-19. Summary of the vestibulo-ocular neuronal network for
horizontal eye movements. MR, medial rectus subgroup of III nucleus; vertical and rotatory eye movements. BC, brachium conjunctivum;
ATD, ascending tract of Deiters; MLF, medial longitudinal fasciculus; IFC, infracerebellar nucleus; MLF, medial longitudinal fasciculus;
NPH, nucleus prepositus hypoglossi. NPH, nucleus prepositus hypoglossi.
 Anatomy of the Central Vestibular System 85

B Figure 3-21. Horizontal section through the abducens nucleus showing

labeled interneurons that project to the medial rectus subgroup of IIIN.
Figure 3-20. A, B, The oculomotor nucleus showing the arrangement MLF, medial longitudinal fasciculus; 7, facial nerve.
of the motor neuron pools of the extraocular muscles. MR, medial rectus;
IR, inferior rectus; SR, superior rectus; IO, inferior oblique.

rectus subnucleus supplies the contralateral eye muscle. conjunctivum to reach the third and fourth nuclei.45 Large
Additional oculomotor neurons are located outside the cells in the infracerebellar division of group Y nucleus also
confines of the nucleus in between the muscle bundles project to the fourth nucleus and some subgroups of the
of the MLF and also in the reticular formation ventral to third nucleus. Since the saccule projects to this nucleus,
the MLF. These neurons belong to the subgroup that sup- group Y provides a pathway for vertical eye movements
plies the inferior rectus muscle.38 from saccular input.29
The trochlear nucleus is the smallest of the extraocular The vestibulo-ocular projections providing horizontal
nuclei, is located immediately caudal to the oculomotor eye movements are provided by the lateral rectus and
nucleus, and is a spherical nucleus that indents the dorsal medial rectus subgroups (see Fig. 3-18). The second-order
surface of the MLF. The majority (approximately 90%) of neurons projecting to the ipsilateral and contralateral
neurons in the trochlear nucleus innervate the contralateral abducens nuclei are located in the medial vestibular nucleus,
superior oblique muscle; approximately 10% innervate the particularly in its most rostral portion.37,46 Excitation is pro-
ipsilateral superior oblique muscle.38 vided to the ipsilateral abducens nucleus and inhibition to
The sixth cranial nerve or abducens nucleus is located in the contralateral abducens nucleus to provide synchronized
the brainstem (medulla oblongata) immediately ventral to eye movement. Interneurons in the abducens nucleus proj-
the genu of the facial nerve root. The multipolar neurons ect contralaterally through the MLF to the medial rectus
in this nucleus are larger than those in the other two cranial subgroup, thereby providing a tight connection from the
nerve nuclei, are compactly arranged, and primarily inner- ipsilateral lateral rectus and contralateral medial rectus
vate the ipsilateral lateral rectus muscle. Approximately motor neurons. Some neurons in the medial vestibular
50% to 65% of neurons project into the abducens nerve to nucleus, together with those in the ventral portion of the
the lateral rectus muscle. The remaining 25% to 50% are lateral nucleus, give rise to the ascending tract of Deiters,
small fusiform neurons, which project contralaterally by which projects outside of the MLF to the ipsilateral medial
way of the MLF to the medial rectus subgroup of the rectus subgroup to provide it with an excitatory input.
oculomotor nucleus (Fig. 3-21).39,40 This neuronal network provides projections to the
The vestibulo-ocular neurons supplying vertical and abducens and medial rectus neurons that can be activated
oblique eye muscle neurons arise primarily from the supe- by both utricular and canal afferents. In addition to these
rior nucleus and rostral portions of the medial nucleus.41,42 more traditional pathways, vestibulo-ocular projections
The superior nucleus projects ipsilaterally and the medial can occur through the reticular formation. However,
nucleus contralaterally via the MLF to the trochlear anatomic verification of such connections is lacking.
nucleus and subgroups of the oculomotor nucleus.41–44
The ipsilateral vestibulo-ocular pathway rising from the Efferent Vestibular Pathway
superior nucleus is inhibitory while the contralateral pro-
jection from the medial nucleus is excitatory. Neurons An efferent vestibular pathway projecting from the brain-
in the dorsal portion of the superior nucleus are driven stem to the vestibular sense organs has been known for more
by the anterior canal and project by way of the brachium than 40 years.47,48 The small cells of origin of this pathway
86 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

of our information on this pathway comes from studies of

the Brodal group, who made discrete lesions in the vestibu-
lar nuclei and studied axonal degeneration emanating from
the lesion.31 These lesions were isolated to the nuclei so
that fairly reliable conclusions could be made regarding
their termination. These studies indicate that the superior
and lateral vestibular nuclei form the major projections
from the vestibular nuclei to the reticular formation. A few
primary vestibular fibers, which project into the lateral
reticular formation for a short distance, have been
reported.18,34 The termination of these first-order fibers has
not been determined. The reticular formation projection
from the superior vestibular nucleus splits off from a large
group of fibers coursing medially in the superior nucleus.
These medially directed fibers are those projecting into
the MLF as well as commissural fibers to the contralateral
superior nucleus. The fibers destined for the reticular for-
Figure 3-22. Summary of the efferent vestibular pathway (solid line). Efferent
mation split off ventrally to terminate in the contralateral
cochlear pathway shown as stippled bundle. nuclei reticularis pontis caudalis and oralis, and a large
number turn ventrally to end throughout the contralateral
nucleus reticularis tegmenti pontis. Some fibers do not
cross the midline but ascend and terminate in the ipsilateral
are located lateral to the abducens nuclei and provide each nucleus reticularis pontis caudalis and the nucleus reticularis
labyrinth with a bilateral and approximately equal projection giganto cellularis. Some of the commissural fibers of supe-
from the groups of neurons in the efferent vestibular rior vestibular nucleus continue into the descending and
nucleus49 (Fig. 3-22). Although the number of efferent medial nuclei and also give off terminal branches to the
neurons is considerably smaller than the afferent (approxi- rostral part of the nuclei reticularis giganto cellularis and
mately 400 to 500 efferent neurons in the cat), the peripheral parvi cellularis.
innervation of sensory epithelium by way of vesiculated After lesions in the lateral vestibular nucleus, fibers pass
terminals is rich because of a complex branching pattern in through the ventral part of the superior nucleus and course
each efferent neuron. The efferent vestibular neurons ventrally to the ipsilateral nucleus reticularis pontis caudalis.
travel with the efferent cochlear bundle in the vestibular However, the majority of fibers passing to the reticular for-
nerve and reach the peripheral sense organs scattered mation leave the lateral nucleus and pass ventromedially
among afferent fibers in the individual vestibular nerve toward the midline and terminate in the contralateral
branches. Both of these efferent systems are associated nucleus reticularis pontis caudalis.
with high levels of acetyl cholinesterase, which can be used The evidence thus accumulated indicates that the lateral
in histochemical preparations to differentiate them from and superior nuclei are associated with the reticular forma-
afferent fibers.50 tion nuclei that project to the cerebellum. These are the
These nerve fibers terminate as small vesiculated endings lateral reticular nucleus and nucleus reticularis tegmenti
on both type I and type II hair cells in all vestibular sense pontis. In turn, the lateral and superior nuclei receive
organs (see Fig. 3-1). However, their mode of termination abundant fibers from the cerebellum and are, therefore,
on the two types of hair cell varies. The efferent terminals interrelated in a circuit through the cerebellum, reticular
contact the calyx type terminal on type I hair cells, while formation, and vestibular nuclei. Those regions of the
they make direct contact with the hair cell membrane of reticular formation that give rise to fiber connections of
type II hair cells. It is therefore possible that activation of the spinal cord receive projections from the superior, lateral,
the efferent component produces different physiologic and descending vestibular nuclei, that is, nuclei that have
effects at the sensory epithelium level. Both excitation and also a close relationship to spinal cord mechanisms.
inhibition51–53 of the vestibular nerve response have been
demonstrated following excitation of the efferent vestibular
pathway. However, inhibition has been the predominant OTHER AFFERENT PROJECTIONS
effect demonstrated and may provide a mechanism by
which self-stimulation of the vestibular system can be pre-
TO THE VESTIBULAR NUCLEI
vented or at least controlled. It may also be possible that
In addition to the vestibular nerve input, there are two major
either excitation or inhibition can be used to modulate the
afferent projections to the vestibular nuclei, as discussed in
resting activity in individual vestibular neurons, thereby
the following sections.
modifying the range over which they can be altered by
peripheral end organ excitation.52
Spinal Vestibular Projections
Vestibuloreticular Projections Direct spinal vestibular fibers are distributed only to
Connections between the vestibular nuclei and the reticular the portions of the vestibular nuclei that do not receive
formation have been sparsely studied, but the major segment primary vestibular afferents.54 Degeneration studies have
 Anatomy of the Central Vestibular System 87

indicated that the spinal vestibular projection (which is organization is also demonstrated in the projection of the
modest compared to the descending vestibulospinal projec- vermal cortex to the fastigial nucleus.60 The fore and hind
tion) originates from the lumbar and sacral portions of the limbs of the vermis, that is, the lobules 1 through 5, project
cord. The projection is entirely ipsilateral and ascends in to the rostral end of the fastigial nucleus with the fore limb
the dorsal portion of the lateral funiculus. Its termination located behind the hind limb terminus in the fastigial
is in the caudal vestibular nuclei, that is, the descending nucleus. The caudal, vermal lobules (VIII and IX) terminate
and medial nuclei, with a small portion also in the dorsal in the caudal portion of the fastigial nucleus, with the fore
caudal portion of the lateral nucleus. The minor cell limb being located rostral to the hind limb.
groups X and Z also receive input from the spinal vestibular The fastigiovestibular projection forms the final link in
pathway.55 this pathway, which is an ipsilateral projection from the
rostral half of the nucleus that relays the projection from
the anterior vermis, which then terminates in the peripheral
Vestibulocerebellar Projections portions of the superior nucleus, the dorsal half of the lateral
Input to the vestibular nuclei from the cerebellum forms nucleus, and the dorsomedial portion of the descending
the largest complement of afferent fibers in the system. nucleus and medial nuclei. The crossed or contralateral
This projection may be divided into a projection from the fastigiovestibular projections form the final link in the pro-
vestibular portion of the cerebellar cortex and the other jection from the caudal vermal cortex. These fibers termi-
from the spinal cerebellar cortex.56 nate in the peripheral portion of the superior nucleus, the
The cerebellovestibular projection originates from the ventral portion of the medial ventral half of the lateral
cortex of that portion of the cerebellum supplied by nucleus, the ventral lateral portion of the descending
the projection from the primary vestibular neurons and nucleus, and groups F and X. These two projections termi-
the uvula and paraflocculus. A portion of the lateral cere- nate in different portions of the major vestibular nuclei, and
bellar nucleus is also included. This projection is entirely this is particularly well demonstrated in the dorsal division
ipsilateral, with a projection from the flocculus that sup- of the lateral nucleus where the ipsilateral cortical fastigial
plies the superior and medial nuclei and a second bundle, vestibular projection terminates ipsilaterally and the posterior
which is more lateral than the first, that gives off fibers or caudal vermal projection terminates in the contralateral
to all four vestibular nuclei and group F. The terminations lateral vestibular nucleus.
in the vestibular nuclei occupy discrete portions of the
nuclei. The paraflocculus does not have a projection in the
vestibular nuclei. HIGHER CENTRAL VESTIBULAR
The nodulus projection terminates in the peripheral CENTERS
portion of the superior nucleus, the caudal and medial por-
tions of the medial nucleus, and the ventral caudal portion Nuclei concerned with higher projections of the vestibular
of the descending nucleus as well as group F and group X. pathway exist both in the midbrain and in the thalamus
The uvula projects to the peripheral portion of the superior and cortex. In the midbrain the two nuclei that receive the
nucleus, to the caudal portion of the descending nucleus, most rostral termination of the vestibulo-ocular projec-
and to group X. As mentioned earlier, the projection of the tions from the major vestibular nuclei are the interstitial
different portions of the vestibulocerebellum are to rather nucleus of Cajal (INC)61 and the nucleus of Dankschewitz
discrete portions of the vestibular nuclei, which suggests (ND) (see Fig. 3-13). These nuclei are adjacent to the MLF
that there are some functional differences between the in the mesencephalon and have been little studied over the
lobules of cortex in the vestibulocerebellum. years. However, recent physiologic as well as anatomic
The projection from the spinal portion of the cerebellum retrograde tracing techniques have revealed some of their
(vermis) to the vestibular nuclei is generally considered the connections. Both nuclei consist of small cells, fairly com-
termination of spinal afferents to the cerebellum.57 This pactly arranged in nuclei that have indistinct borders.
projection is further broken down into a direct projection More is known about the functions and connections of the
from the spinal cerebellum to the vestibular nuclei and an INC.62,63 These studies have demonstrated that the INC
indirect projection, which relays in the fastigial nucleus. projects to the oculomotor nucleus and to several other
The direct spinal vestibular projection terminates primarily centers in the midbrain and the thalamus. In addition to
in the dorsal rostral portion of the descending nucleus and projections from the major vestibular nuclei by way of the
the dorsal portion of the lateral nucleus. The experiments MLF, the INC receives input from the group Y nucleus.
of Walberg and Jansen57 demonstrated that the projection The majority of functional studies have indicated that this
from the vermis of the anterior lobe to Deiters nucleus is nucleus is concerned with the neural integration of verti-
somatopically arranged with the fore limb portion projecting cal eye movements in response to vestibular stimulation.
to the rostral dorsal portion of the lateral nucleus and the By way of its aforementioned projections, this rather
hind limb to the caudal dorsal portion. unique function can be understood.
The indirect projection from the spinal portion of the The ND is somewhat less studied physiologically, but the
cerebellum relays through the fastigial nucleus.58,59 The anatomic connections have demonstrated that it receives
first link in this pathway, that is, the cerebellar fastigial projections from the frontal eye field as well as the thala-
projection, is organized so that the vermal cortex projects mus.64 It projects to both the anterior and posterior lobes of
to the fastigial nucleus, the intermediate portion of the the cerebellum by way of the accessory olivary nucleus.
cerebellar cortex to the nucleus interpositus, and the lateral Some studies have suggested that projections from group Y
hemispheres onto the lateral or dentate nucleus. This nucleus as well as some of the major vestibular nuclei
88 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

provide input to the ND. A proposed functional pathway region of the thalamus.71 Demonstration of this linkage
from the ND is one that conveys information for eye in the ascending pathway will require careful use of intra-
movement from the frontal eye fields in the cortex to the axonal tracers.
cerebellum for ultimate projection to the oculomotor
nuclei.
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 Chapter
Physiology of the Vestibular System

Outline 4
Development of Cerebellar Loop Eye-Head Coordination Dietrich W. F. Schwarz, MD, PhD
the Labyrinth Signal Transformation Habituation R. David Tomlinson, PhD
Labyrinth Fluid Spaces Central VOR Neurons Compensation for Loss of
Hair Cells Burst-Tonic Cells Labyrinth Function
Vestibular Sensory Organs Second-Order Vestibular Vestibulospinal System
Semicircular Canals Neurons Vestibulocollic Reflex
Hydrodynamics Burst Neurons Tonic Labyrinth and Neck
Human Semicircular Canal Pause Cells Reflexes
Afferent Neurons Tonic Cells Falling
Otolith Organs Commissural Connections Pathways
Adequate Stimulus Neuron Activity During Lateral Vestibulospinal
Macula Afferents Nystagmus Tract
Vestibular Efferents Intermediary Neurons Medial Vestibulospinal
Vestibulo-Ocular Reflex Motoneurons Tract
VOR Pathways Visual Vestibular Interaction Caudal Vestibulospinal
Horizontal Canal VOR VOR Neurons Tract
Anterior Canal VOR Nystagmus Projection to Forebrain
Posterior Canal VOR Quantification of Human Motion Sickness
Otolith VOR Vestibulovisual Interaction
Spinal Influences Adaptive VOR Plasticity

T he purpose of this chapter is to provide the neuro-

tologist an overview of vestibular neurophysiology.
A truly comprehensive review is not possible within the
eventually buds off to become the otic cyst, representing
the primordial endolymphatic space lined by ectodermal
epithelium. The labyrinth and its sense organs (semicircular
constraints of this chapter nor is it desirable. An attempt canals, utricle, saccule, and cochlea) develop from the otic
has been made to refer to review articles as much as possi- cyst by further growth and differentiation. The physician
ble so that the interested reader can find additional infor- must realize that the endolymphatic space corresponds
mation if desired. Such reviews are cited at the beginning originally to the exterior environment of the organism.
of each section where possible. The most important The original vertebrate hair cell probably evolved in
general text is the book by Wilson and Melvill Jones.1 aquatic animals before the evolution of terrestrial verte-
More detailed references to the older literature can be brates. Its function was, as it is now in many species, to
found in the handbook edited by Kornhuber.2 Finally, an monitor water currents relative to the body surface. The
excellent overview of the vestibulo-ocular reflex and its apical portions of the hair cell, equipped with stereocilia
associated pathologies can be found in Leigh and Zee.3 and kinocilia, were exposed to the water, whereas the
The material in this chapter concentrates on areas of clinical basolateral cell membrane was contacted by extracellular
relevance. Thus more emphasis is placed on peripheral and fluid. Because of the differences in ionic concentration
vestibulo-ocular physiology. Undoubtedly, the importance between the exterior water, the intracellular milieu, and
of the vestibular system on spinal, cortical, cerebellar, and the extracellular space, continuous ionic currents existed.
autonomic physiology will increase as our knowledge of Deflection of the cilia could alter those currents. The ionic
these systems increases. concentration in the exterior water was subject to changes
that must have affected transducer sensitivity. It was there-
fore an advantage to generate a separate endolymphatic
DEVELOPMENT OF THE LABYRINTH space by encapsulation of the inner ear space so that the
ionic composition could be controlled. Another advantage
The labyrinth is derived from the skin during early was that the physical forces deflecting the cilia could be
embryogenesis. Lateral ectoderm, destined to become the selected very precisely by the evolution of accessory struc-
inner ear (placode), invaginates to form an otic pit, which tures such as the semicircular canal system, the otolithic
91
92 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

system, and vibration-sensitive structures (cochlea, papilla limited access to seawater, a K+-rich milieu is maintained,
basilaries, and so forth). and even the cupula of the toad (Xenopus laevis), which is
exposed to freshwater, contains an enriched K+ concentra-
tion and carries a positive charge.6 It represents a driving
LABYRINTH FLUID SPACES force supporting the K+ current through the hair cell. The
intensity of this current is modulated by deflection of the
If ear development is considered from a teleologic perspec- stereocilia.
tive, much of the mystery surrounding the unique extra-
cellular space within the membranous labyrinth vanishes.
Because the original hair cell had to operate with any ion HAIR CELLS
species available in the exterior water, the receptor current
through the apical end of the hair cell had to be carried by The two hair cell (HC) types found in the human labyrinth
a variety of cations. Contrary to widespread belief, regular are illustrated in Figure 4-1A. The phylogenetically ori-
extracellular fluid (perilymph) can mediate the mechano- ginal type II HCs (right) have cylindrical shapes and are
electric transduction as long as the hair cell remains vital. contacted by afferent dendritic nerve terminal boutons as
Because the predominant extracellular (and perilymphatic) well as efferent axon boutons. Type I HCs (left) are more
ion is sodium, a constant Na+ current would have to flow recent and are concentrated in the central portions of the
through the hair cell. As a result, the Na+ and K+ electro- sensory epithelia, that is, on the cristae crests and within
genic pumps in the hair cell membrane would be rapidly the striolae of the maculae. They are flask-shaped, and a
overburdened, and the cell would die. This problem does calyx-shaped dendritic afferent terminal surrounds most of
not exist for the second most common cation, K+. Thus their basolateral membrane. Thus efferent terminals can
having the K+ concentrated at the apical end of the hair cell only contact the neural calyx membrane of type I HCs, not
and the Na+ removed from this location is advantageous. the cell membrane itself.
The dark cell is specialized for this task. Dark cells are The “hairs” of these cells, the cilia, extend from the apical
strategically located on the slopes of the semicircular canal surface and greatly increase the membrane surface area.
cristae and close to the utricular maculae as well as in the Vestibular hair cells typically have 40 to 200 stereocilia and
stria vascularis of the cochlea. Labeled Na+ and K+ have one kinocilium. The kinocilium is located at the end of the
been demonstrated to move through these cells in a direc- stereocilia bundle (Figs. 4-1A and C). Thus the hair cell is
tion opposite to their gradients.4 The basal portion of these morphologically polarized. Deflection of the cilia bundle
cells, directed toward the basement membrane and capil- toward the kinocilium depolarizes the cell membrane and
laries, is characterized by extensive indentations, which serve leads to afferent nerve fiber activation, whereas deflection
to increase the surface area. Dark cells contain an unusual in the opposite direction has the opposite effect (Fig. 4-1B).
concentration of mitochondria, testifying to high meta- Thus a functional polarization exists as well. Cilia deflec-
bolic activity. Their apical cell membrane bears villi much tion is effective only along this polarization axis. At other
as other secretory cells. Quite possibly, other cells sur- angles of deflection, the response amplitude, measured as
rounding the hair cells are also responsible for the high K+ either membrane potential, receptor current, or spike rate
concentration in the endolymph. change in the afferent neuron, drops off according to a
Because the ionic concentrations within the mammalian cosine function (Figs. 4-1C, D, and E).
endolymph and hair cell intracellular space are similar, As the name implies, the kinocilium is capable of active
little ionic gradient is available to drive a K+ receptor motion. As with other mobile cilia, it is equipped with the
current. The existence of a positive electric charge within typical nine-plus-two axoneme of microtubules that distin-
the endolymphatic space, with respect to the perilymph, guishes mobile cilia in the respiratory tract, sperm cells,
compensates for this deficit. A corresponding potential is and elsewhere. Mammalian vestibular hair cell kinocilia
to be found in the cochlea and is known as the endolym- are longer than the longest stereocilia and extend into the
phatic potential. In the vestibular labyrinth, this potential gelatinous substance of the cupula or otolithic membrane,
appears to be concentrated over the relatively small thus mediating displacement of these structures relative
patches of sensory epithelium (cristae ampullares, otolithic to the epithelial surface. The kinocilium tip is typically
maculae). The positive potential increases when a record- bulb-shaped and connected to the longest stereocilia by
ing electrode is moved from the endolymph into either the fine filaments. The kinocilium appears to store free calcium
cupula or the otolithic membrane and is greatest just above ions, perhaps to safeguard receptor current changes when
the apical surface of the hair cells. In areas far from these stereocilia are deflected.
sites, the endolymphatic potential becomes small. The Transducer function of the HC appears to depend criti-
regional differences in this potential illustrate clearly that cally on stereocilia deflections. Their displacement toward
the high K+ concentration in the endolymph and the the kinocilium causes the resting membrane current
positive endolymphatic potential are independent of one through the apical membrane to increase, presumably by
another. This point has been proven experimentally in the opening membrane ion channels. Stereocilia are arrayed
cochlea where a positive charge over the stria vascularis with the longer ones standing at the excitatory pole adja-
can be recorded after removal of all K+ from the endolym- cent to the kinocilium, their length gradually decreasing
phatic space.5 Both the positive endolymphatic potential toward the inhibitory pole. This length gradient may be
and the high extracellular K+ concentration at the apical important for transduction. With a diameter of 0.2 μm,
surface of the hair cell appear to be fundamental for the they are slightly thinner than the kinocilium (0.25 μm).
hair cell transducer function. In lateral line organs with In contradiction to the classic belief, stereocilia are stiff,
 Physiology of the Vestibular System 93

coupling the stereocilia mechanically to the gelatinous

superstructure (e.g., the cupula) via the kinocilium. Such
mechanical coupling would not be necessary to induce stere-
ocilia deflection; viscous endolymph drag would suffice to
transfer cupula or otolithic membrane movement to the cilia.
Frog saccular HC membranes have been shown to be
tuned electrically.11,12 Their resting membrane potential
oscillates by a few millivolts at a frequency between 0 and
100 Hz. Mechanical stimuli of the same frequency pro-
duce maximum receptor potentials, indicating a resonance.
This preferred frequency can be shifted up and down,
respectively, by depolarizing and hyperpolarizing the
cell membrane. Because efferent volleys cause hyperpo-
larization in the HCs, their activity could shift maximum
receptor sensitivity from high frequencies to lower
frequencies.
The stereocilia bundle apparently can be induced to
A move in response to an electrical polarization stimulus.
Also, chemicals that normally cause muscle contraction
alter the deflection response to a natural stimulus.13
Interestingly, myosin has been located within and close to
the cuticular plate, and striated bands resembling actin-
myosin complexes in skeletal muscle have been observed
around the cuticular plate.14 Active mobility of the stere-
ocilia bundle might be responsible for adaptation. The
response to cilia deflection dies down after 10 to 100 msec,
thus guaranteeing sensitivity to new stimuli even if the full
response range was saturated initially during a head move-
B C ment. Both adaptation rate and cilia mobility change with
Ca2+ concentration in the endolymph.
The cilia deflection required for a maximal response is
quite small; displacement of stereocilia tips by about 1 μm,
leading to a deflection angle of some 3 to 6 degrees is
sufficient. At threshold, the displacement only needs to be
about 4 × 10−3 degrees. Such cilia movement would be
below the dimensions of many protein molecules. Thus,
not surprisingly, a classic threshold (an energy step
required for activation) cannot be defined in the vestibular
system.
The HC response is induced by a conductivity change
D E for cations at the apical cell membrane. The term apical is
Figure 4-1. Hair cells and their mechanoelectric transduction. A, Schematic particularly appropriate in this context, because the maxi-
drawing of type 1 and type 2 hair cells. B, Plot of receptor potential or mal receptor current change has been measured at the
receptor current (y axis) against cilia deflection (x axis). Excitatory deflection location of the stereocilia tips. The current itself is nor-
causes much greater response than inhibitory deflection. C, Schematic top mally carried by K+ because of its high concentration in
view of one hair cell. Viewing direction indicated by arrow in A. The + and −
arrows represent excitatory and inhibitory deflections, respectively. Arrows the endolymph, but Li+, Na+, Rb+, Cs+, NH4+, and to a
labeled 30, 60, and 90 degrees indicate deflections yielding corresponding lesser extent Ca++, as well as tetramethylammonium,
response amplitudes in D. Relative size of receptor potential for various acetylcholine, choline, and other cations can also con-
angles of deflection (top) for same deflection amplitude (bottom). tribute. Apparently charge carrier molecules must not
E, Receptor potential amplitudes drop with deviation of deflection direction
from polarization vector according to cosine function.
exceed the molecular diameter of 0.6 nm to be passed
through the ionic channels. Opening of the membrane
channels in response to cilia deflection depends on small
the result of a skeleton of actin filaments. The actin fila- amounts of Ca2+ in the endolymph, and at this location
ments penetrate into the cuticular plate just below the stere- calcium can be replaced by strontium (Sr2+) and blocked by
ocilia (see Fig. 4-1A). When the stereocilia are deflected, magnesium, cobalt, and barium (Mg2+, Co2+, Ba2+ ) ions
they do not bend but rather lean over like sticks, moving and other compounds. Other systems have shown that one
the cuticular plate with them.7 Stereocilia are stiff enough ionic channel accounts for a conductance of about 50 ps.
to exhibit resonant oscillations, the preferred frequency A measured peak conductance of some 2 to 5 ns at the
being a function of the cilia length.8 Although this charac- stereocilia tips would imply the existence of about one
teristic serves as an auditory tuning mechanism in some channel per stereocilium.
reptilian ears,9,10 it also underlies the need to dampen such The maximal response current is about 200 pA, leading
oscillations within the mammalian vestibular apparatus by to a maximal depolarization of some 5 to 20 mV. Thus the
94 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

typical HC membrane resting potential of about −60 mV Hydrodynamics

is decreased to at most −40 mV. Stereocilia deflection in
the opposite inhibitory direction yields a maximal polar- The canal responses exhibit two time constants, the short
ization change of about one-fifth the excitatory response, time constant T1 reflects the time taken for the cupula to
that is, a hyperpolarization to about −64 mV. The HC deflect when stimulated with a step of head velocity while
therefore is a rectifying transducer, dramatically overem- the long time constant T2 describes the time taken by the
phasizing the excitatory response (see Fig. 4-1B). Note, cupula to return to its rest position.
however, that this asymmetry in the excitatory and The long cupular time constant T2 is of diagnostic
inhibitory responses is much larger than that seen in the significance in Bárány’s classic rotation test, in which a
afferent nerve. The membrane resistance is voltage- velocity step is applied, usually from 0 degrees/sec to some
dependent: the input resistance of some 200 to 300 MΩ value between 10 and 100 degrees/sec (Fig. 4-2). The cupula
drops to about 6 MΩ after depolarization to −50 mV or deflects almost instantly (because the Tl time constant is so
less. This reflects an increased K+ conductance. Similarly, short) and then reverts back to its rest position with a time
Ca2+ conductance is voltage-controlled at the basolateral constant of T2. Postrotatory cupular deflections in the
membrane of the HC. Depolarization results in Ca2+ influx opposite direction follow an identical time course. In addi-
toward the synaptic region of the HC, which is necessary tion, T2 dominates the caloric test; however, diagnostic
to induce fusion of synaptic vesicles with the cell mem- determination of T2 cannot be recommended using caloric
brane and trigger release of the synaptic transmitter. stimuli since the time course of temperature conduction is
Synaptic activity thus depends on the receptor current. highly variable and unknown for each patient.
A constant apical K+ current provides for synaptically Although the time constant of the cupula, T2, lies in the
mediated resting activity in the primary vestibular neuron. range of 5 to 10 sec, the time constant of the nystagmus
Modulation of the receptor current, through membrane that follows step changes in head velocity is much longer.
conductance changes, induces synaptic modulation of the Postrotatory nystagmus, in normal subjects, exhibits a time
resting discharge rate. constant of 18 to 30 sec, or approximately three times that
Thus the transduction theory Davis proposed many years of the cupula. This difference is the result of brainstem
ago has been supported by the rigorous studies in the labo- and cerebellar circuits that act to perseverate the activity
ratories of Flock, Hudspeth, and others.7,15–17 In this theory, generated by the afferent nerve. The precise topography
the high potential between the endolymph and the HC was of these circuits (sometimes called the velocity storage
considered to be a battery driving a current through the cil- system) is not yet fully understood, but they are known to
iated apical membrane, which acted like a variable poten- be related to the optokinetic system. Unilateral peripheral
tiometer capable of controlling the receptor current and vestibular lesions result in a reduction of the nystagmus
potential. time constant to a value close to that of the cupula for
rotations toward the side of the lesion. Finally, the time
constant of postrotatory nystagmus is increased to values
VESTIBULAR SENSORY ORGANS well above normal following lesions involving the cerebel-
lar nodulus. These issues are dealt with in more detail later.
Semicircular Canals
The three coplanar (complementary) canal pairs act recip- Human Semicircular Canal
rocally.1 Because these canal pairs are connected via the
brainstem commissures, the reciprocal arrangement is the The canal time constant T1 depends heavily on the narrow
basis for functional symmetry, compensating for the asym- canal diameter. About one-quarter of the semicircular canal
metrical responses of the individual canals. All HCs in one circumference is occupied by the membranous utricle,
canal are activated by rotation in the same direction: which has a much larger diameter. For this portion, the
toward the ipsilateral side for the lateral canal, during viscous drag becomes negligible. The greater utricular
forward and ipsilateral bending of the head for the anterior volume would probably also increase the moment of inertia
canal, and during backward and ipsilateral head flexions because of the greater endolymph mass. Thus the real canal
for the posterior canal. Thus the three coplanar canal pairs time constant T1 is probably greater than the calculated
are both lateral canals and each of the two ipsilateral ante- one, but it should still only be a few milliseconds.
rior and contralateral posterior canal pairs. The term
coplanar indicates only that the two canals in each pair are
approximately parallel. Both horizontal canal planes are
inclined to each other by about 20 degrees, and in humans
the anteroposterior canal planes deviate by about 24 degrees.
This implies that rotation in any canal plane will cause
some stimulation of all canals.
Horizontal canal planes do not coincide with the stereo-
tactic horizontal plane but are tilted backward by about
25 degrees. Thus a patient’s head must be raised by that
amount during caloric stimulation to position the lateral Figure 4-2. Cupular displacement induced by velocity step. Cupula is
canal vertically. The canal position, however, is kept approx- deflected immediately with short time constant and returns to midposition
imately horizontal during normal behavior. with long time constant (top) during step in rotation velocity (bottom).
 Physiology of the Vestibular System 95

Perilymph fluid dynamics probably do not play an

important role in vestibular function. Because blood ves-
Afferent Neurons
sels and trabeculae in the perilymphatic space are highly A clear concept of primary neuron activity is fundamental
variable, as is the volume of that space, protecting the HCs to both clinical diagnostic studies and physiologic theory.
from this undoubtedly real fluid movement would be All primary vestibular neurons are active at rest.21 This
advantageous. Nonetheless, experiments by Rabbitt and spontaneous activity ranges from about 10 to 200 spikes
Damiano18 have demonstrated that semicircular canal per second with a mean of around 90. This resting dis-
dynamics are more complex than would be expected from charge rate is probably caused by the resting receptor
the old torsion pendulum model and as a result canals current already described and is a prerequisite for bidirec-
remain able to respond at high frequencies even after tional sensitivity. Canal rotation in the excitatory direction
plugging. However, these responses are only significant at leads to an increased firing rate, and rotation in the oppo-
frequencies above those involved in normal human head site direction simply results in a spike rate reduction with-
movements and thus are of little clinical significance. out the need for any synaptic inhibition. The spontaneous
The considerations discussed here explain the semicir- rate also eliminates the need for a definable threshold.
cular canal’s function as an angular accelerometer. During Stimulus detection depends not so much on a minimal
the years many researchers discussed the possibility that spike rate modulation amplitude as on the signal-to-noise
the canals might also be sensitive to linear forces. Guedry ratio. This ratio is severely limited by the binary nature of
kindled interest in this possibility when he observed that pulse rate coding for stimulus intensity in a single neuron,
there is a maintained compensatory nystagmus generated but is enormously improved by averaging over the entire
when the subject is placed horizontally and rotated about neuron population. Thus very sensitive vestibular trans-
his or her longitudinal axis (“barbecue spit” nystagmus19). ducers must be equipped with many neurons.
In this situation the labyrinth is exposed to a constantly Since the two classes of HCs are defined mainly by their
changing gravity vector. This nystagmus is now known to innervation pattern, it is not surprising that two classes of
be generated by the combined action of many otolithic primary afferents have been found: regular and irregular
afferents. neurons. In general, regular units, with narrow ranges of
No conclusive evidence for canal sensitivity to linear interspike intervals, have thin axons with low conduction
accelerations exists under normal circumstances, although velocities, and they innervate predominantly the slopes
almost everyone has experienced linear canal sensitivity of the cristae where mainly type II HCs are found.
under slightly unusual circumstances. Positional alcohol Conversely, irregular firing patterns are associated with
nystagmus and vertigo is caused by slow alcohol diffusion thick axons having high conduction velocities. These
into the endolymph, starting at the well-vascularized axons innervate predominantly the crest of the cristae
crista-cupula region. The cupula density is thought to be where mainly type I HCs are found. This functional clas-
decreased as a result, becoming sensitive to changing grav- sification is not as distinct as the morphologic HC classifi-
ity vectors. Heavy water, resulting in the opposite density cation. Experiments have determined three different
change, has been shown to cause nystagmus and vertigo in morphologic categories of afferent axons based on the
the opposite direction. An appropriate cocktail of alcohol synaptic contacts that they make with the HCs: calyx, bou-
and heavy water can prevent nystagmus and vertigo, as ton, and dimorphic. Calyx-ending axons only synapse on
well as the alcohol-induced nausea, which can be interpre- type I HCs and are only found on the crests of the cristae;
ted as being related to motion sickness.20 they have relatively low sensitivity but are irregular in their
Another example of linear canal sensitivity is benign discharge pattern. Bouton-ending axons are only found in
paroxysmal positional nystagmus. Otolith debris is believed the periphery of the sensory epithelium innervating type II
to fall through the endolymph and cause currents much HCs; they exhibit regular firing patterns and are also
like a stone falling through water will. These currents rather low in sensitivity. Finally, axons with dimorphic
would activate the HC for the time required for the debris endings innervate both type I and type II HCs and are
to reach the bottom of the canal. Any series of head move- found in all parts of the cristae. They exhibit a clear
ments that moved the debris out of the canal lumen would relationship between their degree of regularity and their
alleviate the problem. sensitivity, with low-sensitivity units exhibiting regular
The best known canal response to linear acceleration firing patterns and vice versa.
occurs during caloric stimulation. The amplitude and Regular and irregular neurons differ in their responses
direction of caloric stimulation of the lateral canal should to rotatory stimuli. In general, the more regular the neu-
change according to a cosine function when the canal is ron’s firing rate, the more accurately it will encode angular
tilted away from the proper vertical position. This is clin- head velocity in its firing pattern. If a rotatory stimulus of
ically important because it implies that misalignment of long duration is applied (Figs. 4-3A and B), then regular
the head by 10 to 20 degrees should have very little effect neuron spike rates encode angular velocity quite accurately
on the nystagmus amplitude (1.5% to 6%). The caloric (Figs. 4-3C and D), although the excitatory response is
stimulus is also known to exert a small direct temperature greater than its inhibitory counterpart.
effect on the sensory epithelium such that cooling causes In contrast, the spike rate of irregular neurons peaks
a direct decrease in afferent firing, whereas warming has earlier and adapts exponentially with an adaptive time
the opposite effect. This will result in a slightly faster nys- constant of about 30 sec, which is reminiscent of the HC
tagmus slow phase than would be predicted based on the adaptation already discussed. This adaptive behavior
convection currents alone. accounts for the apparent inhibition after termination of
96 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Semicircular canal afferents can also respond to audio

frequencies if a direct mechanical or acoustic stimulus
vibrates the cupula with sufficient force. In keeping with
the resonant behavior of stereocilia alluded to previously,
a regular tuning curve can be assembled that has a charac-
teristic frequency of about 7 kHz in pigeons. If this stimu-
lus is presented to one ear only, the animal will turn its
head as if the ipsilateral canal were excited (Tullio effect).

Otolith Organs
Figure 4-5 illustrates a schematic view of the orientation of
the otolithic maculae relative to the horizontal stereotactic
plane. The horizontal portion of the utricular macula is
Figure 4-3. Relationship of head rotation stimulus (A and B) to cupular tilted backward and downward by 25 to 30 degrees and
deflection. (C) and primary canal afferent signals (D and E). A, Rotatory head laterally upward by about 10 degrees, just as in the hori-
velocity (Q ). B, Rotatory head acceleration (Q̈). C, Cupular deflection zontal semicircular canals. Since normal head position tilts
following slow time constant. D, Response of regular neuron (firing rate
versus time). E, Response of an irregular neuron. RD, resting discharge; the stereotactic plane by about 25 degrees with the chin
Sp/sec, spikes per second; °/sec, degrees per second. downward, evidently both of these structures are normally
held in the plane of their maximum sensitivity. A small
anterior portion of the utricular macula is bent upward, so
excitation (undershoot) and the overshooting rebound that maximum differential sensitivity would be obtained
following an inhibitory stimulus (Fig. 4-3E). while the subject is in the supine or prone position. The
The rapid rise time of the response in Figure 4-3E saccular macula is oriented almost at right angles to both
reflects a lead element,22 which is best studied using the utricular portions, with its lower end deflected laterally by
Bode plots of Figure 4-4. The gain curve (Fig. 4-4A) for about 18 degrees. Its maximal horizontal sensitivity would
irregular neurons follows the theoretical mechanical fluid occur while lying on one ear. Also shown in Figure 4-5 are
movement reasonably well at low frequencies. At higher the HC orientation vectors for the saccular macula (A) and
frequencies, above 1 Hz, however, a dramatic gain increase the utricular macula (C). Although probably not physio-
occurs. The phase behavior of irregular neurons is charac- logically significant, HC orientation vectors (and thus
terized by a consistent lead throughout the frequency kinocilia) are always directed away from the striola in the
range, with an enormous difference between the fluid saccule and toward the striola in the utricle. More impor-
movement and the neuron firing rate evident in the higher tantly, both maculae contain HC orientation vectors in all
frequency range (Fig. 4-4B). Although much more limited, directions. The striolae in both maculae are the central
a similar difference for high-frequency phase and gain is areas containing a greater density of smaller calcite
seen in regular neurons. As mentioned previously, irregu- otoliths on the otolithic membrane than on more periph-
lar neurons tend to be more sensitive than regular neurons. eral areas. They are equipped with more type I HCs and
In the middle frequency range where gain is nearly constant, are innervated by thicker axons, conducting spikes at
the average sensitivity of nonadapting regular neurons is greater velocities.
about 1.8 spikes per second per degree/sec, whereas the
corresponding value for highly adapting irregular neurons
is 2.5. Efferent innervation is unlikely to play a role in this Adequate Stimulus
difference because semicircular canal neuron behavior is The calcite crystals constituting the otoconia (statoconia)
virtually unchanged when anesthetized and alert animals have a specific gravity of about 2.7 and are moving in
are compared. endolymph with a specific gravity of about 1. Their greater
inertia causes their relative displacement in a direction oppo-
site to an imposed linear acceleration. The amplitude and

Figure 4-4. Relationship between canal dynamics (solid line) and response Figure 4-5. Position of utricular and saccular maculae relative to stereotactic
encoded in regular (dotted line) and irregular (dashed line) neurons. A, Gains horizontal plane. Deflection angles are given in A and B, and hair cell
(discharge rates per velocity). B, Phases. polarization vectors are summarized by arrows in A and C.
 Physiology of the Vestibular System 97

dynamic characteristics of such relative otolith movement change is clearly close to this resting position, whereas
depend on the complex viscoelastic properties of the gelat- minimal sensitivity occurs at positions of either maximal or
inous otolithic membrane, which are not well enough minimal firing rates.
understood for simple analytical treatment such as that As in the canal system, macular units can be classified by
applied earlier to the semicircular canal system. Direct their resting activity into regular, intermediate, and irreg-
measurements have shown, however, that the otolithic ular groups. Irregular neurons tend to have thicker and
layer moves by about 30 μm/g (1 g is the linear acceleration faster conducting axons, lower average spike rates, and
exerted by gravity); threshold movements would be about greater sensitivity. They are concentrated in the striolar
0.15 μm. This would translate into stereocilia deflections region, whereas regular fibers tend to innervate more
of the same small amplitudes discussed earlier for the semi- peripheral macular portions. Figure 4-7A illustrates that
circular canals. Otoconia movement is linear over an ampli- irregular units exhibit far greater adaptation with greater
tude range of 1 g and saturates at higher acceleration values. poststimulatory rebounds to extended acceleratory stimuli
In addition, the movement is damped so that the membrane than do regular neurons. Thus regular neurons appear
does not oscillate after the application of an acceleration to signal steady head position, whereas irregular units
transient, although transient responses are brisk. better encode head position changes. This difference is
quantified further in the Bode plots of Figure 4-7B, in
Macula Afferents which gains are almost independent of frequency for reg-
ular neurons, which represents faithful encoding of head
Gravitational acceleration is always acting on the otolithic position. For irregular units, however, gains are seen to
maculae; therefore attempts to define resting discharges increase with frequency, indicating a relative overemphasis
for afferent neurons are not as easy as in the semicircular on rapid acceleration changes. Figure 4-7A illustrates
canal system.21 Only shearing forces acting at an angle to again the rectifying property of hair cell transducers,
the stereocilia are effective, not compression forces acting which leads to greater excitatory rather than inhibitory
along the axis of the cilia. Thus background activity can responses. As in the canal system, a consequence of this
be defined as the firing rate that occurs when the HC would be a net excitation during vibratory stimuli.
is perfectly horizontal. Since afferent axons collateralize
to innervate several HCs, and since HCs have different
polarization vectors, an average resting position has to
be defined for each afferent fiber. This can be achieved
in three-dimensional space through direct measurements.
For example, the vector component in the pitch plane for
one utricular afferent can be extracted from Figure 4-6, in
which discharge frequency is plotted against head position
while the head is slowly rotated about the interaural axis.
The pitch vector component for this fiber points toward
the occiput, because gravity pull causes maximum firing in
that direction. The roll vector component can then be
measured in the same fashion and the two measurements
combined to yield a complete representation of the polar-
ization vector. The neuronal polarization vector directions
measured in this manner correspond approximately to the
HC vectors illustrated in Figures 4-5A and C; on average
they are oriented horizontally in the utricular macula and
vertically in the saccular macula. The fiber’s resting rate
can then be measured when the gravity vector is oriented
at right angles to the polarization vector. Referring to
Figure 4-6, the fiber’s greatest sensitivity to positional

Figure 4-7. Tilt response of otolith neurons. A, Spike rate versus time plot
illustrates differing adaptation for regular and irregular neurons. B, Gains
Figure 4-6. Static response to various positions in sagittal plane of utricular (spike rate/acceleration) for regular and irregular neurons during oscillatory
neuron. (See text.) tilting.
98 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Vestibular Efferents a few times per second. Reading will become impossible
because the visual tracking reflexes are far too slow to
Labyrinthine HCs are innervated not only by the postsyn- guarantee satisfactory visual stability when the visual target
aptic afferent dendrites, but also by presynaptic terminals is moving at such frequencies. If, however, the book is kept
that contact the HC membrane in type II HCs and the still and the head is gently shaken, reading is easy because
calyx of the afferent ending at type I HCs. These terminals now the relative movements between the visual target and
contain spherical vesicles, much as has been described in the head are compensated for by the VOR, which drives
cholinergic terminals elsewhere in the body, and are derived the eyes at the same velocity as the head but in the opposite
from a small, distinct axon bundle within the vestibular direction. It is possible, however, to exceed the dynamic
nerve that is strongly cholinesterase-positive.23 Cells of performance of even the VOR by vigorous head shaking,
origin for the efferent bundle do not appear to degenerate thus causing the print to blur.
following transection of the vestibular nerve and therefore The dynamics of the human VOR have been studied in
have only been discovered since the development of retro- some detail. Recent experiments have demonstrated that
grade tracer techniques. human subjects are able to generate vestibular eye move-
Most efferent cell bodies in mammals are clustered in a ments that compensate for the head movements up to
small group, termed group E, which is dorsolateral to the 350 degrees/sec. For velocities higher than this, the gain
nucleus of the abducens nerve and adjacent to the genu of (eye velocity/head velocity) is seen to decrease and the
the facial nerve.24 In birds25 and lower vertebrates, the maximum eye velocities observed were about 500 degrees/
efferent cells are scattered in the caudal pontine reticular sec. Since the entire reflex pathway only requires a total of
nucleus, where some of these cells are also found in three neurons, it is not surprising that the latency (the time
rodents.26 Only a few hundred of these cells exist, distrib- from the beginning of a head movement to the onset of the
uting their axons to some 20,000 HCs in the periphery. eye movement) is very short. Although there has been some
Thus many collaterals issue from each efferent cell, and disagreement as to the actual value, most authors now
each cell innervates several semicircular canals or otolithic believe the latency of the human VOR to be 10 to 12 msec.
maculae (or both), with some cells even innervating both
labyrinths.27 This implies that the efferents cannot exercise
a direction-specific control function. Because of the exten- VOR PATHWAYS
sive efferent collateralization, electrical stimuli of one
ampullary nerve can produce trans-synaptic responses in Strictly speaking, the VOR is defined as any compensatory
other subdivisions of the vestibular nerve. These responses eye movement resulting from stimulation of labyrinthine
are simply axon reflexes and do not indicate peripheral receptors by a head movement. It is more practical, how-
interconnections between various labyrinthine sensors. ever, to consider such eye movements as a combination of
It has been suggested that if the efferent system is acti- several separate reflexes that can be studied in isolation
vated in anticipation of movement, then it could be used to and that are transmitted via separate brainstem pathways.
switch the vestibular system from a postural mode to a These reflex pathways are labeled according to their site of
volitional mode by inhibiting units that could be saturated origin within the labyrinth.
by large head movements and activating units that have
large dynamic ranges. Although many theories exist, the
exact function of the efferent system remains elusive. Horizontal Canal VOR
The horizontal canal VOR, which only compensates for
horizontal head rotation, should not be confused with the
VESTIBULO-OCULAR REFLEX horizontal VOR, which must also compensate for lateral
linear motion of the head and is mediated by otolithic
No brain function is as well understood and as thoroughly receptors. To avoid confusion, the canal-based VOR has
studied as the vestibulo-ocular reflex (VOR).1,28–30 There recently been renamed the angular VOR, or aVOR, to
are several reasons for this: distinguish it from the otolith-mediated linear VOR.
1. Detailed knowledge is available about the input from Electric stimulation of one horizontal canal nerve causes a
the vestibular labyrinth and the signals required to pure horizontal deviation of both eyes toward the con-
drive the eye. tralateral side, which is mediated via the three-neuron
2. Input and output are linked by only one brainstem reflex arc summarized in Figure 4-8. The excitation from
neuron. the horizontal canal afferents is fed through excitatory
3. Signal transformation within the brain are well under- interneurons in the vestibular nuclei to the contralateral
stood. abducens nucleus, resulting in excitation of lateral rectus
(LR) muscle motor units. A second group of excitatory
In contrast to many reflexes used in clinical diagnostic vestibular interneurons sends its axons up through the
studies, the VOR’s purpose is understood completely. ascending tract of Deiters (ATD) to terminate on ipsilateral
Thus VOR analysis is a particularly useful diagnostic tool, medial rectus (MR) muscle motor units in the oculomotor
directly assessing the patient’s functional capacity. nucleus. Although the ipsilateral MR and contralateral LR
The VOR’s purpose is to stabilize images on the retina muscles contract simultaneously, the corresponding
during head movements. The reader can immediately ver- vestibular nucleus (VN) neurons do not send axon collat-
ify how critically important this reflex is by attempting to erals to both motoneuron groups. Strict separation of
read this text while shaking the book through a small angle these pathways permits separate regulation of muscle
 Physiology of the Vestibular System 99

Although second-order VOR neurons in the vestibular

nuclei transmit signals to great functional specificity, their
axons do not terminate exclusively around extraocular
motoneurons. For the horizontal VOR, detailed know-
ledge is available on the axon collateralization of these
neurons.32–35
The excitatory axons terminating in the contralateral
abducens nucleus have two main collaterals, which ascend
and descend in the MLF to issue side collaterals toward the
prepositus hypoglossi (PH) nucleus and certain portions of
the reticular formation. The descending collaterals travel
down to at least the second cervical segment of the spinal
cord and thus represent part of the medial vestibulospinal
tract. Some of these neurons send further collaterals into
the contralateral medial vestibular nucleus, where they
excite local interneurons (type II) capable of inhibiting hor-
izontal VOR transmitting neurons. Inhibitory VN neurons
terminating in the ipsilateral abducens nucleus issue only
caudally directed collaterals traveling in the MLF. Both
inhibitory and excitatory VOR-mediating neurons send
Figure 4-8. Direct neuron connections of horizontal VOR. Arrows in eye recurrent collaterals back into the VN, which might be
indicate direction of evoked eye movement. IS, Interstitial nucleus of partly responsible for the integration process discussed in
vestibular nerve; S, L, D, and M, superior, lateral, descending, and medial the following sections.
vestibular nuclei, respectively; PH, nucleus prepositus hypoglossi; III, ocular
motor nucleus; VI, abducens nucleus.
Anterior Canal VOR
contraction to combine vergence movements with the Electrical stimulation of the anterior canal nerve results in
VOR while fixating targets at various distances. These a conjugate upward deviation of both eyes along with
connections suggest that the VOR gain to the separate hor- counterrolling such that the upper poles of both eyes move
izontal eye muscles might be adjusted by vergence signals toward the contralateral side (i.e., the ipsilateral eye intorts
within the vestibular nuclei. These excitatory VN cells are and the contralateral eye extorts) (Fig. 4-9). When the eye
scattered around the border between the medial, lateral, is at primary position, elevation is more pronounced in the
and descending vestibular nuclei, which casts some doubt ipsilateral eye, whereas counterrolling is more pronounced
on the functional significance of these cytoarchitectonic in the contralateral eye. Both elevation and counterrolling
borders. are produced by a contraction of the ipsilateral superior
Because the eyes are always moved in a push-pull fashion, rectus (SR) and the contralateral inferior oblique (IO)
the antagonist eye muscles are relaxed simultaneously by muscles. In contrast, the antagonists of these muscles, the
two separate inhibitory pathways. Inhibitory interneurons ipsilateral inferior rectus (IR) and contralateral superior
excited by the lateral canal nerve project directly to the ipsi- oblique (SO) muscles, are relaxed by inhibition of their
lateral abducens nucleus and thus cause a relaxation of the motoneurons in the ipsilateral trochlear nucleus and the
ipsilateral LR. The inhibitory pathway to the contralateral
MR involves one more neuron (a four neuron reflex arc).
The lateral canal nerve contacts an excitatory VN inter-
neuron, activating in turn an inhibitory interneuron in the
superior vestibular nucleus, which sends its axon through
the contralateral medial longitudinal fasciculus (MLF) to
inhibit contralateral MR motor units. Again, inhibitory
pathways to both eyes are kept strictly separate, presumably
to allow for the influence of vergence during the horizontal
VOR. Both motor nuclei involved in the horizontal VOR
are interconnected by internuclear neurons. Such cells con-
stitute about 50% of the abducens nucleus neuron popula-
tion and act somewhat like surrogate MR motoneurons as
they convey the signals destined for LR motoneurons to the
MR motoneurons on the opposite side. Their axons ascend
in the MLF and it is the interruption of these axons
that results in the MR paresis seen in internuclear ophthal-
moplegia. Internuclear neurons within and around the
oculomotor nucleus31 are excited by axon collaterals from
MR motoneurons and project back to the abducens nucleus
of the other side. A few of these fibers appear to be directed Figure 4-9. Anterior canal VOR connections. Symbols and abbreviations as
to the ipsilateral abducens nucleus. in Figure 4-8.
100 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

IR subdivision of the ipsilateral oculomotor nucleus. The are seen to ramify within the medial and lateral vestibular
inhibition is mediated by one class of interneurons on the nuclei and in the PH nucleus.36 Most of these cells send
superior VN, innervating both of these motoneuron pools a prominent axon branch down into the spinal cord,
via axon collaterals.35 The contraction of the ipsilateral SR although excitatory secondary vestibular neurons without
and the contralateral IO is mediated by one type of excita- such vestibulospinal connections also exist.
tory VN interneuron, also located in the superior VN, The antagonist muscles are relaxed by inhibition of their
which innervates both motoneuron pools within the con- motoneurons in the ipsilateral oculomotor nucleus. This
tralateral oculomotor nucleus. Remember that the SR and inhibition is mediated by inhibitory neurons located in the
SO muscles have their motoneurons located contralaterally superior VN that form synaptic contacts with both SR and
in the brainstem, whereas all other extraocular muscles are IO motoneurons. The SR motoneurons then send their
innervated ipsilaterally, thus the innervation of the vertically axons across the midline to innervate the contralateral eye.
acting extraocular muscles is arranged so that the muscles These inhibitory vestibular neurons form less extensive
that cause intorsion of the eye have their motoneurons collateralizations outside of the oculomotor complex and
located on the contralateral side of the brainstem, while only appear to contact reticular formation neurons close to
muscles that cause extorsion are innervated ipsilaterally. the midline. The final ascending axons appear to project
The wiring diagram for the anterior canal VOR is sim- beyond the midbrain to some higher centers.
pler than that for the horizontal canal VOR because there Excitatory VN cells in all of the canal VOR pathways
are only two classes of VN cells involved as can be seen in exhibit extensive collateralization within their target ocular
Figure 4-9. motor nuclei, with each second-order axon contacting
some 90% of the motoneurons in its specific target nucleus.
This results in a signal-averaging process that lends credi-
Posterior Canal VOR bility to the approach of using a single quantitative equa-
Electrical stimulation of the posterior canal nerve (Fig. 4-10) tion to describe the signal carried by that cell group.
causes counterrolling in the same direction as does ipsilat- Figures 4-9 and 4-10 clearly show that all vertical canals
eral anterior canal stimulation. The rotatory component is participate in the vertical VOR as well as in the counter-
stronger in the ipsilateral eye and the additional downward rolling torsion reflex (tVOR). The discrete connection of
deviation is more apparent in the opposite eye. These certain eye muscles with specified canals in the schemes
movements are caused by contraction of the ipsilateral SO already described must not be viewed as a complete
and contralateral IR. The corresponding motoneuron pools description of the canal-based VOR (aVOR). Rather, the
receive excitatory input from a single class of VN neurons antagonist muscle pairs connected with each canal can only
located in the medial vestibular nucleus, which sends axon be regarded as the prime movers, since all extraocular mus-
collaterals to both the trochlear nucleus and the IR subdi- cles are always involved in all vertical eye movements. The
vision of the oculomotor nucleus, both on the contralateral reasons for this are as follows:
side. These axons travel up and down the MLF to contact
1. Canal pairs are not exactly coplanar, thus during any
cells in a variety of other areas including the pretectal
head movement more than two canals are stimulated.
areas, the interstitial nucleus of Cajal, the nucleus of the
2. About 40% of the secondary vestibulo-ocular neu-
facial nerve, and neuron groups in the reticular formation
rons receive afferents from two canal pairs and 16%
around the abducens nucleus. In addition, axon collaterals
of them from all three canal pairs.37
3. The eye muscle pulling directions are not perfectly
orthogonal to the canal activation axes.
4. The actions of the vertically acting extraocular mus-
cles are dependent on the eye position; for example,
the relative amounts of elevation and intorsion pro-
duced by contraction of the superior rectus vary with
the position of the eye in the orbit.
These multiple input neurons are thought to regulate eye
movements in intermediate planes.

Otolith VOR
For many years, it was widely believed that the otoliths
did not contribute significantly to the VOR because
experiments with linear translation as a stimulus failed to
demonstrate substantial compensatory eye movements.
The reason for this is a geometric one. When a target at
visual infinity (in practice it need only be a few meters
away) is viewed, then the eye movement required to keep
the target on the fovea is negligible. If, however, a near
Figure 4-10. Posterior canal VOR connections. Symbols and abbreviations
target is viewed, then the required tVOR gain for clear
as in Figure 4-8. PrT, Pretectum; IC, interstitial nucleus of Cajal; IV, trochlear vision becomes much greater; indeed, the required gain is
nucleus; VII, facial nucleus. a function of target distance (Fig. 4-11A). Thus if tVOR
 Physiology of the Vestibular System 101

Figure 4-12. If the head moves toward (or away from) a target that is in line
with the right eye, the required compensatory eye movement is a rotation of
the left eye but no rotation of the right eye. Thus the IVOR gain must be a
function of both the target distance and the position of the eye in the head.

be about 12 msec. The latency of the tVOR is similar. This

discovery of the tVOR is of potential clinical relevance
because it offers a means of testing otolith function.
Since the axis of rotation of the eyes is in front of the
axis of rotation of the head, translation of the eyes occurs
with all normal head rotations and thus the tVOR is used
when the head moves while viewing a near target.
Horizontal linear head translations are sensed mainly by
the utricular maculae, whereas the vertical head transla-
tions activate the saccular maculae. Detailed examination
of the pathways from the otolithic maculae to the eye
muscles is much more difficult than it is for the canals,
since the macular nerves carry information about all
Figure 4-11. A, When the head is displaced laterally through a distance X, conceivable directions of movement. Thus stimulation of
the required compensatory eye movement, θ, can be calculated from the these nerves produces eye movements of no functional
formula θ = arctan (X/D ) where D is the distance to the target; thus when the significance. For example, stimulation of the whole utric-
target is moved close to the head, from T2 to T 1 in this instance, the required
eye rotation increases. B, If a subject views a target at the position T, which
ular nerve causes torsional movements of the eyes with
is located closer to the head than the axis of rotation R, then the eye intorsion of the ipsilateral eye and extorsion of the con-
movement required to compensate for a rotation through an angle A is B + C. tralateral eye. In addition, the ipsilateral eye elevates
Note that the eye movement required is in the same direction as the head and adducts while the contralateral eye depresses and
rotation; thus if the head rotates to the right, the eyes must also rotate to the abducts. If small areas of the utricular macula are stimu-
right. In this situation, the aVOR and the IVOR act in opposite directions and
the IVOR must dominate if clear vision is to be maintained. lated, more discrete contractions, apparently of a single
eye muscle in each eye, can be achieved. Similarly, stimu-
lation of the superior saccular area produces upward
gain is measured during linear acceleration while viewing movement, and stimulation of the lower area causes
a near target, the gain is found to be very significant and, downward movement.
in addition, has been found to be a function of the ver-
gence angle of the eyes.38,39 In fact, if a target is closer to Spinal Influences
one eye than it is to the other, and this is often the case, then
the tVOR varies in the two eyes, as it should. Indeed, the The diagrams summarizing the semicircular canal VOR
gain, and even the direction of movement, of the eyes during pathways (Figs. 4-8, 4-9, and 4-10) suggest that vestibulo-
the tVOR needs to be a function of both eye position and ocular neurons are the source of at least part of the medial
vergence angle (Fig. 4-12). For example, if the head is moved vestibulospinal tract. This is largely true for excitatory
in the nasal-occipital direction toward a target that is in line second-order cells, whereas the inhibitory neurons tend to
with one eye, then the required tVOR should produce no be kept separate for ocular and spinal function. Generally,
movement in the eye in line with the target, but an adduc- vestibulo-ocular neurons use γ-aminobutyric acid (GABA)
tion of the other eye (see Fig. 4-12). This is, indeed, just what as a transmitter substance (blocked by picrotoxin), whereas
is observed.40,41 vestibulospinal neurons tend to be glycinergic (blocked by
Many second-order canal neurons also receive input strychnine). Spinal cervical proprioceptive afferents in turn
from the otoliths.42 The latency of the three-neuron arc on can influence the activity of second-order vestibulo-ocular
which the aVOR is based has been measured and found to neurons, which implies that the normally weak neck-to-eye
102 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

reflex is at least partly funneled through VOR pathways. Activity of the CFs is thought to be able to modulate the
It is presumably through this pathway that the effects of efficacy of the parallel fiber-PC synapse, and this type of
neck injury on balance and eye movements are mediated. modulation is thought to be responsible for the adjustment
The corresponding afferent pathways are not as well of motor signals during trained movement coordination.43
understood. Injection of anterograde tracers into the
upper two spinal ganglia revealed a scanty projection sys-
tem into the caudal portions of the descending and medial SIGNAL TRANSFORMATION
vestibular nuclei as well as into the intercalated (Staderini)
nucleus, which is a caudal extension of the PH nucleus If the VOR input and output signals are known, the signal
(D. W. F. Schwarz and I. E. Schwarz, unpublished obser- processing that must take place within the brain can
vations). None of these areas receives primary vestibular be deduced. The semicircular canal input has already
afferents, nor do they contain secondary VOR neurons. been discussed and has been well characterized by a num-
The neck proprioceptive afferent influence on the VOR ber of investigators.44–46 The output elements are the ocu-
thus must be polysynaptic. lar motoneurons and their associated muscle fibers. The
extraocular muscles are very discretely innervated with a
ratio of motoneurons to muscle fibers of nearly 1:1.
CEREBELLAR LOOP Although several types of muscle fibers can be identified
both histologically and functionally, all the motoneurons
Primary vestibular axon collaterals terminate in the caudal behave in much the same fashion. Some of the moto-
vermis of the cerebellum on granule cell (GC) dendrites neurons have low recruitment thresholds (i.e., they are
within the granular layer of the cortex (Fig. 4-13). In addi- recruited into the active pool when the eye is still far in the
tion, axon collaterals convey the same information to the off direction of the muscle), and these units tend to have
fastigial nucleus. Rather surprisingly, the flocculus, a por- low velocity sensitivity as well, resulting in a behavior that
tion of the cerebellum that projects directly to the VN, is more tonic in nature. Others have high thresholds and
does not appear to receive as many direct inputs from tend to have higher velocity sensitivity and thus might be
the vestibular nerve. GC axons, the parallel fibers, excite described as being more phasic in their firing patterns. In
Purkinje cells (PCs), which are the only output of the spite of these differences, all motoneurons are involved in
cerebellar cortex. These PCs send inhibitory GABA- all types of eye movements. Even those with the lowest
ergic axons into the VN, which terminate on VOR neu- thresholds show some phasic behavior, and those with the
rons. Part of the GC excitation within this loop is derived highest thresholds exhibit tonic firing during fixation if the
from VN neurons rather than primaries. This is particu- eye is deviated far enough. Thus they all exhibit both
larly true of the flocculus, which receives a substantial phasic and tonic firing patterns and so can be classified as
input from the VN. Such vestibulocerebellar inhibition is burst-tonic (BT) cells.
available for all coplanar semicircular canal pairs but not The ocular motor apparatus (often called the plant if the
for all secondary VOR neurons. For the horizontal canal motoneurons are included) is simpler than that for skeletal
system, only the VN cells terminating in the ipsilateral joints for a number of reasons. First, the forces resisting
abducens nucleus are so inhibited; in the vertical canal muscle contraction are almost totally due to the viscous
system only secondary cells connected to the anterior drag and elastic tension within the eye muscles, with a
semicircular canals have this inhibitory control, not those small contribution from the other orbital contents. Thus
responding monosynaptically to posterior canal stimula- the system does not have to deal with variable and unpre-
tion. For each canal-specific eye movement plane, a special dictable external loads. Second, the eye muscles insert
microzone of the floccular cortex is responsible for this tangentially to the globe and “peal off ” as the eye rotates.
direct inhibition. Thus their insertion angles, and corresponding mecha-
As indicated in Figure 4-13, the cerebellar loop is closed nical advantage, are essentially constant. The result is that
at the ocular output side. Retinal slip signals carried via the over most of its operating range, the eye represents a
accessory optic tract and relayed in the nuclei of the optic completely predictable load.
tract are carried to these same cerebellar PCs via their Given the mechanical simplicity of the system, it is not
second afferent type, the climbing fibers (CFs). All cere- surprising that the behavior of the motoneurons can be
bellar CFs originate in the inferior olivary nucleus. described with substantial accuracy by means of simple
linear equations. Furthermore, since all the motoneurons
behave in much the same fashion, we can write down a
general equation that will apply for all motoneurons
with the only modification necessary being an adjustment
of a few parameter values in order to specify the behavior
of any particular cell. If average values for the parameters
are measured, a general equation that describes the behav-
ior of the whole pool can be deduced. The neuron dis-
charge rate (Rm) has been shown to be a function of
both eye position and velocity. Therefore the equation
Figure 4-13. Schematic diagram of visual and cerebellar influence on VOR.
VN, Vestibular nucleus; GC, granule cells; PF, parallel fibers; PC, Purkinje
needs to have parameters related to these two variables
cells; CF, climbing fibers; RF, reticular formation; IO, inferior olivary nucleus; along with a description of the eye position at which the
AOT, accessory optic tract; NAOT, nuclei of accessory optic tract. neuron is recruited into the active pool. If we define E as
 Physiology of the Vestibular System 103

eye position, Et as recruitment threshold, and E′ as eye

velocity, then experiments have found that the required
equation is
Rm = k(E − Et ) + rE′ (4-1)
If the eye were to be passively displaced (by pulling on it
when the patient is anesthetized), this equation predicts
that the eye should return to its rest position with an
exponential time course exhibiting a time constant of r/k.
Recordings from awake trained monkeys have demon-
strated the average values of the measured parameters. Et
is about −25 degrees (i.e., the average motoneuron begins
firing when the eye is still deviated 25 degrees into the
field of the antagonist muscle). k is approximately 4.0; and
r is about 0.95. Thus Equation 4-1 becomes
Rm = 100 + 4E + 0.95E′ Figure 4-14. A, Convergence of the vestibular velocity and integrated
position signals on ocular motoneurons as originally proposed by Skavenski
which means that the average motoneuron is firing at and Robinson. B, Corrected version of the same diagram. Note that a portion
about 100 spikes per second when the eye is aimed straight of the eye position signal is already present on the secondary vestibular
neurons. OMN, Ocular motoneurons; VN, vestibular nuclear neurons:
ahead. Thus the eye muscles exhibit a remarkable amount INT, integrator.
of cocontraction. As the fixation position of the eye moves
in the pulling direction of the muscle, the motoneuron fir- have succeeded in completely eliminating integrator func-
ing rate will on average increase by 4 spikes per second for tion. Whether the integrator is located in PH or in VN is
each degree of rotation. In addition, the firing rate will still not completely clear, and the most likely explanation
increase further if the eye is moving (rather than fixating a for the experimental data is that they involve interconnec-
stationary target). This phasic increase will generate an tions among VN, PH, and the cerebellum. Note, however,
additional 0.95 spikes per second for each degree per sec- that one integrator is not sufficient; instead, separate inte-
ond of eye velocity. Finally, the time constant of the system grators are required for each eye movement direction (up,
should be 0.95/4 or about 240 msec, a value close to what down, left, and right). Because the integrator is required to
has been measured under deep anesthesia. maintain the eye in eccentric positions, lesions that affect
Equation 4-1 demonstrates that the oculomotor its performance (most commonly lesions of the posterior
neurons exhibit both an eye position and an eye velocity- cerebellum) will result in an inability to hold eccentric
related discharge. The signal coming from the semicircu- gaze. The nystagmus that results has been termed gaze
lar canals is only related to head velocity. Its amplitude and paretic nystagmus.
direction can be adjusted in the VN so that it is appropri-
ate to drive the eyes, that is, to supply the eye velocity
command to the oculomotor neurons, but the eye position- CENTRAL VOR NEURONS
related part of the signal still needs to be generated in
some fashion. Because, in the mathematical sense, position Figure 4-15 illustrates the oculomotor neuron firing that
can be derived from velocity through the process of inte- would result from an idealized VOR eye movement caused
gration, it has been deduced that a neural integrator must by a rapid head rotation while viewing a stationary target.
exist that generates the eye position signal by integrating The motoneuron discharge rate following the termination
the eye velocity signal. This turns out to be true for all eye of the movement shows a step increase relative to that
movements, not just the VOR; a controller (for saccades before the onset of the movement that reflects the new eye
or quick phases, for example) generates an eye velocity position (as manifested by the kE term in Equation 4-1).
command, which is sent to both the integrator and to the During the actual movement, the rE′ results in a further eye
motoneurons. The integrator output is then also sent velocity-related increase in the discharge rate. Thus the BT
to the motoneurons so that they receive the correct activity is manifest as a pulse-step of activity in the spike rate
mixture of eye position and velocity inputs (Fig. 4-14). versus time plot of Figure 4-15B, a terminology Robinson46
Experiments have strongly suggested that there is a single introduced to describe similar events during saccadic eye
integrator for all types of eye movements. This integrator movements. During a movement of this type, the burst
was originally thought to be located between the VN and would result from semicircular canal activity while the step
the motoneurons (see Fig. 4-14A), because in anesthetized would be the result of the integrator output.
animals the VN neurons carried a head velocity signal
just like the afferents. However, with the advent of single-
neuron recordings in awake animals, the discovery was
Burst-Tonic Cells
made that secondary VOR neurons already possessed an Qualitatively, the same signal as that found on the
eye position signal, and so the situation must be closer to motoneurons has been found in the vestibular nuclei, the
that illustrated in Figure 4-14B. The exact location of the PH nucleus, the paramedial pontine reticular formation
integrator is still not clear. Lesions of the cerebellum (PPRF), the interstitial nucleus of Cajal, and the mesen-
greatly degrade integrator function, but do not eliminate cephalic reticular formation. The function of these cells
it. Recently, lesions involving the VN and PH in primates is unclear; they may be premotor cells, they may subserve
104 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

neurons to eye movements is measured by having an ani-

mal pursue a target. Similarly, the head velocity sensitivity
of these cells can be measured by recording during VOR
cancellation (looking at a target that rotates with the
body). It is then common practice to use these sensitivity
values to predict the behavior of PVPs. However, this form
of linear analysis has not yet been validated. Indeed, it has
been known for many years that linear summation of sig-
nals poorly predicts their behavior during stable gaze.39
The EHV cells, in contrast to the PVP, fire for eye and
head movement in the same direction. Contralateral
EHVs increase their firing rate in response to contralateral
eye and head velocity,51,53 while ipsilateral EHV have
opposite characteristics.56 It is believed that these cells
are a subset of FTNs.51,55,57 Like the EHVs, FTNs also
encode eye velocity, eye position, and head velocity although
their eye velocity signal can be contralateral or ipsilate-
Figure 4-15. Neuronal pulse-step response of a burst-tonic (BT) cell during
rally directed.58-61
idealized VOR eye movement. A, Head and eye position. B, Spike rate versus VO neurons fire during translation and rotation of the
time, indicating combination of pulse (B, burstlike spike activity, bottom) and head and have no eye position on them.39,53,54,62 Their
S, step (tonic rate increase, bottom). behavior is perplexing and their exact role unknown.
Recently it was shown that VO neurons decrease their
sensitivity to head motion during head-on-body move-
an efference copy function, or they may be involved in ment and combined eye-head gaze shifts,62 leading to the
oculomotor control in some other fashion. Since many of hypothesis that efference copy of the neck motor com-
the BT cells in the vestibular nuclei project into the MLF,39 mand suppresses the activity of these cells. These neurons,
it seems likely that at least this subgroup may provide some especially those in the LVN, MVN, and IVN (but not in
drive to the motoneurons. the SVN) project to the spinal cord via the lateral vestibu-
BT neurons carry both eye velocity and eye position lospinal tracts (LVST), the medial VST (MVST), and the
signals. Although the eye position signal is generally caudal VST (CVST).63,64 In addition, these cells project to
independent of the oculomotor system moving the eyes the rostral fastigial nucleus in the rhesus monkey where
(saccades, VOR, smooth pursuit, etc.), the amount of eye most of the neurons also exhibit a combined canal and
velocity modulation is often not. otolith input.65 Indeed, the rostral fastigial nucleus
receives extensive input from the vestibular nucleus66 and
minor input from vestibular afferents, making the cerebel-
Second-Order Vestibular Neurons lum the most likely target of these vestibular neurons. The
The neurons in the vestibular nucleus are diverse and are exact function of these cells is unknown although there do
named based on the types of signals they convey. These exist some hypotheses. For example, they could be a part
cells include (1) position-vestibular-pause (PVP) neurons, of a preprocessing circuit for the VOR,54 or more likely
(2) burst-tonic (BT) cells, (3) eye-head velocity (EHV) they contribute to vestibulospinal reflexes as suggested by
neurons, (4) floccular target neurons (FTN) (although their projections to the fastigial nucleus.67
these may be the same as EHV), (5) vestibular-only (VO) VO neurons are ideal for the study of convergence of
cells, and (6) vestibular pause cells.39,47–54 The firing rate of rotational and translational signals. Given that natural head
PVP cells is proportional to angular head velocity and eye movements are composed of a combination of translation
position when the head is stationary and ceases during a and rotation,68 then elucidating the types of interactions
saccade. It is thought to be the second neuron in the three- between these signals is paramount for the understanding
neuron arc of the angular VOR.39,53 Evidence for this of vestibular reflexes. Both these stimuli have been intro-
comes from the finding that PVP cells involved in gener- duced simultaneously by using eccentric rotation (rotation
ating horizontal eye movements project directly to the around an axis removed from the interaural line).30,69,70
contralateral abducens nuclei and that afferents have been Linear techniques have been applied to PVP, FTN, and
shown to monosynaptically activate PVP cells.34,53 PVPs VO cells in order to calculate the sensitivity of the various
also can make inhibitory connection to the ipsilateral individual signals converging onto them. Experiments
abducens (11% of the population53). There are also PVPs using the previously mentioned method calculated the
that make monosynaptic connections to the oculomotor translational sensitivity of the VO cell by subtracting the
(third) nucleus and participate in vertical eye move- linearly calculated rotational contribution to the firing
ments.39,55 Eye and head velocity signals converging onto rate. Specifically, an animal would be rotated on-axis
PVP cells act synergistically, since eye position sensitivity (about an axis centered on the interaural line so that no
is in the opposite direction to head velocity sensitivity.51,53 translational acceleration exists) while the response of a
This is true for both type I and type II PVPs, where type I neuron is being recorded. Given the rotational attributes,
indicates an increase in the firing rate in response to ipsi- such as velocity or acceleration, the sensitivity of the cell
lateral head velocity and contralateral eye velocity and type to the stimulus can then be easily calculated. Then, the
II is just the opposite. In general, the sensitivity of PVP animal is shifted off-axis, so that eccentric rotation can be
 Physiology of the Vestibular System 105

applied introducing a tangential acceleration. Note that rostral interstitial nucleus of the MLF (riMLF). Consider the
the rotational stimulus does not change during the eccen- horizontal system as an example: The short-lead IBNs are
tric condition since the semicircular canals continue to inhibitory to contralateral abducens motoneurons, and the
sense the same rotational acceleration. The total forces EBNs are excitatory to the ipsilateral abducens. Thus these
during this condition do change though, as tangential two neuron pools are responsible for the bursts and pauses
and centripetal accelerations, which are dependent on the seen in the motoneurons during saccades and quick phases.
distance of the head from the axis of rotation are intro- During light sleep, burst neurons are seen to fire irregularly
duced. Given that the rotational sensitivity has been calcu- even though no saccades are occurring. If the animal is
lated, then the rotational contribution to the response of rotated under these conditions, burst neurons fire in phase
the cell during eccentric rotation was removed, leaving with head velocity and thus must receive a vestibular input.
behind a residual signal. Since translational accelerations Although the function of this vestibular input is unknown, it
represented the additional stimuli during eccentric rota- may be related to the problem of eye-head coordination,
tion, then the additional signals recorded (the residual) which is treated later.
were assumed to be otolith in origin. This methodology Since the burst neurons are responsible for the premo-
makes the bold assumption that the interaction between tor drive signal during all saccades and quick phases, it is
the rotational and translational contribution to the firing not surprising that lesions in medial reticular regions can
rate is linear. result in slow or absent saccades.
No proof of linear behavior exists in the vestibular
nucleus although there may be linear interaction between Pause Cells
vestibulo-ocular reflexes. Sargent and Paige,71 by studying
the VOR during eccentric rotation, have suggested that Although many cells have been demonstrated to pause dur-
signals from different end organs sum linearly. The assump- ing saccades, there is one discrete group for which experi-
tion of linearity in the vestibular nucleus was necessary mental data suggest a functional role. These cells are found
since it was the only way to obtain an estimate of the otolith close to the midline anterior to the abducens nucleus. They
sensitivity. Assuming linearity, the otolith response was exhibit a regular firing rate except that they pause during
obtained by subtracting on-axis responses from eccentric all nystagmus quick phases and saccades. They have been
responses.51,72,73 This method has been applied to cells shown to be monosynaptically inhibitory to the EBNs74
in the vestibular nucleus with and without eye position and IBNs.75 They are believed to function as part of a latch
sensitivity. circuit that prevents neural noise from causing random
The head velocity command is forwarded to the saccades. Thus they must be inhibited in order to initiate
motoneurons by secondary vestibular neurons that behave a quick phase or saccade. Furthermore, stimulation of the
in a manner similar to vestibular primaries during head pause neuron area results in the complete inhibition of all
movements, but exhibit firing patterns related to other eye saccades and quick phases for the duration of the stimulus.
movements (saccades, smooth pursuit, and optokinetic nys-
tagmus) as well. Experiments have shown that FTNs exhibit Tonic Cells
large changes in firing behavior when the VOR gain is
changed as a result of wearing magnifying or minifying The PPRF and PH nucleus also contain cells that encode
lenses, while PVP change very little. As a result, many only eye position by their firing. These cells have been
experimenters currently believe that the VOR is based on termed tonic cells and are thought to represent the output
two parallel pathways: a PVP pathway that is relatively fixed, of the neural integrator. Other cells behave in a manner
and an FTN pathway that is highly modifiable. It is likely similar to tonic cells except they have a weak eye velocity
that the FTN pathway is largely responsible for the com- signal as well and thus may represent an intermediate step
pensation that occurs following unilateral peripheral lesions. in the integration process.

Burst Neurons COMMISSURAL CONNECTIONS

Burst neurons are found in the pontine reticular formation
near the abducens nucleus (horizontal “on” directions) and Virtually all type I (excited by ipsilateral head rotation) VN
in the mesencephalic reticular formation near the midline neurons involved in the VOR send axon collaterals into a
and anterior to the oculomotor nucleus (vertical “on” direc- commissural system that connects both VN complexes
tions). These neurons fire an intense burst of spikes begin- (Fig. 4-16). BT cells monosynaptically excite type II
ning just before the onset of saccades and quick phases but (excited by contralateral head rotation) cells of the oppo-
are otherwise silent. They supply the saccadic pulse to the site side, which in turn inhibit BT cells there. In addition,
motoneurons. Several types of burst neurons exist. type II neurons are monosynaptically inhibited by
Discharges of short-lead burst neurons start 4 to 16 msec contralateral IBNs and BT cells excited by ipsilateral
before the onset of the saccade. They can be further subdi- EBNs. A proposal has been made that the positive feed-
vided into inhibitory burst neurons (IBNs) and excitatory back loop that results from the connections between the
burst neurons (EBNs). For the horizontal system the IBNs BT neurons and the type II neurons might be subject to
are located just caudal and deep to the abducens nucleus, and gain control and time constant modulation via the burst
the EBNs are located in reticular formation just rostral to the neurons. Galiana and Outerbridge76 have suggested that
abducens nucleus. The vertical burst neurons are located in the commissural system functions as a type of oculomotor
a nucleus in the mesencephalic reticular formation called the integrator. Unfortunately, although of theoretical interest,
106 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Figure 4-16. Neuron types mediating VOR from horizontal canal to

contralateral abducens nerve and commissures. VP, Vestibular pause cell;
BT, burst-tonic cell; TVP, tonic vestibular pause cell; PC, Purkinje cell; 2, type
2 cell; VI, abducens motoneuron; EB, excitatory burst cell; IB, inhibitory burst
cell; P, pause cell: LR, lateral rectus muscle; F, neuronal filters. Dotted lines
indicate hypothetic connections. Figure 4-17. Firing behavior of various VOR-mediating neurons during
nystagmus. A, Excitatory slow phase. Eye position (top); discharge rates
of burst tonic (BT), type 2, and vestibular pause (VP) cells (bottom).
B, Excitatory quick phase. Eye position (top); discharge rates of BT, type 2,
few data exist to support this view, especially since recent and VP cells (bottom). C, Inhibitory slow phase. Eye position (top); dis-
lesion studies have implicated the VN and the PH complex charge rate of TVP (tonic vestibular pause) cells (bottom). D, Inhibitory quick
in the integration process. phase. Eye position (top); firing rates of TVP cells and inhibitory burst (IB)
Certain statements concerning the commissures, however, cells (bottom).
can be made. Since many type I neurons are connected to
the opposite canal via type II neurons, these type I neurons
receive two complementary signals during head rotation. would be predicted based on their activity during saccades,
Specifically, they are excited by the ipsilateral canal and periods of fixation, and sinusoidal rotation.
simultaneously they are disinhibited by the contralateral
canal. Thus when one canal is lesioned, the head velocity
sensitivity of type I neurons drops to approximately one-
Motoneurons
half of its normal level (due to the loss of contralateral Activation during both excitatory quick and slow phases in
disinhibition). As a result, following a unilateral peripheral all extraocular motoneurons is caused by a combination of
lesion, the brain needs to compensate for both the unequal EPSPs (excitatory postsynaptic potentials) and a simulta-
activity in the VN on the two sides (resulting in sponta- neous release from synaptic inhibition (disinhibition). The
neous nystagmus) and the reduced sensitivity, which results opposite situation occurs during slow and quick phases
in a subnormal VOR gain. in the inhibitory direction. In this case, there is a drop in
motoneuron firing rate caused by a combination of IPSPs
(inhibitory postsynaptic potentials) and disfacilitation.
NEURON ACTIVITY DURING A notable exception to this is medial rectus motoneurons,
NYSTAGMUS which do not exhibit IPSPs during nystagmus.

Intermediary Neurons
VISUAL VESTIBULAR INTERACTION
Because of the fact that the canals are arranged in comple-
mentary pairs, the two vestibular nuclei fire reciprocally The primary function of the VOR is to stabilize images on
during rotation and its resulting nystagmus.77 Thus the firing the retina during head movements. There are three other
rate increases in the ipsilateral (relative to the rotation eye movement systems with which the VOR must inter-
direction) type I neurons and a parallel decrease results in act.78,79 The optokinetic system (OK) stabilizes images
the contralateral type I cells. The various different cell whenever the entire visual world (or at least a large part of
types found in the VN exhibit characteristic behavior dur- it) moves. The smooth pursuit system (SP) functions to
ing nystagmus. During a slow phase directed toward the stabilize images of smoothly moving foveal targets (e.g., a
contralateral side (which occurs with ipsilateral rotation), bird flying through the air). The saccadic system is used to
VP cells maintain a steady discharge rate proportional to move a target from the peripheral retina onto the fovea.
slow-phase, or head, velocity (Fig. 4-17A). The reciprocal The first two of these, the OK and SP systems, are dis-
pattern of concerted cell firing during excitatory (contra- cussed here. Interactions between the saccadic system and
lateral) quick phases and inhibitory (ipsilateral) movements the VOR are considered later in the section on Eye-Head
is exemplified in Figures 4-17A to D. The behavior of all Coordination. Both of these visual following mechanisms
of the different cell types during nystagmus is simply what are very sluggish relative to the VOR since they require
 Physiology of the Vestibular System 107

substantial processing of visual information and the visual

system is slow.
Due to the nature of the semicircular canals, the infor-
mation that they supply concerning head velocity is only
accurate at frequencies above 0.1 Hz. But what happens if
the rotation frequency is below this value, as it might well
be if one were, for example, running around a curved
track? The answer is simply that the vestibular estimate of
angular head velocity would become inaccurate (as the
cupula moved back to its rest position), the compensatory
eye movements would abate, and the seen world would
become hopelessly blurred. The brain deals with this
problem by using information from the visual system to
supply it with the required data about low-frequency
movements. Indeed, when the seen world moves, the brain
assumes that since the world cannot move, it must be
the body that is moving. This is the cause of a series of
illusions called vection. Circular vection is the illusion of
self-rotation that results from rotation of the visual sur-
roundings (as when one is inside an optokinetic drum), and
linear vection is the illusion that results when the visual
world appears to move linearly. Most people have experi-
enced linear vection at some time in their lives. If you are
sitting in a train looking out the window while the train is
in a station and the neighboring train begins to move, you
feel as if you are moving instead. Figure 4-18. Response of VN neurons (A to D) and nystagmus slow-phase
velocity (E to H) to prolonged rotatory stimulation at constant velocity.
A, Stimulus velocity ramp for B, C, and D. B, VN neuron discharge rate
VOR Neurons versus time during rotation in dark (solid line) or rotation while fixating on
target moving with monkey (dashed line). C, Neuron response to optokinetic
The inability to distinguish between self-motion and stimulation (drum rotating around monkey). D, Neuron firing rate during
environmental motion can be explained by the behavior of rotation in light. E, Stimulus velocity profile for F to H. F, Nystagmus
slow-phase velocities during rotation in dark G, Slow-phase velocities of
second-order vestibular neurons. All VN neurons with canal optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN).
input can also be activated by an OK stimulus in the appro- Dashed line indicates contribution by OK and smooth pursuit (SP) system,
priate plane. For example, a horizontal type I neuron will be respectively. H, Slow-phase nystagmus velocities during rotation in light.
excited by rotation of the visual field (an OK drum) to the Note that firing rate in D represents sum of rates in B and C and that
contralateral side in the horizontal plane. Note that when nystagmus slow-phase velocity in H is obtained by adding SP velocities of
F and OK portion of G.
the drum rotates contralaterally, the movement of the drum
relative to the observer is the same as it would be if the drum
were stationary and the observer rotated ipsilaterally. light inside a stationary drum, the resulting neuron firing
The function of this OK input to VN neurons is to com- precisely mimics the actual rotation velocity profile.
pensate for the poor low-frequency behavior of the canals (Obviously the desired effect as the cell now accurately
and to cause the neurons in VN to behave appropriately reflects the required eye movement command.)
(Fig. 4-18). If a velocity step is used in darkness, the cell The OK signal is derived from specialized retinal gan-
typically reaches its peak firing rate very quickly (Fig. 4-18A), glion cells with large receptive fields covering much of the
but then returns to its background level with a time retinal periphery. Their firing rates encode the velocity
constant of about 25 sec (see Fig. 4-18B). The reason with which the visual field is moving (often called retinal
that the observed time constant is 25 sec instead of the slip velocity) in specific directions. The axons of these cells
cupular time constant is rather complex and is not fully constitute the accessory optic tract (AOT), which termi-
understood. However, both Robinson46 and Raphan and nates in the nuclei of the accessory optic tract (NAOT) in
colleagues80 have suggested ways in which this might be the midbrain. From there the signal is fed to the vestibular
accomplished. Robinson uses a positive feedback loop and nuclei and vestibulocerebellum via the pontine reticular
Raphan uses a velocity storage integrator (separate from formation. Thus the vestibular nuclei generate an estimate
the previously mentioned oculomotor integrator). Which of head velocity based on both vestibular and visual infor-
of these two theories turns out to be correct (if either) mation. The vestibular information is used during high-
remains to be seen, but the effect in either case is to frequency movements, whereas the visual information is
increase the time constant to about three times that of the used during low-frequency movements.
cupula.
If an OK drum is now rotated around the stationary
animal, the firing rate of the VN neurons is seen to build
Nystagmus
slowly with this same 25-sec time constant (see Fig. 4-18C). The responses of secondary VN neurons (see Figs.
Thus, when the vestibular and OK responses are com- 4-18A-D) are reflected in the corresponding nystagmus
bined, as would happen if the animal were rotated in the slow-phase velocities (see Figs. 4-18E-H). Vestibular
108 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

rotatory and postrotatory nystagmus time constants are divided by drum velocity.) For drum velocities greater than
identical to the neuronal time constants (see Figs. 4-18B this value, the gain begins to decrease until the system
and F), and the combined vestibular and OK responses saturates for drum velocities in excess of 120 degrees/sec,
generate a faithful replica of the stimulus in the nystagmus and further increases in stimulus velocity result in lower,
slow-phase velocity profiles when the rotation occurs rather than higher, eye velocities.
in the light (see Fig. 4-18H). The optokinetic response, Horizontal vestibular nystagmus can be driven by either
however, is complicated by the fact that both the OK and the horizontal canals, or, under exceptional circumstances,
SP systems contribute to the overall visual response by the otoliths (during barbecue spit rotation, for example).
(see Fig. 4-18G). We can see in Figure 4-18G that an ini- During normal rotations, the horizontal canal activity con-
tial rapid rise in slow-phase eye velocity occurs followed tributes to the nystagmus in the following two ways:
by a slow increase until finally eye velocity matches drum
velocity. The pattern shown here is commonly seen in 1. Modulation of firing rates in the primary afferents
nonhuman primates. Human subjects, however, exhibit a caused by cupular deflection is responsible for rotatory
slightly different pattern in that there is not normally a and postrotatory vestibular nystagmus; the slow-phase
slowly increasing part to the response. Instead, eye veloc- velocities quickly approach head velocity and then
ity jumps immediately to drum velocity and then stays decay with a time constant of about 20 sec.
there. Other experiments have demonstrated that during 2. The background activity in the lateral canal fibers is
the course of the maintained response, the SP system is essential for normal function of the velocity storage
generating almost all of the nystagmus immediately after mechanism in the VOR and OKN pathways. Thus
the start of the stimulus, but this contribution subseque- the slow decay in OKN after the drum lights are
ntly drops as the OK system increases its contribution (the extinguished, OKAN, is present if the canal’s mechan-
slowly increasing part of the monkey response in ical responsiveness is eliminated by canal plugging,
Fig. 4-18G). When the lights are then switched off, the SP but disappears if the lateral canal nerve is cut.
component decreases very rapidly to zero. As a result, the
residual nystagmus after the lights are extinguished starts If a subject is tilted and then rotated about the new tilted
at a lower velocity (due to the lack of any SP component) axis, which might be earth horizontal (barbecue spit
and is a result of the OK system. It is termed optokinetic- nystagmus82) or merely at some intermediate angle (off
after-nystagmus (OKAN). This OKAN declines with a time vertical axis rotation [OVAR]),19 the resulting nystagmus
constant of about 25 sec, approximately the same as that endures for the duration of the stimulus and does not
of postrotatory nystagmus, and its initial value reflects the decay as it does when the rotation axis is vertical. If the
contribution of the OK system immediately prior to turning lateral canals are plugged, the enduring nystagmus is still
out the lights. Thus, the fact that both the SP and OK present but disappears when the utricular nerve is sec-
systems contribute to optokinetic nystagmus (OKN), tioned. If, however, the lateral canal nerve is sectioned and
whereas OKAN is driven only by the OK system, means the utricular nerve is left intact, the nystagmus cannot be
that only measurements of OKAN reflect OK systems elicited. Thus, although this type of nystagmus seems to
behavior. Indeed, OKN could theoretically be normal even be driven by the otoliths, it requires a certain amount of
with a completely nonexistent OK system; the nystagmus activity in the lateral canal nerve. The most reasonable
would be purely a result of smooth pursuit of the moving explanation for these findings is that the otolith informa-
stripes. tion responsible for generating OVAR nystagmus is fed
OKAN has some function in the diagnostic assessment through the velocity storage system, which depends on
of vestibular function.81 Although its usefulness is limited by lateral canal nerve activity to function. Thus if OVAR
the fact that it exhibits considerable test-to-test and subject- nystagmus is elicited clinically with any kind of rotating
to-subject variability. OKAN is lost following bilateral chair (which, of course, must be able to be tilted) then the
labyrinthectomy, and after loss of only one labyrinth, it is responses can be used to check lateral canal, otolith, and
stronger toward the intact side. Again, following unilateral velocity storage system functions.
lesions, the time constant of OKAN is reduced when the The velocity storage mechanism can be discharged, or
slow phase is directed toward the intact side as is the time “dumped,” by changes in head orientation. For example,
constant of the VOR. Together with the second-order if, during postrotatory nystagmus, the head is suddenly
neuron data (see Fig. 4-18C), all of these observations sug- pitched forward, the nystagmus decay time constant sud-
gest that some form of neural velocity storage mechanism denly drops from the normal value of 20 sec to that of the
is shared by both the OKN and VOR pathways. This is cupula (about 6 sec). Thus this procedure greatly reduces
believed to be the same mechanism that prolongs the time the duration of the postrotatory response. This is believed to
constant of the vestibular system from that of the cupula to be caused by a sudden tilt-induced discharge of the activity
that seen during postrotatory nystagmus. in the velocity storage circuits and is often termed dumping.
In animals with laterally positioned eyes and no fovea This dumping is dependent on the integrity of the cere-
(e.g., the rabbit), there is no SP system. Thus, during OK bellar nodulus. Thus patients with lesions involving the
stimulation, the velocity of the slow phases of the nystag- nodulus do not dump their postrotatory nystagmus when
mus does not exhibit a sudden initial jump as it does in they tilt their heads.
primates. Instead, the velocity is seen to build slowly until A similar simple diagnostic avenue exists for the vertical
it reaches drum velocity. canals. If horizontal rotation is maintained about the
Up to about 60 degrees/sec the OKN system exhibits a normal vertical axis, then the nystagmus will also be main-
gain of about 0.8. (Gain here is defined as eye velocity tained provided the head is pitched (nose up and down)
 Physiology of the Vestibular System 109

periodically.80 In this situation, information about the its effect on the velocity storage system, results in a
rotation is available because the anterior and posterior decrease in the time constant of the nystagmus directed
canals are alternately excited and inhibited during the toward the lesioned side. Thus vigorous head shaking will
pitching as their planes are being moved away from the charge the intact velocity storage system but not the
null (vertical) position. The brain apparently derives lesioned one. This will result in a bias that will in turn
the true axis of rotation from the combined and constantly cause a brief period of nystagmus after the head shaking
changing activity of all six canals. Again this information stops. This head shaking nystagmus will beat away from
seems to make use of the velocity storage system since it the side of the lesion and its existence can be used as a
survives lateral canal plugging but not lateral canal nerve simple test for unilateral lesions.
section. Utricular nerve section has no effect in this case.
Curiously, periodic roll movements (ear up and down) do Quantification of Human
not result in maintained nystagmus. As interesting as these Vestibulovisual Interaction
observations are, they cannot be used for clinical testing
in the way that OVAR can since pitch head movements Eye-tracking reflexes are important for stabilization of the
during horizontal rotation rapidly provoke nausea in visual environment during head movements. If a person is
most subjects. oscillated on a rotating chair strong enough to cover the
An interesting asymmetry exists for vertical nystagmus.83 VOR frequency range of up to 6 Hz, then perfect compen-
Although velocity storage for upward slow phases exists, sation requires a gain (eye velocity/head velocity) of 1
when slow phases are directed downward, little or no (Fig. 4-19A) and a phase shift of 180 degrees (the eyes and
velocity storage seems to occur. Thus if a subject is rotated head must move in opposite directions).85 The ideal gain is
while lying on his or her side with the vertical rotation axis only observed when the subject is fixating a stationary
passing through both ears, then the rotatory and postrota-
tory nystagmus will be markedly different in duration,
reflecting the different up and down time constants. In this
situation, the time constant for downward nystagmus
(upward slow phases) has been found to be about 30 sec,
whereas that for upward nystagmus (downward slow
phases) is only about 7 sec, which is not surprising because
the OK and vestibular system share the same velocity stor-
age system. Downward OKN is prominent but upward
OKN is minimal or even absent. Furthermore, otolithic
input appears to be able to suppress the unidirectional
vertical velocity storage system. When vertical OKN is
evoked with the subject seated in the normal upright
position, minimal OKAN occurs in both up and down
directions. The up and down asymmetry can be restored,
however, if the otolithic maculae are destroyed.84 Finally,
nystagmus behaves as if it wants its direction to be hori-
zontal (perpendicular to the gravity vector). Thus if one
attempts to induce horizontal (relative to the head) OKN
while the subject is lying on his or her side (note that this
means that the OK drum must also be on its side so that
the stripes move horizontally with respect to the head),
the resulting nystagmus beats not purely in the direction
of the drum rotation but instead develops a vertical (with
respect to the head, horizontal with respect to the gravity
vector) component. Thus the otoliths are even able to
modulate the direction of visually induced OKN, not just
its time constant.
When the normal gravitational effect on otolithic input
is reduced under the microgravity conditions that occur
during space flight, the prominence of velocity storage
for upward movements results in a constant bias and
an accompanying circular vection, which may account for
some of the disorientation and space sickness that occurs.
Pigeons in zero gravity fly in a vertical backward circle Figure 4-19. Visual vestibular interaction measured with random and
attempting to compensate for this illusion. A practical sinusoidal stimulation on high-torque hydraulic rotating chair. A, VOR gains
consequence of these observations is that a short and up- (eye velocity/head velocity) in subject watching and earth-fixed target in the
down symmetric time constant for vertical OKAN will be light. B, Gains with random stimuli in dark. Arrows indicate corrective action
by visual tracking necessary to obtain the fully compensatory gains in A.
indicative of a lesion affecting the otoliths. C, Comparison of gains during fixation of target moving with subject (VOR
A similar bias occurs in the horizontal system following suppression) and smooth-pursuit (SP) gains. Solid lines, Random stimuli;
unilateral horizontal canal lesions. The lesion, because of dashed lines, sinusoidal stimuli.
110 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

target.86 When visual fixation is excluded by conducting the following lesions of the cerebellum. Recently, however,
test in the dark or in a visually unstructured but illuminated this view has been called into question. Tomlinson and
environment, the VOR gain drops with decreasing stimu- Robinson39,89 demonstrated that the behavior of many
lus frequency, indicating that at low frequencies the VOR cells in the VN was inconsistent with the notion that the
alone is not adequate to generate accurate compensatory pursuit was used to cancel the VOR. In addition,
eye movements. Clearly, visual tracking mechanisms must Lisberger90 and Cullen and colleagues91 have both demon-
make greater contributions at lower frequencies. This low- strated that under certain circumstances the cancellation
frequency compensation is accomplished mainly by the OK system has a much shorter latency than smooth pursuit
system. Indeed, since the optokinetic signal is fed through (<30 msec versus 100 msec). Thus the current view is that
the vestibular nuclei, it is often useful to think of the OK two separate mechanisms cooperate to cancel the VOR, a
system as part of the VOR even though its input does not short latency system that is probably independent of visual
come from the labyrinth. Many people believe that canal feedback and thus may be viewed as parametric in nature,
function can be measured reliably by rotating the patients and a second, longer latency system that probably corre-
in darkness so as to exclude visual input. This, however, is sponds to smooth pursuit. Finally, there are now reports of
incorrect, since imaginary visual tracking in total darkness patients who exhibit different degrees of deficit in their SP
can have large effects on VOR gain.87 and cancellation systems.92 Given this information, it
At high frequencies (>2.5 Hz) the VOR gain rises with would seem that clinical testing should involve tests of
increasing frequency to values greater than 1, just as the both SP and VOR cancellation since the two systems may
gain of the primary afferents rises at high frequencies. This exhibit differential deficits.
increase, however, is observed only when a randomized,
unpredictable stimulus is employed. When predictable
waveforms are used or during active high-frequency head ADAPTIVE VOR PLASTICITY
shaking,88 the gain remains close to the ideal value of 1,
presumably because of the contribution of predictive motor A disadvantage of the very short latency of the VOR
programs. Indeed, if a subject rapidly shakes his or her head (about 12 msec) is that there is no time for visual feedback
while viewing a distant target, the target appears to move control. (Note, however, that increasing the latency of the
in the opposite direction to the head movement, thus indi- reflex would destroy its usefulness because visual blurring
cating that the VOR gain must be slightly less than 1 under would occur during head movements.) The eyes need to
these conditions. Because high-frequency gains during move too quickly for the long transneuronal delays in the
unpredictable rotations are reduced to the appropriate retina and central visual pathways to supply adequate visual
value of unity as long as the test is performed in light, visual slip information. Since such feedback does not exist, the
tracking mechanisms must be able to make small contribu- VOR is an open-loop system and VOR eye velocity (E′)
tions even at these high frequencies. Under these condi- will depend only on the concurrent head velocity (H′),
tions, retinal slip velocities appear to remain low enough with its size depending only on the value of the parameter
for the pursuit system to largely overcome them. Thus k in the following equation:
at high frequencies, visual tracking mechanisms have the
opposite effect on VOR gain when compared with low E′ = k × H′ (4-2)
frequencies (see Fig. 4-19B).
The level of visual acuity during head shaking is a sensi- The parameter k represents the efficacy of the signal
tive measure of VOR function since even small deviations transduction. It can be adjusted over a slow time course
from a gain of 1 will result in visual blurring. This fact is if gaze is not sufficiently stable during head move-
of substantial clinical importance because it means that ments.93,94 Thus the VOR, lacking closed-loop feedback
if a patient’s head is taken in the hands and gently shaken control, represents an open-loop system that is subject to
through a few degrees in an unpredictable fashion while parametric control, that is, the value of k can be adjusted.
the patient attempts to read a Snellen chart, then VOR There is an obvious necessity for such parametric
deficiencies are easily uncovered. Normal people do not control. It is unlikely that synaptic efficacy would remain
lose more than two lines (relative to their score with the constant throughout a lifetime without some means of
head still), and a loss of more than this can be viewed as a periodic adjustment. In addition, both the degree of ocular
sign of vestibular dysfunction. Although this test does not mobility and the efficiency of the mechanoelectric trans-
yield information about the site of the lesion, it requires no duction in the labyrinth are likely to vary due to disease or
equipment, is more sensitive than the caloric test, and can aging. Common eyeglasses will change visual distances
quickly alert the clinician to a potential problem. by about 3% per diopter and thus will require a parallel
When fixating a visual target that is moving with the change in VOR gain (for example, 2 × lenses cause objects
head during random rotation, the subject is attempting to to apparently move twice as much as the head moves
suppress the VOR, and consequently VOR gain is reduced and thus require a VOR gain of 2.0). This required recali-
at low frequencies although no suppression is seen at bration of VOR gain partly explains the disorientation
high frequencies. The mechanism responsible for VOR associated with a new prescription. Spectacle wearers can
suppression, or cancellation as it is often called, is unclear. easily confirm these facts by fixating a stationary target
It was initially believed to be a function of the SP system while shaking their heads and the repeating the procedure
because cancellation and pursuit exhibit similar frequency after removing their glasses. If they are myopic, the
response curves and show parallel decreases in performance target will appear to move in the direction of the head
 Physiology of the Vestibular System 111

movement; if they are hyperopic, the apparent motion will patient to modify VOR gain in response to reversing
be in the opposite direction. Of course, this only works prisms might be of diagnostic value.
for people who have rather large corrections, because The adaptive process normally requires both visual and
small inaccuracies (a few percent) in VOR gain cannot be vestibular inputs because the gain remains at its adapted
detected. These gain changes are referred to as parametric level if the animal is kept in the dark (no visual input) or
adjustments (the parameter k is being changed) and are has its head immobilized (no vestibular input).
maintained for long periods of time. However, if a subject is rotated in darkness for several
Because of the general applicability of such control to a hours while attempting to fixate an imaginary target that
wide range of brain functions, this phenomenon has been is also moving, the VOR gain drops. This had been attri-
extensively studied in a variety of laboratories.43,93–96 Since buted to VOR plasticity.
visual acuity is maintained provided the retinal image does A number of factors appear to contribute to parametric
not drift at a velocity greater than a few degrees per sec- modification of VOR gain. If the gain is followed over a
ond, the VOR gain is normally kept within 3% of unity,97 period of weeks in animals fitted with telescopic lenses or
at least in subjects with normal vision. If retinal image reversing prisms (which require a reversal of the VOR), the
slip increases during head movements, the VOR gain will gain change is seen to exhibit two time constants; there is
slowly change so as to minimize the slip. Thus if a subject an initial rapid change in gain with a time constant of about
wears telescopic goggles with a magnification factor of 2, 10 h, followed by a slower change with a time constant of
the VOR gain will slowly change during a period of days about 1 week. Thus it seems likely that at least two mech-
until it approaches this value. Similarly, if 0.5 × goggles anisms are involved.
are worn, the VOR gain will drop to about one-half of its The latency data of Lisberger have demonstrated that
normal value. Such gain changes only occur in the plane in the plastic change in VOR gain is not accomplished
which slip occurs. Indeed, the VOR can even be “twisted” through a simple change in the three-neuron arc. Other
if vertical slip is induced during horizontal head movements. evidence also supports this conclusion. If the VOR is
The result is that, after adaptation, horizontal head move- adapted during prolonged rotation at a single frequency,
ments will produce oblique eye movements. Experiments then although the gain change is seen at all frequencies, it
by Lisberger and colleagues96,98 have demonstrated that is greatest at the frequency of the adapting stimulus.100,101
the modified VOR has a different latency than the unmod- Frequency-specific adaptation has been cited to explain the
ified VOR. Thus when a sudden head movement is made, well-known habituation of figure skaters to high rotational
the eyes always follow the same trajectory for the initial velocities, as opposed to that of sailors to low-frequency
short period of 12 msec; however, the eye trajectories movements of their ships. However, habituation is most
obtained at different VOR gains depart from one another likely a different phenomenon from plastic gain changes.
about 19 msec after movement onset. Thus it would In addition, predictive mechanisms seem also to play a role
appear that the three-neuron arc always has the same gain because greater adaptation is seen if the testing is done with
(and a latency of about 12 msec), but other modifiable predictable sinusoidal stimuli rather than randomized stim-
pathways act to change the VOR gain and have an addi- ulation profiles.102 Finally, adaptation is more complete
tional latency of 7 msec. when gains are measured in the light and with active head
The variable gain mechanism is thought to involve movements than with passive rotation in darkness.
modifiable synapses. Since VOR gain plasticity does not Animals without previous visual experience (reared in
survive cerebellar lesions, this was initially thought to be complete darkness) cannot adjust their gain at all, although
the site of the modifiable synapse. This assumption is now the VOR and its cancellation by visual fixation of a target
less certain. Demer and Robinson95 demonstrated that if moving with the head are intact in these animals.103 Gain
the climbing fibers (CF) carrying retinal slip information adaptation is possible in animals reared under stroboscopic
from the inferior olive to the cerebellum were reversibly illumination, although visual motion processing by the
lesioned with lidocaine, then the VOR gain immediately visual cortex and superior colliculus is absent in these
changed to a default value that was essentially independent animals. This suggests that the accessory optic system
of the state of adaptation of the VOR. These experiments must supply the critical visual input as it does for the opto-
imply that the cerebellum may be necessary for plastic kinetic system. The location of the modifiable synapses
modification of the VOR, but it is not sufficient; some still remains elusive in spite of repeated efforts by many
other structures must also be involved. When the lesion is laboratories.
rostral to the inferior olive so that visual input from the
NAOT (see Fig. 4-13) for the CF is eliminated but their
spontaneous firing rate is maintained, the VOR gain is EYE-HEAD COORDINATION
maintained at its adapted value but subsequent modifica-
tion becomes impossible. Thus the CF-cerebellum circuit During normal behavior, targets located more than
seems to be necessary to maintain gain changes that are 20 degrees from the line of sight are acquired with a stereo-
established outside of the cerebellum and to establish new typed combined eye and head movement called a gaze
gains. Indeed, Paige and Sargent99 have demonstrated that saccade (Fig. 4-20A). In this situation, gaze is defined as
elderly patients with poor cerebellar function exhibit the direction of the visual axis and is therefore the sum of
reduced ability to modify their VOR gain. Since such eye-in-head plus head-in-space. The actual movement can
patients would also exhibit reduced ability to compensate be broken down into two parts: the saccade, during which
for unilateral vestibular lesions, testing the ability of a gaze is moving, and the terminal head movement, during
112 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

which the eye is already on the target and is maintained there change in gaze position. Accuracy is maintained, however,
by the VOR as the head continues to rotate. The head move- by the fact that the saccadic system programs the saccade
ment takes longer to execute than the eye saccade because of in gaze (eye-in-space) rather than eye (eye-in-head) coor-
the greater mass of the head and its slower dynamics. At the dinates.104–107 Thus the saccadic system must use informa-
end of the movement, the head will be nearly aligned with tion from the labyrinth to tell it how much the head moved
the target and thus the eye will be near the center of the orbit during the course of the saccade.
(at its primary, or straight ahead, position). This normal pat- Disorders of this system could theoretically result in
tern is altered in predictable fashion if the VOR gain has patients with normal saccades with their heads still, normal
been adapted to a new value. If the VOR gain has been VOR, and abnormal gaze saccades. Such patients might
increased by wearing 2 × lenses (see Fig. 4-20B), the com- find quick head movements disorienting because the eyes
pensatory rollback of the eyes is too great, necessitating a would not be on target after the rapid head movement of a
series of corrective saccades. If, on the other hand, the VOR gaze saccade. Whether such a possibility might account for
gain is too low, the compensatory rollback is inadequate and complaints of disorientation during rapid head movements
again a corrective saccade is required (see Fig. 4-20C). This in certain patients with normal vestibular and oculomotor
latter pattern is also seen if the VOR gain has been reduced examination results is unknown at present.
by labyrinthine disease. Following bilateral labyrinthectomy,
the compensatory rollback is initially lost, but later recovers
due to increases in the cervico-ocular (neck-to-eye) reflex HABITUATION
and the use of predictive eye movements, presumably driven
by the motor program responsible for moving the head. In the previous section, the term adaptation was used to
The mechanism for adjusting the amplitude of the eye describe the adjustment of the VOR to altered conditions
saccade to compensate for variable head contributions (e.g., 2 × spectacles) with the purpose of optimizing the reflex
has recently been the focus of renewed interest. It has performance. In contrast, the term habituation is applied to
previously been proposed that the saccadic command was describe the gradual decline of the response to a normal
summed linearly with the VOR. Thus, if a 40-degree stimulus. These definitions are not identical to those used in
saccade were called for, the saccadic system would pro- classical sensory physiology in which adaptation is normally
gram a 40-degrees saccade and if the head moved during used to describe response decline during a stimulus, whereas
the saccade, the VOR would effectively subtract the head habituation is used to indicate the response attenuation that
contribution. This simple view is now known to be incor- occurs with repeated stimulus presentations.
rect. Instead, VOR gain is substantially reduced during Habituation of vestibular nystagmus is diagnostically
large saccades, allowing the head to contribute to the important because nystagmus slow-phase velocity, fre-
quency, and duration are often used to quantify the VOR.
These parameters are attenuated whenever the stimulus is
repeated frequently.108,109 This phenomenon contributes to
the great variability seen in the bithermal, bilateral caloric,
or postrotatory nystagmus responses. If slow sinusoidal
rotation is applied for a long time, such as 1 h, habituation
will not only cause the gain of the VOR to be reduced, but
in addition, its time constant will shorten. Thus the central
pathways involved in habituation probably include the
velocity storage mechanism. It is not surprising that OK
stimuli can habituate vestibular nystagmus if both stimuli
result in the same sensation of rotation. The converse is
also true: Habituation of the VOR can cause a parallel
habituation of OKAN. Indeed, the stimulus responses of all
central VOR neurons exhibit the same time constant
change as seen in the nystagmus response. Less habituation
occurs in response to continued sinusoidal rotation than in
response to repeated constant velocity rotations, presum-
ably because a sinusoidal rotation is a more natural stimu-
lus than a constant velocity rotation.

COMPENSATION FOR LOSS

OF LABYRINTH FUNCTION
Unilateral labyrinthectomy or sectioning of the vestibular
nerve causes vertigo and several motor symptoms includ-
Figure 4-20. Head-eye coordination. Solid line, Gaze curve; dashed line, eye ing the following:
movement; dotted line, head movement. A, Normal subject. B, Subject after
plastic VOR adaptation to 2 × telescopic goggles. C, Subject after plastic 1. The head and body tilt toward the side of the lesion.
adaptation to 0.5 × goggles. This tendency may be so strong that an animal such
 Physiology of the Vestibular System 113

as a rat can induce active rolling about its longitudi- preventing vision or preventing head movements, seems to
nal axis until it is exhausted. result in a reduction in the amount of recovery that even-
2. Spontaneous nystagmus toward the contralateral side. tually occurs. This result argues strongly in favor of mobi-
3. Reduced VOR gain for rotations toward the ipsilateral lizing patients as quickly as possible following unilateral
side. lesions because the recovery process will be delayed if they
4. Circular locomotion toward the ipsilateral side. do not move their heads. This may in turn result in a
reduction in the degree of recovery ultimately achieved.
Immediately following the lesion, VOR gain is reduced If the second labyrinth is lesioned following compensa-
for rotations in both directions with the greatest reduction tion for the first labyrinthectomy, a mirror image of the
for high-velocity rotations directed toward the side of the original symptoms is observed (Bechterew’s phenomenon).
lesion. A reduction in the time constant to about 6 sec and a For example, the head is tilted toward the side of the
brisk spontaneous nystagmus are also seen. This decrease in second lesion and a spontaneous nystagmus develops that
time constant results in the phase shift during low-frequency beats toward the side of the first lesion. This, of course, is
rotations that is commonly seen during rotation testing of the result of the compensation for the first lesion. In the
patients with unilateral lesions. Over time, these symptoms course of the compensation for the original lesion, the
are alleviated.110–112 The spontaneous nystagmus is greatly background activity in the two vestibular nuclei was equal-
reduced within a few days. This nystagmus results from an ized. The second lesion now results in a depression of
inequality between the firing rates in the two vestibular activity levels in the ipsilateral nucleus and the resulting
nuclei, creating a sense of rotation toward the side contralat- inequality results in the new symptoms. This is a demon-
eral to the lesion. The recovery from spontaneous nystagmus stration of the fact that it is not an inequality between the
has been demonstrated to not require vision, but does firing in the two vestibular nerves that is important, but
depend on the integrity of the cerebellum. The recovery of rather an inequality between the two nuclei.
VOR gain is much slower and has been demonstrated to Although some researchers originally believed that
require several months. Gain recovery, however, is never denervation hypersensitivity of VN neurons on the side of
complete, particularly for high rotational velocities where the lesion accounted for the compensation for unilateral
the gain exhibits a permanent reduction, particularly for vestibular loss, this explanation seems unlikely. Following
rotations toward the side of the lesion.38,110 Since this gain unilateral lesions, both the excitatory and inhibitory
reduction is much more modest when low-velocity stimuli commissural connections originating on the intact side
are used (<100 degrees/sec), it is often not seen during con- and terminating on the VN cells on the lesioned side have
ventional rotational testing. Paige38 evaluated the perform- been shown to exhibit an enhanced synaptic connectivity,
ance of the VOR in patients following unilateral vestibular with the resulting postsynaptic potentials having lower
ablation surgery by using a range of different stimulus veloc- thresholds, faster rise times, and higher amplitudes. Also,
ities, up to 300 degrees/sec. Although he only followed the electron microscopic evidence has shown new synapse
patients for 4 months following the surgery, he found that formation in the denervated VNs.115,116 Transection of the
performance approached normal values when using a 0.25- commissural system between the two VN prevents com-
Hz stimulus and a peak velocity of 50 degrees/sec. However, pensation and the development of Bechterew symptoms.
when the peak velocity was increased to 300 degrees/sec, the Nonetheless, the commissural system alone is clearly
patient gains were less than half of those recorded in normal insufficient for the compensatory process because com-
controls. In addition, a large gain asymmetry was present pensation can be prevented by cerebellar lesions. In addi-
during high-velocity stimuli that was not present at lower tion, cerebellar lesions in animals that have compensated
velocities. Although substantial improvement in function for a previous unilateral loss result in the reappearance of
was seen over the 4-month period when low-velocity stimuli symptoms for which no compensation is possible. Thus
were used, very little recovery was seen with high-velocity care must be taken when contemplating a surgical solution
stimuli. He concluded from his studies that high-velocity for unstable peripheral lesions (e.g., Ménière’s disease). If
stimuli were more likely than other more conventional the patient has compromised cerebellar function, compen-
methods to identify and lateralize even subtle vestibulopathy. sation for labyrinth destruction will not occur and the
Halmagyi and his coworkers113 have demonstrated that symptoms may get worse instead of better.
sudden impulsive movements of the head (accelerations of Although the commissural system and the cerebellum
>2000 degrees/sec) are accompanied by a very marked and seem to be particularly important for recovery from
permanent VOR gain reduction when the movement is unilateral lesions, other brain systems must contribute as
directed toward the side of the lesion. This same group114 well. Furthermore, since different symptoms seem to
has also demonstrated that unilateral lesions result in resolve with different time courses, different pathways
marked ocular torsion, presumably due to asymmetric must be involved, at least to some extent. Sensory experi-
otolith input, but this sign disappears with time. ence during active locomotion undoubtedly plays an
Although some improvement is seen in VOR gain fol- important role.117 Such compensation largely depends on
lowing unilateral lesions, this improvement is dependent information from the intact labyrinth. For example, com-
on retinal slip occurring during activation of the reflex. pensation for the head tilt is accomplished much faster
Thus, although elimination of vision does not disrupt the when the gravitational force is enhanced in a centrifuge.
resolution of the spontaneous nystagmus, it does prevent Even the remnants of the VN on the side of the lesion
improvement in VOR gain. Although the evidence is not may contribute because dendrites regrow into the periph-
conclusive at this time, prevention of retinal slip during ery118 and the deafferented nerve develops background
head movements, which can be accomplished either by activity.119
114 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

If a critical role of the vestibular commissural system in the the head to one side (in the roll plane) requires a different
compensation process is accepted, it should not be surprising postural adjustment in order to maintain an upright posture
that commissurotomy causes an immediate and complete than does a tilt of the whole body. Since the vestibular
decompensation; that is, all primary symptoms reappear. labyrinth is located in the head, it is unable to distinguish
Varying degrees of decompensation, however, are also seen between tilting of the body and tilting of the head. Given
after many other CNS lesions, including spinal cord transec- this situation, it is not surprising that the vestibular nuclei
tion, hemispherectomy, bilateral fastigial nucleus lesions, require information from other sensory systems than
inferior olive lesions, and cerebellectomy. Lesions of the lat- the labyrinth in order to make the appropriate postural
eral reticular nucleus decompensate the skeletal motor adjustments.
symptoms more than the oculomotor effects. All of these The two most important sensory systems contributing
structures have connections with the vestibular nuclei and to the resolution of this problem are the visual system,
therefore can influence the dynamics of the commissural which provides information concerning the relationship
loops. Galiana, Flohr, and Melvill Jones120 assume that this is of the body to the visual surround, and the somatosensory
also possible by much more general changes in brain activity, system (particularly proprioceptors), which provide infor-
such as that induced by certain drugs.121 For example, gen- mation about the postural state of the body. Continuing
eral depressants, such as barbiturates and chlorpromazine, with the same example cited previously, if information
retard the compensation process, and a decompensation is from neck proprioceptors, signaling head-on-body position,
seen after administration of ether, alcohol, and muscimol is combined with information from the otoliths, signaling
(a GABA agonist). Indeed, even moderate doses of barbitu- head-in-space position, then the relationship of the body
rates can produce nystagmus in some people, which may be to the gravity vector can be calculated. The major function
the result of decompensation of minor peripheral inequali- of the vestibulospinal reflexes is to keep the head and body
ties. The physician must realize that drugs, especially alcohol, stable in space. This task is far more complex than the
can cause symptoms associated with long-past pathologic oculomotor analogue, the VOR, for two main reasons:
events for which complete compensation has occurred.
1. Vestibulospinal reflexes act on many joints and the
The central cholinergic system plays an important role in
required muscle tension at any joint must depend on
compensation. Cholinesterase inhibitors such as physostig-
the forces acting on other relevant joints (including
mine, paraoxon (E600), parathion (E605), and diisopropyl
forces external to the body, such as weights carried in
fluorophosphate (DFP, or isoflurophate), when applied sys-
the hands). Thus an analytic treatment of the VOR
temically, can cause an immediate dose-dependent decom-
action on any single joint is an extremely complex
pensation. This is also seen after use of cholinomimetics,
task.
such as nicotine, muscarine, and oxotremorine. This
2. Although labyrinthine head stabilization reflexes serve
decompensation occurs at much lower dosages if the drugs
to prevent head movement, the head must move to
are applied into the cisterna magna, suggesting localized
induce these reflexes. This head movement becomes
effects in the brainstem. Cholinolytics, such as atropine and
the error signal of a negative feedback control system,
scopolamine, have a direct antagonistic effect and can cause
perhaps best illustrated by the vestibulocollic reflex
overcompensation, such as spontaneous nystagmus and
(VCR).
head tilt to the wrong side. When cholinergic drugs are
repeatedly given to animals during the compensation
process, the repeated periods of decompensation result in
increased error signals, causing the compensation process VESTIBULOCOLLIC REFLEX
to occur with an accelerated time course. Similarly, when a
unilateral lesion is produced not in one but in several If a subject is suddenly and unexpectedly rotated with the
successive subtotal surgical procedures, the presence of head free to move, the head tends to maintain its original
repeated new symptoms induces an accelerated and more position in space. This is partly the result of the inertia of
complete final compensation. the head itself and partly due to an active head rotation,
opposite to the rotation of the body, driven by information
from the semicircular canals. Because of the greater mass
VESTIBULOSPINAL SYSTEM of the head, this reflex is slower than the VOR. When sub-
jects are rotated at constant velocity in darkness, they may
In addition to the VOR, the vestibular sensory input pro- execute head and eye nystagmus in the same direction
vides the drive to a series of reflex systems capable of without necessarily being aware of either. In this situation,
affecting almost all of the skeletal muscles that contribute saccadic repositioning of the eyes and head occurs almost
to the stability of the body with respect to gravity.1,122 simultaneously and the VCR and VOR both contribute to
Obviously, direction of the gravity vector with respect to the overall gaze stabilization.
the otolithic maculae changes with head position. In addi- Rotatory head perturbations in the vertical plane will
tion, the net vector sensed by the otoliths will be a func- result in a head tilt and will therefore activate both the
tion of both the head position (with respect to gravity) and otolithic maculae and both semicircular canals. In this
any linear accelerations that the head is undergoing. It is situation, the canal input is primarily responsible for the
equally obvious that the reflex changes in muscle force high-frequency component of the VCR, bringing the head
necessary for the maintenance of any particular body pos- back quickly, while the maculae are more important for low-
ture will differ if the whole body moves relative to what is frequency corrections and thus maintain the long-term head
required when only the head moves. For example, tilting position with respect to gravity. When all the semicircular
 Physiology of the Vestibular System 115

canals are inactivated by plugging and the otolith organs

are left intact, the VCR still operates, although only in the
lower frequency range. Cats with plugged canals
can still hold their heads erect, albeit with increased sway.
After complete labyrinthectomy, however, head position in
darkness appears to be largely uncontrolled.
Direct electrical stimulation of the peripheral nerve
branches has demonstrated directional specificity in the
VCR, as would be expected. For example, stimulation of
the right lateral canal nerve causes head rotation to the
left. Similarly, stimulation of both anterior canal nerves
results in an upward pitch of the head (elevation of the
chin); bilateral posterior canal nerve stimulation results in
a downward pitch; and stimulation of both vertical canal
nerves on the same side results in a head tilt toward the
opposite side. Thus the induced head movement always
occurs in the plane of the canal(s) stimulated, in a direction
opposite to that which would produce an activation of the
stimulated canal. When one canal becomes inactivated, the
error signal necessary to correct head deviation in its plane
will become greater (since only one side is functional),
resulting in greater head instability in that plane. This
principle is illustrated when the swimming behaviors of
lampreys and eels are compared. Lampreys, lacking
horizontal canals, execute horizontal sinusoidal head
movements, whereas eels, with lateral canals, proceed with
their heads along a straight line.

TONIC LABYRINTH Figure 4-21. Tonic neck and labyrinth reflexes and dynamic labyrinth reflex.
AND NECK REFLEXES N, Reflex pattern caused by neck flexion; L, labyrinthine reflexes causing
mirror image of neck reflexes; N + L, neck and labyrinth reflexes cancel each
other. Bottom, Quick, dynamic linear acceleration causing ipsilateral limb
When higher motor control is removed by decerebration extension and contralateral flexion.
in animals or functional decerebration during brain disease
in humans, several positional reflexes become apparent
that cannot normally be elicited. If the body is turned any movement of the body, the two effects cancel and no
about the neck joints while the head is maintained stable in reflex change in limb position results (see Fig. 4-21, N + L
space so as to result in neck bending but no change in reflex pattern). This is of course precisely what is necessary
vestibular input, the tonic neck reflexes can be demon- because there is no danger of loss of balance in this situa-
strated (Fig. 4-21, N reflex pattern). For example, if the neck tion. Thus these two reflex systems cooperate to produce
is bent toward one side, a reflex flexion of the ipsilateral always the correct change in body support musculature
limbs results, as well as an extension of the contralateral for any change in head and body position.
limbs. Thus the tonic neck reflexes tend to compensate for The maintained limb position of the tonic labyrinthine
surface support tilt when the head is kept in the upright reflexes is derived from the otolithic maculae. More rapid
position with respect to gravity. The patterns of flexion stabilization adjustments in the same directions depend
and extension are changed with different directions of on canal input. For example, if all of the semicircular canals
neck flexion so as to compensate for all directions of tilt. of a cat are inactivated by plugging, the animal is still able
For example, when the neck is flexed upward in a to compensate for slow platform tilts, but is thrown off
labyrinthectomized animal, the hind limbs flex and the balance by rapid tilts that would be easily handled by the
forelimbs extend, with the opposite occurring for down- normal animal. Following complete labyrinthectomy,
ward neck flexion. however, both slow and rapid tilts result in loss of balance.
If neck afferent input is prevented by the use of a cast The effect of rapid linear translation on the limbs appears
(thus preventing the neck from bending) or deafferenta- to be quite different from that of the tonic labyrinthine
tion of the upper cervical segments, the tonic labyrinth reflexes. For example, rapid linear translation to the left of
reflexes can be demonstrated. These reflexes again func- a mobile platform results in ipsilateral (left) limb extension
tion to stabilize body position on a tilting platform (see and contralateral flexion, the exact opposite to that
Fig. 4-21, L reflex pattern). Note that the tonic labyrinth induced by the tonic reflexes generated by the same direc-
reflexes act in exactly the opposite direction to the tonic tion of utricular hair cell deflection (see Fig. 4-21). Mayne123
neck reflexes, resulting in limb extension on the side and Nashner124 have therefore proposed that tonic gravi-
toward which the head is tilted and flexion on the tational reflex actions are processed separately from dynamic
contralateral side. Because the two reflexes induce oppo- linear signals within the CNS. Nonetheless, the complex-
site effects, if the head is simply tilted to one side without ity of these systems is such that considerable confusion still
116 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

remains as to the functional responses of the body to tilts inputs to the vestibular nuclei for the generation of vestibu-
and translations, and even the relative importance of the lospinal and oculomotor reflexes.
vestibular input, compared with visual and proprioceptive
cues, remains unclear.
PATHWAYS
FALLING Four pathways are available to mediate vestibulospinal
reflex activity:1 the lateral vestibulospinal tract, the medial
If a cat is falling, it will always right itself during the fall so vestibulospinal tract, the caudal vestibulospinal tract, and
that it lands on its feet regardless of the original body posi- the vestibuloreticulospinal tract.
tion. If the apparent gravity vector is inclined for a long time,
as demonstrated by driving a car round and round on a cir- Lateral Vestibulospinal Tract
cular track (the centrifugal acceleration results in an apparent
change in the gravity vector orientation), then the motor Figure 4-22 summarizes the organization of the lateral
system slowly changes its responses to the new vector orien- vestibulospinal tract (LVST). It originates from both large
tation. Thus when the cat fell after reentering a straight and small neurons in the lateral vestibulospinal nucleus
stretch of road, the animal aligned its head and body with the (Deiters’ nucleus), sending axons through the ipsilateral
previously tilted gravity vector. anterior funiculus into the gray matter of the cord and, to
Otolithic effects on skeletal muscles, however, can be a lesser extent, directly to the motoneurons. LVST cells
very rapid. Electromyography (EMG) has revealed that with shorter axons terminating in the cervical cord are
four peaks occur in the extensor activation when a subject located ventrorostrally in the nucleus, whereas those with
is falling. The first two peaks occur prior to landing and longer axons terminating at lumbar levels are located more
are the result of labyrinthine reflexes. The second two dorsocaudally. From a functional point of view, this appar-
peaks occur just after landing and are the result of the seg- ent somatotopic arrangement is not strict since caudally
mental myotatic (stretch) reflex and the so-called func- directed axons give off many collaterals at more rostral lev-
tional long-loop reflexes, respectively. The earliest els. Stimulation of Deiters’ nucleus increases extensor tone
component, which occurs about 75 msec after the start of via both mono- and polysynaptic excitation of alpha and
the fall in the human gastrocnemius muscle (the latency is gamma motoneurons. All monosynaptic PSPs are excita-
a little shorter in more proximal muscles), probably tory, and no IPSPs, either mono- or polysynaptic, are seen
reflects saccular activity, which is still present after canal in neck muscle motoneurons. However, polysynaptic
plugging but is eliminated by labyrinthectomy. Its ampli- IPSPs have been recorded in motoneurons supplying the
tude is directly proportional to the acceleration and does antagonists of the antigravity muscles in the limbs. The
not habituate. This earliest activity safeguards the body polysynaptic effects are mediated by interneurons located
against the impact associated with unexpected short falls. in the spinal gray matter. The LVST reflex connections
If the fall distance is too short for the reflex to act (about
5 cm), landing is much less comfortable than for greater
heights.
When the falling distance is greater, the second EMG
burst can also be seen. Its timing depends on the falling
distance and its amplitude can be altered by visual cues and
experience. This burst has been suggested to be a prepro-
grammed preparation for landing, although the fact that it
is influenced by visual cues may mean that it is at least
partly visual in origin.
Muscle activity during vertical falls is subject to visual
suppression. If the entire visual field moves with the head,
the second EMG burst is greatly attenuated, whereas little
amplitude change is seen in the first component. Conversely,
if the visual field moves upward as the subject falls down-
ward, an amplitude increase can be seen, but only if
downward acceleration is reduced below the normal value
of 9.8 m/sec2 so that the saturation limit of the OK system
is not exceeded. Thus this experiment provides further
evidence that the second EMG burst depends on visual
input.
After labyrinthectomy, visual cues contribute to the
recovery of the early muscle response during the first two
to three postoperative weeks. This visual influence is more
evident on the side of the lesion after a unilateral labyrinthec-
tomy, which suggests that the corresponding modulation
occurs at the source of the vestibulospinal pathways. All of
this evidence serves to point out the importance of visual Figure 4-22. Lateral vestibulospinal tract.
 Physiology of the Vestibular System 117

can be gated by other motor areas. For example, when of the collateralization patterns for VOR neurons (see
Deiters’ nucleus is electrically stimulated during different Figs. 4-8 and 4-10) reveals that some cells in this area
phases of the step cycle in the decerebrate cat, a facilitation belong to both the VOR and the MVST systems. In con-
of gastrocnemius muscle activity can be seen only during trast to the LVST, the MVST contains many inhibitory
the extension phase and not during flexion. Thus these fibers that mediate monosynaptic IPSPs in many neck
reflexes can be modulated according to the circumstances. motoneurons. These IPSPs can be blocked by strychnine,
Not all LVST neurons receive monosynaptic indicating that the transmitter is glycine rather than GABA.
labyrinthine input because vestibular afferents are con- Excitatory MVST fibers, however, also make monosynaptic
centrated in the ventral portion of the nucleus. As the contacts with cervical motoneurons. Polysynaptic excitation
antigravity function of this system would predict, most and inhibition mediated via this tract are also seen. Most
vestibular input arises from the otolithic maculae, includ- MVST neurons are second-order vestibular cells, which are
ing the saccular macula. Neurons whose axons project monosynaptically activated by semicircular canal afferents.
exclusively to the cervical segments tend to exhibit an Characteristically, type 1 or type 2 canal responses are rare;
alpha response to tilting (excitation when the ipsilateral however, many vestibulospinal neurons exhibit type 3
eye is tilted down and inhibition for tilts in the opposite response patterns (excitation with rotations in both direc-
direction). Cells with axons directed to the lower spinal tions). Evidence also suggests utricular input. MVST neu-
segments more frequently exhibit a gamma response rons with canal input receive commissural inhibitory
pattern (excitation for tilts to both sides). Tilt-sensitive connections, just as VOR neurons do. Although only a few
neurons do not receive commissural inhibition from the MVST neurons do not receive direct labyrinthine input,
contralateral side, although the less common canal driven even those are driven by vestibular stimuli via interneurons.
LVST neurons do. An indirect input to Deiters’ nucleus MVST neurons in Deiters’ nucleus are subject to cere-
travels via the fastigial nucleus of the cerebellum, as well bellar control, but the functional relationship between the
as through the posterior vermis and anterior lobe of the vestibulocerebellum and MVST neurons is not well under-
cerebellar cortex. Deiters’ nucleus could be considered a stood. Nonetheless, it is known that fastigial nucleus neurons
cerebellospinal relay rather than a strictly vestibular struc- can excite type 1 MVST neurons bilaterally.
ture since most LVST neurons receive cerebellar input, Fredrickson, Kornhuber, and Schwarz125 observed a
and many neurons, particularly in the dorsal half of the strong somatosensory input to the VN region containing
nucleus, do not exhibit monosynaptic inputs from the MVST neurons. This input did not appear to be organized
vestibular nerve. somatotopically since the neurons were typically activated
Deiters’ cells receive somatic sensory input via the by a coordinated joint movement pattern involving several
spinocerebellar tracts as well as through the mossy fiber proximal joints. In keeping with the MVST action, the
(MF) inputs derived from the reticular system and the strongest input was derived from the neck.
climbing fiber (CF) system originating in the inferior MVST cells can also be influenced by stimulation of
olive. All this somatic sensory input does not appear to be the rostral brainstem, particularly the interstitial nucleus
somatopically organized, and modalities include muscle of Cajal.
afferents and other proprioceptive and skin afferents.
Deiters’ cells excited by somatosensory input are generally
inhibited via the MF or CF cerebellar loop (or both)
Caudal Vestibulospinal Tract
(see Fig. 4-22) since all Purkinje cells (PC), which termi- The caudal vestibulospinal tract is a newly discovered
nate on Deiters’ neurons or elsewhere are inhibitory. pathway originating from the most caudal aspects of the
Removal of the anterior lobe of the cerebellar cortex, medial and descending vestibular nuclei and projecting as
which projects to Deiters’ nucleus, results in increased far down as the lumbar spinal cord. Its functional signifi-
extensor tonus and opisthotonos, which disappears after cance is still unknown. However, the most caudal portions
ipsilateral labyrinthectomy. In the intact cat, Deiters’ cells of the descending and medial vestibular nuclei, as well as
often respond to tilt in a phasic fashion, that is, only dur- the intercalated (Staderini’s) nucleus, receive direct input
ing the tilting movement. However, after cerebellectomy from peripheral cervical nerves (D. W. F. Schwarz and
these neurons exhibit the typical static response seen in I. E. Schwarz, unpublished observations). Proprioceptive
otolithic afferents. Many Deiters’ neurons are strongly afferents from the most rostral cervical segments are
modulated when a cat walks on a treadmill, with activation known to play an important role in the maintenance of
coinciding with the stance phase. After cerebellectomy, the balance. In cats, denervation of the first two segments, or
spontaneous firing rate of the cells is seen to increase but merely severing cervical muscle tendons at their insertion,
the modulation during locomotion is lost. causes a severe imbalance with a marked hind limb
ataxia.126 Thus it seems very likely that information from
neck proprioceptors is combined with all the other inputs
Medial Vestibulospinal Tract concerned with movement sensation within the central
The medial vestibulospinal tract (MVST) descends bilat- vestibular system.
erally in the MLF and terminates mainly in the cervical Some vestibulospinal neurons with canal input also
spinal cord, with its most caudally directed afferents ter- respond to a comparable neck flexion.127 Movement of the
minating in thoracic segments. Cells of origin are located body with respect to the fixed (in space) head can even
within the same VN area that contains VOR neurons, that induce a sensation of rotation if the movement is slow.128
is, a region around the borderline between the medial, At higher velocities, trunk movement is perceived. Clinical
descending, and lateral vestibular nuclei. Examination neurotologists are familiar with the fact that neck injury
118 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

can cause severe vertigo, and even nystagmus, without any Vestibular input is certainly necessary for spatial orien-
indication of vascular impairment. Thus the preponder- tation. Children or rats without functional labyrinths
ance of evidence certainly indicates that the vestibular cannot remember a path through which they have been
nuclei utilize information from a variety of sources in passively transported. Such egocentric orientation capabil-
order to estimate the movements of the body. ity appears to be mediated via a pathway through the VN,
the magnocellular medial geniculate body, and the caudal
caudate nucleus.131 As a result, rats with caudate lesions
PROJECTION TO FOREBRAIN cannot find their way back to a location from which they
have been passively transported.
The vestibular organs are represented in the cerebral cor-
tex as other senses are, but the projection differs from
other sensory systems.125,129 To date, no cortical area has MOTION SICKNESS
been found to be specifically and exclusively dedicated to
vestibular input; rather, vestibular signals appear to blend Clinically, the most important vestibular sensations are
into the representation of other senses. Early evoked dizziness and vertigo associated with autonomic reactions
potential studies, as well as cortical stimulation in alert such as sweating, salivating, and vomiting.132 This syn-
human subjects, had suggested the existence of at least one drome can be elicited by a variety of different peripheral
specific vestibular cortical field in the parietal lobe. and central vestibular lesions and is undoubtedly related to
Subsequent single-unit investigations, however, have motion sickness. A prerequisite for motion sickness is
revealed that vestibular responses can be found over wide labyrinthine input that conflicts with a central representa-
areas of the somatic parietal fields (areas 3a, 2, and 5). This tion of a stable world. After bilateral labyrinthectomy,
input is derived from thalamic cells located in the ventral motion sickness does not occur; however, an OK stimulus
posterior complex (ventroposterolateral nucleus [VPL], its can evoke the syndrome in healthy subjects. The visual
oral portion [VPLo], and the ventroposteroinferior stimulus needs to be a smooth retinal image slip, since
nucleus [VPI]), which in turn receive axon terminals from motion sickness caused by visual direction reversal (pro-
the contralateral lateral and medial vestibular nuclei. It is duced by wearing spectacles fitted with reversing prisms)
not clear how much of this sensory convergence is simply does not occur under conditions of stroboscopic illumina-
the consequence of the convergence already present in the tion. Visual fixation on a steady-reference horizon can be
VN. It is known, however, that thalamic neurons transmit- used effectively to prevent sea and car sickness.132
ting vestibular information to the parietal lobe also carry Conversely, car sickness is exacerbated by attempting to
somatic sensory signals, usually from proximal joints and read in a moving vehicle.
muscles. Because all secondary vestibular neurons with For the past 40 years, researchers believed that motion
canal input also receive visual information from the OK sickness depended on activity in the vestibulocerebellum
system, this signal must also be present. Thus the vestibu- and on secretion of a humoral mediator to the emetic trigger
lar system is unique among sensory systems because its zone in the area postrema. Cats, however, are still suscepti-
estimates of head angular velocity are based on informa- ble to motion sickness after posterior cerebellectomy134
tion from a variety of sources including the labyrinth, the or ablation of the area postrema. If the aqueductus cerebri
retina, and joint and muscle proprioceptors. (sylvian aqueduct) is blocked, and thus the flow of the puta-
The visual cortex also appears to receive vestibular tive humoral mediator from the third ventricle to chemore-
input. Researchers have shown that the orientation of ceptors further caudally, motion sickness apparently does
certain visual cortical receptive fields can be changed by not occur.135 If the emetogenic compound is secreted into
otolithic stimulation. Reinis and colleagues130 also showed the third ventricle, it must be derived from very caudal
that semicircular canals stimulated with heavy water can structures lining its wall, since motion sickness can be
influence visual cortical background firing rates as well as evoked in decerebrate animals. Conceivably, not one but a
the size of complex visual cortical receptive fields. variety of natural brain chemicals can mediate the emetic
The superior temporal gyrus has been suspected to con- response. Interestingly, a number of external poisons
tain a specific vestibular projection field ever since Penfield (pilocarpine, lobeline, L-dopa, and apomorphine) will no
evoked sensations of rotation and imbalance from this longer cause emesis after bilateral labyrinthectomy.136
general area by electrical stimulation in human subjects. These somewhat conflicting findings show that a coherent
However, no confirmation of this finding using neurophys- physiologic framework for those vestibular sensations that
iologic methods has been made. bring many patients to their physicians is not yet available.
One might reasonably postulate that no specific vestibu-
lar cortical area should exist, since no specific and detailed
vestibular sensations exist. What is sensed is always move-
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 Chapter
Molecular Genetics in Neurotology
5 Outline

Anand N. Mhatre, PhD Introduction Genetics and Genetic Parent-Specific

Inherited Disorders and Their Epidemiology of Transmission and Loss
Anil K. Lalwani, MD Nonsyndromic Hereditary
Inheritance Patterns of Heterozygosity
Autosomal-Recessive Hearing Loss Intracochlear Transgene
Inheritance Connexin 26 Expression and Its Potential
Autosomal-Dominant Pendrin Therapeutic Application
Inheritance Myosins Animal Models and Gene
X-Linked Inheritance Molecular Genetics of Transfer Vectors
Variations on Mendelian Vestibular Schwannomas Intracochlear Gene Delivery
Principles and Glomus Tumors Modalities
Linkage and Recombination Neurofibromatosis Type 1 Preclinical Applications
Mitochondrial Inheritance Neurofibromatosis Type 2 Risks and Limitations
X Chromosome Inactivation Familial Paragangliomas Summary
Genomic Imprinting Genetic Mapping of the PGL
Trinucleotide Repeat Loci and Identification of
Expansion the PGL1 Gene
Multifactorial Inheritance PGL2, PGL3, and PGL4

INTRODUCTION provides a critical assessment of the intracochlear gene trans-

fer studies that are directed toward treatment of hearing loss.
Applications of the molecular genetic techniques toward
hereditary hearing loss (HHL) have led to the identification
and characterization of a large number of “deafness genes,” INHERITED DISORDERS AND THEIR
encoding a wide variety of protein products with differing INHERITANCE PATTERNS
biologic roles. Each of these “deafness genes” represents a
genetic tool or a probe for deciphering the molecular patho- Roughly half of the observed severe hearing loss seen in
physiology of hearing loss precipitated by the mutant allele childhood has been attributed to genetic factors.
and thus contributing toward our understanding of the Approximately one in every 1000 children is born with a
molecular circuitry responsible for hearing. The immediate severe hearing loss with the estimated prevalence of genetic
clinical impact of these discoveries includes the development hearing loss around 1 in 2000.1 Of these cases, approximately
and deployment of genetic tests for molecular diagnosis of 75% exhibit an inheritance pattern that is consistent with an
hearing loss in the general population, thus affecting their autosomal-recessive trait, 23% exhibit autosomal-dominant
care and management. The long-term clinical impact inheritance, 2% appear to be X-linked, and less than 1% are
includes the development and application of gene-based caused by deleterious mutations in the mitochondrial
therapy that can correct certain forms of inherited and genome.
acquired hearing loss.
The objective of this brief review is to inform the neuro-
tologist of the progress in hearing research, its impact upon
Autosomal-Recessive Inheritance
our understanding of hearing loss, and its application to An autosomal-recessive trait is characterized by having
current and future clinical practice. The review begins with a two unaffected parents who are heterozygous carriers for
brief overview of Mendelian genetics, illustrated through mutant forms of the gene in question but in whom the
analysis of inherited disorders and their inheritance patterns. phenotypic expression of the mutant allele is masked by
This is followed by a review of molecular genetic analysis and the normal allele. These heterozygous parents (A/a) can
genetic epidemiology of nonsyndromic hereditary hearing each generate two types of gamete, one carrying the
loss. Genetics and genetic analysis of vestibular schwannomas mutant copy of the gene (a) and the other having a normal
and glomus tumors are also described. Finally, the review copy of the gene (A). Of the four possible combinations of
122
 Molecular Genetics in Neurotology 123

these two gamete types from each parent, only the offspring expression is consistent with autosomal-recessive inheri-
that inherits both mutant copies (a/a) will exhibit the trait. tance in fact possess mutations in two distinct genes that
Of the three remaining possibilities, all will have a normal are in trans to each other. Such noncomplementary double
hearing phenotype but two of the three will be heterozygous heterozygotes, or digenic individuals, have been identified
carriers of the mutant form of the gene, similar to the carrier in retinitis pigmentosa within several families in which
parents. mutations in unlinked photoreceptor-specific genes ROM1
Although relatively uncommon, it is permissible for and peripherin/RDS were identified.2 Only the double
more distant relatives such as first or second cousins to heterozygotes were observed to develop retinitis pigmen-
marry and have children. This practice, known as consan- tosa. These cases represent the first example of digenic
guineous mating, greatly increases the potential to produce inheritance in human disease. Potential double heterozy-
a child affected by a recessive disorder. Figure 5-1 illustrates gotes have also been identified in nonsyndromic hearing
the inheritance pattern of an autosomal-recessive trait in loss within the Ashkenazi Jewish population. The affected
offsprings of consanguineous mating in a pedigree spanning individuals possess a common mutation 167delT in the
several generations. A consanguineous mating of first cousins GJB2 gene in trans to a major deletion spanning the GJB3
can generate a risk of 1 in 64 for having a child affected gene, thus suggesting digenic mode of inheritance.3
with an autosomal-recessive disorder from unaffected However, the effect of the deletion upon transcription of
parents with a common grandparent. With approximately the adjacent GJB2 gene remains to be determined. If the
1 in 2000 children born having a genetic form of hearing deletion adversely affects transcription of GJB2, then
loss and 75% of these due to autosomal-recessive inheri- the deletion effectively represents another example of
tance, a generalized risk of having such an affected child is recessive mutation.
on the order of 1 in 2700 for any two unaffected parents.
Thus the increased risk that a consanguineous mating will
produce a child with autosomal-recessive hearing loss is
Autosomal-Dominant Inheritance
1:64 divided by the frequency of autosomal-recessive hearing For autosomal-dominant disorders, the transmission of a
loss in the general population (random mating) 1:2700. rare allele of a gene by a single heterozygous parent is
This represents a 42-fold increase over the odds of two sufficient to generate an affected child. A heterozygous
unrelated individuals giving rise to a child with autosomal- parent can produce two types of gamete. One gamete will
recessive hearing loss. carry the mutant form of the gene of interest, and the
Autosomal-recessive deafness is extremely heterogeneous, other the normal form. Each of these gametes then has an
as inferred from frequent examples of families where both equal chance of being used in the formation of a zygote.
parents are deaf while their children have normal hearing. Thus, the chance that an offspring of an autosomal-
Thus, the generalized risk of having such an affected dominant affected parent will itself be affected is 50%. Equal
child is a simplification based on an assumption of a single numbers of affected males and females are expected for an
causative locus and consequently an overestimate. It is autosomal-dominant trait and roughly half of the offspring
possible that individuals with a mutant phenotype whose of an affected individual will be affected. If male-to-male
transmission of the trait is observed, the possibility that the
trait is X-linked can be eliminated. Figure 5-2A illustrates
the inheritance pattern of an autosomal-dominant trait
with complete penetrance. Thus all carriers of the disease
allele express the disease trait.
Autosomal-dominant traits often exhibit incomplete
penetrance and variable expressivity. Variable expressivity
refers to the differences in the observed effects of a given
allele in related and unrelated individuals. Incomplete pen-
etrance is an extreme form of variable expressivity and is
characterized by the absence of expression in persons
known to carry the mutant allele. Variation in the age of
onset for symptoms associated with a genetic disorder is
common for traits that are not expressed at birth or prena-
tally. Variation in age of onset is often treated as incom-
plete penetrance in linkage analysis. An example of this
variation in the age of onset is seen in a single, large pedigree
from Costa Rica, affected by nonsyndromic autosomal-
dominant hearing loss. In that nine-generation pedigree
all affected individuals have one affected parent, a hallmark
of autosomal-dominant disorders with high penetrance.
Figure 5-1. A pedigree pattern illustrating transmission of autosomal- Also the ratio of affected males to affected females appro-
recessive trait. The affected individuals (shaded) have parents who are first aches unity and male-to-male transmission of the hearing
cousins as well as carriers of the recessive trait. The double horizontal line loss phenotype is observed, thus ruling out X-linked
between the parents of the affected children indicates that this is a
consanguineous mating between first cousins. When the recessive allele is
inheritance. All affected offsprings developed bilateral
rare, it is more likely to become homozygous through inheritance from a sensorineural hearing loss greater than 80 dB by their
common ancestor than from parents who are completely unrelated. mid-thirties to early forties and had normal intelligence
124 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Costa Rican family.5 This “deafness gene” is a member of

the formin gene family, expressed in multiple tissues,
including brain, heart, placenta, lung, kidney, pancreas,
liver, and skeletal muscle and involved in cytokinesis and
establishment of cell polarity.
If the mutant phenotype is always expressed in individuals
who carry the disease allele, then its penetrance is said to
be complete; otherwise, it is incomplete. Where penetrance
of the affected gene is complete, or 100%, then the pattern
of its inheritance may be discerned relatively straight-
forwardly. Complete penetrance of the dominant allele
will result in expression of the disease phenotype in all
carriers of that allele without skipping generations. However,
with incomplete penetrance of the affected gene, the
inheritance pattern of the affected trait becomes relatively
harder to discern; that is, one cannot easily distinguish
A between dominant inheritance with reduced penetrance
and more complicated modes of inheritance. If the pene-
trance of an allele is very low, the parents of the affected
child may not initially recognize the existence of similarly
affected relatives who are distantly related. Figure 5-2B
illustrates a pedigree expressing transmission of autosomal-
dominant trait with incomplete penetrance. Note that not
all carriers of the disease allele are affected. The presence of
low-penetrance-dominant alleles causing the phenotype to
be transmitted through unaffected carriers cannot be ruled
out without a thorough pedigree analysis that includes the
ancestors and relatives of the affected individual. The gene
may fail to express itself for a variety of reasons. The most
common rationale put forth to explain reduced penetrance
is the effect of genetic background. Factors such as genetic
redundancy, presence of more than one gene for the per-
formance of a given function, and modifiers affect variety
of genes. Incomplete penetrance can also be seen in traits
B
that are inherited in an autosomal-recessive, X-linked
Figure 5-2. A, A pedigree pattern illustrating transmission of autosomal- recessive, and X-linked dominant manner.
dominant trait (shaded). The autosomal-dominant trait is transmitted Variable expression of different aspects of syndromes,
from the affected parent to the offsprings, who have 50% probability of including hearing loss, is common. Some aspects may be
inheriting the disease allele. All carriers of the mutant gene express the dis-
ease trait, indicating complete penetrance of the mutant allele. B, A pedigree expressed in a range from mild to severe, or different
pattern illustrating transmission of autosomal-dominant trait with incomplete combinations of associated symptoms may be expressed in
penetrance. Not all carriers of the mutant gene are affected, indicating different individuals carrying the same mutation within a
incomplete penetrance of the mutant allele. single pedigree. An example of variable expressivity is seen
in families transmitting autosomal-dominant branchio-
oto-renal (BOR) syndrome. For BOR syndrome, aplasia or
and fertility. Thus, the penetrance of the mutant allele was stenosis of the lacrimal duct is reported in approximately
shown to be complete in older individuals. However, the 10% of cases; diagnosed structural anomalies of the renal
age of onset of the hearing loss was variable. All affected system occurs in 12% to 20% of cases; branchial cysts or
individuals were born with normal hearing followed by fistulas are present in approximately 60% of cases; anom-
degeneration of their hearing ability beginning between alies of the inner ear occur in 30% to 60% of reported
the ages of 6 to 16 years and continuing into their third cases; and hearing loss is found in approximately 75% of
decade of life, when the rate of hearing loss plateaus. The reported cases. Of the hearing loss seen in BOR syndrome
initial linkage analysis of this family excluded children cases, 50% is mixed, 30% is conductive, and 20% is
younger than 16 years to avoid problems of misdiagnosing sensorineural loss. All three forms of hearing loss have
carriers of the mutant allele who had not yet expressed been seen in affected members of the same family. In
the phenotype. The gene for this nonsyndromic hearing several individuals the type of hearing loss appears to dif-
loss was mapped to chromosome 5q31 by genetic linkage fer between the two ears. Positional cloning approach led
analysis and the locus was identified as DFNA1, denoting to the identification of EYA1 as the disease gene responsi-
mapping of the first nonsyndromic deafness gene with ble for the BOR syndrome and has been shown to be the
autosomal-dominant mode of inheritance.4 The DFNA1 human homologue of the Drosophila eyes absent gene
gene was subsequently determined to be diaphanous (EYA).6 Analysis of its murine orthologue, EYA1, suggests
(DIAPH1) several years later through the identification of a role in the development of the inner ear and the kidney.
a splice-site mutation, leading to a frameshift in the The range of variation observed in dominant disorders
DIAPH1 mRNA in only the affected members of the is generally wider than in recessive disorders. A major
 Molecular Genetics in Neurotology 125

contributing factor to the variation observed in the dominant

disorders is the presence of a functional product from the
wild-type allele. Variable regional concentration of the
functional product may lead to the variable phenotype in
the affected individuals. The wide range of phenotypic
expression of the syndrome may also reflect the epistatic
effects of different genetic backgrounds in the affected
individuals; that is, different alleles for other genes interact
with the major causative gene or genes. Additionally, variable
expression may be influenced by environmental exposures
and random stochastic events, which occur during
development.
The ability of a single mutant allele to express its aberrant
Figure 5-3. A pedigree pattern illustrating transmission of an X-linked
phenotype, despite the presence of a normal allele, as recessive trait (shaded). The affected males inherit the X-linked recessive
observed in transmission of dominant disease traits, can disease allele from their unaffected carrier mother. The X-linked trait is
occur via several mechanisms. These in turn depend on characterized by absence of male-to-male transmission; all daughters of the
the nature of the protein encoded by the gene and the affected male are heterozygous or carriers for the disease allele.
nature of the pathogenic mutation. If the mutant protein is
involved in transcriptional regulation or functions that are
sensitive to its quantity, then its dysfunction would reduce by chance has an abundance of cells with the mutant allele
the available product by a half. This pathologic reduction being expressed. Transmission of an X-linked-recessive trait
in total amount of the active product is referred to as hap- in a pedigree is illustrated in Figure 5-3.
loinsufficiency. For example, PAX3 is considered to encode The X-linked diseases were some of the first well-
a transcription factor and its haploinsufficiency resulting documented genetic disorders in humans because of their
from a mutant allele is postulated to cause the expression of unique inheritance patterns. Hemophilia A is one the most
the disease phenotype, the dominantly transmitted type I well known X-linked human diseases resulting from defi-
Waardenburg’s syndrome. Another group of genes that can ciency in a blood-clotting factor, factor VIII, encoded by
cause expression of the disease phenotype are those that its gene located on the X chromosome. While comprising
encode structural proteins or membrane proteins that phys- only approximately 2% of cases, X-linked transmission of
ically interact to yield functional product. Mutations within alleles involved in inherited hearing loss is significant.
genes that encode collagens or connexins represent exam- Examples of such disorders include Norrie’s syndrome,
ples of such dominantly inherited disorders.7,8 However, X-linked congenital sensorineural hearing loss, and X-linked
not all mutations in genes whose products are part of an high-frequency sensorineural hearing loss. In pedigrees
oligomeric assembly are dominant. For example, both exhibiting X-linked-recessive traits, many more males are
dominant and recessive forms of a disease can result from affected than females because males have only one X chro-
different mutations of the same gene. This has been demon- mosome. Thus, a recessive allele for hearing loss is not
strated for autosomal-dominant and -recessive forms of masked in males. Females have two X chromosomes, allow-
Stickler’s syndrome, a syndromic sensorineural deafness that ing the masking of a recessive allele on one X chromosome
results from different mutations within COL11A2 gene. by a normal allele of the gene on their other X chromo-
some. Females who express a true X-linked-recessive trait
X-Linked Inheritance have inherited a mutant form of the gene from both
parents. Approximately half of the sons are affected and
In humans, females have 22 pairs of autosomes and a pair half are unaffected when a female carrier of an X-linked-
of X chromosomes (46,XX); males have 22 autosomes, 1 X recessive gene has children with a normal male. No affected
chromosome, and 1 Y chromosome (46,XY). Accordingly, offspring will result from the mating of a male affected by
males always receive their Y chromosome from their an X-linked-recessive disorder with a homozygous normal
father and their X chromosome from their mother, and female; however, all of his daughters will be carriers. The
females receive one of their X chromosomes from each absence of father-to-son transmission is a unique charac-
parent. Because males have one copy of the X chromosome, teristic of all X-linked traits because males always receive
they are hemizygous for genes on the X chromosome and their X chromosome from their mother.
the X chromosome is active in all their nucleated cells. In DFN3 represents one of the most frequent forms of
general, only one of the two X chromosomes carried by a X-linked deafness. Affected males have conductive hearing
female is active in any one cell, while the other is rendered loss (as a result of stapes fixation) and progressive sen-
inactive by a natural process known as lyonization. This sorineural deafness. The DFN3 gene has been cloned and
random inactivation process makes all females, who are is referred to as POU3F4, a member of a multigene family
heterozygous for X-linked traits, mosaic at the tissue level, that encodes nuclear transcription factors.9 POU3F4
resulting in variable expression of the mutant gene. represents the first cloned gene whose mutant allele was
Diseases that are rarely expressed clinically in heterozygous identified in individuals with nonsyndromic deafness.
females are called X-linked recessive. In female tissues,
various proportions of cells may exist in which one or the Variations on Mendelian Principles
other of two alleles for an X-linked locus is expressed.
Occasionally, a carrier female manifests some symptoms of Mendel established the two fundamental principles of
an X-linked-recessive disorder due to this mosaicism if she genetics: segregation of genes and their independent
126 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

assortment. These principles refer to processes that occur

in the formation of germ cells known as meiosis. Segregation 1 2 3 4
refers to separation of homologous genes, representing the I
paternal and the maternal contribution to the individual’s
genotype, into two separate daughter cells. Thus, the dip-
loid genome is reduced to the haploid state in the germ
cells. The principle of independent assortment states that II 1 2 3 4
segregation of one gene occurs independent of other
genes. These principles have served well for analysis and
understanding of inheritance of traits through a single
locus. However, a number of variations on these principles
do exist, some of which have already been stated implicitly. III 1 2 3 4
These variations and their underlying principles have Figure 5-4. A pedigree pattern illustrating mitochondrial inheritance of the
increased our understanding of genetic etiology of disease. disease trait (shaded). The disease trait is transmitted maternally, through its
mitochondrial genome, to both male and female offsprings.

Linkage and Recombination

Not all genes assort independently of each other. Thomas observation is possibly due in part to the fact that a popu-
Hunt Morgan initially identified this variation on the lation of mitochondria, which can itself be genetically
Mendelian principle in fruit flies through analysis of trans- heterogeneous, is actually transmitted by the mother. If all
mission of selected traits. Experiments showed inheritance of the mitochondria transmitted by the mother are of the
of a specific pair of alleles in a combination not present in same genotype, it is called homoplasmia; if there are genetic
the parental phenotype. This new combination of alleles differences between them, it is call heteroplasmia.
was considered to result from crossover and exchange of Despite its small size relative to the nuclear genome,
genetic material between two homologous chromosomes, 1:200,000, mutations of the mitochondrial genome are a
known as homologous recombination, yielding the new com- significant contributor to human disease. This is in part
bination of alleles not present in the original parental due to the 10-fold higher mutation rate that is associated
chromosomes. Analysis of recombination frequencies with the replication of mitochondrial genome relative to
between two traits considered to be controlled by genes the nuclear genome and that it consists of proportionately
residing on the same linkage group (i.e., the same chro- far less noncoding sequence. To date there are 326 syn-
mosome) provided two essential concepts that led to the dromes, disorders, and peculiar phenotypes associated with
development of the genetic map: Genes are arranged in a mutations in the mitochondrial genome.10 Twenty-one of
linear order and the frequency with which two alleles are these disorders have some involvement with sensorineural
inherited together is a function of the relative physical hearing loss, which indicates that the requirement for a
distance from each other. Thus, the closer the two genes, healthy population of mitochondria is very important to
the greater the chance that they will remain linked post the cells involved in normal hearing.11–14 One of the most
meiosis. The relative chromosomal positions of genes may striking examples of a mitochondrially inherited trait whose
be readily mapped through the application of these princi- expression is environmentally affected is the hearing loss
ples of linkage and recombination to generate genetic caused by hypersensitivity to aminoglycosides.12 Hyper-
maps. The genetic distance between two linked genes as sensitivity to aminoglycosides phenotype is the result of a
measured through frequency of recombinants between the single base transition of A to G at position 1555 in the
two alleles is measured in centimorgans (cM). These two mitochondrial 12S rRNA. This mutation causes a portion of
loci are one cM apart on the genetic map if there is a 1% the 12S rRNA transcript structure to closely resemble the
chance of a recombination between them in meiosis. Thus, binding site of aminoglycosides to bacterial rRNA. When
genes that are far apart on a chromosome will assort in an an aminoglycoside such as streptomycin is administered to
apparent independent manner and genes that are close will patients who carry this mutation, it binds to the mutant
tend to remain linked post meiosis. Applying the principles 12S rRNA and prevents it from functioning in the transla-
of genetic linkage, Morgan and his colleagues were able to tion of mitochondrially transcribed genes. This results in
order more than several hundred genes in D. melanogaster the loss of mitochondria that may lead to cell death or loss
via recombination analysis by the year 1922. of their normal function. Screening for this mutation
before initiation of aminoglycoside therapy may reduce
Mitochondrial Inheritance the incidence of ototoxicity.

Not all genes are inherited equally from both parents. The
X Chromosome Inactivation
extranuclear genome is inherited solely through the
mother. Male mitochondria are not contributed to newly The chromosome can be identified in nondividing cells of
formed zygotes. This inheritance pattern, illustrated in females (within the interphase nuclei) as a darkly staining
Figure 5-4, gives rise to pedigrees in which all the children mass called the Barr body attached to nuclear membrane.
of an affected mother may be affected and none of the The Barr body represents the X chromosome that has
children of an affected father will be affected. In practice, been inactivated and thus appears as a condensed mass
the expression of mitochondrially inherited disorders is (heterochromatization). This X-chromosome inactiva-
often variable and may be incompletely penetrant. This tion in females is also known as lyonization, named after
 Molecular Genetics in Neurotology 127

Mary Lyon, who first offered an explanation for its pres-

ence in females. Thus, lyonization represents a dosage
compensation mechanism to correct for differences in sex 2
chromosome constitution between sexes and targeted
toward the X chromosome. This mechanism ensures that
genes located on the X chromosome are not expressed in
proportion to the number of X chromosomes but equiva- I 2 3 4 5 6 7 8 9
lent to a single X chromosome that is present in both male
and female cells. Thus, both the male and female cells are
balanced with respect to the expression of their X-linked
genes. Consequence of X inactivation in females and hem-
II 2 3 4 5 6 7 8
izygous expression of X-linked genes in males as it relates
to inheritance patterns of familial Mendelian disorders is
discussed under the heading X-Linked Inheritance.

Genomic Imprinting III 1 2

Some genetic disease occur more often if inherited from Figure 5-5. A pedigree pattern illustrating transmission of autosomal-
dominant trait (shaded) that is genomically imprinted. A pedigree
the fathers than from mothers or vice versa. This occurrence demonstrating a maternally imprinted autosomal-dominant transmission of a
is considered to result from “genomic imprinting.”15 This disease allele. Individuals are affected only if they receive the mutant allele
phenomenon runs counter to the teachings of Mendelian through paternal and not maternal transmission. Furthermore, the affected
genetics, which emphasize equal contribution from paternal carrier male who has received the mutant allele through maternal inheritance
and maternal genes, with the obvious exception of genes can then transmit the allele.
on the sex chromosomes. Thus, in certain instances, despite
the presence of both the paternal and maternal alleles, only
one parental allele is expressed. This differential expression
of the parental alleles is detected in certain disease states paragangliomas (glomus tumors) have shown an autosomal-
when inheritance of that disorder depends on the sex of dominant inheritance with genomic imprinting of the
the parent that transmits the mutant gene. maternal allele. Thus, the transmission of the disease occurs
The gene-specific imprinting, as with the X-chromosome via the affected paternal allele and not the maternal allele.18,19
inactivation, is presumed to be the consequence of reversible The genetic basis of the head and neck paragangliomas
“epigenetic” modification of the parental allele during game- and the observed parent-specific transmission pattern are
togenesis, leading to its differential expression. The precise discussed in greater detail in a later section.
mechanism of imprinting and its evolutionary significance
remain unknown. Imprinting is considered to be established Trinucleotide Repeat Expansion
prior to or during gametogenesis and is known to persist sta-
bly throughout somatic cell divisions. Hypermethylation of Another type of deviation from Mendelian genetics has
the imprinted gene represents one possible mechanism. This been identified through analysis in six neurologic disorders
process involves the covalent addition of a methyl group to that are characterized by increased severity or an earlier
the C5 position of the cytosine ring. The role of methylation onset of the disease in successive generations. This phe-
for mediating the imprinting process is supported by the nomenon, unique to these disorders, is termed anticipation.
observations that all of the imprinted sequences that have These include the fragile X syndrome (FRAXA), spinal
been analyzed are methylated. It is possible that methylation and bulbar muscular atrophy (SBMA), Huntington’s disease
of the imprinted gene is secondary to a prior imprinting step (HD), and muscular dystrophy (MD). Analysis of mutation
and its role may be stabilizer of the imprinted signal. in the affected individuals has revealed a pathologic expan-
The gene-encoding IGF-II, a potent growth factor and sion of a region of DNA, known as trinucleotide repeats,
a mitogen, was the first identified example of an autosomal- beyond the normal range observed in the unaffected,
imprinted gene.16,17 The expression of IGF-II was shown within genes linked to disorders characterized by anticipa-
to be restricted to its paternal allele, the maternally derived tion. A progressive increase in the size of these trinu-
allele was transcriptionally silent. Several other imprinted cleotide repeats is correlated with the increased severity
loci or genes have been identified in humans based on and/or age of onset of the disease. The mechanism of
inheritance patterns of familial disorders that are consistent pathophysiology caused by this dominantly inherited
with imprinting phenomenon. These include the Prader- pathologic mutation remains relatively unknown.
Willi syndrome, where the affected gene is maternally In patients affected by fragile X syndrome, the syndrome
imprinted, and the Angelman syndrome, where the affected can be transmitted not only by heterozygous female carriers
gene is paternally imprinted. A pedigree transmitting but also by unaffected (hemizygous) males. The “carrier
a maternally imprinted disease gene is illustrated in males” possess expanded repeat numbers of 60 to 230, rela-
Figure 5-5. An example of genomic imprinting at the tive to normal controls who express an average repeat
level of a specific gene has also been identified in familial number of 29. The unaffected paternal carriers of X-linked
cases of nonchromaffin paragangliomas, benign tumors of disorders or the phenomenon of anticipation associated
the paraganglionic cells. Although benign, their enlarge- with trinucleotide repeat expansion could not have been
ment can cause deafness and facial palsy. Familial cases of predicted from principles of Mendelian genetics.
128 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

interaction of multiple genes (polygenic).21 This interaction

Multifactorial Inheritance
is apparently distinct from that presumed for Mendelian
An expression of a phenotype whose outcome is determined traits. But this distinction may be at a quantitative rather
by a single gene is termed a Mendelian trait. Its pattern of than qualitative level. For example, instead of a predominant
transmission within a pedigree can be readily discerned in influence or effect of one gene upon expression of the
most cases, as described in previous sections. On the other phenotype, the multifactorial trait is characterized by a
hand, most common human diseases and traits show irreg- number of genes with equivalent influence or effect. The
ular inheritance patterns. These traits are considered to be genetic component of multifactorial traits is referred to by
determined from action of multiple genes and nongenetic terms such as increased risk, predisposition, and susceptibility.
factors. A phenotype that is an outcome of both genetic Because of their complexity, the factors that contribute to
and environmental factors is called a multifactorial, or com- the multifactorial traits are poorly defined. Several well-
plex, trait. The low proportion of Mendelian traits relative studied diseases that are classified as multifactorial include
to number of multifactorial traits in humans is better illus- cardiovascular conditions, diabetes, and distinct behavioral
trated by considering the proportion of total number of disorders. Influence of nongenetic factors, such as environ-
Mendelian traits known, approximately 6,000 according to mental agents and stochastic processes during developmen-
McKusiak,20 to the total number of genes that are estimated tal outcome of variety of traits, is also clearly illustrated in
to exist, approximately 30,000. It should be emphasized the studies of identical twins.
that classification of Mendelian traits as being determined
by single genes is an oversimplification. As more Mendelian
disorders are identified and their phenotypes investigated, GENETICS AND GENETIC EPIDEMIOLOGY
the phenotypic variability and complexity of each Mendelian OF NONSYNDROMIC HEREDITARY
trait is becoming increasingly clear and concomitantly its HEARING LOSS
distinction from complex or multifactorial trait is becoming
increasingly blurred. Phenotype variability or variable expres- Hearing loss is the most common form of sensory loss in
sion seen in a single gene disorder such as Waardenburg’s humans. Nearly 10% of the U.S. population, or 30 million
syndrome may reflect interaction of that major gene, such Americans, have significant auditory dysfunction. For some,
as PAX3, with “modifier” genes. Identification of these the hearing loss is present at the beginning of life. The
modifier genes has important implications for understanding prevalence of permanent, moderate to severe sensorineural
and treatment of the Mendelian disorders with variable hearing loss (SNHL) is estimated to be between 1 and 3 per
expressivity. 1000 live births.1 Historically, infectious disorders such
One of the clearest examples of interaction of other genes as otitis media, maternal rubella infections, and bac-
and their products (termed epistatic effects) or nongenetic terial meningitis, as well as environmental factors such as
factors during development of a particular Mendelian intrauterine teratogenic exposure and ototoxic insult were
phenotype is provided by the large variation of the clinical the dominant causes of congenital and acquired hearing
phenotype observed in individuals with an identical muta- losses. The introduction of antibiotics and vaccines and
tion in a given gene. A classical example of a single mutant the increasing awareness of teratogens has led to a decline
allele yielding a varying phenotype is the hemoglobin βS in hearing loss resulting from infectious and environmental
mutation that results in substitution of valine or glutamine agents. Currently, more than half of childhood hearing
at position six of the β-globin chain. In the homozygous loss is thought to be hereditary.22
state, this mutation usually causes sickle cell anemia of Genetic analysis of hereditary hearing loss has benefited
varying clinical severity. The identity of the modifying significantly from the development of critical resources
genetic factors that interact to yield the variable clinical and techniques. The development of a high-resolution
severity in sickle cell anemia remain as yet undetermined. map of the human genome characterized by closely spaced
Such phenotypic heterogeneity despite the identity of genetic markers (1 centimorgan or 1 megabase separation)
mutation has been described in number of disorders and the application of the polymerase chain amplification
including Waardenburg’s syndrome (WS), cystic fibrosis, (PCR) technique for rapid characterization of these
phenylketonuria (PKU), Duchenne’s muscular dystrophy genetic markers (genotyping) has enabled the localization
(DMD), retinitis pigmentosa (RP), and Marfan syndrome, and identification of genes responsible for variety of inher-
as well as XY gonadal dysgenesis ( XYGD). Thus, muta- ited disorders in humans. This genetic approach has also
tion analysis alone is insufficient in predicting the clinical been applied toward determining the genetic basis of
phenotype of the affected individual. Conversely, the pheno- syndromic and nonsyndromic hereditary hearing loss. In
typic outcomes do not depend on the nature of mutations syndromic hearing loss, more than 100 genes have been
only. As seen in the examples cited, the primary structural identified since 1990, showing a large heterogeneity even
change in the DNA sequence can result in spectrum of within a single type of syndromic hearing loss [e.g., Usher
consequences depending on the individual’s genotype or syndrome type Ia-f with 6 different genetic loci (Table 5-1)].
genetic background. This can range from complete blocking In nonsyndromic hearing loss, as of January 2004, 51 auto-
of the pathway to complete compensation of the defect, somal-dominant, 39 autosomal-recessive, 8 X-linked,
depending on interactions with other genes and their 1 modifier, and 2 mitochondrial loci have been mapped on
products and their relative influence for the specific the human genome. From these 101 mapped loci, 37 genes
process or the role that is mediated by the mutant gene. have been identified (Table 5-2).23
The relatively irregular mode of inheritance that char- The 37 “deafness genes” that have been identified
acterizes a multifactorial trait is presumed to result from encode a variety of protein products that play different
TABLE 5-1. Genes and Loci for Syndromic Hearing Loss
Locus Syndrome Gene Function Inheritance Clinical Features Associated in Development

Alport syndrome COL4A5 Formation of basement membrane structures in X-linked dominant Focal thinning and thickening with eventual basement
COL4A3, COL4A4 the cochlea (immunolocalization to kidney Autosomal-recessive membrane splitting in the glomerulus
glomerculus)
BOR Branchio-Oto-Renal EYA1 Development of all components of the inner Autosomal-dominant Branchial, otic, and renal anomalies
syndrome ear, from the emergence of the otic placode
Crouzon syndrome FGFR2 Formation of cell-surface binding sites for Autosomal-dominant
fibroblast growth factors
DFN1, Mohr-Tranebjaerg DDP Mitochondrial protein-import system X-linked
syndrome (neurologic development)
JLNS1 Jervell and Lange-Nielsen KVLQT1 Formation of a delayed rectifier potassium Autosomal-recessive Prolongation of the QT interval, torsade de pointe
JLNS2 syndrome KCNE1 (IsK) channel in the inner ear arrhythmias, sudden syncopal episodes, and
severe-to-profound sensorineural hearing loss
Mitochondrial syndromes Leucine tRNA Mitochondrial encephalopathy, lactic acidosis and
stroke-like episodes, diabetes mellitus
Lysine tRNA Myoclonic epilepsy and ragged red fibers
Lysine tRNA Myoclonic epilepsy and ragged red fibers
Several Kearns-Sayre syndrome, progressive external
ophthalmoplegia
Neurofibromatosis type II NF2 Tumor suppression Autosomal-dominant
ND Norrie’s disease Norrin Neuroectodermal cell–cell interaction X-linked Ocular symptoms, progressive sensorineural hearing
loss, and mental disturbance
PDS Pendred’s syndrome SLC26A4 Hydrophobic proteins containing the sulphate Autosomal-recessive Congenital deafness and thyroid goiter
transporter signature
STL1 Stickler’s syndrome COL2A1 Encoding of a structural protein Autosomal-dominant
STL2 COL11A2 Skeletal morphogenesis Progressive myopia, vitreoretinal degeneration, premature
STL3 COL11A1 Formation of the human vitreous joint degeneration with abnormal epiphyseal
development, midface hypoplasia, irregularities of the
vertebral bodies, cleft palate deformity, and variable
sensorineural hearing loss
TCOF1 Treacher Collins syndrome TCOF1 Nucleolar-cytoplasmic transport Autosomal-dominant Coloboma of the micrognathia, microtia, hypoplasia of
the zygomatic arches, respect to the medial canthilower
eyelid (the upper eyelid is involved in Goldenhar
syndrome), hearing impairment and retinitis pigmentosa
USH1A Usher syndrome Unknown
USH1B MYO7A Development of critical neuroepithelium
where auditory transduction takes place in
hair cells of the cochlea

Continued
Molecular Genetics in Neurotology
129
 130

TABLE 5-1. Genes and Loci for Syndromic Hearing Loss—cont’d

Locus Syndrome Gene Function Inheritance Clinical Features Associated in Development

USH1C USH1C Unknown

USH1D CDH23 Member of cadherin superfamily; involved
in establishment of cell–cell contacts and
organization of extracellular matrix
USH1E Unknown
USH1F PCDH15 Member of cadherin superfamily; putatively Autosomal-recessive Hearing impairment and retinitis pigmentosa
ANATOMY, PHYSIOLOGY, AND PATHOLOGY

plays a role in lock-and-key molecular

mechanism involved in synaptic sorting
USH1G Unknown
USH2A USH2A Production of a tissue-specific extracellular
matrix protein
USH2B Unknown
USH2C

USH3 USH3 Two predicted transmembrane domains;

function unknown
Waardenburg’s syndrome PAX3 Production of a protein that contains the paired Autosomal-dominant
domain structural motif and regulates the
expression of other genes
MITF Production of a protein that is a homodimeric Autosomal-dominant
transcription factor expressed in adult skin
and in embryonic retina, otic vesicle and
hair follicles
SLUG Zinc finger transcription factor Dystopia canthorum, pigmentary abnormalities of hair,
iris, and skin, sensorineural deafness
EDNRB Formation of endothelin-signaling pathways Autosomal-recessive
EDN3 Formation of endothelin-signaling pathways Autosomal-recessive
SOX10 Encoding of a transcription factor Autosomal-recessive
 Molecular Genetics in Neurotology 131

TABLE 5-2. Genes and Loci for Nonsyndromic Hearing Loss

Locus Gene Biological Role Inheritance

DFNB1 GJB2 (CX26) A gap junction protein that forms intercellular channels Autosomal-recessive
DFNB1 GJB6 (CX30) A gap junction protein that forms intercellular channels Autosomal-recessive
DFNB2 MYO7A Moves different macromolecular structures relative to actin filaments Autosomal-recessive
DFNB3 MYO15 Organizes actin in hair cells Autosomal-recessive
DFNB4 SLC26A4 Encodes highly hydrophobic proteins containing the sulphate transporter signature Autosomal-recessive
DFNB6 TMIE Transmembrane inner ear expressed gene Autosomal-recessive
DFNB7/DFNB11 TMC1 Transmembrane protein expressed in cochlear hair cells and vestibular end organs Autosomal-recessive
DFNB8/DFNB10 TMPRSS3 Transmembrane serine protease Autosomal-recessive
DFNB9 OTOF Involved in trafficking of membrane vesicles Autosomal-recessive
DFNB12 CDH23 Cadherin superfamily Autosomal-recessive
DFNB16 STRC Protein stereocilin associated with stereocilia on mechanosensitive hair cells Autosomal-recessive
DFNB18 USH1C Unknown Autosomal-recessive
DFNB21 TECTA Includes an aminoterminal hydrophobic signal sequence for translocation across the Autosomal-recessive
membrane and a carboxyterminal hydrophobic region characteristic of precursors
of glycosylphosphatidylinositol-linked membrane-bound proteins
DFNB22 OTOA A glycosylphosphatidylinositol-anchored protein with weak homology to Autosomal-recessive
megakaryocyte potentiating factor/mesothelin precursor
DFNB23 PCDH15 Morphogenesis and cohesion of stereocilia bundle
DFNB29 CLDN14 Protein component of tight junctions between cells Autosomal-recessive
DFNB30 MYO3A Class III myosin with hybrid motor-signaling function Autosomal-recessive
DFNB31 WHRN PDZ domain molecule involved in stereocilia elongation Autosomal-recessive
DFNB37 MYO6 A molecular motor involved in intracellular vesicle and organelle transport Autosomal-recessive
PRES (Prestin) A motor protein of the outer hair cell Autosomal-recessive
DFNA1 DIAPH1 Involved in cytokinesis and establishment of cell polarity Autosomal-dominant
DFNA2 GJB3 (CX31) Gap junction protein that forms intercellular channels Autosomal-dominant
KCNQ4 Forms potassium channel
DFNA3 GJB2 (CX26) A gap junction protein that forms intercellular channels Autosomal-dominant
GJB6 (CX30) A gap junction protein that forms intercellular channels
DFNA5 DFNA5 Unknown; related to a gene that is upregulated in estrogen-receptor-negative Autosomal-dominant
breast carcinomas
DFNA6/DFNA14 WFS1 Protein with nine putative transmembrane domains and putative role Autosomal-dominant
in protein sorting or trafficking
DFNA8/12 TECTA Includes an aminoterminal hydrophobic signal sequence for translocation across Autosomal-dominant
the membrane and a carboxyterminal hydrophobic region characteristic of
precursors of glycosylphosphatidylinositol-linked membrane-bound proteins
DFNA9 COCH Involved in hemostasis, complement system, immune system, and extracellular Autosomal-dominant
matrix assembly
DFNA10 EYA4 Member of the vertebrate EYA family of transcriptional activators Autosomal-dominant
DFNA11 MYO7A Moves different macromolecular structures relative to actin filaments Autosomal-dominant
DFNA13 COL11A2 Collagen protein Autosomal-dominant
DFNA15 POU4F3 Serves as a critical developmental regulator for the determination of Autosomal-dominant
cellular phenotypes
DFNA17 MYH9 Conventional heavy chain nonmuscle myosin Autosomal-dominant
DFNA20/26 ACTG1 An actin molecule, a major component of the cytoskeletal system of nonmuscle cells
DFNA22 MYO6 Unconventional myosin Autosomal-dominant
DFNA28 TFCP2L3 Transcription factor cellular promoter 2-like 3 Autosomal-dominant
DFNA36 TMC1 Transmembrane cochlear-expressed protein Autosomal-dominant
DFNA48 MYO1A Unconventional myosin
CRYM A thyroid hormone-binding protein (THBP) Autosomal-dominant
DFN3 POU3F4 Serves as a critical developmental regulator for the determination of cellular X-linked
phenotypes

roles in cellular physiology (Table 5-3). These protein a single gene have a differing effect upon the encoded
products include the following: cytoskeletal proteins protein, thus affecting the mode of inheritance and/or the
important in maintaining cellular structure, division, and clinical phenotype associated with the disease gene. Thus,
intracellular transport; transcription factors that regulate mutation of the gene-encoding myosin VIIA can cause either
the expression of other genes; ion channels important dominant or recessive forms of nonsyndromic deafness.24,25
in transport of sodium, potassium, chloride, and iodine; This phenomenon has also been documented for connexin
developmental genes that regulate morphogenesis; and 26: Different mutations of CX26 are associated with dom-
proteins involved in intercellular communications such as inant and recessive mode of transmission.8,26 The dominant
gap junctions and tight junctions. or recessive mode of inheritance for a specific mutation is
Genetic analysis of hearing loss has profoundly altered considered to reflect the disruptive effect of the mutant
conventional notions of the relationships between genes, protein upon functional integrity of the multimeric assem-
mutations, and the corresponding disease phenotype. blies formed by the individual subunits. Syndromic and
Numerous examples illustrate that distinct mutations within nonsyndromic deafness associated with mutations of
132 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

TABLE 5-3. Gene Transfer Vectors

Insert Cell
Vector Genome Size Site Efficiency Division Expression Advantages Disadvantages

AAV ssDNA 4.5 kB Genome Variable Not required Permanent No human Difficult to
disease produce
Retrovirus RNA 6–7 kB Genome Low Required Permanent Suited for Insertional
neoplastic cells mutagenesis
Adenovirus dsDNA 7.5 kB Episome Moderate Not required Transient Ease of Inflammatory
production response
Herpesvirus dsDNA 10–100 kB Episome Moderate Not required Transient Neural tropism Human disease
Plasmid RNA/DNA Unlimited Episome Very low Not required Transient Safe, easy Low
production transfection
Liposome RNA/DNA Unlimited Episome Very low Not required Transient Safe, easy Low
production transfection

myosin VIIA, an intracellular motor protein, represents an are responsible for both recessive (DFNB1) and dominant
excellent example of differing clinical phenotypes due to (DFNA3) forms of HHL.8,26 Several studies have demon-
mutations in a single gene. Similarly, mutant alleles of strated prevalence of CX26 mutations in 50% of individuals
pendrin, encoding a solute transporter, can cause either with recessive deafness with a carrier rate as high as
Pendred’s syndrome or isolated (nonsyndromic) large 4%.32,33 Given the large genetic heterogeneity of HHL,
vestibular aqueduct. evidenced by the 93 distinct loci that have been mapped,
The patient’s genetic background is a critical factor in the predominance of a single gene’s being responsible for
determining the clinical phenotype that results from a the majority of the hearing loss in the general population
specific mutation. The genetic background represents other is a surprising outcome with significant implications for
genes that interact with the mutated gene via its protein screening and clinical management.
products. These genes are known as modifier genes and Studies investigating physiologic role of CX26 in the
their interactions can determine the clinical severity of the cochlea suggest that it serves as the structural basis for
disease trait predicated by the mutant allele. For example, recycling of potassium ions back to the endolymph of the
affected individuals within a family carrying an identical cochlear duct after stimulation of the sensory hair cells.34
mutation in PAX3 gene, associated with Waardenburg’s Dysfunction of CX26 is believed to affect homeostasis of
syndrome type I, can display a clinical phenotype of varying potassium ions in the cochlear duct, thus affecting
severity, corroborating the important contribution of mechanotransduction and resulting in hearing loss.
differing genotypes in determining the phenotype.27 Currently, more than 60 mutations have been identified.28
Several of the genes whose mutant alleles have been Two single base pair deletions account for nearly half of all
causally linked to nonsyndromic deafness are especially mutations in this gene: 35delG and 167delT.32,33 The
important in clinical otology on the basis of their prevalence 35delG mutation has been found to be common in several
or their associated histopathology. These include gene- populations, accounting for up to 70% of CX26 mutant
encoding connexins, PDS, and the myosins. Each of these alleles in families from the United Kingdom, France,
is discussed here. Italy, Spain, Tunisia, Lebanon, Israel, Australia, Greece,
United States, and New Zealand, as well as up to 40% of
sporadic cases of congenital deafness in these countries.
Connexin 26 The 35delG mutation leads to frameshift and early termina-
Connexin 26 is a member of a family of proteins that are tion of the nascent protein and a nonfunctional intracellular
involved in the formation of gap junctions. Connexins are domain in the protein. Alternatively, this mutation may
transmembrane proteins that form channels to allow lead to an unstable RNA, leading to its early degradation
transport of ions or small molecules between adjacent or absence of its translation into protein. Clinically, homo-
cells. Each connexin subunit contains three intracellular zygous patients with the 35delG mutation show a variable
domains and two extracellular domains, crossing the phenotype, ranging from mild to profound hearing loss.
plasma membrane four times. The second intracellular However, most patients with homozygous 35delG muta-
domain (IC2) contains the cytoplasmic loop. The other tion show a severe to profound phenotype. The differences
two intracellular domains consist of the N terminus and in the worldwide populations are also reflected in the vary-
C terminus. Six connexin subunits join to form a connexon. ing prevalence of the common CX26 mutant alleles. Thus,
A pair of connexons, one in each adjacent cell, comes although common in most populations, the 35delG muta-
together to form an intercellular channel. tion is much less frequent in the Japanese populations in
The connexin gene family plays an important role in which 235delC is the prevalent CX26 mutation.35,36
normal hearing; mutations in several members of the family Likewise, in the Ashkenazi Jewish population, the 167delT
are associated with hearing loss. To date, mutations in five mutation has been found to be more common than the
members of the connexin gene family—CX26, CX30, 35delG mutation with a carrier rate of 4%.33
CX31, CX32, and CX4—have been implicated in hearing The high frequency of mutant CX26 alleles associated
loss.28 Among them, mutations of CX26 are the most com- with recessive forms of hearing loss, presence of a single
mon and represent a major cause of inherited and sporadic coding exon of a relatively small size, and predominance of
nonsyndromic deafness.29–31 Specifically, CX26 mutations two mutations collectively represent attributes of an ideal
 Molecular Genetics in Neurotology 133

gene for mutation screening. Correspondingly, screening hearing and its dysfunction has led to the generation of
for the two common CX26 mutations is now available at knockout mice carrying null allele of SLC26A4.43 These
numerous medical centers and laboratories; however, its knockout mice (Slc26a4–/Slc26a4–) have both auditory and
role in the diagnosis and management hearing loss in vestibular dysfunction. However, goiter or other abnormal-
children needs to be determined. We have recently screened ities of thyroid function are absent.
154 individuals with SNHL for mutations in CX26 by SLC26A4 mutations are also responsible for nonsyn-
DNA sequencing and identified 34 patients with mutations dromic hearing loss associated with the large vestibular
for an overall incidence of 22% in the study population.37 aqueduct. Isolated presence of a large vestibular aqueduct
Of all CX26 mutations, the 35delG mutation accounted for (LVA) is one of the most common forms of inner ear anom-
26%. The 35delG mutation was present in a homozygous alies. Genetic studies of families with LVA disorder identi-
state in only 4 individuals (each of the two chromosomes fied a recessive nonsyndromic locus, DFNB4 that also
harbored the 35delG mutation) and heterozygous in 6 mapped to the same region as the PDS gene. This led to the
individuals (only one chromosome had the 35delG muta- evaluation of PDS gene and the subsequent identification of
tion). Herein lies the fundamental problem with screening seven PDS mutations responsible for LVA with nonsyn-
for only 35delG: only 4 of 34 individuals (12%) with CX26 dromic HHL.44 Like Pendred’s syndrome, different muta-
mutations, or 154 individuals in total (3%), had homozygous tions, V480D, V653A, I490L, and G497S, have been found
mutation that would be required to clearly implicate CX26 to be commonly associated with LVA. In review of our expe-
as the causative gene. The identification of a single copy of rience at the University of California–San Francisco, LVA
35delG mutation does not implicate this gene in deafness was the most common imaging abnormality detected in
and may simply reflect the high carrier rate in the popula- children with nonsyndromic SNHL.45 At least 40% of chil-
tion. In this case, the rate of identifying the cause of child- dren with LVA will develop profound SNHL. Patients with
hood SNHL by genetic testing is significantly less than LVA are at risk for progressive hearing loss after minor head
that of radiologic imaging. Therefore, genetic testing for trauma. Identifying this anomaly influences parent counsel-
35delG and 167delT mutation only, without sequencing ing with respect to the dangers of incidental head trauma.
the entire CX26 gene, is inadequate. In summary, the spectrum of PDS mutations and the
wide range of phenotypic manifestations show that pendrin
is an important but only one participant in ear structural
Pendrin development and in the normal functioning of the inner
Mutations of the SLC26A4 ( PDS) gene are the pathogenic ear and thyroid. Screening for mutations may play an
cause of isolated large vestibular aqueduct, the most important role in the diagnosis and management of a child
common radiologic abnormality associated with childhood as well as siblings with hearing loss.
deafness, as well as Pendred’s syndrome. The SLC26A4
( PDS) gene on chromosome 7q31 consists of 21 exons and Myosins
encodes an 86 kDa polypeptide known as pendrin that is
expressed in the kidney, thyroid gland, and cochlea.38 The importance of myosins in inner ear function is widely
Comparative sequence analysis indicated that this gene is a recognized by the growing list of unconventional (non-
member of a gene family that is involved in sulfate transport. class II) myosin-heavy-chain genes pathogenically linked
However, functional studies have shown this transmembrane to HHL. These disease genes encode the heavy chains of
protein to be an energy- and sodium-independent trans- myosin IA, IIIA, VI, VIIA, and XV. Myosin VIIA was the
porter of iodide and chloride ions, primarily.39 In the mouse first of the unconventional myosins that was causally linked
inner ear, pendrin localizes to the endolymphatic duct and to hereditary hearing loss in both rodents and humans.
sac, distinct areas in the utricle and saccule, and the external Mutations in the gene-encoding myosin VIIA are respon-
sulcus region within the cochlea, implicating a possible sible for mouse shaker 1, human Usher syndrome type 1,
role in endolymph resorption and/or homeostasis. How- human nonsyndromic hearing loss DFNB2 and DFNA11.
ever, the specific substrate and the biological role of Shaker 1 mice are deaf and have vestibular defects. Mice
Pendrin in the inner ear remain undetermined. that are homozygous for mutant shaker 1 allele display
It has been estimated that mutations of SLC26A4 may be progressively disorganized stereocilia. Myosin XV is the
responsible for as much as 10% of HHL and thus represents largest of all myosin-heavy chains, having a molecular weight
the most common cause of syndromic HHL.40,41 Two fre- of 395 kDa. Mutations in myosin XV have been pathogen-
quent missense mutations of SLC26A4, L236P (707 T to C), ically linked to DFNB3 in humans and the shaker 2 phe-
and T416P (1246 A to C) were initially identified40; subse- notype in mice. Myosin VI was initially identified as the
quently, a third common mutation, E384G (1151 A to G) deafness gene in a mouse model of inherited hearing loss;
has also been identified. Although the gene is too large for the cochlear and vestibular neurosensory epithelium in
screening by direct sequencing, identification of common this mouse model, known as Snell’s waltzer, degenerates
mutations opens the opportunity for screening for these iso- soon after birth. A mutant allele of myosin VI is consid-
lated mutations. Goiter that is associated with Pendred’s ered to be responsible for the DFNA22, the human non-
syndrome results from the reduced ability of the thyroid syndromic, form of hereditary hearing loss. Mutant alleles
gland to organify iodine into the thyroid hormone.42 of myosin IA and IIIA have also been recently identified as
However, goiter is not considered to be a specific marker responsible for DFNA48 and DFNB30, respectively.
of the Pendred syndrome due to its variable expression and Expression of these unconventional myosins is not limited
phenocopies. The hearing loss is usually congenital and to the cells and tissues of the inner ear. Yet, the expression
profound. However, there are reports of a milder or pro- of their dysfunction is largely restricted to hearing loss.
gressive hearing loss. Investigation of the role of pendrin in The unconventional myosins are distributed throughout
134 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

the mechanosensory hair cells. Moreover, histopathology seen in NF1 is the neurofibroma and the second most com-
of mouse models of myosin XV dysfunction has been mon tumor is the optic pathway glioma. The diverse pheno-
valuable for understanding the consequences of myosin type associated with NF1 is the consequence of mutations
dysfunction upon the sensory hair cells. Myosin VI is local- within a single gene located on chromosome 17q11.2, which
ized in the actin-rich cuticular plate and in the rootlet actin was identified in 1990 through positional cloning and desig-
filaments that descend from stereocilia into the cuticular nated NF1.54–56 The gene spans 350 kilobases of genomic
plate, suggesting a role in stabilizing the basal attachment of DNA, contains 60 exons, and encodes a large cytoplasmic
stereocilia.46,47 Myosin VIIA is localized in the stereocilia and protein product known as neurofibromin, a member of a
cell body of hair cells.47 Postulated roles for myosin VIIA family of proteins known for their GTPase activation.56
include maintaining stereocilia integrity and membrane traf- Mutations of NF1 have been identified throughout the
ficking in the inner hair cells. Histopathology of the inner gene. Most studies have not found an obvious relationship
ears of mouse models of myosin XV dysfunction revealed between particular NF1 mutations and resulting clinical
significantly shortened stereocilia in the sensory hair cells, manifestations in a patient. However, attempts at genotype-
demonstrating the importance of myosin XV in the mainte- phenotype correlation in NF1 are confounded by the
nance of hair cell structure and thereby its function. effect of age, which increases the frequency of disease
A mutation in a conventional or class II myosin, MYH9, manifestations and the likelihood of serious complications
resulting in nonsyndromic has also been described. The in all patients. In addition, there is no consensus regarding
class II myosins, broadly expressed in skeletal, cardiac, and how to define NF1 severity. While some mutations recur
smooth muscles as well as nonmuscle tissues, consist of a in different families, no true “hotspots” have been found in
pair of heavy chains, a pair of light chains, and a pair of NF1. The most frequently recurring alteration is a nonsense
regulatory light chains.48 The N-terminal motor domain is mutation in exon 31 (R1947X), which accounts for 1% to
the most highly conserved region of the myosin heavy 2% of NF1 mutations identified. The wide variability of
chain and contains the ATP and actin binding sites. The the NF1 phenotype, even in individuals with the same NF1
apparent molecular weight of the class II myosin heavy gene mutation, suggests a contribution of other protein
chain is 200 kDa. The myosin that mediates skeletal muscle products in determining the clinical manifestations.
contraction, also known as the sarcomeric myosin, repre- Screening of individuals with a hereditary form of NF1
sents the most well characterized representative of class II has linked them to the single NF1 locus at 17q11.2. This
myosin family. Cardiac and smooth muscle cells also finding negates genetic heterogeneity of NF1 or mutations
express isoforms of class II myosin, distinct from the sar- at more than one locus/gene responsible for the tumor
comeric myosin that mediate contraction in these muscle phenotype. Due to absence of locus or genetic heterogeneity
cells. Mutation in MYH9, a conventional nonmuscle myosin, of NF1, frequency of mutant NF1 genes can directly be
was described in an American family with autosomal- inferred from the incidence of the disease at birth, esti-
dominant nonsyndromic hereditary hearing loss (DFNA17) mated to be 1 in 2500. Thus, the mutant gene frequency is
associated with cochleosaccular degeneration.49,50 The approximately 1 in 5000, or half of the estimated prevalence
affected members of the DFNA17 family exhibit progressive, of NF1 at birth. It is estimated that about half of all NF1
postlingual onset of hearing loss, a pattern that is observed patients represent new mutations since a positive family
in the majority of nonsyndromic autosomal-dominant history is confirmed in half of all NF1 cases and penetrance
HHL. The cosegregation of the mutant MYH9 with non- is presumed to be complete. Thus, the rate of new NF1
syndromic hearing loss illustrates a biologically significant mutations is estimated to be as high as 1 per 10,000 gametes,
role for MYH9 in hearing and an organ-specific pathology representing one of the highest single-locus mutation rates
associated with the mutant allele. known in humans. Interestingly, more than 80% of new
Two other myosin genes have been predicted to have an mutations are considered to be of paternal origin. However,
important role in hearing. Myosin V is an abundant protein the predominance of paternal mutations in NF1 has not
of afferent nerve fibers that innervate both inner and outer yielded a significant correlation between risk of sporadic
hair cells.51 Myosin Iß has been implicated as an effector of NF1 and paternal age.
adaptation of the hair cell transduction apparatus.52 The The loss-of-function results suggest that neurofibromin
diverse classes and subtypes of myosins whose dysfunction acts as a tumor suppressor. The proposed tumor suppressor
can result in hearing loss is not surprising given the varying function is supported by the findings of somatic “second hit”
forms of actin filament systems in the inner ear.53 mutations of the NF1 gene in benign and malignant tumors
from NF1 patients carrying a germline mutation of the NF1
gene. Although, neurofibromin is expressed in number of
MOLECULAR GENETICS neuronal cell types as well as in the gonadal tissue and the
OF VESTIBULAR SCHWANNOMAS white blood cells, histopathologic and molecular analysis of
AND GLOMUS TUMORS the NF1-associated tumors has shown that the neoplastic
cell of origin in the neurofibromas is the Schwann cell.57,58
Neurofibromatosis Type 1 The molecular factors that contribute to the loss of regu-
latory control in the Schwann cell with the mutant NF1
Neurofibromatosis 1 (NF1), also known as von Reckling- allele remain to be determined. The physiologic role of neu-
hausen’s disease, is one of the most common Mendelian rofibromin has been investigated though analysis of mouse
diseases that affects the nervous system. NF1 is characterized models deficient in NF1 and drosophila NF1 mutants. These
by autosomal-dominant inheritance with complete penetrance studies indicate that defects in neurofibromin function affect
but extremely variable expression. The most common tumor diverse signaling pathways in different cell types.59
 Molecular Genetics in Neurotology 135

addressed through development of transgenic mouse

Neurofibromatosis Type 2 models. Mice homozygous for the NF2 null allele die during
Neurofibromatosis 2 (NF2) is characterized by autosomal- early embryonic development as a consequence of their
dominant inheritance that predisposes the carriers to nerv- inability to induce mesoderm formation.65 Mice that are
ous system tumors in their second and third decades of life. heterozygous for the NF2 null allele are viable but develop
The hallmark central nervous system tumor in NF2 is the malignant sarcomas, tumors that are not seen in humans
schwannoma, which affects the eighth cranial nerve and affected with NF2. To be able to assess the biologic effect
results in bilateral vestibular schwannoma (VS), also referred of the loss of merlin within the glial cells, a conditional
to as acoustic neuroma. Continued growth of the vestibular knock-out was generated where merlin expression was
schwannomas leads to deafness and balance problems. In specifically interrupted in the Schwann cells. These condi-
addition to the eighth cranial nerve, schwannomas can occur tional knock-outs developed schwannomas that histologi-
on other cranial or peripheral nerves throughout the body. cally resemble human schwannomas.66 Thus, the conditional
Ninety percent of patients with NF2 also have ocular abnor- knock-outs support the hypothesis that the loss of merlin is
malities, causing blurred or loss of vision. Patients with NF2 sufficient for the onset of schwannomas.
who have bilateral vestibular schwannomas represent 2% to To date more than 200 mutations of the NF2 gene have
4% of all occurrences of vestibular schwannomas, which in been identified, including single-base substitutions, inser-
turn represent approximately 8% of intracranial tumors. tions, and deletions. Most mutations lead to truncation of
The majority of vestibular schwannomas are sporadic and the C-terminal end of the protein as only 13 missense
unilateral, presenting in the fifth decade. mutations have been identified. Ruttledge and colleagues67
The incidence of NF2 is estimated to be between have found that mutations in the NF2 gene that result in
1:33,000 and 1:50,000,60 or approximately 10-fold less protein truncation are associated with a more severe clinical
than the frequency of NF1. In approximately 50% of cases, presentation of NF2 and missense and splice-site muta-
there is no family history and these patients are considered tions are associated with a milder form of the disease.64
to carry new germline mutations.61 The genetic differentia- Similarly, Parry and colleagues68 have reported that retinal
tion of NF1 and NF2 as distinct disease entities did not abnormalities were associated with the more disruptive
occur until 1987. Molecular genetic analysis of these disor- protein truncation mutations of the NF2 gene.68 Both
ders localized the disease gene for NF1 near the proximal studies showed intrafamilial variability of phenotypic
long arm of chromosome 17. At the same time, the gene expression. The more severe phenotype in patients with
responsible for NF2 was localized to chromosome 22.62 In mutations that result in protein truncation may be due
1993, the NF2 gene, designated merlin or schwannomin, to the dominant negative effect of the mutant protein,
was isolated by two groups working independently.63,64 negating the biologic function of the protein product of
The NF2 gene is spread over approximately 100 kB on the wild-type allele.
chromosome 22q12.2 and contains 17 exons. The coding Mutations involving the NF2 gene have also been
sequence of the messenger RNA is 1785 base pairs in observed in 22% to 59% of patients with sporadic vestibular
length and encodes a protein of 595 amino acids. Compara- schwannomas. Included in this group are individuals with
tive sequence analysis has led to classification of merlin as de novo germline mutations as well as those with somatic
a member of the protein 4.1 subfamily, which includes mutations that are detected in the DNA of their tumor
ezrin, radixin, and moesin (ERM proteins). These proteins tissue. The large fraction of the sporadic cases of NF2 who
are involved in linking cytoskeletal components with the are negative for NF2 mutation suggests a non-NF2 etiology.
plasma membrane and are located in actin-rich surface However, no evidence exists that substantiates or contests
projections such as microvilli. Like other ERM proteins, genetic homogeneity of NF2. To date, only mutation in
merlin binds to actin and is associated with actin cytoskele- the NF2 gene has been identified as the causal event in
ton. However, a distinct role of merlin relative to the ERM schwannoma formation. Defects of the NF2 gene have also
proteins is emphasized by its unique subcellular distribution been detected in other malignancies including meningiomas,
in the peripheral nerve Schwann cells. malignant mesotheliomas, melanoma, and breast carci-
The NF2 gene has been hypothesized to function as a noma. These findings suggest that the NF2 gene may also
growth regulator or a tumor suppressor. Support for this be the critical tumor suppressor in these sporadic tumors.
role is derived from studies demonstrating germline muta- The precise mechanism by which merlin regulates cellular
tions in the NF2 gene in patients with NF2 and biallelic proliferation within the cell types that are tumor-prone
inactivation of NF2 in NF2-associated tumors, including (i.e., Schwann cells) remains to be determined.
schwannomas, ependymomas, and meningiomas. Support The identification of the gene responsible for NF2 has
for the tumor-suppressing role of NF2 is derived from in significantly advanced our understanding of the molecular
vitro studies that include the demonstration of growth pathology as well as factors responsible for the clinical het-
suppression as a consequence of NF2 gene expression in erogeneity among patients with NF2. Understanding of
merlin-deficient meningiomas and schwannoma cells. the function of merlin may lead to the development of
Expression of NF2 mutant allele encoding dysfunctional novel therapies that may eventually alleviate the suffering
merlin had no effect on growth in these cell lines. The associated with NF2.
predilection for tumor growth in the superior vestibular
branch of the eighth cranial nerve remains to be determined,
as does its suppressing-suppressing role, which is expressed
Familial Paragangliomas
predominantly within the Schwann cells. Dissection of the Paragangliomas (PGLs) are rare tumors of the paraganglia,
potential mechanism of action of Merlin is also being an assembly of neuroendocrine tissues and small organs
136 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

distributed throughout the body. The tumors are identified Following genetic mapping, the disease locus was then
within two major sites, the carotid body of the head and physically mapped to identify the set of genes present.
neck and the adrenal medulla. The carotid body is the Thus, the linked locus defined by genetic recombination
largest of all paraganglia and is considered to function as events is isolated in overlapping large- and small-capacity
an oxygen sensor. Genetic analysis of hereditary paragan- cloning vectors. Physical mapping of the overlapping
glioma has served to disclose its molecular etiology and clones, or the contig, includes determining their size in base
provided an insight into its underlying pathophysiology. pairs and localization of various polymorphic markers such
Currently, three genes have been identified whose mutant as short sequence repeat polymorphisms (SSRPs) and
alleles have been pathogenically linked to hereditary para- nonpolymorphic markers such as sequence tag sites
ganglioma. All of these genes encode distinct subunits of a (STSs), anonymous sequences that serve as landmarks and
hetero-oligomeric protein known as the mitochondrial expressed sequence tags (ESTs), short sequences that are
complex II. This heteromeric protein consisting of four identified from cDNA libraries. The physical map facilitates
separate subunits is a component of the mitochondrial subdivision of the contig and thus aids in the identification
ETC and the Krebs cycle. Dysfunction of the mitochon- of candidate genes spanning the cloned region. This strategy
drial complex II is considered to result in malfunction of of physically mapping the linked locus is also referred to as
the oxygen-sensory apparatus and thus activate the patho- positional cloning.69
physiologic pathway that leads to the development of Physical mapping of the PGL1 identified a minimum of
paragangliomas. Identification of the disease genes and the 10 distinct genes within the linked locus. Based on their
protein that they encode has enabled us to address and physical locations, all of these genes are considered posi-
understand some of the questions and paradoxes raised by tional candidates for PGL1. Screening of all of these genes
genetic analysis of familial PGL. for a pathogenic mutation would have represented a mon-
umental, labor-intensive task. A critical factor in hunting
Genetic Mapping of the PGL Loci for disease genes is to determine which of the positional
and Identification of the PGL1 Gene candidates might have a role in the etiology of the disease
on the basis of function. Although intuitive, this principle
Unraveling the genetic basis of the hereditary PGL followed is very difficult to apply since histopathologic analysis of
a well-established pathway for finding disease genes,69,70 the disorder does not by itself enable determination of the
which begins with the identification of affected families and underlying molecular pathophysiology. Under these cir-
determination of the mode of inheritance of the disorder. cumstances, the gene hunter must be highly resourceful in
This is followed by two-point linkage analysis to localize the searching for parallel cases that may provide clues concern-
disease gene to a chromosomal locus. The resolution of the ing the molecular etiology of the disease under study.
locus may vary from 1 to 12 centiMorgans in genetic dis- Identification of the PGL1 gene represents an excellent
tance or equivalent to 1 to 12 megabase pairs. Localization illustration of this principal. Baysal and colleagues72
and resolution of the disease locus sets the stage for the end focused their search on a single candidate gene on the basis
game. Identifying the disease gene within the linked locus of an insight derived from study of the histopathology of
can be the most challenging stage of the genetic study of the the PGL and its similarity to carotid body tumors found in
affected family. The difficulty of this task is demonstrated by people living at high altitudes.73 In these tumors, the
the presence of several hundred genes that can potentially observed hyperplasia of the carotid body chemoreceptor
occupy the linked locus, many of which remain to be cloned cells was inferred to be the result of their sustained stimu-
and characterized. Further compounding the difficulty of lation by chronic hypoxia. The observed link between
the task is that the pathogenic sequence alteration can be as hypoxic stress and carotid body tumors and the physio-
subtle as a single-base pair change within a gene whose logic role of the carotid body in oxygen sensing led to the
sequence length can span several thousand nucleotides. A hypotheses that chronic stress upon the oxygen-sensory
sequence alteration in the candidate gene affecting the apparatus or a mutation in its molecular components
coding sequence or splice signals can then be considered causing its malfunction can both serve to trigger its hyper-
pathogenic if it is shown to cosegregate with or be inher- plasia. Supporting evidence for this hypothesis included
ited by the affected and not the unaffected in a family that enlargement of carotid body in rats exposed to hypoxic
is under study. conditions.73
Genetic linkage analysis of a large Dutch family with Thus, the 10 candidate genes were evaluated on basis of
hereditary PGL mapped the disease locus to the short arm of their potential role in oxygen sensing and signaling. The
chromosome 11, 11q22–q23 in 1991.18 This disease locus, candidate gene selected encoded SDHD, a small subunit
designated PGL1, was further resolved to approximately 11 of cytochrome b in the mitochondrial complex II, one of
megabase region at 11q23.71 This finding was later con- the five protein assemblies or complexes that form the
firmed in several North American families and the critical electron transport chain. Through its production of reactive
region was further resolved to a 2-megabase interval through oxygen molecules, the electron transport chain was consid-
the presence of informative individuals displaying a recom- ered to play a pivotal role in the signaling and detection of
bination event in the linked locus and the use of new poly- oxygen tension. The gene encoding SDHD consists of
morphic markers.72 Both the Dutch and the North American 4 exons and yields 159 amino acid polypeptides. Screening
families that mapped to the PGL1 locus were shown to carry of the families with hereditary PGL identified various
an identical haplotype, or set of markers, indicating that mutations of the SDHD gene that segregated with the
these apparently unrelated families likely carried an identical disease.74 These mutations were subtle alterations of the
mutation that had occurred in a distant ancestor. gene sequence, affecting post-transcriptional processing of
 Molecular Genetics in Neurotology 137

the transcript or the amino acid sequence of the primary also been associated with paragangliomas in the adrenal
polypeptide. None of the pathogenic sequence alterations medulla, conventionally referred to as phaeochromocy-
were detected in more than 100 normal individuals. tomas.81,82 Although, they differ in their anatomic location,
The predisposition of the PGL due to inheritance of a innervation, and specific function, both the paraganglia of
single mutant allele is consistent with the predicated role the head and neck region and the adrenal medulla are
of the SDHD as a tumor-suppressor gene that is subjected linked by their common embryologic origin, their similar
to “two-hit inactivation.” The classification of PGL1 as a morphology, and their general role in responding to acute
tumor suppressor was initially based on the observation alterations in the surrounding environment. Thus, it is not
that the genome of the tumor cells from affected individuals surprising that specific mutations of SDHB and SDHD
did not reveal the expected heterozygosity for a genetic result in familial forms of head and neck paraganglioma as
marker at their PGL1 locus.75 This loss of heterozygosity well as phaeochromocytoma.79 However, in general, muta-
(LOH) was inferred to be due to deletion or other muta- tions of these three subunits are linked with either the
tional event within the normal allele that renders the cell head and neck paraganglioma or the phaeochromocytoma.
either hemizygous (one deleterious allele and one deleted Pathogenic mutations have also been identified in
allele) or homozygous for the deleterious allele. The SDHA. However, germline mutations in this subunit of
occurrence of somatic mutation leading to LOH can cause complex II do not result in paragangliomas. The clinical
complete inactivation of SDHD within the cell type. This phenotype characterized by mutations in SDHA result in
cell type carrying the two “hits” will no longer possess reg- optic atrophy, ataxia, myopathy, and Leigh syndrome.83
ulatory growth control due to loss of both alleles encoding The dissimilar clinical phenotype suggests a distinct role
SDHD as a consequence of germline and somatic muta- for the SDHA subunit and its apparent separation from the
tions and will no longer behave normally. Thus, the “second task of oxygen sensing and signaling that is linked to
hit” catapults the cell on the biologic pathway toward SDHB, SDHC, and SDHD. The mechanism of this
hyperplastic and neoplastic proliferation. The “two-hit” dichotomy remains to be determined.
paradigm has also been used to explain the occurrence of Identification of several of the genes underlying
certain sporadic tumors. Unlike the inherited predisposition hereditary PGL has led investigators to assess their preva-
to the tumors, the sporadic tumors are considered to be lence among both familial and sporadic cases of PGL in
caused by two independent somatic mutations inactivating which the affected individuals have no family history of
the two wild-type alleles of the tumor-suppressor genes. this tumor. These studies have been carried out using
This proposed mechanism is consistent with the relatively population samples in the United States84 and in the
rare occurrence of sporadic tumors and has been validated Netherlands.85 Germline mutations in SDHD, SDHB, and
by genetic analysis of sporadic cases of NF1 and retino- SDHC have been identified in the majority of patients with
blastoma.76,77 The sporadic occurrence of paragangliomas positive family history. Amongst these three candidate
without family history is also observed. Genetic studies genes, mutations of SDHD are most common. Molecular
have yet to determine if mutation of the SDHD gene also epidemiologic studies of hereditary head and neck para-
accounts for sporadic cases of paragangliomas. gangliomas (HNPs) in the Dutch population has identified
two common mutations of SDHD, D92Y and L139P.
These are considered to be founder mutations; that is, the
PGL2, PGL3, and PGL4
affected individuals who are positive for this mutation are
Given that SDHD is a subunit of a the mitochondrial linked through their common ancestry. In contrast to the
respiratory chain complex II, it was inferred that mutation Dutch population, the common SDHD mutation in the
in the other subunits can also cause dysfunction of the U.S. sample is P81L. However, this particular site is con-
complex II and the onset of neoplasia. This hypothesis has sidered to be a mutational hotspot and hence not all indi-
been validated for two of the three subunits, SDHC and viduals carrying P81L are considered to share common
SDHB, through identification of mutations in their genes ancestry. The presence of SDHB mutations among the
that are causally linked to hereditary PGL.78,79 SDHC affected with positive family history is considerably lower
located on chromosome 1q21 was found to be within the than that of SDHD, accounting for up to 20% of the sam-
PGL3 locus that was mapped using a German PGL family. ple population. No mutations of SDHC were identified.
Mutation analysis of SDHC, consisting of six exons and Up to 30% of the familial HNP samples in the U.S. study
yielding a polypeptide of 169 amino acids, identified the were negative for mutations in the candidate genes.
pathogenic sequence alteration in the affected German Contribution of noncomplex II genes, including the PGL2
family. Unlike the mapping studies that were used for gene, toward etiology of familial HNP represents a valid
selecting SDHD and SDHC for mutation screening, muta- explanation for this outcome.
tions in SDHB, consisting of eight exons and yielding a In the absence of positive family history, the association
polypeptide of 280 amino acids, were identified in small of complex II gene mutations is significantly less. The
families in which linkage analysis was not possible due to Dutch study identified founder mutations of SDHD in the
their limited numbers. Linkage analysis in an extended germline of 36% of the affected while the U.S. study iden-
Dutch family has also linked a distinct locus on chromo- tified germline mutations of SDHD or SDHB in 8% of
some 11q13 cosegregating with familial PGL.80 However, nonfamilial samples. The presence of germline mutations
the responsible gene within this locus, designated PGL2, of the complex II genes in the apparently sporadic PGL
remains to be identified. cases may be explained by variable penetrance or imprinting
Mutations of SDHB, SDHC, and SDHD linked to the of the mutant allele or an occurrence of a de novo muta-
head and neck tumors localized to the carotid body have tion. Both of these alternatives attempt to account for the
138 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

absence of positive family history despite the presence of and the rapid advances in therapeutic applications of gene
a germline mutations associated with familial PGL. These transfer in various diseases, including cancer, intracochlear
alternatives may be verified through genetic analysis of gene therapy represents a promising treatment modality
family members of the affected individual. Mutation that is under development.
screens of the candidate genes in the DNA from sporadic Much of the experimental data to date addresses the
tumors did not detect mutated alleles of the complex II utility of various gene transfer vectors for expression of
genes that were not present in the germline, thus eliminating marker genes within the cochlea and the vestibular end
the contribution of somatic mutation. organs. These studies have demonstrated that the transgene
can be expressed in the inner ear and that the transfer vector
Parent-Specific Transmission and the mode of its delivery represent the critical determi-
and Loss of Heterozygosity nants of tissue or cell specificity and duration of the trans-
gene expression.87 Despite the promising advances, much
Hereditary PGL has generally been observed to follow the work remains to be carried out before application of intra-
autosomal-dominant inheritance pattern. However, a vari- cochlear gene transfer can be clinically applied to specific
ation on this pattern is observed for families with mutation forms of hearing loss.
in the SDHD. In these families, the disease phenotype
is transmitted only through the fathers; the mothers do Animals Models and
not transmit the disease.86 The sex-specific transmission
pattern is an example of the phenomenon referred to as Gene Transfer Vectors
genomic imprinting. The mechanism of imprinting remains Preliminary studies in intracochlear gene transfer used the
unknown but its effect is to silence the expression of the guinea pig as the animal model because of the relatively
imprinted allele. large size of its cochlea compared to mice and rat and the
The SDHD mutations have provided an excellent case ease of surgical manipulation in this species. Subsequent
study for assessing and deciphering the molecular basis of studies have shifted their focus to using a mouse as the
parent-specific gene expression pattern. Analysis of SDHD model organism. The mouse genome is the most extensively
expression in various tissues has shown expression of both characterized of all mammalian model organisms. The
the maternal and the paternal alleles.74 These results argue intrinsic value of the mouse as a model organism in hear-
against a widespread silencing of the maternal allele but ing research is the availability of a number of mutant mice
do not exclude imprinting of SDHD limited to the para- with inherited hearing loss.88 These mutant mice have
ganglionic tissue. The inference of maternal imprinting been well characterized and the genetic basis of their hear-
specifically within the paraganglion is at odds with the ing loss identified. In addition, a number of transgenic
observation of preferential deletion of the maternal SDHD mice have been generated to assess the effect of specific
allele in the tumor DNA, as determined through LOH candidate genes whose mutant alleles have been linked to
analysis.75 This leads one to question the mechanism of nonsyndromic and syndromic hearing loss.89 Both the
maternal imprinting that is put forward to explain the mutant and the transgenic mice represent excellent animal
observed parent-specific (paternal) transmission of PGL. models to assess the utility and efficacy of intracochlear
Thus, if the onset of tumor is believed to be initiated by gene therapy.
inactivation of the normal allele through somatic mutation Both viral and nonviral vectors have been used to transfer
in accordance with the two-hit pattern of tumor initiation, and express genes in the inner ear of animal models. A
then the mechanism is yet unknown by which the children major advantage of nonviral vectors is the lack of immuno-
of an affected mother carrying one mutant SDHD allele are genic components. However, the nonviral vectors are still
refractory to developing tumors, since they already have in a developmental state and in competition with viral
one inactive copy in their germline. This paradox remains vectors, which have the advantage of having developed
to be resolved. There is no evidence for parent-specific through evolution. Thus, individual virions represent a
disease transmission in families with SDHC and SDHB highly efficient means of introducing the viral genome
mutations. into the nuclei of target cells followed by the use of the
cellular machinery to express the viral genes. These viral
agents have been adapted for the purpose of gene transfer
INTRACOCHLEAR TRANSGENE by altering their genome so that they can no longer repli-
EXPRESSION AND ITS POTENTIAL cate within the transduced cell and lead to cellular lysis.
THERAPEUTIC APPLICATION These replication-defective viruses are engineered to func-
tion solely to introduce the desired gene into the nuclei of
Concurrent with the enlarging list of deafness genes is a target cells. Viral vectors have been developed from both
steady progress in the development of intracochlear gene DNA (e.g., adeno, adeno-associated, and herpes) and RNA
transfer technology. The simple and powerful objective of (e.g., retro and influenza) viruses.
this technology is to introduce a “therapeutic gene” (e.g., Feasibility of intracochlear gene therapy was initially
a normal version of the defective gene) into appropriate demonstrated through intracochlear transgene expression
target cells of the affected individual. Expression of the using the guinea pig as an animal model.90 A viral vector
exogenous therapeutic gene would then alter the target derived from the adeno-associated virus (AAV ) capable of
cell and the clinical phenotype. In the absence of effective transducing nondividing cells and considered to be safer
conventional therapy for most types of hearing disorders than other viral vectors, in view of its nonimmunogenicity
 Molecular Genetics in Neurotology 139

and nonpathogenicity, was used to deliver a marker trans- is a low transfection rate compared with other vectors.
gene to the cochlea via steady-state infusion using an The feasibility of inner ear gene transfer with liposome
osmotic minipump. Based on expression of the marker vectors has been demonstrated by several in vivo studies.93
transgene encoding a bacterial enzyme β-galactosidase, The attributes of the gene transfer vectors that have been
AAV vector was found to transduce the spiral limbus, spiral used in intracochlear gene transfer are summarized in
ligament, spiral ganglion, and the organ of Corti. The Table 5-3. These parameters provide a guide for assessing
marker gene expression was shown to be present up to suitability of a given vector for a specific objective. Thus,
24 weeks after osmotic minipump mediated infusion of the if a transgene expression is required for a short period
AAV-βgal.90 Subsequent studies investigating intracochlear only, then an adeno-associated or adenoviral vector may be
gene transfer have characterized a variety of vectors for suitable. However, if sustained gene expression is required
their efficacy and safety as well as their mode of introduction that replaces a nonfunctional mutant gene product, then a
into the cochlea. retroviral vector will be more suitable because the transgene
The adenoviral (Ad) vector represents one of the well- carried by the retroviral vector will be stably integrated
characterized vectors used for intracochlear gene transfer. into the genome.
The attributes of adenoviral vector for gene transfer The cochlear expression of the transgenes mediated by
include its capacity to carry large transgenes (8 kB) and the transfer vectors described in Table 5-3 is summarized
that it can be generated at high titer and can transduce in Table 5-4. The different cell types and tissues transduced
both dividing and nondividing cells. However, the Ad vector by these expression vectors likely reflect the unique property
has been reported to elicit a strong immune response, thus of individual transfer vectors, each being similarly intro-
contravening its attributes.91 A lentiviral vector, based on duced within the cochlear perilymph and carrying marker
the human immunodeficiency virus (HIV ), can integrate genes driven by strong viral promoters. The variability in
into the chromosome of both dividing and nondividing or the transgene expression pattern is likely a consequence of
mitotically quiescent cells, leading to a potentially stable, number of factors including the size of the viral particle,
long-term expression of a transgene spliced into the viral presence or absence of viral receptors, and mode of delivery.
vector. Thus, the postmitotic cochlear neuroepithelia and Inspection of the table allows some generalization about
the spiral ganglion neurons represent suitable targets for the ability of various viral vectors in transfecting cochlear
a stable long-term transgene expression via lentivirus- tissues. The spiral ganglion cells, spiral ligament, and
mediated gene transfer. Infusion of the lentiviral vector Reissner’s membrane were transfected by every virus
carrying a marker transgene into a guinea pig cochlea tested. On the other hand, only adenovirus demonstrated
has revealed a highly restricted fluorescence pattern transgene expression within the stria vascularis. Immune
limited to the periphery of the perilymphatic space.92 response was present in the cochlea following transfection
Transduction of spiral ganglion neuron (SGN) and glial cells with adenovirus, HSV, and Vaccinia virus.
by lentivirus in vitro but not in vivo suggests limited dis-
semination of the viral vector from the perilymphatic Intracochlear Gene Delivery
space. Restricted transduction of cell types confined to the
periphery of the perilymphatic space by the lentivirus is
Modalities
ideal for stable production of gene products secreted into Local gene transfer to the inner ear is feasible because of
the perilymph. its relatively closed anatomy. However, developing a deliv-
In addition to viral vectors, cationic lipid vesicles, or ery method for genetic vectors to the inner ear without
liposomes, have also been used for intracochlear gene causing local destruction and concomitant hearing loss is a
transfer. The liposomes coupled to the transgene integrated significant obstacle. The general strategy behind these
within a plasmic vector bind to the plasma membrane of delivery modalities is to introduce the transgene-carrying
the target cells, releasing the DNA into the cytoplasm, vector into the inner ear circulation, enabling its diffu-
where it is eventually incorporated into the host genome. sion to the surrounding tissues. Most of the delivery meth-
Liposome vectors are nonimmunogenic and easy to produce. ods introduce the gene transfer into the perilymphatic
Furthermore, the DNA introduced into the host cell is circulation. These methods include microinjection via
incorporated by recombination, so there is little risk of the round window membrane (RWM), microinjection or
insertional mutagenesis. The drawback of liposome vectors miniosmotic pump infusion following cochleostomy, and

TABLE 5-4. Transfection of Cochlear Cells and Tissues by Viral Vectors

Supporting Auditory Stria Reissner’s Spiral Immune
Vector Hair Cells Cells Neurons Vascularis Membrane Ligament Response

AAV + + + − + + −
Adenovirus + + + + + + +
Herpes virus − + + − + + +
Vaccinia + + − + + +
Lentivirus − − + − + + −
Liposomes + + + − + + −
140 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

diffusion across the RWM after local Gelfoam placement. Staecker and colleagues100 used a herpes simplex virus-1
Gene transfer vectors have also been introduced into the (HSV-1) vector to deliver BDNF to the inner ear and
endolymphatic circulation through injection into assessed its protective effect against neomycin. The gene
endolymphatic sac94 or into the scala media following therapy group demonstrated a 94.7% salvage rate for SGNs,
cochleostomy.95 in contrast to a 64.3% loss of SGNs in control animals
Introduction of viral vector via infusion with a minios- (without the BDNF transgene). Interestingly, BDNF
motic pump was characterized by evidence of trauma at the expression was ubiquitous in inner ear tissues, but this was
basal turn adjacent to the cochleostomy associated with an not the case for the reporter gene, β-galactosidase. This
inflammatory response and connective tissue deposition. reporter gene was detected in only 50% of the cells, thus
Carvalho and colleagues96 demonstrated preservation of identifying the cells specifically transduced by the HSV-1
preoperative ABR thresholds in the lower frequencies vector. This transduction rate was sufficient to affect
(1 to 2 kHz), mild postoperative elevation of thresholds cochleawide BDNF distribution and ensure 95% SGN
(<10 dB) in the mid frequencies (4 to 8 kHz), and marked rise survival. The authors speculate that SGNs must require
(>30 dB) in ABR thresholds at higher frequencies (>16 kHz) only a small number of BDNF-producing cells to ensure
after miniosmotic pump infusion via a cochleostomy.96 the survival of the entire ganglion.100
However, in general, cochleostomy has been shown to cause Lalwani and colleagues used both in vitro and in vivo
histopathologic alterations (including localized surgical models to test the protective effect of AAV-mediated
trauma and inflammation) and may lead to hearing loss. BDNF expression.101 They found a significant survival rate
A much less traumatic alteration to cochleostomy is the of SGN in cochlear explants transduced with AAV-BDNF
direct microinjection through the RWM without causing and challenged with aminoglycoside relative to controls.
permanent hearing loss or tissue destruction. Histolog- Although direct expression of transgenic BDNF could not
ically, cochleae microinjected through the round window be recorded, the vector’s ability to salvage SGNs was
demonstrated intact cochlear cytoarchitecture and an tested against a gradient of known BDNF concentrations
absence of inflammatory response 2 weeks after microinjec- applied directly to the cochlear explants. They found that
tion. Further, microinjection through the round window the vector system was able to achieve the same protective
membrane did not cause permanent hearing dysfunction.97 effects as 0.1 ng/mL of BDNF. However, this protective
To avoid hearing loss associated with the direct manipulation effect is subtherapeutic, as the most efficient dose was
of the cochlea, gene transfer vectors have also been delivered determined to be 50 ng/mL, a concentration of BDNF
through the vestibular apparatus via canalostomy.98 This that results in almost total SGN protection. In the in vivo
delivery modality yielded transgene expression mainly in experiment, animals infused with AAV-BDNF with an
the perilymphatic space with the preservation of cochlear osmotic minipump displayed enhanced SGN survival. The
function. protection from AAV-BDNF therapy was region-specific;
The potential for surgical trauma, inflammation, and there was protection at the basal turn of the cochlea but
hearing loss associated with these infusion or microinjection not at the middle or apical turn. The authors propose that
techniques has led to the investigation of a less invasive this regional selectivity is a pharmacokinetic phenomenon.101
delivery method. Jero and colleagues99 investigated the Neurotrophin-3-mediated protection against cisplatin-
potential to deliver a variety of vectors across an intact induced ototoxicity has been documented using an HSV-1
RWM by loading vectors onto a Gelfoam patch that was derived viral vector. Chen and colleagues102 established that
placed in the round window niche. Adenovirus and lipo- efficacy of the vector in an in vitro study, where HSV-
some vectors, but not the AAV vector, effectively infected 1-mediated transfer of NT-3 (demonstrated by production
inner ear tissues, as evidenced by detection of reporter of NT-3 mRNA proteins and by reporter gene expression)
genes. Thus, diffusion across the RWM has been shown to conferred increased survival to cochlear explants after
be an effective, atraumatic, but vector-dependent method cisplatin exposure.102 Bowers and colleagues103 confirmed
of delivery for gene transfer vectors.99 these effects in an in vivo model, where HSV-1-mediated
An effective test of the delivery modality as well as the transfer of NT-3 to SGNs suppressed cisplatin-induced
transfer vector will have to await the generation of a mouse apoptosis and necrosis. The authors suggest that these
model with inherited hearing loss that can potentially be findings may not only be useful to prevent cisplatin-related
corrected with the introduction of a normal gene. injury, but may also provide preventive treatment for hearing
degeneration due to normal aging.103
Several studies have established the efficacy of an
Preclinical Applications Ad vector carrying the GDNF gene (Ad.GDNF) to protect
The preclinical applications for gene transfer in the inner against a variety of ototoxic insults. When administered
ear have focused on protective effects of various neu- prior to aminoglycoside challenge, Ad.GDNF significantly
rotrophins and growth factors against ototoxic agents, protects cochlear104 and vestibular105 hair cells from cell
including noise, aging, and aminoglycoside-based antibi- death. Pretreatment with Ad.GDNF also provides signifi-
otics. These neurotrophins and growth factors, including cant protection against noise-induced trauma.106 Finally,
brain-derived neurotrophic factor (BDNF), neutroophin-3 Ad.GDNF enhances SGN survival when administered 4
(NT3), and glial cell line–derived neurotrophic factor to 7 days after ototoxic deafening with aminoglycosides.107
(GDNF), have been expressed within the cochlea as trans- The studies described here have assessed the therapeu-
genic products and have served to protect sensory hair tic efficacy of gene transfer against chemically or physi-
cells and the primary auditory neurons against atrophy and cally induced ototoxicity in animal models. The results of
degeneration. these studies are promising as preventive countermeasures
 Molecular Genetics in Neurotology 141

in preservation of spiral ganglion neurons following loss SUMMARY

of sensory hair cells. In addition, these results provide
proof of the principle of therapeutic efficacy of gene ther- Identification of deafness genes and the determination of
apy. However, correction or amelioration of hearing dys- their prevalence in the human population have had a sig-
function in mouse models with hereditary hearing loss nificant impact on diagnosis and treatment of HHL. Thus,
through the use of gene transfer technology remains to be it is critical to practicing otologists and neurotologists to
addressed. Replacement or correction of a defective gene understand the principles of molecular genetics so that
underlying inherited hearing loss that results in a signifi- they may selectively apply the appropriate diagnostic tests
cant change in the animal’s ability to hear will represent a and therapeutic interventions and judiciously interpret
defining test for the therapeutic application of intra- their results.
cochlear gene therapy.

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SDHB, SDHC, and SDHD germline mutations in clinic patients damage from noise trauma by an iron chelator, a free radical scav-
with head and neck paragangliomas. J Med Genet 39:178–183, enger and glial cell line-derived neurotrophic factor in vivo. Brain
2002. Res 815:317–325, 1999.
85. Dannenberg H, Dinjens WN, Abbou M, et al: Frequent germ-line 107. Yagi M, Kanzaki S, Kawamoto K, et al: Spiral ganglion neurons are
succinate dehydrogenase subunit D gene mutations in patients protected from degeneration by GDNF gene therapy. J Assoc Res
with apparently sporadic parasympathetic paraganglioma. Clin Otolaryngol 1:315–325, 2000.
Cancer Res 8:2061–2066, 2002. 108. Stover T, Yagi M, Raphael Y: Transduction of the contralateral ear
86. van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, et al: after adenovirus-mediated cochlear gene transfer. Gene Ther
Genomic imprinting in hereditary glomus tumors: Evidence for 7:377–383, 2000.
new genetic theory. Lancet 2:1291–1294, 1989. 109. Kho ST, Pettis RM, Mhatre AN, Lalwani AK: Safety of adeno-
87. Lalwani AK, Jero J, Mhatre AN: Developments in cochlear gene associated virus as cochlear gene transfer vector: analysis of distant
therapy. Adv Otorhinolaryngol 61:28–33, 2002. spread beyond injected cochleae. Mol Ther 2:368–373, 2000.
 Chapter
Pathologic Correlates in Neurotology
6 Outline

A. Julianna Gulya, MD, FACS Vestibular Schwannomas Facial Nerve Patterns

(Acoustic Neuromas) of Degeneration
Neurofibromatosis Internal Carotid Artery
Meningiomas Serpentine Aneurysms
Glomus Tumors Vascular Loops
Metastatic Tumors Dural Arteriovenous
Auditory Implants Malformations
Pacchionian Bodies Jugular Bulb

I mplicit in the title of this chapter is the concept that its

scope does not encompass an in-depth examination of
the pathology and biology of the myriad of disorders
direct cellular continuity of the two, without any interven-
ing capsule or margin. Even immunohistochemical studies7,8
have been unable to discern a distinct tumor-nerve inter-
encountered in neurotologic practice. Such information face in some instances.
should be sought in the chapters focusing on the particu- In subsequent studies, Neely and Hough5 focused on
lar pathologic process of interest. Instead, this chapter cochlear nerve involvement with small schwannomas. In
concentrates on the intradural pathologic correlates to the evaluation of a superior vestibular nerve schwannoma, a
neurotologic symptomatology, as well as the pathologic separation of the tumor from the cochlear nerve was main-
features of neurotologic entities that have implications in tained throughout its length. With schwannomas of inferior
the medical and surgical treatment of the patient. vestibular nerve origin, however, Neely and Hough5 found
that the cochlear nerve, initially separate from the tumor,
rotated about and progressively became more tightly
VESTIBULAR SCHWANNOMAS applied to and incorporated within the tumor as evaluation
(ACOUSTIC NEUROMAS) progressed laterally. Cochlear nerve fiber incorporation
progressed, with loss of expected fiber orientation, until
Vestibular schwannomas give rise to symptoms such as no identifiable cochlear nerve fiber aggregates remained.
sensorineural hearing loss (SNHL), tinnitus, disequilib- Paradoxically, the superior vestibular nerve schwannoma,
rium, and other neurologic symptomatology through the which had the greater number of cochlear nerve fibers, was
direct effects of the tumor, namely, compression and associated with poorer hearing than the inferior vestibular
destruction of neural structures,1–3 as well as by indirect nerve schwannoma.
effects. Studies of the pathology of the vestibular schwan- Ylikoski and associates,9 based on a similar study encom-
noma can be divided into two groups: those that use the passing larger, predominantly inferior vestibular nerve-
tumor or nerve specimen obtained at the time of surgery derived tumors, described three stages of tumor growth
and those that make use of the temporal bone specimens (Fig. 6-1). In stage I, the tumor only invades its nerve of
harvested at the time of the patient’s death. Tumor-nerve origin and displaces the facial nerve and the remainder of
specimens obtained at the time of surgery allow for elec- the eighth cranial nerve. In the second stage, the tumor
tron microscopic and immunohistochemical studies, invades the adjacent cochlear nerve and compresses both
which in turn facilitate the analysis of the tumor-nerve the superior vestibular nerve and the facial nerve, while the
interface with respect to both the cochlear and vestibular third stage involves tumor invasion of all components of
nerves, as well as analysis of neural integrity. the eighth cranial nerve and extensive compression of the
Neely and colleagues4–6 have presented detailed studies facial nerve. They10 also found a gradual transition from
of three small vestibular schwannomas completely resected tumor to cochlear nerve, with no correlation between the
by the translabyrinthine approach. Considering nerve VIII number of preserved fibers and auditory function as mea-
as a unit, they4 identified two types of tumor interface sured by standard clinical audiologic techniques.
simultaneously coexisting in the same tumor at different Because auditory function fails to reflect the remaining
locations; the first constituted a distinct separation of the cochlear nerve fiber population,11 it has been suggested
tumor and the nerve, whereas the other was described as a that a cochlear nerve “conduction block” exists, stemming
144
 Pathologic Correlates in Neurotology 145

Figure 6-1. A, Internal auditory canal relationships of an inferior vestibular nerve schwannoma at stage I. All nerves remain discretely identifiable, although
there may be some displacement of the superior vestibular nerve and the cochlear nerve. B, In stage II, the inferior vestibular nerve schwannoma has invaded
the cochlear nerve. Both the cochlear and superior vestibular nerves are flattened, but the facial nerve remains intact. C, In stage III, the entirety of the eighth
cranial nerve is involved with tumor. The facial nerve is flattened but not invaded. T, Transverse crest; SV, superior vestibular nerve; IV, inferior vestibular nerve;
C, cochlear nerve; F, facial nerve. (From Ylikoski J, et al: Eighth nerve in acoustic neuromas, special reference to superior vestibular nerve function and
histopathology. Arch Otolaryngol 104:532–537, 1978. Copyright 1978, American Medical Association.)

from a tumor pressure effect.10 Ylikoski12 and Neely and origin from24–26 labyrinthine structures are not rare occur-
Hough6 have presented histologic evidence supportive of rences, vascular, biochemical, and perhaps viscosity
the conduction block idea with the demonstration of changes indirectly stemming from a vestibular schwannoma
“onion bulbs”—concentric layers of Schwann cell processes appear to be more important in peripheral dysfunction.
among which are interspersed an increased number of DeMoura and associates21,27 conducted detailed clinico-
collagen fibers. The onion bulbs are thought to result pathologic studies of 11 vestibular schwannomas. Loss of
from repetitive demyelination and remyelination, and are cochlear neurons most severe in the basal turn was the most
manifested in a marked decrease in the conduction veloc- frequently observed finding; basal hair cell loss also was
ity of the affected fiber. seen but to a lesser degree. Cochlear neuronal loss out of
These pathologic correlates have at least theoretic impli- proportion to hair cell loss manifests with loss of speech
cations in the concept of total tumor removal with attempt discrimination out of proportion to pure tone thresholds in
at hearing preservation. First, the degree of cochlear nerve neural presbycusis28 and perhaps in vestibular schwannomas
involvement with the tumor is not reflected by auditory as well.
function, although the auditory brainstem response (ABR)13 Suga and Lindsay22 reviewed the temporal bone pathol-
may be able to prognosticate to some extent the likelihood ogy of three cases of vestibular schwannoma with a partic-
of successful hearing preservation. Second, the lack of a ular interest in validating the concept that impairment
clear interface between cochlear nerve and tumor implies of blood supply to the inner ear was the cause of the
that in some proportion of cases, tumor inevitably will be manifested alterations. In the animal model, Perlman and
left behind in the hearing preservation attempt.14 One fac- associates29 showed that temporary occlusion of the
tor playing a role in the lack of a clear interface between the labyrinthine artery was associated with a predominant loss
cochlear nerve and the vestibular schwannoma may relate of cochlear neurons, atrophy of the spiral ligament, vari-
to the infiltrative tendency of the vestibular schwannoma, able hair cell loss in the organ of Corti, and little effect on
but it may also derive from the fact that in 25% of normal the tectorial membrane. In contrast, permanent obstruc-
eighth nerves15 no cleavage plane is evident between the tion of the labyrinthine artery30 precipitated a cascade of
cochlear and vestibular components in the cerebellopon- events, from hair cell changes and supporting structure
tine angle, with vestibular fibers imperceptibly blending degeneration to the end stages of fibrosis and ossification.
into the substance of the cochlear component.16 Practically Venous obstruction (vein at the cochlear aqueduct)31 results
speaking, such microscopic remnants do not inevitably give in scattered hemorrhages, progressive outer hair cell loss,
rise to tumor recurrences,17–19 but they do, particularly in severe strial atrophy, mild spiral ligament atrophy, and no
the younger patient, represent a source of concern. tectorial membrane alterations. Since the main venous
Clearly, restricting histologic evaluation to merely the drainage of the human inner ear is by the vein of the
internal auditory canal (IAC) components disregards con- cochlear aqueduct and the vein of the vestibular aqueduct,
sideration of the effect of various end organ changes and the arterial supply is provided by the arteries in the
evidenced in the temporal bones of individuals with ves- IAC, notably the labyrinthine artery, Suga and Lindsay22
tibular schwannomas. Although direct invasion of 20–23 and reasoned that vestibular schwannomas should disrupt
146 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

arterial supply to the inner ear to a greater extent than prone to injury, even if distant from the area of compres-
venous drainage; moreover, the obstruction should sion by retraction, and Sekiya and Møller36 believe the
be chronic and partial. Using the nontumor ear as a ref- transition from the fragile glia of the central portion to the
erence, they22 attributed degeneration of nerve fibers, collagen-reinforced Schwann sheath of the peripheral
ganglion cells, the stria vascularis, and the tectorial mem- portion of the cochlear nerve, in combination with the
brane; fibrosis and ossification of a semicircular canal; significantly greater vascularity of the peripheral portion,
and relatively good preservation of sensory cells seen in explains the predilection of this region for injury. Kveton
the tumor to the presence of the vestibular schwannoma. and associates37 suggest that the spontaneous improvement
They22 believed that their constellation of findings, partic- in hearing experienced by four patients several months after
ularly the good preservation of sensory cells in the pres- suboccipital/transmeatal acoustic neuroma removal may be
ence of extensive degeneration of the nerve fibers, ganglion due to a reversible nerve conduction block phenomenon at
cells, and stria, reflected partial vascular obstruction of the the OR zone.
IAC blood supply by the vestibular schwannoma. Alternatively, Fukaya and associates38 concluded that
Johnsson and colleagues32 used the surface preparation “occlusion of perforating arteries . . . caused lateral brain
method to study the putative vascular alterations related stem infarction around the entry zone of nerves VII and
to a vestibular schwannoma by comparing the normal and VIII,” which triggered the transient, low-frequency (retro-
tumor-associated inner ears. Although they found fewer cochlear) SNHL they found in 14 of nearly 1000 patients
red blood cells in the vessels of the tumor-affected ear than undergoing microvascular decompression for hemifacial
the normal ear, an observation confounded by the patient’s spasm. They38 based their conclusion on (1) the association
death some 2 weeks after surgery for tumor removal, they of Horner’s syndrome or bulbar palsy in more than one-third
did not find any excessive capillary atrophy or devascular- of the patients with low-frequency SNHL, (2) audiometric
ization, as they had noted in association with presbycusis. findings, especially ABR and electrocochleographic (ECoG),
Thus the role of ischemia in precipitating end-organ dys- suggestive of brainstem pathology, and (3) surgical records
function remains debatable. uniformly describing “extremely short perforating arteries
Changes in the biochemistry of the inner ear may under- surrounding the entry zone of nerves VII and VIII, so
lie some of the peripheral manifestations of the vestibular that they had to be stretched during surgery.” No patho-
schwannoma. Eosinophilic staining of inner fluids reflects logic study has been provided, but the observation
their increased protein content,3,21,33 which may be 5 to 15 seems to have some relevance to acoustic recess surgery in
times normal.34 Using immunoelectrophoresis, immuno- general.
diffusion, and disc electrophoresis, Silverstein34 and Palva
and associates35 found that the increased protein levels in
perilymph represent an accumulation of blood serum NEUROFIBROMATOSIS
proteins and not those from cerebrospinal fluid (CSF).
Schuknecht3 proposed that “biochemical alterations in the Cytologically, the vestibular schwannomas of neurofibro-
inner ear fluids are responsible, in part at least, for the hear- matosis type 2 (NF2) are indistinguishable from unilateral
ing losses showing flat audiometric patterns and loudness schwannomas, but histopathologically there are some
recruitment” (similar to metabolic presbycusis). Johnsson differences. The schwannomas seen in NF2 generally
and associates32 theorized that the increased protein (1) are larger and more often multicentric; (2) are more
content of the inner ear fluids leads to an increase in their frequently multilobular39; (3) more often infiltrate, rather
viscosity and hence cochlear dysfunction based on altered than splay, the facial and cochlear nerves39,40,41 (Fig. 6-2);
hydrodynamics. No concrete evidence supporting either of (4) are associated with more extensive bony erosion and
these theories can be found, yet how rapidly such abnor- enlargement of the IAC; and (5) tend to invade temporal
malities are corrected, if ever, subsequent to tumor treatment bone air cells and marrow spaces.1,2,42 Such characteristics
would seem of practical importance in the maintenance or can render hearing conservation attempts more problem-
improvement of hearing. atic. In addition, as emphasized by Linthicum and
Hearing loss is a frequent occurrence after tumor Brackmann,43 the multicentricity of the vestibular schwan-
removal, even in the majority of instances in which preser- nomas of NF2, for example, simultaneous intracochlear
vation is attempted. Vascular disruption, spasm, and frank or intralabyrinthine schwannomas distinct from the IAC
injury to the cochlear nerve are most commonly impli- tumor, may foil even the most skilled surgeon’s attempts
cated, but the idea of a “conduction block” is perhaps at complete tumor removal, at least when the surgeon is
worthy of consideration as well. Sekiya and Møller36 used using the standard translabyrinthine approach.
the canine model to study the effect of surgical manipula- Widening of the IACs, asymmetrical or symmetrical,
tions (e.g., retraction), thought to be analogous to those usually betrays the presence of vestibular schwannomas.
performed in acoustic recess tumor removal, on the Rarely, however, in neurofibromatosis patients at least,
cochlear nerve. Light and electron microscopic studies ectasia of the dural sheath of the IAC may mimic a vestibu-
were correlated to alterations in the recorded compound lar schwannoma both in terms of symptomatology and
action potential (CAP). With reversible changes in the the finding of uni- or bilateral widening of the IACs.44–46
CAP, such as latency, they found microhemorrhages Pantopaque,45,46 air,44 and metrizamide44 cisternography
within the cochlear nerve; abrupt amplitude decrease in have been used in the past to ascertain the absence of
the CAP was associated with near avulsion of the tumor, confirmed by several-year imaging follow-ups; now
Obersteiner-Redlich (OR) zone (the glial-Schwann cell gadolinium-enhanced magnetic resonance imaging (MRI)
sheath junction).36 The OR zone in particular seems to be is recommended for optimal evaluation.
148 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

A
A

B
B
Figure 6-6. A, A meningioma has densely infiltrated the petrous apex, as
Figure 6-5. A, This vertical section through the labyrinth shows seen in this vertical section (C ). B, Infiltration of the carotid canal with some
meningioma tissue invading the fallopian canal (arrow). B, At a higher compression of the internal carotid artery (arrow). (From Nager GT, Heroy J,
magnification, the meningioma can be seen abutting the facial nerve (F ). Hoeplinger M: Meningiomas invading the temporal bone with extension to
(From Nager GT, Heroy J, Hoeplinger M: Meningiomas invading the temporal the neck. Am J Otolaryngology 4:297–324, 1983.)
bone with extension to the neck. Am J Otolaryngology
4:297–324, 1983.)
55 sphenoid wing/parasellar meningiomas that were excised
and recurred, one-third had no new symptoms referable to
producing progressive hearing loss, headache, vertigo, tin- the recurrence and 42% had no new physical findings.
nitus, otalgia, and facial paresis.47 Recurrent otitis media with
otorrhea and the development of granulation tissue may be
seen. In addition, the jugular foramen syndrome (usually GLOMUS TUMORS
Vernet’s) as well as cerebellar and brainstem involvement
can be seen.47,51 The heritage of the chief cell of the paraganglioma and its
The diagnosis of meningioma must be considered when implications in the biologic behavior of these tumors is
dealing with a temporal bone, parapharyngeal space, or reviewed elsewhere in this text; this section concentrates
jugular foramen lesion. The rarity of the primary, purely on the patterns of growth and extension of jugulotympanic
intratympanic meningioma51 demands thorough imaging and vagale tumors, which are relevant to the planning of
evaluation for an intracranial component. The difficulty in surgical extirpation.
discerning normal from meningioma tissue requires wide Reminiscent of meningiomas, paragangliomas tend to
surgical margins47,50; for example, as cited by Maniglia,51 if expand within and traverse the temporal bone by means
the site of dural attachment is coagulated rather than of preformed pathways that offer minimal resistance.53–55
excised, the recurrence rate of intracranial tumor after The pneumatized air cell tracts of the temporal bone are the
removal is 19%. The need for long-term follow-up after most important route of spread; for instance, by means of
apparent excision, commensurate with the slow growth the peritubal air cells, glomus tumors can invade the petrous
rate of meningiomas, is evident.47 Recurrent symptomatol- apex and involve the internal carotid artery, clivus, dorsum
ogy alone should not serve as the indicator for follow-up sella, and sphenoid sinus.53 Extension along the facial nerve
imaging; as reported by Leonetti and colleagues,52 of can occur in the fallopian canal.53 The eustachian tube can
 Pathologic Correlates in Neurotology 149

TABLE 6-1. Classification of Neural Invasion

by Jugulotympanic Paragangliomas

Grade I Tumor is no closer than 1 mm to the perineurium

Grade II Tumor is less than 1 mm from perineurium
and involves epineurium
Grade III Tumor infiltrates perineurium
Grade IV Tumor involves endoneurium

From Makek M, et al: Neural infiltration of glomus temporale tumors. Am J Otol 11:1–5,
1990.

Of 83 cases scrutinized, 66 had some degree of cranial

nerve infiltration involving, in descending order of fre-
quency, the vagus, facial, spinal accessory, glossopharyn-
geal, and hypoglossal nerves. The mastoid segment was
A
the most common area of involvement of the facial nerve.
Preoperative physical findings of, and intraoperative
confirmation of, neural infiltration were found with tumors
of at least a C2 (Fisch classification) magnitude. Physical
findings did not predict neural involvement reliably.
Histopathologic examination permitted the creation of a
classification system (Table 6-1) of the neural infiltration
by paragangliomas following a sequence of the tumor
approaching the nerve, contacting the epineurium, invad-
ing the perineurium along the perivascular spaces of the
neural capillary supply (Fig. 6-8), and penetrating the
endoneurium (Fig. 6-9). With grade I and grade II inva-
sion, it is possible to dissect tumor away, leaving behind
intact nerve; however, grade III and grade IV invasion
require segmental nerve resection.60 Intracranial exten-
sion, according to Spector and colleagues,57 is most likely
B to occur within two “dangerous triangles”: the hypotym-
Figure 6-7. A, This vertical section through the skull base in the
panic and the protympanic (Fig. 6-10).
region of the jugular foramen shows extensive infiltration by a meningioma. The hypotympanic triangle is delimited by the inferior
C, Internal carotid artery; X, vagus nerve; J, jugular bulb. B, The meningioma petrosal sinus, the sigmoid sinus, and the internal jugular
encroaches on the vagus nerve (X ). (From Nager GT, Heroy J, Hoeplinger M: vein. Extension from the hypotympanic triangle may occur
Meningiomas invading the temporal bone with extension to the neck. Am J intraluminally in the great veins of the triangle, extralumi-
Otolaryngology 4:297–324, 1983.)
nally along the carotid sheath into the neck, or along the
cranial nerves at the base of the skull.
serve as a conduit beyond the temporal bone to the The protympanic triangle is determined by the eustachian
nasopharynx.53 The lumens of the internal jugular vein and tube opening, the tensor tympani tendon, and the zygomatic
sigmoid sinus are likewise avenues for tumor extension root cells. Further growth may then progress along the
beyond the temporal bone, extraordinarily as far as the
atria.56 Spector and associates 57 warn that extension into the
sigmoid sinus is evidence for posterior fossa involvement.
The carotid sheath lends access to the neck, and the various
foramina and sutures of the skull base also allow for tumor
expansion with neural compression, especially the lower cra-
nial nerves, and the hallmark erosion of the caroticojugular
crest. Perforation of the tympanic membrane permits exten-
sion along the external auditory canal. The tumors tend to
expand through multiple pathways simultaneously.53,57
Invasion of the labyrinth may occur along the nerves of
the IAC.53,54 Paragangliomas tend to ramify within the bony
labyrinth before causing complete bony destruction58;
labyrinthine ossification is believed to reflect interference
with the vascular supply of the end organs by the tumor.53
The ossicular chain, even with extensive tumor53 or with
primary tympanicum tumors,59 remains relatively unscathed. Figure 6-8. Paraganglioma contacts the perineurium of the facial nerve
Makek and colleagues60 have published a unique study (stage II invasion). (From Makek M, et al: Neural infiltration of glomus
of neural infiltration by jugulotympanic paragangliomas. temporale tumors, Am J Otol 11[1]:1–5, 1990.)
150 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

well as the relative impenetrability of the CNS to many

chemotherapeutic agents.62,63 Clinical recognition of
metastatic temporal bone involvement in all probability
lags the true incidence both because of the paucity of
evoked symptoms63 and the rarity with which the temporal
bone is surveyed as a matter of routine in patients with
possible metastatic disease.64
In general, the distribution of temporal bone involvement
depends on its avenue of access to the temporal bone.63
Modes of dissemination to the temporal bone include the
following: hematogenous from a distant primary (carcinoma
or sarcoma) or leukemia/lymphoma; direct extension from a
primary extracranial tumor, for example, pharyngeal cancer;
direct extension from a primary intracranial tumor, as dis-
cussed with meningiomas; and leptomeningeal spread, both
Figure 6-9. Stage IV invasion: paraganglioma tissue involves the by distant and intracranial primary tumors.
endoneurium of the facial nerve. (From Makek M, et al: Neural infiltration Metastatic tumors most commonly gain access to the
of glomus temporale tumors, Am J Otol 11[1]:1–5, 1990.)
temporal bone by hematogenous spread.64 Breast, lung,
kidney, prostate, and stomach carcinoma, in descending
lumen of the eustachian tube to the nasopharynx, within order of frequency, have been reported as metastasizing to
air cell tracts to the petrous apex, or along the IAC into the the temporal bone.63 Deposition of tumor cells occurs pre-
middle cranial fossa. dominantly in the petrous marrow (Fig. 6-11); the sluggish
Kinney61 found that intracranial extension most com- flow in the sinusoidal capillaries promotes filtering of the
monly involves the posterior cranial fossa, inferior and tumor cells from the circulation.64,65 Involvement of the
medial to the IAC. petrous apex can be found nearly uniformly.63 Metastatic
In a fashion similar to that occurring in meningiomas, deposition within the air cell spaces of the temporal bone is
paragangliomas extend predominantly along preformed also quite common and leads to tympanic cavity and facial
pathways, and their complete extirpation mandates thorough nerve involvement.62 Invasion of the otic capsule is uncom-
preoperative imaging evaluation and wide-field exposure. mon, reflecting its resistance to neoplastic invasion.64
Lymphomas and leukemias infiltrate the petrous apex
almost without exception, subsequently following the sub-
METASTATIC TUMORS mucosal plane of the mastoid air cells, the ossicles, the
middle ear muscles and tendons, the eustachian tube, the
Secondary involvement of the temporal bone by malignant IAC, and the subcutaneous tissues of the external auditory
processes is a problem of increasing magnitude, relating to canal.62,66
improved chemotherapeutic regimens that allow for longer Regional, extracranial neoplasms, most commonly pha-
survival and the development of intracranial extension, as ryngeal carcinoma, extend directly into the temporal bone

Figure 6-11. Breast adenocarcinoma metastatic to the right temporal bone.

Tumor (arrows) occupies the petrous apex and the internal auditory canal,
with partial destruction of the cochlear, vestibular, and facial nerves.
Clinically, the patient had sudden right facial paresis, hearing loss, and
Figure 6-10. The protympanic and hypotympanic triangles allow for central vertigo, and examination documented a right profound SNHL and a right
extension of paraganglioma. (From Spector GJ, et al: Panel discussion: absent vestibular response. (Reprinted by permission of the publishers from
Glomus jugulare tumors of the temporal bone. Patterns of invasion in the Schuknecht HF: Pathology of the Ear. Cambridge, MA, Harvard University
temporal bone. Laryngoscope 89:1628–1639, 1979.) Press, Copyright © 1974 by the President and Fellows of Harvard College.)
 Pathologic Correlates in Neurotology 151

by many of the same preformed pathways discussed previ- suggestive of leptomeningeal temporal bone involvement;
ously, particularly the eustachian tube, the carotid canal, lumbar puncture is particularly helpful in establishing the
the foramen lacerum, the foramen ovale, and the jugular diagnosis.62,67
foramen.63,64 Similarly, malignant intracranial tumors may Facial paralysis may be caused by metastatic tumor infil-
secondarily involve the temporal bone by routes described trating and destroying the facial nerve,62,64 but may also
in the discussion of meningiomas, paragangliomas, and reflect compression by tumor nodules.3
vestibular schwannomas. Chloromas are localized, green masses of leukemic cells,
Leptomeningeal extension, in which the malignant associated particularly with acute myeloblastic leukemia.
tumor cells diffusely proliferate in a lamellar manner along Shanbrom and Finch68 have cited data indicating that of
the pia-arachnoid of the brain and spinal cord, may develop those patients with chloromas, approximately half will
both with distant primary neoplasms and primary intracra- have temporal bone involvement. Leukemic infiltrations
nial tumors, especially medulloblastomas.62 Bilateral IAC in general may precipitate recurrent otitis and acute symp-
invasion with disruption of the facial and cochleovestibular tomatology related to hemorrhage.62,68 Chloromas have
nerves is characteristic and may lead to transgression of the been associated with compressive effects on both the facial
cribrose areas and membranous labyrinth.62 and cochleovestibular nerves, tympanomastoiditis, otalgia,
Symptomatic manifestations of metastatic temporal bone hearing loss, and vertigo.
disease are conspicuous by their absence; Nelson and In general, the diagnosis of temporal bone metastasis
Hinojosa63 found that of 33 patients with metastatic tempo- is based on clinical suspicion confirmed by appropriate
ral bone involvement, nearly 60% were asymptomatic, and diagnostic imaging. Temporal bone biopsy may be helpful,
that “diffuse metastases . . . were present in all cases . . . when although the metastatic lesions are often less well differen-
the petrous apex was involved by the hematogenous route.” tiated than the primary tumor, foiling attempts to determine
It is self-evident then that metastatic temporal bone inva- the probable site of the primary.64
sion is a late development in the course of the disease, and
that the diagnosis of the underlying primary tumor or
metastatic disease will have been previously established.63 AUDITORY IMPLANTS
Schuknecht and associates64 emphasized hearing loss
as a common early manifestation of hematogenous or Labyrinthitis ossificans (LO) and alterations in the cochlear
directly extending metastatic tumors of the temporal bone, nuclei are pathologic findings with relevance to neurotol-
with conductive hearing loss reflecting eustachian tube ogy, particularly in the consideration of cochlear implanta-
dysfunction and secondary serous otitis media (Fig. 6-12); tion or auditory brainstem implant (ABI) placement.
less frequently, ossicular destruction, mucosal invasion, Suga and Lindsay69 defined LO as replacement of the
and tympanic membrane infiltration precipitated the fluid spaces of the inner ear by fibrous tissue and new bone.
conductive hearing loss. SNHL is a manifestation of LO may develop as a consequence of severe inflammation,
cochlear nerve compression or destruction, or cochlear trauma, or vascular compromise of the inner ear.69–71
invasion along the IAC. Rapidly progressive uni- or bilat- Specific entities associated with LO include labyrinthitis
eral SNHL, especially if associated with uni- or bilateral (bacterial or viral, tympanogenic or meningogenic), far-
facial paresis, vertigo, and widespread neurologic signs, is advanced otosclerosis, autoimmune inner ear disease,
labyrinthine artery occlusion, and leukemia.70
The details of the rate of progression of LO are
unknown,70 although Novak and associates72 suggest, on
the basis of serial temporal bone computerized tomogra-
phy (CT) scans, that intracochlear osteoneogenesis begins
within the first 4 to 8 weeks following the acute phase of
meningitis. Irrespective of cause, the basal scala tympani
(Fig. 6-13) is the most likely site for cochlear LO; despite
this relatively consistent finding, differing patterns of
cochlear involvement with LO have been associated with
different causes.70
Meningogenic labyrinthitis appears to be the most com-
mon cause of LO.70 In one series of children profoundly
deafened by meningogenic labyrinthitis who subsequently
underwent cochlear implantation,73 80% had some degree
of cochlear ossification noted at the time of surgery. In 3 of
24 cases studied, Green and associates70 found ossification
of the middle and apical cochlear turns which exceeded that
found in the basal turn (Fig. 6-14). They hypothesized that
Figure 6-12. A chondromyxosarcoma (C ) has destroyed the right petrous the distribution of ossification reflected the spread of
apex and has compressed and occluded both the internal carotid artery infection along the cochlear aqueduct and modiolus.70
and the eustachian tube. Clinically, the patient experienced right serous Tympanogenic labyrinthitis tends to provoke new bone
otitis media and left hemiparesis. (Reprinted by permission of the publishers
from Schuknecht HF: Pathology of the Ear. Cambridge, MA, Harvard
formation only in the scala tympani near the round window
University Press, Copyright 1974 by the President and Fellows of membrane, consistent with the round window membrane
Harvard College.) allowing inner ear access to a middle ear infection.70
152 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Figure 6-13. This cochlea shows new bone formation in the basal scalae of a
gentleman who was profoundly deaf from meningitis (presumably meningo- Figure 6-15. Complete obliteration of the cochlea by labyrinthitis ossificans,
coccal). (Reprinted by permission of the publishers from Schuknecht HF: as seen here in an 84-year-old patient who suffered a febrile illness
Pathology of the Ear. Cambridge, MA, Harvard University Press, Copyright © (presumably meningococcal meningitis) at the age of 2 months, is unusual.
1974 by the President and Fellows of Harvard College.) (Reprinted by permission of the publishers from Schuknecht HF: Pathology
of the Ear. Cambridge, MA, Harvard University Press, Copyright © 1974 by
the President and Fellows of Harvard College.)

The cochlear ossification of otosclerosis characteristically

is restricted to the basal-most 6 mm of the scala tympani.70 intracochlear electrode into the scalae vestibuli of two
In general, total obliteration of the cochlear fluid spaces patients with scala tympani occlusion by LO. Alternatively,
with new bone is rare (Fig. 6-15) and can be seen with both Balkany75 has described endoscopically guided laser eradi-
meningogenic and tympanogenic labyrinthitis.70 In addi- cation of LO for cochlear implantation.
tion, scala tympani occlusion with new bone tends to pre- Extreme LO may require extensive coring out of the
cede ossification of the scala vestibuli, and the scala media cochlear modiolus, as described by Gantz and associates.76
and vestibule are ossified only in the most severe cases.70 The degree of LO has implications in the survival of the
The predilection for ossification of the basal scala tym- cochlear neuronal population and their fibers, apparently
pani after labyrinthitis mandates that the cochlear implant the elements stimulated by the intracochlear electrode.77
surgeon be prepared to perform the required cochlear Nadol and Hsu78 have shown that, even in those cochleae
“drill out.” The excessive LO of the middle and apical turns with severe occlusion by LO related to meningogenic
may explain the occasional inability to pass entirely a long labyrinthitis, “significant numbers” of spiral ganglion cells
intracochlear electrode.70 remained. More specifically, Linthicum and colleagues77
Because the scala vestibuli seem to be less affected by the have reported that “as few as 3212 cells may produce a
ravages of LO, Steenerson and associates74 have proposed, useful auditory sensation.”
and have apparently successively performed, insertion of the The ABI holds hope for those profoundly deafened
individuals with loss of both cochlear nerves, as in NF2.79
Although still considered experimental at this time, it is
reasonable to expand our database regarding the pathology
of the cochlear nuclei to establish which diseases may
allow for ABI placement and which might not. It is partic-
ularly important to know the status of the ventral cochlear
nucleus (VCN), because the VCN has extraventricular
surface exposure and hence is surgically accessible.
It seems logical to assume that a viable population of
cochlear nuclear neurons is key in the successful use of the
ABI. Some data indicate that with aging loss of cochlear
neurons takes place in both the VCN and the dorsal
cochlear nucleus80,81 and that those with hyperbilirubine-
mia similarly suffer a depopulation of cochlear neurons in
the VCN.81 In theory, these individuals might be expected
to perform less well with the ABI.

PACCHIONIAN BODIES
Figure 6-14. Labyrinthitis ossificans predominantly in the apical portion of
this cochlea of a patient who was profoundly deafened by meningitis
(probably meningococcal). (Reprinted by permission of the publishers from Pacchionian bodies, commonly referred to as arachnoid
Schuknecht HF: Pathology of the Ear. Cambridge, MA, Harvard University granulations,82 consist of multiple arachnoid villi (see the
Press, Copyright © 1974 by the President and Fellows of Harvard College.) earlier section, Meningiomas) found in close relationship
 Pathologic Correlates in Neurotology 153

to (i.e., projecting intraluminally) the major venous

sinuses. The space within the villi contains loose arachnoid
tissue48 and represents a continuation of the subarachnoid
space82 (Fig. 6-16). Thus, the bodies are thought to func-
tion in the resorption of CSF into the intracranial venous
system. Protrusion through the dura by the pacchionian
bodies eventuates in bony resorption and the creation of
depressions in adjacent bone, known as foveolae granulares,48
and may occur in relationship to the middle and posterior
cranial fossa aspects of the temporal bone (Figs. 6-17 and
6-18). Ordinarily, surgical exposure of such granulations
does not provoke CSF leakage.82 However, Gacek83 has
provided evidence that pacchionian bodies, associated with
bone erosion into the pneumatized air cell spaces of the
mastoid, are pathologic correlates of spontaneous (nontrau-
matic) adult-onset fluid in the tympanomastoid compart-
ment,84 which may manifest with CSF otorrhea/rhinorrhea, Figure 6-17. This horizontal section shows a pacchionian body impinging
on the middle cranial fossa surface of a right temporal bone. (Reprinted by
conductive hearing loss, meningitis with acute otitis media, permission of the publishers from Schuknecht HF, Gulya AJ: Anatomy
or intracranial extension of chronic otitis media. of the Temporal Bone with Surgical Implications. Philadelphia, Lea &
The detection of bony-dural defects associated with Febiger, 1986.)
pacchionian bodies requires scanning in both the axial and
coronal planes, because either the middle cranial fossa or
posterior cranial fossa plates may be involved, whereas various locations along its path from the pons through the
CSF flow into the mastoid may be detected either by mastoid. Two general conclusions they made are particu-
intrathecal metrizamide–enhanced CT scanning or MRI.83 larly germane to neurotology: (1) The facial nerve (both
The surgical exposure is dictated by the size of the motor and sensory divisions) adapts well to space-occupy-
defect(s) and the multiplicity of defects found.83,85 Small ing lesions in the IAC; in the fallopian canal both divisions
(<1 cm) isolated defects may be managed through a simple are “highly prone” to pressure atrophy. (2) Destruction of
mastoidectomy, but multiple or large (>1 cm) defects any segment of the motor division results in distal atrophy.
generally require additional middle cranial fossa exposure. A lesion of the sensory division central to the geniculate
Whatever herniated brain tissue is encountered is nonfun- ganglion results in atrophy central to the lesion, while a
ctional and is resected. lesion distal to the geniculate ganglion results in distal
atrophy.
The details of four of the illustrative cases are sufficiently
FACIAL NERVE PATTERNS relevant to neurotology to warrant expanded discussion.
OF DEGENERATION An intra-axial lesion of the pons is exemplified by the
case of a 4-year-old child who presented with a progres-
Schuknecht and Shinozaki-Hori86 presented clinicopa- sive (>2 weeks) facial paralysis and ipsilateral, profound
thologic studies of 12 cases as illustrative of patterns of SNHL. An autopsy, performed 9 months later when the
degeneration of the facial nerve associated with disorders at patient died, disclosed a pontine astrocytoma. The motor

Figure 6-16. Arachnoid granulations consist of a peripheral layer of Figure 6-18. A pacchionian body interdigitates with the bony septa of
arachnoid cells and fibrous tissue surrounding a central core (C ) of loose the posterior cranial fossa surface of the temporal bone. (Reprinted by
arachnoid tissue. (Reprinted by permission of the publishers from permission of the publishers from Schuknecht HF, Gulya AJ: Anatomy
Schuknecht HF, Gulya AJ: Anatomy of the Temporal Bone with Surgical of the Temporal Bone with Surgical Implications. Philadelphia,
Implications. Philadelphia, Lea & Febiger, 1986.) Lea & Febiger, 1986.)
154 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

component of the left facial nerve (Fig. 6-19) was comple-

tely degenerated throughout, but the sensory division
(nervus intermedius, greater superficial petrosal nerve, and
the chorda tympani nerve) appeared normal.
An intracanalicular vestibular schwannoma and a
somewhat more extensive meningioma illustrate the con-
sequences of facial nerve compression in the environs of
the IAC. The vestibular schwannoma manifested with
SNHL and tinnitus 18 years before the death of an
81-year-old man. Temporal bone histopathologic exami-
nation (Fig. 6-20) revealed a left intracanalicular vestibular
schwannoma with flaring of the IAC and distortion, ante-
rior displacement, and flattening of, but apparently no
invasion of, the facial nerve. Both the motor and sensory
divisions of the facial nerve were normal peripheral to A
the lesion. The meningioma developed in a 56-year-old
woman who had a history of headaches, left otalgia, and
left facial paralysis. Her death, at age 60, occurred 3 days
after attempted removal of the petrous ridge and cerebel-
lopontine angle (CPA) meningioma. Temporal bone
histopathologic examination (Fig. 6-21) showed the tumor

B
Figure 6-20. A, In this schematic, the vestibular schwannoma is depicted
compressing neural structures in the internal auditory canal. B, The
intracanalicular vestibular schwannoma (S) is seen flattening the facial
nerve (arrow) in this horizontal section of a left temporal bone. (From
Schuknecht HF, Shinozaki-Hori N: Patterns of degeneration of the
facial nerve. Am J Otol 6(Suppl):47–54, 1985.)
A
to be invading the IAC and compressing the geniculate
ganglion, the neuronal population of which remained
within normal limits. The motor division of the facial
nerve, in contrast, was completely degenerated, whereas
the greater superficial petrosal nerve, chorda tympani
nerve, and sensory bundle showed partial degeneration.
Compression of the vertical segment of the facial nerve,
the most common area of facial nerve involvement by
paragangliomas,60 was also found in the left temporal bone
of a 49-year-old woman who died 5 months after the
development of a rapidly progressive left facial paralysis
caused by diffuse carcinomatosis related to an undifferen-
tiated carcinoma of the lung (Fig. 6-22).3 The facial nerve
was found to be compressed at the superior aspect of its
vertical segment. Medial to the metastatic nodule, the
motor and sensory divisions were normal, but distally they
B showed severe degeneration.
Figure 6-19. A, Summary diagram of the effect of an astrocytoma In treating the patient with facial nerve symptomatology,
(glioblastoma) of the pons on the facial, cochlear, and vestibular nerves. such as progressive paresis, the neurotologist must deter-
B, This horizontal section through the vertical segment of the facial nerve mine the area(s) of involvement of the facial nerve with
demonstrates pale staining consistent with degeneration of the motor
component (m). The chorda tympani nerve and sensory component are
clinical examination supplemented by medical imaging.
intact. (From Schuknecht HF, Shinozaki-Hori N: Patterns of degeneration of Therapeutic deliberations are guided by an understanding of
the facial nerve. Am J Otol 6(Suppl):47–54, 1985.) the pathologic consequences of lesions at various locations.
 Pathologic Correlates in Neurotology 155

A A

B
Figure 6-21. A, A meningioma, in this diagram, extends along the internal B
auditory canal to the geniculate ganglion. B, Despite compression by the Figure 6-22. A, The metastatic nodule compresses the facial nerve in its
meningioma, there is no obvious loss of neurons in the geniculate ganglion. vertical segment. B, Both motor and sensory components of the facial nerve
C, Complete degeneration of the motor component and partial degeneration (F ) show the degenerative effects of compression by the tumor nodule (T ).
of the sensory bundle of the facial nerve occurs. (From Schuknecht HF, (From Schuknecht HF, Shinozaki-Hori N: Patterns of degeneration of the
Shinozaki-Hori N: Patterns of degeneration of the facial nerve. Am J Otol facial nerve. Am J Otol 6(Suppl):47–54, 1985.)
6(Suppl):47–54, 1985.)

ICA at the origin of the branch and deviating the ICA

INTERNAL CAROTID ARTERY posterior and lateral to its usual course during the remain-
der of development.88 Fisch89 proposes alternatively that
The internal carotid artery (ICA) serves as a landmark to the aberrant vessel in the tympanic cavity represents the
the neurotologic skull base surgeon in much the same enlarged inferior tympanic and caroticotympanic arteries,
fashion as the facial nerve guides the contemporary otolo- which substitute for the “original atrophic” vessel. Despite
gist. Just as the normal anatomic relationships of the facial the rarity of this anomaly, it is an element in the differen-
nerve, as well as their variations, are key data in surgical tial diagnosis of a jugulotympanic paraganglioma.
undertakings, similar knowledge regarding the ICA is crit- A marked diminution in the tissues of the carotid canal
ical. In addition, it is important to be cognizant of the pos- can occur with aging; in extreme cases, the wall of the ICA
sible alterations of the ICA with age when contemplating is reduced to a mere intimal layer. Clearly, in such instances,
surgical interventions in the elderly. skeletonization of the ICA would be fraught with the hazard
The details of the anatomic relationships of the ICA of ICA rupture, or the ICA may be more susceptible to
within the temporal bone and cranial cavity have been pub- tumor invasion (Fig. 6-25).
lished elsewhere.82,87 For the neurotologic surgeon, it is par- Arteriosclerotic plaques may also involve the ICA
ticularly important to be aware of the ICA as it runs medial (Fig. 6-26), with the possibility of arterial manipulation
to the eustachian tube (Fig. 6-23) and anterolateral to the sending a shower of obliterative emboli. MRA (magnetic
basal turn of the cochlea (Fig. 6-24). According to Leonetti resonance angiography) may prove invaluable in estimating
and associates87 the mean distance of the ICA to the basal arterial obliteration by plaques; it is less invasive than stan-
turn of the cochlea, measured at the level of the tensor tym- dard cranial arteriography.
pani muscle, is 2.83 mm, with a range of 1.14 to 5.52 mm. Aneurysmal dilatation of the ICA most commonly
The congenitally ectopic ICA is theorized to derive from develops immediately proximal to the external carotid
an anomalous or anomalously persisting branch, fixing the foramen,89 but traumatic aneurysms develop at the site of
156 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Figure 6-23. The internal carotid artery (C) lies medial to the eustachian
tube (e). (Reprinted by permission of the publishers from Schuknecht HF, Figure 6-25. With age, extreme thinning of the wall of the internal carotid
Gulya AJ: Anatomy of the temporal bone with surgical implications. artery may occur (compare with Fig. 6–23). (Reprinted by permission of the
Philadelphia, Lea & Febiger, 1986,) publishers from Schuknecht HF: Pathology of the Ear. Cambridge, MA,
Harvard University Press, Copyright 1974 by the President and Fellows of
Harvard College.)
injury, for example, the tympanic cavity with laceration
during tympanostomy tube insertion.90 Extraordinarily, an
intrapetrous carotid artery aneurysm can present with SERPENTINE ANEURYSMS
facial paralysis.91
Large (Fisch types C and D) paragangliomas generally Massive ectasia and serpentine tortuosity of the vertebro-
involve the intratemporal ICA.89 No methodical study basilar system is most appropriately referred to as a serpen-
of invasion of the ICA akin to that published detailing tine aneurysm of the involved artery, although the term
facial nerve invasion by paragangliomas could be found, dolichoectasia is also used.92,93 The basilar artery is most
yet frank invasion of the ICA is thought to be unusual commonly involved, but often the vertebral and internal
(Fig. 6-27). Perhaps the periosteum of the carotid canal carotid arteries are distorted as well.93 The typical patient
presents a protective barrier: Inadvertent disruption of the is a man in his mid-60s with a history of hypertension and
ICA can occur with removal of invasive tumor, but more arteriosclerosis. Suggestive symptoms relate to compres-
significant in paraganglioma surgery are the caroticotym- sion of the pons, medulla, lower cranial nerves, and
panic arteries, which supply the anteromedial portion of ventricular system, and/or embolism from mural thrombi.94
the tumor and which can be avulsed in operative dissection Atypically, the serpentine aneurysm may present with
at the level of the tympanic orifice of the eustachian tube.89 vertigo, with94–96 or without97,98 SNHL and tinnitus. Central
The lining matrices of congenital epidermoids and der- facial nerve paralysis94 and facial numbness96 have also been
moid cysts generally can be peeled from the ICA.89 reported.

Figure 6-26. An atherosclerotic plaque (a) partially occludes the lumen of

Figure 6-24. The basal turn of the cochlea (b) lies adjacent to the internal the intratemporal internal carotid artery. (Reprinted by permission of the
carotid artery (C). (Reprinted by permission of the publishers from publishers from Schuknecht HF: Pathology of the Ear. Cambridge, MA,
Schuknecht HF, Gulya AJ: Anatomy of the Temporal Bone with Surgical Harvard University Press, Copyright 1974 by the President and Fellows
Implications. Philadelphia, Lea & Febiger, 1986.) of Harvard College.)
 Pathologic Correlates in Neurotology 157

Figure 6-27. A paraganglioma (glomus jugulare) has invaded the internal

carotid artery (A) adventitia (arrow) as seen at the level of the petrous apex. Figure 6-28. A loop of the anterior inferior cerebellar artery (arrows) indents
(From Dayal VS, Hinojosa R, Amenta CA III: Surgical interferences from the posterior aspect of, and enters, the internal auditory canal. (Reprinted by
study of temporal bones with glomus jugulare tumor. Otolaryngol Head Neck permission of the publishers from Schuknecht HF, Gulya AJ: Anatomy of the
Surg 102:690–697, 1990.) Temporal Bone with Surgical Implications. Philadelphia, Lea & Febiger, 1986.)

Contrast-enhanced CT scanning or MRI can be diagnos- injury) has also been implicated.104 Pure DAVMs are depend-
tic. MRA promises to be a minimally invasive manner in ent on a meningeal arterial supply and are limited to the
which to confirm the diagnosis; it can be substituted for a dura, but the clinical presentation relates to the route of
formal vertebral arteriography. venous drainage.104
The occipital DAVM presents with pulsatile tinnitus
and headache and may also provoke increased intracranial
VASCULAR LOOPS pressure, subarachnoid hemorrhage, and seizures.105 A
characteristic bruit is heard loudest in the mastoid region
The compression of neural structures by vascular loops, and decreases with ipsilateral carotid artery compression.
either within the IAC or at the nerve root entry zone has Treatment, either embolization or surgical excision, is
been implicated in the generation of symptoms such as offered according to the severity of the symptomatology.
tinnitus, vertigo, and SNHL, with “decompression” or
nerve section offered as treatment.99–101
Mazzoni102 conducted a detailed study of the vascular JUGULAR BULB
relationships of the IAC. The 100 temporal bones used were
harvested in such a fashion as to leave attached contiguous The jugular bulb is a landmark in neurotologic surgery,
portions of the brainstem and cerebellum. He found an for example, leading to the cochlear aqueduct and the
arterial loop, most commonly the anterior inferior cerebel- inferior margin of the IAC, and its variants, the high
lar artery, within the IAC in 40% of his specimens (Fig. 6-28). (enlarged) jugular bulb, the dehiscent jugular bulb, and the
In 27% of his specimens the loop was located at the porus;
in the remaining 33% it was in the CPA.
More recently, Reisser and Schuknecht103 attempted to
correlate clinical symptomatology (unexplained audio-
vestibular symptoms) with the presence of an IAC loop.
Although their method for harvesting temporal bone did
not ensure uniform preservation of intact IAC/vascular
relationships, in the 12.3% of 1327 temporal bones studied
that did have these loops in the IAC, no correlation could
be made between ante mortem symptoms and the presence
of, or laterality of, the vascular loop.

DURAL ARTERIOVENOUS
MALFORMATIONS
Dural arteriovenous malformations (DAVMs) are rare
lesions and even more rarely cause objective pulsatile
Figure 6-29. This high-riding jugular bulb (j ) also has areas of bony
tinnitus.94 They are usually considered to be congenital in dehiscence. (Reprinted by permission of the publishers from Schuknecht HF,
origin, stemming from a disturbance in vascular develop- Gulya AJ: Anatomy of the Temporal Bone with Surgical Implications.
ment at 3 weeks’ gestation,94 but trauma (surgery or head Philadelphia, Lea & Febiger, 1986.)
158 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

TABLE 6-2. Distinguishing Characteristics—High Jugular 7. Hebbar GK, McKenna MJ, Linthicum FH Jr: Immuno-
Bulb vs. Jugular Bulb Diverticulum histochemical localization of vimentin and S-100 antigen in small
acoustic tumors and adjacent cochlear nerves. Am J Otol
Jugular Bulb 11:310–313, 1990.
High Jugular Bulb Diverticulum 8. Marquet JFE, et al: The solitary schwannoma of the eighth cranial
nerve. An immunohistochemical study of cochlear nerve-tumor
Lateral/Anterior Location Medial/Posterior
interface. Arch Otolaryngol Head Neck Surg 116:1023–1025, 1990.
9. Ylikoski J, Palva T, Collan Y: Eighth nerve in acoustic neuromas.
Yes Tympanic cavity extension No
Otoscopy Diagnostic study Radiology Special reference to superior vestibular nerve function and
Conductive Hearing loss Sensorineural histopathology. Arch Otolaryngol 104:532–537, 1978.
Uncommon Tinnitus Continuous or 10. Ylikoski J, et al: Cochlear nerve in neurilemomas. Audiology and
intermittent histopathology. Arch Otlaryngol 104:679–684, 1978.
No Vertigo Yes 11. Neely JG: Hearing conservation surgery for acoustic tumors a
No Ménière’s symptoms Yes clinical-pathologic correlative study. Am J Otol 6(Suppl):143–146,
Yes? Expansion Yes? 1985.
12. Ylikoski J: Light and electron microscopic findings in a case of small
acoustic schwannoma (associated with a schwannoma of the facial
nerve). J Laryngol Otol 100:785–795, 1986.
jugular diverticulum are entities of which the neurotolo- 13. Shelton C, et al: Acoustic tumor surgery. Prognostic factors in
gist should be aware in order to avert potential surgical hearing conservation. Arch Otolaryngol Head Neck Surg 115:
misadventure. 1213–1216, 1989.
The high (enlarged) jugular bulb (Fig. 6-29) protrudes 14. Neely JG: Is it possible to totally resect an acoustic tumor and
conserve hearing? Otolaryngol Head Neck Surg 92:162–167, 1984.
above the level of the tympanic annulus and may attain
15. Silverstein H, et al: Combined retrolab-retrosigmoid vestibular
prodigious proportions (the so-called jugular mega- neurectomy. An evolution in approach. Am J Otol 10:166–169, 1989.
bulb).106,107 The high jugular bulb has been reported to occur 16. Silverstein H, et al: Cochlear and vestibular gross and histologic
in 3.5%108 to 7.0%109 of temporal bones studied, more anatomy (as seen from postauricular approach). Otolaryngol Head
commonly occurs on the right side, and arguably has been Neck Surg 92:207–211, 1984.
related to the degree of pneumatization of the peri- and 17. Cohen NL, Ransohoff J: Hearing preservation-posterior fossa
infralabyrinthine regions.110,111 The high jugular bulb may approach. Otolaryngol Head Neck Surg 92:176–183, 1984.
be confused with a paraganglioma by the unwary clinician 18. Rosenberg RA, Cohen NL, Ransohoff J: Long-term hearing preser-
and serves primarily as a nuisance in both translabyrinthine vation after acoustic neuroma surgery. Otolaryngol Head Neck Surg
and retrosigmoid tumor extirpation. The high jugular bulb 97:270–274, 1987.
19. Shelton C, et al: Hearing preservation after acoustic tumor removal:
has been incriminated in subjective pulsatile tinnitus112
Long-term results. Laryngoscope 100:115–119, 1990.
with mixed reports of successful symptomatic control with 20. Amoils CP, Lanser MJ, Jackler RK: Acoustic neuroma presenting as
surgical ligation of the internal jugular vein.106,113 a middle ear mass. Poster presentation at the 95th annual meeting
The high jugular bulb may or may not have an intact of the American Academy of Otolaryngology-Head & Neck
bony covering, that is, be dehiscent. Clearly, in the latter Surgery, Kansas City, MO, September 22, 1991.
situation, it is prone to inadvertent penetrating injury.114 21. DeMoura LFP, Hayden RC Jr, Conner GH: Further observations
An entity distinct from the high jugular bulb is the jugular on acoustic neurinoma. Trans Am Acad Ophthal Otolaryngo
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Cantrell115 the jugular diverticulum is a true venous anom- 22. Suga F, Lindsay JR: Inner ear degeneration in acoustic neurinoma.
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23. Tran Ba Huy P, et al: Acoustic schwannoma presenting as a tumor
guish it from a high jugular bulb (Table 6-2). Notably, the
of the external auditory canal. Case report. Ann Otol Rhino
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25. Huang T-S: Primary intralabyrinthine schwannoma. Ann Otol
Rhinol Laryngol 95:190–192, 1986.
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38. Fukaya T, Nomura Y, Fukushima T: Transient retrocochlear low- 77:5–22, 1968.
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39. Martuza RL, Ojemann RG: Bilateral acoustic neuromas: Clinical 66. Adams GL, Paparella MM, El Fiky FM: Primary and metastatic
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43. Linthicum FH Jr, Brackmann DE: Bilateral acoustic tumors. A 71. Nadol JB Jr: Histological considerations in implant patients. Arch
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44. Egelhoff JC, et al: Dural ectasia as a cause of widening of the implications for cochlear implantation. Otolaryngol Head Neck
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17:7–9, 1987. 73. Eisenberg LS, et al: Electrical stimulation of the auditory system in
45. Hill MC, Oh KS, Hodges FJ III: Internal auditory canal enlarge- children deafened by meningitis. Otolaryngol Head Neck Surg
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122:730, 1977. 74. Steenerson RL, Gary LB, Wynens MS: Scala vestibuli cochlear
46. Sarwar M, Swischuk LE: Bilateral internal auditory canal enlarge- implantation for labyrinthine ossification. Am J Otol 11:360–363,
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129:935–936, 1977. 75. Balkany T: Endoscopy of the cochlea during cochlear implantation.
47. Nager GT, Heroy J, Hoeplinger M: Meningiomas invading Ann Otol Rhinol Laryngol 99:919–922, 1990.
the temporal bone with extension to the neck. Am J Otolaryngol 76. Gantz BJ, McCabe BF, Tyler RS: Use of multichannel cochlear
4:297–324, 1983. implants in obstructed and obliterated cochleas. Otolaryngol Head
48. Nager GT, Masica DN: Meningiomas of the cerebellopontine angle Neck Surg 98:72–81, 1988.
and their relation to the temporal bone. Laryngoscope 80:863–895, 77. Linthicum FH Jr, et al: Cochlear implant histopathology. Am J Otol
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49. Guzowski J, et al: Meningiomas of the temporal bone. 78. Nadol JB Jr, Hsu W: Histopathologic correlation of spiral ganglion
Laryngoscope 86:1141–1146, 1976. cell count and new bone formation in the cochlea following
50. Rietz DR, et al: Significance of apparent intratympanic menin- meningogenic labyrinthitis and deafness. Ann Otol Rhinol Laryngol
giomas. Laryngoscope 93:1397–1404, 1983. 100:712–716, 1991.
51. Maniglia AJ: Intra and extracranial meningiomas involving the 79. McElveen JT Jr, et al: Electrical stimulation of cochlear nucleus in
temporal bone. Laryngoscope 88(Suppl 12):1–58, 1978. man. Am J Otol 6(Suppl):88–91, 1985.
52. Leonetti JP, et al: Meningiomas of the lateral skull base: neuroto- 80. Arnesen AR: Presbyacusis—loss of neurons in the human cochlear
logic manifestations and patterns of recurrence. Otolaryngol Head nuclei. J Laryngol Otol 96:503–511, 1982.
Neck Surg 103:972–980, 1990. 81. Dublin WB: Central auditory pathology. Otolaryngol Head Neck
53. Belal A Jr, Sanna M: Pathology as it relates to ear surgery. Surg 95(Part 2):363–424, 1986.
I. Surgery of glomus tumours. J Laryngol Otol 96:1079–1097, 1981. 82. Schuknecht HF, Gulya AJ: Anatomy of the temporal bone with sur-
54. Myers EN, et al: Glomus jugulare tumor—A radiographic- gical implications, Philadelphia, Lea & Febiger, 1986.
histologic correlation. Laryngoscope 81:1838–1851, 1971. 83. Gacek RR: Arachnoid granulation cerebrospinal fluid otorrhea. Ann
55. Rosenwasser H: Monograph on glomus jugulare tumors. Arch Otol Rhinol Laryngol 99:854–862, 1990.
Otolaryngol 88:3–40, 1968. 84. Schuknecht HF, Zaytoun GM, Moon CN Jr: Adult onset
56. Winship T, Klopp CT, Jenkins WH: Glomus jugularis tumors. fluid in the tympanomastoid compartment. Arch Otolaryngol 108:
Cancer 1:441–448, 1948. 759–765, 1982.
57. Spector GJ, et al: Panel discussion: glomus jugulare tumors of the 85. Kemink JL, Graham MD, Kartush JM: Spontaneous encephalocele
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Laryngoscope 89:1628–1639, 1979. 112:558–561, 1986.
58. House WF, Glasscock ME III: Glomus tympanicum tumors. Arch 86. Schuknecht HF, Shinozaki-Hori N: Patterns of degeneration of the
Otolaryngol 87:550–554, 1968. facial nerve. Am J Otol 6(Suppl):47–54, 1985.
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87. Leonetti JP, Smith PG, Linthicum FH: The petrous carotid artery: 101. McCabe BF, Harker LA: Vascular loop as a cause of vertigo. Ann
anatomic relationships in skull base surgery. Otolaryngol Head Otol Rhinol Laryngol 92:542–543, 1983.
Neck Surg 102:3–12, 1990. 102. Mazzoni A: Internal auditory canal arterial relations at the porus
88. Steffen TN: Vascular anomalies of the middle ear. Laryngoscope acusticus. Ann Otol Rhinol Laryngol 78:797–814, 1969.
78:171–197, 1968. 103. Reisser C, Schuknecht HF: The anterior inferior cerebellar artery
89. Fisch U: Carotid lesions at the skull base. In Brackmann DE (ed.): in the internal auditory canal. Laryngoscope 101:761–766, 1991.
Neurological Surgery of the Ear and Skull Base. New York, 104. Nabors MW, et al: Delayed postoperative dural arteriovenous mal-
Raven Press, 1982. formations. Report of two cases. J Neurosurg 66:768–772, 1987.
90. Glasscock ME III, et al: Management of aneurysms of the petrous 105. Jungreis CA: Imaging case study of the month: pulsatile tinnitus
portion of the internal carotid artery by resection and primary from a dural arteriovenous fistula. Ann Otol Rhinol Laryngol
anastomosis. Laryngoscope 93:1445–1453, 1983. 100:951–953, 1991.
91. Brandt TW, Jenkins HA, Coker NJ: Facial paralysis as the initial 106. Buckwalter JA, et al: Pulsatile tinnitus arising from jugular megabulb
presentation of an internal carotid artery aneurysm. Arch deformity: A treatment rationale. Laryngoscope 93:1534–1539, 1983.
Otolaryngol Head Neck Surg 112:198–202, 1986. 107. Mueller DP, Dolan KD: Imaging case study of the month.
92. Sacks JG, Lindenburg R: Dolichoectactic intracranial arteries. Enlarged jugular foramen. Ann Otol Rhinol Laryngol 97:326–327,
Symptomatology and pathogenesis of arterial elongation and 1988.
distention. Johns Hopkins Med J 125:95–106, 1969. 108. Subotic R: The high position of the jugular bulb. Acta Otolaryngol
93. Stehbens WE: The pathology of intracranial aneurysms and their (Stockh) 87:340–344, 1979.
complications. In Fox JL (ed.): Intracranial Aneurysms, vol 1. 109. Overton SB, Ritter FN: A high placed jugular bulb in the middle
New York, Springer Verlag, 1983. ear: A clinical and temporal bone study. Laryngoscope
94. Gulya AJ, Kobrine AI, Davis DO: “Nonotologic” causes for oto- 83:1986–1991, 1973.
logic symptoms: Two unusual cases. Otolaryngol Head Neck Surg 110. Orr JB, Todd NW: Jugular bulb position and shape are unrelated
95:615–620, 1986. to temporal bone pneumatization. Laryngoscope 98:136–138,
95. Campbell JB, Pearman K, Nahl SS: Basilar artery ectasia: a rare 1988.
cause of sensorineural deafness. J Laryngol Otol 100:333–335, 111. Wilbrand HF, Stahle J, Rask-Andersen H: Tomography in
1986. Ménière’s disease why and how. Morphological, clinical and radi-
96. Musiek FE, Geurkink NA, Spiegel P: Audiologic and other clini- ographic aspects. Adv Otorhinolaryngol 24:71–93, 1978.
cal findings in a case of basilar artery aneurysm. Arch Otolaryngol 112. Adler JR, Ropper AH: Self-audible venous bruits and high jugular
Head Neck Surg 113:772–776, 1987. bulb. Arch Neurol 43:257–259, 1986.
97. Benecke JE Jr, Hitselberger WE: Vertigo caused by basilar artery 113. Kennedy DW, EI-Sirsy HH, Nager GT: The jugular bulb in oto-
compression of the eighth nerve. Laryngoscope 98:807–809, 1988. logic surgery: Anatomic, clinical, and surgical considerations.
98. Smith BD, Cunningham D: Basilar artery aneurysm: A cause of Otolaryngol Head Neck Surg 94:6–15, 1986.
vertigo. Otolaryngol Head Neck Surg 96:573–576, 1987. 114. Smith B, Myer CM III, Towbin RB: X-ray study of the month.
99. Applebaum EL, Valvasorri G: Internal auditory canal vascular Dehiscent jugular bulb. Ann Otol Rhinol Laryngol 96:232–233,
loops: Audiometric and vestibular system findings. Am J Otol 1987.
16(Suppl):110–113, 1985. 115. Jahrsdoerfer RA, Cail WS, Cantrell RW: Endolymphatic duct
100. Jannetta PJ, Moller MB, Moller AR: Disabling positional vertigo. obstruction from a jugular bulb diverticulum. Ann Otol Rhinol
N Engl J Med 310:1700–1705, 1984. Laryngol 90:619–623, 1981.
 Chapter
Hearing Loss
in Neurotologic Diagnosis

Outline 7
Types and Mechanisms of Hearing Loss Michael A. Novak, MD
Clinical Differentiation of
Hearing Loss: Cochlear Versus
Noncochlear
Presentation of Cerebellopontine Angle Lesions
Sudden or Fluctuating Hearing Loss
Normal Hearing
Progression of Hearing Loss
Hearing Loss Secondary to Lesions Other Than Acoustic
Neuroma
Summary

H earing loss and tinnitus, in their various manifesta-

tions, have historically been the hallmark of neuroto-
logic disorders. This chapter examines the characteristics
continued to be years rather than weeks or months. As
seen in this chapter, the incidence of auditory symptoms in
retrocochlear disorders is so great that a high index of sus-
and incidence of hearing loss in neurotologic disease picion should be maintained for any unexplained auditory
states. Much of the attention focuses on acoustic neuromas symptoms to encourage early evaluation and diagnosis of
(AN) (or vestibular schwannomas), since they are generally these disorders. At present, readily available, accurate
the most common neoplasm seen in neurotology practices audiologic and imaging techniques exist such that the
and also represent a prototype for hearing loss in neuroto- delay between onset of symptoms and diagnosis can be
logic diagnosis. shortened significantly if the awareness of patients and
The association of hearing loss with AN has long been health care providers can be heightened.
recognized. Harvey Cushing,1 in his classic 1917 mono- In this chapter, the types of hearing loss encountered in
graph on AN, wrote: neurotologic diagnosis, the pathophysiology of these
losses, and the incidence and exceptions are examined. As
The chronology of symptoms in the foregoing series of cases mentioned earlier, the primary focus is on AN diagnosis;
makes it clear that the clinical diagnosis of an acoustic tumor can other diagnostic entities will be mentioned to contrast
be made with reasonable assurance, only when auditory manifes-
tations definitely precede the evidence of involvement of other
with the AN presentation.
structures in the cerebellopontile angle. This is characteristic of Historically, since the first description of a definite AN
so large a percentage of the clinical histories that the exceptions seen at autopsy by Charles Bell2 in 1830, the recognition of
. . . merely serve to make it more striking . . . The significance of hearing loss as a diagnostic indicator for AN has undergone
this does not seem to have been heretofore sufficiently empha- a very slow evolution. Cruveilhier3 recognized the first com-
sized, nor was it appreciated when the study of these cases was plete clinical and pathologic description of AN, noting the
first undertaken, and it must be confessed that in most of the primary deafness in 1835. Stevens4 (1879) noted the first
clinical histories, the fact was hidden in a mass of symptomatic case of a tumor of the auditory nerve that was diagnosed
details, while in others it has only been brought to light by sub- prior to death based on symptoms. In 1904, Stewart and
sequent inquiries directed towards this particular matter. It Holmes5 described in the English literature a study of
would appear that patients rarely call attention to the premoni-
tory auditory symptoms, which are either forgotten or are not asso-
40 cases of extracerebellar and intracerebellar tumors and
ciated with the subsequent and more incapacitating phenomena, drew a distinction between the two based on symptoms. As
and it is equally certain that the sequences apt to be slighted by noted previously, Cushing’s book1 in 1917 still noted that
the questioner. the hearing loss of retrocochlear lesions was often recog-
nized very late and lost in the midst of other symptoms
The retrospective, frequent association of hearing loss because the tumors were diagnosed very late in their course.
with neurotologic problems has been noted many times Gradual improvements in audiometry and imaging have
throughout the succeeding 85 years; however, as noted led to earlier diagnosis of tumors. Therefore, especially in
even in very recent AN evaluations, the time between the the last decade, the clinical picture has slowly changed.
onset of symptoms and first evaluation, or more impor- Tumors are now being found earlier, and the degree of
tantly, between the onset of symptoms and diagnosis, has hearing loss associated with AN is also changing. In 1992

163
164 SYMPTOMS OF NEUROTOLOGIC DISEASE

Tos, Thomsen, and Charabi6 examined tumors diagnosed brainstem or direct lesions of the auditory nerve or central
in the period from 1983 to 1990 and compared them with pathways may also be causes.
tumors diagnosed from 1976 to 1983. In a stable popula- Most ANs arise from one of the vestibular nerves at the
tion with centralized medical care, the incidence of tumors junction of the proximal and distal nerves (also the junc-
was 9.4 per million in the second 7-year period versus 7.8 tion of the oligodendroglia and Schwann cells), usually
tumors per million in the first 7 years. Fewer tumors were near the porus acusticus internus. They occasionally arise
more than 4 cm in diameter in the second 7-year period, more distally in the internal auditory canal (IAC) in
but the total number of medium-sized and large tumors tumors that originate in the cochlear nerve.14 These slow-
was still the same. With the widespread use of gadolinium- growing lesions within the confines of the bony IAC will
enhanced magnetic resonance imaging (MRI) an increase cause slow compression of the cochlear nerve. The hear-
has occurred in diagnosis of tumors in the 1- to 10-mm ing loss will reflect this compression of auditory nerve
range. Associated with this earlier identification of tumors, fibers. The rate and amount of hearing loss will vary
the index of suspicion and criteria for work-up of hearing depending on the rate of growth of the tumor, the plastic-
loss has slowly changed. Numerous authors have noted an ity of the nerve, the consistency of the tumor, the location
increase in identification of tumors in the small to medium within the IAC, and the amount of early expansion into the
size range, and an associated increase in the number of CPA. The pure tone loss may be seen quite late in the
patients with symmetrical or normal hearing, or minimal course of the tumor growth, because as Schuknecht and
hearing loss at the time of diagnosis. Woellner15 demonstrated, if the organ of Corti is intact,
75% of the auditory nerve fibers need to be destroyed
before pure tone hearing is affected. This mechanism,
TYPES AND MECHANISMS more than most others, explains the typical, slowly pro-
OF HEARING LOSS gressive hearing loss of CPA tumors. This mechanism also
partially explains the middle- and high-frequency hearing
Hearing losses are generally characterized as conductive or losses usually associated with eighth nerve tumors. Sando16
sensorineural losses. Sensorineural losses can be further demonstrated anatomically that the high-frequency audi-
subdivided into sensory or cochlear losses and neural or tory nerve fibers from the basal turn of the cochlea are
retrocochlear losses. With rare exception, neurotologic located inferiorly and laterally all the way from the spiral
diseases cause a sensorineural type of hearing loss. ganglion to the cochlear nuclei in the brainstem, whereas
Conductive losses are rarely seen, except for glomus jugu- the middle and apical fibers twist about the axis from the
lare tumors, neuromas of the facial nerve with extension spiral ganglion to the cochlear nuclei. The apical fibers
into the middle ear, rare middle ear tumors, or actually make approximately 13/4 turns about the long axis
cholesteatomas or cholesterol granulomas. This chapter before reaching the brainstem. Low-frequency apical
focuses on the nonconductive or sensorineural losses. fibers also are more centrally located within the nerve.
Sensory or cochlear losses resulting from peripheral hair These differences of position within the nerve may allow
cell damage typically manifest by decreased sensitivity to for earlier involvement of the high-frequency basal fibers
pure tones, the phenomenon of recruitment7,8 intact auditory and a variable involvement of the middle- and low-
brainstem responses (ABR), loss of otoacoustic emissions frequency fibers from the middle and apical turns of the
(OAEs), and relatively preserved speech discrimination until cochlea. In addition to direct tumor compression of the
widespread hair cell damage has occurred.9 Neural or retro- auditory nerve, Badie and colleagues17 proposed a theory
cochlear losses typically show decreased speech discrimina- of increased pressure in the IAC as a cause for tumor-
tion out of proportion to the relatively unaffected pure related hearing loss. They measured the intracanalicular
tones,9 auditory fatigue or tone decay,10 abnormal or absent pressure in 15 patients undergoing tumor resections.
ABR,11 and intact OAEs.12 As widespread hair cell damage Intracanalicular pressure directly correlated with the
occurs in cochlear losses, speech discrimination will deterio- amount of tumor in the IAC. There was a strong trend
rate, but in neural losses, as increasing numbers of auditory toward lower IAC pressure in patients with better preop-
nerve fibers are damaged, pure tone thresholds will elevate. erative hearing, but the differences did not reach statistical
Theoretically, retrocochlear lesions should produce the pic- significance.
ture of a pure neural loss, but in reality they often appear to Vascular compression as a cause of the hearing loss in
be cochlear in nature or to show elements of both types of AN has also been theorized. Since the anterior inferior
hearing losses on objective, behavioral, or speech perception cerebellar artery loops into the internal auditory meatus a
auditory testing.13 variable distance, and the internal auditory artery arises
The exact cause of hearing loss in most neurotologic from the loop of the anterior inferior cerebellar artery
lesions is unknown; however, in tumors of the eighth nerve about 80% of the time,18 the blood supply to the cochlea
and cerebellopontine angle (CPA), a number of mecha- should be at risk with expanding lesions of the IAC. The
nisms have been theorized. Direct eighth nerve compres- internal auditory artery divides into the cochlear-anterior
sion, stretching of the nerve, vascular compression or vestibular and vestibulocochlear arteries within the inter-
occlusion of the blood supply to the eighth nerve or blood nal auditory meatus, so lesions of the internal artery should
supply to the cochlea, damage to the cochlear efferents, result in vertigo or in very rapid deterioration of cochlear
biochemical changes within the inner ear, and hemorrhage hair cell function, especially in the low frequencies since
within the nerve or into the tumor all may have a place in the cochlear apex blood supply is the most tenuous.13,19
the etiology of hearing loss. In other neurotologic entities, These symptoms are not typically seen in AN. In fact, sel-
neurovascular compression of the eighth nerve near the dom is a cochlear pure tone hearing loss seen before
 Hearing Loss in Neurotologic Diagnosis 165

decreased speech discrimination or neural type changes. reversible biochemical changes but permanent hair cell
Also, acute vascular compression should cause electro- injury.
cochleographic changes identified by a decreased cochlear Grabel and colleagues27 suggested that the chronic
microphonic, which is not often seen.20 effect of high tumor volume within the infratentorial com-
In an attempt to explain the different types of hearing partment may also play a role in AN hearing loss when
losses seen in AN, Lehnhardt21 suggested a theory involv- they showed a strong positive correlation between maxi-
ing both myelin and axon compression damage. He theo- mum tumor volume and prolonged ABR interpeak laten-
rized that early in the course of compression, the myelin cies for waves III through V following stimulation of the
damage might be the only lesion, allowing for tone decay nontumor side. This suggests tumor volume-generated
and acoustic reflex decay without recruitment. Auditory distortion as an additional factor in tumors that extend
brainstem evoked responses would also be delayed. This into the CPA.
would be the typical picture of AN. Later on, as myelin Sekiya and colleagues28 demonstrated in dogs that gen-
and axon compression both become involved, the ABR tle traction on the eighth nerve in the CPA could lead to
would be delayed, still without recruitment. If the tumor hemorrhages within the nerve and secondary auditory
compression changes, for instance, in cessation of tumor deficits. This mechanism may help explain the hearing loss
growth or recovery from intratumor hemorrhage, enough associated with other tumors within the CPA that cause
axons may remain to allow for adequate nerve conduction nerve distortion without significant compression. It may
and remyelinization may occur. Therefore recruitment also help explain the tinnitus and hearing loss that may
may be positive, the ABR may be positive, but tone decay accompany neurovascular compression of the eighth nerve
may not occur. in the CPA.29
Lesions of the olivocochlear system or auditory effer- Direct auditory nerve or brainstem auditory pathway
ents22 have also been implicated in early hearing losses lesions30 have also been associated with neurotologic hear-
with auditory distortion, but little pure tone threshold ing loss in cases of multiple sclerosis (MS).
increase. Deficits of the efferent system will affect the The hearing losses associated with neurotologic entities,
outer hair cells of the cochlea, allowing for difficulty with and especially those of AN, most likely involve multiple
speech understanding in noise and the subjective sensation mechanisms, any or all of which may be seen in any one
of distortion while having little effect on the pure tone lesion. The variety of mechanisms possible for the hearing
hearing thresholds. Outer hair cell function as evaluated loss of neurotologic lesions also helps explain the variety of
by otoacoustic emissions should be reduced or absent in hearing losses that may be seen.
ears affected by cochlear hearing losses.12 Distortion prod-
uct otoacoustic emissions (DPOAEs) should be normal in
AN patients if the hearing thresholds are better than 45 to
50 dB HL and the loss is purely retrocochlear (neural CLINICAL DIFFERENTIATION
compression), and DPOAEs should be abnormal in losses OF HEARING LOSS: COCHLEAR
that have a cochlear (vascular or inner ear biochemical) VERSUS NONCOCHLEAR
component. Telischi12 reported on 97 patients with AN
who underwent DPOAE testing. He found that from 37% Until the past two decades, the literature reflected efforts
to 57% of tumors were classified as having a cochlear loss to diagnose AN by the characteristics of the hearing loss it
pattern, and 41% to 59% had a retrocochlear pattern induces. As mentioned under the discussions of the differ-
depending on the analysis method used. He concluded ent mechanisms of hearing loss, the loss from an AN or
that the majority showed evidence of reduced outer hair other CPA lesion was considered noncochlear or retro-
cell function in at least one frequency. The effects on the cochlear. The characteristics of a cochlear loss should
OAEs did not reverse after tumor resection even when reflect hair cell damage with an intact eighth nerve (i.e.,
other behavioral and objective hearing measures recruitment, pure tone hearing loss with intact discrimina-
improved, implying a nonreversible cochlear or efferent tion, evidence of hair cell damage, and the absence of audi-
pathway damage. These findings are compatible with pre- tory fatigue). A number of test batteries were developed,
vious studies that have demonstrated biochemical and all with a high degree of false negativity. No one test, until
magnetic resonance image (MRI) changes in the ipsilateral the ABR, had a sufficiently high rate of diagnostic selectiv-
cochlea of some AN patients. As early as 1950, Dix and ity to stand on its own or to guide further radiologic eval-
Hallpike23 found changes in the characteristics of peri- uation. Now the role of the ABR, in the MRI era, is
lymph in AN patients. Other authors24,25confirmed these changing.
changes. Somers and coworkers26 reported on MRI studies The phenomenon of auditory fatigue has been used to
in AN and meningiomas, and showed increased postoper- try to differentiate cochlear versus retrocochlear losses.
ative hearing preservation in ears with normal intral- The stapedial reflex decay or its absence has also been used
abyrinthine and lateral IAC fluid characteristics versus ears diagnostically for this purpose. Thomsen and coworkers31
with hypointense perilymph and fundus cerebrospinal noted positive stapedial reflex decay or an absence stape-
fluid (CSF) images. They theorized that an arterial vascu- dial reflex in 78% of their 59-patient series in 1983.
lar compromise in the IAC secondary to mechanical Kanzaki and colleagues32 found absent stapedial reflex, ele-
obstruction by the tumor leads to reversible and irre- vated threshold of the reflex, or positive decay in approxi-
versible intracochlear changes. Some MRI changes mately 75% of their 132-patient series. The absence of the
returned to normal after tumor removal, but many times reflex or positive decay did not depend on tumor size.
OAEs do not revert to normal, again suggesting possible Moffat and coworkers33 identified only one of their 49
166 SYMPTOMS OF NEUROTOLOGIC DISEASE

CPA tumor patients as having a normal stapedial reflex the cochlear traveling wave to initiate the response. This
pattern. would account for the reduced synchronization of firing of
Hirsch and Anderson10 demonstrated 73 of 75 AN nerve fibers without necessarily a change in the hearing
patients as having no stapedial reflexes or positive reflex itself.
decay, and Harner and Laws34 demonstrated 49 of 61 AN Historically, the ABR has changed the evaluation of uni-
patients as having positive reflex decay or absent stapedial lateral or asymmetrical sensorineural hearing losses, but
reflexes. Anderson and colleagues35 examined 17 patients the trend is toward finding more normal ABRs with the
with CPA tumors and hearing thresholds of less than 60 earlier identification of very small or intracanalicular
dB. Twelve of the tumors were ANs and five were not. Six lesions. In the past decade gadolinium-enhanced MRIs
patients had normal hearing. The stapedial reflex decay have become more widely available, and tumors smaller
was positive in all 10 patients who attained reflex thresh- than 15 mm are more routinely identified. In tumors less
olds. than15 mm, and especially those that are intracanalicular,
Thomsen and coworkers31 further tried to differentiate there may be insufficient neural compression to cause a
between AN hearing losses and that due to other causes. retrocochlear hearing loss as defined by an abnormal ABR.
They compared three groups of patients. The first group Table 7-1 shows ABR results for several series of small
had AN verified at surgery, the second group was evaluated ANs. ABR continues to show a consistent asynchronous,
for an AN but found to be negative, and the third group retrocochlear pattern in tumors >2 cm but, in intracanalic-
was diagnosed with Ménière’s disease. In their comparison ular tumors, a much greater percentage will show a normal
of the three groups, the AN patients had significantly (or cochlear) pattern.
worse hearing at high frequencies, significantly worse The ABR is not specific for AN. In the series of Laird
speech discrimination, significantly less recruitment, but and coworkers38 and of Granick and colleagues39 six out of
no significant difference in stapedial reflex decay. They did six meningiomas of the posterior fossa that had an ABR
find a significantly greater incidence of a progressive hear- were positive in each series. House and Brackmann37 also
ing loss as the first symptom of the disorder. Again, gross demonstrated that only about 75% of patients with CPA
group distinctions were noted between AN patients and lesions that were not ANs had abnormal ABRS. Marangos
other types of sensorineural hearing losses, but on an indi- and coworkers40 found 23.5% of meningiomas had a
vidual basis, the cochlear versus noncochlear distinction is normal ABR.
difficult to use as a diagnostic criterion. The diagnostic accuracy and sensitivity of the ABR is
Beginning in the 1970s, diagnosis of neurotologic not matched by electrocochleography (ECoG).
lesions by the identification of retrocochlear hearing loss Eggermont and colleagues20 evaluated the use of ECoG in
began to take on a new picture with the advent of the ABR. retrocochlear lesions. They found the slope of the action
Selters and Brackmann,36 House and Brackmann,37 and potential amplitude versus intensity function similar in
Clemis and McGee11 in the late 1970s began to demon- range and dependent on the action potential threshold, as
strate the high rate of abnormality of the ABR in AN it was in Ménière’s disease. Narrowband ECoG analysis
patients. These authors demonstrated 92% to 98% sensi- suggested the same number of viable neurons in AN
tivity for absent or abnormal ABR in AN patients. patients as in normal or recruiting cochlear losses. They
Eggermont and colleagues20 suggested that the abnormal felt that for tumors with milder losses (those <60 dB)
ABR was probably from abolition of the synchronized fir- the loss may be more cochlear in origin, possibly a slow
ing of nerve fibers rather than a prolongation of the nerve compression of the vascular supply with a secondary meta-
conduction velocities. This was especially true for the bolic dysfunction accounted for the hearing loss in AN
high-frequency fibers, which run around the outside of the patients.
auditory nerve, versus the middle and apical turn fibers, As mentioned previously, even though DPOAEs logi-
which are positioned more toward the middle of the nerve cally should help differentiate cochlear from retrocochlear
and possibly are less disturbed in the early stages of tumor causes of hearing loss, in CPA lesions about half demon-
growth. The responses from the middle and apical turns strated both patterns so DPOAEs have therefore not been
are longer in latency, due to the greater time needed for helpful as a diagnostic tool.

TABLE 7-1. Tumors with Normal Auditory Responses

% Intracanalicular % Tumors % Tumors >2 cm
Tumors with Normal <15 mm with with Normal ABR
Series Year ABR Normal ABR ABR Latency & Morphology

Grabel et al.27* 1991 30

Levine48 1991 37
Gordon75* 1995 31 15.5
Chandrasekhar73* 1995 16.9
Zappia76* 1997 11
Marangos40† 2001 41.7 3.3‡

*Normal ABR=Wave V interaural or interpeak I-V latency difference < 0.2 msec.
†
Normal ABR=Wave V interaural difference <0.3 msec or interpeak I-V difference < 0.2 msec.
‡
Tumor >25 mm.
 Hearing Loss in Neurotologic Diagnosis 167

PRESENTATION OF CEREBELLOPONTINE and Selesnick and colleagues43 have demonstrated shorter

ANGLE LESIONS times from onset to diagnosis in intracanalicular and small
tumors than in medium and large tumors.
In this section, the typical presentation of CPA tumors is The signs and symptoms present at diagnosis are almost
examined. The focus, again, is on AN, since few differ- exclusively auditory, and only rarely are other neurologic
ences exist in the presentation of hearing loss from other symptoms found in the absence of auditory symptoms.
tumor types found in this area. Significant differences, Table 7-4 demonstrates the signs and symptoms at the
when present, are identified in this section, and hearing time of diagnosis. The percentage of patients with hearing
losses related to other nontumor diagnostic entities are loss or tinnitus (or both) at the time of diagnosis is about
discussed in later sections. 95% or greater in AN patients even in patients with small
The typical picture or presentation of a CPA tumor, as tumors; however, hearing loss or tinnitus was found in
can be imagined from gradual compression of a slow- 60% of meningioma patients by Laird and coworkers38
growing mass, is that of a very slowly progressive sen- and in 75% by Granick and colleagues.39
sorineural hearing loss with speech discrimination much Unilateral tinnitus at diagnosis is identified in 56% to
worse than would be expected for the given degree of pure 85% of patients with AN. Again, in the meningioma series,
tone hearing. As mentioned by Cushing,1 the hallmark of tinnitus was identified in only 34% to 50% of patients at
AN is auditory dysfunction with hearing loss or tinnitus. the time of diagnosis. The hearing loss identified is usually
The incidence is so high that absence of these symptoms is moderately severe, with typical pure tone averages (PTA)
striking. As seen in Table 7-2, a number of authors verify of 50 to 55 dB usually worse in the high frequencies. The
that the initial or presenting symptom is hearing loss with percentage of patients with a PTA worse than 80 dB was
or without tinnitus in about 80% of patients. Tinnitus as 15% to 35%. A small correlation may exist between the
the only presenting symptom is found in about 7% of degree of hearing loss and the amount of time symptoms
patients, and hearing loss without tinnitus is identified in have been present, but such a wide variation exists that
between 40% and 80%. generalization is difficult. Other auditory symptoms such
The picture changes when examining initial or present- as aural fullness are occasionally identified; however, aural
ing symptoms versus symptoms present at the time of fullness is rarely found in the absence of other auditory
diagnosis for two reasons: one of which is the long delay symptoms or signs. The symptoms of hearing loss or tin-
between onset of symptoms and diagnosis, and the other is nitus are independent of tumor size, but there is a definite
the proportion of patients with subjectively normal hear- trend toward better hearing in tumors less than 1 cm.
ing, but identifiable audiometric abnormalities on exami- Atypical presentations, such as normal hearing and sudden
nation. As seen in Table 7-3, the average number of years or fluctuating hearing loss, are examined separately in a
from onset of symptoms to diagnosis is about four. This later section.
has changed somewhat as diagnostic methods and aware- Classically, the patient with an AN or other CPA tumor
ness have improved; however, a long delay is still identi- has been described as having a high-frequency sloping
fied. Time from onset of symptoms to diagnosis is less sensorineural hearing loss. Table 7-5 outlines the shape of
than 1 year in only about 20% of patients. Delays of 7 to the audiometric configuration in several large series of
10 years are not uncommon. In Table 7-3, the reports by patients. The category of high tone loss is broken down in
Glasscock and coworkers41 and Hirsch and Anderson10 some cases to an abrupt loss, in which hearing shows a
reflect diagnostic delays only in patients who have moder- steep drop of at least 15 dB at frequencies greater than
ate hearing losses or better. All severe and profound losses 2000 Hz, or a gradual high-frequency loss, in which the
have been excluded. This delay should decrease with the hearing threshold increases less than 15 dB per octave.
advent of the MRI. Using MRI, Kanzaki and colleagues42 The U-shaped configuration has the greatest hearing loss

TABLE 7-2. Initial or Presenting Symptoms of Acoustic Neuroma

No. with Tinnitus, No. with Hearing
No. of No. with Hearing No. with Tinnitus with or without Loss and/or Vertigo
Authors Year Patients Loss Only (%) Only (%) Hearing Loss (%) Tinnitus (%) (%)

Cushing1 1917 30 25 (83)

Erickson et al.78 1965 129 45 (35) 15 (12) 80 (63)
Ellis and Wright78 1974 214 90 (42) 8 (4) 160 (75)
Hart and Davenport79 1981 20 14 (70)
Thomsen et al.31 1983 59 47 (80) 4 (7) 51 (87)
Thomsen and Tos58 1990 300 245 (82) 22 (7) 267 (89)
Kanzaki et al.42 1991 132 79 (60) 66 (50)
Levine et al. (>4 cm)80 1991 19 18 (95) 5 (26)
Levine et al. (<4 cm)80 1991 8 7 (88) 4 (50)
Selesnick et al.43 1992 136 84 (67) 45 (36) 2 (3)
Dornhoffer et al.44* 1994 70
Chandrasekhar et al.73 1995 197 128 (65) 31 (16) 159 (81)
Magdziarz et al.48 2000 369

*All tumors <2 cm.

168 SYMPTOMS OF NEUROTOLOGIC DISEASE

TABLE 7-3. Duration of Symptoms from Onset to Diagnosis

No. of Patients with Durations of Symptoms
No. of Years from
Authors Year Patients Onset to Diagnosis <6 mo. 7–12 mo. 1–3 yr. >3 yr.

Erickson et al.77 1965 129 4.6

Johnson45 1977 500 84 (17) 25 (5) 202 (40) 188 (38)
Mathew et al.57 1978 206 43 (21)* 60 (29) 103 (50)
Hirsch and Anderson10† 1980 96 2 26 (27) 11 (11) 20 (21) 39 (41)
Glasscock et al.81 pre-1975 100 3.3
Glasscock et al.81 post-1975 100 2.4
Glasscock et al.41‡ 1987 47 1.2
Thomsen and Tos58 1990 300 7.1§ 67 (22)*
Kanzaki et al42 1991 119 4.1||
Kanzaki et al.42 1991 13 2.2||
Selesnick et al.43 1992 126 3.9

*Symptoms for 0-12 months.

†
All patients had pure tone average < 60 dB.
‡
All patients had pure tone average < 50 dB.
§
Average for patients with symptoms > 1 year.
||
119 patients excluding those with intracanalicular tumors; 13 patients with only intracanalicular tumors.

at 2000 Hz. The peak configuration has the best hearing small and intracanalicular tumors had a U-shaped audio-
thresholds at 2000 Hz, with increasing losses at the low metric configuration.
and high frequencies. As can be seen, the majority of losses The degree of hearing loss and speech discrimination
are of the high-frequency nature with abrupt high tone deficits varies widely, but historically patients have had
losses a major proportion. If the abrupt and gradual high- moderate to severe pure tone losses with poor speech dis-
frequency losses are combined, they account for anywhere crimination scores (SDS) on presentation. Table 7-6 out-
from 32% to 68% of the configurations, with the majority lines the findings from several large series of tumor
between 50% and 60%. However, large minorities of con- patients with audiometric examinations. In AN, anywhere
figurations are flat or U-shaped. The percentages vary from 3% to 22% of patients have three frequency PTA
from 16% to 47%, with most lying in the 20% to 30% (500, 1000, and 2000 Hz) thresholds better than 20 to 25
range. Ten to 25% of patients have severe to profound dB, and 16% to 45% of patients have PTA worse than 70
hearing losses, with PTA greater than 80 dB at the time of dB. The figures of Kanzaki and colleagues32 include a PTA
their initial audiogram. Low tone losses are very uncom- for five frequencies from 250 to 4000 Hz. Their category
mon. Other configurations of audiograms can be found, of 18% of patients in the better hearing group comprises
but were too few to be classified into one of the character- patients with PTA between 0 to 30 dB. This group roughly
istic shapes. Generally, no typical shape is found for any corresponds to the other groups, because the hearing at
one type of tumor; however, Kanzaki and colleagues32 and 4000 Hz is characteristically considerably worse than that
Dornhoffer and coworkers44 noted that 20% to 22% of in the nontumor ear in AN patients. Of note is the series

TABLE 7-4. Signs and Symptoms at the Time of Diagnosis of Acoustic Neuroma or Meningioma
No. of No. with No. with Hearing Mean PTA No. (%) with PTA Vertigo
Authors Year Patients Tinnitus (%) Loss and/or Tinnitus (%) or SRT or SRT >80 dB (%)

Erickson et al.77 1965 129 1 %* 125 (98)

Ellis and Wright78 1974 214 206 (96)
Clemis and Mastricola82 1976 121 120 (99) 50 dB 16 (13)
Johnson44 1977 500 474 (95) 56 dB 75 (15)
Mathew et al.57 1978 206 135 (66) 199 (97) 60 (29)
Harner and Laws34 1983 131 92 (70) 128 (98) 52 dB
Thomsen and Tos83 1988 300 291 (97) 55 dB 105 (35)
Moffat et al.33 1989 66 64 (97) 17 (25)
Kanzaki et al.32 1991 132 112 (85) 125 (95) 59 (45)
Selesnick et al.43 1992 126 71 (56) 107 (85) 46 dB 19 (15)
Laird et al.†38 1985 20 10 (50) 12 (60)
Granick et al.†39 1985 32 11 (34) 24 (75)
Dornhoffer et al.‡44 1994 70 45 (60) 66 (95) 29.2 27 (39)
Chandrasekhar et al.73 1995 197 157 (80) 171 (87) 112 (57)
Magdziarz et al.48 2000 369 290 (79) 346 (97) 77 (21)

*Tinnitus without hearing loss.

†
All tumors were posterior fossa meningiomas.
‡
All tumors <2 cm.
PTA, pure tone average; SRT, speech reception threshold.
 Hearing Loss in Neurotologic Diagnosis 169

TABLE 7-5. Audiogram Shape for Acoustic Neuroma Patients

Abrupt Gradual No. (%) of Patients With:
No. of High Tone High Low Tone Peak- PTA
Authors Year Patients Loss No. (%) Tone Loss Loss Flat Loss U-Shaped Shaped >80 dB

Clemis, Mastricola82 1976 121 91 (75)* 15 (12) 16 (13)

Johnson45 1977 500 282 (66)†‡ 39 (9) 55 (13) 49 (12) 75 (15)
Hirsch, Anderson10 1980 69 39 (57) 5 (7) 6 (9) 9 (13) 10 (15)
Thomsen et al.31 1983 59 35 (59) 7 (12) 2 (4) 15 (25)
Brunás et al.84 1984 141 21 (18) † 57 (50) 17 (15) 12 (11) 27 (19)
Glasscock et al.41 1987 47§ 25 (53) 22 (47)
Moffat et al.33 1989 66 37 (56) ‡ 9 (14) 1 (2) 17 (25)
Kanzaki et al.32 1991 132 26 (20) 16 (12) 34 (26) 7 (5) 15 (11)
Dornhoffer et al.44|| 1994 70 50 (71) 3 (4) 13 (19)
Saunders et al.51¶ 1995 92 48 (52) 1 (1) 17 (18) 18 (20) 9 (10)

*Combines abrupt high tone and flat losses.

†
Based on patients with recordable audiograms (%).
‡
Combines abrupt and gradual high tone losses.
§
All patients had PTA <50 dB.
||
All tumors <2 cm.
¶
Patients with sudden hearing loss only.
PTA, pure tone average.

of meningioma patients. Laird and colleagues38 identified had a SDS better than 60%. Again, the meningioma
8 of 15 patients, or 53%, as having a PTA of 0 to 20 dB. patients experienced less effect on their speech discrimina-
Granick and coworkers39 identified 6, or 26%, of their tion than the AN patients. Laird and colleagues38 found
group with a PTA of 0 to 20 dB. that 40% of meningioma patients had discrimination better
As mentioned earlier, characteristically, speech discrim- than 90%, 47% had discrimination better than 80%, and
ination for the eighth nerve tumor patients is quite poor. 60% of their patients had discrimination better than 60%.
Table 7-6 also lists the SDS for several large series of sub- Historically, no correlation has been found between the
jects with eighth nerve lesions. The mean SDS is very degree of hearing loss or speech discrimination deficit and
poor, with the best being from the series of meningioma tumor size.13,46 Beginning in the MRI era, however, a trend
patients of Laird and colleagues.38 For an SDS greater is developing toward better hearing thresholds and SDS in
than 90%, the Kanzaki series32 found 13% of patients in patients with very small tumors. Selesnick and coworkers43
that category, and Harner and Laws34 found 9 of 117 found that patients with tumors less than 1 cm in diameter
patients, whereas, in the Dornhoffer series of subjects with had average pure tone loss of 40 dB, and 50% of those
small tumors,44 37% had normal discrimination and the patients had a SDS of greater than 81%, and the series of
mean speech score was 82%. Speech discrimination less than 2-cm tumors of Dornhoffer44 found 37% with
greater than 80% was found in 24% of subjects in the normal speech discrimination. In patients with medium
series by Kanzaki and colleagues,32 18% of Harner and and large-sized tumors, the average speech reception
Law’s,34 and in 30% in the series by Selesnick and cowork- threshold was 47 and 58 dB, respectively, and only 25% of
ers.43 In the older series by Johnson,45 only 24% of patients patients with medium or large tumors had a SDS better

TABLE 7-6. Degree of Hearing and Discrimination Loss in Patients with Acoustic Neuromas or Meningiomas
No. (%) with Speech
No. (%) with PTA or SRT Discrimination
No. with Mean
Author Year Audiogram 0–20 0–25 20/25–45 ≥90% ≥80% ≥60% Discrimination

Johnson45 1977 500 120 (24)

Josey85 1980 52 11 (21) 15 (29)* 56%
Harner and Laws34 1983 117 14 (12) 11 (9) 22 (18) 8%
Thomsen et al.58 1990 300 9 (3) 48 (16)
Kanzaki et al.32 1991 132 24 (18)† 17 (13) 32 (24) 37%
Selesnick et al.43 1992 130 29 (22) 39 (30) 53%
Laird et al.38‡ 1985 15 8 (53) 3 (20) 6 (40) 7 (47) 9 (60) 76%
Granick et al.39‡ 1985 23 6 (26)
Dornhoffer et al.44§ 1994 70 4 (6) 26 (37) 82%

*PTA >56 dB.

†
5 frequency PTA for 0.25-4 kHz <30 dB.
‡
All tumors were posterior fossa meningiomas.
§
All tumors <2 cm.
SRT, speech reception threshold; PTA, pure tone average.
170 SYMPTOMS OF NEUROTOLOGIC DISEASE

than 81%. As is seen in the discussion of CPA tumor loss in 15%, and a low tone loss in 6%. The degree of hear-
patients with normal hearing,47–49 a poor correlation ing loss did not correlate with tumor size. Saunders and
occurs between normal hearing and tumor size, though a colleagues51 also showed a very low incidence of
definite trend exists toward better hearing in intracanalic- low-frequency losses especially compared with sudden
ular tumors. hearing losses not secondary to tumors. Pensak and
The very poor SDS for the tumors in general supports a coworkers50 suggested the possibility of a vascular occlu-
hearing loss mechanism of neural compression. Thomsen sion with degeneration of the organ of Corti, although the
and colleagues31 discussed the concept that discrimination findings are too inconsistent to adequately differentiate the
at high presentation levels is primarily an inner hair cell vascular occlusion effect from rapid eighth nerve compres-
function, and 95% of the fibers in the auditory nerve orig- sion due to hemorrhage in a tumor. In the series by Ogawa
inate in the inner hair cells. Therefore, the neural com- and colleagues,52 29 patients, or 22%, had a sudden hearing
pression would inhibit inner hair cell function with the loss or exacerbation of an existing loss. They felt that the
resultant poor discrimination, especially at increasing characteristics of AN with sudden hearing loss differed
presentation levels. from other AN presentations in several ways: (1) smaller
tumor, (2) shorter duration after onset, (3) lower incidence
of dizziness or other neurologic symptoms, (4) a trough-type
Sudden or Fluctuating Hearing Loss audiogram configuration, and (5) a higher incidence of a
Though not common, space-occupying lesions of the CPA normal caloric response on electronystagmography. A
and IAC can present as a sudden hearing loss or as a sud- higher incidence of the subjective symptom of aural
den exacerbation of an existing hearing loss. Table 7-7 fullness was also noted. Of note, of their 14 patients with
summarizes the incidence of sudden hearing loss in a num- intracanalicular tumors, 5, or 36%, had a sudden hearing
ber of large series of patients with AN and other CPA loss. They questioned a vascular cause and supported a
tumors. As can be seen, about 10% (4% to 26%) of patients cause from nerve compression, due to the high incidence of
with AN present with a sudden hearing loss. In those man- midfrequency losses and the low incidence of dizziness.
uscripts that specified the sudden hearing loss as a pre- Berg and colleagues53 identified 13 of 133 patients with
senting symptom, the incidence is 7% to 14%, with an a sudden sensorineural hearing loss, 4 of whom recovered
exacerbation of an existing loss occurring in 7% or 8%. A some auditory function. In evaluating their series of sud-
number of the other series did not differentiate specifi- den hearing loss patients, no clinical distinction was noted
cally, and in fact Selesnick and colleagues43 combined both between sudden hearing loss caused by tumors and that
types of sudden loss for the incidence of 26%. The large caused by other disease states, other than a positive ABR
series by Pensak and coworkers50 described 77 patients (69 test. Saunders and coworkers51 felt that associated symptoms
had AN and 7 had meningiomas) who complained of a of pain, facial paresthesias, or unilateral tinnitus preceding
sudden hearing loss. Of the 77, 25 patients had a PTA for the sudden hearing loss might suggest a tumor. Hallberg54
the frequencies from 500 to 4000 Hz of better than 35 dB, and Shaia and colleagues55 found a 0.6% and 0.8%, respec-
and of these 25 patients, 11 had an SDS of better than 88%. tively, incidence of AN in a large series investigating sudden
Two additional patients of the 77 had an SDS better than sensorineural hearing loss from any cause. Saunders and
88%, even though their PTA fell between 35 and 60 dB. coworkers51 studied only patients with sudden hearing losses
Twelve of the 77 patients had a PTA worse than 60 dB. who had MRIs, and found an incidence of tumors of 2.7%.
They described a configuration of the audiogram as a high Again, the distinction between hearing loss caused by
tone loss in 60%, a flat loss in 19%, a U-shaped (trough) vascular disease or neural compression is blurred. Certainly,

TABLE 7-7. Cerebellopontine Angle Tumors Presenting as Sudden Hearing Loss

No. with Sudden Hearing No. with Sudden Time From
No. of Loss or Sudden Change in Change in Existing No. with Recovery Onset to Diagnosis
Author Year Patients Existing Loss (%) Loss (%) or Fluctuation (%) (mo.)

Higgs86 1973 44 4 (9)

Ellis and Wright78 1974 214 11 (5)
Mathew et al.57 1978 206 9 (4)
Hirsch and Anderson10 1980 96 7 (7)
Thomsen et al.31 1983 59 5 (8)*
Pensak et al.50 1985 506 77 (15) 39.8
Berg et al.51 1986 133 17 (13) 4/17 (23)
Kanzaki 87 1986 90 12 (13)* 6 (7)
Thomsen and Tos83 1988 300 21 (7)*
Ogawa et al.52† 1991 132 19 (14)* 10 (8) 41.3
Selesnick et al.43 1992 136 33 (26)
Chandrasekhar et al.73 1995 197 26 (13)
Saunders et al.51 1995 1204 79 (5)
Aslan et al.88 1997 192 14 (7.3) 6/14 (43)
Magdziarz et al.48 2000 369 38 (10.3)

*Initial symptom was sudden hearing loss.

†
Also Kanzaki.
 Hearing Loss in Neurotologic Diagnosis 171

aspects of both are involved in sudden hearing loss, but so speech discrimination. This finding is not generalized
are aspects that mitigate against one or the other causes, throughout all series, but the majority of authors report a
suggesting a combination of mechanisms in the majority of decrease in the number of patients with normal discrimi-
these losses. nation versus the number with normal PTA.
It is interesting that, even with a sudden change in hear- Several series used 4000 Hz in their PTA, which seems to
ing, the delay between onset of symptoms and diagnosis is be a significant differentiating factor between normal and
more than 3 years on average. The series by Pensak and abnormal hearing. The hearing loss at 4000 Hz is often a
colleagues50 had an average time of 39.8 months between marker for unilateral losses in cases of AN, whereas a PTA,
onset of symptoms to diagnosis, and the series by Ogawa based only on 500, 1000, and 2000 Hz, may misidentify
and coworkers56 and the one by Kanzaki and colleagues42 patients, calling them normal when they would otherwise fit
had an average time of 41.3 months. In some cases, the the category of a someone with a unilateral sensorineural
patients had presented themselves for evaluation, but a loss. Two series24,58 looked at hearing loss at 4000 Hz. In the
diagnosis of AN was not made until much later. In the series by Beck and colleagues,47 of 21 patients with normal
Saunders and colleagues51 series, patients who were not hearing, the pure tone thresholds at 4000 Hz averaged
diagnosed in the 6 months after onset of hearing loss often 35 dB on the ear with the tumor and averaged 14 dB on the
went more than 2 years before diagnosis. tumor-free ear; while in the series of Selesnick and col-
leagues,43 85% of patients had an asymmetry of greater than
15 dB between the two ears at 4000 Hz.
Normal Hearing Interestingly, in the series that reported the symptom of
Patients with CPA tumors can present with normal hear- subjective hearing loss, most showed a very high percent-
ing. This fact has been recognized for some time, but has age of patients reporting a subjective hearing loss, even
become more significant in the current climate of early though the audiometric examination was normal.
identification and hearing preservation surgery for these Anywhere from 20% to 70% of the patients with normal
tumors. Table 7-8 represents the summation of a number audiometric examinations had a subjective hearing loss,
of series on patients with AN and other CPA tumors that 40% to 70% had tinnitus, and 16% to 66% demonstrated
have presented with normal hearing. The definition of dizziness. In the series by Beck and colleagues,47 only 1
normal hearing varies with the different series. As can be patient out of 408 was truly asymptomatic at the time of
seen, the number of patients with a PTA or speech recep- diagnosis. Magdziarz and coworkers48 reported an inci-
tion threshold less than 20 or 25 dB varies from 3% to dence of 2.7% with completely normal hearing (PTA <20
22%; however, when patients with an SDS greater than or dB, discrimination >90%, and interaural differences <10
equal to 90% are included, the number with normal PTA dB at any frequency), but again at least 40% of that group
or speech reception threshold and normal speech discrim- had subjective hearing loss or tinnitus (and 70% had an
ination is only 4% to 12%. The majority of series demon- abnormal ABR). Therefore even the patient with a normal
strate about a 5% to 7% incidence of truly normal hearing. audiometric examination frequently had objective or sub-
Generally, there was little correlation of normal hearing jective symptoms that were otologic in nature. When
and tumor size. adding the objective and subjective symptoms, only the
The decrease in SDS in AN patients is again seen to be very rare patient is truly asymptomatic on presentation,
out of proportion to the pure tone findings. As seen in the though this will probably change with the common use of
series of Mathew and colleagues,57 Selesnick and cowork- MRI for other intracranial diagnoses.
ers,43 and Beck and colleagues,47 possibly only about one- The other patient who can be considered to have normal
fourth of the patients with a normal PTA also have normal hearing is the one with binaurally symmetrical hearing,

TABLE 7-8. Acoustic Neuroma Patients Presenting with Normal Hearing

Number of Patients With (%): Number of Patients With (%):
No. of PTA or Normal PTA & Binaural Subjective Positive
Author Year Patients SRT <20 dB SDS ≥90% Symmetry Hearing Loss Tinnitus Dizziness ABR

Johnson45 1977 500 26 (5)

Mathew et al.57 1978 118 24 (20)* 8 (7)
Harner and Laws34 1983 117 14 (12)* 14 (12)
Beck et al.47 1986 408 21 (5)* 5 (1) 5 (1) 13 (62) 9 (43) 14 (66) 8/9 (89)
Roland et al.46 1987 614 30 (5) 31 (5) 8 (1) 16 (42) 24 (63) 6 (16) 31/33 (94)
Thomsen and Tos58 1990 300 9 (3)
Ogawa et al.49 1991 132 10 (8)† 6 (5)‡ 10 (8) 7 (70) 7 (70) 3 (30) 9 (90)
Selesnick et al.43 1992 130 29 (22) 5 (4) 9 (7) 33/35 (94)
Dornhoffer et al.44§ 1994 70 4 (6) 6 (8)
Magdziarz et al.48 2000 369 10 (2.7) 2 (20) 4 (40) 4 (40) 7 (70)

*PTA 0.5-2 kHz <25 dB.

†
PTA 0.5-4 kHz <25 dB.
‡
SDS ≥80%.
§
All tumors <2 cm.
PTA, pure tone average; SRT, speech reception threshold; SDS, speech discrimination score.
172 SYMPTOMS OF NEUROTOLOGIC DISEASE

regardless of the hearing level of the tumor ear. Most of Eight of the 28 had serviceable hearing at the beginning of
these patients are normal, and this rate is from 1% to 8%, the follow-up. The average deterioration of the PTA was
with the average being about 5% to 7%. 6 dB/year. The mean annual growth rate of the tumors in
Normal hearing on presentation is more common in the same series was 0.22 cm/year, with the median annual
patients with noneighth nerve tumors. Hirsch and growth rate of 0.1 cm/year. The range was 0.05 to 0.69
Anderson10 reported that of their 97 patients with hearing cm/year.
thresholds of 60 dB or better, 28 had hearing that was Thomsen and colleagues31 had 19 of 59 patients with
within normal limits with respect to age and sex. They did AN who had an audiogram 1 to 10 years prior to their
not specify objective audiometric criteria. In their series of most recent audiogram. The average time was 4.2 years
97, 22 did not have an AN. There were six meningiomas, between audiometric examinations. The mean deteriora-
six gliomas or astrocytomas, four cholesteatomas, two neu- tion of the PTA, 500 through 2000 Hz, was 9 dB/year. The
romas not of eighth nerve origin, and several other space- average deterioration at 1000 Hz was 9.9 dB/year, and
occupying lesions. In the 75 AN patients, 17, or 23%, met the average deterioration at 125 Hz was 6.1 dB/year. The
their criteria for normal hearing with respect to sex and range was from 10 dB over 6 years to 60 dB in 1 year. They
age, whereas 50%, or 11 of the 22 non-AN patients, were found no relationship between age or tumor size in the
classified as normal. progress of the hearing loss.
There is no good correlation between tumor size and Massick and coworkers60 followed 21 patients with a
the occurrence of normal hearing46–49 though a trend exists small (<19 mm, mean diameter 7.8 mm) AN for least 2
toward patients with intracanalicular tumors having a years (mean of 3.8 years). Tumor growth by volumetric
higher likelihood of normal hearing.44 Patients with nor- analysis occurred in 66%, 24% showed no growth, and
mal hearing usually are younger48 and have a much shorter 10% receded. Changes in audiometric function were clas-
length of time between onset of symptoms and diagnosis. sified by the American Academy of Otolaryngology-Head
Thomsen and Tos59 found a positive correlation between and Neck Surgery 1995 guidelines. They demonstrated a
severity of hearing loss and the duration of symptoms. The significantly different mean deterioration of PTA and SDS
patients in most of the normal-hearing series have had a depending on the initial hearing. Seventy-five percent of
shorter average time between presentation and diagnosis the patients in the best hearing group (class A) remained in
than AN patients in general. This is certainly logical when the best group throughout the study. Whereas 50% of the
studying an entity known for producing gradually progres- group with class B hearing deteriorated to class D (non-
sive hearing loss, and possibly the patient presenting with serviceable), and those initially with class D hearing
normal hearing may not represent as much a difference in showed the largest drop in PTA and SDS. They demon-
tumor type or consistency, as it does the amount of time strated a significant correlation between tumor volume
for the tumor effects to take place. growth and changes in PTA and SDS, with the rate of
As a diagnostic indicator, the ABR has a high incidence change dependent on the initial hearing status. There was
of positive findings, even in patients with normal hearing. no difference between the groups in initial tumor location
In the series in Table 7-8, from 70% to 94% of the patients or size. Interestingly, one patient had a regression in tumor
were identified by a positive (abnormal) ABR. The patient size and an improvement in audiometric function.
with the small tumor with normal hearing, however, seems Ogawa and colleagues56 examined the progression of
to be the one in whom the ABR may be negative. In the hearing loss in 42 patients who could be tested for at least
series of Selesnick and colleagues43 2 patients out of 35 had 6 months before surgery. They used a five-frequency PTA
a normal ABR, both had normal hearing, and both had from 250 to 4000 Hz and identified three separate groups:
tumors less than 1 cm in diameter. Magdziarz and cowork- (1) 5 of the 42, or 12%, recovered at least 11 dB during the
ers48 found three of nine patients with normal hearing had period, (2) 28 of the 42, or 66%, showed less than a 10 dB
a normal ABR. Marangos and colleagues40 studied 50 (of change, and (3) a third group, 9 patients, or 21%, showed
261) AN patients and 4 (of 17) meningioma patients who deterioration greater than 10 dB during the follow-up.
had a normal ABR and found 20% of the AN group had The length of time from onset of symptoms to the first
normal hearing (PTA) and 18% had binaurally symmetri- visit was 49 months in the unchanged group, 28 months in
cal hearing. Twenty-five percent of the patients in the the recovery group, and 8 months in the deterioration
meningioma group had a normal PTA, and 50% had bin- group. The rate of change for all patients averaged −1.1
aural symmetry. dB/month, with a rate of +5.7 dB/month in the recovery
Again, in the consideration of mechanisms of hearing group, −0.3 dB/month in the unchanged group, and −8.2
loss in patients with CPA and IAC tumors, those with dB/month in the deterioration group. The deterioration
objectively normal hearing, but subjective complaints of group on average had the smallest tumor size. In fact, all
hearing loss and tinnitus, and frequently an abnormal ABR patients with tumors greater than 3 cm were in the
support the concept of slow nerve compression coupled unchanged group. Overall, the hearing loss in 88% of the
with the fact that 75% of the auditory nerve fibers can be patients was either unchanged or had deteriorated (20%
damaged without a change in pure tone hearing.15 deteriorated). The average deterioration of −1.1 dB/month
for the entire group equals 13 dB/year.
Progression of Hearing Loss The probability and rate of progression of tumor
growth and hearing loss are important considerations
Four studies31,56,60,61 have examined the progression of when determining the timing of hearing preservation
hearing loss in AN patients. Nedzelski61 followed 28 eld- surgery, the selection of nonsurgical treatment, or the
erly patients with AN who chose no surgical treatment. treatment of bilateral AN.
 Hearing Loss in Neurotologic Diagnosis 173

HEARING LOSS SECONDARY TO LESIONS and most often within the first year after the onset of neu-
OTHER THAN ACOUSTIC NEUROMA rologic symptoms.68 Franklin and coworkers69 and Furman
and colleagues30 identified sudden hearing loss as a pre-
Two series of patients with posterior fossa meningiomas senting symptom of MS.
were examined. Granick and colleagues39 and Laird and Another possible cause of retrocochlear hearing loss is
coworkers38 examined 32 and 20 patients, respectively, neurovascular compression of the eighth nerve in the CPA.
with meningiomas of the CPA. Meyerhoff and Mickey29 described two patients who had
As can be seen in Tables 7-4 and 7-6, the incidence of undergone microvascular decompression of the cochlear
tinnitus and hearing loss is somewhat lower than in AN nerve to treat incapacitating tinnitus. They had normal
patients, with only 60% to 75% of patients showing one or neurologic and psychological examinations, the MRI test
the other auditory symptoms at the time of diagnosis, was normal, both had unilateral high-frequency sensori-
compared with 95% or more of patients with AN. The neural hearing losses with retrocochlear findings, and no
patients with meningioma also showed a higher percent- other cause was identified. Both patients underwent decom-
age with hearing loss less than 20 dB and discrimination pression of the cochlear nerve, one from an offending
greater than 80% than did AN patients; otherwise, the posterior-inferior cerebellar artery and the other from an
configuration of the loss and appearance audiometrically is anterior-inferior cerebellar artery. Both obtained sympto-
identical with that for patients with AN. Marangos and matic relief, and improvement was reported in the high-
colleagues40 demonstrated a higher incidence of normal frequency sensorineural losses. These finding correlate
hearing, binaural symmetry, and normal ABR in patients with those of Sekiya and colleagues,28 who demonstrated
with meningiomas than those with AN. that traction on the eighth nerve in dogs might lead to
In glomus jugulare tumors, the hearing loss can be secondary auditory deficits.
either sensorineural or conductive. As described by Alford A variety of other CPA pathologies have been associated
and Guilford62 and Brammer and coworkers63 more than with hearing loss. Patients with schwannomas of the facial
90% of patients with glomus tumors present with hearing nerve70 in the CPA are known to present with hearing loss
loss. In one series,62 25 patients were examined; 13 had that can be conductive, sensorineural, or mixed. Patients
infralabyrinthine tumors and 12 had glomus tympanicum with petrous apex cholesteatomas and cholesterol granulo-
tumors. All the patients in this series with sensorineural mas typically present with either sensorineural or mixed
hearing loss had infralabyrinthine tumors. Only one of the losses.71 Lipomas72 are rare but are also associated with
patients with infralabyrinthine tumors had normal hear- hearing loss in at least two thirds of the cases. As a general
ing, but the ABR was positive in this case. rule, these other lesions in the CPA cause a hearing loss
MS is also a cause of retrocochlear hearing loss. Cure that is indistinguishable from AN.
and colleagues64 examined 167 patients with hearing loss
or tinnitus who had undergone MRI. Fourteen of the 167
patients had multifocal white matter disease as the only SUMMARY
positive finding. Of the 14, 4 had unrecognized, clinically
probable MS that was previously unsuspected. In 9 of the The typical presentation of a CPA lesion is a slowly pro-
14, the demyelinating disease was the probable cause of gressive, unilateral, sensorineural hearing loss with tinni-
the auditory symptoms due to the identification of lesions tus and poor speech discrimination. However, a number of
in the auditory pathways. The lesions in the auditory path- authors have clearly demonstrated that the hearing loss of
ways in MS are usually in the brainstem, where the MRI neurotologic disorders can be of any configuration, with
may be relatively insensitive because the lesions may be any type of presentation, including that similar to a sudden
microscopic or too small to be demonstrated by the imag- sensorineural cochlear loss. The mechanism of the hearing
ing. Bauch and coworkers58 examined 255 patients with loss, whether it is direct compression of the auditory
suspected retrocochlear hearing loss. Twenty-six of them nerve, compression of the vascular supply to the cochlea,
had surgically confirmed AN, and 6 were felt to have a or a combination of many factors, is not clearly under-
retrocochlear hearing loss secondary to MS. The ABR was stood. Very likely, it is a combination, varying with the
positive in four of the six MS patients. Hearing loss is not specific site and lesion involved. The typical picture
a common presenting symptom of MS. Mustillo65 noted may also be changing, as demonstrated by several
that only 7% of their series of patients had hearing loss as authors.6,27,42,43,48,59,73–75 More tumors are being picked up
a presenting symptom of MS. A number of authors11,30,66,67 in the less than 1-cm range, and more tumor patients are
noted that while the hearing loss as a presenting symptom being seen with normal or near-normal hearing than pre-
is not common, a large percentage of patients with MS viously noted. The presentation in patients with neuroto-
have objective findings of auditory pathway dysfunction. logic lesions, and those with AN in particular, almost
Jerger and colleagues66 found a 95% prevalence of audi- always includes auditory symptoms. Even in the face of
tory abnormalities by acoustic reflex testing, speech objectively normal hearing, subjective complaints of hear-
audiometry, or ABR testing. In 62 patients with definite ing loss or tinnitus frequently occur. The long delay
MS, the acoustic reflex was abnormal in 71%, speech between onset of symptoms and diagnosis continues, and
audiometry was abnormal in 55%, and the ABR was as noted in the series of Selesnick and colleagues,43 the
abnormal in 52%. No typical pattern of hearing loss is average time from hearing loss onset to diagnosis was still
seen in MS. The loss can be unilateral or bilateral, sudden, 3.9 years in 1992. This delay, of course, may partially be
progressive, temporary, or permanent. The loss usually due to the patient not presenting for evaluation, but also
presents itself within the first 4 years after the onset of MS is due to physicians and audiologists not pursuing the
174 SYMPTOMS OF NEUROTOLOGIC DISEASE

evaluation of symptoms far enough. If neurotologic lesions 24. O’Connor F, Luxon L, Shortman RC, et al: Electrophoretic separa-
are to be diagnosed as early as possible, allowing for the tion and identification of perilymph proteins in cases of acoustic
best treatment results, the general rule of completely neuroma. Acta Otolaryngol 93:195–200, 1982.
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 Chapter
Symptoms of Vestibular Disease
8 Outline

John F. Kveton, MD Common Symptoms Symptoms of Specific

Vertigo Vestibular Disorders
Imbalance The Labyrinth
Dizziness Vestibular Nerve
Syncope Central Nervous System

COMMON SYMPTOMS and vegetative symptoms. Symptoms can last for hours
with prostration. For a period of hours to days the resting
Symptoms of vestibular dysfunction are as variable as the tone of the intact side is reduced through central effects,
disorders that produce them. This variation in symptoms thus reducing the acute symptoms. At this point the whole
for such a specific organ site as the labyrinth can be vestibular system is functioning at a lower level and is not
explained by the particular pathology of the process affect- as sensitive to stimuli. Symptoms now are less severe,
ing the vestibular system and, as importantly, by the gen- mainly involving mild vertigo on positional changes, light-
eral physiologic recovery process that takes place after any headedness, spatial disorientation, dysequilibrium, or
insult to the system has occurred. An understanding of unsteadiness. The duration of this stage of recovery
these compensatory mechanisms for vestibular injury in depends on the severity of the vestibular injury and can
relation to the type of vestibular damage must be incorpo- last from days to months. The system compensates as
rated into the interview of patients presenting with the lesion progresses; the near constant feelings of light-
vestibular symptoms. headedness and spatial disorientation disappear, and dyse-
Certain vestibular disorders are episodic, with vestibular quilibrium and unsteadiness occur only with extreme
dysfunction punctuated by normal function, and other changes in head position or loss of other sensory cues that
disorders produce acute, single-event injury to the vestibu- affect balance. Symptoms become sporadic and eventually
lar system. In addition, chronic or progressive vestibular disappear in the course of weeks to months.
dysfunction can also occur. Vestibular dysfunction may For the majority of patients, this pattern of recovery is
be primary, with actual deterioration or damage to neural complete, with the disappearance of all symptoms. If the
elements, or secondary, in which metabolic or other systemic compensation process stalls or is interrupted at any stage,
changes produce reversible neural dysfunction. These the patient may continue to have symptoms according to
types of vestibular dysfunction will have characteristic symp- the stage of compensation the patient has reached. In fact,
toms, depending on the stage in which these disorders this disruption of complete compensation from vestibular
present to the otologist. In any case, preliminary under- dysfunction can be as debilitating as any recurrent, acute
standing of the process of vestibular compensation is the process and comprises a greater number of patient visits
foundation for accurate interpretation of vestibular symp- and treatment challenges than the acute, more easily iden-
toms to arrive at a diagnosis (Table 8-1). tifiable process.
Acute vestibular injury produces symptoms because the Although past emphasis of vestibular diagnosis has
resting tone of the vestibular system is disrupted. The loss focused on differentiating between peripheral and central
of tone produced by the damaged side allows for greater, vestibular lesions, it is the identification of the degree of
uninhibited input from the normal side, producing vertigo compensation after vestibular dysfunction that is clinically

TABLE 8-1. Symptoms During Stages of Vestibular Compensation

Initial Injury Early (hours/days) Mid (days/weeks) Late (months)

Whirling vertigo Less severe vertigo Positional vertigo Rare positional vertigo
Nausea, vomiting Nausea Mild nausea Dysequilibrium
Prostration Severe dysequilibrium, spatial disorientation Dysequilibrium; spatial disorientation Spatial disorientation

176
 Symptoms of Vestibular Disease 177

more critical. Knowledge of the extent of compensation will Dizziness

determine treatment choices as much as knowledge of the
location of the lesion. The particular symptoms of vestibu- Any vague sensations of discomfort in the head can be
lar dysfunction can be reviewed in relation to these features. described as dizziness. Other descriptors include light-
headedness, wooziness, or disorientation. This is the most
common symptom that the patient describes on initial con-
Vertigo sultation with the otologist. Spatial disorientation is the best
A sensation of motion without external stimuli broadly term to describe these symptoms as they relate to vestibu-
defines vertigo. Vertigo can be a symptom of either central lar dysfunction. These symptoms must be sought out in the
or peripheral vestibular pathology, but its absence does not history since they are difficult for the patient to describe.
preclude the possibility of primary vestibular disease. The Spatial disorientation is the prime indicator of poor
character and severity, onset, duration and frequency, and vestibular compensation and includes head-eye dyscoordi-
precipitating factors are all useful qualities of vertigo that nation and postural dysfunction. Most patients with poor
must be determined. The severity of the vertigo usually vestibular compensation are visually dependent, so that
depends on the abruptness of the process. Whirling or either loss of visual cues or conflicting or ambiguous sen-
turning denotes an acute unilateral process, whereas sway- sory cues enhance the symptoms (supermarket syndrome).
ing, rocking, staggering, weakness, or a swimming or wavy Head-eye dyscoordination occurs in bilateral vestibular
sensation is associated with a unilateral subacute or bilat- loss or cerebellar dysfunction. In less severe conditions
eral injury. Sudden onset of vertigo cannot differentiate only active head movements produce dyscoordination,
peripheral from central lesions, but the duration of the whereas in severe cases with high-frequency range vestibu-
vertigo can help to identify the source. Classic Ménière’s lar loss, the visual field cannot be stabilized with passive
attacks have a sudden onset and duration of 1 to several whole-body movement (oscillopsia). Postural dysfunction
hours. Acute toxic labyrinthitis produces a more persistent occurs in bilateral vestibular loss and demonstrates itself
vertigo that seems to build for 24 to 48 hours before sub- as postural disorientation or abnormal postural motor
siding. Central vestibular disorders may produce sudden responses to movement. It is exemplified by the develop-
vertigo and more prolonged symptoms that last up to ment of a wide-based gait and loss of hip strategy for pos-
several weeks. When the duration of the vertigo is similar tural control in patients with bilateral vestibular lesions.
to peripheral disorders, central pathology can usually be
differentiated by additional central nervous system (CNS) Syncope
symptoms. Knowledge of precipitating factors can direct
Episodic loss of consciousness is a rare presentation of
diagnosis in some peripheral lesions. Changes in head or
vestibular dysfunction because either the function of both
body position suggest acute posterior canal dysfunction
cerebral hemispheres or the brainstem reticular formation
when symptoms resolve during a period of weeks to
must be compromised to produce the symptom. Sudden
months or uncompensated unilateral peripheral disorders
onset without prodromal features; focal sensory or motor
when symptoms are chronic. Stress is recognized to pre-
phenomena; and olfactory, gustatory, or other hallucina-
cipitate vertigo in Ménière’s disease. A prodromal viral ill-
tions indicates seizure activity. Syncope as the cause for loss
ness is seen in vestibular neuritis, and prior consumption
of consciousness is explained on a vascular basis. Diffuse
of foods, medications, or alcohol can also produce vertigo.
CNS dysfunction produced by reduced cerebral blood flow
is indicated by progressive lightheadedness, faintness, or
Imbalance dimming of vision. The causes for hypoperfusion are gen-
erally cardiac (Table 8-2).
Imbalance, unsteadiness, or dysequilibrium describes a loss
More rarely, ischemia of the posterior cerebral circulation
of equilibrium on movement or in situations in which con-
produces syncope. In such cases vertigo may be associated
flicting sensory cues arise (mainly visual). These symptoms
represent the normal pattern of compensation after an acute
vestibular lesion and can last weeks to months depending on
the severity of the injury (see Table 8-1). Persistent symp- TABLE 8-2. Causes for Hypoperfusion
toms reflect either poor compensation after an acute vesti-
bular loss or gradual, continuous loss of vestibular function. Valvular stenosis (aortic, pulmonic, mitral)
The symptoms worsen with fatigue or in darkness. Acoustic Mitral valve prolapse
Hypertrophic cardiomyopathy
neuromas or other space-occupying lesions in the posterior Left atrial myxoma or thrombus
fossa are the most common causes of gradual deterioration Constrictive pericarditis
of vestibular dysfunction. Cardiac tamponade
A bilateral symmetrical loss of vestibular function builds Atrial flutter/fibrillation
to a maximum intensity of dysequilibrium for days. Vertigo Paroxysmal atrial tachycardia
Sinus bradycardia
at times precedes the progressive symptoms relating to sta- Sinus arrest
tion and gait. Young healthy patients stagger in early stages Second- or third-degree heart block
of bilateral loss, and the elderly may require a walker. The Sick sinus syndrome
greatest improvement in station and gait occurs within Pacemaker failure or malfunction
Ventricular tachycardia
6 weeks. Within 6 months the young patient walks with a Ventricular fibrillation
wide-based gait, but still feels imbalance on bending or Drug toxicity
other rapid changes in head or body position.
178 SYMPTOMS OF NEUROTOLOGIC DISEASE

with other symptoms such as diplopia, dysphagia, dysarthria, loss associated with the infection may be sensorineural, indi-
occipital headaches, and other motor or sensory symptoms. cating that permanent labyrinthine damage has occurred.
Chronic otitis media can also cause transitory or progressive
vestibular symptoms relating to the stage of the infection.
SYMPTOMS OF SPECIFIC Benign paroxysmal positional vertigo (BPPV ) is a benign,
VESTIBULAR DISORDERS self-limiting form of vestibular dysfunction that can be
diagnosed accurately through history. Known as postural
Although not completely reliable, specific vestibular symp- vertigo, positional vertigo, and cupulolithiasis, this condi-
toms generally do relate to particular areas of the vestibular tion produces sudden attacks of brief vertigo through head
apparatus. The labyrinth and vestibular nerve are consid- movement. Attacks can be induced by rolling in bed or
ered the peripheral vestibular system, whereas the brain- turning the head from one side to the other, but not both
stem is the site of central vestibular pathology. Although sides. Extending the head to look up, turning the head, or
somewhat artificial, it is helpful to group vestibular disor- looking down precipitates the symptoms. The vertigo is
ders according to the location of the dysfunction to arrive at associated with an intense feeling of dysequilibrium, but
a better understanding of the symptoms associated with patients rarely lose motor control and fall. Mild nausea can
each region. occur during or immediately after an attack. Vomiting
after the positional change is rare. Vertigo will subside
The Labyrinth when the provocative position is maintained, but patients
do not retain this position because of the often intensely
Peripheral disease is the most common cause for vestibular disagreeable feeling encountered on assumption of the
dysfunction. Symptoms are most severe and are associated provocative position. BPPV classically persists for several
with vegetative symptoms. In the acute stages of the disease, weeks with complete resolution of vertigo. It is not unusual
symptoms are self-limiting, with periods of normal func- for patients to have a recurrence of symptoms months to
tion interspersed between symptomatic events. Symptoms years later. On rare occasions, positional vertigo persists. In
become more chronic and usually less severe when the dis- such cases a complete vestibular test battery should be per-
ease causes permanent neural damage. In many cases the formed to identify a more significant vestibular pathology
symptoms of the vestibular disorders are on a continuum, as the source of the symptoms.
and the diagnoses must be considered on such a dynamic The accepted, although unproven, explanation for BPPV
disease continuum rather than a simply static condition. stems from the deposition of inorganic deposits on the
Acute labyrinthitis is the most common form of episodic cupula of the posterior semicircular canal. Schuknecht has
vestibular dysfunction. The cause of this condition is usu- demonstrated basophilic deposits in the cupula of the pos-
ally viral, but can also be bacterial. A previously asympto- terior canal in two patients, loosening of otoconia from the
matic patient experiences an acute onset of whirling otolithic membrane in cats after section of the anterior
vertigo that builds over 1 hour to severe prostration with vestibular artery, and the production of pure rotatory
nausea, vomiting, pallor, diaphoresis, and a complete nystagmus by stimulation of the posterior canal in isolation
inability to function in the upright position. Symptoms can to support the theory of cupulolithiasis. Loss of otoconia
last from 12 to 36 hours. The patient is bedridden for 1 to from the macula through linear acceleration and impact
3 days. The vertigo gradually resolves with brief, symptoms decelerations has been identified by several authors.
recurring with head movement or perceived rapid move- Symptoms of BPPV are recognized to occur spontaneously
ments. Sudden movement or bending may produce stag- or following labyrinthine concussion, otitis media, otologic
gering or falling. Driving is difficult. Within 5 to 10 days surgery, or occlusion of the anterior vestibular artery.
the patient resumes near-normal activity. Recovery is age- Endolymphatic hydrops produces vestibular dysfunction
dependent, with little or no residual symptoms present by associated with auditory symptoms of fullness, tinnitus,
2 to 3 months. and hearing loss. A change in one or several of these audi-
Most cases of acute labyrinthitis of viral origin do not tory symptoms often precedes the vestibular symptoms.
demonstrate auditory symptoms. When auditory symp- Vertigo is sudden and is not precipitated by physical exer-
toms are associated, a more definitive diagnosis may be tion or movement. Emotional stress and fatigue can precip-
possible. Deafness and vestibular loss is associated with itate or enhance an attack and can extend the symptomatic
4% to 10% of measles infections and is mainly bilateral. time period by either initiating repeated attacks of vertigo
Mumps, on the other hand, is usually associated with a uni- or prolonging recovery from an attack. Vertigo varies in
lateral hearing loss of varying degrees. Infectious mononu- severity and duration, although the classic attack lasts up to
cleosis, although rare, should be considered in teenagers, several hours. Patients most commonly describe severe
and cytomegalic inclusion disease can produce severe audi- whirling vertigo with nausea, vomiting, and prostration,
tory and vestibular dysfunction in infants. The diagnosis of but symptoms may be as mild as swaying, to-and-fro eye
herpes zoster as the cause of acute labyrinthitis can be made movements, or dysequilibrium. Vestibular symptoms can
in the presence of facial paralysis and a vesicular eruption in totally disappear within hours. In severe cases or the
and around the external auditory canal. Herpes zoster is middle to late stages of the disease, however, patients may
associated with varying degrees of hearing loss as well. experience unsteadiness or spatial disorientation for hours
Either acute or chronic bacterial infections may produce to days afterward. The frequency of the vertigo attacks is
vestibular dysfunction. Acute labyrinthitis may be caused by partly dependent on the stage and severity of the disease.
penetration of bacterial toxins through the round window Patients may experience isolated attacks punctuated by
membrane during acute otitis media. At times the hearing months to years of symptom-free existence. Other patients
 Symptoms of Vestibular Disease 179

experience attacks in series, for weeks to months, between vestibular symptoms occur in approximately 80% of
extended periods of remission. Decreasing intervals between patients and can vary from recurrent, episodic vertigo to
attacks or increasingly severe episodes of vertigo reflect positional vertigo, dysequilibrium, spatial disorientation,
progression of the disease. In addition, the appearance of motion intolerance, or a combination of these. The symp-
chronic vestibular symptoms such as positional vertigo, toms are generally episodic and can often be related to
dysequilibrium, and spatial disorientation indicate that per- exertion or straining. Dysequilibrium occurs in almost all
manent vestibular dysfunction has occurred. Rarely, in cases. Spatial disorientation is more common than vertigo,
advanced stages of the disease, patients may experience which occurs in about 75% of patients. Nausea is a more
abrupt falling attacks (otolithic crisis of Tumarkin). prominent feature than vomiting, which occurs in less than
The high degree of variability of vestibular dysfunction in half of patients. Auditory symptoms are the sole presenting
endolymphatic hydrops is reflected even more by reviewing symptom of perilymph fistula in less than 10% of patients.
subclasses of the disorder. Ménière’s disease is the classic Hearing loss, tinnitus, aural fullness, and hyperacusis occur
form of endolymphatic hydrops, composed of unilateral alone or in combination in more than 80% of perilymph
sensorineural hearing loss, tinnitus, aural fullness, and fistula patients with vertigo.
episodic vertigo. The severity of this condition varies greatly Fistulization of the bony labyrinth produces a variety
from patient to patient, and symptoms within the patient of vestibular and auditory symptoms. Symptoms of the
can change from episode to episode as well. Loudness superior canal dehiscence syndrome are more specific than
recruitment and intolerance and acoustic distortion are those of a perilymph fistula. This unusual condition must
common auditory symptoms, as is hearing loss. Little corre- be considered when vertigo or oscillopsia is evoked by
lation exists between the auditory and vestibular symptoms. loud sounds or activities that change middle ear or
Hearing loss characteristically fluctuates, with primarily intracranial pressure. Patients often develop chronic dyse-
low-tone sensorineural hearing loss being identified first. quilibrium, hyperacusis, and gaze-evoked tinnitus, but
Hearing loss progresses to a flat severe loss in most cases, hearing is normal. Fistulization of a semicircular canal,
with total hearing loss rarely occurring. Classic auditory usually the lateral canal, occurs in 7% to 14% of patients
(cochlear Ménière’s) or vestibular (vestibular Ménière’s) with cholesteatoma. Vertigo often occurs suddenly and is
symptoms alone constitute atypical forms of this disorder. associated with hearing loss. Sudden vertigo with deafness
Other variations in auditory and vestibular symptoms of and a history of chronic ear disease should alert the otolo-
endolymphatic hydrops have been identified. Delayed gist to the diagnosis of a labyrinthine fistula.
endolymphatic hydrops can occur in patients with unilateral Traumatic head injury, especially if the temporal bone is
congenital deafness. Vestibular symptoms usually begin involved, can produce either immediate or delayed symp-
abruptly in the mid-20s. Episodic, severe, whirling vertigo toms of vestibular dysfunction. Positional vertigo commonly
lasting minutes occurs frequently, often several times a day. occurs after any head injury. Labyrinthine concussion can be
Vertigo can be aggravated by positional changes or per- associated with any head injury and produces mild unsteadi-
ceived visual motion. Nausea can be a predominant feature, ness or lightheadedness, especially on changes in head
and vertigo and prostration are less common. Tinnitus and position. An associated high-frequency sensorineural hear-
aural fullness may be appreciated in the ear as well. Post- ing loss may be present. The vestibular symptoms generally
traumatic endolymphatic hydrops can develop months resolve during a period of several months. Cupulolithiasis
to years after traumatic injury to the labyrinth. The symp- can be caused by head injury. Temporal bone fractures are
toms can range from a classic Ménière’s disease picture to associated with more severe injury to the labyrinth. Abrupt
isolated episodes of fullness associated with vestibular symp- onset of severe vertigo with nausea and vomiting indicates
toms. Some type of auditory symptom is present in this con- that a transverse temporal bone fracture has occurred. Total
dition. Vertigo is generally episodic but less severe than the hearing loss is also noted. Because many patients with
classic Ménière’s attack. Whirling vertigo, swaying, and severe head injury are comatose, labyrinthine injury may be
severe dysequilibrium are all described. The attack may be identified in various stages of vestibular compensation.
more prolonged than the classic syndrome. Vegetative Often the patient describes dysequilibrium as the first
symptoms are often less severe, with an annoying sensation symptom once ambulation has begun. Mild unsteadiness
of nausea lingering in many patients. This sensation some- may persist for 3 to 6 months, with the patient falling to
times is unrelated to noticeable vestibular symptoms. Drop the involved side. Labyrinthine concussion in the opposite
attacks are slightly more frequent in post-traumatic patients ear may muddy the picture. Longitudinal temporal bone frac-
than in classic Ménière’s disease. Vestibular symptoms simi- tures are more common and produce less severe vestibular
lar to endolymphatic hydrops have been recognized on a symptoms. Unless a perilymphatic fistula has occurred
limited basis in otosclerosis. Aural fullness is associated with because of ossicular chain damage (which is common),
the acute vertigo attacks, which are less severe than classic severe vertigo is rare. Symptoms of labyrinthine concussion
Ménière’s disease. Other patients with otosclerosis complain are more likely, with vertigo or dysequilibrium noted on
of positional vertigo or episodic dysequilibrium. movement or changes in head position.
Vestibular symptoms associated with perilymph fistula are Sudden, severe, incapacitating vertigo with roaring tinnitus
at times indistinguishable from those of endolymphatic and total hearing loss (labyrinthine apoplexy) usually sug-
hydrops. An abrupt onset of whirling vertigo with vegeta- gests labyrinthine hemorrhage. Vertigo slowly resolves during
tive symptoms after straining, exertion, or head trauma may a period of 3 to 4 weeks with slow vestibular compensation.
be the initial symptoms. The vertigo can last several hours, The presentation of the symptoms can lead to a fairly close
with the usual vestibular compensation occurring if the presumption of the type of vascular injury that has occurred.
fistula closes. In cases of persistent perilymph fistula, Symptoms that began in the early morning or shortly after
180 SYMPTOMS OF NEUROTOLOGIC DISEASE

arising reflect a thrombotic phenomenon, but vertigo Both acquired and congenital syphilis predominantly demon-
appearing after exertion or a hypertensive crisis suggests vas- strate hearing loss and often acute vestibular dysfunction.
cular rupture. The possibility of perilymphatic fistula must Congenital syphilis may present symptoms that are similar
also be entertained with the exertional history. Other causes to classic Ménière’s disease. Lyme disease is a similarly com-
of labyrinthine hemorrhage include leukemic infiltrates and plex spirochetal disorder that presents with a myriad of
hemorrhage and sickle cell crisis with thrombosis. systemic symptoms. Patients with the disorder can present
Metabolic derangements may produce vestibular symptoms with acute vertigo, nausea, vomiting, malaise, and fluctuat-
primarily or interfere with the compensatory mechanisms ing hearing loss. Such patients have symptoms similar to
of a preexisting vestibular dysfunction. Elevated serum those for syphilitic dysfunction with otic involvement. A
lipids, diabetes mellitus, hypothyroidism, and allergy may common helpful diagnostic feature in these patients is a pos-
produce the spectrum of vestibular symptoms. Vertigo is itive Tullio’s sign. Both disorders may produce vestibular
usually not as severe and not associated with such severe symptoms by otic capsule or leptomeningeal involvement.
vegetative symptoms as cases of unilateral loss of vestibular
function. Symptoms appear more constant than episodic. Vestibular Nerve
Dysequilibrium and spatial disorientation are common and
can be almost continuous. Auditory symptoms are unusual Certain disorders affect the vestibular nerve alone and
in these conditions. produce symptoms that reflect the same variety of symp-
The aminoglycoside class of antibiotics is well recognized toms as disorders that primarily involve the labyrinth.
as a cause for vestibular damage. Streptomycin, gentamicin, Vestibular neuritis (vestibular neuronitis, vestibular paraly-
tobramycin, amikacin, and viomycin are primarily vestibu- sis, or epidemic vertigo) produces sudden severe vertigo
lotoxic. In general, symptoms of ototoxicity include a pro- with nausea and vomiting. Vertigo often begins at night
gressive unsteadiness followed by ataxia, anorexia, nausea, and the duration of severe vertigo is longer than a classic
and occasional vomiting. Acute vertigo is an unusual pres- Ménière’s attack. There is no hearing loss. Vertigo sub-
entation of ototoxicity. Ataxia commonly persists to a mild sides over days, and the length of time for vestibular com-
degree afterward. If total ablation of vestibular function pensation is variable, with dysequilibrium subsiding within
has occurred, the patient will complain of oscillopsia. 6 months. Persistence of symptoms suggests other diag-
Intravenous erythromycin or minocycyline not uncom- noses, including multiple sclerosis, acoustic neuroma, and
monly causes mild, transient vertigo with or without hear- vascular occlusion of the posterior fossa circulation.
ing loss. These symptoms are often reversible with cessation Vestibular symptoms are uncommon as the presenting
of therapy. symptom of an acoustic neuroma, despite the fact that the
Acute vestibular dysfunction, usually associated with tumor originates on the vestibular nerve. This partly may
severe hearing loss or deafness, can be seen in collagen be due to the slow-growing nature of the tumor so that an
vascular diseases, which include rheumatoid arthritis, episode of vertigo years prior may be forgotten. Sudden
polyarteritis nodosa, temporal arteritis, nonsyphilitic inter- vertigo with nausea and vomiting, similar to vestibular neu-
stitial keratitis, dermatomyositis, scleroderma, disseminated ritis, is reported to occur in 5% to 19% of patients. This
lupus erythematosus, Wegener’s granulomatosis, rheumatic presenting symptom mainly occurs in patients with small
fever, and relapsing polychondritis. Sudden, severe vertigo tumors. Compensation can be complete with no residual
with roaring tinnitus and total hearing loss (labyrinthine symptoms. Dysequilibrium or unsteadiness is a more
apoplexy) can be a result of an acute hemorrhage often common symptom later in the course of acoustic neuroma.
seen in Wegener’s granulomatosis. These symptoms usually Patients may note the symptoms on rapid motion of the head
occur later in the disease along with granulomatous involve- or body only or as a constant state. Constant symptoms are
ment of the upper respiratory tract, maxillary swelling, associated with increasing tumor size, with impingement
saddle nose deformity, proptosis, and palatal ulcerations. on the cerebellum and brainstem occurring in addition to
By this stage most patients also demonstrate pulmonary encroachment on the vestibular nerves.
and renal involvement. The other connective tissue disor- Vascular compression of the eighth nerve (cochleovestibular
ders produce similar acute symptoms that often can be nerve compression syndrome) remains a controversial diag-
improved with corticosteroid therapy. Nonsyphilitic intersti- nosis, because it is mainly a diagnosis of exclusion. This
tial keratitis (Cogan’s syndrome) occurs in young adults and diagnosis is made by magnetic resonance imaging or air-
usually begins with auditory and ocular symptoms. Sudden contrast computed tomographic scan identification of a ves-
onset of vertigo with nausea, vomiting, and tinnitus can sel impinging on the eighth nerve. Vestibular symptoms
occur with rapid onset of deafness. The disease is often have ranged from acute vertigo with vegetative symptoms
bilateral and pathologically resembles endolymphatic to positional vertigo to continuous motion intolerance and
hydrops. Temporal arteritis occurs in the elderly and is asso- dysequilibrium. Motion intolerance is the most common
ciated with temporal headache, scalp tenderness, and fever feature, and this symptom worsens as the day progresses.
in addition to inner ear symptoms. Relapsing polychondritis Patients often demonstrate mid- or high-frequency sen-
produces systemic symptoms such as joint pains, cough, sorineural hearing loss and tinnitus. The precise pathogenic
fever, malaise, and fatigue in addition to intermittent mechanism remains in question.
hyperemia and swelling of the auricles or nasal septum and
eye findings 2 to 3 years prior to the onset of acute vestibu- Central Nervous System
lar symptoms.
Spirochetal disorders can produce vestibular symptoms Classically, the differentiation between central and periph-
that resemble the range found in endolymphatic hydrops. eral causes of vertigo has been made by the duration of
 Symptoms of Vestibular Disease 181

vertigo attacks, that is, episodic or constant. Although con- are common, and their extent depends on the degree of the
stant vertigo is definitely associated with a central cause, infarct. Cerebellar infarction may present with similar
many central processes produce episodic vertigo, especially symptoms. Severe unsteadiness or ataxia combined with
in the early stages. Careful attention to other symptoms ophthalmoplegia and confusion compose the classic triad
referable to CNS dysfunction are important in diagnosing of Wernicke’s encephalopathy. This disorder, most common
these disorders. in alcoholics, is the result of thiamine deficiency with
Multiple sclerosis can present with transient episodes of involvement of the brainstem and cerebellum. The
vertigo, blurred vision, focal weakness, numbness, tingling, vestibular symptoms can often be reversed over weeks to
or limb unsteadiness. Dysequilibrium is a more common months with administration of thiamine.
presenting symptom than acute vertigo, although severe Vestibular symptoms often occur after cervical injury.
acute vertigo with vegetative symptoms has been known to Patients may experience brief episodes of vertigo, espe-
occur. Because the symptoms are transient early in the dis- cially on positional changes, or may complain of dysequi-
ease, mild vertigo or dysequilibrium may be confused with librium. Labyrinthine concussion may be coincident and
mild vestibular neuritis or acute, mild labyrinthitis. Sudden therefore complicate the patient’s symptoms. In the
sensorineural hearing loss can occur, with some recovery of absence of positive findings on the vestibular test battery,
auditory function occurring in many patients. the source for the vestibular symptoms must relate to the
Episodic vertigo may be a symptom of temporal lobe or interaction of the neck proprioceptors with the vestibular
complex partial seizures. The symptoms vary, but they are nuclei. This cervical vertigo is usually self-limited and usu-
stereotypical for the individual. The average length of the ally responds to physical therapy to reduce the neck
seizure is 1 to 3 minutes and includes epigastric sensations spasms associated with the injury.
along with affective, cognitive, and sensory symptoms.
Coordinated involuntary motor activity (automatisms)
occur in the orobuccolingual region and other areas of the BIBLIOGRAPHY
head and neck in most patients.
Acute vertigo may be part of the aura associated with a Alpers BJ: Vertigo: Its neurological features. Trans Am Acad Ophthalmol
classic migraine headache. This is usually a throbbing, unilat- Otolaryngol 46:38–54, 1941.
eral hemicranial pain that occurs after vertigo. Visual alter- Ballenger JJ: Diseases of the Nose, Throat, Ear, Head, and Neck.
ations (hemianopic field defects, scotomas and scintillations, Philadelphia, Lea & Febiger, 1977.
photophobia), nausea, and vomiting are common. Less Black FO, et al: Surgical management of perilymph fistulas. Arch
commonly, diarrhea, light-headedness, fainting, and fluid Otolaryngol Head Neck Surg 117:641–648, 1991.
retention can be present. Vestibular symptoms may also Drachman DA, Hart CW: Dizziness as a symptom of vestibular disease.
occur during the headache-free interval (migraine equiva- Neurology 22:323–334, 1973.
Harker LA, Rassekh C: Episodic vertigo in basilar artery migraine.
lent). Severe whirling vertigo may last from minutes to
Otolaryngol Head Neck Surg 96:239–250, 1987.
hours and is often associated with nausea and vomiting. In Harker LA, Rassekh C: Migraine equivalent as a cause of episodic
severe cases hearing loss and tinnitus may accompany the vertigo. Laryngoscope 98:160–164, 1988.
vertigo. Vertigo may occur several times a year or on a more Igarashi M: Vestibular compensation: An overview. Acta Otolaryngol
frequent basis. Occasionally, near-constant dysequilibrium (Stockh) 406:78–82, 1984.
and unsteadiness may occur. Other neurologic symptoms McCabe BF: Vestibular physiology: Its clinical application in under-
such as slurred speech, leg weakness, or diplopia and a standing the dizzy patient. In Paparella M (ed.): Otolaryngology,
history of migraine are important diagnostic features. vol 1. Philadelphia, WB Saunders, 1980.
Vascular disorders are the most common cause of cen- McNally WJ, Stuart EA: Vertigo from the standpoint of the otolaryngol-
tral vestibular dysfunction and present with the entire ogist. Trans Am Acad Ophthalmol Otolaryngol 46:33–37, 1941.
Minor LB: Superior canal dehiscence syndrome. Am J Otol 21:9–19, 2000.
spectrum of vestibular symptoms. Vertebrobasilar ischemia, a
Paparella MM, Chasin WD: Otosclerosis and vertigo. J Laryngol Otol
result of arteriosclerosis, generally occurs in the older age 80:511–519, 1966.
group. Spontaneous, short episodes of vertigo occur and Paparella MM, Sugiura S: The pathology of suppurative labyrinthitis.
recur frequently. Such attacks may be precipitated by head Ann Otol Rhinol Laryngol 76:554–586, 1967.
movement. With increasing hypoxia, facial numbness or Schuknecht HF: Pathology of the Ear. Cambridge, MA, Harvard
tingling, slurred speech, and other sensory disturbances University Press, 1974.
may occur. Thrombosis of the internal auditory artery Schwaber MK: Cochleovestibular nerve compression syndrome. I.
(labyrinthine apoplexy), usually a branch of the anterior Clinical analysis and audiovestibular test findings. Laryngoscope 102:
inferior cerebellar artery, produces severe, sudden vertigo, 1020–1029, 1992.
roaring tinnitus, and total hearing loss. Acute vertigo, Selesnick SH, Jackler RK: Clinical manifestations and audiologic diagno-
sis of acoustic neuromas. Otolaryngol Clin N Am 25:521–552, 1992.
nausea, and vomiting, along with dysphagia, hoarseness,
Seltzer S, McCabe BF: Perilymph fistula: The Iowa experience.
Horner’s syndrome, limb ataxia, sensory impairment over Laryngoscope 94:37–49, 1986.
the face, and loss of touch and position in the limbs is evi- Sidorov JE, et al: Metabolic abnormalities and vertigo. Arch Intern Med
dence of a lateral medullary infarct ( Wallenberg’s syndrome). 147:197–203, 1987.
Patients note lateral pulsion to the side of the lesion. Simon RP, Aminoff MJ, Greenberg DA: Clinical Neurology. East
Hearing loss is generally not associated. Residual symptoms Norwalk, CT, Appleton & Lange, 1989.
 Chapter
Tinnitus
9 Outline

Aage R. Møller, PhD Nature of Subjective Tinnitus

Quantification of Tinnitus
Pathogenesis of Subjective Tinnitus
Pathophysiology of Subjective Tinnitus
Location of the Anatomic Abnormality that Causes Tinnitus
Abnormalities that Cause Tinnitus
Cochlear Injuries as a Cause of Tinnitus
Tinnitus Caused by Injuries to the Auditory Nervous System
Tinnitus Generated by Functional Changes in Auditory Brainstem
Nuclei
Tinnitus and Neural Pathways Activated by Sound
Similarities between Severe Tinnitus and Other Phantom
Sensations
Interaction with Tinnitus from Other Sensory Systems
Tinnitus and Affective Disorders
Treatment of Tinnitus
Masking
Tinnitus Retraining
Electrical Stimulation
Medical Treatment
Surgical Treatment

R ecent developments in the treatment of certain types

of tinnitus have increased the interest of neurotolo-
gists in the differential diagnosis of this disorder and its
eustachian tube may cause tinnitus by transmitting sound
from the nasopharynx to the middle ear cavity. Because
objective tinnitus is not a result of abnormal function of
management. These developments have also encouraged the auditory system but is caused by a physical sound gen-
research directed at the identification of the cause of tinni- erated in the body and sensed in the normal way, this type
tus, and attempts have been made to determine the of tinnitus can usually also be heard by an observer when
anatomic location of the physiologic abnormalities that proper auscultation techniques are used. We will not dis-
cause specific types of tinnitus. cuss further this particular type of tinnitus, which presum-
There are essentially two types of tinnitus. One type, ably is processed by the auditory system in a way similar to
known as objective tinnitus, is a result of sounds that are gen- the way any other sound is processed. (For details about
erated in the body. The second type, subjective tinnitus, can objective tinnitus, see Schleuning1 and Andersen and
be heard only by the individual experiencing the tinnitus. Meyerhoff 2).
Objective tinnitus, which is rare, may be caused by vas- Subjective tinnitus is characterized by an individual’s
cular anomalies that facilitate turbulent blood flow in the perception of a sound in the absence of any physical sound,
region of the ear. This type of tinnitus represents a normal and of course this sound cannot be heard by an observer.
perception of the sound, possibly conducted to the cochlea Subjective tinnitus is more common than objective tinni-
by bony tissue, that results from such turbulent flow. Such tus and reflects an abnormality of the ear or the auditory
tinnitus may be pulsatile in nature, with the frequency of nervous system. Subjective tinnitus is similar to paresthe-
the pulsations being the same as the individual’s heart rate. sia of the somatosensory system, but many forms of tinni-
Pulsatile tinnitus may occur in association with arterio- tus have even greater similarities with central neuropathic
venous malformations, glomus tumors, or aneurysms. pain.3 The visual, olfactory, and gustatory sensory systems
Objective tinnitus may also present as a clicking sound in are rarely affected by phenomena similar to tinnitus.
association with, for example, temporomandibular joint Most adults have occasionally experienced low-intensity
disorders or as a result of spontaneous contractions of tinnitus or a more constant type of tinnitus that can easily
middle ear muscles or palatal myoclonus.1 A patulous be masked by another sound. Tinnitus of this nature is
182
 Tinnitus 183

normally benign and it does not require any medical atten- been used to quantify the nature and loudness of tinnitus,
tion, but patients with that kind of tinnitus may benefit but the correspondence is typically poor between the
from appropriate neurotologic examination to ensure that results of masking and matching studies and the degree of
tinnitus is not due to a treatable condition, such as a annoyance the tinnitus causes in different patients. Studies
vestibular schwannoma. However, when subjective tinni- agree that masking and matching tests show very low
tus is so intense that it interferes noticeably with a person’s estimates of sound intensities even by patients who experi-
daily life, it must be of concern to the neurotologist. The ence severe annoyance from the tinnitus.7,8 For example,
pathophysiology and subjective nature of that kind of tin- one study estimated the loudness of tinnitus by matching
nitus has many similarities with neuropathic (central) the loudness of a sound presented to the ear without
pain,3 including that of being a formidable challenge to the tinnitus (or the lesser affected ear) and found that 75% of
physician. It may be associated with a history of exposure the patients matched their tinnitus to sounds that were at
to noise, vestibular schwannomas, or with Ménière’s dis- a 10-dB sensation level (SL) or less. In fact, in about half
ease, but often no cause can be identified. of the patients tested, the loudness of the sounds to which
In this chapter, the nature, pathogenesis, and patho- they matched their tinnitus was only a 5-dB SL. Vernon9
physiology of different forms of subjective tinnitus are reported that only 1 of the 513 patients he tested had
discussed and the literature regarding the treatment of tinnitus that the individual matched to a high-intensity
tinnitus is reviewed. (70-dB SL) sound. Estimating tinnitus loudness by
matching the tinnitus to a sound presented to the same ear
rather than the opposite ear yielded slightly higher values
NATURE OF SUBJECTIVE TINNITUS (23.9 versus 6.6 dB, averaged in nine subjects),10 but even
these higher values seem low compared with the degree of
Subjective tinnitus may be perceived as coming from one annoyance reportedly caused by tinnitus.
ear only, from both ears with different or nearly equal These studies thus show that masking does not have the
intensity, or from inside the head. (Often when tinnitus in same effect on tinnitus as it would if the sound sensa-
one ear has reached an incapacitating level, it is also per- tion were caused by a physical sound. This discrepancy
ceived to be in the other ear.) Tinnitus may be constant between the results of loudness matching and the degree
or may vary in severity from time to time, without any of annoyance reported by patients with has led to specula-
apparent cause for the variation. Conversely, variations in tion that the methods used to estimate loudness were
intensity may be related to external events such as expo- invalid, that loudness recruitment somehow affected the
sure to loud sounds, ingestion of certain drugs or food, or results, or that the level of annoyance caused by tinnitus is
to changes in the patient’s stress level or physical activities. not directly related to its perceived loudness.9 Some inves-
Considerable individual differences exist in the intensity tigators have interpreted these findings to indicate that
and regularity of tinnitus, and the effects that subjective emotional factors play a role in the way patients perceive
tinnitus have on everyday life are related to these factors. their tinnitus.8,9,11,12 It seems more likely, however, that the
The benign tinnitus that most people occasionally experi- neural code generating the tinnitus is different from the
ence may appear as a weak pure tone, a ringing sound, or one generated by physical sounds. The neural activity that
a soft hissing sound. Most patients with tinnitus find it dif- causes the tinnitus is either generated by neurons of the
ficult to describe how their tinnitus sounds. The intensity ascending auditory pathways independent of input from
and character of the type of tinnitus that is incapacitating the periphery of the auditory system, or it may be gener-
may be likened to a shrill chirping sound, similar to that ated by neural structures that are not normally activated by
made by crickets, or to a roaring noise like that made by a sounds. This latter possibility may explain why the results of
jet engine at close proximity. Severe tinnitus is often asso- matching studies seem to underestimate the loudness of the
ciated with hypersensitivity to sound and an exaggerated tinnitus and thus its severity.
perception of loudness (hyperacusis). (Individuals with Therefore a classification system based on the patients’
Williams syndrome, infantile hypercalcemia, have a high own estimate of the severity of the tinnitus8 seems to be
incidence of hyperacusis4,5). Patients with severe tinnitus more valuable than one based on matching or masking
may perceive some sounds as distorted, and some of these studies. The proposed classification defines three degrees
patients experience a sensation similar to pain from sound, of severity: slight, moderate, or severe. Slight is used to
which they often describe as being more troublesome than describe tinnitus that is not constant and usually bothers
the tinnitus itself. In some patients, strong impulsive the patient only in a quiet environment; moderate
sounds can cause their tinnitus to increase, and that describes tinnitus that is more intense and constantly
increase may be maintained long after the sounds that present and bothers the patient when he or she tries to
caused the increase in the tinnitus have disappeared. concentrate; it also disturbs sleep. Tinnitus that elicits
Tinnitus is often associated with affective disorders such as serious complaints from the patient, interferes greatly with
depression, and some sounds can elicit fear in some indi- the patient’s ability to concentrate, and inhibits sleep is
viduals with pain (phonophobia).3,6 classified as severe. The classification of severe is used for
incapacitating tinnitus.
The present diagnostic methods, such as various forms
QUANTIFICATION OF TINNITUS of imagining techniques, cannot identify the morphologic
and functional abnormalities that cause tinnitus, thus mak-
Several methods have been devised to quantify the intensity ing differential diagnosis of tinnitus a challenge for the
and character of tinnitus. Matching and masking have physician. Although it may be helpful to determine
184 SYMPTOMS OF NEUROTOLOGIC DISEASE

whether tinnitus is pulsatile and the pulsations are syn- Noise-induced tinnitus is perhaps the most common
chronous with the patient’s heartbeat, it is of little impor- type of tinnitus, but tinnitus is not always associated with
tance to know the nature of the sound perceived, such as noise-induced hearing loss. The most severe noise-
whether the tinnitus resembles a high-frequency or low- induced tinnitus is caused by impulsive noise. Tinnitus
frequency sound, because no relationship has been estab- caused by noise is worse immediately after exposure to
lished between these factors and the anatomic location of noise and then gradually decreases after the end of the
the abnormality causing the tinnitus. exposure. Hearing loss that affects high frequencies and
Considerable similarities occur between severe tinnitus occurs gradually through the process of aging (presbycusis)
and pain,3,13 especially central neuropathic pain. Both is sometimes accompanied by tinnitus.
severe tinnitus and neuropathic pain occur in the absence The first symptom of a vestibular schwannoma is almost
of objective signs, and the perception of both tinnitus and always tinnitus, and such tinnitus frequently persists after
pain vary as a result of circumstances. Both symptoms the tumor has been removed even when the patient’s hear-
are difficult to describe, and different individuals may ing has been successfully preserved during tumor removal.
describe symptoms differently. Patients with chronic neu- In fact, tinnitus may even be worse postoperatively, prob-
ropathic pain typically experience normal stimulation of ably as a result of intraoperative injury to the auditory
the skin to be painful (allodynia*), and such patients may nerve as a result of surgical manipulation.17 Surgical
also have an exaggerated sensation from acute somatic pain manipulations of the intracranial portion of the eighth
(hyperpathia†). nerve in other types of operations such as microvascular
In a similar way many patients with severe tinnitus often decompression (MVD) to relieve hemifacial spasm (HFS),
perceive normal sounds as stronger than normal (hypera- trigeminal neuralgia (TGN), or disabling positional ver-
cusis), and sounds that normally do not elicit any unpleas- tigo (DPV) can cause tinnitus in addition to hearing loss.
ant sensations may be perceived as unpleasant or even Recently it has been recognized that vascular compres-
painful. Many individuals with severe tinnitus perceive sion of the intracranial portion of the auditory portion of
strong sounds as being extremely unpleasant and even the eighth cranial nerve can cause tinnitus. Tinnitus due to
painful, thus experiencing a phenomenon similar to hyper- this cause may be alleviated by moving the blood vessel off
pathia. Individuals with neuropathic central pain often the eighth nerve.18–20
experience increasingly painful sensations from somatic Many pharmacologic agents can induce tinnitus.21 Two
stimulation repeated at short intervals. This phenomenon, of the best known of these agents are aspirin (acetylsalicy-
known as the “wind-up” phenomenon13,15,16 often occurs late) and aminoglycoside antibiotics. Other drugs that can
together with severe pain and is described as a worsening cause hearing loss and induce tinnitus as well are loop
of pain sensations from repeated stimulation with the same diuretics (furosemide, ethacrynic acid), quinine, indo-
stimulus. Many individuals with severe tinnitus have anal- methacin, aminoglycoside antibiotics, and cisplatin.21,22
ogous sensations from sounds that are repeated. Exposure Carbamazepine, tetracycline, antipsychotic drugs, lithium,
to strong sounds may cause a patient’s tinnitus to increase tricyclic antidepressants, monoamine oxidase inhibitors,
for a long time after the sound has ended. antihistamines, beta-adrenergic receptor blockers, local
As in many patients with severe neuropathic pain, no anesthetics, and steroids (to name only a few) are other
treatable cause can be found in many patients with severe drugs that can induce tinnitus, although they have not
tinnitus. When it has been determined that the tinnitus is been associated with hearing loss. Caffeine and alcohol can
not caused by a treatable illness, the objective of treatment also cause tinnitus. Tinnitus caused by pharmacologic
is to eliminate or alleviate the symptoms. agents is usually (but not always) reversible by cessation of
administration of the offending agents. (For more details
about drugs that induce tinnitus, see Simpson and
PATHOGENESIS OF SUBJECTIVE TINNITUS Davies21). Little is known about the mechanism by which
any of these agents produce tinnitus.
The cause of subjective tinnitus is unknown in most
patients and not related to a specific disorder. The cause of
the tinnitus in most cases eludes identification by currently PATHOPHYSIOLOGY OF SUBJECTIVE
available diagnostic modalities. Some conditions, however, TINNITUS
are well known to cause subjective tinnitus, including noise
exposure, particularly exposure to impulsive noise; many As for other diseases, we want to know (1) the anatomic
pharmacologic agents; and some pathologic conditions, location of the abnormality that causes the symptoms (tin-
such as vestibular schwannoma, vascular compression of nitus, hyperacusis, and affective symptoms such as phono-
the auditory nerve, and arteriovenous malformations. phobia and depression), and (2) the nature of the
Subjective tinnitus is one of the three symptoms that abnormalities (morphologic or functional).
define Ménière’s disease. Otosclerosis may also be associ-
ated with tinnitus, specifically the cochlear type. Location of the Anatomic Abnormality
that Causes Tinnitus
*The term allodynia is usually defined to mean the pain elicited by stim- Because the patient with subjective tinnitus often refers to
uli that ordinarily are innocuous.14
†
The word hyperpathia is used to describe an explosive increase in reac-
sensation as being “in the ear,” it has generally been
tion to pain when a painful stimulus exceeds a certain threshold, with a assumed that the anatomic location of the physiological
continuing sensation of pain after the stimulation has ceased.14 abnormality causing the tinnitus is in the ear. Therefore,
 Tinnitus 185

tinnitus has often been associated with pathologic auditory pathways.25,26 These central changes may explain
processes involving the ear, and many studies of the patho- how cochlear injuries cause tinnitus.
physiology of tinnitus have focused on the ear as the Conflicting results have been found in studies of the
location of the physiological abnormality that causes the spontaneous activity of single auditory nerve fibers in ani-
symptoms. Subsequent studies have found evidence that mals that were treated with pharmacologic agents, such as
the anatomic location of the generation of the abnormal salicylate and aminoglycoside antibiotics, known to induce
neural activity that causes tinnitus is not always the ear. tinnitus in humans.27,28 Some investigators27,29,30 found
Severe tinnitus is probably most often caused by func- that salicylate and administered acutely to experimental
tional abnormalities in the auditory nervous system such as animals caused an increase in the spontaneous discharge
those induced by neural plasticity. Severe tinnitus can rates of single auditory nerve fibers, and other investiga-
probably also be caused by morphologic changes in the tors have reported decreased spontaneous activity after
auditory nerve and, rarely, in the nuclei of the ascending administration of kanamycin, an ototoxic antibiotic that
auditory pathways. Tinnitus is often associated with other may cause hearing loss and tinnitus.28 Other experiments
symptoms such as hyperacusis and phonophobia, the revealed reduced spontaneous activity in animals after
anatomic location of which may be the same as or differ- exposure to sounds that caused hearing loss (and presum-
ent from the place where the neural activity engendering ably tinnitus)31–33 and in animals that have experienced
the tinnitus arises. other forms of acute injury to the cochlea.34 These con-
flicting results regarding the relationship between changes
Abnormalities that Cause Tinnitus in the spontaneous activity of auditory nerve fibers and
tinnitus indicate that tinnitus is not related directly to the
Some forms of tinnitus may be caused directly by abnor- discharge rate of auditory nerve fibers. Other properties
malities in the ear. Studies in animals have shown that of auditory nerve activity such as phase-locking of the
direct electric current passed through the cochlea can activity in many nerve fibers or the time pattern of the
change the spontaneous activity in single auditory nerve discharge may be more closely related to tinnitus than
fibers. Studies of tinnitus have shown that electric current the discharge rate.35,36
passed through the cochlea (positive current applied to In summary, there is little support for tinnitus being
the round window) can reduce the tinnitus in some caused by increased activity of auditory nerve fibers due to
patients,23,24 supporting the hypothesis that tinnitus is injuries of the cochlea. Rather, considerable evidence
associated with the function of the cochlea and possibly points to deprivation of input to the auditory nerve as
with increased spontaneous activity in auditory nerve causing hyperactivity in more central auditory structures,
fibers. and it seems likely that such hyperactivity may be respon-
Tinnitus, at least in some patients, may also be caused by sible for some forms of tinnitus and hyperacusis. This is
abnormalities in the function of the auditory nerve or similar to some forms of central neuropathic pain.3,6
more rostral structures of the ascending auditory path-
ways. Studies in animals have shown that functional Tinnitus Caused by Injuries to the
changes may occur in auditory nuclei as a result of pathol-
ogy of the auditory periphery.25,26 Such electrical anom- Auditory Nervous System
alies in specific nuclei of the ascending auditory pathway Injuries of various kinds to the auditory nerve are very
may develop over time as an expression of neural plasticity likely the cause of tinnitus. Tinnitus from injury of the
evoked by abnormal input or lack of input from the audi- auditory nerve is commonly caused by vestibular schwan-
tory periphery. These anomalies may be in the form of noma, which almost always has tinnitus as its first symp-
reorganization of the nuclei, which may result in hyperac- tom, indicating that tinnitus can be triggered by injury,
tivity. Changes in brainstem nuclei caused by abnormal irritation, or compression of the intracranial portion of
input (or absence of input) usually take time to reverse the auditory nerve. This does not necessarily mean that the
after cessation of the abnormal input, or the changes may neural activity producing the tinnitus is generated in the
in fact be irreversible. Abnormalities of central nuclei may auditory nerve, but the tinnitus can also result from func-
rarely also develop as a result of a disease process or injury tional changes in more rostral portions of the auditory
to a nucleus. nervous system, induced by abnormal or decreased neural
activity in the auditory nerve through the expression of
Cochlear Injuries as a Cause neural plasticity. Deprivation of input is a strong promoter
of Tinnitus of neural plasticity, which can bring about reorganization
of neural circuits as well as hyperactivity and hypersensi-
Injury to the cochlea from disease processes such as tivity (see Møller and Rollins13).
Ménière’s disease, noise exposure, or administration of It is also known that close contact between the auditory
ototoxic drugs can cause verifiable morphologic changes in nerve and a blood vessel can induce tinnitus,18,19 but stud-
the sensory epithelium in the cochlea. The fact that these ies of patients undergoing MVD to relieve incapacitating
morphologic changes are related to hearing loss has led to tinnitus who had surgically verified vascular contact
the assumption that the tinnitus often accompanying such (vascular compression) of their auditory nerve did not
changes is caused by similar pathologic cochlear changes demonstrate any noticeable abnormalities in the function
as those causing the hearing loss. However, animal studies of the nerve.37 Compound action potentials (CAPs)
have shown that hearing loss can also cause changes recorded directly from the exposed intracranial portion of
(hyperactivity of neurons) in nuclei of the ascending the eighth nerve were not noticeably different from those
186 SYMPTOMS OF NEUROTOLOGIC DISEASE

recorded from patients who had similar hearing loss but no may cause changes in the function of neurons in more
tinnitus, and who were operated on to relieve vascular central nuclei of the ascending auditory pathways.
compression of other cranial nerves.37 The latencies of
peak III of the brainstem auditory evoked potentials Tinnitus Generated by Functional
(BAEP, AEP, or ABR) were not statistically different in
these two groups of patients either.37 Since approximately
Changes in Auditory Brainstem Nuclei
40% of patients who undergo MVD to treat tinnitus are Studies in animals and patients with tinnitus have indi-
cured or their tinnitus is considerably relieved after the cated that subjective tinnitus is unlikely to be directly
procedure,37 it seems highly likely that the tinnitus in these caused by neural activity in the auditory nerve. It seems
patients was indeed caused by the effect of vascular com- more probable that higher auditory centers are involved
pression of the eighth nerve. Because of the absence of and that tinnitus may be caused by a complex interplay
statistically significant abnormalities in responses from between the auditory periphery (ear and auditory nerve)
the auditory nerve and the cochlear nucleus (peak III and more rostral structures of the ascending auditory
of the BA EP), we concluded that the anatomic location of pathway in the brainstem.
the physiological abnormality that generated the tinnitus It is likely that abnormal input or lack of input from the
in these patients must have been rostral to the structures ear can, over time, cause reorganization of central auditory
from which we recorded and most likely induced by reor- structures in such a way that they become hyperactive.
ganization of neural structures through expression of neural Animal experiments have shown that deafferentation
plasticity.6,38 (cochlear removal) can produce increased metabolic activity
Another hypothesis suggests that tinnitus may result in auditory nuclei,45 or changes in temporal integration
from a pathologic correlation between the neural activity in in the inferior colliculus (IC),26 which is another sign of
individual auditory nerve fibers.35,39 Such correlations may hyperactivity. In other animal experiments strong sound
be caused by abnormal communication between auditory stimulation has been shown to trigger hyperactivity in the
nerve fibers or hair cells.35 When no sound is present, the IC and to alter temporal integration.46
time pattern of the spontaneous neural activity in auditory If hyperactivity caused by reorganization of auditory
nerve fibers is assumed to be uncorrelated. Sounds elicit nuclei becomes established, it may produce abnormal
neural activity that is phase-locked to the waveform of a neural activity for some time after normalization of the
sound, and the neural discharges in such nerve fibers will peripheral anomaly that caused the reorganization. This
become correlated. Such correlation may be important for may explain why the expected effect of MVD of the audi-
detecting the presence of sounds.35,36 Abnormal correlation tory nerve in patients with tinnitus is often delayed.18
of neural activity in many nerve fibers that is not a result of Intracranial recordings from patients undergoing MVD
sounds in the ear may therefore cause tinnitus.35,39 operations for incapacitating tinnitus have shown that the
The time pattern of spontaneous activity in single audi- latency of peak V in the click-evoked BAEP was slightly
tory nerve fibers in animals receiving salicylate has been shorter (but statistically significant) than that obtained in
found to be abnormal.29 The fact that salicylate can induce patients with matched hearing loss and no tinnitus47 who
tinnitus in humans supports the hypothesis that tinnitus is underwent MVD operations for other cranial nerve disor-
associated with an abnormal time pattern of spontaneous ders such as TGN. The shorter latency of peak V may be
firing of auditory nerve fibers. It is known from other a sign of hyperactivity of auditory nuclei. Also other stud-
systems that nuclei may be hyperactive because of novel ies indicate that the IC is involved in tinnitus.48
stimulation or deprivation. For example, some evidence The pathophysiology of severe of tinnitus may have
suggests that the cause of spasm in hemifacial spasm40,41 similarities with that of other disorders produced by vas-
is an example of hyperactivity resulting from abnormal cular compression of a cranial nerve, such as HFS and
input to the facial motonucleus. The changes in the TGN.40,41,49 Recent intraoperative studies of patients
facial motonucleus has been likened to the “kindling” undergoing MVD to relieve HFS have shown that the
phenomenon*.40 signs of physiological abnormalities in patients with HFS
The fact that tinnitus cannot be masked in the same way are not caused by the vascular compression of the facial
as an external sound also supports the assumption that tin- nerve itself (or rather vascular contact with the facial
nitus is not usually associated with the same type of auditory nerve), but instead are a result of hyperactivity of the facial
nerve activity evoked by sound. Individual variability in the motonucleus induced by abnormal neural activity in the
efficacy of masking (i.e., sometimes contralateral masking is facial motonucleus from the irritation caused by the vascu-
effective) and the phenomenon of residual masking support lar contact with the nerve.40,41 There are also indications
the hypothesis that tinnitus is not associated with the type that the pain of TGN, which can be cured with a high
of neural activity evoked by sounds.44 degree of success (80% to 85%) by MVD of the trigemi-
There are thus indications that abnormal correlation nal nerve, is a result of abnormalities in the trigeminal
between activity in many auditory nerve fibers, abnormal sensory nucleus.20,50,51
time pattern of firings of those fibers, or reduced activity Other similarities exist between incapacitating tinnitus
and disorders such as TGN and HFS. For example,
patients with incapacitating tinnitus usually have, at most,
*The kindling phenomenon was first described by Goddard,42
who noted that animals (rats) whose amygdala nuclei were electrically
moderate degrees of hearing loss similar to patients with
stimulated periodically over weeks developed seizures in response to the HFS, who have little or no detectable facial weakness, and
stimulation.43 patients with TGN, who have little loss of sensation in the
 Tinnitus 187

face, despite excruciating pain or involuntary muscle con- with sounds. This means that tinnitus is either caused by
tractions that may involve the entire face. activation of neural circuits that are not normally activated
Vascular compression (or rather irritation) of cranial by sounds or by neural circuits that are normally activated
nerves is common in asymptomatic individuals with tinni- by sounds but altered (reorganized). The subcortical clas-
tus and other hyperactive disorders such as HFS, TGN, sical auditory pathways have no known input from other
and glossopharyngeal neuralgia (GPN) that can be cured sensory systems, and the finding that tinnitus can be
by MVD of cranial nerves.49,52 Therefore, vascular com- affected by somatosensory stimulation38,58,59 and by muscle
pression of cranial nerves is not a sufficient condition for activity60 and other forms of cross-modulation61 therefore
manifestation of pathology in these disorders, but since indicates an abnormal involvement of neural circuits not
these disorders can be cured effectively by MVD, the vas- normally activated by sound.
cular contact must be regarded as a necessary condition.41,49 Some neurons of the nonclassical auditory path-
The disorder that perhaps has the greatest similarity ways6,62–65 (known as the polysensory pathway65) receive
with some forms of severe tinnitus is central neuropathic input from the somatosensory system.64,66–68 This makes
pain. Tonndorf was one of the first to publish a possible it possible to test the hypothesis that the polysensory
analogy53 between tinnitus and pain. His proposal sug- auditory pathway is involved in severe tinnitus. If the pol-
gested a similarity with the Melzack-Wall gating hypoth- ysensory system is involved in tinnitus, stimulating the
esis for pain.54 This hypothesis postulates that input median nerve electrically would be expected to alter the
from A-fibers normally suppresses neural transmission in perception of the tinnitus.
C-fibers, which conduct pain. More recently it has been Studies involving electrical stimulation of the median
hypothesized that some forms of tinnitus have similarities nerve at the wrist (that gave a strong tingling sensation
with neuropathic pain.3,13 Such pain is assumed to be a but no pain) have shown indications that the nonclassical
result of functional changes in the central nervous system auditory pathways are involved in some forms of tinnitus.
(CNS) that are caused by the expression of neural plastic- Such activation of the somatosensory system affected the
ity. That pain may be caused by reorganization of the nerv- tinnitus in 10 of 26 patients (6 experienced a decrease
ous system induced by expression of neural plasticity has and 4 experienced an increase in the loudness).38 The input
been known for a long time.55,56 These changes may be from the somatosensory system is excitatory in some
associated with hyperactivity, hypersensitivity, and altered neurons and inhibitory in others,64 which may explain
temporal integration. (Temporal integration means that why some individuals experienced an increase in the
the response to a stimulus is affected by previous stimula- perception of their tinnitus while others experienced a
tion, which is mostly a property of the CNS.) decrease.
Animal experiments have shown that normally the The nonclassical system receives its auditory input from
behavioral threshold of the response to electrical stimula- the traditional classical auditory system at the level of the
tion of auditory nuclei decreases exponentially with the IC64 to the external nucleus and the dorsal cortex of the
number of impulses presented, but after impairment of IC. These nuclei project to the dorsal thalamus, which
hearing the threshold became lower and the threshold projects to association cortices and directly to the amyg-
did not decrease with an increasing number of impulses, dala6,69 (Fig. 9-1) (see also Chapter 2). The existence of
thus altering temporal integration.25,26 These changes are direct connections from the thalamic auditory nuclei to
similar to those of the somatosensory system present in the amygdala may explain the affective components associ-
patients with neuropathic pain of central origin.57 In indi- ated with some forms of tinnitus as well as the abnormal
viduals without chronic pain, the threshold of pain to elec- involvement of endocrine and sympathetic systems. The
trical stimulation of the skin decreases exponentially as a hypothesis of abnormal activation of the amygdala in some
function of the repetition rate of the stimulation, but in patients with severe tinnitus has been supported by studies
individuals with chronic pain, the pain threshold is much using functional MRI.70
lower and nearly independent of the stimulus rate, indicat- Little is known about the normal role of the nonclassi-
ing that both the threshold and temporal integration of cal ascending auditory pathway but a recent study has
painful stimuli are altered in individuals with chronic shown evidence that the nonclassical auditory system is
pain.57 The “wind-up” phenomenon15,16 in pain is also an commonly involved in the perception of the loudness of
expression of abnormal temporal integration. sounds in children but rarely in adults.13
A change in temporal integration is just one sign of Abnormal activation of the nonclassical pathways may
involvement of neural plasticity that may occur in some be caused by neural plasticity, resulting in functional reor-
forms of severe tinnitus. Rerouting of information is ganization of the nervous system. The efficacy of synapses
another change that may be induced by neural plasticity that connect the classical pathways with the nonclassical
and may be involved in chronic severe pain. How changes pathways may increase as an expression of neural plasticity
in the organization of the CNS may cause different forms elicited by deprivation of input, as happens in the spinal
of tinnitus is, however, not known in detail. cord after severance of dorsal roots,6,71 known as “unmask-
ing of dormant synapses.” In the auditory system, this
Tinnitus and Neural Pathways may occur at the midbrain level as well as probably at
Activated by Sound the pontine level of the auditory system. Deprivation
of input to the auditory system may occur as a result
Tinnitus is often associated with hyperacusis, phonopho- of hearing loss (most patients with severe tinnitus have
bia, and emotional reactions not normally associated hearing loss).
188 SYMPTOMS OF NEUROTOLOGIC DISEASE

Figure 9-1. Schematic diagram showing connec-

tions from the classical and the nonclassical
ascending auditory pathways to the nuclei of the
amygdala. Some connections from the amygdala
nuclei are also shown. AAF, Anterior auditory field;
ABL, basolateral nucleus of the amygdala;
ACE, central nucleus of the amygdala; AI, primary
auditory cortex; AII, secondary auditory cortex;
AL, lateral nucleus of the amygdala; DC, dorsal
cortex of the inferior colliculus; ICC, central
nucleus of the inferior colliculus; ICX, external
nucleus of the inferior colliculus; MGB, medial
geniculate body.

Similarities between Severe Tinnitus Several studies have shown that eye movements can
and Other Phantom Sensations affect tinnitus in some individuals58,59,61 as can contraction
of other muscles75 in other individuals.
Tinnitus has been likened to phantom perception,30 and it
has been suggested that the prefrontal cortex is involved in
tinnitus. Jastreboff has discussed the similarity between Tinnitus and Affective Disorders
some forms of tinnitus and other phantom sensations.30 Tinnitus is often accompanied by affective symptoms such
Out of that work grew a method for treating patients with as depression and phonophobia. These symptoms may be
tinnitus (see section on Tinnitus Retraining Method). related to involvement of the nonclassical auditory path-
ways, which use the dorsal and medial portion of the tha-
Interaction with Tinnitus from Other lamic auditory nucleus (medial geniculate body, MGB).6
Sensory Systems These nuclei provide direct input to the lateral nucleus of
the amygdala and thereby channel “raw” auditory infor-
Involvement of the nonclassical auditory system was indi- mation to limbic structures6,69 (see also Chapter 2). The
cated by the finding that stimulation of the somatosensory amygdala nuclei connect to many parts of the CNS (see
system could interact with the perception of tinnitus in some Fig. 9-1). Involvement of the nonclassical auditory system
individuals with severe tinnitus.37 Subsequent studies have in some individuals with severe tinnitus37 may therefore
confirmed and extended these observations, and other forms explain why tinnitus is often accompanied by affective dis-
of cross-modality interaction with tinnitus have been orders such as depression and why sound in such individ-
described.58,59,61 The relief of tinnitus by electrical stimula- uals many evoke fear (phonophobia) and hyperacusis.76
tion of the skin behind the ears72 may act through stimula- This hypothesis was supported by studies using functional
tion of the somatosensory system (trigeminal system) rather MRI that show an abnormal activation of limbic structures
than the cochlea. It has been shown recently that the audi- in some forms of tinnitus.70
tory system (cochlear nucleus) receives connections from the The direct route from the thalamic nucleus (dorsal and
trigeminal sensory ganglion.66–68 That the somatosensory medial geniculate body) to limbic systems (the “low
system (dorsal column nuclei) provides input to the nonclas- route”)69 may conduct auditory information to the amyg-
sical parts of the midbrain auditory nuclei64 (see Chapter 2 dala in a pathway that it is little controlled by the CNS
and Møller6) may explain the relief of tinnitus by electrical (see Fig. 9-1). The amygdala nuclei normally receive
stimulation of the somatosensory system.73,74 auditory input through a much longer route (the “high
 Tinnitus 189

route”),69 where there are ample possibilities for process- pain by electrical stimulation (transdermal electric nerve
ing the information before it reaches the amygdala, and stimulation, TENS83,84).
the information may be modulated by input from higher The outcome of TRT has been difficult to evaluate and
CNS centers. the reported outcome of improvement of tinnitus and
That different hypotheses are considered regarding the hyperacusis from long-term treatment (1 year or more)
anatomic location of the physiologic abnormalities that varies among investigators.81,82 The selection criterion is
cause severe tinnitus may indicate that tinnitus has many no doubt an important factor in obtaining good results. It
different causes or, alternatively, a lack of knowledge about has been claimed that counseling in itself is not new in
the disorder (or perhaps both). One fact seems evident: The being beneficial to patients with tinnitus.85
pathophysiology of tinnitus is much more complex than
previously assumed. We can only hope that these hypothe- Electrical Stimulation
ses will help to suggest experimental studies and guide the
interpretation of the results of such studies so as to eventu- Research has shown that direct electric current passed
ally identify the cause(s) of this (or these) disorder(s). through the cochlea can reduce tinnitus in some
patients.23,24,86 In these studies an electrode was placed
on the round window or the promontorium, and when a
TREATMENT OF TINNITUS positive current was passed through the cochlea, six of
seven patients obtained relief.24 Such stimulation is
This section discusses treatments of tinnitus, hyperacusis, assumed to be effective because electric current passing
and other related disorders. Treatment is severely ham- through the cochlea affects the hair cells so that the spon-
pered by the insufficient knowledge about the mechanisms taneous activity in auditory nerve fibers decreases. It is
and the cause of tinnitus and the individual differences also possible that the electric current affects the auditory
between the causes of tinnitus. nerve directly.
Although a variety of treatments have been tried for Despite such positive effects from electrical stimulation
alleviating tinnitus and many of these are effective for of the ear, this method has not yet become widely used in
some patients, no treatment can alleviate tinnitus in all the treatment of patients with tinnitus. The tinnitus of
patients. One reason is that tinnitus is not one disorder but deaf people can be reduced by the electrical stimulation
many with similar symptoms. Few possibilities exist for provided by a cochlear implant.11,87 This seems reasonable
eliminating the cause of tinnitus. Most treatments for tin- because cochlear implants represent a way of activating
nitus are therefore directed at reducing the symptoms. auditory nerve fibers and thereby reversing the deprivation
The treatments currently in use are medical (pharmaco- of input to these nerve fibers caused by the cochlear
logic), masking by sound retraining, and surgical. injuries that resulted in the patient’s deafness.
TENS trough electrodes placed on the skin near the ear
has also been tried to treat severe tinnitus, but it seems to
Masking help only some patients.72,88,89 In some investigations
The annoyance caused by some forms of tinnitus can be about a third of the patients studied experience a pro-
decreased by masking77,78 and in some patients exposure to longed relief from tinnitus after a few minutes of TENS.
sound (masking) reduces the tinnitus for a longer or Such stimulation may have its effect by stimulating the
shorter period after termination of the noise exposure trigeminal sensory system rather than the ear. Electrical
(residual masking).44,77 Many patients with mild to moder- stimulation applied to the skin of the hand has also been
ate levels of tinnitus experience a lessening of discomfort used in treatment of tinnitus.73,74
when hearing background sounds from a radio (or other
soft sounds such as that produced by a fish tank filter Medical Treatment
motor). A hearing aid can often be of help to patients with
severe tinnitus, maybe because it amplifies background Numerous drugs have been tried to manage tinnitus.21,90
sounds. However, some patients with severe tinnitus do The drugs most consistently able to alleviate tinnitus are
not seem to benefit noticeably from such masking treat- local anesthetics, the most commonly used of which has
ment, and in fact external sounds often make the tinnitus been lidocaine (Lignocaine, Xylocaine, Procaine). It is still
worse in some individuals. not known which one of the several actions of these drugs
makes them effective in alleviating tinnitus. The effect
of local anesthetic drugs such as Procaine and Lignocaine
Tinnitus Retraining on peripheral nerves is assumed to be related to their
The tinnitus retraining (TRT) program79,80 grew out of blockage of sodium channels, but these drugs also have a
the assumption that tinnitus is a phantom sensation.30 It is considerable effect on the CNS. Lidocaine has been
now widely used for treatment of tinnitus and hyperacu- widely used, for example, to stop epileptic seizures.91
sis.81,82 The method makes use of a combination of coun- Studies using recordings of auditory evoked potentials
seling and exposure to moderately strong sounds. showed that the later peaks of the BAEP are affected (pro-
The beneficial effect of sound exposure depends on the longation of the interpeak latency of peaks I to V),92–94
sounds used; moderate sound levels seem to help some indicating that lidocaine affects the central auditory nerv-
patients.80-82 The fact that tinnitus can be relieved by expo- ous system and not the ear. These studies indicate that
sure to specific sound stimulation may be regarded as a lidocaine affects tinnitus due to an action on the CNS and
method similar to that used to treat central neuropathic not on the ear.
190 SYMPTOMS OF NEUROTOLOGIC DISEASE

The consistent efficacy and sometimes dramatic effect patients were most likely caused by the same or related
of IV lidocaine have motivated a search for other oral mechanisms. The patients who obtained total relief or
drugs with similar and longer-lasting results. So far, the considerable improvement (40.3%) had endured their tin-
search has had little success. Tocainide, which is similar to nitus for a much shorter time than those whose tinnitus
lidocaine and can be administered orally,93,95 has proven did not improve (48.6%) (2.8 years vs. 7.1 years). This is in
beneficial to some patients with tinnitus, but only in good agreement with the experience of MVD for TGN.104
dosages that were often associated with intolerable side Apfelbaum104 found that the average duration of symptoms
effects. More recently Mexiletine, another drug similar to of TGN for those who had excellent results following
lidocaine, has also been tried with moderate success.96 MVD was 70.9 months, whereas the average duration of
Inspired by the success of lidocaine and recognizing symptoms for those who had recurrences of TGN follow-
lidocaine’s anticonvulsant effect, several investigators have ing MVD was 109.4 months. This supports the hypothesis
tried various other anticonvulsant drugs such as carba- that severe tinnitus may, after a time, become less respon-
mazepine and dilantin.97 Unfortunately, these drugs have sive to treatment; it may also indicate that treatment of
also been found unacceptable or impractical for use in patients with incapacitating tinnitus should not be post-
treating tinnitus.97 Because a patient with incapacitating poned unnecessarily.
tinnitus would most likely have to take a medication for More surprising was the finding that the success rate
the rest of his or her life, the side effects of the medication was much higher in women than in men (54.8% vs.
are an important consideration. 29.3%), despite similar selection criteria and intraopera-
The benzodiazepines hold some promise, especially tive findings in men and women.18 Of 31 female patients
because some of them (diazepam, alprazolam, and clon- who were operated on with the MVD procedure, 54.8%
azepam)98 are documented as being effective and having few were either free from symptoms or markedly improved,
side effects in preliminary studies.98 These drugs may be but only 29.3% of the 41 male patients obtained similar
effective because they enhance the effect of γ-aminobutyric results from the operation.18 Although the reason for the
acid (GABA) and because at least some forms of tinnitus difference is unknown, it may indicate that many factors
may be caused by a reduction of inhibition in neurons in such as reproductive hormones may be involved.
the ascending auditory pathway, in which GABA is the MVD is most effective in patients with unilateral tinni-
inhibitory neural transmitter.99 Animal experiments have tus. In a study of 22 patients, 11 with unilateral and 11 with
shown that benzodiazepines (GABAA receptor agonists) bilateral tinnitus, the outcome was favorable in 33% over-
can reduce signs of hyperactivity and restore temporal all, but it was favorable in 63% of those 11 patients with
integration after prior exposure to loud noise in auditory unilateral tinnitus, but only 2 of the 11 patients with bilat-
midbrain nuclei (IC).100 Other pharmacologic agents eral tinnitus improved (18%).105
having GABA or GABA-like effects, such as baclofen, In a recent study of 59 patients who were operated on by
(a GABAB receptor agonist), would seem to be good can- MVD, more than 75% improved (30 were free of tinni-
didates for managing tinnitus, a hypothesis supported by tus).106 In another study of 18 patients, 8 were free of tin-
studies in animals.100 However, clinical experience of nitus after MVD, and improvement of the tinnitus was
baclofen in tinnitus treatment has not confirmed that achieved in 17 of 18.107 The anterior inferior cerebellar
hypothesis. artery (AICA) is usually found to be in contact with the
Antidepressants such as the tricyclic drugs (e.g., Elavil) auditory nerve. Because the MVD procedure is similar for
can sometimes be beneficial, but these drugs can also cause all of these disorders, it does not seem likely that these dif-
tinnitus or increase the tinnitus of patients who already ferences in the success of the surgical procedure are due to
have this disorder. Calcium channel blockers also have the procedure itself but rather the result of the criteria for
positive effects in some patients. selection of the patients to undergo the procedure.
In summary, MVD of the auditory nerve in the hands of
experienced surgeons is effective in treating severe tinnitus
Surgical Treatment in carefully selected patients, but MVD also carries a sub-
Surgical treatment of tinnitus has consisted of severing the stantial risk for making the tinnitus worse, and intraoper-
auditory nerve, or microvascular decompression (MVD) ative monitoring of auditory nerve function is essential in
or sympathectomy. Each of these treatments has had some reducing such risks.47
success. There is considerable evidence that severing the audi-
MVD is a nondestructive surgical procedure to move a tory portion of the eighth nerve can alleviate the tinnitus
blood vessel off the intracranial portion of the auditory in many patients with Ménière’s disease,108 but the results
nerve.41,49,101–103 In the hands of surgeons with extensive are much less convincing in patients with tinnitus who do
experience of this type of procedure, MVD of the intracra- not have Ménière’s disease. Pulec109 reported complete
nial portion of the auditory nerve can provide a permanent relief from tinnitus in 67% of 91 patients with Ménière’s
cure for specific selected patients.18,19,41,49,101–103 For exam- disease. In a more recent study, Pulec reported complete
ple, in a recent study18 in which 73 patients were operated relief achieved in 101 of 151 patients with tinnitus.110
on with the MVD technique, tinnitus was totally relieved Others17,111 have obtained similar results. Relief or
or greatly improved in 40%. It is interesting to note that improvement in tinnitus was reported in 36% of patients
the patients who underwent MVD of the auditory nerve with vertigo who had undergone retrolabyrinthine section
and obtained total relief from tinnitus also obtained relief of the vestibular portion of the eighth nerve and in 31% of
from their hypersensitivity to sound,18 which indicates that patients who had undergone vestibular nerve section using
the tinnitus and the hypersensitivity to sound in these a retrosigmoid approach.112
 Tinnitus 191

This means that the results of auditory nerve section for 5. Borsel van J, Curfs LMG, Fryns JP: Hyperacusis in Williams
tinnitus varies among investigators. The difference in the syndrome: A sample survey study. Genet Couns 8:121–126, 1997.
selection criteria used most likely contributes noticeably to 6. Møller AR: Sensory Systems: Anatomy and Physiology.
Amsterdam, Academic Press, 2003.
this variation. Treating tinnitus by sectioning the eighth
7. Fowler EP: The illusion of loudness of tinnitus—Its etiology and
nerve seems to be more effective in patients whose tinni- treatment. Ann Otol Laryngol 52:275–285, 1942.
tus is caused by Ménière’s disease than in patients with tin- 8. Reed GF: An audiometric study of 200 cases of subjective tinnitus.
nitus of another cause. It must be remembered that this is Arch Otolaryngol 71:94–104, 1960.
a destructive treatment limited to individuals who have no 9. Vernon J: The loudness of tinnitus. Hear Speech Action 44:17–19,
usable hearing in the ear with tinnitus, but good hearing in 1976.
the ear that will not receive treatment. 10. Goodwin PE, Johnson PM: The loudness of tinnitus. Acta
Some of the benefit of vestibular nerve section may Otolaryngol (Stockh) 90:353–359, 1980.
result from sectioning of the cochlear efferent bundle, the 11. McKerrow WS, Schriener GE, Snyder RL, et al: Tinnitus
fibers of which travel with the proximal portion of the suppression by cochlear implants. Ann Otol Rhinol Laryngol
100:552–558, 1991.
vestibular nerve and therefore may also be severed when
12. Hazell JWP: Measurement of tinnitus in humans. In Tinnitus
the vestibular nerve is cut. The efferent fibers have a sup- (Ciba Foundation Symposium 85). London, Pitman Books, 1981.
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electrically, but their normal function is largely unknown in children but not in adults. Neurosci Lett 319:41–44, 2002.
(see Chapter 2). 14. Anonymous: Pain terms: Current list with definitions and notes of
Sympathectomy has been used with some success in usage. Pain Supp 3:215–221, 1986.
managing tinnitus113 as well as for pain.114 One study 15. Woolf CJ, Thompson SWN: The induction and maintenance of
showed that stellate ganglion block in patients with central sensitization is dependent on N-methyl-D-aspartic acid
Ménière’s disease has a beneficial effect on tinnitus, as receptor activation: Implications for the treatment of post-injury
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16. Mendell LM: Modifiability of spinal synapses. Physiol Rev
of tinnitus other than Ménière’s disease benefited less
64:260–324, 1984.
(27% relief rate) from this procedure. Sympathectomy is 17. House JW, Brackmann DE: Tinnitus: Surgical treatment. In
seldom done now. Tinnitus (Ciba Foundation Symposium 85). London, Pitman
A study of patients with otosclerosis who also had tinni- Books, 1981.
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ing successful stapedectomy.116 Biofeedback has been pression surgery for severe tinnitus: Selection criteria and results.
shown helpful in treating tinnitus, as has various forms of Laryngoscope :421–427, 1993.
psychotherapy. These topics, however, are outside the 19. Kondo A, Ishikawa J, Yamasaki T, Konishi T: Microvascular
scope of this chapter, since these treatments do not seem decompression of cranial nerves, particularly of the seventh cranial
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98. Johnson RM, Brummett R, Schleuning A: Use of alprazolam for 114. Loh L, Nathan PW: Painful peripheral states and sympathetic
relief of tinnitus. Arch Otolaryngol Head Neck Surg 119:842–845, blocks. J Neurol Neurosurg Psychiat 41:664–671, 1978.
1993. 115. Adlington P, Warrick J: Stellate ganglion block in the management
99. Krnjevic K: Significance of GABA in brain function. In Tunnicliff G, of tinnitus. J Laryngol Otol 85:159–168, 1971.
Raess BU (eds.): GABA Mechanisms in Epilepsy. New York, Wiley 116. Glasgold A, Altman F: The effect of stapes surgery on tinnitus in
Liss, 1991. otosclerosis. Laryngoscope 76:1524–1532, 1966.
 Chapter
Otalgia
10 Outline

John S. McDonald, DDS, MS, FACD Pain Characteristics Temporomandibular Disorders Migraine
Anatomy Atypical Facial Pain Tension-Type Headache
Primary Otalgia Neurologic Disorders Cervicogenic Headache
Referred Otalgia Trigeminal Neuralgia Cluster Headache
Differential Diagnosis of Pain Glossopharyngeal Neuralgia Chronic Paroxysmal
Referred to the Ear Postherpetic Neuralgia Hemicrania
Acute Referred Otalgia Vagal and Superior Laryngeal Traction and Inflammatory
Chronic Referred Otalgia Neuralgia Headache
Orofacial Pain Headaches Neoplastic Disease

O talgia, or pain perceived by the patient to be emanat-

ing from the ear, is a common otolaryngologic prob-
lem in all age groups and both sexes. In many cases it
inflammatory processes, contraction, ischemia, rapid disten-
tion, or other visceral stimuli. A prolonged increase in nox-
ious input may make the nociceptors more responsive to
presents a vexing problem to the clinician. Although the noxious stimulation or nociceptors may begin to respond to
source of the pathology may be the ear or temporal bone, stimuli that are normally innocuous. This process is called
in 50% or more of patients who complain of otalgia, the peripheral sensitization and may contribute to hyperalgesia
pain is referred from a source other than the ear.1 As and allodynia.
with other complaints of pain in the head and neck, otal- Sensory innervation to the ear and periaural region is
gia may be accompanied by protean symptoms, which may derived from cranial nerves V, VII, IX, and X as well as cer-
be described as aching, boring, sharp, throbbing, burning, vical nerves 2 and 3. Nociceptive impulses in the distribution
itching, pressure-like, or the sensation of fullness. The of cranial nerves V, VII, IX, and X synapse with second-
severity of the pain may be disproportionate to the nature order neurons in the part of the trigeminal brainstem
of its underlying cause; that is, an acute inflammatory sensory nuclear complex known as the subnucleus caudalis or
process involving the external ear may present with pain of the medullary dorsal born (MDH). Nociceptive pain impulses
much greater severity than a primary neoplasm emanating from cervical nerves 2 and 3 activate neurons in the spinal
from the pharynx but referring pain to the ear. dorsal horn. It has also been pointed out3 that there is an
unusually high degree of nociceptive convergence of the
upper cervical nerves and the trigeminal system, providing
PAIN CHARACTERISTICS overlap of peripheral C2 and C3 nociceptive fibers with
the other cephalic nociceptive nerves—V, VII, IX, X, and
Pain is defined as an unpleasant sensory and emotional XII. The three types of neurons in the MDH are low-
experience associated with actual or potential tissue damage threshold mechanoreceptors (LTM), which respond only
or is described in terms of such damage.2 Pain may be char- to nonnoxious stimuli; wide dynamic range (WDR) neurons,
acterized in a variety of ways. The terms paresthesia and which respond to both noxious and nonnoxious stimuli;
dysesthesia both imply an abnormal sensation, either spon- and high-threshold nociceptive-specific (NS) neurons,
taneous or evoked, with dysesthesia being used to denote an which respond exclusively to noxious stimuli.
unpleasant abnormal sensation. Examples of dysesthetic Central to the theme of referred pain to the ear is the
pain include allodynia or a painful response to a stimulus concept of central convergence of primary afferent neurons
that does not usually evoke pain, and hyperalgesia, which at a single WDR or NS neuron in the MDH or spinal
implies an increased response to a stimulus that would dorsal horn. A substantial number of the WDR and NS
normally produce pain. Noxious stimulus or tissue damage neurons show extensive convergence and can be excited
activates nociceptors at the termination of myelinated by peripheral afferent inputs from skin, mucosa, visceral
A-delta and unmyelinated C-afferent nerve fibers in the (laryngeal), temporomandibular joint (TMJ), jaw or
skin, muscles, joints, fasciae, and other deep somatic struc- tongue muscle, tooth pulp, and neck afferents, hence the
tures. Cutaneous receptors may be activated by mechanical, spread and referral of pain.4 Pain referral depends not only
thermal, chemical, or other algesic stimuli, and nociceptors on the convergent afferent input patterns of nociceptive
in the deep somatic structures may be activated by disease, neurons but also on the so-called neuroplasticity or central
194
 Otalgia 195

sensitization (an increase in neuronal excitability) that may between muscle fibers, in the walls of blood vessels, and
be generated in the neurons by these inputs as a result of in tendons and many of these fibers act as muscle noci-
injury or inflammation.5 Some of the afferent inputs to the ceptors (this is more certain for the C-afferent [group IV]
nociceptive neurons may be “unmasked” as a result of this units than for the A-delta [group III] fibers).6,7
nociceptive input and become more effective in exciting Electromyographic studies of both the tensor tympani and
these second-order neurons with the result that pain is per- stapedius muscles have demonstrated contraction of both
ceived as coming from the tissue supplied by these afferents.5 muscles concomitantly with a number of complex move-
Pain may also be characterized as either acute or chronic ments including tight closure of the eyes, jaw opening and
in nature. Acute pain has been defined as a complex con- jaw clenching, swallowing, and speaking.8 It has been
stellation of unpleasant sensory, emotional, and mental pointed out that tonic contractions of the tensor tympani
experiences and certain autonomic (involuntary) responses muscle may be accompanied by otalgia, a sense of pressure
and psychological and behavioral reactions provoked by and aural fullness, and tinnitus or other transient acoustic
tissue damage.2 Chronic pain has been defined as pain that sensations.8 Hence the middle ear may not only be a site of
persists a month beyond the usual course of an acute disease referred pain but primary otalgia may arise from chronic
or a reasonable time for an injury to heal or that is associated contraction of the tensor tympani muscle along with, for
with a chronic pathological process that causes continuous instance, chronic contraction of the masseter muscle in
pain or the pain reoccurs at intervals for months or years.5 cases of temperomandibular dysfunction worsened by brux-
Acute pain may result from a variety of causes including ism. The question may then be: Is the middle ear pain
trauma, infection, or neoplasm. Relatively speaking, acute primary or secondary in nature?
pain conditions are usually readily diagnosed and have The seventh CN supplies sensory innervation for a por-
well-defined treatment parameters. As the causative condi- tion of the posterior and posterosuperior auricle, an adjacent
tion is resolved, the resultant acute pain subsides usually portion of the external auditory canal and lateral aspect of
leaving no disability. This is in contrast to the chronic pain the tympanic membrane, and a small area of skin in the
patient who may demonstrate little or no pathology and postauricular area. CN VII also supplies innervation to the
when pathosis is present it is frequently disproportionate stapedius muscle in the middle ear. The ninth CN provides
to the degree of discomfort experienced. Unlike acute sensory innervation to part of the posterior portion of the
pain, chronic pain does not tend to be a protective phenom- external auditory canal and meatus, an adjacent portion of
enon and thus serves no useful purpose. The treatment of the lateral surface of the tympanic membrane, and the
chronic pain tends to be less well defined and successful majority of the mastoid air cells and the eustachian tube.1
with rehabilitation rather than cure being a realistic goal. The middle ear including the medial aspect of the tympanic
Compared to acute pain, chronic pain therapy tends to be membrane receives its sensory innervation from the tym-
protracted, frequently leaving the patient with some panic plexus, which is comprised of the tympanic branch of
resultant limitation of function. the glossopharyngeal nerve (Jacobson’s nerves) and the
superior and inferior caroticotympanic branches of the
sympathetic plexus surrounding the internal carotid artery.
ANATOMY The auricular branch of the tenth CN (Arnold’s nerve)
innervates a portion of the posterior wall and floor of the
From an anatomical perspective cranial nerves (CNs) V, VII, external auditory canal and the corresponding external
IX, and X, cervical nerves 2 and 3 through the cervical surface of the tympanic membrane.
plexus, and the caroticotympanic nerves derived from the The upper cervical nerves (C2, C3) also supply sensory
carotid sympathetic plexus of the internal carotid artery pro- innervation to the ear or periauricular structures. The pos-
vide afferent pathways for the transmission of sensory stim- terior branch of the great auricular nerve supplies sensory
ulation of the auricle, the external auditory canal, tympanic innervation to the majority of the posterior portion of the
membrane, middle ear, and immediately adjacent areas. auricle as well as a portion of the skin over the mastoid
The auriculotemporal branch of the mandibular or third region, which also receives some overlapping communica-
division of the fifth cranial nerve provides sensory inner- tion with the lesser occipital nerve (C2) in the mastoid
vation for the tragus, anterior, and superior aspects of the region.
auricle and external auditory canal as well as the anterosu- Although pain may be referred to the ear by means of
perior two-thirds of the lateral or external wall of the tym- any of the cranial or cervical nerves mentioned, the most
panic membrane. Located in the middle ear and in the common source of referred pain to the ear is through the
eustachian tube, respectively, the tensor tympani and tensor fifth CN. For example, pain may be experienced in the
palati muscles are derivatives of the mandibular or first external ear including part of the external auditory canal
branchial arch and are innervated by the third division of and the tympanic membrane by convergence of primary
CN V. The masticatory muscles innervated by the third A-delta or C-afferent nociceptive fibers from the auricu-
divisions of CN V receive innervation from both motor lotemporal branch of CN V3 with primary A-delta or
and sensory nerve fibers and there is no reason to assume C-nociceptive afferent trigeminal nerve fibers, most com-
that sensory innervation has been lost to the tensor tympani monly other branches of CN V3, at WDR neurons in the
and tensor palati muscles merely because they have been medullary dorsal horn. It is also possible that pain may be
“borrowed” by the ear through phylogenetic development. referred to the middle ear or eustachian tube by convergence
The majority of the sensory innervation of skeletal muscles of primary afferent nociceptors from the tensor tympani
is derived from thinly myelinated A-delta (group III) and and tensor palati muscles with other primary nociceptive
unmyelinated C-afferent (group IV) fibers in muscle fascia, afferents at WDR neurons in the medullary dorsal horn.
196 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

It is likely then, as illustrated in the preceding example REFERRED OTALGIA

of pain sensed in the ear through the auriculotemporal
branch of CN V, that convergence of primary nociceptive Differential Diagnosis of Pain
afferent fibers from CNs V, VII, IX, and X with WDR and Referred to the Ear
possibly NS neurons in the medullary dorsal horn (trigem-
inal subnucleus caudalis) may be the means by which pain Disorders that may produce referred pain to the ear can be
may be referred to the ear.4 It is also thought that pain either acute or chronic in their nature. For ease in differen-
referred to the preauricular region from C3 may be facili- tial diagnosis, disorders that present primarily as acute pain
tated through overlap of C2 and C3 nociceptive fibers with are discussed first followed by disorders that tend to become
afferent nociceptive fibers from cranial nerves V, VII, IX, chronic or may present as a chronic pain condition on
and X.3 clinical examination. Table 10-1 lists the more frequently
encountered “acute” disorders that may produce a feeling
of pain in the ear, and Table 10-2 lists those disorders that
are more typically chronic in nature that may refer pain to
PRIMARY OTALGIA the ear.

Otalgia, pain in the ear or earache, may be either primary

in the ear (primary otalgia) or referred to the ear (secondary
Acute Referred Otalgia
otalgia). As previously indicated, a patient with an earache Orofacial pain disorders are arguably the most frequent
has at least as good a chance that they have a normal ear cause of referred pain to the ear. The most common cause
with referral of pain to the ear from another site as they of acute pain in the orofacial region, which is innervated in
have of being diagnosed with primary ear disease. Because the maxillary arch by CN V2 and in the mandibular arch by
the practicing otolaryngologist and in particular the otolo- CN V3, is dental or periodontal in origin. This may include
gist should already have a good working knowledge of the exposed dentin on root surfaces, pulpitis or pulpal necrosis
differential diagnosis of primary otalgia, only a list is pro- with or without periapical pathosis or formation of an
vided here: abscess, and either superficial or deep periodontal infections.
• Otitis externa (bacteria or fungal)
• Myringitis TABLE 10-1. Acute Referred Otalgia: Common Causes
• Cerumen impaction by Region of Referral
• Foreign body in the ear canal
• Perichondritis or chondritis of the auricle Orofacial Region
• Relapsing chondritis Exposed root surfaces
• Carbuncle or furuncle Pulpitis or pulpal necrosis
• Frostbite or burn of the auricle Periapical infection
• Trauma to the external canal Periodontal infection (superficial or deep)
Unerupted or impacted teeth
• Traumatic perforation of the tympanic membrane Traumatic occlusion
• Hemotympanum Ill-fitting dental appliances
• Eustachian tube dysfunction Recent adjustment of arch wires (orthodontic therapy)
• Eustachian tube obstruction Primary or recurrent herpetic infection
Acute herpes zoster
• Otitis media and mastoiditis (may be confounded by) Recurrent aphthous stomatitis
• Petrositis Mucocutaneous disorders (i.e., lichen planus)
• Subperiosteal abscess Geographic tongue
• Extradural/subdural abscess Burning mouth or burning tongue
• Venous sinus thrombus Maxillary sinusitis
Nasal infections
• Brain abscess Parotiditis
• External canal, middle ear, or skull base neoplasms
including metastatic disease Pharynx
Inflammatory disorder hypo-, oro-, nasopharynx
In most cases primary causes of otalgia involving the Tonsillitis and peritonsillar abscess
external ear will be readily obvious, although potentially Post-tonsillectomy pain
the most ominous, primary malignancy in the external Eagle’s syndrome
canal may not be at all obvious in the early stage and may Larynx and Esophagus
be overlooked. Conversely, however, the presence of mild Laryngitis
erythema of the tympanic membrane or erythema and/or Perichondritis or chondritis
mild swelling of the external auditory canal should not Arthritis of cricoarytenoid joint
Hiatal hernia
preclude a thorough head and neck examination to rule Infection or foreign body in esophagus
out pathology that may refer to the ear. A classic example
is the patient with temperomandibular (TMD or TMJ) Other Sources
pain with referral to the ear who may then rub the exter- Traction or inflammation involving cerebrovascular blood supply
nal ear canal with a finger or foreign object in attempts to Thyroiditis
Angina
alleviate their pain, resulting in the appearance of bacterial Aneurysm of great vessels
or fungal otitis externa.
 Otalgia 197

TABLE 10-2. Referred Otalgia, Typically Chronic Disorders may originate from inflammatory processes in other visceral
sources such as the thyroid gland and also from angina and
Orofacial Pain (Chronic) aneurysms of the great vessels.
Temporomandibular disorders (TMD, TMJ); includes myofascial facial pain
and intra-articular TMJ pain
Atypical facial pain Chronic Referred Otalgia
Neurologic Disorders To many practitioners chronic pain remains an enigma
Trigeminal neuralgia from the standpoint of diagnosis and management. This is
Glossopharyngeal neuralgia explained to a large extent by the fact that, of necessity, the
Postherpetic neuralgia emphasis in most training programs and hence in most prac-
Vagal and superior laryngeal neuralgia tices centers on the diagnosis and management of “acute”
Headaches pain conditions, resulting in attempts to treat individuals
Migraine headache with chronic pain by therapies designed only for the short
Tension-type headache term. Even those patients with more chronic conditions
Cervicogenic headache such as malignancy tend to be treated with the acute pain
Cluster headache
Chronic paroxysmal hemicrania
model.
Traction and inflammatory headache (includes temporal arteritis) The differential diagnosis of conditions that may produce
chronic pain in the head and neck is a broad one and includes
Neoplastic Disease
orofacial pain, neurologic disorders, headache, and pain
Carcinoma, sarcomas (including Hodgkin’s and non-Hodgkin’s lymphomas),
and metastatic disease
due to cancer. The remainder of this section is a discussion
of those chronic pain disorders that may present primarily
or concomitantly with other diseases as referred otalgia.
As a disclaimer, it should be mentioned that there are a
Other dental factors such as unerupted or impacted teeth, variety of potential pitfalls in formulating a differential
traumatic occlusion, ill-fitting dental appliances, or even diagnosis for chronic head and neck pain. The first and
recently adjusted arch wires in a patient undergoing ortho- potentially most significant pitfall is that chronic pain is
dontic therapy may also be causative factors. A variety of usually viewed from an individual specialist’s perspective,
other painful oral inflammatory disorders may also refer to which is frequently less than “global” in nature and may
the ear including primary or recurrent herpetic gingivos- lead to diagnostic bias. The second is that, because the clas-
tomatitis, acute herpes zoster, recurrent aphthous stomatitis sification of these conditions is difficult, it tends to be based
(primarily the major scarring form), mucocutaneous disor- more on opinion than on an understanding of pathogenesis.
ders such as erosive lichen planus, inflammatory lesions of This is further complicated by the fact that differential diag-
the tongue such as geographic tongue and less well under- nosis always tends to be more straightforward in the litera-
stood processes such as burning mouth syndrome. ture than in the examining room where textbook distinctions
Other disorders of the orofacial region that may be are seldom as clear as anticipated.
referred to the ear along either the second or third divi-
sions of CN V include maxillary sinusitis, nasal infections,
and parotiditis caused by either infection or obstruction of
OROFACIAL PAIN
Stensen’s duct by a stone. Some of the dural blood vessels
are innervated by fibers from CN V3 (CN V1 provides the
Temporomandibular Disorders
majority of the sensory trigeminal vascular innervation) Acute orofacial pain conditions as a cause of otalgia are
and because pain is the only sensation that may be evoked described in an earlier section of this chapter. Chronic oro-
by inflammatory or traction stimuli to the cerebral vascular facial pain conditions include temporomandibular disorders
blood supply, then disease in this area will nonselectively (TMD, TMJ pain), atypical facial pain (AFP) and atypical
present as pain. Although temporomandibular dysfunction odontalgia. Temporomandibular disorders present a com-
of intra- or extra-articular origin may be acute in nature, this plex problem from a standpoint of both diagnosis and
is covered in the differential diagnosis of chronic disorders management. The differential diagnosis of TMD includes
leading to otalgia. nonarticular conditions mimicking TMD, extra-articular
Disorders of the pharynx are also relatively common causes of jaw limitation, true pathology of the TMJs where
causes of referred pain to the ear with inflammatory disor- the disorder in question begins primarily in the joint and
ders of the oro-, naso-, or hypopharynx, tonsillitis, periton- remains limited to it, and finally myofascial pain dysfunction
sillar abscesses, and post-tonsillectomy pain being (MPD), which is far and away the most common cause
common causes of referred otalgia. Also, Eagle’s syndrome of TMD and hence the most common cause of chronic
caused by an elongated styloid process may present as referred pain from the orofacial region to the ear.
referred pain to the ear and may classically be confused At this point some explanation of the term MPD is war-
with or mimic glossopharyngeal neuralgia, which is dis- ranted. Myofascial pain dysfunction has also been termed
cussed later in this chapter. myofascial pain syndrome, musculoskeletal or muscle
Inflammatory disorders of the larynx and esophagus contraction pain, myofascitis, myofibrositis and myalgia.
may be referred to the ear through the vagus nerve and Myofascial pain is the most frequently encountered type of
include laryngitis, perichondritis, chondritis, arthritis of the chronic facial, head, and neck pain and according to
cricoarytenoid joint, hiatal hernia and inflammation, and Laskin9 it accounts for as many as 90% of cases of TMJ
infection or foreign body in the esophagus. Referred otalgia pain. It has been characterized as a regional pain syndrome
198 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

often with sudden onset and with trigger points causing Atypical Facial Pain
locally referred pain.10 It has been defined as pain, tender-
ness, or other referred phenomena, with the dysfunction The term atypical facial pain (AFP) is used as a moniker
attributed to myofascial trigger points.11 The diagnosis of for persistent chronic facial or intraoral pain that does not
MPD is predicated on finding a trigger point. A myofascial fit into the diagnostic criteria for a specific orofacial pain
trigger point is a hyperirritable spot in skeletal muscle that disorder. It is usually a poorly defined, unilateral, deep,
is associated with a hypersensitive palpable nodule in a taut continuous, or nearly continuous aching, boring, or burn-
band, which is painful on palpation and can give rise to ing pain not limited to the distribution of the fifth or ninth
characteristic referred pain, referred tenderness, motor cranial nerves which may actually spread over the area sup-
dysfunction, and autonomic phenomena.12 Trigger points plied by the cervical nerve roots. Although trigger zones
may be latent or active. An active trigger point will pro- are absent, attacks of atypical facial pain may be set off by
duce or reproduce a clinical pain complaint while latent mechanical stimulation including percussion or chewing.
trigger points, while tender to palpation and often causing The majority of patients are women, with the most frequent
motor dysfunction with stiffness and restricted range of age of occurrence being the fourth through sixth decades
motion, are pain free.13,14 of life.16 The term atypical odontalgia has been used when
Trigger points occur primarily in the deep midportion the patient is convinced that their pain is emanating from
of the muscle and are best discovered by examining a muscle a tooth or several adjacent teeth.
while it is relaxed, and being passively stretched by the Although its underlying mechanisms are unknown,
examiner.10 The examiner first establishes the sensation of potential etiologic factors may include trauma, hormonal
finger pressure by palpating a nonpainful area and then factors (based largely on its strongly female prevalence),
instructs the patient to respond when the pain or tenderness psychological factors, and local irritation.17 The action of
other than the pressure from finger palpation is noted. these different factors may involve peripheral sensitization
This is done by rolling the muscle transversely under the following the presence of chronic irritation or inflammatory
fingers. Usually a nodule or taut band will be felt. Many stimuli or endodontic, surgical, or other traumatic events
times a verbal response by the patient is unnecessary, as he that may produce ectopic activity along a peripheral nerve.
or she may exhibit an involuntary “jump sign” when a tender As alluded to earlier in this chapter, these peripheral
trigger point is located. changes may result in central sensitization, which appears
The concept of myofascial pain is discussed here not to be a key mechanism in many of these idiopathic orofacial
only with regard to TMD but also in later sections in con- pain conditions. Sympathetic nervous system involvement
junction with tension-type headache pain including cer- may participate in the maintenance of the central sensiti-
vicogenic headache of myofascial origin. Women are zation. Loss of segmental inibition from deafferentation
affected more frequently than men and although it may following nerve injury or impairment or loss of inhibitory
appear at virtually any age, myofascial pain appears to interneurons may also be possible mechanisms. A neu-
occur most commonly in the third, fourth, and fifth ropsychiatric assessment of patients with this disorder may
decades of life. Historically, the etiology of TMD was show a significant number of them to have a specific psy-
thought to be related to occlusal irregularities and dys- chiatric diagnosis as classified by DSM-IV criteria. In one
functional occlusal contact.15 This misconception that study of 68 patients with AFP, 46 (68%) had a specific
occlusion was the primary etiologic factor in temporo- diagnosis by DSM-IV criteria covering a wide variety of
mandibular pain and dysfunction continues today to result disorders predominantly somatoform, affective, adjustment,
in diagnostic errors, unnecessary irreversible dental treat- or personality disorders.18 While AFP may be refractory to
ments, and treatment failures. Over time, researchers and both medical and dental therapies, some patients may
clinicians have looked beyond occlusal dysfunction to the respond to antiepileptic medications such as gabapentin,
musculature and the mechanics of joint function and dys- topiramate, tiagapine, and others as well as tricyclic antide-
function as the causative factors in TMD pain. pressants and trazadone. Patients with AFP may experience
TMD patients may present with pain, muscle tender- referred otalgia or its diffuse nature may approximate the
ness, popping or clicking of the TMJ(s), limitation and/or ear in the preauricular region.
deviation of jaw movement, and otologic manifestations.
They may have jaw pain, frontal, frontotemporal or occip- NEUROLOGIC DISORDERS
ital headache pain, toothache, sinus pain, earache, pre- or
postauricular pain, sore throat, dysphagia, a sense of an The categorization of neuralgias of the face, head, and neck
object in the throat, or periorbital pain. can be both difficult and confusing. Although not usually
Both acute and chronic orofacial pain conditions considered a prime suspect in the differential diagnosis of
(toothache, periodontal infection, TMD, etc.) frequently referred otalgia, trigeminal neuralgia is included in this
result in referred pain to the ear. This likely occurs as a section not only because it is by far the most frequently
result of the convergence of nociceptive pain impulses occurring neuralgic condition in the head and neck but
from the offending structure along primary afferent nerve also because of the close proximity of occurrence of pain to
fibers to WDR neurons in the medullary dorsal horn with the ear in some patients and the fact that it occasionally
thinly myelinated A-delta and unmyelinated C-afferent will refer pain to the ear. The etiology, pathogenesis, and
muscle nociceptors from the auriculotemporal branch of management of trigeminal neuralgia has been studied far
CN V3 innervating the external ear and possibly primary more than any of its other head and neck counterparts;
nociceptive afferents from the tensor tympani and tensor hence the classic features of the CN neuralgias are briefly
palati muscles. described in the discussion of trigeminal neuralgia.
 Otalgia 199

Also included in this section are glossopharyngeal neural- it is a nonfatal one and therefore the primary approach to
gia, postherpetic neuralgia, and vagal and superior laryngeal treatment should be medical intervention with surgery
neuralgia. The term atypical facial neuralgia is synonymous being reserved for patients who become refractory to or
with AFP and is discussed in the previous section of this unable to tolerate available medications. Various antineu-
chapter. Also, because the vast majority of patients with ralgic medications, the majority of which are anticonvul-
occipital neuralgia have muscle contraction or tension-type sants, are available for use singly or in combination and
headaches following the distribution of the occipital nerve, include baclofen (antispastic category), carbamazepine,
it is included in the discussion of muscle contraction oxcarbazepine, gabapentin, lamotrigine, topiramate, tia-
headaches under the term cervicogenic headache. gapine, sodium valproate, clonazepam, and phenytoin. It is
recommended that in view of its greater safety, baclofen
Trigeminal Neuralgia should be the initial drug of choice in treating trigem-
inal neuralgia. In those cases where baclofen is ineffec-
Trigeminal neuralgia or tic douloureux is an episodic symptom tive or not tolerated, carbamazepine, oxcarbazepine, or
complex characterized by agonizingly intense paroxysmal gabapentin is the next drug of choice. In those patients
attacks of sharp, stabbing, burning, or electric shocklike who do not respond to therapy with either drug alone, the
pain confined to one side of the face in the trigeminal dis- combination of baclofen and carbamazepine may be effec-
tribution. These attacks of pain, which may last from a few tive.23 It has also been reported that baclofen and pheny-
seconds to a few minutes, can be triggered by a light touch toin may be used in those patients who cannot take
to the face including such light stimulus as a breeze or carbamazepine because baclofen and phenytoin have a
vibration. Trigger points are particularly common around synergistic action.23 The use of lamotrigine in combina-
the mouth and nose with pain often being exacerbated by tion with carbamazepine or phenytoin has been reported.24
simple acts such as taking food or fluids orally, which may In some cases tricyclic antidepressant and nonsteroidal
result in severe weight loss and dehydration. Whereas anti inflammatory analgesic medications may be used in
light touch and vibration are the most effective triggering combination with antineuralgic drugs as mentioned above.
stimuli, pinching or pressing the trigger area is unlikely to The clinician will find that the right combination of med-
provoke an attack.19 As previously mentioned, trigeminal ications often becomes very individualized from patient to
neuralgia may occasionally be a source of referred pain to patient and is often found by trial and error with the use of
the ear and also may occur in close proximity to the ear. multiple medications being involved. Unfortunately some
Physical examination is essentially unremarkable, with the patients who have achieved good control of their symp-
absence of any detectable neurologic deficit or a subtle toms over time may decide on their own to wean them-
sensory deficit within the distribution of the trigeminal selves from their medications with resultant return of their
nerve. Although in the majority of cases no identifiable pain. It is the author’s experience that in many cases pain
etiology for the trigeminal neuralgia is noted, in as many relief is not again achieved at the same combination and/or
as 15% of patients there may be an underlying cause such dosage of medication as the patient was previously taking.
as the presence of a benign or malignant neoplasm in the Nerve blockade with local anesthetic may be effective
posterior fossa or multiple sclerosis which will present at a in breaking this new cycle of pain in combination with
later point in the disease process.20 Hence, when considering antineuralgic medications. In cases where adequate control
the diagnosis of trigeminal neuralgia, a magnetic resonance of symptoms is not achieved or where medication is
imaging (MRI) study paying particular attention to the no longer effective, surgical intervention may then be
posterior fossa should be performed as a mass lesion in this indicated.
area may cause symptoms typical of trigeminal neuralgia in
the absence of other neurologic signs and symptoms.21 Glossopharyngeal Neuralgia
A broad range of other entities must be considered in
the differential diagnosis of trigeminal neuralgia. These Glossopharyngeal neuralgia is a relatively uncommon
include a variety of dental causes of pulpal origin, including episodic symptom complex characterized by unilateral
dental infection or cracked teeth; periodontal pathology; paroxysmal attacks of sharp, stabbing, burning, or electric
denture pain from pressure on the mental nerve; TMD, shock–like pain that may be felt in the posterior tongue,
primarily myofascial pain; atypical facial pain including tonsil, lateral pharyngeal wall, nasopharynx, and ear. The
atypical odontalgia; glossopharyngeal neuralgia; postherpetic trigger zone is usually located in the lateral pharyngeal
neuralgia; cluster headache; and chronic paroxysmal hemi- wall, tonsillar fossa, or in the area of the external ear pos-
crania and temporal arteritis. terior to the ramus of the mandible with pain referring
It is now believed that 80% to 90% of cases of trigeminal outward from the trigger point. Episodes of pain may be
neuralgia result from specific abnormalities of trigeminal provoked by stimulation of the trigger zone during the act
afferent neurons in the trigeminal root or ganglion resulting of swallowing, yawning, or coughing. Some patients with
in hyperexcitable afferents that give rise to paroxysmal glossopharyngeal neuralgia may experience bradycardia,
epsodes of pain as a result of synchronized after discharge syncope, and seizure with the attack of pain.25 As with
activity.17,22 trigeminal neuralgia, physical examination is essentially
Both medical and surgical therapies have been used to unremarkable, with the absence of any detectable neurologic
treat trigeminal neuralgia. While trigeminal neuralgia is deficit. When considering the diagnosis of glossopharyngeal
an excruciatingly painful and in some cases disabling, neuralgia, care should be taken to rule out the presence
debilitating disorder, it should also be pointed out that in of a carcinoma or other mass lesion in the oro-, hypo-, or
the absence of a malignant neoplasm as its primary cause, nasopharynx or at the cerebellopontine angle.
200 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

A useful technique in diagnosing true glossopharyngeal imipramine may be used for both their potential pain
neuralgia is cocainization or blocking of the trigger point relieving and sedative properties. Anxiolytic agents such as
with a local anesthetic. The pathophysiology of glossopha- lorazepam, alprazolam, or diazepam may also be used on a
ryngeal neuralgia is thought to be the same as trigeminal short-term basis.26 Sympathetic nerve blocks may be per-
neuralgia with involvement of the ninth instead of fifth formed as well as subcutaneous infiltrations in the areas of
cranial nerve. In some cases however, a specific cause for the vesicular eruption with a mixture of local anesthetic
glossopharyngeal neuralgia can be found that, in addition and steroid.26
to mass lesions, includes pharyngitis or tonsillitis, tonsillec- Initial therapy for postherpetic neuralgia centers on the
tomy, radiation therapy to the pharynx and an elongated use of medications such as nonsteroidal anti-inflammatory
styloid process. The treatment for glossopharyngeal neural- analgesics and tricyclic antidepressants alone or in combina-
gia is the same as that for trigeminal neuralgia except tion with phenothiazines such as fluphenazine. Gabapentin
in those cases where it is secondary to an elongated is regarded as first-line therapy. The use of other anticon-
styloid process in which case relief may be effected by vulsants as previously discussed for trigeminal neuralgia may
styloidectomy. be useful in the management of postherpetic neuralgia,
especially where shooting or stabbing pain is experienced.
As previously alluded to, time is of the essence in treating
Postherpetic Neuralgia postherpetic neuralgia whose duration is of 6 months or
Following a primary infection with the varicella-zoster less, because the likelihood of achieving satisfactory pain
virus (VZV) the VZV lies dormant in trigeminal and dorsal relief after this time is considerably diminished.
root ganglia and may in later life reactivate to cause herpes Sympathetic blockade in the form of as series of stellate gan-
zoster (shingles). It is theorized that following reactivation glion blocks should be performed by experienced personnel
the virus transmigrates in a segmental fashion along spinal at the first sign of postherpetic neuralgia. Where persistent
or cranial nerves, resulting in a localized painful vesicular severe pain is present, sustained release opioids such as
eruption of the skin along the distribution of the involved methadone and long-acting oral forms of morphine and
nerve. Although the pain and vesicular eruption usually oxycodone and the fentanyl skin patch may be helpful.
resolve within 2 to 3 weeks, pain in the form of postherpetic Transcutaneous electrical nerve stimulation (TENS) may
neuralgia may persist beyond resolution of these initial also be a useful adjunct.
symptoms. Although pain may be referred to the ear from
involvement of the cranial and cervical nerves and may Vagal and Superior Laryngeal
mimic geniculate or nervus intermedius neuralgia, it is not
uncommon for herpes zoster of the external ear to occur
Neuralgia
with referral of pain to the face, mastoid, and occipital Vagal and superior laryngeal neuralgia is an episodic symp-
regions as well as the neck. tom complex characterized by sudden severe attacks of brief
The primary goal in the treatment of acute herpes zoster lancinating electric shock–like pain in the side of the thyroid
is to palliate the patient’s pain and effect early resolution of cartilage, pyriform sinus, and angle of the jaw; it rarely
the acute stage of the disease and prevent the development involves the ear. Attacks are precipitated by talking, swallow-
of postherpetic neuralgia. It is felt that in young healthy ing, yawning, or coughing and usually occur in combination
patients with acute herpes zoster, only symptomatic treat- with glossopharyngeal neuralgia.27,28 Physical examination is
ment is indicated.26 In patients more than 50 years of age, essentially unremarkable with no neurologic deficit being
however, treatment for prevention of postherpetic neural- noted within the distribution of the vagus nerve. As with the
gia in addition to symptomatic relief is thought to be other cranial neuralgias, diagnosis is established by history
essential.26 The pain of postherpetic neuralgia is described and by identifying a trigger zone. Laryngeal topical anesthe-
as a persistent severe burning pain in the affected area and sia or blockade of the superior laryngeal nerves is said to stop
is often debilitating in its nature. In cases where the acute the pain and is a useful diagnostic and prognostic proce-
herpes zoster went untreated or was treated inadequately and dure.29Also, as with the other CN neuralgias, pharmacologic
the symptoms of postherpetic neuralgia are noted, initial therapy is indicated for the management of this disorder
early aggressive intervention is of the utmost importance. and is identical to that used for trigeminal neuralgia and
Although various treatment approaches have been taken glossopharyngeal neuralgia. Surgical management may be
in the management of acute herpes zoster, including the indicated if pharmacologic therapy is unsuccessful.
use of antiviral medication such as valacyclovir, cortico-
steroids, analgesics, antidepressants, or topical therapy,
there is increasing evidence that an invasive approach HEADACHES
including the use of sympathetic nerve blocks, somatic
nerve blocks, and subcutaneous infiltration of combinations Despite attempts at clarification, the classification of
of local anesthetic and steroid alone or in combination with headaches remains quite complex and often controversial,
noninvasive therapies are indicated. generally being based on the supposed pathophysiology. In
Nonsteroidal anti-inflammatory analgesics may be useful 1988 the International Headache Society (IHS) published,
in controlling the mild pain in an attack of acute herpes on the basis of empirical findings, the first ever operational
zoster, with opioid therapy being reserved for severe pain classification of headache.20 Those forms of headache that
exacerbations. Tricyclic antidepressant medications such may present with referred pain to the ear will be discussed
as amitriptyline, nortriptyline, doxepin, desipramine, or in this section.
 Otalgia 201

Migraine accompanied by photophobia, periorbital pain, lacrimation,

tinnitus, vertigo, and, as previously mentioned, otalgia.
Group 1 of the IHS classification of headaches comprises
the various categories of migraine headache, most com-
monly migraine with and without aura (classic and common Cervicogenic Headache
migraine). Migraine headaches with and without aura differ Although cervicogenic headache is a headache form that
primarily in the presence or absence of premonitory tran- may derive its origin from one of several structures in the
sient focal neurologic symptoms known as the aura, the neck or back of the head including the nerves, ganglia,
most common of which are visual disturbances, including nerve roots, uncovertebral joints, intervertebral joints, discs,
the scintillating scotomata, also known as the fortification bone, periosteum, muscle, and ligaments, among other
spectrum.30 The fortification spectrum is characterized by structures,33 experience would indicate that arguably the
an area of blurred or cloudy vision, superimposed with most common cause of this type of headache involves the
bright zigzag lines often of various colors and usually in cervical musculature in the occipital and suboccipital
only one visual field, This phenomenon is so highly char- regions. As the term implies, cervicogenic headache origi-
acteristic that it is said to be pathognomonic of migraine nates in the neck with a referral pattern to the head, fre-
with aura.31 Somatosensory symptoms consisting of a feeling quently the ophthalmic division of the trigeminal nerve
of “pins and needles” often beginning in the fingers of one presenting as retro-orbital and frontal headache pain. This
hand and extending gradually up the arm, ultimately involv- is explained by the very close proximity of the cervical
ing the ipsilateral side of the face particularly the nose and spinal and medullary dorsal horns with apparent conver-
mouth, may also be seen.13,30 gence of some cervical nociceptive afferent fibers in the
The headache phase of migraine headache with or with- medullary dorsal horn.3 Through this pattern of conver-
out aura most commonly presents as unilateral pain in the gence, pain may also be referred to the vertex along the
head, which may initially be dull in nature evolving into a midline, the periaural region, the pinna, and jaw.
severe throbbing, boring pain that may spread to the con- Although the pathogenesis of tension-type headache
tralateral side. Migraine headache is frequently accompa- may vary from individual to individual, in the end the pri-
nied by nausea, vomiting, diarrhea, photophobia, vertigo, mary underlying cause is pain of myofascial origin. It may
tremors, excess perspiration, and chills.30 The diagnosis of be difficult to differentiate a tension-type headache that
“migraine” headache unfortunately is often used as a generic includes occipital, parietal, or frontotemporal pain from
term to indicate a variety of chronic recurring headaches, TMD or cervicogenic headache of myofascial origin. All of
including tension-type headache and headache for which these may present as frontotemporal, temporal, or occipi-
no satisfactory cause can be found. tal pain often with neck and shoulder tightness and all may
be a source of referred pain to the ear or periaural region.
Many patients with myofascial facial pain will relate a his-
Tension-Type Headache tory of tension-type headache just as patients with tension-
The most common headache is the tension-type headache type headaches will frequently mention facial pain. Another
(Group 2 in the IHS classification), which has also been confounding issue is the frequent bias and lack of global
termed muscle contraction headache. It has been esti- perspective on the part of the examiner. The average physi-
mated that of all patients who seek medical care for their cian may not take the time to examine the orofacial struc-
headaches, 80% suffer from tension-type headache.32 tures and musculature with the resulting diagnosis of
Tension-type headache may be either episodic or chronic. tension-type headache, while the average dentist frequently
The criterion for chronic tension-type headache is that a may not examine beyond the orofacial region and make the
headache must be present for at least 15 days a month dur- diagnosis of TMD. Musculoskeletal examination of the
ing at least 6 months. Episodic or acute muscle contraction patient with tension-type headache, TMD, or cervicogenic
headache usually responds to analgesics available over the headache of myofascial origin will demonstrate nodular or
counter.29 bandlike tender muscle trigger points, which on finger pal-
Tension-type headache is usually characterized as a pation will produce the classic active trigger points repro-
steady, nonpulsatile ache, which may be localized unilaterally ducing the patient’s pain. The appropriate diagnosis should
or bilaterally to a single region in the head or may be gener- be made based on the primary region from which the pain
alized. It may occur in the frontotemporal region, occipital complaint is found to emenate on clinical examination.
region, parietal region, or any combination of these sites,
often with a feeling of tightness, drawing, or bandlike
pressure. The pain of tension-type headache, especially
Cluster Headache
that occurring in the temporal region unilaterally or bilater- Cluster headache falls under Group 3 of the IHS classifi-
ally, may refer to the ear presenting as otalgia. The severity cation of headaches: cluster headache syndrome. The most
of the headache pain will vary from soreness to gnawing or portentous of the primary headache disorders, it has been
a dull ache to a sharp, episodic, or continuous stabbing known by a variety of appellations including erythro-
pain. Frequently, the patient will complain of a feeling of prosopalgia of Bing, ciliary neuralgia, migrainous neuralgia,
tightness or cramping in the neck or shoulder regions. erythromelalgia (Horton’s headache), histaminic cephalgia
Tension-type headache may begin as either unilateral or (Horton’s syndrome), lower half headache, Vidian neuralgia,
bilateral headache pain and may progress from a localized Sluder’s neuralgia, sphenopalatine neuralgia, and hemicrania
type of headache to a generalized headache pain frequently periodica neuralgiformis.34,35
202 ANATOMY, PHYSIOLOGY, AND PATHOLOGY

This type of headache is comprised of two major subtypes: patient with deep, intense, throbbing pain in the temple,
episodic cluster headache and chronic cluster headache. especially if there is accompanying loss of vision. The region
Episodic cluster headache, the most common type, is said should be palpated, looking for the presence of a distended
to account for 80% of all cases. In episodic cluster headache throbbing temporal artery. The diagnosis is made by biopsy
the patient experiences recurring clusters of headaches, of the affected temporal artery; however, multiple biopsies
which occur regularly and usually on a daily basis, alternat- may be necessary, as the histologic changes, essentially a
ing with periods of refractoriness or remission. The term giant cell arteritis, are patchy in their distribution. The
chronic cluster headache is used when a remission has not erythrocyte sedimentation rate is almost invariably ele-
occurred for 1 year.32 vated. Claudication of the jaw is strongly suggestive of
Cluster headache is described as a steady, excruciating, temporal arteritis and is characterized by pain as soon as
searing, stabbing, boring, or burning pain around the eye chewing begins, as opposed to myofascial pain in which pain
and frontotemporal region that occasionally may refer to is usually noted on prolonged chewing.
the occipital region, the ipsilateral maxilla and mandible
including the teeth, and the cheek extending into the neck
on the affected side.36 The onset of the painful episode NEOPLASTIC DISEASE
may be preceded by feeling a fullness or pressure in the
area where the headache will occur. Unlike other primary As should be clear from the preceding sections, disorders
headache disorders such as migraine and tension-type included in the differential diagnosis of referred otalgia are
headache, which affect women more frequently than men, many and varied and, as in the case of orofacial pain includ-
cluster headache predominantly affects31 men more than ing TMD, quite common. Although many more cases of
women by a ratio of up to 6:1. The differential diagnosis referred ear pain secondary to toothache, sinus infection,
of cluster headache includes migraine headache, trigeminal tonsillitis, TMD, and so on, are encountered than from
neuralgia, temporal arteritis, pheochromocytoma, and neoplastic disease, this possibility should always be consid-
Reader’s paratrigeminal syndrome.32 ered, especially in high-risk populations such as smokers.
Even when the diagnosis seems obvious, a thorough head
Chronic Paroxysmal Hemicrania and neck examination, including imaging studies as neces-
sary, should be performed to assure that the “obvious”
Chronic paroxysmal hemicrania is a rare headache disorder cause is not a “red herring.” For example, there is no rea-
thought to be a variant of cluster headache. It is similar to son to assume that referred pain from pharyngitis will
a cluster headache in character but differs from it in the present differently from an occult carcinoma in the
fact that its attacks are more frequent and of shorter duration nasopharynx. All suspicious lesions should be biopsied and
and it responds dramatically to indomethacin and partially there must be careful follow-up to assure that as the
to salicylates.37,38 assumed cause for the referred pain is resolved, the pain
itself is also resolved.
Traction and Inflammatory Headache Although carcinomas are the most common cause of
neoplastic disease referred to the ear, mesenchymal malig-
Traction and inflammatory headache is a broad category of nancies must also be considered. Pain may be referred to
headache pain, which crosses several sections of the IHS the ear from carcinomas arising in the soft tissues of the
headache classification. It is caused by traction, stretching, oral cavity, tonsillar pillars and base of tongue, nasopharynx,
compression, or inflammation of pain-sensitive structures soft palate, oropharyngeal wall, hypopharynx, larynx
in the skull or its components including the brain, meninges, (including epiglottis, vocal cords, and pyriform sinus),
arteries, veins, eyes, ears, teeth, nose, and paranasal sinuses. lung, and thyroid gland.
It denotes a nonspecific headache, which may be caused by Pain may be referred to the ear from carcinoma arising in
mass lesions, hemorrhages, or inflammatory disease and the maxilla or centrally within the mandible and from carci-
includes inflammatory processes outside the skull such as noma or adenocarcinoma involving the salivary glands.
temporal arteritis. Because branches of the trigeminal Mesenchymal malignancies including rhabdomyosarcoma,
nerve, CN V1, and some CN V3 fibers supply the cere- fibrosarcoma or neurofibrosarcoma (in soft tissue or bone),
brovascular innervation, pain may be referred to the ear by osteosarcoma or chondrosarcoma, and malignant prolifera-
any event that produces traction on, or inflammation of, tive disorders from both lymphatic and extralymphatic
these vessels. Innervation of this blood supply is selectively sites may also present as otalgia. Intracranial neoplasms
nociceptive in its nature and hence pain is the only sensation producing traction on structures innervated by the cranial
that may be evoked. or cervical nerves as well as metastatic disease to the distri-
Temporal arteritis is included in the category of traction bution of CN V, VII, IX, X, C2, and C3 must also be
and inflammatory headache and is characterized as an considered.
intense, deep, persistent, throbbing, aching, burning pain,
which may be accompanied by hyperalgesia of the scalp
and extreme tenderness of the distended arteries. Patients REFERENCES
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3. Poletti CE: C2 and C3 radiculopathies: Anatomy, patterns of for headache disorders, cranial neuralgias and facial pain. Cephalalgia
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Philadelphia, Lippincott, Williams & Wilkins, 1999, p 5. Febiger, 1953, pp 790–797.
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International Headache Society: Classification and diagnostic criteria
 Chapter
Pulsatile Tinnitus
Advances in Diagnosis and Treatment
11 Outline

Aristides Sismanis, MD, FACS Pathophysiology and Palatal, Stapedial, and

Classification Tensor Tympani Muscle
Arterial Causes Myoclonus
Atherosclerotic Carotid Evaluation
Artery Disease History
Intracranial Vascular Examination
Abnormalities Audiologic and
Venous Causes Electrophysiologic Testing
Pseudotumor Cerebri Metabolic Work-up
Syndrome Ultrasound Studies
Idiopathic Tinnitus Radiologic Evaluation
Nonvascular Causes Management

P ulsatile tinnitus (PT) is an uncommon otologic symp-

tom that often presents a diagnostic and management
dilemma to the otolaryngologist. In contrast to continuous
Arterial Causes
Atherosclerotic Carotid Artery Disease
subjective tinnitus, the majority of patients with PT have a In the author’s experience, atherosclerotic carotid artery
treatable underlying process. Furthermore, identifying the disease (ACAD) has been the most common cause of PT
cause of this symptom is imperative in order to avoid dis- in patients older than 50 years of age, especially when
astrous consequences from associated life-threatening associated with certain risk factors such as atherosclerosis,
intracranial pathology. hypertension, angina, hyperlipidemia, diabetes mellitus, or
smoking. Objective PT can be the first manifestation of
ACAD in these patients.2 Pulsatile tinnitus in ACAD is
PATHOPHYSIOLOGY AND secondary to bruit(s) produced by turbulent blood flow at
CLASSIFICATION stenotic segment(s) of the carotid artery. In a series of
12 patients with PT secondary to ACAD, an ipsilateral
Pulsating tinnitus most commonly originates from vascu- carotid bruit was present in all of them.2 Diagnosis can
lar structures within the cranial cavity, head, and neck be established by duplex ultrasound studies.2 In cases of
region, as well as the thoracic cavity, and is transmitted to suspected intracranial atherosclerotic vascular disease, head
the cochlea by vascular and bony structures. Pulsatile tin- magnetic resonance angiography (MRA) can be very useful.
nitus can arise either from increased blood flow or steno-
sis of the vascular lumen.
Intracranial Vascular Abnormalities
Vascular PT can be classified as arterial or venous
according to the vessel of origin. Differentiation between Intracranial vascular abnormalities are uncommon causes of
these two types is made by applying light digital pressure tinnitus; however, misdiagnosis may have catastrophic con-
over the ipsilateral internal jugular vein (IJV). This sequences for the patient. In the author’s experience, the
maneuver does not affect the intensity of arterial PT, but it most common of these abnormalities presenting with PT
makes the venous type subside. The venous type can orig- have been dural arteriovenous fistulae (AVFs). Aneurysms,
inate not only from primary venous pathologies, but also with the exception of dissecting aneurysms of the internal
indirectly from conditions causing increased intracranial carotid and vertebral arteries, do not present with PT.
pressure (ICP) by transmission of arterial pulsations to Dural AVFs constitute approximately 15% of intracranial
the dural venous sinuses.1 Pulsatile tinnitus originating arteriovenous malformations (AVMs) and usually become
from nonvascular structures is classified as nonvascular. symptomatic during the fifth or sixth decade of life.3,4
Classification of PT as objective or subjective is based on The transverse and sigmoid sinuses are the most common
whether it is audible by both patient and examiner or by dural sinuses involved, followed by the cavernous sinus.
the patient only. In contrast to AVMs, AVFs are usually acquired and thought
204
 Pulsatile Tinnitus: Advances in Diagnosis and Treatment 205

to result from dural venous sinus thrombosis. Thrombosis subarachnoid hemorrhage.4 Sudden head rotation, especially
may be caused by trauma, obstructing neoplasm, surgery, or when accompanied by extension (i.e., the tennis “ace serve”),
infection, or it may occur spontaneously. As the thrombosed is the most likely precipitating event.5 Fibromuscular dys-
segment recanalizes, ingrowth of dural arteries takes place plasia, various arteriopathies such as Marfan syndrome, and
and artery-to-sinus anastomoses are formed.4 osteogenesis imperfecta are predisposing factors. A patient
Patients with dural AVFs usually present with PT of the with ICA dissection following a severe episode of vomiting
arterial type. A loud bruit over the involved dural sinus as was recently seen by the author. Pulsatile tinnitus and ipsi-
well as objective PT are audible. Mortality from hemor- lateral retroauricular bruit were present.
rhage of a dural AVF is 10% to 20%.4 In cases with retro- Table 11-1 summarizes the arterial causes of PT.
grade drainage into the cortical veins, the chance of
subarachnoid or parenchymal hemorrhage is much higher.4
The following are two representative cases. Venous Causes
Dissecting aneurysms are rare and more often involve the
Pseudotumor Cerebri Syndrome
internal carotid artery (ICA) and less often the vertebral
artery. Manifestations include PT, pain, transient ischemic In the author’s experience, pseudotumor cerebri syndrome
attacks, cranial neuropathies, Horner’s syndrome, and has been the most common cause of venous PT in obese

ILLUSTRATIVE CASE HISTORIES

Case 1
Fifty-five-year-old female presented with left PT of 8 months’ angiogram, anterior-posterior view, of the left middle meningeal
duration. A bruit over the left retroauricular area as well as artery demonstrating an AVF with rapid shunting between the
objective tinnitus were audible. Figure 11-1 is a selective occipital meningeal branch and the transverse sinus.

Case 2
Forty-five-year-old male presented with right PT of 6 months’ orbit. Figure 11-2 shows a carotid angiogram, lateral view,
duration. Six months prior to this he had sustained a demonstrating an AVF between the right internal carotid artery
severe facial injury. A loud bruit was audible over the right and the cavernous sinus.

Figure 11-2. Right carotid angiogram, lateral view, in case 2 shows a

carotid-cavernous fistula between the right internal carotid artery (A) and the
cavernous sinus (B). Note the rapid shunting through the cavernous sinus
into the “arterialized” ophthalmic vein (E) and both the superior (C) and
Figure 11-1. Angiography, anterior-posterior view, in case 1. Microcatheter inferior (D) petrosal sinuses.
placed in the left middle meningeal artery (A) demonstrates a small AVF (B)
with rapid shunting between an occipital meningeal branch (C) and the
transverse sinus (D).
206 SYMPTOMS OF NEUROTOLOGIC DISEASE

TABLE 11-1. Arterial Causes of Pulsatile Tinnitus TABLE 11-3. Medications Associated with Pseudotumor
Cerebri Syndrome
Atherosclerotic carotid artery disease2
Intra- and extracranial arteriovenous malformations6–8 Steroids
Dural arteriovenous fistulas and aneurysms7–10 Dilantin
Atherosclerotic subclavian artery disease11 Chlorpromazine
Atherosclerotic occlusion of the contralateral common carotid artery12 Lithium
Fibromuscular dysplasia of the internal carotid arteries13–15 Tetracycline
Carotid artery dissection4,5,16 TMP/SMX
Intrapetrous carotid artery dissection17 Amiodarone
Brachiocephalic artery stenosis18 Growth hormone
External carotid artery stenosis19 Oral contraceptives
Ectopic intratympanic carotid artery20–22 Indomethacin
Persistent stapedial artery23 Nalidixic acid
Aberrant artery in the stria vascularis24
Vascular compression of the eighth nerve25 TMP/SMX, trimethoprim/sulfamethoxazole.
Increased cardiac output anemia, thyrotoxicosis, pregnancy26,27 From Fishman RA (ed.): Benign intracranial hypertension. In Cerebrospinal Fluid in
Aortic murmurs28 Disease of the Nervous System. Philadelphia, WB Saunders, 1980, pp 128–139.
Paget’s disease9,29,30
Otosclerosis31
Hypertension—antihypertensive agents31
Vascular neoplasms of skull base and temporal bone32–35 self-limiting course; however, in 25% of patients it may
Tortuous carotid and vertebral arteries36 become chronic.37
The exact pathophysiology of this syndrome remains
unclear; however, increased resistance to cerebrospinal fluid
(CSF) absorption resulting in interstitial brain edema is sus-
female patients. This syndrome is characterized by pected.38 Increased intracranial venous pressure secondary
increased intracranial pressure without any focal signs of to elevated intraabdominal, pleural, and cardiac filling pres-
neurologic dysfunction with the exception of occasional sures has been documented in patients with central obesity
fifth, sixth, and seventh cranial nerve palsies.37 Synonyms and associated pseudotumor cerebri.39–41 This is consistent
of this entity include idiopathic intracranial hypertension with the theory according to which increased resistance to
and benign intracranial hypertension syndrome. CSF absorption results in pseudotumor cerebri syndrome.
Diagnosis of this syndrome is made by exclusion of Although the classic presentation of pseudotumor cerebri
lesions producing intracranial hypertension such as syndrome consists of headaches or visual disturbances (or
obstructive hydrocephalus, mass lesions, and venous sinus both), PT alone or in association with hearing loss, dizzi-
occlusion. Pseudotumor cerebri syndrome is of unknown ness, and aural fullness has been reported as the main man-
cause; however, it has been associated with various medical ifestation(s) of this syndrome.1,42–46 Many of these patients
conditions and intake of certain medications.38 Tables 11-2 are morbidly obese (body weight more than 100 lb above
and 11-3 summarize the various conditions and medica- ideal weight) and have associated papilledema. Absence of
tions associated with pseudotumor cerebri syndrome. In papilledema, however, does not exclude this entity.47–49
the majority of patients, this syndrome has a benign and Head CT or MRI is normal in the majority of these
patients, although an empty sella or small ventricles and
cortical sulci may be present.31 Diagnosis is established by
TABLE 11-2. Conditions Associated with Pseudotumor
lumbar puncture and confirmation of CSF pressure of more
Cerebri Syndrome
than 200 mm H2O with normal constituents. The modified
Obesity Dandy diagnostic criteria for pseudotumor cerebri syn-
Anemia drome are summarized in Table 11-4.50
Iron deficiency Pulsatile tinnitus in these patients is believed to have the
Pernicious following pathophysiology. Systolic CSF pulsations
Polycythemia
Steroids
originating from the pulsations of the circle of Willis
Deficiencies arteries are transmitted to the exposed and compressible
Addison’s disease medial aspects of the dural venous sinuses, resulting in
Steroid withdrawal
Excess
Cushing’s disease
Iatrogenic TABLE 11-4. Modified Dandy Diagnostic Criteria
Hypoparathyroidism for Pseudotumor Cerebri Syndrome
Hyperthyroidism
Pituitary adenoma Symptoms and signs of increased intracranial pressure
Uremia Absence of localizing neurologic findings except for occasional sixth and
Cystic fibrosis seventh nerve palsies
Vitamins Awake and alert patient
Deficiencies Absence of deformity, displacement and obstruction of the ventricular system,
Vitamin D and otherwise normal neurodiagnostic studies except for increased CSF
Excess pressure
Vitamin A No other cause of increased intracranial pressure

From Fishman RA (ed.): Benign intracranial hypertension. In Cerebrospinal Fluid in From Wall M, George D: Idiopathic intracranial hypertension a prospective study of
Disease of the Nervous System. Philadelphia, WB Saunders, 1980, pp 128–139. 50 patients. Brain 114:155–180, 1991.
 Pulsatile Tinnitus: Advances in Diagnosis and Treatment 207

alterations of the lumen diameter and conversion of the 0

Hearing level (HL) in dB (RE: ANSI, 1964)

X
normal laminar blood flow to abnormal turbulent flow and 10 X X X X X
PT.1,51 The low-frequency sensorineural hearing loss,
present in many of these patients, is secondary to the 20
masking effect of the PT since light digital compression 30
over the ipsilateral IJV results in immediate cessation
of this symptom and improvement or normalization of 40
hearing.1 Figures 11-3 and 11-4 show representative 50
audiograms of a pseudotumor cerebri patient with low-
60
frequency hearing loss secondary to the masking effect of
PT. This type of hearing loss should be from the low- 70
frequency hearing loss seen in patients with Ménière’s 80
disease by performing this very simple maneuver.
Stretching or compression of the cochlear nerve and 90
brainstem, caused by the intracranial hypertension or pos- 100
sible edema, could also play a role in the hearing loss and
dizziness encountered in these patients. This is supported 110
by the abnormal auditory evoked responses present in one
third of these patients.52 125 250 500 1,000 2,000 4,000 8,000
Frequency in hertz (Hz)
Idiopathic Tinnitus Figure 11-4. Repeated audiogram while digital pressure is applied over the
ipsilateral internal jugular vein reveals normalization of hearing.
Idiopathic or essential PT and venous hum are synonyms
used interchangeably in the literature to describe patients
with PT of unclear cause.6,53,54 The most common age increased ICP, it is suspected that in at least some of them
group of patients with idiopathic PT is between 20 and this symptom was secondary to undiagnosed pseudotumor
40 years, and there is a marked female preponderance.55 cerebri syndrome. Associated symptoms of headaches and
A possible cause of idiopathic PT is believed to be blurred vision, especially in morbidly obese female
turbulent blood flow produced in the IJV as it curves patients, should alert the physician to pseudotumor cerebri
around the lateral process of the atlas.55 Other anatomic syndrome.
abnormalities of the IJV and dural venous sinuses can also Table 11-5 summarizes the venous causes of PT.
produce PT. Diagnosis of this condition should be made
only after appropriate evaluation and elimination of other
disorders such as pseudotumor cerebri syndrome. Since Nonvascular Causes
many of the idiopathic PT patients reported in the litera- Palatal, Stapedial, and Tensor Tympani
ture have not had an adequate work-up to rule out Muscle Myoclonus
Myoclonic contractions of the tensor veli palatini, levator
veli palatini, salpingopharyngeus, and superior constrictor
0 muscles can result in objective PT. These contractions
Hearing level (HL) in dB (RE: ANSI, 1964)

X
10 X X X X X can range between 10 and 240 per minute and should not
[ be confused with the arterial pulse. This disorder is seen
20
in young patients, usually within the first 3 decades of
30 [ life, although it may be encountered in older individuals
[
40
as well.63,64 Neurologic disorders such as brainstem infarc-
tions, multiple sclerosis, trauma, and syphilis have also been
50 reported in association with this condition. Involvement of
60 the olivary tracts, posterior longitudinal bundle, dentate
nucleus, and reticular formation has been identified in
70 these patients.63,65
80 Myoclonic contractions of the stapedial muscle have
also been reported as a cause of pulsatile tinnitus.53,66
90
100
110 TABLE 11-5. Venous Causes of Pulsatile Tinnitus
Pseudotumor cerebri syndrome1
125 250 500 1,000 2,000 4,000 8,000 Jugular bulb abnormalities56–59
Frequency in hertz (Hz) Hydrocephalus associated with stenosis of the sylvian aqueduct60
Increased intracranial pressure associated with Arnold-Chiari malformation60
Figure 11-3. Pure tone audiogram of a patient with PT and associated Abnormal condylar and mastoid emissary veins61,62
pseudotumor cerebri without neck pressure. A low-frequency “sensorineural” Idiopathic or essential tinnitus6,53–55
hearing loss is present.
208 SYMPTOMS OF NEUROTOLOGIC DISEASE

EVALUATION postauricular/upper neck regions, since most dural AVFs

occur in this area. Presence of a bruit in this area should be
History considered an intracranial vascular abnormality until proven
otherwise. Auscultation should be performed in a very quiet
The history is of utmost importance in evaluating patients room, preferably in an audiology booth using a modified
with PT. Most patients will describe their symptom as electronic stethoscope. Auscultation with an electronic
hearing their “own heartbeat” or a “thumping noise,” stethoscope has been found to be more sensitive than
making diagnosis of PT apparent. Occasionally, however, traditional auscultation techniques.67,68 The Litmann
patients may not volunteer the pulsatile component of electronic stethoscope model 2000 can be used for this
their tinnitus and this may lead to overlooking this very purpose. When objective PT is detected, its rate should be
important information. compared with the patient’s arterial pulse. The effect of
Associated symptoms of hearing loss, aural fullness, light digital pressure over the ipsilateral IJV should be
dizziness, headaches, and visual disturbances, such as visual checked. Pulsatile tinnitus of venous origin such as in
loss, transient visual obscurations, retrobulbar pain, and patients with pseudotumor cerebri syndrome decreases or
diplopia are highly suggestive of associated pseudotumor completely subsides with this maneuver.1,46 In patients
cerebri syndrome.1,46 Older patients with a history of with an arterial type of PT this maneuver has no effect on
cerebrovascular accident, transient ischemic attacks, the intensity of the tinnitus. The effect of head rotation on
hyperlipidemia, hypertension, diabetes mellitus, and tinnitus intensity should also be evaluated since venous PT
smoking should be suspected of having ACAD.2 Females often will decrease or completely subside when the head is
with associated headaches, dizzy spells, syncope, fatigue, rotated toward the side of the PT. This is probably due to
and lateralizing neurologic deficits should be evaluated for compression of the IJV between the contracting sterno-
fibromuscular dysplasia (FMD).13–15 The clinician should cleidomastoid muscle and the transverse process of the
highly suspicious of extracranial or intrapetrous carotid atlas.1,46 A complete neurologic examination, including
artery dissection in patients with sudden onset of PT in cranial nerve examination, should also be performed.
association with cervical or facial pain, headache, and Consultation with neurology or neuro-ophthalmology
symptoms of cerebral ischemia.16,17 should be obtained for patients suspected of pseudotumor
cerebri syndrome. Papilledema is compatible with pseudo-
Examination tumor cerebri syndrome; its absence, however, does not
exclude this entity.47–49 Diagnosis of this condition is estab-
Pseudotumor cerebri syndrome should be strongly sus- lished by lumbar puncture and documentation of CSF
pected in young and morbidly obese females with PT.1,45 pressure greater than 200 mm H2O.50 The characteristics
Otoscopy is essential for detecting middle ear pathology of PT in patients with pseudotumor cerebri syndrome,
such as a high or exposed jugular bulb, aberrant carotid ACAD, glomus tumors, and AVFs are summarized in
artery, glomus tumor, and Schwartze’s sign. Rhythmic Table 11-6.
movements of the tympanic membrane can be present in
patients with tensor tympani myoclonus.
Complete head and neck examination is also very Audiologic and Electrophysiologic
important. A palpable thrill may be present with cervical
AVM.8 Myoclonic contractions of the soft palate can be
Testing
identified in patients with palatal myoclonus. Wide opening Pure tone (air and bone conduction) and speech audiome-
of the oral cavity during examination may result in elimi- try should be performed in all patients. When hearing loss
nation of the soft palate contractions.7 of 20 dB or more is detected, a repeat audiogram should be
Auscultation of the ear canal, periauricular region, obtained while the patient is applying light digital pressure
orbits, neck, and chest should be performed for detection over the ipsilateral IJV. Due to elimination of the masking
of objective PT, bruits, and heart murmurs. Particularly effect of the tinnitus, this maneuver typically results in
special attention should be paid when auscultating the improvement or normalization of pure tones in patients

TABLE 11-6. Characteristics of Pulsatile Tinnitus

Pseudotumor Cerebri
Syndrome ACAD Glomus Tumors AVF

Age <40 years >50 years 40 years, average 40 years, average

Sex More common in females More common in females More common in females NR
Weight Obese NR NR NR
Retrotympanic mass − − + −
Objective PT + + − +
Arterial PT − + + +
Venous PT + − − −
Head bruit − − − +
Neck bruit − + − −
Papilledema Common − − −

ACAD, Atherosclerotic carotid artery disease; AVF, arteriovenous fistula; NR, not relevant; PT, pulsatile tinnitus.
 Pulsatile Tinnitus: Advances in Diagnosis and Treatment 209

with venous type PT such as in pseudotumor cerebri syn- abnormalities are diagnosed, no other imaging stud-
drome.1 Discrimination is typically excellent in these ies are needed. For patients with glomus jugulare
patients. tumors, CT examination of the neck should also be
Impedance audiometry should be obtained for suspected obtained to assess for additional chemodectomas
cases of tensor tympani myoclonus. along the carotid arteries. Carotid angiography is
Auditory brainstem evoked responses (ABR) should be indicated only for prospective surgical cases to evalu-
considered in patients with suspected pseudotumor cerebri ate the collateral circulation of the brain (arterial and
syndrome. Abnormalities of this test, consisting mainly of venous) in anticipation of possible vessel ligation or
prolonged interpeak latencies, have been detected in one preoperative tumor embolization.28
third of patients with this syndrome.52 Normalization or
improvement of these abnormalities has been noticed Figure 11-5 depicts a diagnostic algorithm for patients
in the majority of these patients following successful with pulsatile tinnitus.
management.52

Metabolic Work-up MANAGEMENT

Complete blood count and thyroid function tests should Management should be directed toward treating any
be obtained in cases of suspected anemia and hyperthy- underlying cause. Management of the most common
roidism, respectively. Serum calcium levels and studies for causes of PT are as follows:
systemic lupus erythematosus should be considered when Pulsatile tinnitus secondary to idiopathic pseudotumor
pseudotumor cerebri syndrome is suspected. Serum lipid cerebri syndrome responds well to weight reduction
profile and fasting blood sugar should be performed in and medical management with acetazolamide (Diamox)
suspected cases of ACAD. 250 mg tid or furosemide (Lasix) 20 mg bid.1,49 Both of
these medications are thought to reduce CSF production.
Ultrasound Studies Short courses of steroids should be considered only for
acute exacerbations of the syndrome. Lumbar–peritoneal
Duplex carotid ultrasound (including the subclavian shunt should be considered for patients with progressive
arteries) or echocardiogram studies (or both) should be deterioration of vision, persistent headaches, and disabling
obtained in suspected cases of ACAD, atherosclerotic PT.1,31,46 In morbidly obese patients, however, this
subclavian artery disease, or valvular disease.2,31 In partic- procedure is often complicated by shunt occlusion due to
ular, patients with carotid bruits should have a carotid increased intraabdominal pressure.71 Weight reduction
ultrasound study prior to any radiologic evaluation surgery has been found effective in relieving PT in mor-
because if diagnosis of ACAD is established, the need for bidly obese patients with associated pseudotumor cerebri
any radiologic evaluation may be obviated. syndrome and should be considered when conservative
management has failed. Thirteen out of 16 patients who
Radiologic Evaluation underwent this procedure experienced complete resolution
of their PT.72 Optic nerve sheath fenestration has been
Radiologic evaluation should to be individualized accord-
reported to be very helpful for patients with progressive
ing to the history and physical examination findings such
visual loss and headaches.73
as retrotympanic mass, objective PT, bruit, and
Repair of a symptomatic high-dehisced jugular bulb has
papilledema. The following represents the author’s current
been reported by using pieces of mastoid cortical bone and
radiologic evaluation algorithm:
septal, conchal, or tragal cartilage and surgical wax.21,74–76
1. For patients with normal otoscopy, screening with Pulsatile tinnitus secondary to otosclerosis may respond to
high-quality MRA/magnetic resonance venography stapedectomy.31 Tensor tympani and stapedial myoclonus
(MRV) in conjunction with brain magnetic resonance may respond to sectioning of the respective muscles via
imaging (MRI), should be initially obtained. Small tympanotomy.77 Botulinum toxin has also been reported
ventricles or empty sella are findings occasionally seen for the management of palatal myoclonus.78,79
in patients with pseudotumor cerebri syndrome.31 Patients with ACAD benefit from carotid endarterec-
MRI demonstration of dilated cortical veins is tomy when carotid obstruction is more than 60%.80
suggestive of an AVM; however, neither the arterial Angioplasty has relieved PT secondary to atherosclerotic
supply nor the nidus of an AVM may be detectable on obstruction of the subclavian and intracranial carotid
MRI.69 In 12 patients with angiographic diagnosis of arteries.81,82 Pulsatile tinnitus secondary to antihyperten-
AVMs, 8 had dilated cortical veins on MRI.70 Dural sive medication such as enalapril or verapamil subsides
venous sinus thrombosis also can be diagnosed with soon after discontinuation of these agents.31
MRV. In patients with normal MRI/MRA/MRV Dural AVFs can be treated in the majority of patients with
associated with objective arterial PT or a head bruit, selective embolization.83,84 Figures 11-6 and 11-7 are the
carotid angiography should be strongly considered to postprocedure films of the internal carotid artery/cavernous
exclude dural AVFs and fibromuscular dysplasia.23,70 sinus fistula (case 2) following embolization with platinum
2. Patients with a retrotympanic mass should have a high- coils. Radiosurgery or selective embolization followed by
resolution, temporal bone computed tomography (CT) radiosurgery are other modalities of treatment.85,86
as their initial evaluation.31 If glomus tympanicum, Vascular neoplasms such as glomus jugulare tumors can
aberrant internal carotid artery, or jugular bulb be treated surgically in the majority of patients.
210 SYMPTOMS OF NEUROTOLOGIC DISEASE

Retrotympanic Mass Present

CT of temporal bones

Glomus tympanicum Glomus jugulare

Aberrant carotid artery
Jugular bulb abnormalities
Neck CT
Carotid angiography?

Normal Otoscopy

Suspicion of Suspicion of carotid

increased ICP artery abnormality

MRI-MRA, funduscopy Duplex ultrasound

Hydrocephalus LP ACAD MRI-MRA

Thrombosis of Carotid
dural sinuses tortuosity
Pseudotumor Normal
cerebri syndrome

Carotid angiogram if
head bruit present
LP: Lumbar puncture
ICP: Intracranial pressure
ACAD: Atherosclerotic carotid artery disease

B
Figure 11-5. Pulsatile tinnitus diagnostic algorithm.

Figure 11-6. Carotid angiogram, lateral view, of case 2 following

embolization of the fistula with platinum coils (single arrow). The normal Figure 11-7. Postembolization transorbital view of case 2 showing the
ophthalmic artery can now be identified (double arrows). platinum coils in the area of the right cavernous sinus (arrow).
 Pulsatile Tinnitus: Advances in Diagnosis and Treatment 211

Stereotactic surgery may be considered for patients who 18. Campbell JB, Simons RM: Brachiocephalic artery stenosis presenting
are poor surgical candidates.87 with objective tinnitus. J Laryngol Otol 101:718–720, 1987.
Finally, in patients with idiopathic PT, tinnitus typically 19. Fernandez AO: Objective tinnitus: A case report. Am J Otolaryngol
4:312–314, 1983.
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66:273–281, 1968. 1999.
56. Overton SB, Ritter FN: A high placed jugular bulb in the middle ear: 77. Badia L, Parikh A, Brookes GB: Management of middle ear
A clinical and temporal bone study. Laryngoscope 83:1985–1991, myoclonus. J Laryngol Otol 108(5):380–382, 1994.
1983. 78. Jero J, Salmi T: Palatal myoclonus and clicking tinnitus in a
57. Buckwalter JA, Sasaki CT, Virapongse C, et al: Pulsatile tinnitus 12-year-old girl: Case report. Acta Otolaryngol Suppl 543:61–62,
arising from jugular megabulb deformity: A treatment rationale. 2000.
Laryngoscope 93:1534–1539, 1983. 79. Bryce GE, Morrison MD: Botulinum toxin treatment of essential
58. Robin PE: A case study of upwardly situated jugular bulb in the left palatal myoclonus tinnitus. J Otolaryngol 27(4):213–216, 1998.
middle ear. J Laryngol Otol 86:1241–1245, 1972. 80. Executive Committee for the Asymptomatic Carotid Atherosclerosis
59. Smythe GO: A case of protruding jugular bulb. Laryngoscope Study: Endarterectomy for asymptomatic carotid artery stenosis.
75:669–672, 1975. JAMA 273(18):1421–1428, 1995.
60. Wiggs B, Sismanis A, Laine FJ: Pulsatile tinnitus associated with 81. Onald JJ, Raphael MJ: Pulsatile tinnitus relieved by angioplasty.
congenital central nervous system malformations. Am J Otol Clin Radiol 43:132–134, 1991.
17:241–244, 1996. 82. Emery DJ, Ferguson RDG, Williams JS: Pulsatile tinnitus cured by
61. Lambert PR, Cantrell RW: Objective tinnitus in association with angioplasty and stenting of petrous carotid artery stenosis. Arch
abnormal posterior condylar emissary vein. Am J Otolaryngol Otolaryngol Head Neck Surg 124:460–461, 1998.
7:204–207, 1986. 83. Vinuela F: Update of intravascular functional evaluation and ther-
62. Forte V, Turner A, Liv P: Objective tinnitus associated with abnor- apy of intracranial arteriovenous malformations. In: Vinuela F,
mal emissary vein. Otolaryngology 18(5):232–235, 1989. Dion J, Duckwiler G (eds.): Neuroimaging Clinics of North
63. Herrmann C, Crandall PH, Fang HC: Palatal myoclonus: A new America, volume 2, number 2. Philadelphia, WB Saunders,
approach to the understanding of its production. Neurology pp 279–289, 1992.
7:37–51, 1957. 84. Urtasun F, Biondi A, Casaco A, et al: Cerebral dural arteriovenous
64. Bjork H: Objective tinnitus due to clonus of the soft palate. Acta fistulas: Percutaneous transvenous embolization. Radiology
Otolaryngol Suppl (Stock) 116:39–45, 1954. 199:209–217, 1996.
65. Heller MF: Vibratory tinnitus and palatal myoclonus. Acta 85. Flickinger JC, Kondziolka D, Lunsford LD: Radiosurgery of benign
Otolaryngol (Stock) 55:292–298, 1962. lesions. Semin Radiat Oncol 5(3):220–224, 1995.
66. Pulec JL, Hodell SF, Anthony PF: Tinnitus: Diagnosis and manage- 86. Link MJ, Coffey RJ, Nichols DA, Gorman DA: The role of radio-
ment. Ann Otol Rhinol Laryngol 87:821–833, 1978. surgery and particulate embolization in the treatment of dural
67. Sismanis A, Williams GH, King MD: A new electronic device for arteriovenous fistulas. J Neurosurg 84(5):804–809, 1996.
evaluation of objective tinnitus. Otolaryngol Head Neck Surg 87. Jordan JA, Roland PS, McManus C, et al: Stereotactic radiosurgery
100:644–645, 1989. for glomus jugulare tumors. Laryngoscope 110:325–338, 2000.
68. Sismanis A, Butts FM: A practical device for detection and recording of 88. Jackler RK, Brackmann DE, Sismanis A: A warning on venous
objective tinnitus. Otolaryngol Head Neck Surg 110:459–462, 1994. ligation for pulsatile tinnitus. Otol Neurotol 22:427–428, 2001.
 Chapter
The Neurotologic Examination

Outline 12
General Physical Cochlear Timothy E. Hullar, MD
Examination Vestibular
Lloyd B. Minor, MD, FACS
Cranial Nerve I Oculomotor Examination
Cranial Nerve II Cranial Nerves IX, X
Cranial Nerves III, IV, VI Cranial Nerve XI
Cranial Nerve V Cranial Nerve XII
Cranial Nerve VII
Cranial Nerve VIII

T he bedside neurotologic examination allows the exam-

iner to gather information efficiently and accurately.
In many cases, more sophisticated tests simply verify
simple otitis externa, or it may be a manifestation of
a first branchial arch sinus or parotitis tracking through
the fissures of Santorini into the external canal. Post-
a diagnosis initially made on clinical impression alone. auricular edema occurs in 76% of patients with mastoidi-
This chapter reviews the general physical examination of tis.3 Tenderness and redness of the mastoid cortex and
neurotologic patients with special focus on the function of stand-off of the external ear, a softening of the postauricu-
their cranial nerves. lar skin and inability to palpate bony contours behind
the ear, or effacement of the postauricular crease can
indicate a subperiosteal abscess, a complication in 50%
GENERAL PHYSICAL EXAMINATION of patients with coalescent mastoiditis.4 Battle’s sign, or
postauricular ecchymosis,5 has a 100% positive predictive
Physical clues to a patient’s pathology may be obvious value for recent skull base fracture.6 An earlobe crease,
before formal examination even begins. An abnormal gait, although not indicative of otologic disease, may be noted
stance, or head tilt may indicate pathology of the vestibular by the neurotologist and is an indicator (with a sensitivity
system in patients complaining of vertigo or dizziness. of 73% and a specificity of 84%) for coronary artery
Physical deformities associated with neurotologic disease disease.7
may accompany rheumatoid arthritis, congenital syphilis, Although handheld otoscopic examination is handy and
or Paget’s disease. Skin stigmata, such as those associated quick, patients referred to a neurotologist deserve the more
with scleroderma, neurofibromatosis, or lupus, may be thorough examination only a binocular microscope and
associated with neurotologic symptoms. Other findings thin-walled metal speculum allows. The microscope
associated with syndromic disease, such as branchio- increases the examiner’s sensitivity to small movements of
otorenal, Waardenburg’s, or Pendred’s, may be obvious the tympanic membrane caused by muscular contraction,
on meeting the patient. Sometimes, evidence of previous respirations through a patulous eustachian tube, or autoin-
injury or surgery leads the clinician to consider trauma, sufflation.8 A Siegle speculum’s angled faceplate allows pneu-
metastatic disease, or iatrogenic causes of neurotologic matic otoscopy under the microscope without glare; using
symptoms. this technique, “perforations” diagnosed with a handheld
Formal examination of the neurotologic patient begins otoscope are sometimes shown to be monomeric tympanic
with the external ear. Congenital conditions such as preau- membranes. Microscopy frees both of the examiner’s hands
ricular pits or aural atresia suggest internal malformations, to manipulate the patient’s head and speculum, allowing
while an aural polyp is a sign of cholesteatoma with a safe removal of foreign bodies or tightly impacted cerumen.
sensitivity of 33% in previously unoperated ears and A video camera mounted on the microscope can feed paired
71% in ears with an attic or marginal defect.1 Signs of video monitors so the supine patient may follow the clini-
trauma or scars from previous surgery, including evidence cian’s exam of either ear.
of cartilage grafts, can provide the examiner with valuable The otoscope allows visualization of many otologic
information about the patient’s otologic history. Chronic disease processes or their stigmata. The external canal
inflammatory conditions, such as chondrodermatitis may show signs of infection, such as fungus associated with
nodularis chronica helicis or relapsing polychondritis, may otitis externa or vesicles of the Ramsay Hunt syndrome.9
cause a painful, reddened pinna.2 Otorrhea may represent Mechanical obstructions including osteoma or exostoses
215
216 NEUROTOLOGIC DIAGNOSIS

of the ear canal can predispose patients to infection. CRANIAL NERVE I

Inflammatory processes such as Wegener’s granulomatosis
can cause otitis media and otorrhea.10 Aural tuberculosis Olfaction in humans is derived from both cranial nerves I
can cause multiple perforations of the drum with painless and V. Noxious chemicals such as ammonia, acids, and the
otorrhea.11 Otoscopy may reveal masses, such as a high- penetrating odors of peppermint and menthol stimulate
riding jugular bulb, cholesteatoma, glomus tumor, or aural intranasal branches of cranial nerve V.27 What we perceive
foreign body, and can sometimes allow visualization of a as taste is largely a function of cranial nerve I, although
dislodged stapes prosthesis. Hypervascularity on the cranial nerve VII carries fibers to chemoreceptors on the
promontory due to otosclerosis causes Schwartze’s sign, a oral tongue and soft palate and IX carries fibers to the
blush behind the drum.12,8 oropharynx.
A general otolaryngologic examination may uncover find- Lesions attributable to cranial nerve I are analogous to
ings pointing to a particular neurotologic source. This those of VIII in that they are either conductive or neural in
examination includes an ocular examination, detailed in a origin. Conductive losses prevent airborne molecules from
later section under the cranial nerves responsible for ocular reaching the olfactory epithelium in the superior nasal
movement. A nasal exam can show a bluish nasal mucosa, cavity. Air bypasses the nasal mucosa entirely in laryngec-
especially over the inferior turbinates, indicating allergies tomees and patients with nonfenestrated tracheostomies.
contributing to eustachian tube dysfunction. Irritative Patients with nasal masses or deforming nasal trauma suf-
lesions of the nose, including mucosal contact points, may fer olfactory loss due to mechanical obstruction. Localized
cause patients to present with headache or ear pain.13 inflammation, perhaps incited by a prior upper respiratory
Examination of the mouth may reveal a submucous cleft infection, may also block olfactory receptors, although
palate causing eustachian tube dysfunction, or poor denti- respiratory pathogens may be directly toxic to olfactory
tion leading to temporomandibular joint dysfunction and neurons as well.28 Neural losses include those of the olfac-
referred otalgia. Cervical lymphadenopathy can represent tory epithelium itself, such as caused by chemicals or topical
metastases from a nasopharyngeal carcinoma obstructing medications, or central injury due to head trauma shearing
the eustachian tube or pharyngeal malignancy, whereas a the fibers as they enter the cribriform plate or expanding
neck abscess under the sternocleidomastoid may be a tumors. Neurodegenerative diseases such as Alzheimer’s
Bezold’s abscess derived from a suppurative mastoiditis.14 can also cause olfactory loss.29
Pain can be referred to the ear from pathology in the A quick bedside test of olfaction is the alcohol sniff
distributions of the 5th, 7th, 9th, and 10th cranial nerves test.30 A 70% isopropyl alcohol wipe is gradually moved
as well as the cervical plexus. Some causes of referred otal- closer to the nose of a patient until he smells the odor of
gia are erupting teeth, pharyngeal malignancies, periton- the alcohol; this process is repeated five times. An average
sillar abscess, pathology of the temporomandibular joint, distance less than 5 cm indicates anosmia, although this
peritonsillar abscess, laryngitis, thyroiditis, and Eagle procedure may give false-negatives due to activation of
syndrome, consisting of pain secondary to styloid process cranial nerve V. A commercial version to test sensory
irritation.15 thresholds of cranial nerve I is the Smell Threshold
Palpation of the scalp may find crepitus in patients with Test using rose scent (phenyl ethyl alcohol). This type
syphilis, infantile rickets, hydrocephalus, or other causes of of test provides a more quantitative measure of thresh-
bony loss,16 whereas the occiput may be tender in patients old than other odor identification tests, such as the
with tumors of the posterior fossa.17 Tenderness over the 40-odorant scratch-and-sniff University of Pennsylvania
maxillary and frontal sinuses may reveal sinus disease with Smell Identification Test, known commercially as the SIT;
a sensitivity of 48% to 50% and a specificity of 62% to the 12-odor Brief Smell Identification Test (B-SIT),
65%.18 Percussion of the head can elicit a dull “cracked- also known as the Cross-Cultural Smell Identification Test;
pot” sound in children with hydrocephalus, a finding known and the 3-odor Pocket Smell Test (all from Sensonics, Inc,
as Macewen’s sign.19 Haddon Heights, NJ).31
Auscultation helps in the diagnosis of some patients.
The Toynbee tube can be used to listen for a crackle when
the eustachian tube opens,20 although the relative patency CRANIAL NERVE II
of the eustachian tube can also be determined from the
approximate length of time it takes for a patient with a Examination of the optic nerve includes measuring pupil-
perforated drum to note the taste of antibiotic drops lary reflexes, acuity, color perception, visual fields, and
placed in the ear. Pulsatile tinnitus may be due to a glomus funduscopy. Illuminating each eye in succession deter-
tumor, but noise transmitted from turbulent flow in a mines whether defects in the pupillary reflex are afferent
diseased carotid artery or stenotic aortic valve can cause or efferent in nature. Both eyes should contract consen-
a similar perception. Auscultation of the neck and chest sually. Failure to constrict the illuminated eye only
can discriminate between these causes. The most common indicates a defect in the efferent parasympathetic pathway
site of vertebral artery stenosis is at its branch from on that side. Failure to constrict either eye indicates
the subclavian and is best heard in the supraclavicular an optic nerve problem. With vergence, normal pupils
fossa.21,22 Intracranial bruits are best heard over the constrict slightly. The Argyll Robertson pupil of patients
globes17 although reported sensitivity for this test varies with syphilis is small, irregular, and does not react to
widely.23 Palatal24 or laryngeal25 myoclonus can cause light but does react to accommodation. Other conditions
objective tinnitus, as can myoclonus of the intrinsic mus- affecting pupillary function include diabetes, encephalitis, sar-
cles of the middle ear.26 coidosis, Horner’s syndrome, Lyme disease, and intracranial
 The Neurotologic Examination 217

mass; these patients require prompt ophthalmologic CRANIAL NERVES III, IV, VI
referral.
Acuity is measured using a standard Snellen chart at 20 ft. The third nerve innervates all extraocular muscles except
Dynamic visual acuity is a measure of the vestibulo-ocular the abducens (from cranial nerve VI) and the superior
reflex and is described under the vestibular examination. oblique (from cranial nerve IV). A significant palsy of any of
Loss of color perception is an early indicator of loss these nerves will cause diplopia, although central processes
of function of the optic nerve. Ishihara or other standard such as multiple sclerosis (MS) may cause similar symptoms.
tests can be used to measure color perception. Abnormal Restriction of extraocular muscle movement due to entrap-
findings can be seen in patients with pituitary lesions32 or ment, mass effect, or endocrine orbitopathy may mimic a
pathology of the optic nerve. nerve palsy.33 These conditions can be distinguished from a
Visual fields can be tested at the bedside using confronta- true palsy using a forced duction test, during which the
tion or in a formal visual field testing booth. To test the sclera of the anesthetized eye is grasped using a forceps and
visual fields using confrontation, the patient and examiner passively drawn toward the side of the apparent paresis.
sit closely looking at each other with the patient covering A true third nerve palsy leaves the eye laterally deviated
one eye and the examiner covering his opposite eye. The from unopposed action of the lateral rectus muscle, mydri-
examiner then moves his outstretched hand in from the atic from loss of third nerve parasympathetic input, and
four quadrants of the patient’s visual field until the patient with a ptosis of the upper lid from paralysis of the levator
can see his gently wiggling fingers. The test is repeated palpebrae muscle. A unilateral complete paralysis can be
after switching eyes. Common field cuts and their causes caused by elevated intracranial pressure, posterior commu-
are shown in Figure 12-1. nicating artery aneurysm, or subarachnoid hemorrhage;
Funduscopy is the specialty of the ophthalmologist and more benign conditions such as diabetes may reassuringly
requires dilation for anything more than a cursory examina- spare pupillary reflexes.34 Other causes of ptosis include
tion. Elevated intracranial pressures, such as caused by congenital ptosis, myasthenia gravis, aging, or Horner’s
meningitis, sigmoid sinus thrombosis, or bleed, cause a loss syndrome paralyzing Müller’s muscle. Loss of function of
of venous pulsations and papilledema. Signs of papilledema Müller’s muscle leaves the superior orbital crease intact,
include a blurring of the margin of the optic disc, engorged while a ptosis due to third nerve palsy relaxes the levator
veins, and “cotton-wool” spots, each of which is caused aponeurosis insertion on the eyelid and may obliterate
by increased intracranial pressure. Papilledema and optic this fold. Other findings in a Horner’s syndrome include
neuritis cause elevation of the optic disc, with the latter ipsilateral anhidrosis and anisocoria (inequality of pupil
usually accompanied by an early loss of vision. Cavernous size, with the smaller, miotic pupil on the affected side).
sinus thrombosis can cause venous stasis in the entire orbit Any interruption of the cervical sympathetic pathway
including the fundus and sclera. within the skull base, neck, or thorax can cause these
symptoms. A suspected Horner’s syndrome can be con-
firmed by instilling 4% cocaine in the eyes bilaterally. A
Horner’s-induced miotic pupil will not dilate, whereas a
normal variant will.35
The Paredrine test determines the site of a lesion pro-
Homonymous hemianopsia
ducing a Horner’s syndrome. In this test, 1% hydroxyam-
phetamine (Paredrine) instilled in the eyes bilaterally
should cause symmetrical dilation if the postganglionic
nerve is intact, as is common in brainstem lesions, such as
Wallenberg’s syndrome,36 or other interruptions of the
preganglionic pathways. The eyes of a patient with a
Bitemporal hemianopsia postganglionic lesion will not dilate normally, although
false-negatives have been reported.37
The fourth (trochlear) cranial nerve controls the superior
oblique muscle, rotating the eye downward and causing
inward torsion. Its downward effect is more prominent on
medial gaze and its torsional effect more evident on lateral
gaze. It is particularly susceptible to trauma , probably due
Binasal hemianopsia
to its intracranial course, the longest of any cranial nerve.
Injuries to the trochlear nerve cause extorsion and hyper-
tropia of the affected eye with consequent diplopia;
Figure 12-1. Binocular field defects. Visual field defects are represented in a patient can partially compensate for this by tipping the
black, from the patient’s perspective. Homonymous hemianopsia is a conse-
quence of a postchiasmal defect. The degree of the defect (from a “pie
head toward the unaffected side. This effect should not
wedge” to half of the entire field) and the congruity of the defect between be confused for torticollis caused by birth trauma or other
the two sides can help determine the exact position of the defect. A total causes, including an attempt by the patient to extinguish a
homonymous hemianopsia, as shown here, can be caused by any postchias- positional nystagmus. The Bielschowsky head-tilt test can
mal defect. Bitemporal hemianopsia is caused by a chiasmal lesion if the help distinguish the side of a superior oblique lesion caus-
defect respects the vertical meridian, as shown here. A binasal defect can
be due to optic nerve disease or, rarely, compression of the lateral optic ing diplopia: By tilting the head toward the side of the
chiasm. (From Wilson-Pauwels L, Akesson E, Stewart P: Cranial Nerves. lesion, the diplopia should worsen with the unbalanced
Toronto, BC Decker, 1988.) action of the contralateral, intact superior rectus.38
218 NEUROTOLOGIC DIAGNOSIS

The abducens nerve innervates the lateral rectus muscle. cold objects for temperature, and a pin or sharply broken
This nerve is commonly affected in cases of skull base wooden stick for pain. A cotton-tipped swab touched to the
trauma or inflammatory conditions and in MS via inter- mucosa of the nose is a noxious but inoffensive stimulus
ruption of the medial longitudinal fasciculus. Tumors of to rouse an unresponsive patient. Corneal reflexes are a
the cerebellopontine angle can affect the sixth nerve, occa- particularly important part of the neurotologic examina-
sionally bilaterally.35 Along with cranial nerves III, IV, V1, tion. If possible, the patient turns his eyes to the opposite
and V2, pathology in the vicinity of the cavernous sinus can side to expose as much sclera as possible, protecting the
affect function of the sixth nerve. A paralysis of lateral gaze cornea and preventing the patient from observing the test.
in an immunocompromised patient with fungal sinusitis, The examiner then “walks” a fine wisp of cotton across the
for example, indicates cavernous sinus involvement and is sclera (which should not be reactive) toward the cornea
a contraindication to surgical intervention.39 Möbius syn- (which should be). A bilateral blink indicates an intact
drome includes congenital paralysis of nerves VI and VII40 V1 on the tested side and seventh nerve bilaterally; a con-
although this term has also been applied to episodic cranial tralateral blink indicates loss of seventh nerve function on
nerve III palsy associated with migraine.41 Gradenigo’s the tested side, and no response indicates loss of the fifth
syndrome, caused by petrosal disease, comprises the symp- nerve on the tested side or loss of seventh nerve function
toms of a draining ear, pain in the distribution of V1, and bilaterally.
abducens palsy. It can also cause excessive lacrimation.42,43 The muscles of mastication, including temporalis, mas-
seter, and medial and lateral pterygoid as well as the mylo-
hyoid, anterior belly of digastric, and tensor veli palatini
CRANIAL NERVE V and tensor tympani muscles, are controlled by the fifth
nerve via V3. Pronounced wasting of the temporalis can be
The fifth cranial nerve has three major branches: the oph- due to chronic disease or starvation or, in unilateral cases,
thalmic (V1), maxillary (V2), and mandibular (V3) divisions nerve or CNS injury. A significant weakening of the tem-
(Fig. 12-2). V1 provides sensation to the upper face, including poralis or masseter will prevent the patient from closing his
the cornea, bridge of nose, upper nasal mucosa, and frontal mouth tightly. A reflex jaw jerk will stimulate the muscles
sinus. V2 provides sensation to the midface, including the of mastication to close the partially opened mouth after
lower nose and nasal mucosa, cheek, maxillary sinus, and a sharp tap on the chin, although this response may give
entire oral cavity except the lower lip. V3 provides sensation little information about degree of strength. Oropharyngeal
to the lower teeth, lower lip, and tongue (except for taste, inflammation, mass, or tumor invasion can cause spasm
supplied from cranial nerve VII via the chorda tympani). of the pterygoids and trismus; a process involving the
Sensation on the face should be tested in the conven- pterygoids can be palpated transorally. A temporomandibu-
tional way, using a wisp of cotton for light touch, warm and lar joint disorder is much more likely than a muscular

Frontal
nerve
Lacrimal
gland

Deep temporal
nerve
Lacrimal
nerve Mesencephalic
nucleus
Ciliary Pontine
ganglion trigeminal
Nasociliary nucleus
nerve Trigeminal Figure 12-2. Trigeminal nerve. Major
Zygomatic ganglion motor and sensory branches of the
nerve Motor fifth cranial nerve are shown.
(masticator) (From Wilson-Pauwels L, Akesson E,
nucleus Stewart P: Cranial Nerves. Toronto, BC
Nucleus of the Decker, 1988.)
spinal
Infraorbital trigeminal
nerve tract
Pterygopalatine
ganglion
Pterygopalatine Foramen ovale
nerve (cut) Foramen rotundum
Lingual Nerve to the medial pterygoid
nerve Auriculotemporal nerve
Mental Superior orbital tissue
nerve Inferior alveolar nerve
Buccal Masseteric nerve
Nerve to anterior belly nerve
of the digastric
and mylohyoid
 The Neurotologic Examination 219

problem to cause deviation in jaw movement, although in substance causes reflex tearing if the GSPN is intact. The
unilateral muscular paralysis the jaw will deviate to the test itself is performed after protecting or topically anes-
affected side. thetizing the eye against direct irritation. The examiner
places folded pieces of filter paper from the lateral portion
of the lower eyelid, with the rounded tip of filter paper
CRANIAL NERVE VII inserted in the conjunctival fornix without stimulating the
cornea. Five minutes of tear absorption onto the filter
The facial nerve is of utmost importance to neurotologists. paper are measured and compared; a distance in the tested
Careful appreciation of its function in all branches before eye of less than 50% of the control eye indicates dysfunc-
treatment allows accurate monitoring of pathologic tion.44 Patients with unilateral Bell’s palsy may have bilat-
processes and surgical results. Thorough examination of erally reduced lacrimation, so false-negatives may result
the facial nerve includes evaluation of its intracranial and unless a minimum total distance (summed from both eyes)
extracranial branchings and of both its sensory and motor of 25 mm is reached.45
fibers. The facial nerve contributes parasympathetic fibers to
The initial branch of the facial nerve is at the geniculate the submandibular ganglion via the chorda tympani. A loss
ganglion, where the greater superficial petrosal nerve of parasympathetic function from a lesion of the facial
(GSPN) travels forward as the nerve turns toward the tym- nerve may reduce salivary flow enough to cause symptoms
panic segment (Fig. 12-3). Preganglionic parasympathetic of xerostomia. Fibers of taste innervating the anterior two
fibers in the GSPN synapse in the pterygopalatine gan- thirds of the tongue originate in the nervus intermedius
glion before innervating the nasal mucosa and lacrimal and branch from the facial nerve in the mastoid process,
glands. Lesions of the facial nerve can cause either a dry cross the inner ear as the chorda tympani, and join the
eye or excessive tearing: Division of the nerve proximal to lingual nerve. In addition to lesions of the facial nerve,
the geniculate causes a dry eye, but distal division of the MS, hypothyroidism, diabetes mellitus, liver or kidney
nerve can allow exposure and irritation of the eye and exces- failure, vitamin deficiency (zinc or B3), or a history of oral
sive tearing. The modified Schirmer test is a semiquantita- radiation treatment can alter taste. Some free endings of
tive way to measure lacrimal function. It depends on a the fifth cranial nerve are also present on the tongue, and
noxious stimulus, such as ammonia or mechanical irritation disorders of this nerve can cause altered taste sensation.
of the nasal mucosa with a cotton swab that stimulates Fibers of the seventh nerve innervate taste buds on the
cranial nerve V and stimulates tearing. Inhalation of the ipsilateral tongue with sensation for sweet, sour, salty, and

Lacrimal
gland

Pterygopalatine
ganglion

Motor
nucleus
of VII
Superior salivatory
(lacrimal)
Figure 12-3. Facial nerve. Major motor nucleus
and sensory branches of the seventh Nucleus solitarius
cranial nerve are shown. (From Wilson- (rostral gustatory
Pauwels L, Akesson E, Stewart P: portion)
Cranial Nerves. Toronto, BC Decker,
1988.) Spinal nucleus
of trigeminal nerve

Internal acoustic
meatus
Stylomastoid
foramen
Submandibular Petrotympanic
ganglion fissure
(chorda tympani
Submandibular nerve)
gland
Sublingual
gland
220 NEUROTOLOGIC DIAGNOSIS

bitter. Inspection of the taste buds may reveal a loss of their the cornea from desiccation during sleep. Eye patches are
normal pink velvety texture on the side of a tongue affected not appropriate for these patients as they may not prevent
by a chorda tympani injury, as denervation disrupts actin opening of the eye and may allow drying of the eye hidden
filaments in taste pore cells.46 Chemical testing involves behind the patch. Any question about ability of the patient
placing a cotton-tip applicator soaked in salty or sugary to close the eye warrants examination of the cornea using
water or weak vinegar on the tongue. The patient must fluorescein and a Wood’s lamp or a slit lamp to rule out
indicate the taste by pointing rather than speaking, as conjunctival irritation or keratitis.
pulling the tongue into the mouth to speak permits rapid Overactive movements of the facial nerve can give diag-
diffusion and a false-negative result for unilateral loss. In nostic information. Hemifacial spasm can be caused by
cases of Bell’s palsy, taste may return quicker than muscle arterial irritation of the facial nerve at the root entry zone51
function.47 Electrogustometry may be a valuable addition and may be a symptom of acoustic neuroma.52
to bedside testing for taste if further questions persist.
A tiny branch of the facial nerve supplies the stapedius
muscle in the middle ear. Tonic motion of this muscle may CRANIAL NERVE VIII
cause objective tinnitus,26 while patients with hypofunc-
tion of this muscle (following section of its tendon during Cochlear
stapes surgery, for example) may complain about hypera-
cusis. An audiologist can directly test its function by elicit- Examination of the eighth nerve is divided into cochlear
ing stapedial reflexes, a test also critical in distinguishing and vestibular segments (Fig. 12-4). Audiologic assessment
otosclerosis from superior canal dehiscence. is an integral part of the examination of the cochlear nerve,
The seventh nerve supplies sensation to the posterior but bedside tests can guide initial diagnostic thinking. The
tympanic membrane and external auditory canal, lateral most common tuning fork tests are the Weber and Rinne
concha and helix, lobule, and mastoid. Loss of sensation in tests, both commonly performed with a 512-Hz fork. The
the external auditory canal may be an early indicator of Weber is usually performed by placing the vibrating tun-
acoustic neuroma.48 Motor branches carry fibers to the ing fork on the patient’s forehead; the patient will lateral-
posterior auricular muscles, to the stylohyoid and posterior ize the sound to the ear with a conductive loss or away
belly of the digastric, and to the muscles of facial expres- from the ear with a sensorineural loss.53 Placing the han-
sion via the temporal, zygomatic, buccal, marginal dle of the fork on the upper teeth or gums increases the
mandibular, and cervical branches. Weakness of the mar- patient’s awareness of the tone by 10 dB.54 Sensitivity of
ginal mandibular nerve can be mimicked by separation of this test is 58% for sensorineural loss greater than 30 dB
the platysma muscle during neck dissection. Lyme disease, and 54% for conductive loss greater than 20 dB, while
syphilis, Guillain-Barré syndrome, amyotrophic lateral specificity is 79% and 92%, respectively.55 The air-
sclerosis, tuberculosis, or MS may accompany weakness or conduction Rinne test is performed with the tines of the
paralysis of the facial nerve.49 Crossed central fibers some- fork along the interauricular axis and the bone-conduction
times allow the ipsilateral forehead to function normally test on the mastoid cortex.56 To avoid overtones, the fork
after a central lesion. must not be struck on a hard surface or too forcefully.57
The House-Brackmann scale affords a quantifiable way A Rinne test is termed positive if the air-conduction signal
to evaluate facial nerve weakness (Table 12-1).50 Paramount is louder than the bone-conduction signal.58 A negative
on this scale is noting if the patient has a rating of 4 or Rinne test with a 512-Hz tuning fork indicates a 25- to
greater, indicating incomplete eye closure. Serious corneal 30-dB hearing loss. A similar result with a 256-Hz fork
damage and permanent loss of vision can occur rapidly in implies a gap of 15 dB, while at 1024 Hz the gap is at least
patients with exposed corneas, especially in those with 35 dB.59 There is no need to use masking during a Rinne
lesions of cranial nerve V rendering the cornea anesthetic. test.60 The sensitivity of the Rinne test at 512 Hz is 60%
Lubricant and a moisture chamber should be placed over to 90% and the specificity is 95% to 98%.61,62
the eye of any patient with questionable closure, as an Infrequently used tuning fork examinations include the
intact Bell’s phenomenon cannot be relied on to protect Bing test and the Schwabach test. In the Bing test, the tuning

TABLE 12-1. The House-Brackmann Facial Nerve Grading System

Grade Description Gross Function Resting Appearance Dynamic Appearance

1 Normal Normal Normal Normal

2 Mild dysfunction Slight weakness with possible Normal Slight oral asymmetry; complete eye
slight synkinesis closure with minimum effort; moderate
to good forehead function
3 Moderate dysfuntion Obvious asymmetry; noticeable but Normal Slight oral asymmetry; complete eye
not severe synkinesis, contracture, closure with effort; slight to moderate
or hemifacial spasm forehead movement
4 Moderately severe Obvious weakness or disfiguring Normal Asymmetrical mouth, incomplete eye
dysfunction asymmetry closure, no forehead movement
5 Severe dysfunction Barely perceptible motion Asymmetrical Slight oral movement, incomplete eye
closure, no forehead movement
6 Total paralysis None Asymmetrical No movement
 The Neurotologic Examination 221

Figure 12-4. The labyrinth. Major

structures of the right inner ear, seen
from the lateral aspect. Structures shown
include the utricle (utr.), sacculus, ante-
rior or superior semicircular canal (sup.),
posterior semicircular canal (post.) and
horizontal or lateral semicircular canal
(lat.). The superior vestibular nerve
innervates the horizontal and anterior
semicircular canals and the utricle.
The inferior vestibular nerve innervates
the posterior semicircular canal and the
saccule. The cell bodies for the
vestibular nerves are located in Scarpa’s
ganglion (Gangl. Scarpae). (Drawing
from the Brödel Archives, No. 933. With
permission of the Department of Art as
Applied to Medicine, Johns Hopkins
University.)

fork is placed on the mastoid and the external auditory sensations of vertigo (illusory sense of rotatory, linear, or
canal is alternately occluded and opened. A patient with tilting motion) or just light-headedness; direction of
conductive hearing loss will note no change in intensity, perceived motion; sensitivity to head motion leading to
while normal patients or those with sensorineural hearing oscillopsia (sensation of movement of objects known to be
loss will find that the tone becomes louder with occlusion. stationary); relationship to other otologic symptoms
This test is not as sensitive as the Rinne test but its speci- such as hearing loss, fullness, and tinnitus; duration and
ficity is equivalent.63 The Schwabach test consists of placing frequency of symptoms; exacerbating or provoking factors;
a vibrating tuning fork on the patient’s mastoid and remov- and other medical problems, including psychological disor-
ing it when he can no longer hear it. If the examiner can ders and conditions requiring medications that may cause
still hear the fork, the patient has a sensorineural loss, but symptoms of dizziness. In some patients, this history com-
if the patient hears the fork longer than the examiner, the bined with a thorough bedside examination is sufficient to
loss is conductive.64 This test depends, of course, on an make a diagnosis and treatment plan, but many others
examiner with normal hearing. will require further testing such as calorics, rotatory chair
Although more formally tested by an audiologist, a neu- testing, and imaging in order to make a diagnosis.
rotologist can also test a patient’s response to words at the
bedside. The examiner must mask the contralateral ear Oculomotor Examination
and cover his mouth to prevent lip reading or stand behind
the patient while whispering letter or number triplets as The exquisite control of eye movements by the vestibular
quietly as possible. If the patient fails to recognize more system allows them to serve as particularly valuable meas-
than 50% of the items, the test is positive. Patients with ures of vestibular function. Eye movements are classified
pathology of the auditory nerve (rather than the cochlea) into several categories. Fixation allows an image to be held
may have more difficulty with words than suggested by steady on the retina, while saccades bring an image onto the
their response to tuning forks or other pure tones. The fovea and smooth pursuit holds it there as it moves across the
sensitivity of this test is greater than 90% and its specificity field of view. Vergence moves the eyes in opposite directions
greater than 80%.65 to keep an image on the foveae as it approaches or moves
away from the observer. Nystagmus is oscillatory movement
of the eyes and can be normal or pathologic.
Vestibular The examiner must understand the physiological mecha-
The clinical history is critical to guiding appropriate exam- nisms underlying nystagmus in order to use it as a diagnos-
ination of the vestibular system. History-taking is notori- tic tool. Normally, three neurologic mechanisms collaborate
ously difficult in patients complaining of disturbed to control the eye’s position in the orbit: gaze-holding, or
equilibrium, however, because normal sensation depends the ability to hold the eye at an eccentric position despite
on subconsciously integrating inputs from somatosensory its natural tendency to drift back to neutral position; visual
receptors, vision, and the vestibular system. Particular fixation, which detects drift of images across the retina and
attention should be paid to whether the patient has actual suppresses unwanted saccades; and the vestibulo-ocular
222 NEUROTOLOGIC DIAGNOSIS

reflex (VOR), which uses vestibular input to keep the fovea The vestibular system is the third source for the signals
directed stably at a target despite head motion in space.66 that produce nystagmus. Nystagmus may originate any-
Nystagmus is a characteristic finding in disorders of any of where in the vestibulo-ocular pathway, including the
these three mechanisms. It can consist of either sinusoidal vestibular periphery, the eighth nerve, and the vestibular
movements, termed pendular nystagmus, or alternating nucleus and cerebellum. Unilateral vestibular hypofunction
slow and fast phases, called jerk nystagmus. Jerk nystagmus causes a static imbalance in the activity of the semicircular
is described by the direction of its fast phases, although canal-related VOR and results in a spontaneous jerk nystag-
these are simply resetting motions separating the physio- mus. This can be either centrally based, as in the case of
logically more relevant slow phases that guide the eye periodic alternating nystagmus, or due to a peripheral
smoothly across the orbit. lesion. Peripheral dysfunction tends to cause motion of the
Failure of the gaze-holding system can cause several eyes in the planes of the semicircular canals, such as with the
types of jerk nystagmus: gaze-evoked nystagmus, cen- horizontal-torsional nystagmus typically observed acutely
tripetal nystagmus, or rebound nystagmus. The “neural following unilateral labyrinthectomy. The horizontal com-
integrator” is responsible for holding the eye at an eccen- ponent fast phases beat toward the “stronger” (intact) ear,
tric position and is typically weakened following unilateral and the torsional component involves beating of the supe-
vestibular loss. Gaze-evoked nystagmus is characterized by rior poles of the eyes toward the intact ear. The speed of the
slow phases caused by the drift of the eye toward its neutral slow phase is generally constant for peripheral vestibular
position in the orbit. Centripetal nystagmus is the reversal disturbances. Because nystagmus caused by peripheral
of this direction. Rebound nystagmus is the short-lived lesions is relatively suppressed with visual input, examina-
nystagmus, also opposite to the direction of gaze-evoked tion is best carried out using Frenzel lenses. These special
nystagmus, that occurs after the eye returns from an high-diopter goggles prevent patients from fixating on their
eccentric to a neutral position. The patient’s gaze-holding environment while allowing magnified examination of the
ability is tested by maintaining eccentric horizontal, then eyes, making them an essential tool for the neurotologist.
vertical positions of gaze (approximately 30 degrees from Vestibular imbalance may also cause a skew deviation, or
center orientation). Minimal drift should normally be vertical misalignment of the eyes caused by an imbalance
encountered for periods up to 15 sec. Nystagmus due to of input along otolith-ocular pathways. Both a skew devi-
errors in gaze-holding is most commonly found as a side ation and an ocular motor palsy can present with diplopia,
effect of medications (including sedatives67 and anticon- although the misalignment due to a skew deviation is usu-
vulsants68 although it can also indicate a structural lesion in ally constant, while a fourth cranial nerve palsy’s effects
the nucleus prepositus hypoglossi, medial vestibular worsen with gaze downward and medially. Patients with a
nucleus,69 or interstitial nucleus of Cajal.70 It is also seen in skew deviation often complain of vertical or torsional
familial episodic ataxia, a channelopathy responsive to diplopia (two images tilted relative to each other). A subtle
acetazolamide.71 Gaze-evoked nystagmus is a normal skew can be detected as the eyes are alternately covered by
finding at extremes of gaze, where it is called “end-point” the examiner, or by covering one eye with a red lens
nystagmus. End-point nystagmus may be asymmetrical, (Maddox rod) to dissociate the images and allow the
sustained, occur with less than full deviation of the eye, and patient to describe the diplopia. The lower (hypotropic)
may even have a torsional component. It has a relatively eye is usually on the side of the lesion, although lesions
slow velocity and is not accompanied by other pathologies. higher than the vestibular nucleus (where the pathways
Disorders of the visual pathway can cause either jerk decussate) may cause the higher eye to be on the side of
or pendular nystagmus. Vertical, horizontal, or torsional the lesion. The head is usually tilted toward the lower eye.
jerk nystagmus with a drifting “null” position can result A combination of defects in gaze-holding and vestibular
in patients with total blindness.72 Pendular nystagmus can input contribute to several types of nystagmus. Bruns’ nys-
occur in patients with subtotal visual loss preventing rapid tagmus, found in patients with cerebellopontine angle
feedback during normal drifting of the eye; corrective tumors, is a combination of gaze-evoked nystagmus with
motions are therefore delayed and ocular oscillations result.73 low-frequency, large-amplitude fast phases on looking
Pendular nystagmus may be congenital, although acquired toward the side of the lesion and jerk nystagmus with high-
pendular nystagmus may be seen in demyelinating disorders, frequency, small-amplitude fast phases on looking away
brainstem injury, or hypoxic encephalopathy. Congenital from the lesion.74 The gaze-holding nystagmus may repre-
nystagmus, likely due to miswiring of anterior visual path- sent the body’s way of canceling the jerk nystagmus caused
ways, characteristically shows an increase in velocity during by vestibular imbalance.75 Nystagmus arising from a
each slow phase, and patients may favor an eccentric angle of peripheral lesion and many central lesions is more intense
gaze where the nystagmus is minimized.66 Dynamic eye (slow-phase velocity higher) when the eye is deviated in
motion is first tested by asking the patient to perform the direction of the quick phase (Fig. 12-5).76 Known as
saccades. The patient fixates on the examiner’s nose, then Alexander’s law, this effect is due to the addition of gaze-
shifts rapidly to a finger target held about 15 degrees away. evoked nystagmus caused by loss of the neural integrator
Velocity, accuracy, and latency are noted. Smooth pursuit is following a peripheral lesion and the vestibular nystagmus
tested by having the patient follow a target moving horizon- caused by the static asymmetry of the lesion itself. The two
tally at less than 20 degrees/sec. Corrective saccades in one factors tend to add when looking away from the lesion and
direction reflect asymmetries in horizontal tracking and are cancel each other out when looking toward it.75
more significant than a symmetrical decrease in smooth Head shaking nystagmus (HSN) evaluates the patient
tracking. VOR cancellation is tested by following a target for an imbalance in dynamic vestibular function. The
(e.g., the examiner’s finger) by turning the head. patient is instructed to shake the head vigorously about
 The Neurotologic Examination 223

sensitivity of the test can be improved by beginning each

head movement with the patient’s eyes in primary gaze
position and moving the head at random intervals and
order to the right and left. The test can also be used to
Vestibular detect dysfunction in the vertical canals by delivering the
Gaze-holding head thrusts in approximately the plane of each anterior
canal, moving the head down and to the ipsilateral side,
and each posterior canal, moving the chin up and to the
contralateral side.80 Side-to-side “head heaves” are being
investigated as an analogous measure of high-frequency
otolith function.81
Vestibular Patients with reduced vestibular function, particularly
Gaze-holding bilaterally, may show up to a five line decline in acuity with
head movement while reading a Snellen chart.82 Normal
subjects typically show no more than a one line decline
in visual acuity. Dynamic visual acuity is tested during
horizontal head oscillations at a frequency of about 2 Hz.
Vestibular Subjects with corrective lenses are instructed to wear their
Gaze-holding glasses or contact lenses during this testing. A general
Figure 12-5. Alexander’s law. After unilateral vestibular loss, the eye tends to measure of these changes can be determined with bedside
drift to center. The addition of this effect and the imbalance in vestibular tests, although predictive mechanisms during repetitive
activity between the two labyrinths causes nystagmus to be more pro- oscillations of the head may augment performance during
nounced when looking away from the lesion. In straight-ahead gaze (top), this test and decrease its sensitivity.83
only the imbalance in vestibular activity caused by a right-sided vestibular
lesion (denoted with an X) causes eye motion; the direction of slow phases Patients often complain of dizziness on moving their head
are indicated with an arrow. When the eyes look to the direction of the slow into a certain position. Positional (sustained) and positioning
phase (middle), the eyes drift back towards the center, subtracting from the (transient) nystagmus are tested in these patients. Dix-
vestibular slow phase. When the eyes look away from the direction of the Hallpike positioning for identification of posterior canal
slow phase (bottom), the same centripetal drift of the eyes adds to the
vestibular slow phase, and the net slow phase velocity increases. (After
benign paroxysmal positioning vertigo (BPPV) is performed
Carey JP, Minor LB: Mixed peripheral and central vestibular disorders. first (Fig. 12-7).84 The patient sits upright on an examina-
In JA Goebel, [ed.]: Practical Management of the Dizzy Patient, Philadelphia, tion table. For testing to detect the presence of right poste-
Lippincott, Williams, and Wilkins, 2000, p 237.) rior canal BPPV, the head is turned 45 degrees such that the
chin is toward the right shoulder. The patient is then
brought straight back rapidly into a right head-hanging
30 times horizontally with the chin placed about 30 position. This position is maintained for at least 30 sec.
degrees downward while wearing Frenzel goggles. The
examiner looks for any nystagmus immediately after the
patient stops shaking the head. Normal subjects usually
have none or occasionally just a beat or two of HSN. With
a unilateral loss of labyrinthine function, however, there is
usually a vigorous nystagmus with slow phase components
initially directed toward the lesioned side.77 HSN arises
because there is asymmetry of peripheral inputs during
high-velocity head rotations, with more activity generated
during rotation toward the intact side than toward the
affected side. This asymmetry allows an accumulation of
activity within central “velocity storage” mechanisms dur-
ing head shaking, and nystagmus following head shaking
reflects discharge of that activity. The amplitude and dura-
tion of the initial phase of HSN depends on the state of the
velocity storage mechanism. Because velocity storage is
typically ineffective during the immediate period after an
acute unilateral vestibular loss, the primary phase of HSN
may be absent or attenuated in these circumstances.
The head thrust test examines more rapid, high-acceler-
ation motion than does the test for HSN (Fig. 12-6). With
the patient looking carefully at the examiner’s nose, the Figure 12-6. Head-thrust test in a case of left horizontal canal paresis.
head is turned rapidly a small arc to the right or left. Eye The patient’s head is turned slightly off center (A) and then thrust rapidly
movements of abnormally low amplitude will be evoked in to her right (B). Note that her eyes remain fixed on the examiner during this
response to head thrusts toward a lesioned or hypoactive maneuver toward the intact side. After the identical maneuver toward the
affected side, her eyes lag momentarily (C) before refixating on the examiner
labyrinth78 and will be followed by the corrective saccade (D). This test is essentially a high-acceleration version of the familiar doll’s
required to bring the eyes back to the intended point eyes maneuver (After Halmagyi GM, Curthoys IS: A clinical sign of canal
of fixation.79 These saccades can be quite subtle, but the paresis. Arch Neurol 45:737, 1988).
224 NEUROTOLOGIC DIAGNOSIS

Right horizontal canal excitation asymptomatic human subjects.85 A central lesion is most
likely when positional nystagmus is purely vertical or
purely torsional, or if there is a sustained unidirectional
horizontal positional nystagmus of high enough intensity
to be observed without Frenzel lenses.
Valsalva-induced nystagmus is produced either with the
glottis open, by pinching the nose, or with the glottis closed.
Right superior canal excitation With the glottis open, middle-ear pressure is raised, while
with the glottis closed, intracranial pressure increases.
Craniocervical junction anomalies (e.g., Arnold-Chiari
malformation), superior semicircular canal dehiscence syn-
drome, and perilymph fistula can produce nystagmus with
this maneuver; superior canal dehiscence can reverse its
direction depending on whether intracranial or intratym-
Right posterior canal excitation panic pressure increases.
Tullio’s phenomenon is the occurrence of vestibular
symptoms and eye movements with sound. Hennebert’s
sign is the occurrence of these symptoms and signs with
motion of the tympanic membrane and ossicular chain.
Eye movements evoked by sound or changes in middle ear
pressure are observed using Frenzel lenses while giving
Figure 12-7. Eye movements evoked by vestibular stimulation. The effects of pure tones from 500 to 4000 dB at intensities of 100 to
individual stimulation of each of the right semicircular canals is shown. The
arrows depict the slow-phase components of the nystagmus. Excitation of 110 dB. Hennebert’s sign is elicited with tragal compres-
the right horizontal canal causes a horizontal nystagmus with leftward slow sion or insufflation through a Siegle’s speculum (fistula
phases. A vertical-torsional nystagmus is caused by excitation of the superior test). Otic syphilis, Ménière’s disease, and perilymph fistula
or posterior canals. Note that, while turning the eyes toward the side of the have also been reported to cause these signs, although
stimulus, the superior canal induces a predominantly linear motion and the
posterior canal a rotatory motion. Turning the eyes away from the side of
the specific features of the evoked eye movements have
the stimulus causes the superior canal to induce a more rotatory motion and not been well characterized. These signs, have recently
the posterior canal a more linear motion. This distinction can be helpful in been documented in patients with superior semicircular
diagnosing BPPV and superior canal dehiscence syndrome. (After Minor LB: canal dehiscence syndrome,86,87 with the evoked eye move-
Superior canal dehiscence syndrome. Am J Otol 21:9, 2000.) ments aligning with the plane of the affected superior
canal (Fig. 12-8).88
Hyperventilation may provoke symptoms in patients with
The nystagmus characteristic of BPPV begins after a anxiety or phobic disorders but does not usually produce nys-
latency of 2 to 10 sec, increases in amplitude over about tagmus. Patients with demyelinating lesions of the vestibular
10 sec, and declines in velocity over the next 30 sec. Posterior nerve (e.g., an acoustic neuroma or through compression by
canal BPPV results in a vertical-torsional nystagmus with the a small blood vessel) or of central structures (e.g., caused by
slow phase components of the nystagmus directed inferiorly MS) may show hyperventilation-induced nystagmus.89
and toward the uppermost ear. Thus, the fast-phase compo- Hyperventilation reduces PCO2, which leads to an increase
nents of the nystagmus are superior and toward the lower in serum and cerebrospinal fluid (CSF) pH. This relative
ear. Due to the orientation of pulling directions for the alkalosis increases the binding of extracellular calcium to
oblique and vertical recti muscles, the planar characteristics albumin and leads to an increase in the discharge rate and
of the nystagmus change with direction of gaze (when conduction in partially demyelinated axons. Because of this
described with respect to an eye-fixed coordinate system): sudden jump in activity of the lesioned nerve, the direction
On looking to the dependent ear it becomes more torsional; of nystagmus with hyperventilation reflects a relative weak-
on looking to the higher ear it becomes more vertical. ness on the contralesional side.
BPPV can also involve the horizontal canal. In affected The vestibulospinal system is critical for maintaining
patients, a strong horizontal nystagmus builds up and posture and balance and is evaluated as part of a work-up
declines over the same time course as for posterior canal for dizziness and imbalance. A complete examination of
BPPV. The nystagmus either beats toward the dependent (1) gait; (2) strength, reflexes, and sensation in the legs;
ear (geotropic) or away from the dependent ear (ageotropic) and (3) cerebellar function is essential for the interpreta-
depending on where in the canal the pathology is located. tion of postural instability and dysequilibrium. Both static
The standard Dix-Hallpike maneuver may not elicit nys- and dynamic balance are tested.
tagmus in cases of horizontal canal BPPV, but nystagmus Static imbalance in vestibulospinal reflexes is identified
can be provoked by bringing the patient backwards into from Romberg testing, tandem walking, stepping tests,
the supine, head-hanging position and then turning the and evaluation of past-pointing. The Romberg test was
head left ear down or right ear down. The nystagmus seen originally described in syphilitic patients with tabes dor-
with horizontal canal BPPV may last longer than that seen salis90 but was later applied to cerebellar disorders by
in posterior canal BPPV. Babinski and Duchenne.91 In the standard Romberg test,
A sustained, usually horizontal, positional nystagmus of the patient stands with eyes closed and feet together; half
low velocity is a common finding in patients with central of patients with sensory ataxia last only 10 sec in this posi-
or peripheral vestibular lesions and may also be present in tion, while all normals and half of those with cerebellar
 The Neurotologic Examination 225

Anterior
canal

Figure 12-8. The Dix-Hallpike maneuver. Lateral

A medial view of the right labyrinth, canal
showing debris in the posterior canal,
is pictured along with the patient’s
corresponding position. 1. Initially, the
patient’s head is turned slightly to the
side and the otoconial debris is located in
the inferior portion of the posterior
canal near the ampulla. 2. The patient is
then brought flat, with the head hanging Posterior 1.
and the neck extended. The motion
causes the crystals to fall away from the
canal
ampulla, eliciting a sensation of rotatory
motion. The patient’s head is supported
at all times during the maneuver. (From 2.
Hullar TE, Minor LB: Vestibular
physiology and disorders of the labyrinth
In Glasscock E 3rd, Gulya AJ, [eds.]:
Surgery of the Ear, 5th ed. Hamilton,
Ontario, BC Decker, 2003.)

ataxia may be able stand a minute or more.92 Increased sensation during testing of the gag reflex. Cranial nerve
swaying is common in normals and the degree of swaying X is responsible for elevation of the palate via the levator
cannot differentiate among peripheral vestibular and cere- palati muscle.
bellar disorders.93 Falls during tandem walking may be Difficulties voicing normally or swallowing without
indicative of horizontal canal dysfunction. Fukuda step- coughing can indicate disorders of the tenth nerve. When
ping tests (marching in place for 30 sec with eyes closed) appropriate, flexible laryngoscopy can help distinguish tenth
can show excessive turning toward the side of a unilateral nerve disorders from other problems. A new technique has
vestibular lesion.94 An ataxic gait may also be noted during been reported for measuring the sensory component from
walking tests. Ataxia is characterized by a widened base the superior laryngeal nerve using an air puff from a modi-
(more than the normal 2 to 4 in. separating the feet later- fied laryngoscope onto the supraglottic mucosa.97 Damage
ally) and irregular or even staggering steps. Sensory ataxia to the recurrent laryngeal nerve often results in a flaccid,
is caused by proprioceptive loss; patients tend to look at lateralized cord with a breathy voice that gradually medial-
their feet, which often slap on the ground. Patients with a izes to a paramedian position. Spasmodic dysphonia can
reeling, staggering gait are more likely to have a cerebellar cause medialization of the vocal cord and a choking voice or
ataxia, which is often accompanied by other cerebellar lateralization of the cord and a breathy voice, depending
signs. There is poor interobserver reliability of what con- which set of laryngeal muscles is most affected.98
stitutes an “abnormal gait”.95 Past-pointing of the arms to
previously seen targets with eyes closed may also be a sign
of vestibulospinal imbalance. CRANIAL NERVE XI
Dynamic vestibulospinal function is assessed by observing
postural stability during rapid turns or in response to The spinal accessory nerve innervates the trapezius and
external perturbations imposed by the examiner (i.e., a gentle sternocleidomastoid muscles. The sternocleidomastoid is
shove forward, backward, or to the side). The “eyes-closed tested for symmetry by feeling the muscle’s contraction
turning test” (staggering when turning to the side of the while pushing against the patient’s chin on the opposite side.
lesion after walking with eyes closed) has been described with Weakness of the trapezius can be evaluated by examining
a sensitivity of 88% in patients with a perilymph fistula.96 the muscle for symmetry, observing the shirtless patient
from behind. Shrugging of the shoulders is insufficient to
test the eleventh nerve, as patients can mimic this motion
CRANIAL NERVES IX AND X with spinal muscles to compensate for shoulder weakness.
Raising the arm laterally (not anteriorly) above the level of
The vagus nerve, via its auricular division (Arnold’s nerve), the shoulder indicates adequate trapezius function.
carries sensation from the concha, inferoposterior external
auditory canal, a portion of the external surface of the tym-
panic membrane, and postauricular skin. The glossopha- CRANIAL NERVE XII
ryngeal nerve, as Jacobson’s nerve, carries sensation from
the entire middle ear including the eustachian tube and The hypoglossal nerve supplies the intrinsic muscles
mastoid cells and carries taste sensation from the posterior of the tongue. The tongue of a patient with an acutely
one third of the tongue. Cranial nerve IX is responsible for denervated hypoglossal will deviate toward the affected
226 NEUROTOLOGIC DIAGNOSIS

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26. Bento R, Sanchez T, Miniti A, et al: Continuous, high-frequency
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objective tinnitus caused by middle ear myoclonus. Ear Nose
susceptible to inflammation or edema of the dura from Throat J 77:814, 1998.
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the dura.99 Psychophysiol 36:155, 2000.
28. Kern R: Chronic sinusitis and anosmia: pathologic changes in the
olfactory mucosa. Laryngoscope 110:1071, 2000.
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 Chapter
Neuro-Ophthalmic Manifestations
of Neurotologic Disease
13 Outline

Steven A. Newman, MD Ocular Stabilizing Systems Seesaw Nystagmus

Vestibulo-Ocular Reflexes Dissociative Nystagmus
Paul R. Lambert, MD
Symptoms Periodic Alternating
Decreased Visual Acuity Nystagmus
Diplopia Physiological Nystagmus
Oscillopsia Misalignment of the Visual
Pain Axes
Signs Afferent System Pathology
Nystagmus Horner’s Syndrome
Vestibular Nystagmus Evaluation
Gaze Paretic Nystagmus History
Congenital Nystagmus Examination
Central Nystagmus Specific Disease Processes
Downbeat Nystagmus Conclusions
Upbeat Nystagmus

T he contralateral vestibular nuclei provide direct

dynamic input to the position of the globe in the
orbit. It is therefore not surprising that any disturbance in
bringing the fovea into alignment with an object of inter-
est, while the pursuit system uses continuous visual feed-
back to maintain foveal alignment when the target moves.
the normal function of the vestibular apparatus or its con- The third reason for ocular motility is the consequence of
nections has a direct and immediate effect on the orienta- forward ocular migration resulting in overlapping visual
tion of the globes and on their ability to move. Vestibular fields. Thus to maintain simultaneous foveal alignment of
pathology is often brought to the attention of the clinician both visual axes while a target moves closer or further
by patient complaints of diplopia and blurred vision and away, the eyes must move relative to each other. This is
can be diagnosed specifically by studying ocular motility. accomplished by the convergence system.
Although the vestibular ocular connection probably repre- A primary function of the vestibular system is to coordi-
sents the phylogenetically oldest ocular motor system, its nate eye movements with rotational and translational
importance has only recently been recognized. Erasmus movements of the head, thus maintaining clear and stable
Darwin in 1796 first noted ocular movement induced by retinal images. Visual pursuit relies on relatively slow
body rotation.1 In 1824, Flourens2 recognized the physiol- (approximately 75-msec) retinal processing, and therefore
ogy of the semicircular canals. It has only been within the cannot maintain image stability during natural head rota-
20th century that detailed central vestibular connections tions, which occur at frequencies of 0.5 to 5.0 cycles/sec.7,8
and vestibular testing have been outlined. The semicircular canals, by contrast, can respond in less
The role of the vestibular system in the generation of than 16 msec to drive the eyes at exactly the head velocity,
eye movements is better understood if the five major eye but in the opposite direction.9,10 Compensatory eye move-
movement systems are examined teleologically. The eyes ments for linear head movement are generated by the
need to move for three basic reasons. The first is to main- otolithic organs with a latency of less than 35 msec.11
tain a stable image of the world around us. Image drag
across the retina at more than 3 to 5 degrees/sec results in
a marked degradation of the image and consequent loss of OCULAR STABILIZING SYSTEMS
acuity.3–6 The vestibular system is responsible for main-
taining the eye stable in space during head movements, Because final eye movements are a combination of the
while the optokinetic system matches the movement of the action of all the ocular motor systems, it is often possible
surrounding environment with an appropriate eye move- for one or more of the intact systems to compensate for
ment. The second reason eyes move is based on our devel- a compromised vestibular system. Thus, it is important
opment of a specialized area of maximal spatial resolution to be able to evaluate all ocular motor systems, not just
(acuity), the fovea. The saccadic system is responsible for the vestibular. Ocular stability requires the integration of
228
 Neuro-Ophthalmic Manifestations of Neurotologic Disease 229

a number of visual systems with the vestibulo-ocular reflex pathways (contralateral oculomotor nucleus/medial rectus
(VOR), including the optokinetic, smooth pursuit, and muscle and ipsilateral abducens nucleus/lateral rectus
saccadic systems. The pursuit system in particular can be muscle). This is coordinated through the horizontal gaze
used to compensate for abnormalities or asymmetries center located within the ipsilateral sixth nerve nucleus in
within the vestibular system, and it may therefore prevent the dorsal pontine tegmentum.25 Its primary input is the
development of immediate symptomatology or obvious contralateral medial vestibular nucleus.
pathologic findings with local vestibular damage. Attempts The vertically oriented canals also produce a combina-
to track a moving object by moving the head require addi- tion of excitatory and inhibitory signals. While excitatory
tional neural mechanisms that combine pursuit and vestibu- signals cross to the contralateral midbrain, inhibitory
lar signals.12,13 Some evidence suggests that the VOR is information remains ipsilateral. Electrical stimulation of
suppressed.14 These neural pathways are incompletely neural fibers from the anterior semicircular canal causes
understood, but appear to involve activation of the ocular both upward and torsional eye movements, with the upper
motor neurons by the VOR signal or its copy with an pole of each eye moving toward the contralateral side. The
opposite sign.15,16 It should be apparent that these stabi- vertical eye movement is stronger ipsilaterally. The ipsilat-
lization systems require visual input and are absent with eral superior rectus and contralateral inferior oblique mus-
severely compromised vision.17–19 cles are excited, and the ipsilateral inferior rectus and
The ability to maintain eccentric gaze requires a gaze- contralateral superior oblique muscles are inhibited. This
holding neural integrator mechanism.20 Aside from the is largely mediated by fibers crossing in the rostral medulla
dynamic forces producing changes in ocular position, to ascend in the contralateral medial longitudinal fascicu-
static “elastic restoring forces” within the orbit tend to lus (MLF) to the contralateral third nerve nucleus where
bring the eyes back to the primary position. These may be the superior rectus and inferior oblique subnuclei are stim-
modeled simply as a system of soft tissue “springs” that ulated. As the superior rectus subnucleus innervates the
increase their tension as the eye is directed relatively more contralateral superior rectus, both eyes rise.
eccentrically. To supply an appropriate continuous signal Electrical stimulation of neural fibers from the posterior
that overcomes the elastic restoring forces, a “tonic” semicircular canal produces conjugate deviation of the eyes
increase must be made in the input to the extraocular mus- downward, with torsional eye movements directed again
cles. Obviously, this tonic force must be increased as the contralaterally. The downward eye movement is stronger
eccentricity becomes greater. A neural integrator located in the contralateral eye, and eye rotation is more apparent
in the area of the nucleus propositus hypoglossi adjacent to in the ipsilateral eye. The ipsilateral superior oblique and
the medial vestibular nucleus21 automatically adjusts the contralateral inferior rectus muscles are stimulated,
tonic signal to match the dynamic impulse needed to move whereas their antagonists, the ipsilateral inferior oblique
the eyes eccentrically. The pathology that affects this neu- and contralateral superior rectus muscles, are relaxed.
ral integrator results in what is referred to as a pulse-step Stimulatory projections from the posterior semicircular
mismatch. Although the “pulse” produces an appropriate canal also travel in the MLF to innervate the contralateral
saccadic (rapid) conjugate movement of the eyes to a par- trochlear nucleus and the inferior rectus subnucleus within
ticular eccentric position, the inadequacy of the subse- the oculomotor complex. In addition, evidence shows that
quent “step” results in a drift of the eyes back toward the accessory pathways from the vertical canals cross at the
primary position. As the elastic restoring forces increase pontomedullary junction rising in the brachium conju-
with increasing eccentricity, the drift back toward fixation neticum.26,27 The anterior semicircular canal pathways are
results in an exponentially decreasing slow velocity. This anatomically separated from those arising in the posterior
characteristic waveform may be helpful in distinguishing semicircular canals, which makes them asymmetrically
various abnormalities in ocular motility. sensitive to pathology. Selective involvement of the path-
ways from the anterior or posterior canals leads to vertical
drift of both eyes and upbeat or downbeat nystagmus.26,28
Vestibulo-Ocular Reflexes Balanced input from the left and right utricles also
The anatomy of the vestibular system is covered else- affects globe position. The utricular fibers project to the
where. Briefly, stimulation of the semicircular canal results ipsilateral medial rectus and to the contralateral superior
in a three-neuron reflex arc involving the vestibular gan- oblique, superior rectus, inferior oblique, inferior rectus,
glion, vestibular nuclei, and ocular motor nuclei. This reflex and lateral rectus muscles.29 Thus, stimulation of the utric-
arc and alternative interneuron projections result in eye ular nerve leads to torsion of the eyes toward the contralat-
movements parallel to the plane of the stimulated canal.22 eral side while the ipsilateral eye rises and the contralateral
Theoretically, therefore, identification of a diseased semi- eye falls.30
circular canal could be readily ascertained by noting the
direction of nystagmus. It is instructive to review briefly
extraocular muscle movement in response to stimulation SYMPTOMS
of a specific semicircular canal.23,24
Electrical stimulation of neural fibers from the horizon- Decreased Visual Acuity
tal semicircular canal results in horizontal conjugate devi-
ation of both eyes toward the contralateral side. This eye Although the vestibular system may be affected in myriad
movement involves both excitatory pathways (contralat- ways, the symptoms appreciated by the patient are limited.
eral abducens nucleus/lateral rectus muscle and ipsilateral Patients may occasionally complain of decreased visual acu-
oculomotor nucleus/medial rectus muscle) and inhibitory ity. This can occur when the image slip across the retina
230 NEUROTOLOGIC DIAGNOSIS

cannot be controlled to within 3 to 5 degrees/sec. The is distinctly uncommon in patients with congenital nystag-
patient may be aware that this visual “blurring” increases mus.37 Primary overaction of one or more of the extraocu-
with eccentric gaze or in one particular position. This may lar muscles, as in superior oblique myokymia, is another
represent local increase in abnormalities of visual stabiliza- uncommon cause of oscillopsia. In this syndrome, repeti-
tion. This symptom is usually binocular, but it can be tive firing of the fourth nerve results in tiny torsional and
monocular31 or substantially asymmetrical. In that case, the vertical oscillations of the eye, accompanied by a unilateral
patient may complain of unilateral decreased visual acuity. sensation of the world jumping.
Lack of attention to ocular motor problems may lead to a Oscillopsia has its highest frequency of occurrence in
misdirected work-up conversely. Careful attention to asym- patients with bilateral peripheral vestibular pathology.28 Such
metrical spontaneous eye movements may provide an expla- patients frequently report the inability to read signs while
nation for unilateral decreased visual acuity. Thus, it is walking.38 When the head is stabilized, however, the vision
imperative to check for an afferent pupillary defect (Marcus- is normal. Central abnormalities in VOR gain may also lead
Gunn pupil) or optic atrophy, which would indicate definite to severe motion-induced oscillopsia. Oscillopsia may occur
pathology within the optic nerve or visual pathways. at rest in the setting of acquired pendular nystagmus.39

Diplopia Pain
The major eye complaints related to vestibular pathology Pain associated with neurotologic disease may also be
are diplopia and oscillopsia. Diplopia arises from misalign- accompanied by ocular complaints. In Gradenigo’s syn-
ment of the two visual axes. This can be horizontal, but drome, infection involving the petrous bone (usually fol-
vertical deviations are more commonly associated with lowing otitis media) results in pain due to stimulation of
vestibular abnormalities. Partial involvement of the sixth the recurrent dural branches of the fifth cranial nerve.40
cranial nerve or of the MLF will lead to horizontal mis- Diplopia develops secondary to involvement of the sixth
alignment. The sixth cranial nerve and its nucleus are located cranial nerve as it crosses the petrous apex in Dorello’s
just rostral to the vestibular nuclei in the area of the pon- canal. More commonly, however, painful double vision rep-
tomedullary junction. Tumors of the cerebellopontine resents pathology affecting the skull base in the area of the
angle often compromise abducens function occasionally cavernous sinus.41 Here, involvement of the fifth cranial
bilaterally. nerve in combination with the third, fourth, and sixth nerves
When lesions affect the MLF, the patient will usually produces ocular misalignment and discomfort. In the older
complain of horizontal diplopia on contralateral gaze. As population, a pseudo-Gradenigo’s syndrome is not uncom-
additional vertical inputs are carried by the MLF, more monly related to nasopharyngeal carcinoma, which invades
extensive lesions, particularly with bilateral involvement, that base of the skull through the foramen lacerum.
may also produce problems with vertical gaze and vertical
diplopia.32 This is usually seen as vertical gaze paresis and
a skew deviation, as discussed later. SIGNS
Vertical double vision occurs when relative vertical sep-
aration of the visual axes occurs. Involvement of the fourth In neuro-ophthalmology, signs are usually separated
cranial nerve exiting the brainstem dorsally in the mid- into those affecting the afferent visual system (those con-
brain is a frequent cause. If the classical findings of a fourth nections between the eye and visual cortex responsible
nerve palsy are not present, the most likely central cause of for visual perception) and the efferent visual system
vertical diplopia is a skew deviation representing asymmet- (those pathways responsible for ocular motility, simulta-
rical involvement of the vertical prenuclear input.33,34 neous binocular alignment, and ocular stabilization).
Vertical double vision can also occur as an isolated phe- Neurotologic pathology most frequently affects the
nomenon due to local orbital pathology such as occurs efferent visual system and, in particular, the vestibular
following orbital trauma (blowout fracture) or as related to input and connections.
extraocular muscle tightening seen in thyroid orbitopathy
or orbital inflammatory disease. Less commonly, neoplas- Nystagmus
tic processes may affect the muscles. Restrictive problems
usually can be distinguished from paretic abnormalities by Nystagmus is a repetitive oscillation of the eyes.42
performing forced duction testing or checking intraocular Although some individuals may produce a nystagmus-like
pressure in eccentric gaze. Local pathology may also be picture voluntarily,43 most nystagmus is the result of asym-
suspected in the setting of proptosis, injection, numbness, metrical tonic input into either the horizontal or vertical
or globe displacement (dystopia). gaze center, resulting in a tendency of the eyes to drift.
When not suppressible by the fixation system or by smooth
pursuit, the resultant drift and secondary corrective eye
Oscillopsia movements occur in a rhythmic fashion. Nystagmus is
Oscillopsia is one of the most suggestive complaints seen most commonly binocular, although it may be asymmetri-
with vestibular dysfunction.35 This is the abnormal per- cal. It is also usually conjugate. That is, the two eyes are
ception that a stationary object is in motion.36 It may be moving in the same direction simultaneously. Disconjugate
distinguished from vertigo, in which the subjective sensa- nystagmus in which the eyes are moving in different direc-
tion is of the entire world spinning. Oscillopsia rarely tions, includes retraction convergence nystagmus and
occurs with abnormalities of eye movements, and in fact it seesaw nystagmus.
 Neuro-Ophthalmic Manifestations of Neurotologic Disease 231

Nystagmus has been classified in a number of ways. does not record torsional eye movement; therefore, the
Probably the simplest is based on direction. The repetitive main eye movement noted will be vertical.
eye movements may be purely vertical, purely horizontal,
purely torsional, or some combination of the three. The
Gaze Paretic Nystagmus
second method of classification is based on the motility pat-
tern. Nystagmus is termed pendular when the eyes move to Impairment of the neural integrator causes gaze-evoked
and fro with equal velocity and jerk when there is a fast or gaze paretic nystagmus.21 In this circumstance, the
component in one direction and a slow drift in the other. tonic extraocular muscle activity needed to keep the eyes
Although nystagmus is usually “defined” (labeled) by the in a certain eccentric position is inadequate, thus allowing
direction of the fast component, it is the slow drift that the eyes to drift back toward fixation in an exponentially
indicates pathology in tonic input. Nystagmus can be fur- decreasing form. Corrective saccades return the eyes to
ther characterized by the waveform of its slow component.42 the desired eccentric position. Multiple pathophysiologic
Although this usually requires ocular motor recording tech- processes may affect the neural integrator. These include
niques, this characterization can be valuable in separating lesions of the brainstem and cerebellum, especially the
out the presumptive pathophysiology. The slow phase may flocculus and paraflocculus, and various drugs such as
be of constant velocity, exponentially decreasing, or expo- sedatives,47 alcohol,48 and anticonvulsants.49–52
nentially increasing. Gaze-evoked nystagmus can be symmetrical or asym-
Nystagmus has also been defined by degrees: In first- metrical. Symmetrical gaze-evoked nystagmus has equal
degree nystagmus, the abnormal ocular movements are amplitude with right and left lateral gaze. The most com-
present only while looking in the direction of the quick mon cause of this nystagmus is ingestion of drugs such as
phases. In second-degree nystagmus, abnormal ocular move- alcohol48 and anticonvulsants.53,54 It is also frequently
ments occur in the primary position, and with third-degree noted in patients awakening from various general anes-
nystagmus, movements are present in all fields. However, thetics, and therefore must be differentiated from patho-
a relative area of least motility (a relative null point) may logical nystagmus secondary to otologic or neurotologic
still be present. surgery. Specific central nervous system (CNS) lesions
such as multiple sclerosis55 and cerebellar atrophy56 are
additional causes of symmetrical gaze-evoked nystagmus.
Vestibular Nystagmus
Asymmetrical gaze-evoked nystagmus is caused by
Nystagmus usually arises from one of two basic abnormal- asymmetrical involvement of the neural integrator often
ities: vestibular pathology or pathology affecting the neu- due to structural lesions of the cerebellum or brainstem.
ral integrator. Asymmetrical input from the vestibular Large cerebellopontine angle tumors42,57,58 that produce
nuclei or secondarily from dysfunction of the vestibular brainstem and cerebellar compression can cause asymmet-
end organ can result in ocular drift. Lesions of the periph- rical gaze-evoked nystagmus (Bruns’ nystagmus).59 Bruns’
eral vestibular system rarely affect just one semicircular nystagmus is characterized by a low-frequency, large-
canal, but rather involve the entire labyrinth or vestibular amplitude nystagmus with ipsilateral gaze due to the leaky
nerve on one side. The resulting imbalance in neural activ- neural integrator. This in turn is secondary to the com-
ity reaching the central vestibular system causes eye move- pression of the area of the nucleus propositus hypoglossi
ments that reflect the summed influence of each by the extra-axial mass. When the patient gazes in the
semicircular canal. Nystagmus therefore often has both a opposite direction, a higher frequency, small-amplitude
horizontal and torsional component; the vertical eye nystagmus secondary to the vestibular imbalance is
movement from the anterior and posterior semicircular induced by the compression of the ipsilateral vestibular
canals negate each other. Because the tonic input is con- pathways to the contralateral horizontal gaze center.
tralateral in the case of the horizontal canals, pathology
affecting the vestibular system on one side will produce a
Congenital Nystagmus
drift of the eyes toward the affected side. This is due to the
loss of tonic input into the contralateral horizontal gaze Both gaze paretic nystagmus, due to a leaky neural inte-
center, whereas the ipsilateral gaze center supplied from grator, and vestibular nystagmus, representing the most
the opposite vestibular system is unaffected. Thus, the eyes common form of acquired nystagmus, must be distin-
will drift toward the pathologic side, with quick corrective guished from congenital nystagmus. Certain characteris-
phases away from it. tics of hereditary nystagmus, if present, can help with this
In almost all cases of vestibular pathology, loss of signal differential diagnosis. As a rule, congenital nystagmus has
from part of the vestibular system leads to relative drift. an exponentially increasing slow phase (although pendular
One exception to that rule is benign paroxysmal positional nystagmus is possible).60,61 Although it is possible for con-
vertigo (BPPV). In this syndrome periodic over-reaction genital nystagmus to be vertical or torsional, horizontal
from debris on the cupula is induced by change in position. movement is most common. Classically, congenital nys-
BPPV is thought to involve only the posterior semicircular tagmus remains horizontal with both up and down gaze.
canal.44,45 The nystagmus noted when a patient is placed in Additional characteristics of congenital nystagmus include
a provocative position corroborates this hypothesis.46 The accentuation by visual fixation62 and diminution by con-
pathologic eye movement is both vertical (stronger in the eye vergence63 or by gaze in a certain direction (null region).
contralateral to the diseased posterior semicircular canal) Congenital, vestibular, and gaze paretic nystagmus tend to
and torsional (stronger in the eye ipsilateral to the diseased follow Alexander’s law; that is, the amplitude and possibly
posterior semicircular canal). An electronystagmograph even the frequency of the corrective saccadic movements
232 NEUROTOLOGIC DIAGNOSIS

increase with gaze in the direction of the quick phase.64 affecting the cerebellum or brainstem, including multiple
The cause of congenital nystagmus is unknown, but sclerosis71,76 and anticonvulsant therapy.77,78
presumably represents asymmetrical tonic input into the Several interesting clinical aspects surround downbeat
horizontal gaze centers that is not compensated for by nystagmus. Its intensity is consistently increased with
other eye movement systems. Because most of these other lateral gaze and often increased with downward gaze.79
systems require visual input, it is not surprising that the Thus, in cases of subtle downbeat nystagmus, more dra-
incidence of congenital nystagmus is higher in patients with matic clinical findings may be elicited by having the patient
various afferent system pathologies that cause decreased gaze laterally and downward. Patients with downbeat nys-
visual acuity. This undoubtedly explains in part the associ- tagmus also have a very high incidence of associated pursuit
ation of albinism and a number of other ophthalmologic deficit.76 Asymmetrical downbeat nystagmus may be seen
abnormalities with congenital nystagmus.65–67 with more of a torsional component in one eye. This is
usually accompanied by evidence of an internuclear
ophthalmoplegia.80
Central Nystagmus
The presence of vertical or torsional nystagmus implies a Upbeat Nystagmus
relatively selective involvement of either the anterior or
posterior semicircular canal or of the utricle. This is possi- Upbeat nystagmus,81–85 represents relative selective
ble because of the anatomic separation, seen particularly in involvement of input from the anterior canals.86
the area of the pontomedullary junction, as discussed earlier. Unlike downbeat nystagmus, upbeat nystagmus does
The posterior canal inputs cross dorsally in the medulla not usually increase on lateral gaze,76 but it is enhanced by
beneath the nucleus propositus hypoglossi prior to the looking upward. Selective involvement of the anterior
ascending in the MLF. Except for the condition of BPPV, canal input may occur from the same anatomic separation
a peripheral vestibular lesion does not affect just one ver- at the level of the pontomedullary junction, but interest-
tical canal. Thus vertical nystagmus almost always represents ingly in the cat there is also additional anterior canal input
central vestibular pathology. Isolated torsional nystagmus through the ventral tegmentum of the medulla.86 Selective
also strongly suggests a central origin.68 When vertical and involvement of this area could lead to a slow drift of the
torsional nystagmus are combined, a peripheral cause is eyes down and compensatory rapid up movements. An
possible. Most frequently, nystagmus is not pure, but rather alternative explanation for upbeat nystagmus is based on
combines varying degrees of torsional, horizontal, and the selectivity of neural transmitters. In rabbits, flocculus
vertical movements. Purkinje cells project inhibitory stimuli to the anterior
It is usually possible on clinical examination to distinguish canal projections, but not to the posterior canal projec-
nystagmus due to peripheral vestibular pathology from that tions.87 Thus, pharmacoselective involvement may provide
caused by central abnormalities. Peripheral vestibular nys- an explanation for this form of central vestibular dysfunc-
tagmus is often suppressed by visual fixation and, in fact, tion. Clinically, upbeat nystagmus is usually secondary to
may only become apparent when fixation is prevented infarction, tumor infiltration, or multiple sclerosis involv-
(e.g., through the use of Frenzel lenses or recording eye ing the midbrain, medulla, or cerebellum.82,83,85,88–90
movements in the dark). The patients’ ability to use intact
smooth pursuit and visual fixation systems to negate a ten- Seesaw Nystagmus
dency toward drift accounts for this phenomenon.
Conversely, visual fixation has little or no effect on central Pathology of the otolith pathways produces a unique form
nystagmus, including both downbeat and upbeat varieties. of nystagmus.91–93 In seesaw nystagmus, the ipsilateral eye
One exception to this is the upbeat nystagmus presumably rises and intorts while the contralateral eye falls and extorts.
related to nicotine seen in smokers only when fixation is As mentioned earlier, it is also likely that this asymmetri-
interrupted.69 Habituation may occur with time in the set- cal otolith input is responsible for the ocular tilt reaction
ting of peripheral involvement, but usually does not occur and the development of a skew deviation94 usually with an
with nystagmus of central origin. ipsilateral hypotropia.95 In this setting, an incomitant ver-
tical separation is present between the visual axes. Thus,
the deviation changes with change in gaze position. Seesaw
Downbeat Nystagmus
nystagmus and the ocular tilt syndrome may both arise
Two relatively pure isolated forms of central nystagmus are with pathology in the area of the interstitial nucleus of
downbeat and upbeat nystagmus. In the case of downbeat Cajal,96 which is located just rostral to the third cranial
nystagmus pathology usually interrupts the fibers crossing nerve nucleus within the midbrain. This area receives
in the dorsal tegmentum of the medulla. This relatively input from the vertically oriented semicircular canals as
selective involvement of information coming from the well as the otolithic organs.97 Large parasellar masses are
posterior canals leads to a slow phase drift of the eyes up the most frequent cause.91,92,98 Mesencephalic skew devia-
and a secondary correctional movement with a fast phase tions usually have the pathology ipsilateral to the hyper-
down.70 Clinically, downbeat nystagmus is usually seen tropic eye.34
with cerebellar degeneration or pathology at the cervical
medullary junction.28,71–73 Specific causes include Arnold- Dissociative Nystagmus
Chiari malformation,74,75 basilar invagination, and tumors
(most commonly meningiomas) at the craniocervical junc- Asymmetry in nystagmus may also occur when an abnor-
tion. It can also be seen in a number of other conditions mality is present in the ocular motor cranial nerves or their
 Neuro-Ophthalmic Manifestations of Neurotologic Disease 233

internuclear connections. An example of dissociative nys- brainstem origins. Pathology that is likely to affect both
tagmus is that seen with an internuclear ophthalmoplegia the cranial nerves and the vestibular system includes
(INO).99 Involvement of the MLF causes weakness in adduc- vascular abnormalities, neoplastic processes, and inflam-
tion associated with abducting nystagmus in the contralateral matory lesions.
eye. An INO is most frequently seen with small vessel
disease (vertebrobasilar insufficiency) in the elderly popu-
lation100 and occurs secondary to demyelinating disease101
Afferent System Pathology
in the young. Any pathology that affects the MLF within Although far less common than efferent system involve-
the brainstem, including vascular anomalies, neoplastic, and ment, the afferent visual pathways may be pathologically
infectious processes, may produce a similar picture. involved in association with neurotologic disease. Pathol-
ogy that obstructs normal cerebrospinal fluid (CSF) out-
flow may result in increased intracranial pressure with
Periodic Alternating Nystagmus
secondary evidence of disc edema. In this setting, trans-
Nystagmus may not remain fixed in pattern. Periodic mission of the elevated intracranial pressure along the
alternating nystagmus (PAN) is an acquired or congenital optic nerve sheath to the optic disc at the back of the eye
horizontal nystagmus in which a slow drift occurs in results in constipation of axonal transport. This is manifest
the null point from one side to the other over a cycle of clinically as hyperemia, disc elevation, and obscuration of
approximately 4 minutes.102 Thus the nystagmus will beat the nerve fiber layer as it crosses the disc margin. Variable
in one direction for approximately 1.5 to 2 minutes, stop hemorrhage and soft exudates may occur over the optic
beating, then reverse direction for the remaining 1.5 to nerve head surface. Clinically, the patients often complain
2 minutes. This abnormality in null point position is of headache and may have visual obscurations (transient,
thought to be secondary to pathology within the vestibulo- characteristically brief, visual loss), particularly in associa-
cerebellum,103 including the nodulus.104–107 Discovery that tion with change in position (bending or rising rapidly).
the inhibitory pathways were controlled by γ-aminobutyric Although visual acuity is often normal until late in the
acid (GABA) lead to the theoretical use of baclofen course of this condition, variable optic nerve dysfunction
(a GABA agonist) in patients with PAN.108 This has often may occur.113 This can manifest itself as visual field defects,
been successful in abolishing the drifting null position, including a combination of superior and inferior arcuate
although not in patients with congenital PAN. defects, often described as peripheral constriction. If not
treated, the optic neuropathy may be progressive and can
lead to permanent irreversible visual loss. The optic neu-
Physiologic Nystagmus
ropathy associated with increased intracranial pressure is
Nystagmus is not always pathologic. Simple rotation, usually symmetrical. On occasion, however, it may affect
which produces a normal vestibular slow phase in the oppo- one eye more than the other, resulting in an afferent pupil-
site direction, does induce nystagmus as the rotation con- lary defect. This is detected with a swinging flashlight test
tinues. Similarly, a moving background target produces not and may be quantified by the use of neutral density filters.
only the slow phase drift to compensate for the full-field Involvement of the optic nerve, however, will not produce
movement, but also the compensatory reset saccades seen inequality in the pupil size.
in optokinetic nystagmus. After sustained movement of the Rarely, visual acuity may be affected by an autoimmune
environment, slow phase drift will continue as optokinetic- phenomenon that attacks both the auditory system and the
after-nystagmus (OKAN). This has been conceptualized as cornea. In Cogan’s syndrome, an interstitial keratitis is
a slow discharge of the “capacitor,” which has been charged associated with auditory nerve involvement, resulting in
by the moving environment. Teleologically, the presence decreased visual acuity.114,115
of OKAN is important to counteract the induced VOR in Other forms of afferent visual system pathology include
the opposite direction that is seen when persistent rotation the occurrence of visual field defects. These are probably
is suddenly stopped.109,110 even less common than involvement of the optic nerves due
Endpoint nystagmus is a common finding in normal to papilledema, but they can happen when distal verte-
patients when eye deviation from midposition is extreme brobasilar system pathology results in compromised circu-
(greater than 40 degrees).111,112 The low intensity of the lation to the occipital lobe. Embolism, dissection, or simple
nystagmus (slow phase velocity of less than 3 degrees/sec) atherosclerosis can all affect posterior fossa circulation and
and the absence of other ocular abnormalities confirm its lead to various forms of homonymous hemianopsia.
benign nature.
Horner’s Syndrome
Misalignment of the Visual Axes It is possible to see inequality in pupil size (anisocoria)
Static misalignment of the visual axes is another form of associated with neurotologic disease. This most commonly
efferent visual system abnormality that can be present with occurs as a manifestation of Horner’s syndrome. Interrup-
neurotologic disease. This may be due to pathology affect- tion of the sympathetic fibers, usually as they descend within
ing the ocular motor cranial nerves, their internuclear the intermediolateral column in the brainstem, results in a
connections, or the horizontal and vertical gaze centers. smaller pupil on that side. The difference between the two
The pathophysiology may be due to intrinsic brainstem pupils is exaggerated in a low-light environment. Other
pathology or more commonly to extrinsic lesions that sec- manifestations of sympathetic denervation to the orbit
ondarily affect either the peripheral cranial nerves or their include a small amount of ptosis and anhydrosis over the
234 NEUROTOLOGIC DIAGNOSIS

ipsilateral forehead. Horner’s syndrome may be confirmed paraneoplastic syndrome with autoantibodies to cerebellar
with the cocaine test. Placement of a drop of 4% to 10% tissue should be suspected.122 When confined to the hori-
cocaine in both eyes will result in normal dilation of the zontal, rapid eye movements without intersaccadic latency
larger pupil. On the side of the smaller pupil, however, are referred to as ocular flutter. Patients with this symptom
lack of normal sympathetically released norepinephrine have a pathophysiology similar to opsoclonus. In the young
leads to failure of dilation, thus exaggerating the difference adult group, demyelinating disease is a strong possibility.
in size. If nystagmus is observed, it is most important to estab-
Most patients with Horner’s syndrome have pathology lish whether it is acquired or congenital. Old ophthalmic
affecting the carotid artery and secondarily the third-order records can be very useful. As mentioned, it would be highly
sympathetic neuron, which runs in the adventitia of that unlikely for congenital nystagmus to be associated with
artery. When associated with neurotologic pathology, how- vertigo or oscillopsia. On the other hand, these patients may
ever, it is most likely that the first-order neuron extending have problems with blurred vision, particularly when look-
from the hypothalamus to the cervical thoracic junction is ing in a certain direction. Patients can discover their own
affected. The Paredrine test can distinguish first-order from null point, and a prior history of head posturing suggests a
the more common form of third-order neuron involvement problem of long duration. Details from the patient’s history
in Horner’s syndrome. Hydroxyamphetamine 1%, when that suggest specific disease processes include exacerbation
placed in both cul-de-sacs, will cause dilation of both of vertigo and blurred vision with change in posture or
pupils even in the setting of Horner’s if the third-order head position (BPPV) or with straining, sneezing, or laugh-
neuron is intact. If, however, the pathology affects the ing (perilymph fistula or Arnold-Chiari malformation).
carotid artery and therefore the third-order neuron, no
dilation is seen. Horner’s syndrome in the setting of neuro- Examination
tologic disease is frequently seen as part of Wallenberg’s
lateral medullary plate syndrome, as discussed later. The second part of the evaluation involves accurate obser-
vation of the visual system. A neuro-ophthalmic examina-
tion is appropriate for any patient who complains of
oscillopsia, blurred vision, or diplopia. Complete evaluation
EVALUATION includes a detailed exam of both the afferent and efferent
visual systems. Although the incidence of afferent visual
History pathology is far lower in neurotologic disease, it is impor-
As in all other areas of medicine, a detailed history can tant to document the patient’s best corrected visual acuity,
often provide clues to a specific diagnosis. In the case of the lack of an afferent pupillary defect, and the normality
diplopia, it is clearly important to distinguish local effects of visual fields. Patients should always be checked wearing
from intracranial pathology. A prior history of thyroid dis- their appropriate glasses or lens prescription. When it is
ease or trauma, and certainly the occurrence of increasing impossible to do a complete refraction, a pinhole acuity
proptosis or globe displacement, suggests a local cause for test may indicate that reduction in vision is related to an
the misalignment. A progressive neoplastic or inflamma- uncorrected refractive cause. In patients with complaints
tory process affecting the cavernous sinus region should be of oscillopsia, visual acuity should be assessed with the
considered, especially with a prior history of facial pain or head at rest and in motion. The patient is asked to read a
numbness. Complaints of decreased hearing, associated with Snellen chart, first with the head stationary, then with the
diplopia on ipsilateral gaze, raise the question of Gradenigo’s head randomly rotated about the visual axis by the
syndrome. In an older patient, this would require exclusion examiner. A drop of four lines or more in visual acuity
of nasopharyngeal carcinoma. with motion indicates a problem with the VOR. The fundus
The unusual complaint of tilt in the environment should be carefully checked for evidence of increased
strongly suggests involvement of the otolith pathways and intracranial pressure, optic atrophy, hemorrhages, exudate,
the vestibular system.116 When combined with Horner’s syn- or nerve fiber bundle dropout. Vascular sheathing or
drome, a lateral medullary plate syndrome may be suspected. cotton wool spots may be a clue of a microvasculopathy or
Vertical oscillopsia involving one eye raises the possibil- a systemic vasculitis.
ity of superior oblique myokymia.117 Oscillopsia in general Any degree of head posturing should be noted; old pho-
suggests an acquired disorder of ocular motility most tographs may be of help in this regard. A head turn may
commonly associated with pathology of the vestibular indicate a long-standing problem either with restriction or
pathways. When exacerbated by any head movement, severe with a paretic lateral rectus muscle. Similarly, a head tilt
bilateral vestibular dysfunction may be suspected. A prior may indicate a congenital fourth nerve palsy, compensated
history of aminoglycoside therapy is often elicited.38,118 for by tilting the head away from the side of the lesion.
Oscillopsia may also occur in association with other dis- The efferent system remains of paramount concern.
orders of spontaneous ocular motility. Opsoclonus repre- The initial portion of the examination of the efferent
sents a condition in which spontaneous conjugate irregular system is to ensure that the eyes are stable in primary
movements occur in all directions without an intersaccadic position. Subtle low-amplitude nystagmus may be over-
latency characteristic of nystagmus.119 This is felt to repre- looked on direct examination, but is often brought out by
sent pathology affecting the pause cells within the brain- the use of Frenzel glasses that both illuminate and magnify
stem120 and may be seen with various toxic and inflammatory the globe. If these are not available, a simple means of
causes. In a young patient, the possibility of neuroblastoma picking up subtle ocular instability is to examine the disc
should be investigated,121 and in the older age group, with the direct ophthalmoscope after the patient’s eyes
 Neuro-Ophthalmic Manifestations of Neurotologic Disease 235

have been dilated.123 Although microsquarewave refixation and slow-motion analysis. Much better data may be obtained
movements are always present in normals, even extremely through the use of electronystagmography, in which an
low amplitude nystagmus (less than 0.5 degree in excur- electro-oculogram (EOG) signal is generated by placing
sion) may be readily appreciated with the direct ophthal- electrodes on either side of the eye. This gives a largely
moscope. If nystagmus is present in the primary position, linear signal that corresponds to ocular position. Absolute
it is essential to observe the direction of both the slow and numbers require suitable calibration, but relatively detailed
the fast phases to characterize the amplitude and velocity data are possible. Simultaneously, vertical eye movements
and to ensure no change takes place over time. As men- may be studied in a similar fashion with electrodes placed
tioned earlier, it is important to distinguish among hori- above and below the eye.
zontal, vertical, oblique, and torsional components. When A somewhat more sophisticated approach to ocular
both a vertical and a horizontal component are present, motor recording is the use of infrared (IR) tracking. This
the nystagmoid movements may be either in phase, result- requires specialized equipment, but gives an even more
ing in oblique nystagmus, or out of phase, resulting in cir- detailed and linear recording of ocular motility. Unfortu-
cular or elliptical nystagmus (often occurring in the setting nately, it is not good for recording vertical movements
of demyelinating disease124). because of problems with lid occlusion. In addition, most
Several provocative stimuli should be employed to see if systems available will not track with the lids closed and
nystagmus can be induced. These include positional therefore will suffer multiple interruptions with normal
changes (Hallpike’s maneuvers) when BPPV is suspected, blink frequency. Nonetheless, it is still a simple, noncon-
as outlined in other chapters. When an inner ear fistula is tact means of obtaining extremely accurate recordings.
suspected, the Valsalva maneuver, a loud noise, or pneu- Earlier systems were fixed, requiring the use of a rein-
matic otoscopy may result in change in the ocular drift. forced head fixation device or bite bar. More recent IR
Subtle abnormalities in the normal VOR may be detected systems use detectors mounted on spectacles.
by rotating the patient’s head around an ocular axis in the Currently, the gold standard in ocular motor recording
dark while monitoring the optic disc with a direct oph- is that of the magnetic search coil. Placement of a fine cop-
thalmoscope.123 If the VOR is entirely normal, the disc will per coil within a contact lens on the surface of the eye will
remain stationary. If the gain is greater than 1, the disc will yield a signal linearly related to the position of the globe
drift in the direction of the head rotation; if the gain is less when the patient’s head is placed within a uniform mag-
than 1, the drift will be in the opposite direction. Even netic field. Extremely detailed recordings are thus possible
after adaptation, abnormalities in the peripheral vestibular not only of horizontal and vertical movements, but also of
system may be detected by having patients rapidly shake torsional movements, when a specially designed double
their heads horizontally and then open their eyes.125,126 coil is used. By combining an eye coil with a coil placed on
Examining the patient with a direct ophthalmoscope in the the patient’s head, both eye and head movements as well as
dark will indicate subtle drift of the eyes. This will occur if eye in space movements may be studied accurately. Because
asymmetrical involvement of the vestibular system is pres- of the equipment involved, as well as the need for placing
ent with the eyes drifting toward the side of the affected the contact lenses directly on the eye, this testing remains
peripheral vestibular system, even if habituation has led to largely a research tool in certain academic centers. Fortu-
stability of the eyes when not stimulated. nately, this degree of precision is usually not necessary to
Having established the patient’s stability in primary distinguish the various forms of nystagmus discussed.
position, the effect of change in gaze position should be The problem of ocular misalignment may be examined
sought. Evidence of centripetal drift with eccentric sac- by measuring the relative displacement of the two visual
cades suggests an abnormality in eccentric gaze position axes with loose or bar prisms. By simply alternating fixa-
holding, most likely related to abnormalities in the neural tion occlusion and adding prism until any movement of
integrator. This may be isolated only to the horizontal, but redress is abolished, a good measurement of ocular mis-
usually occurs in all directions. Attention should also be alignment may be obtained in the primary position and in
directed to the effect of eccentric gaze into all nine cardi- all nine cardinal positions of gaze. When the deviation is
nal positions on nystagmus already noted to be present. equal in all nine positions it is said to be comitant. Although
Alexander’s law holds that in most forms of nystagmus, the this usually represents long-standing or congenital strabis-
amplitude and possibly the velocity will be exacerbated mus, paretic (ocular motor disorders), restrictive (most
when the eye looks in the direction of the fast phase.127 If frequently seen with thyroid disease or following trauma),
a patient’s nystagmus changes as gaze direction is altered, or even the rare causes of primary extraocular muscle over-
notation should be made of a possible null point where the action may progress to increasingly comitant deviations
nystagmus is least apparent. Often a change in the tor- with time. This so-called spread of comitance probably
sional component occurs as the patient looks either up or represents the ocular motor system’s plasticity in separately
down, as well as eccentrically. This may represent relative adjusting individual gain.
involvement of the utricular connections. It certainly sug- With cross cover testing, any tendency for the eyes to
gests some variety of vestibular involvement. As men- deviate (phoria) is measured along with the manifest
tioned earlier, it is common to find downbeat but not deviation (tropia). Any system that dissociates the two
upbeat nystagmus exacerbated by lateral gaze. Although it eyes will also permit phorias to become manifest. The
is sometimes possible to judge the waveform of the slow difference between the tropia (actual deviation) and the
velocity by simple observation, particularly with Frenzel phoria is referred to as the fusional vergence. Fusional ampli-
glasses, detailed evaluation requires ocular motor record- tudes are much greater in the horizontal than the vertical
ing. This could be done most simply with video recording and also greater for convergence than for divergence.
236 NEUROTOLOGIC DIAGNOSIS

Increased vertical fusional amplitudes suggest an extremely infectious, neoplastic, compressive, traumatic, toxic, degen-
long-standing deviation such as that seen with a congeni- erative, vascular, and idiopathic pathologies are all possible.
tal fourth nerve palsy. Vergence amplitudes are affected by The end organs are most commonly affected by ototoxins
generalized health. Fatigue, stress, alcohol, and various such as aminoglycosides; idiopathic or degenerative
drugs may substantially reduce the fusional vergence pos- processes, such as Ménière’s disease and BPPV; inflamma-
sible and result in the development of a tropia in the place tory conditions; trauma; and vascular disease. The neural
of a previously compensated phoria. pathways are frequently affected by tumors of the cerebello-
The simplest means of dissociating the visual axes is pontine angle, including acoustic neurinomas, meningiomas,
with a red glass placed over one eye. The patient then epidermoids, and metastatic disease.128–132 Inflammation
reports the separation between the red and white spots, (e.g., meningitis) may affect the eighth nerve directly. The
seen when a flashlight is directed toward the patient’s eyes. labyrinth or the eighth cranial nerve may be injured in the
This may produce both a horizontal and vertical compo- petrous bone secondary to basilar skull fracture or shear-
nent. A Maddox rod consisting of a set of parallel small half ing forces.133,134 Ectatic vessels or aneurysms in the poste-
cylinders is more dissociative. When looking at light rior fossa may secondarily exert a mass effect directly on
through a Maddox rod a line is seen running perpendicular the eighth cranial nerve.
to the orientation of the half cylinders. Therefore the rod Demyelinating disease usually affects the central
is placed horizontally if a horizontal deviation is suspected vestibular connections, but may also result in peripheral
or vertically if there is a problem with vertical separation. cranial nerve involvement. Microvasculopathy and ischemic
In the usual situation both are done with the flashlight changes are possible, particularly in the elderly vasculo-
briskly moved through all nine cardinal positions. pathic patient. They may or may not be associated with
Although this can be made more quantitative by placing more systemic involvement, such as polyarteritis, allergic
prisms in front of one eye, usually the deviation is simply vasculitis, or giant-cell arteritis (a disease almost exclu-
estimated by the patient. By identifying the field where sively of the elderly). Vascular changes may also be induced
maximal separation occurs, one can frequently identify the by inadvertent embolization of the vascular supply during
paretic (or restricted) muscles. Although using a Maddox interventional neuroradiologic procedures.
rod requires more time than a red glass (needs to be done Prior damage of any kind to the vestibular nerve makes
both for horizontal and vertical separation), breaking down it more susceptible to dysfunction associated with change
the deviation into a horizontal and vertical component in pH and calcium concentration. This may be brought
actually makes analysis easier and therefore is in many out clinically by hyperventilation.
ways preferred. The central vestibular system and its cerebellar connec-
Dissociation of the visual axes may be obtained with tions may similarly be affected by a myriad of pathophysi-
higher technical approaches (amblyoscope, Maddox wing, ologic processes. The same tumors that affect the peripheral
etc.), although these offer little advantage over the combi- vestibular nerve in the cerebellopontine angle may also
nation of Maddox rod and cross-cover prism testing. An compress the brainstem, resulting in central vestibular
exception, the Lancaster red-green test or Hess screen, pathology. In addition, primary intra-axial tumors, such as
however, does offer one additional advantage. This test gliomas, ependymomas, and medulloblastomas135 in young
will not only identify the area of maximal deviation, but will patients may produce central vestibular dysfunction.136,137
give a hardcopy recording so that the patient’s deviation Metastatic disease is uncommon. Unusual tumors, includ-
may be compared over time. Thus one can determine ing hemangioblastomas,138 hemangiomas,139 and germ cell
whether the problems with ocular alignment are progress- line tumors, may also present with neurotologic signs.
ing or improving. Arteriovenous malformation may produce a mass effect,
One additional useful technique is assessment of the but also may cause local irritating phenomena or other
area of binocular single vision. This is usually done on a effects when associated with a bleed. Compromise of the
Goldmann perimeter and makes use of a size III test object. vascular supply to the lateral portion of the medulla (usu-
The patient has both eyes opened and the machine is cen- ally the posterior inferior cerebellar artery) produces the
tered on the bridge of the nose. By indicating when two so-called lateral medullary plate syndrome of Wallenberg.140
objects are visible instead of one, areas of diplopia can be In this syndrome, torsional nystagmus141 is often com-
identified. This is a very useful functional test because it bined with a skew deviation94 and an associated ipsilateral
gives the investigator an immediate idea of the direction of Horner’s syndrome. An almost unique complaint in these
the patient’s visual gaze that will not result in double vision. patients is the perception of the world being tilted by 90 or
This also can be followed over time. 180 degrees.116 An additional finding is ipsilateral pulsion
of saccades142 in contradistinction to the lateropulsion seen
with infarction in the territory of the superior cerebellar
SPECIFIC DISEASE PROCESSES artery.143–145
Certain inflammatory lesions may affect both the
Many neurotologic disease processes will have neurooph- vestibular system and the efferent visual pathways. The
thalmic manifestations. Without attempting to duplicate inflammatory process may be idiopathic, as with systemic
what exists in other chapters, we can briefly outline those lupus erythematosus and nonspecific neuronitis,146 or it
processes. It is most convenient to separate them into ones may be related to a specific infectious agent, such as the
that involve the end organ (semicircular canals, utricle, herpes viruses,147 HIV, various gram-positive and gram-
saccule, and their nerves) and ones that involve the central negative bacteria, mycobacteria, or syphilis.148,149 Inflamma-
vestibular pathways and connections. Inflammatory, tory lesions may be due to local contiguous spread or to
 Neuro-Ophthalmic Manifestations of Neurotologic Disease 237

embolic phenomena associated with subacute bacterial disease.159 White matter plaques can affect any of the
endocarditis. An uncommon form of involvement, partic- vestibular pathways and connections, producing a plethora
ularly in patients who are immunosuppressed, is that of the of findings. Degenerative disease that includes cerebellar
gram-positive rod, Listeria. A peculiar syndrome referred and olivopontocerebellar degeneration160 may produce var-
to as rhombencephalitis results from an abscess in the area ious degrees of abnormalities affecting both the vestibular
of the connection between the cerebellum and the lower system and the efferent visual pathways.56,161,162 Paraneo-
brainstem. These patients often present with motility dis- plastic syndrome is most frequently seen with small cell
turbance, diplopia, and various auditory and vestibular carcinoma, but has also been reported with carcinoma of
complaints. the ovaries and breast, and occasionally with gastrointesti-
In patients who are immunosuppressed secondary to nal tumors. This often produces opsoclonus or flutter, but
HIV infection, parasitic infections may also occur in an may also underlie downbeat nystagmus or various prob-
abscess form. Toxoplasmosis represents a common form of lems with vestibular gain.163
intracranial posterior fossa pathology that may produce a Metabolic depletion syndromes may also affect central
myriad of visual as well as neurotologic symptoms. A gaze vestibular function. These include Wernicke’s encephalopa-
palsy is frequently the consequence of involvement of the thy,164,165 B12 deficiency, and magnesium depletion.166
horizontal or vertical gaze centers (pons or midbrain).
These may go unnoticed unless they are also associated
with involvement of the ocular motor nerves. If there is
pure gaze palsy, there is no disconjugate eye movement, CONCLUSIONS
and therefore the patient may not have diplopia and may
be unaware of other problems. The patient may note that The vestibular system is the primary input for tonic activ-
he or she has to turn the head more often and may describe ity to the extraocular muscles. Any abnormality within the
the problem as visual “blurring.” peripheral or central vestibular systems is likely to produce
Toxins, including inadvertent poisoning and routine both static and dynamic abnormalities in ocular position.
medications, can affect the central vestibular system. This can be manifested symptomatically as diplopia and
Lithium taken as an antidepressant medication, for example, less commonly as oscillopsia. It may be discovered on clin-
can potentially cause downbeat nystagmus.150,151 Nicotine ical testing as nystagmus, skew deviation, or other forms of
can produce upbeat nystagmus,69 but this is latent unless ocular misalignment. A detailed neuro-ophthalmic exami-
fixation is abolished. Alcohol may produce abnormalities nation is likely to add substantial information about the
in the neural integrator as well as a direct decrease in the location of pathology affecting the vestibular and neuroto-
vestibular gain.48 logic pathways. Although high-technology detailed eye
Hydrocarbon solvents have been increasingly recog- movement recording may be necessary for precise defini-
nized as toxic to the central vestibular system.152–155 tion of waveforms, careful direct examination will often
Patients complain of unsteadiness and difficulty coordinat- supply information adequate to produce a precise localiz-
ing eye movements, not of vertigo. The most common ing diagnosis and an appropriate differential. Information
objective abnormality is loss of VOR cancellation. It has obtained on clinical examination may be most helpful in
been hypothesized that solvents act acutely by blocking the directing further testing, including the selection of imag-
inhibitory neurotransmitter GABA; long-term solvent ing studies and possible therapeutic intervention.
exposure may actually cause loss of neurons.156
Anatomic abnormalities, either developmental or
degenerative, may result in pathology at the cervical
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144. Ranalli PJ, Sharpe JA: Contrapulsion of saccades and ipsilateral encephalopathy. Ann Neurol 26:669–674, 1989.
ataxia: A unilateral disorder of the rostral cerebellum. Ann Neurol 165. Victor M et al: The Wernicke-Korsakoff Syndrome. Philadelphia,
20:311–316, 1986. FA Davis, 1971.
145. Uno A et al: Lateropulsion in Wallenberg’s syndrome and 166. Saul R, Selhorst JB: Downbeat nystagmus with magnesium deple-
contrapulsion in the proximal type of the superior cerebellar artery tion. Arch Neurol 38:650–652, 1981.
syndrome. J Neuroophthalmol 9:75–80, 1989.
 Chapter
Otolith Dysfunction and
Semicircular Canal Dysfunction

Outline 14
Introduction Air Travel Post-Traumatic Vertigo Vincent B. Ostrowski, MD
Otolith Organ Dysfunction Underwater Diving Eighth Nerve Trauma
Dennis I. Bojrab, MD
Otolith-Ocular Reflexes Hearing Loss Etiology Labyrinthine Concussion
Otolith Anatomy Treatment Options Post-Traumatic BPPV
Otolith Symptoms Decompression Sickness Post-Traumatic Endolymphatic
Testing Otolith Function Labyrinthitis Hydrops
Superior Semicircular Canal Viral Luetic Vestibulopathies
Dehiscence Syndrome Serous Ototoxicity
Pathology Suppurative Aminoglycosides
Symptoms Perilymph Fistula Loop Diuretics
Etiology of Symptoms Pathogenesis Salicylates
Examination and Testing Symptoms Cisplatin
Treatment Diagnosis and Testing Diagnosis
Labyrinthine Hemorrhage Management Management
Otic Barotrauma Congenital Perilymph Fistula

INTRODUCTION human head tilts from side to side, the otoliths provide
a compensatory ocular torsion or ocular counterrolling.
This chapter is concerned with the less common etiologies Otoliths also provide compensatory ocular torsion as the
of peripheral vertigo. Emphasis is on the understanding and head tilts forwards and backwards. Human ocular roll or
definitions of these conditions, although it will be necessary tilt is inefficient with a maximum torsion of about 5 to
to include some of the evaluation and treatment of these 6 degrees or a gain of about 0.1.1 Linear stimulation is the
conditions to explain these entities. Although many techno- strongest stimulation to the otolith organs. Acceleration
logic advances have occurred in the field of neurotology, the along the interaural axis causes a compensatory horizontal
history remains the most important part of the evaluation eye movement, whereas acceleration in the occipital nasal
of a patient complaining of dizziness. A complete history axis does not induce horizontal eye movements.2 The pur-
should include a patient’s description of the character of the pose of the reflex is to enhance visual pursuit during linear
dizziness, time course, precipitating factors, associated displacement of the head.
symptoms, and predisposing factors. Following a thorough Most natural head movements are a combination of
history, a complete otoneurologic examination should be linear and angular displacements. In contrast to the semi-
performed. The diagnostic evaluation and management circular canals, the otolith organs sense change in linear
differ markedly depending on the category of dizziness; velocity, or acceleration, and sense static changes of the
therefore, it is critical that the examining physician deter- head with regard to the gravitational vector. In contrast, the
mine the type of dizziness before proceeding with exhaustive semicircular canals sense angular acceleration. As the canals
diagnostic studies. It is crucial that the clinician be available mediate compensatory reflexes for head rotation, the otoliths
to reexamine the patient when the symptoms are present to are responsible for otolith ocular reflex eye movements
confirm the diagnosis. Only with this approach can appro- (OOR), which compensate for linear components of head
priate therapeutic plans be instituted to treat the patient. motion. The function of the otolithic organs is to perceive
gravity, linear acceleration, and centrifugal force.
The utricle detects both translations and tilt in the
lateral, fore, aft, and side-to-side directions. The saccule
OTOLITH ORGAN DYSFUNCTION senses the pull of gravity, as well as up and down and fore
and aft translations of the head. The canal and otolith ocu-
Otolith-Ocular Reflexes lar reflexes must work in unison to permit stable ocular fix-
The otolith organs elicit eye movements provoked by static ation. Only one functioning otolith set is needed to maintain
head tilt as well as during periods of acceleration. As the a normal OOR. In patients with bilateral vestibulopathy,
241
242 NEUROTOLOGIC DIAGNOSIS

the OOR may be absent or hypoactive patients with uni- the gelatin layer are the calcium carbonate otoconial crystals
lateral loss have a normal OOR.3 In combined linear and or otoliths. Otoconia are produced by the macular sup-
angular acceleration, the velocity of the eye adjustments is porting cells and after fracturing and becoming dislodged
too fast to be visually directed. The ocular system uses a from the macula are absorbed by the dark cells.8 Linear
rapid, nonvisual estimate of current target location relative displacement of the otoconial-gelatinous layer stimulates
to the head by combining available visual, auditory, and the afferent nerves of the otoliths, allowing linear move-
proprioceptive information.4 The velocity storage feed- ment detection. (See Fig. 14-1.) The maculae are at a
back pathways in the central vestibulo-ocular reflex (VOR) 90-degree angle to one another. The utricle is a curved
provides a key mechanism for otolith canal interactions.5,6 structure roughly parallel to the lateral canal and the macula
of the saccule is a curved structure in a parasagittal plane.9
The horizontal portion of the macula is tilted back
Otolith Anatomy and down by 25 degrees and laterally upward by about
The utricle and saccule are two individual structures 10 degrees. A small anterior portion of the utricular macula
contained within the vestibule. The utricle belongs to the is curved upward. The saccular macula is oriented almost
pars superior of the inner ear, and the saccule belongs to at right angles to the utricle. Within each macula, the sen-
the pars inferior of the inner ear. The otoliths contain sory hair cells (HCs) are morphologically oriented in oppo-
endolymph and are surrounded by perilymph. The endo- site directions on either side of, and at right angles to, a
lymph of the utricle has five paths of egress: the utricular central line of demarcation named the striola. Kinocilia are
duct joining to the endolymphatic duct, the saccular duct directed away from the striola in the saccule and toward
joining the utricle to the saccule, and ducts joining to each the striola in the utricle. In the striolae, the otolithic layer
semicircular canal. The vestibular aqueduct or the endolym- of the utricle is thinnest and that of the saccule is the
phatic duct joins the utricle to the endolymphatic sac.7 The thickest. Both maculae contain HC orientation vectors in
saccule communicates with the endolymphatic duct by the all directions. Striolae have more type I HCs and are
saccular duct and with the cochlear duct by the ductus innervated by thicker axons, conducting at greater velocities.
reuniens. The otoconia inertia causes their relative displacement in
The utricle and saccular sensory neuroepithelium is the a direction opposite to an imposed linear acceleration.
macula. The utricular macula is 2.2 by 2.2 mm and the With both maculae nonplanar and both striolae curved,
saccular macula is 2.4 by 1.3 mm.7 Hair cells of the otoliths the hair cell activation patterns are complex. Detailed
have cilia embedded in a gelatin layer. On the surface of examination of the pathways from the otolithic maculae to

Figure 14-1. Three-dimensional spatial orientation of the inner ear with its associated otolith organs. Inset shows detail of the utricle and saccule.
 Otolith Dysfunction and Semicircular Canal Dysfunction 243

the eye muscles is much more difficult than it is for the rocking motions while symptomatic. Sudden changes in
canals because the macular nerves carry information about endolymphatic fluid pressure with inappropriate otolith
all conceivable directions of movement. Gross stimulation stimulation have also been proposed as a source of vestibular
of the whole utricular nerve causes torsional movements of drop attacks, or Tumarkin crisis. Sudden otolithic stimulation
the eyes with intorsion of the ipsilateral eye and extorsion may elicit a reflex-like vestibulospinal loss of postural tone.12
of the contralateral eye. The ipsilateral eye elevates and Additionally, post-traumatic forms of imbalance have
adducts and the contralateral eye depresses and abducts. been linked to otolithic stimulation. A sudden shearing
force applied to the head can be severe enough to shear to
otoconia from the macula. This may lead to unequal tone
Otolith Symptoms between the right and left otoliths, resulting in asymmetric
Symptoms of otolithic dysfunction have not been widely vestibular input to the brain.13 Barotrauma or surgical
described in the otolaryngologic literature. Practitioners trauma has been associated with perilymphatic fistula forma-
may not be familiar with the symptoms of otolithic dysfun- tion and pathologic otolith stimulation.14 Rocking vertigo
ction and thus cannot easily or confidently attribute symp- and imbalance with sneezing, coughing, or straining can
toms to a diagnosis. Patients may present with symptoms be associated with leakage of perilymph fluid. This may be
suggestive of a vestibular disorder but without the typical secondary to stapes subluxation onto the otolith or otolith
signs of vestibular disease such as spontaneous nystagmus movement with leakage of the surrounding perilymph.
and asymmetrical rotational and deranged caloric responses. Observations have also been made where the membra-
Patients may complain of a sensation of linear motion such nous lining of the vestibule pulls away from the bony walls
as rocking or that the ground is moving up and down. and lies directly on the otolith organ. This vestibular atelec-
Feelings of falling or actual falls, lateropulsion sensations, or tasis may then become a mechanical link between the under-
inability to align things horizontally or vertically are also surface of the footplate and the membrane of the otolith
possible complaints. organ.15 A similar mechanism has been proposed as the
Potential etiologies of otolith dysfunction are numerous. etiology behind the otolith: Tullio’s phenomenon, in which
(See Fig. 14-2.) Benign paroxysmal positional vertigo has the patient may experience paroxysms of head tilt, ocular tor-
been linked to dislodged otoconia from an otolith macula sion, and tilting of the visual surround with certain tonal
causing stimulation of the cupula of the semicircular canal, stimulation.14,16,17
most commonly the posterior canal. This may be related to Unilateral vestibular loss results in asymmetric otolith
a post-traumatic event to the head that caused otoconia to function. In the weeks following the loss, there is a pro-
separate from the macula.10 Otoconia could theoretically be gressive recovery of the asymmetrical response, suggesting
released from a vascular insult to the otolith, freeing the that otolith symptoms recover after vestibular damage, just
crystals. Also, dysfunction of the dark cells, thought to be as some static canal symptoms recover. There is likely a
responsible for otoconia resorption, could lead to an excess process of otolithic compensation as well as one of canal
of freed otoconia. Symptoms can arise not only from the compensation.18
free otoconia causing stimulation of the semicircular canals
but also from the resultant asymmetric loading between Testing Otolith Function
right and left maculae after otoconia are dislodged.
Patients with endolymphatic hydrops or Ménière’s Direct testing of otolith function is difficult and currently
disease may receive pathologic stimulation of the otoliths.11 requires a specialized testing environment. The contribu-
Deformation or pressure changes in the membranous tions of the otoliths to the vestibulo-ocular reflex can be
labyrinth may result in pushing or pulling forces on the classified into several categories:19 (1) compensation for
maculae, giving the patient sensations of linear, vertical, or translational components of head motion, (2) compensation

Figure 14-2. Multiple pathologic states can

arise from a variety of etiologies that affect
the otoliths.
244 NEUROTOLOGIC DIAGNOSIS

for rotational components of head motion when the axis include looking for head tilt, skew deviation, and elicitation
of rotation is directed away from the pull of gravity (off- of these symptoms or signs on application of pressure or
vertical axis rotation), and (3) compensation for static tilt sound to the offending ear. Signs of otolith dysfunction can
of the head or ocular counterroll. Gresty and colleagues be observed as a tonic (constant) OTR and skew deviation
were the first to use off-vertical axis rotation or eccentric in the settings of perilymphatic fistula, stapes hypermobil-
yaw rotation to assess otolith function.20 The subject is ity or subluxation, acute labyrinthine loss, or posterior fossa
seated in a rotational chair and leaning forward such that lesion.28 These patients may have pressure sensitivity or
the head is anterior to the vertical axis of rotation (off-axis Tullio’s phenomenon.29
or eccentric rotation). These tests stimulate both the Certain tones may provoke a tonic OTR or skew
otoliths and the horizontal canals. Translational testing is deviation in patients with utricular imbalance known as
able to test only the otolith functions and can be performed Tullio’s phenomenon.30 Separately, these tests may not be
on a linear sled, cart, or parallel swing. This testing requires specific to otolith dysfunction; however, combinations of
specialized equipment and currently does not lend itself tests should increase overall specificity, sensitivity, and
well to office testing. reliability. It remains to be shown whether isolated unilateral
With a tonic lateral head tilt, the eyes counterroll, deficits of otolith function, that is, otolithic defects in the
presumably as part of a normal attempt to align the hori- presence of normal semicircular canal functions, and partial
zontal meridian of the retina with the horizon. Spon- deficits of otolith function can be detected with these tests.
taneous ocular tilt reactions presumably reflect otolith, It is difficult to develop a clinical test for patients suspected
particularly utricular, imbalance. The ocular tilt reaction of suffering from otolith dysfunction when there is an
(OTR) has also been associated with both midbrain and absence of an adequate criterion reference group of patients
peripheral lesions.21–23 OTR is part of the expected com- with proved, isolated, complete or partial, unilateral deficits
pensatory postural reaction to an unexpected lateral tilt of only of otolith function. Another obstacle to testing isolated
the body. The otolith response of OTR consists of a vertical otolith function is the convergence of otolith and semicir-
ocular skew deviation, ocular counterroll, and head tilt. The cular canal inputs on secondary vestibular neurons in the
alternate cover test can aid the detection of skew deviation. vestibular nuclei.31
A vertical corrective eye movement on switching a cover
from one eye to the other eye can detect a vertical misalign-
ment. With peripheral and vestibular nucleus lesions, the SUPERIOR SEMICIRCULAR CANAL
lower eye is on the side of the lesion. The otolith ocular DEHISCENCE SYNDROME
pathway crosses at the level of the vestibular nuclei, so that
with lesions above the decussation, the higher eye is on the Pathology
side of the lesion.24 In a peripheral lesion, the eye on the
side of the head tilted toward the ground has a downward Dehiscence of the superior semicircular canal is an entity
vertical deviation and the eye opposite the side tilted first described by Minor and colleagues in 1998.32 In these
toward the ground has an upward vertical deviation. Also, patients the bony covering between the top of the superior
the superior pole of the eye on the side of the head tilted semicircular canal and the middle cranial fossa is missing.
toward the ground extorts while the superior pole of the (See Fig. 14-3.) This can be spontaneous or presumably
eye opposite the side tilted toward the ground intorts. The congenital. The most likely explanation of patient
head usually tilts toward the side of the lesion with periph- symptoms of imbalance is that the superior canal dehiscence
eral labyrinthine and lateral medullary lesions.19 creates a mobile third window to the inner ear. With this
Utricular function can be assessed in the office using the third mobile window, the endolymphatic system has an
subjective vertical visual (SVV) test. The SVV is a measure increased compliance. Pressure or sound creates a pressure
of otolith and especially utricular function. Bilateral differential across the ampulla, which in turn allows the
otolith inputs provide humans with their dominant per- canal ampulla to be responsive to changes in inner ear pres-
ception of gravity. A patient sits with the head fixed in the sure associated with sound stimulation. Superior canal
upright position and looks forward at an illuminated line dehiscence is rare, arising in 0.5% of temporal bones in a
in darkness. The patient adjusts the line from various start- temporal bone survey or 0.7% of individuals. The condition
ing positions to his or her SVV. This is repeated 10 times is often bilateral. Also, an additional 1.4% of temporal bones
for each eye. With acute peripheral vestibular lesions have a very thin bony covering (smaller than 0.1 mm) such
including the utricles, there is an ipsilateral deviation of that they might appear dehiscent on high-resolution CT
the SVV of about 10 to 15 degrees.25,26 Patients with scan of the temporal bone.33
otolithic dysfunction, however, are not the only patients
who have difficulty with the SVV test. Patients with acute Symptoms
unilateral brainstem infarctions may also exhibit patho-
logic tilts of static SVV from the true vertical.27 The SVV Patients with superior semicircular canal dehiscence (SCD)
test is simple and cost effective; however, it lacks specificity may experience vertigo, tilting of their visual surround, and
at this time—it shows positive results with both vestibular nystagmus without skew deviation when pressure changes
and nonvestibular mechanisms. occur in the external auditory canal, the middle ear, or the
Clinically, patients must be queried about vertical diplopia, intracranial space.34 Also, these patients may experience
tilting of their visual surround, and sound or pressure trig- imbalance and nystagmus with applications of certain tones
gers to their imbalance. In such patients, examination must or sounds to the ear, or Tullio’s phenomenon.35
 Otolith Dysfunction and Semicircular Canal Dysfunction 245

Figure 14-3. A coronal view, high-

resolution, CT scan of the temporal bone
demonstrating a dehiscence of the right
superior semicircular canal.

Etiology of Symptoms infectious etiologies such as syphilis and chronic ear pathol-
ogy,40 trauma,42 perilymphatic fistula,43 and iatrogenic
Patients may experience sensitivity to pressure or certain fistulae, that is, fenestration surgery.44
tones applied to the external ear canal. The origin of the
nystagmus in patients with SCD has been determined. From
Ewald’s first law, one would expect eye movement directed Examination and Testing
in the plane of the affected canal. Vector analysis of the
elicited nystagmus during stimulation has mapped the source A keen examiner must inquire about pressure sensitivity
of the nystagmus to the superior semicircular canal in symptoms as well as sensitivity to certain sounds or tones.
patients with SCD.35,36 The axis of evoked nystagmus in the A patient with pressure sensitivity or Tullio’s phenomenon
superior canal dehiscence syndrome aligns with the plane warrants consideration for SCD. During testing, the
of the affected superior canal, indicating that the response patient’s vision must be controlled to eliminate visual fixation
originates mainly from that canal. The chinchilla has been during the exam. This can be accomplished with Frenzel
used as an animal model of SCD.37 Fenestration of the supe- lens testing, examination in the dark with infrared video
rior semicircular canal produced an increase in superior oculography, or scleral search coil. If the patient is allowed
canal afferents after positive pressure in the external canal visual fixation, nystagmus will likely be suppressed and
and a decrease in firing with negative pressure. Responses abnormalities not appreciated. Patients will present with
could be ablated by rigidly repairing the dehiscence. vertical-torsional eye movements consistent with activation
The ocular movements elicited on tests were initially of the superior semicircular canal. A high index of sus-
thought to be results of possible utricular stimulation. picion is needed to differentiate SCD from perilymphatic
Although appropriate stimulation of the utricle could fistula (PLF). Detailed imaging and careful observation of
produce ocular torsion with horizontal eye movement, and eye movements during exam aids in the diagnosis. High-
stimulation of the saccule could produce vertical eye move- resolution CT scan of the temporal bone is needed to show
ment, one would expect a tonic response with otolith stim- a superior canal dehiscence.
ulation rather than the phasic-torsional nystagmus responses
that are observed.29,35,36 The evoked eye movements in Treatment
patients with SCD syndrome arise from the superior canal,
not the utricle. For symptomatic patients, middle fossa craniotomy may
In some patients, vertigo is elicited by sound applied to be needed to allow plugging of the canal or resurfacing of
the ear. Tullio’s phenomenon is the combination of vertigo the dehiscence. Imbalance symptoms are improved or
and abnormal eye and/or head movements provoked by eliminated after surgery.45 Animal models of SCD have
sound. This vestibular response to sound was first described shown that rigid repair of the dehiscence eliminates symp-
by Tullio, who studied fistulized labyrinths of pigeons in toms better than soft-tissue patch repair.46 If the trigger of
1926.38 Two possible sources of Tullio’s phenomenon have vertigo is sound, avoidance of the offending tone may be
been put forth: otolithic and semicircular canal stimula- all that is needed. If pressure sensitivity is the trigger, a trial
tion.39,40 Tullio’s phenomenon has been associated with with a simple ventilation tube may be beneficial to eliminate
Ménière’s syndrome,39 congenital inner ear anomalies,41 the pressure differential across the tympanic membrane.
246 NEUROTOLOGIC DIAGNOSIS

This, however, would not alleviate symptoms caused by opened to equilibrate pressure. One usually experiences
intracranial pressure fluctuations. otalgia when a pressure differential across the tympanic
membrane exceeds 60 mm Hg and the eustachian tube
“locks” at 90 mm Hg. To rupture the tympanic membrane
LABYRINTHINE HEMORRHAGE (TM), 100 mm Hg to 500 mm Hg is needed.52 Goodhill’s
“implosive” and “explosive” mechanisms for ear trauma
A rare but notable condition described more recently in the are applicable.53 Implosive ear trauma is caused by an acute
literature is vertigo associated with spontaneous hemorrhage increase in middle ear pressure or ossicular pressure forcing
into the vestibule, labyrinth, and cochlea. This condition has the stapes footplate into the vestibule. Explosive ear trauma
been described in the radiology literature in patients with a is caused by either an increase in cerebrospinal fluid (CSF)
history of sickle cell anemia. Patients can present with sud- pressure or forceful Valsalva’s maneuver, resulting in an
den onset of vertigo, sensorineural hearing loss, and patho- increase in intracochlear pressure and possible rupture of
logic findings on magnetic resonance imaging (MRI). High a round or oval window.
signal intensity can be seen on T1-weighted images without
contrast in the vestibule and labyrinth. Patients present Underwater Diving
spontaneously similarly to a sickle cell crisis. Sickling of red
blood cells causes capillary occlusion with resultant ischemia Otolaryngologic barotrauma is most common with diving.
that may lead to spontaneous bleeding.47 This may be sec- Pain and damage usually occur during descent (middle ear
ondary to injury to the capillary vascular bed. Labyrinthine squeeze) due to the inability or failure to equalize pressure.
hemorrhage has been described in conjunction with Symptoms include facial, tooth, or ear pain; sudden hearing
leukemia and thrombocytopenia,48,49 aplastic anemia,50 loss; vertigo; tinnitus; or fullness. Otologic findings include
leukemoid reactions of malignant neoplasms, and in the set- petechial hemorrhages, blebs in the EAC, serous effusion,
ting of DIC.51 As a group, these case reports have a uni- TM retraction, conductive or sometimes a sensorineural
formly poor prognosis of regaining vestibular or cochlear hearing loss, and TM rupture. As a pressure reference,
function after hemorrhage. An MR screening examination sea level is 1 ATM, 33 feet below sea level is 2 ATM, and
consisting of either a high-resolution T2-weighted sequence 150 feet below sea level is 3 ATM. Farmer described a grad-
or a contrast-enhanced T1-weighted sequence will not by ing system for middle ear barotrauma: type I is middle ear
itself accurately diagnose hemorrhage. Noncontrast, thin- fullness, pain, but normal otoscopy; type II is pain, hearing
section, T1-weighted MR images are the study of choice for loss, TM erythema, effusion, and hemotympanum; and
diagnosing intralabyrinthine hemorrhage.1,47 type III is TM perforation.54

Hearing Loss Etiology

OTIC BAROTRAUMA
Hearing loss can be either conductive or sensorineural.
Barotrauma can be defined as tissue damage resulting from Conductive etiologies include serous effusions, hemotym-
a change in gas pressure present in a closed space. The panum, ossicular disruption, and tympanic membrane
air-filled spaces of the middle ear and mastoid constitute a perforation. Neural loss etiologies include gas embolus in the
closed volume if the eustachian tube is malfunctioning. cochlea, labyrinthine membrane tear, intracochlear hemor-
Using the universal gas law, PV/T = PV/T, as ambient rhage, and perilymphatic fistula.55,56 Hearing prognosis from
pressure varies, the pressure within a closed volume must intracochlear hemorrhage is poor due to the resultant
also change. When the normal communications between fibrosis. Prognosis for return of hearing is excellent if the
the air-filled spaces and the environment are blocked, patient presents only with auditory symptoms.57
pressure cannot equilibrate. This pressure differential
causes tissue injury. The usual mechanisms include Treatment Options
underwater diving, flying or air travel, blunt head trauma,
and hyperbaric oxygen therapy. A sudden change in To prevent or avoid barotrauma, several conservative and
ambient pressure is the common denominator. preventive measures can be performed. These may include
no flying within 24 hours of diving, staying awake on
airplane descent, yawning, swallowing, and maintaining
Air Travel good control of allergies. Pressure relief measures are also
As a pressure reference, sea level is 1 atmosphere (ATM), available. Self-politzerization involves pinching the nose,
18,000 feet of altitude is 1/2 ATM. During ascent in closing the mouth, and gently exhaling to force air back
an aircraft, air pressure decreases at an approximate rate into the middle ear or sinuses. The Toynbee maneuver
of 15 mm Hg every 400 feet of altitude. During descent, involves pinching the nose, closing the mouth, and swal-
relative air pressure increases. “Pressurization” in an aircraft lowing to increase nasopharynx pressure. Last, the Frenzel
is a relative term and not all aircraft are equal. A typical maneuver involves contracting the muscles of the floor of
airliner may be pressurized to 8.5 psi, which translates into the mouth and nasopharynx with the mouth closed.
a “sea-level” cabin up to 16,000 feet but a 7,000-foot cabin Medications can also provide benefit to the patient.
altitude when the aircraft is at 40,000 feet. Overall, pressur- Oxymetazoline HCl and pseudoephedrine taken 1 to 2 days
ization reduces but will not eliminate the risk of barotrauma. before a flight might provide some degree of deconges-
Air usually flows passively from the middle ear on ascent; tion and vasoconstriction. A myringotomy with or with-
however, on descent the eustachian tube must be actively out a tube is indicated in refractory conditions as long as
 Otolith Dysfunction and Semicircular Canal Dysfunction 247

a nasopharyngeal mass is ruled out. A middle ear explo- of the organ of Corti, tectorial membrane, and stria vascu-
ration may be needed if severe cochleovestibular symptoms laris. These findings are similar to the histopathologic
are present. studies of patients with mumps and measles.

Decompression Sickness Serous

Decompression sickness (DCS) occurs when the surrounding Serous labyrinthitis is a sterile inflammatory condition of
atmospheric pressure decreases too rapidly. As the atmos- the inner ear, induced by chemical or toxic irritation of the
pheric pressure decreases, the nitrogen-carrying capacity of membranous labyrinth. This may occur from acute or
the blood decreases. If the atmospheric pressure decreases chronic otitis, or from trauma or surgery. Patients typically
too rapidly, the excess nitrogen coming out of solution develop mild to moderate vertigo with nystagmus directed
from the blood will not be able to be excreted by the lungs toward the affected ear. Mild to moderate, temporary or
quickly enough. DCS arises when nitrogen bubbles form in permanent, sensorineural hearing loss is common especially
the blood. The body tries to rid nitrogen faster than the in the high-frequency range nearest to the oval window and
lungs can exchange it with the environment. Type I DCS presumed proximity to toxins in the middle ear.
includes musculoskeletal pain and cramping, cutaneous
modeling, skin discoloration, and joint pain. Type II DCS
includes severe, emergent symptoms.58 Neurologic signs Suppurative
include deafness, vertigo, loss of vision, paraplegia, and in Suppurative labyrinthitis occurs when pyogenic bacteria
some cases cardiopulmonary shock. Factors potentiating enter the inner ear. This may occur in acute or chronic
DCS include unpressurized altitudes above 25,000 feet, otitis media with or without cholesteatoma, meningitis, or
long duration at altitude, a rapid ascent (either flying or rarely, in systemic bacterial infections. Iatrogenic fistula
diving), and flying within 24 hours of diving. during middle ear surgery may also result in suppurative
To reduce the risk of DCS, one can ascend from a labyrinthitis. Patients are often violently ill with fever,
dive slowly with decompression stops and use pressu- severe vertigo, and profound hearing loss. The route of
rized aircraft when flying. “Prebreathing” pure oxygen for meningitic spread is via the cochlear aqueduct to the scala
30 minutes before a deep dive or high-altitude flight makes tympani and is usually bilateral. Ossification of the cochlea
a nitrogen diffusion gradient so as to reduce the overall may ensue within weeks to months after recovery of menin-
volume of nitrogen in tissues. Mixing helium with oxygen gitis, necessitating prompt consideration of and cochlear
instead of nitrogen for deep dives reduces the risk of implantation if warranted. Nystagmus is directed away
nitrogen bubbles forming in the bloodstream. from the affected ear and the patient falls and past points to
Type I DCS treatment includes 100% oxygen and obser- the affected side. In suspected cases of fistula, caloric investi-
vation with the expectation that symptoms will resolve in gation is contraindicated because it may spread the infection
a matter of hours. Type II DCS treatment necessitates a by intralabyrinthine fluid.60 The combined vestibular and
hyperbaric oxygen chamber with recompression to 3 ATM auditory loss is usually permanent. Fortunately, suppurative
greater than when the symptoms started. Transport to the labyrinthitis is rare in the antibiotic era.
hyperbaric oxygen (HBO) facility should be at no greater Treatment of the vestibular symptoms in all forms of
than 800 to 1000 feet above ground level or in a pressurized labyrinthitis involves use of vestibular suppressant medi-
transport.59 cations for the acute attack and vestibular rehabilitation to
enhance compensation as soon as practical after the acute
LABYRINTHITIS stage has passed. If no contraindications exist, high-dose
steroids may be given for a viral labyrinthitis. Parenteral
Viral antibiotics will likely be needed for patients with a suppu-
rative labyrinthitis.
Viral labyrinthitis is the most common form of membranous
labyrinthitis seen in clinical practice. It may complicate the
course of systemic viral infections such as measles, mumps, PERILYMPH FISTULA
influenza, and chickenpox. Viral labyrinthitis may also occur
in the absence of systemic viral disease. A perilymphatic fistula (PLF) is an abnormal connection
The initial symptoms are severe vertigo exacerbated between the inner and middle ear due to a defect in the
by head movement. When associated with systemic viral labyrinthine bone or in the round or oval windows. Such fis-
infection, patients often develop a sensorineural hearing tulas cause sudden or fluctuating sensory hearing loss and
loss. The hearing loss may be transient but is more often dizziness. There are various causes of perilymphatic fistula
permanent. Early examination usually reveals an irritative including both acquired and, more rarely, congenital causes.
nystagmus toward the affected ear. The vestibular symptoms Acquired PLF may arise secondary to erosive cholesteatoma,
usually improve in 48 to 72 hours but may take weeks to syphilitic gummas, benign or malignant neoplasm, or
resolve. Lingering episodes of dysequilibrium or unsteadi- traumatic and iatrogenic etiologies. Congenital PLF may
ness may follow the acute episode for a variable time depend- be present with or without cranial anomalies. The exis-
ing on the patient’s physical activity level and other factors tence of other causes that do not involve the labyrinthine
that affect compensation. bone but involve one of its windows is not well accepted by
Histopathologic study of the temporal bones of such all surgeons. The reason for this is that there is no clear
patients has shown the principal changes to consist of atrophy method of determining the diagnosis preoperatively, and
248 NEUROTOLOGIC DIAGNOSIS

even surgical exploration often depends on subjective inter- after pressurization of the external ear canal on the side of
pretation of the findings. the fistula. Observing this phenomenon, the fistula test was
first described by Lucae in 1881.66 It consists of registration
Pathogenesis of ocular deviation or nystagmus following pressurization
of the external ear canal. There are three types of ocular
The arguments of Goodhill53 regarding the “implosive and response to the fistula test thought to indicate abnormality
explosive” etiology of perilymph fistula and those of and the potential presence of fistula. The fistula sign is a
Simmons61 regarding an alternate lesion causing the same nystagmus that continues for 10 to 15 seconds following
symptoms have received the most attention, and both have application of positive or negative pressure.67,68 Hennebert’s
supporting experimental findings. Goodhill theorized that sign is a slow conjugate horizontal ocular deviation at the
sudden or severe changes in middle ear pressure, via the onset of pressurization and a movement in the opposite
eustachian tube, could direct force internally toward direction at the end of stimulation.66,67,69 The ocular tilt
the inner ear, causing rupture of the oval window or round reaction, described more recently, is a combined vertical
window seals (implosive route). Autoinsufflation of the and torsional movement of the eye, of rapid onset and
eustachian tubes may cause fistula by this mechanism. Blunt resolution, provoked by pressure.14,70
head trauma including whiplash and even low-velocity head The fistula test is used to select patients for exploratory
trauma can result in PLF.62 Acoustic trauma or external tympanotomy in an attempt to detect and repair a PLF.
atmospheric pressure, which causes relatively large displace- However, inconsistent criteria are often used to interpret
ment of the tympanic membrane, may also cause fistula by the fistula test. The fistula test as conventionally performed
this mechanism, according to Goodhill. Similarly, force is insensitive for the diagnosis of PLF.71 In normal subjects,
could be directed externally toward the inner ear by the change in nystagmus between prepressure and post-
increased CSF pressure, via the cochlear aqueduct or inter- pressure tests ranged from −1.3 to 0.9 degrees per second.
nal auditory canal (explosive route). Physical exertion such In patients, change in nystagmus greater than the 95th
as lifting weights, coughing, and sneezing could cause fis- percentile limits of normal was not a reliable indication of
tula this way. In humans, we know that a patent cochlear PLF.71 The test may be falsely positive in patients with
aqueduct can exist and that the largest volume displacement Ménière’s disease and caloric testing is nonspecific. Patients
of perilymph occurs at relatively low-pressure changes.63 with fistula present with a wide variety of hearing loss
Furthermore, round window ruptures have been docu- patterns, and in fact no audiometric parameter has been
mented after barotraumatic events such as scuba diving.64,65 found to be predictive of a perilymph fistula.
Just prior to Goodhill’s presentation on the theory of Accurately diagnosing a fistula remains difficult and
labyrinthine window rupture, Simmons had presented an disputed. Each surgeon must establish reasonable guidelines
alternative theory for sudden sensorineural hearing loss. His before considering surgical exploration of patients with
theory suggested the CSF pressure changes are transmitted dizziness. A diagnosis may be considered when a clear his-
to the labyrinth, which result in intracochlear membrane tory of a traumatic event or other predisposing cause is doc-
breaks, and the subsequent mixing of endolymph and peri- umented. Furthermore, the presence of vestibular symptoms
lymph causes the symptoms.61 This theory was based on ear- alone, with no hearing loss or tinnitus, makes the diagnosis
lier experimental evidence in cats showing intralabyrinthine less tenable. There is no clear evidence for the existence of
membrane rupture and deafness.64 spontaneous (idiopathic) perilymph fistula. In the experience
of most practitioners, perilymph fistula remains a relatively
Symptoms uncommon cause of dizziness and hearing loss.72
The classic symptoms of perilymph fistulas are sudden
severe sensorineural hearing loss, vertigo, and tinnitus. Management
Several of the early reports emphasized sudden sensory
hearing loss as the presenting symptom of perilymph fistula, Initial care of a patient with perilymph fistula involves
particularly seen related with a history of physical exertion. conservative measures. Bed rest, head elevation at all
Further experience has shown that many patients actually times, avoidance of physical straining and blowing of the
complain of fluctuating hearing loss.64,65 As such, the symp- nose, and controlled sedation is advised for 10 days.
toms of perilymph fistula can often be identical to those of Persistent otologic symptoms after this period, particularly
Ménière’s disease. The severity of the hearing loss bears no with a history of recent trauma, warrant an exploratory
relationship to the extent of the perilymph leakage, nor does tympanotomy for definitive diagnosis and repair of a fistula.
it help predict the likelihood of finding a perilymph fistula. Under local anesthesia with sedation, the surgeon can
In some, PLF symptoms may arise immediately or within carefully expose and observe the round and oval windows.
days after head trauma; however, Ménière’s type symptoms Placement of the patient in the Trendelenburg position,
may take months to years to develop. Patients with fistula application of external pressure on the jugular vein, and the
can present with vertigo, positional dizziness, or dysequilib- Valsalva maneuver will help reveal a fistula. Because laby-
rium. Findings of nystagmus have shown no definite pattern rinthine defects are not always associated with perilymph
and have not been predictive for fistula. leakage, repair at the windows is undertaken whether or not
a fistula is clearly seen. Small pieces of autogenous perichon-
Diagnosis and Testing drium can be packed over the round window membrane and
around the annular ligament and stapes footplate after the
The fistula test is the most widely used clinical test for this respective niche is scarified with a fine pick or knife. Hearing
condition. Patients with PLF often become vertiginous improvement after fistula repair is infrequently seen (about
 Otolith Dysfunction and Semicircular Canal Dysfunction 249

25% of patients) but improvement in vertigo occurs in a Treatment resides in determining a peripheral source of
majority of patients (60% to 80%). the vertigo. If the vertigo persists following rehabilitation,
the patient may obtain relief from a chemical or surgical
Congenital Perilymph Fistula labyrinthectomy or a vestibular nerve section. Before any
destructive means are taken, the diagnosis must be certain,
Congenital perilymph fistulas are unlike acquired perilymph central etiologies must be ruled out, and the patient should
fistulas in the character of the leakage and in etiology. be capable of postoperative rehabilitation to speed com-
Suspect a congenital perilymphatic fistula when progressive pensation. Ideally, the patient’s vision and proprioceptive
sensorineural or mixed hearing loss, with or without senses are intact.
vertigo, is associated with one or more of the following:
otitis media, labyrinthitis, or meningitis.73 These patients
may present with CSF otorrhea or rhinorrhea and frequently Post-Traumatic BPPV
have had recurrent episodes of meningitis because commu- The sudden blunt force from head trauma can result in
nications between the intracranial space and the middle ear direct shearing force to the utricle. The otoconia from the
provide an easy pathway for the spread of infection. The otolith organ can be sheared off their gelatinous matrix into
most common finding has been leakage from the oval the endolymph. The patient not only will have the BPPV-
window area. Anatomic anomalies of the ossicles, windows, like symptoms and positive Dix-Hallpike test, but also may
or labyrinth are often noted. have resultant otolith dysfunction. This otolith dysfunc-
tion may persist several weeks until new otoconia are
POST-TRAUMATIC VERTIGO formed and the otolith organ ad can restore the structure
and function to the utricle or saccule. The examiner
Eighth Nerve Trauma should be aware of this possible dual diagnosis and be keen
during the history and examination to detect multiple
Blunt head trauma can cause shearing force on intracranial complaints and findings that do not necessarily “fit” the
structures due to sudden head acceleration forces. A collision classic diagnosis of BPPV.
of only 8 mph can generate a 5g force on the head.74
These shearing forces can cause damage to the eighth nerve
root entry zone of the brainstem. Petechial hemorrhages may Post-Traumatic Endolymphatic
be observed in the region of the vestibular nuclei.75,76 These Hydrops
patients may have a persistent form of imbalance that
compensates poorly. This compensation is poor due to only Post-traumatic endolymphatic hydrops is an entity that
partial damage to the end organ as well as damage to the presents with aural fullness, tinnitus, fluctuating sensori-
vestibular nuclei. For compensation to be effective, one needs neural hearing, and episodes of vertigo. This presentation
a normally functioning vestibular nucleus on the side of the is very similar to that of classic Ménière’s disease. Hydrops
acute loss.77 Symptoms may persist because of an incomplete can arise even without evidence of temporal bone fracture.
unilateral loss as well as a dysfunctioning vestibular nucleus. Intralabyrinthine hemorrhage can theoretically cause
Testing may show an acute hemorrhage on MRI. scarring of the vestibular aqueduct and delayed symptoms
Electronystagmography (ENG) may show a unilateral that may arise months to years following the traumatic
caloric hypofunction. Rotary chair testing may demonstrate event.84–86 Treatment options are similar to those for
an asymmetry of gain during low-frequency sinusoidal Ménière’s disease, as described elsewhere in this text. The
harmonic acceleration testing and an increased phase lag practitioner should also be aware of the possible risk of CNS
at low frequencies. With time, the asymmetry of gain may etiology due to the trauma as well as possible bilaterality.
disappear, but the increased phase lag would remain These factors may reduce the efficacy of treatment when
indefinitely.78,79 Treatment may include intensive vestibular compared with success rates with conventional treatment of
physical therapy to maximize compensation. If conservative Ménière’s disease. Also, since symptoms may be similar and
measures fail, consideration can be given to chemical or traumatic in etiology, traumatic perilymphatic fistula may
surgical labyrinthectomy or vestibular nerve section to be possible and should be considered in a patient with
eliminate a partially functioning vestibular system. temporal bone fracture, pressure sensitivity, or penetrating
mechanism.
Labyrinthine Concussion
Following blunt head trauma, the semicircular canals LUETIC VESTIBULOPATHIES
can be injured even if there is no obvious temporal bone
fracture. The complete pathophysiologic mechanisms of Otologic syphilis can arise from either a congenital or an
trauma are not yet fully understood. Mechanisms for laby- acquired infection, and symptoms may occur either early or
rinthine concussion have been proposed. Sudden accelera- late in the infection. It is a multisystem, multistage disease
tion forces can cause shearing trauma to the vestibular end caused by infection with the spirochete, Treponema pallidum.
organs and disruption of the sensory epithelium.80 Laby- Infection can be present with long periods of latency and late
rinthine hemorrhage may result in fibrous tissue deposition, progression. Otosyphilis should be considered in any patient
scarring, and new bone growth.81,82 The delicate vasculature with unexplained vestibular symptoms. Vestibular symptoms
to the vestibular end organs can be disrupted by shearing may be the sole presentation of the infection.87 Awareness of
forces, and small clot formation results.83 this disease is especially relevant because of the increased
250 NEUROTOLOGIC DIAGNOSIS

incidence of syphilitic infections in recent years. This rise absorption test (FTA-ABS). This test may be false-positive
has been directly correlated to the spread of the human in autoimmune diseases and hepatic cirrhosis.
immunodeficiency virus (HIV).88 Surgical treatment in the form of endolymphatic sac
Congenital syphilis has two stages. The early stage results surgery has been found by most to be unsuccessful in
from transplacental infection from the mother. Thirty-eight alleviating symptoms.95 Failure is presumed to result from
to 64% of patients may be asymptomatic. Those affected obstruction in the vestibular aqueduct proximal to the site
may have profound hearing loss and multisystem disease.89 of surgery. Linthicum and Abd El-Rahman have shown
Late-stage congenital syphilis is disease presenting after microgammas obstructing the endolymphatic duct.96
2 years of age. Children usually present with hearing loss Medical treatment includes benzathine penicillin 2.4 million
with vestibular symptoms, whereas adults may present units intramuscularly once weekly for 3 weeks. Prednisone
with episodes of vertigo, tinnitus, and fluctuating hearing may be considered in the face of rapidly declining otologic
loss. Most late-stage, congenital syphilitic patients have function. Doxycycline 200 mg twice daily for 30 days can be
other physical findings including interstitial keratitis, used for penicillin-allergic patients. If neurosyphilis is
Hutchinson’s teeth, saber shins, frontal bossing, and confirmed by lumbar puncture, penicillin desensitization
Clutton’s joints (painless hydrarthrosis).90 may have to be considered because it remains the only
Acquired syphilis can be divided into various stages. proved therapy for neurosyphilis.97
Primary stage is evident by a painless solitary chancre on
the skin. Secondary stage presents several months after the
initial infection as a fever, malaise, rash, and constitutional OTOTOXICITY
complaints. Vestibular symptoms are usually minimal.
A latent period then follows for a variable length of time, Ototoxicity is “the tendency of certain therapeutic agents
often years. Forty percent to 70% of patients do not and other chemical substances to cause functional
progress beyond this phase. The remaining patients progress impairment and cellular degeneration of the tissues of the
to tertiary syphilis. These are partitioned approximately inner ear, and especially of the end organs and neurons of
equally between gummatous syphilis (benign late syphilis), the cochlear and vestibular divisions of the eighth cranial
cardiovascular syphilis, and neurosyphilis.91 nerve.”98 This entity has been recognized since the late
Vestibular symptoms vary depending on the stage of 1800s when quinine and acetylsalicylic acid produced
active syphilis. In the early stage (less than 2 years after dizziness, tinnitus, and hearing loss. Streptomycin in the
exposure) of both the congenital and the acquired forms, 1940s had great therapeutic potential as an antibiotic to
vestibular symptoms are rare.90,92 With late stages of syphilis, treat tuberculosis, but the delayed ototoxic effects
the audiovestibular symptoms are variable. Symptoms may devastated patients and the earlier form was discontinued.
be indistinguishable from those of Ménière’s disease.93 The Since then, other drugs have been found to have ototoxic
patient may also demonstrate vertigo or imbalance when effects, such as newer antibiotics, antineoplastic agents,
exposed to certain sounds or tones (Tullio’s phenomenon). and diuretics. Many reports concerning ototoxic agents
The patients may demonstrate vestibular symptoms with must be reviewed quite carefully since the compromised
atmospheric pressure change suggestive of a perilymphatic patient who develops ototoxicity may have previously
fistula. There may be no other “classic” syphilis findings received other potentially ototoxic agents or actually may
on exam. Unsteadiness or vertigo as the initial symptom has be receiving synchronously ototoxic agents or potentiating
been found in 20% to 100% of all congenital and 30% to medications. Also, one must carefully review the condition
50% of all acquired forms of otosyphilis.93,94 of the patient at the time the medication is used to see if
Apart from episodes of vertigo, the patient may have that patient may be in an oliguric state or receiving
fluctuating sensorineural hearing loss, relatively poor speech chemotherapy or radiation therapy.
discrimination, tinnitus, and bilateral, somewhat symmetric Patients who receive ototoxic drugs are often bedridden
decreased caloric responses. The signs easily mimic and suffer from multiple symptoms of systemic illness, so
Ménière’s disease, perilymphatic fistula, or autoimmune additional symptoms of auditory and vestibular dys-
hearing loss. Other diseases that must be kept in the function may be easily overlooked. Vestibular symptoms
differential diagnosis are multiple sclerosis, migraine variant, are particularly difficult to identify in this setting. Only
Cogan’s syndrome, Vogt-Koyanogi Harada syndrome, after the patient begins to recover will the devastating
cerebellopontine angle masses, and vasculitic diseases. effects of vestibular loss become apparent. By this time, the
Syphilitic infection of the otic capsule starts as a mononu- damage is irreversible. The examining physician must be
clear leukocyte infiltration and progresses to an obliterative keenly aware of the potential auditory and vestibular
endarteritis and osteitis of all three layers of the otic capsule. toxicity of any drug that is used if ototoxicity is to be
This results in narrowing of the endolymphatic duct and sac prevented. Currently, there is no standard of practice as to
with resultant hydrops. Additionally, a gummatous deposit the appropriate auditory or vestibular monitoring test to
can form a perilymph fistula. obtain or guidelines as to the frequency of any monitoring
Physical exam may produce a positive Hennebert’s sign technique.
or Tullio’s phenomenon. Slit-lamp exam of the cornea may
reveal an interstitial keratitis in 90% of late-stage syphilis.93 Aminoglycosides
ENG findings often show either unilateral or bilateral
reduced vestibular response.94 Along with the appropriate All aminoglycoside antibiotics can produce both auditory
cochleovestibular symptoms, the diagnosis of otosyphilis and vestibular damage. Streptomycin and gentamicin are
rests on a positive serum fluorescent treponemal antibody relatively specific for the vestibular system and kanamycin,
 Otolith Dysfunction and Semicircular Canal Dysfunction 251

tobramycin, and amikacin produce more damage to the ototoxic effect is not completely known, although these
auditory system.99,100 Aminoglycosides have bactericidal drugs clearly influence ion pumps in the kidney and in the
activity that results from inhibition of protein synthesis cochlear duct. The ototoxic effects of the loop diuretics
at the level of the ribosome. This class of antibiotic is appear to be confined mostly to the cochlea, although
used to treat serious aerobic gram-negative infections. The histopathologic changes in the vestibular end organ have
aminoglycosides do not undergo any significant degradation been documented.111 About 6% of patients who receive
in the body and are excreted unaltered into the urinary tract furosemide develop a temporary hearing loss that is nearly
by glomerular filtration. The concentration of aminogly- always reversible. Several characteristic features of loop
coside in the perilymph rises slowly, reaching its peak diuretic ototoxicity are readily apparent because most
2 to 5 hours after injection, at a level 3% to 5% of peak patients affected have concomitant renal disease and most
serum level. The half-life of aminoglycoside in perilymph receive furosemide intravenously. Other case reports involve
has been reported to be from 3 to 5 hours, which permits the co-administration of an ototoxic drug such as an amino-
significant accumulation of aminoglycosides.101,102 Patients glycoside, or in fact the drug was given to an oliguric patient.
with renal impairment cannot excrete the drug, so the Histologically, the major changes that have been
aminoglycoside accumulates in the blood and inner ear observed in animal temporal bones involved the stria
tissues. Aminoglycosides have been shown to cause ototox- vascularis: intercellular edema, capillary narrowing, and
icity by several means. Outer hair cells, spiral ganglion degeneration of the intermediate cell layer. Degeneration
cells, dark cells, and stria vascularis structures can all be of the outer hair cells, primarily of the basal turn, have also
damaged by aminoglycosides.103 Toxicity is seen at the been observed, but are less common. Changes in the
level of the cochlear hair cell calcium channels, transduction vestibular labyrinth have also been observed, with degener-
channels at the stereocilia tips, and N-type and P/Q-type ation of both type I and type II hair cells in the ampullae
channels in the neurons in addition to uptake mechanisms and maculae.112
and cellular actions.104 Clinical experience with ethacrynic acid and furosemide
The earliest effect of the vestibulotoxic compounds such indicates that they may produce transient or permanent
as streptomycin and gentamicin is a selective destruction hearing loss following either oral or intravenous admini-
of type I hair cells in the crista. Later, type II hair cells are stration. There are certainly risk factors in their administra-
destroyed, but the supporting cells remain unaffected. tion that have been identified. One must consider the rate of
With the cochleotoxic agents such as kanamycin and intravenous infusion, the dosage, and other potentiating
amikacin, selective destruction of the outer hair cells in the medication that the patient may be receiving. The renal
basal turn of the cochlea occurs first, followed by total hair status is particularly important for the oliguric patient who
cell loss throughout the cochlea as the dose and duration may receive a relatively high dose intravascularly since it is
of treatment are increased. Even after treatment is not cleared effectively.
terminated, some of the aminoglycosides (dihydrostrepto-
mycin, gentamicin, and tobramycin, in particular) have
been shown to produce continued damage to the sensory
Salicylates
structures of the organ of Corti. Patients receiving high-dose salicylate therapy frequently
Experimentally, certain growth factors such as neu- complain of hearing loss, tinnitus, loss of balance, and
rotrophin-3 can at least partially protect against aminoglyco- occasionally of vertigo. Sensorineural hearing loss involves
side-induced ototoxicity. However, systemic application has all frequencies and is associated with recruitment, which
been limited due to the significant amount of cell cycle medi- suggests a cochlear rather than a nervous system etiology.
ation of nonotic cell lines.105 Brain-derived neurotrophic fac- The tinnitus is high pitched and frequently precedes the
tor (BDNF) has also shown protective properties for the hair onset of the hearing loss. Both hearing loss and tinnitus
cells against aminoglycosides in experimental models.106 invariably occur when the plasma salicylate level approaches
Also, studies of the NMDA excitotoxic pathway have 0.35 mg/ml. Caloric testing often reveals bilateral depressed
demonstrated that antagonizing the NMDA system allows responses consistent with bilateral vestibular end organ
cytoprotection of vestibular hair cells and only partial loss of damage.113 All symptoms and signs are rapidly reversible
apical sensory hair cells in experimental studies.107 Recently, after the cessation of salicylate ingestion (usually within
Sha and Schacht108 found that salicylates protect against 24 hours). As with the aminoglycosides, salicylates are highly
gentamycin-induced ototoxicity, putatively by serving as both concentrated in the perilymph.
antioxidants and iron-chelating agents. Salicylates decreased
threshold shifts and basal outer hair cell loss in the guinea pig Cisplatin
model. Genetics of aminoglycoside ototoxicity appear to
have a random or multifactorial inheritance pattern related Cisplatin is commonly associated with both auditory and
to the ribosomal RNA gene of mitochondrial DNA.109 vestibular toxicity. It is an extremely effective drug in the
treatment of patients with nonseminomatous germ cell
tumors, ovarian carcinoma, and squamous cell carcinomas
Loop Diuretics of the head and neck, cervix, and genitourinary tract.
The two main ototoxic loop diuretics, furosemide and Cisplatin is administered intravenously. It appears to
ethacrynic acid, act by inhibiting active resorption of undergo basically renal excretion without metabolism in the
chloride in the loop of Henle of the proximal renal tubule, body. The drug is frequently administered with the patient
thereby preventing the renal resorption of sodium that well hydrated, with mannitol being administered to protect
passively follows chloride.110 The mechanism of their against nephrotoxicity.
252 NEUROTOLOGIC DIAGNOSIS

Cisplatin effects its activity in at least two mechanisms. available that may be useful in certain bedside situations.
The first involves the blockade of ion transduction channels A large-scale prospective study simultaneously comparing
within the membranes of outer hair cells, producing hair cell the efficacy of conventional audiometry, high-frequency
hyperpolarization and auditory threshold elevations.114 The audiometry, and otoacoustic emissions in detecting
other mechanism of cisplatin ototoxicity involves the forma- ototoxicity does not yet exist.118
tion of reactive oxygen species in the cochlea. Free radicals Assessing vestibulotoxic effects of potentially ototoxic
deplete intracellular glutathione levels and alter antioxidant medications is important. Identifying vestibular hypofunction
enzyme activity. Lipid peroxidation increases, resulting in early in its course prior to development of end-stage
hair cell, supporting cell, stria vascularis, and auditory nerve oscillopsia is the goal in ototoxic vestibular testing. Bedside
cell apoptosis.115 Ototoxicity induced by cisplatin has been vestibular testing incorporates head thrust testing and
directly related to damage within the organ of Corti. The assessment of dynamic visual acuity. When fixation is inhib-
cochlear hair cells visualized by scanning electron microscopy ited, spontaneous nystagmus and positional nystagmus can
showed actual degeneration. The outer hair cells are more be identified with the use of Frenzel glasses. One must
involved than the inner hair cells, as well as the basilar turns remember to test these at-risk patients if possible so as to
being more involved than the apical turns. Although the have a baseline for comparison. In our experience, bedside
vestibular effects were markedly less than cochlear effects fol- caloric evaluation is useful only in the severely vestibular
lowing the chemotherapy, reports have demonstrated exten- ablated patient. Ambulatory patients may be assessed with
sive degeneration changes of the vestibular receptor organs. quantitative caloric and rotation testing as part of the
Cristae showed dramatic hair cell loss (type I involvement is ENG examination. High-frequency rotational chair testing
greater than type II). Advanced neuroepithelial degeneration is ideal for identifying early vestibular ototoxic effects and
was also seen in the otolith organs, where there was almost is the testing method of choice in patients suspected of
total loss of otoconia as well as hair cell loss. There has also having a bilateral vestibular loss or those patients who have
been some direct neural effects and decreased myelinization. minimal remaining vestibular function. Rotational chair
A cytoprotective effect has been found with D-methionine testing stimulates the VOR at higher frequencies (usually
in the rat model. Reduction in outer hair cell loss and 2 Hz or less, some can test up to 10 Hz) than does caloric
reduction in auditory brainstem response (ABR) threshold testing (0.025 Hz). Cost and availability of this testing
shifts is evident. D-methionine may function as both a equipment may be an issue in vestibular labs.
metal binder and an antioxidant.116 Feghali and colleagues Head autorotation testing, which relies on voluntary head
have demonstrated protective effects of L-N-acetylcysteine movements by the patient, tests the VOR at 2 to 6 Hz. Head
on auditory neurons and hair cells from the toxic effects of velocity is recorded using a velocity sensor attached to a
cisplatin in vitro.117 In vivo studies have not yet been per- special helmet. Cost is usually low and the unit is portable.
formed, and applications to prevent vestibulotoxicity have Autorotation testing has not yet gained wide clinical appeal
yet to be assessed. secondary to issues of test-retest reliability and need for
Clinically, hearing tests are performed with conventional standardization of tests.119 Also, self-generated predictable
frequencies from 250 to 8000 Hz and demonstrate that head movement paradigms, such as head autorotation
the first sign of hearing loss usually appears within 3 to testing, are less accurate than passive (examiner-initiated)
4 days of cisplatin administration. Recent studies using head thrust testing. The patient controlling his or her own
ultrahigh-frequency measurements indicated that substan- head movements can preprogram expected eye movement
tial shifts in hearing thresholds occur initially and in some strategies and thus artificially augment an otherwise defi-
cases are restricted to frequencies above the conventional cient VOR and compensate for a planned or anticipated
range of 8000 Hz. head movement. Tests using passive high-acceleration head
Wide variations in individual ototoxic susceptibility thrusts delivered unpredictably in time and direction should
to cisplatin have been reported. Ototoxicity appears to be more sensitive for discerning VOR hypofunction than
be directly related to several factors: the method of admin- tests using active and predictable stimuli.120
istration (bolus versus slow infusion), the dose per
treatment, and total accumulated dose. Patients older than Management
40 years of age, patients with previous hearing or vestib-
ular conditions, patients with previous renal conditions, The key to the management of ototoxicity is prevention.
or patients in whom other ototoxic agents are used appear Kidney function should be measured before beginning a
to be at a higher risk for the development of cisplatin potentially ototoxic drug. Drug levels are not necessarily
ototoxicity. predictive of ototoxicity risk. Patients in high-risk groups
should be monitored with periodic auditory and vestibular
testing, although the standard of measurement has not
Diagnosis been established. When the earliest detection of ototox-
The clinician must be constantly alert for the early detection icity is detected, adjustments in the dosage schedule often
of symptoms or signs of ototoxicity. This is particularly can reduce the degree or likelihood of symptom progres-
important in critically ill patients, bed-confined patients, or sion. Sometimes drugs with fewer ototoxic effects may be
any patient who has renal impairment, particularly renal substituted.
failure. Clinical bedside evaluation of these individuals Management of patients with permanent bilateral vestibu-
becomes very important because of their limited access to lar ablation should be directed at retraining the nervous
a soundproof audiologic testing center or vestibular testing system to use other sensory signals to replace the lost vestibu-
center. Some high-frequency hearing testing equipment is lar signals. Younger patients will have a greater propensity
 Otolith Dysfunction and Semicircular Canal Dysfunction 253

to recover substantial vestibular activity over a period of 21. Halmagyi GM, Brandt TH, Dieterich M, et al: Tonic contraver-
years, but elderly patients are rarely able to compensate fully. sive ocular tilt reaction due to unilateral meso-diencephalic lesion.
In a retrospective study, 51% of patients were found to Neurology 40:1503–1509, 1990.
22. Halmagyi GM, Gresty MA, Gibson WPR: Ocular tilt reaction
improve after vestibular rehabilitation therapy, 34% showed
with peripheral vestibular lesion. Ann Neurol 6:80–83, 1979.
little or no change, and 15% were lost to follow-up. Patients 23. Brandt T, Dieterich M: Pathological eye-head coordination in roll:
without improvement are those with chronic disorders and Tonic ocular tilt reaction in mesencephalic and medullary lesions.
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constants (<2 sec) on rotatory chair testing were also seen in 24. Brandt T, Dieterich M: Skew deviation with ocular torsion:
the patients that did not improve.121 Vestibular rehabilitation A vestibular brainstem sign of topographic diagnostic value. Ann
progress can be measured through platform posturography Neurol 33:528–534, 1993.
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during rotatory chair testing. J Neurol 247:335–342, 2000.
26. Curthoys IS, Dai MJ, Jalmagyi GM: Human ocular torsional
position before and after unilateral vestibular neurectomy. Exp
Brain Res 85:218–225, 1991.
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 Chapter
Dynamic Posturography
15 Outline

Courtney D. Hall, PhD Introduction Treatment

Historical Perspective Considerations and
Susan J. Herdman, PhD
Methodology Limitations
Sensory Organization Test Sensory Organization Test
Limits of Stability Test Conditions 1 and 2
Motor Control/Adaptation Tests Age
Reliability and Validity of Diagnosis
Dynamic Posturography Motor Control/Adaptation
Application to Patient Tests: Automatic Postural
Management Responses
Risk for Falls in Older Adults Center of Gravity Alignment
Vestibular Deficits Subject Characteristics
Central Balance Deficits Initial Center of Gravity
Nonphysiological Component Alignment
of Balance Summary

INTRODUCTION problems, its utility is limited. It is not sensitive to subtle

problems of postural instability, can be normal in the pres-
Postural control involves the dynamic interplay between ence of relatively severe postural deficits, and cannot be
multiple body systems, including the sensory, central used to distinguish among deficits from different causes.
nervous, and musculoskeletal systems. In order to meet The use of computerized force plates in clinical assessment
the demands of a constantly changing environment has extended our ability to identify subtleties of postural
(1) body position and movement must be detected via sway in patients and better define patients’ problems.
information gathered from the visual, somatosensory, and Dynamic posturography can quantify multiple aspects of
vestibular systems; (2) the central nervous system must postural control including quiet stance, the use of sensory
integrate this sensory information and select an appropri- cues, voluntary weight shifting, and automatic postural
ate response; and (3) the response must be executed by the reactions. Recent advances include the assessment of daily
musculoskeletal system with adequate force and within a activities including sit-to-stand, turns, and gait. At this
task-appropriate time. Failure in any one of these systems time, there are little data on the use of dynamic posturog-
can result in an impaired ability to control posture. By raphy to assess these latter activities, so discussion of these
incorporating dynamic posturography into the balance assessments will not be included in this chapter. While
assessment, clinicians and researchers can quantify each dynamic posturography itself does not allow the clinician to
aspect of postural control and identify specific system identify the cause of dysfunction, some of the force plat-
impairments or functional limitations. Appropriate inter- form measures yield information that aids in diagnosis. For
ventions to improve balance can then be initiated. Research the most part, however, dynamic posturography test results
demonstrates that interventions targeted to improve spe- are used to improve patient treatment by identifying func-
cific deficits are successful in improving postural control tional deficits and establishing and monitoring treatment.
and in reducing risk for falls.1

Historical Perspective METHODOLOGY

The measurement of postural sway during static stance has A dynamic posturograph, or a computerized dynamic pos-
been used for over 100 years in the clinical assessment of turograph, as it is often called, is a device with a force
patients with neurologic disorders. The Romberg test was platform and a computerized system that controls it.2
originally used to distinguish between cerebellar and Critical elements of dynamic posturography include the
somatosensory deficits. Although the Romberg test is now ability of the force platform to move abruptly in a transla-
a standard part of the assessment of patients with balance tional or rotational (pitch) direction, as well as the ability
256
 Dynamic Posturography 257

to synchronize movements of the force platform and a visual and somatosensory cues are altered rather than min-
visual surround with an individual’s movements. Finally, imized or absent. Other systems (e.g., Balance System,
dynamic posturography must include the collection and Biodex Medical Systems, Shirley, NY; Balance Quest,
analysis of the force data. Micromedical Technologies, Chatham, IL; the modified
The most common method of measuring the vertical clinical test of sensory interaction in balance [M-CTSIB]
and horizontal forces applied to the force platform uses test, NeuroCom International, Inc.) alter somatosensory
transducers located under a separate force plate for each feedback by having the individual stand on dense foam or
foot. The sums of the vertical and horizontal forces for an unstable surface, rather than by sway-referencing the
each foot are calculated and combined to locate the center support surface. In addition, vision is not sway-referenced;
of (foot) pressure. The patient’s height and force data are rather, it is removed by closing the eyes. These tests are
used to estimate the vertical location of the center of grav- modifications of the SOT and comprise four other condi-
ity (COG) of the body. The force plate system does not tions (eyes open/closed and firm/compliant surface) that
directly measure COG because this requires information can be assessed.
about the position of each body segment in space. Rather The SOT is organized into a series of six conditions
COG is estimated based on theoretical assumptions about of increasing difficulty. The first three conditions are
the location of COG relative to height, ankle position, and performed on a firm surface with eyes open, eyes closed,
center of pressure.3 COG angle of sway is also estimated. and finally with vision sway-referenced. The final three
Data from dynamic posturography can be expressed as conditions are performed with the support surface sway-
peak-to-peak anterior–posterior or medial–lateral sway, referenced with eyes open, eyes closed, and with vision
sway path length and time, sway frequency and velocity, sway-referenced (see Table 15-1). Results of the SOT
direction of sway, and reaction time. are calculated based on maximum peak-to-peak AP sway
expressed as an equilibrium score ranging from 0 to 100,
Sensory Organization Test with 0 indicating loss of balance and 100 indicating
perfect stability (Figure 15-1).
The dynamic posturography test that assesses use of sen- Data also include sway path and COG alignment at the
sory information is known as the sensory organization test start of each trial. Performance on the different conditions
(SOT). Postural sway is measured under conditions in is used to determine relative use of different sensory cues
which visual and somatosensory feedback is altered and is depicted in bar graph form. Determination of motor
(Table 15-1). In the most commonly available apparatus strategy used (ankle or hip) is inferred from the relative
(NeuroCom International, Inc., Clackamas, OR), the amount of shear force during each trial. The ankle strat-
change in sway angle is used to move either a visual surround egy, in which the body primarily rotates about the ankle
or the support surface in synchrony with the individual’s joint, is defined by the predominance of vertical forces.
sway.4 Movement of the visual surround in parallel with The hip strategy, in which movement occurs about the hip,
the individual alters visual cues normally used for postural is defined by the predominance of horizontal (or shear)
stability. For example, in quiet stance we normally have a forces.
small amount of anterior and posterior (AP) sway. This
sway results in changes in retinal disparity and image size, Limits of Stability Test
which are visual cues used to determine whether you or
the world is moving.5 If the visual world around you (visual The test of voluntary sway is known as the limits of stabil-
surround) is moved in parallel with your sway, these visual ity (LOS) test. LOS measures the maximum COG sway
feedback cues are inaccurate and cannot be used effectively angle an individual is willing or able to shift the COG.
to maintain postural stability. Similarly, when the support During the test, the individual views a screen that displays
surface is moved in parallel with sway there is little change the COG location and a series of visual targets. The
in ankle angle. This alteration in somatosensory feedback patient is required to shift his or her weight to move the
renders it a less effective signal in the maintenance of COG cursor toward a visual target, without moving the feet.
upright posture. The ability of the visual and somatosen- The support surface does not move during this test. The
sory surrounds to be moved in parallel with AP sway is individual is instructed to move directly to the target as
imperfect, however. At frequencies of sway greater than quickly as possible. The targets are positioned at eight
0.3 Hz, the mechanism cannot perfectly match sway, so places around a circle at either 75% or 100% of limits

TABLE 15-1.
Sensory
Organization Test
Conditions Sensory Cues Cues Available for Stability

Condition 1 (C1) Eyes open, visual surround and platform stable Normal visual, somatosensory, and vestibular cues
Condition 2 (C2) Eyes closed, visual surround and platform stable No visual cues, normal somatosensory and vestibular cues
Condition 3 (C3) Eyes open, moving visual surround, platform stable Normal somatosensory and vestibular cues, altered visual feedback
Condition 4 (C4) Eyes open, visual surround stable, platform moving Normal visual and vestibular cues, altered somatosensory feedback
Condition 5 (C5) Eyes closed, visual surround stable, platform moving Normal vestibular cues, no visual cues, altered somatosensory feedback
Condition 6 (C6) Eyes open, visual surround and platform moving Normal vestibular cues, altered visual and somatosensory feedback
258 NEUROTOLOGIC DIAGNOSIS

EQUILIBRIUM SCORE of stability based on patient’s height (Figure 15-2).

100 Data include reaction time, movement velocity, end point
excursion, maximum excursion, and directional control.
Reaction time is the time between the “go” signal and the
75
patient’s first movement. Movement velocity is the average
speed of COG movement in degrees per second. End
50 point excursion is the distance of the initial movement of
the COG toward the target as a percentage of maximum
25 LOS distance. Maximum excursion is the maximum dis-
tance the COG moved during the trial. Directional control
Fall is an indication of the amount of deviation from a direct
1 2 3 4 5 6 Composite path to the target and is expressed as a percentage, with
88 100% representing a direct path.
A Conditions

Motor Control/Adaptation Tests

COG ALIGNMENT Successful mobility in the environment requires an indi-
vidual to react to external disturbances of balance, such as
occurs when a bus suddenly starts or stops or the individ-
ual steps in a hole because of uneven terrain. Therefore,
tests of reactive balance involve sudden, brief displacement
of the support surface in order to assess automatic postural
responses used in the recovery of balance. These responses
must be appropriately timed and scaled to prevent a loss of
balance or fall. Muscle activity in the distal musculature
occurs at approximately 110 msec following movement of
the support surface, while center of pressure changes (i.e.,
as a result of active application of force or torque) begin at
B approximately 130 msec.6 Both timing and amplitude of
surface reactive force are measured to assess the automatic
postural responses. The motor control test (MCT) uses
Trial 1 Trial 2 Trial 3 forward and backward translational movements of the sur-
C1 face, and the adaptation test uses rotational pitch (either
Normal vision toes up or toes down) of the surface.
Fixed surface The MCT involves three trials in each of three progres-
sively larger translations of the support surface (Figure 15-3).
C2 The weight symmetry, or relative weight distribution on
Absent vision each leg, latency of onset of force development used to
Fixed surface regain postural stability, and the amplitude or strength of
C3 the response is recorded (Figure 15-3B, C). The larger the
SwayRef vision displacement of the support surface, the greater the
Fixed surface response needed to regain balance. Normal subjects and
patients with bilateral vestibular deficits exhibit a relative
C4 increase in the initial rate of change of torque developed
Normal vision as the amplitude of surface displacement increases. In
SwayRef surface contrast, patients with cerebellar disorders fail to modify
C5 their automatic postural responses as measured by surface
Absent vision reactive force.7
SwayRef surface The adaptation test uses a sudden tilt of the support sur-
face in a pitch (toes up or down) direction to evoke postural
C6 responses. This shifts the COG alignment and destabilizes
SwayRef vision the individual. Measurements of the magnitudes of response
SwayRef surface to five identical toes-up or toes-down perturbations are used
to assess motor learning or adaptation. Repeated perturba-
10 degrees
tions of the same amplitude should result in a decrease in
C the amplitude of the force developed to maintain postural
stability (Figure 15-3D). Normal individuals quickly learn
Figure 15-1. Normal sensory organization test (SOT) results: A, Equilibrium to maintain their balance during this paradigm, and loss of
scores for three trials of each condition with 100 indicating perfect stability; the balance is unusual except during the initial trial in younger
shaded area indicates performance outside of age-referenced norms; B, each
mark represents center of gravity (COG) alignment at the start of each trial
subjects.8 In older subjects (>70 years), the likelihood of loss
relative to the center of the force plate; C, sway path of COG during each trial of balance increases on all trials of toes-up perturbations,
with reference to the center of the force plate; C1–C6 indicates conditions 1–6. although adaptation still occurs.8
 Dynamic Posturography 259

LIMITS OF STABILITY The addition of electromyography (EMG) during toes-up

perturbations allows the clinician to measure muscle activity.
Rotation of the support surface results in a very different
pattern of muscle activity from translational perturbations
(Figure 15-4). The toes-up movement of the platform elicits
both a short-latency and a middle-latency response in
the gastrocnemius–soleus muscle group (Figure 15-4B, D).
The short-latency response is equivalent to the monosy-
naptic stretch reflex, and the middle-latency response is a
multisegmental spinal reflex.9 This is followed by a long-
latency response in the anterior tibialis muscle, which acts
to shift the COG alignment forward (Figure 15-4C, E). The
long-latency response is believed to encompass a transcor-
tical pathway.9 Examination of the presence, absence, or
A 100% LOS delay in any of the reflex responses has been correlated with
site of neurologic lesion (Table 15-2).

Reliability and Validity of Dynamic

Sec REACTION TIME (RT)
Posturography
2.0
1.6 Two important attributes of any assessment tool are
1.2 reliability and validity.10 Good test–retest reliability must
0.8 be established if dynamic posturography is to be used to
0.4 identify changes in postural control associated with treat-
0.0 ment. At present, there are few studies on the reliability
of dynamic posturography testing. Studies of SOT in
B Forward Back Right Left Comp
community-dwelling older adults show that the test-retest
reliability is greater when the average of three trials is used
rather than the first trial score only, although reliability
across the six conditions ranges from poor to good (ICCs
MOVEMENT VELOCITY (MVL)
Deg/sec = 0.26 to 0.68).11 The use of a composite score (average
10.0 of C1 + average of C2 + all other trials for C3 to C6/14)
8.0 also improves reliability to good (ICC = 0.66). Test-retest
6.0 reliability of the LOS has been found to be moderate to
4.0 high for two days of testing in community-dwelling older
2.0 adults who have not fallen (generalizability coefficients
0.0 = 0.69 to 0.89),12 as well in individuals after a stroke (ICCs
C Forward Back Right Left Comp = 0.84 to 0.88).13 No studies examining reliability of the
motor control tests were found.
Validity refers to whether a test measures what it intends
ENDPOINT & MAX EXCURSIONS to measure. Dynamic posturography was developed as an
% (EPE & MXE) objective measure of postural control. Because postural
120
control is multifaceted, any tool claiming to evaluate the
100 construct of posture must assess multiple dimensions.
80 Dynamic posturography is capable of assessing voluntary
60 (LOS) and reactive postural control (MCT/adaptation), as
40 well as balance under differing sensory conditions (SOT).
20
0 Thus, dynamic posturography appears to have content
validity.
D Forward Back Right Left Comp Another test of validity is concurrent validity, in other
words, the degree to which the results of dynamic postur-
ography correlate with a measure known to be valid.
% DIRECTIONAL CONTROL (DCL)
100
Figure 15-2. Normal limits of stability (LOS) test results: A, sway path of
80 center of gravity to each target located at 100% limits of stability, B, reaction
60 time in seconds, C, movement velocity in degrees/second, D, endpoint (EPE)
40 and maximum excursion (MXE) in percentage of total possible excursion,
20 and E, directional control in percentage value indicating directness of path to
0 target. In graphs B-E, the shaded area represents performance outside of
age-referenced norms. Forward, back, right, and left is
E Forward Back Right Left Comp calculated to indicate performance in those primary directions, and
Comp is a calculated composite score from all the targets.
260 NEUROTOLOGIC DIAGNOSIS

WEIGHT SYMMETRY WEIGHT SYMMETRY

Backward translation Forward translation
Left Right Left Right
S S
M M
L L
A 0 100 200 0 100 200

LATENCY (ms) LATENCY (ms)

Backward translation Forward translation
200 200

180 180

Figure 15-3. Motor test scores

include A, weight symmetry at the 120 120
onset of the perturbation, B, latency
until reactive force is developed, and
C, relative amplitude of response 4 4 4 4 4 4 4 4
during backward and forward 80 80
translational perturbations of three M L M L M L M L
different magnitudes for a normal
subject. Note that the latency B Left Right Left Right
decreases and the “force” of the
response increases with larger
perturbations. D, Five repeated AMPLITUDE SCALING AMPLITUDE SCALING
perturbations of the same magnitude
(shown here for rotational or pitch 25 25
perturbations) result in a reduction in
the amplitude or strength of the 20 20
response (the scale ranges from 0 to
200) in normal subjects. In graphs 15 Left = + 15
A–D, the shaded area represents
performance outside of age-referenced 10 Right = X 10 +
+ X
norms. 5 X 5 +
X
+
X +
X +
X
0 0
C S M L S M L

ADAPTATION–TOES UP ADAPTATION–TOES DOWN

200 200

150 150

100 100

50 50

0 0
D 1 2 3 4 5 1 2 3 4 5

There is no gold standard against which to judge dynamic to have construct validity, it should be able to predict falls.
posturography. However, postural sway does correlate The results regarding the ability of posturography to identify
with the Berg balance scale, which is an accepted test of older individuals as either fallers or nonfallers have been
functional balance.14 mixed.4,15,16 Although a single measure of postural stabil-
The final aspect of validity is construct validity, which ity—sway velocity—did not successfully differentiate older
implies predictive capabilities. Because balance impairment fallers from nonfallers,4 the use of composite scores (from
is a major risk factor for falls, if dynamic posturography is SOT or LOS) or a combination of variables—reaction time
 Dynamic Posturography 261

A AVERAGE 20 OF 20 TRIALS

Fast toes-up rotation

100 0 100 200 300 400 msec

B 312 ␮v
L. GASTROC

L. GASTROC SL1 ML1

SL ML Time (ms) 35 73

Figure 15-4. Automatic response of a normal subject, averaged

from a series of 20 pitch (toes-up) perturbations of the support
C 625 ␮v L. TIBIA LL1 surface (A). The ramped line indicates the perturbation of the
support surface with the arrow indicating the initiation of the
L. TIBIA

Time (ms) 102 perturbation. Short-latency (SL) and middle latency (ML; B, D)
LL responses elicited in the left (L) and right (R) gastrocnemius/
soleus muscles. The long-latency response (LL; C, E) occurs in
the left (L) and right (R) anterior tibialis muscles and acts to
correct for the sudden shift in the center of mass posteriorly.

D 312 ␮v
R. GASTROC

R. GASTROC SL1 ML1

SL ML
Time (ms) 37 66

E 625 ␮v R. TIBIA LL1

R. TIBIA

Time (ms) 111

LL

TABLE 15-2. Short-, Middle- and Long-Latency Responses and Site of Lesion
Lesion Short-Latency Response Middle-Latency Response Long-Latency Response

Normal (mean + 1 SD) 43.5 + 4.2 msec 89.5 + 10 msec; absent in 25% 125.3 + 17.8 msec; duration 76 + 19 msec
Normal (mean + 2 SD) 51.9 msec Latency = 109.5 msec Latency = 160.9 msec; duration = 114
Peripheral neuropathy Delayed Delayed Delayed
Anterior lobe cerebellar Delayed due to concomitant Normal Increased duration in 66%
atrophy; diffuse cerebellar peripheral neuropathy
disease
Friedreich’s ataxia Absent in 66%; Absent in 66%; when present, is Prolonged rate of rise (>50 msec); delayed
delayed (>225 msec);
Cerebellar hemispheric Normal Normal Delayed (146 msec)
Parkinson’s disease Absent if is peripheral Normal latency; greatly increased Normal latency; normal integral
neuropathy, normal integral
latency; integral normal
Spinal cord lesion Normal Absent 50% of subjects Delayed (>164 + 36.5 msec)
Intra-cranial lesions Normal latency Normal latency Delayed latency

From Diener HC, Dichgans J: Long loop reflexes and posture. In Bles W, Brandt T (eds.): Disorders of Posture and Gait. Amsterdam: Elsevier Science, pp. 41–51, 1986.
262 NEUROTOLOGIC DIAGNOSIS

and movement velocity from LOS and sway velocity during balance systems acting in concert. In contrast, caloric and
condition 1 (eyes open, firm surface) of the M-CTSIB—did rotary chair tests assess only one system, the vestibulo-
differentiate between these groups.15,16 ocular system.20 Thus, during posturography testing,
vestibular deficits may be masked by other functioning
balance systems. Second, the caloric, rotary chair, and
APPLICATION TO PATIENT MANAGEMENT posturography tests assess the function of different
components of the vestibular apparatus (horizontal canals
versus vertical canals plus otoliths, respectively). This
Risk for Falls in Older Adults might result in different test results in some vestibular
The increased incidence of falling in older adults is well disorders, such as vestibular neuronitis, where the deficit
documented. Nearly one third of adults older than age 65 can be limited to only the distribution of the inferior
experience a fall in a given year, and this incidence increases vestibular nerve. Finally, balance, as measured by dynamic
to 50% by the age of 80.17 Of those who do fall, 10% to posturography, may recover fully,21 whereas caloric and
15% experience a fall-related injury. Given the conse- rotary chair test results continue to be abnormal in the
quences of falls, it is important to identify individuals at risk majority of patients. In terms of identifying individuals
before they fall in order to provide appropriate interven- with vestibular deficits, dynamic posturography has sensi-
tion. Several studies have found the use of dynamic postur- tivity and specificity of approximately 50% compared with
ography valuable in identifying older individuals who are at other tests of vestibular function including caloric and
risk for falling. In a study comparing performance-based rotary chair testing.22 When used as an adjunct to caloric
tests and posturography-based tests, the LOS maximum and rotary chair tests, posturography testing increases the
excursion composite score was the most accurate at pre- likelihood of identifying a vestibular problem.19,23
dicting fallers, whereas the performance-based tests such as Although the SOT dynamic posturography should not
Tinetti’s performance-oriented mobility assessment and be used as a diagnostic tool, the results of studies on
the timed up and go were most accurate at identifying patients with different problems show performance pat-
nonfallers.15 The combination of reaction time and move- terns that are useful as guides to expectations for certain
ment velocity composite scores from LOS and sway velocity diagnoses (Table 15-3). The overlap in findings across diag-
during condition 1 (eyes open, firm surface) of the M- noses can be clearly seen; therefore, difficulty on tests 5 and
CTSIB was found to have an overall accuracy of 73% in 6 cannot be interpreted as indicating a vestibular deficit.
differentiating fallers from nonfallers.15 In a comparison Although it is well documented that patients with severe
among the functional reach, SOT (composite score), and bilateral vestibular loss are unable to maintain their balance
LOS (anterior score only),16 only the SOT (composite under conditions in which both visual and somatosensory
score) differentiated between older fallers and nonfallers. cues are altered,24–27 the results of the SOT are not specific
Thus, dynamic posturography appears to be useful in for vestibular loss. Patients with other balance problems, as
identifying older adults at risk for falls, but only if composite diverse as Huntington’s disease and fear of falling, may lose
scores or multiple measures are used. their balance under these same conditions.4,28
It is probably most appropriate to interpret the results
of the SOT in terms of the functional implications of the
Vestibular Deficits test performance. Several common patterns in test per-
Dynamic posturography, by itself, is not an appro- formance have been identified and ascribed to difficulties
priate tool for the identification of vestibular deficits. in using different sensory cues (Table 15-4) rather than
Posturography and rotary chair test results agree in only diagnoses. It is important to remember that although this
25% of all patients.18,19 The difference in test results may test provides us with reliable data, test performance can be
be ascribed to several factors. First, dynamic posturogra- strongly influenced by subjective factors, including patient
phy measures the output of the vestibulospinal and other effort, fear, and cognition.

TABLE 15-3.
Diagnosis Posturography Performance Pattern

Peripheral vestibular deficits24,25,30 Abnormal sensory organization tests; Rare motor test abnormality (<2%)
Severe bilateral vestibular loss24,25,39 Loss of balance C5, C6 with increased sway C3, C4; Correlation of sensory organization
tests with severity of deficit (VOR Tc)
Incomplete bilateral vestibular deficit Increased number of falls C3, C5, C6 but not necessarily on all trials
Acute unilateral vestibular deficit31 Increased sway or loss of balance especially on C5, C6;
Can be normal within few days postonset
Compensated unilateral vestibular deficit40,42 Normal sensory organization tests but evidence on decrement in performance several
months out
Benign paroxysmal positional vertigo46–48 Increased sway C3, C6 in BPPV plus head injury
Increased sway C5, C6 in BPPV, no head injury
Increased sway all tests pretreatment, improved with remission of symptoms following
treatment
Central deficits30 >90% have abnormal motor tests (especially latencies) as well as abnormal sensory
organization tests
 Dynamic Posturography 263

TABLE 15-4.
Test Performance Pattern Possible Interpretations

Loss of balance or increased sway on C2, C3, C5, C6 Visual dependency

Loss of balance or increased sway on C4, C5, C6 Somatosensory dependency
Loss of balance or increased sway on C5, C6 Vestibular deficit or reflects increased difficulty of these conditions
Generally increased sway, stopping test by putting hands out to Fear of falling
touch wall; verbalized expression of concern or fear
Increased sway or loss of balance occurring on later trials only Fatigue
with normal performance on initial trials of same condition
Loss of balance or increased sway on initial trial of each sensory Inability to handle novel postural challenges
condition
Regular periodicity of sway across all SOT trials and conditions Functional or nonphysiological
Better performance on more difficult conditions than on easier
conditions
Inconsistency in performance from trial to trial on SOT
Abnormal responses to support surface perturbations including
inconsistent responses and exaggerated responses

Central Balance Deficits or with Friedreich’s ataxia have large-amplitude, omni-

directional sway with a tendency for more lateral sway.29
Although dynamic posturography is less sensitive for Patients with atrophy of the anterior lobe of the cerebel-
identifying peripheral vestibular dysfunction than ENG, it lum display prominent AP sway with markedly increased
can provide significant information for certain central amplitude of sway with eyes closed.29
disorders.22,23 Although the amplitude of peak-to-peak AP Research paradigms use Fourier analysis of sway to
sway seen during conditions 1 and 2 of the SOT does not identify the dominant sway frequency when a subject is
discriminate among different balance disorders, direction standing quietly. Although this analysis is not used exten-
of sway and sway frequency sometimes can be useful sively in clinical studies, it is available and promises to
diagnostically.29 Normal subjects present with omnidirec- contribute significantly to the ability of posturography to
tional sway of small amplitude (Figure 15-5). Eye closure aid in diagnosis. Studies reveal a dominant frequency of
(no vision) results in a small increase in sway amplitude. In sway (2.5 to 3.5 Hz) in subjects with atrophy of the ante-
contrast, patients with lesions of the vestibulocerebellum rior lobe of the cerebellum that is not found in normal

NORMAL VESTIBULO-CEREBELLAR LESION

10 cm 10 cm 10 cm 10 cm

Sway path 10 cm 10 cm 10 cm 10 cm Figure 15-5. Patients with cerebellar

disorders differ from normal subjects
both in their sway path and in the
sway direction as indicated by a
5 cm 5 cm 5 cm 15 cm histogram. All patients had increased
sway paths compared with the
Sway normal subject with both the eyes
direction 5 cm 5 cm 5 cm 15 cm open and the eyes closed. The patient
histogram with the vestibulocerebellar lesion
and the patient with Friedreich’s
ataxia showed more lateral sway
Eyes open Closed Open Closed while the patient with atrophy of the
anterior lobe of the cerebellum had
marked increase in anterior/posterior
FRIEDREICH’S ATAXIA ANTERIOR LOBE DEGENERATION sway. Note the different scales for the
sway direction histogram for both the
patient with Friedreich’s ataxia and
10 cm 10 cm 10 cm 10 cm
the patient with atrophy of the
anterior lobe of the cerebellum.
Sway path 10 cm 10 cm 10 cm 10 cm (Modified from Dichgans J, Clinical
Symptoms of Cerebellar Dysfunction
and Their Topodiagnostical
Significance in Human Neuro-biology
30 cm 75 cm 10 cm 540 cm 1984, vol 2, pages 269–279.)
Sway
direction 30 cm 75 cm 10 cm 540 cm
histogram
264 NEUROTOLOGIC DIAGNOSIS

subjects.29 This characteristic frequency is present during better performance on the more difficult conditions than on
the earlier stages of degeneration and may disappear in the easier conditions of the SOT (Fig. 15-6). Additionally,
patients with chronic degeneration of the anterior lobe. they described a discrepancy between the patients’ abnor-
Assessment of automatic postural responses is also useful mal performances on dynamic posturography and their
in identifying patients with central lesions affecting stabil- ability to walk. Goebel and colleagues34 identified two addi-
ity.30 In patients with nonvestibular central balance prob- tional criteria from the MCTs—exaggerated responses to
lem, either the latency or symmetry of the reactive torque small perturbations and inconsistent responses to small and
is abnormal in 80% of patients. In contrast, the automatic large perturbations—that had a high specificity for identify-
postural responses are rarely abnormal in patients with ing persons who were deliberately feigning instability. By
peripheral vestibular deficits.24,30,31 combining criteria from the SOT and MCT, the false-
Delays in the onset of the short-, middle- and long- positive rate (i.e., identifying a problem where there is no
latency responses give site of lesion information (see organic cause) was reduced to zero.34 The criteria used to
Table 15-2).8,32,33 The short-latency response is affected by identify nonphysiological sway was validated in a recent
peripheral neuropathy. The middle-latency response is study, which found that only 8% of patients without sec-
delayed in patients with spinal cord disease such as multi- ondary gain exhibited exaggerated patterns, but 76% of
ple sclerosis or syringomyelia. The long-latency response those with secondary gain had exaggerated patterns.36
can be delayed with lesions in the peripheral nerve or One concern about the use of computerized posturogra-
anywhere in the long tracts of the central nervous system. phy in identifying malingerers is that individuals may learn
The short- and middle-latency responses appear to be to successfully manipulate their results. That is, people
independent of cerebellar influences, but the cerebellum deliberately malingering may learn how to produce results
may modulate the long-latency response.9 that mimic real disorders rather than producing results
that are clearly identifiable as nonphysiological patterns.
Nonphysiological Component of Balance Fortunately, Morgan and colleagues38 showed that an indi-
vidual’s ability manipulate the results does not improve
Poor performance on the SOT does not necessarily indi- when they have additional information regarding dynamic
cate a specific physiological problem. One of the difficul- posturography.
ties in medicine is identifying those patients with
psychological or functional components to their postural Treatment
instability. These functional components can include fear
of falling as well as anxiety, somatoform disorders, and true Dynamic posturography is useful in establishing treatment
malingering. For example, older individuals who report and in monitoring patient recovery, especially as part of the
fear of falling exhibit increased sway velocity during the rehabilitation process. For example, patients may use differ-
M-CTSIB compared with those who were not fearful.4 ent sensory cues to maintain postural stability. Figure 15-7
Nonphysiologic balance problems (e.g., occurs in conver- illustrates the results of the sensory organization test in
sion disorder or malingering) can be characterized by three patients with bilateral vestibular loss secondary to
several components of the patient’s performance on the aminoglycoside ototoxicity. None of the patients can
SOT and the motor tests (Table 15-5).34–37 Cevette and maintain balance when both visual and somatosensory
colleagues35 found that patients with symptoms unrelated cues are altered (conditions 5 and 6), which is consistent
to organic findings had erratic performance within each with the findings of numerous studies on patients with
condition (i.e., greater intertrial variability) and relatively bilateral vestibular loss.24,25,39 The first patient (Fig. 15-7A),

TABLE 15-5.
Citation Criteria for Nonphysiological

Goebel et al 1997; Substandard performance on C1

Otolaryngol Head Neck Score = number of points below norm for the best trial of C1
Surgery 117:293–30234 Exaggerated motor responses to small translations
Score = average number of degrees of sway across trials for small forward and backward translations (should be <2 degrees)
Inconsistent motor responses to small and large translations
Score = number of tests with at least 2 of 3 concordant trials per tests (max = 4)
Cevette et al 1995; Lower scores on C1 and 2, higher on C5 and 6 Score =
Otolaryngol Head Neck Surg [(C1−norm1) + (C2-norm2)] – [(C5-norm5) + (C6-norm6)]
112:676–68835 Highest score on the following 3 equations:
Nonphysiologic = −158.2 + (1.94 × C1) + (1.09 × C2) + (1.37 × C4) – (0.15 × C6)
Normal = −238.14 + (2.24 × C1) + (1.45 × C2) + (1.70 × C4) – (0.13 × C6)
Vestibular = −251.21 + (2.31 × C1) + (1.54 × C2) + (1.89 × C4) – (0.58 × C6)
Gianoli et al 2000; Substandard performance on C1 and C2
Otolaryngol Head Neck Surg Large amplitude AP sway without falls
122:11–1836 Score = average number of AP sways >5 degrees on C4, 5, 6 without falls
Large amplitude lateral sway
Score = average number of lateral sways >1.25 degrees on C4, 5, 6 without falls
Excessive intertrial variability (no score calculated)
Circular sway (no score calculated)
 Dynamic Posturography 265

100

75

50

25 FF F F
AA A A
LL L L
LL L L
FALL
1 2 3 4 5 6 Composite
38
A Sensory test condition

Trial 1 Trial 2 Trial 3

1
Shear

AP sway Figure 15-6. A, Performance on the sensory organization

test by patients with nonphysiological balance problems is
characterized by inconsistent performance on different trials
2 of the same condition and by better performance on more
difficult conditions than on easier conditions (compare
condition 3 to 1 and condition 5 to 2). B, Inspection of
the anterior/posterior sway trace often reveals a regular
periodicity to sway.
3

6 degrees; 35 lb force
B 20 seconds

however, is able to maintain balance within normal limits section. They found that all patients had normal sensory
as long as either visual cues (conditions 1 and 4) or organization tests by one month after surgery. Surprisingly,
somatosensory feedback (conditions 2 and 3) is present. In 21% of the patients showed a decrease in stability 3 to
contrast, other patients rely on somatosensory cues for 20 months after surgery, suggesting that reevaluation and
stability and therefore lose their balance when somatosen- possible reinstitution of vestibular exercises would be
sory feedback is altered (Fig. 15-7B). Similarly, patients appropriate in these patients.
may rely on visual cues (Fig. 15-7C). Identifying reliance Computerized dynamic posturography results also have
on a particular sensory cue can then be used to establish been used in numerous studies to monitor the effective-
specific exercises for the patient. ness of vestibular rehabilitation of patients with vestibular
Studies have reported the rapid spontaneous recovery of disorders.31,43–45 Improved postural stability has been doc-
postural stability in patients with acute and chronic unilat- umented in patients with acute and chronic vestibular
eral vestibular deficits.31,40,41 Cass and colleagues42 followed deficits compared with control groups21,31,44 and in patients
patients for up to 20 months following vestibular nerve with benign paroxysmal positional vertigo.46–48 Dynamic
266 NEUROTOLOGIC DIAGNOSIS

100 posturography can be used to predict the outcome of

vestibular rehabilitation. Patients with a poor prerehabili-
75 tation condition (including severe disability or sponta-
neous or continuous symptoms in conjunction with
50 motion sensitivity) and abnormalities on four or more of
the sensory organization tests have poorer outcomes
25 following a course of rehabilitation.41,42,50

stop
stop
stop
stop
stop
stop
Computerized dynamic posturography has many poten-
0 tial benefits as an adjunct to treatment: The patient can be
A 1 2 3 4 5 6 safely exposed to challenging balance situations including
perturbations; the visual component of the computerized
system gives useful biofeedback that can be withdrawn; the
immediate feedback on performance is motivating.
100 Controlled studies using computerized balance training
have demonstrated improvements in postural stability
75 (as measured by SOT and LOS), as well as functional
improvements on the Berg balance scale and fall reduction
50 in community-dwelling older adults.51,52
25
CONSIDERATIONS AND LIMITATIONS
stop
stop
stop
stop
stop
stop
stop
stop
stop

0
B 1 2 3 4 5 6 Sensory Organization Test
Conditions 1 and 2
100 The first two conditions (C1 and C2) of the SOT are static
conditions (eyes open and closed) and as such have limited
75 utility in documenting changes in postural stability with
time or treatment. Most patients with unilateral vestibular
50 lesions, for example, have normal static postural control,
for their age, within 3 to 6 days after onset.31 The results
25 from C1 and 2 may be more useful in documenting change
in patients with bilateral vestibular loss. These patients
stop

stop
stop

stop
stop
stop
stop
stop
stop

0 have increased peak-to-peak AP sway during the early

1 2 3 4 5 6 period after onset and continue to have a small but signif-
icant increase in AP sway even in the chronic stage.25
C Sensory test condition
Figure 15-7. Performance of three patients with bilateral vestibular loss Age
secondary to aminoglycoside ototoxicity on the sensory organization test
demonstrates the variability in test performance that can occur even within Equilibrium scores results obtained during testing must be
the same diagnostic groups. A, One subject loses his balance only when interpreted based on the age of the subject (Figure 15-8).
both visual and somatosensory cues are altered (conditions 5 and 6). The
other two subjects have additional difficulty when B, somatosensory feed- Across all ages, AP sway increases (lower equilibrium
back is altered (condition 4) or C, when visual feedback is altered (conditions scores) for conditions in which somatosensory feedback is
2 and 3). Equilibrium scores (higher number indicates more stable) for three altered (conditions 4, 5 and 6).8,53,54 Additionally, perform-
trials of each condition are shown. Loss of balance is indicated by “stop.” ance on tests in which both visual and somatosensory cues
are altered (tests 5 and 6) shows the greatest instability in
all normal subjects, suggesting that these are the more
posturography has been used to document that a super- difficult test conditions. The effect of altering both visual
vised program of customized vestibular exercises results in and somatosensory cues is greatest in subjects older than
a greater improvement in stability than unsupervised 70 years.8,53 Presumably, when both visual and somatosen-
generic exercises.45 In fact, subjects with peripheral sory cues are altered, the subject must rely on vestibular
vestibular dysfunction who underwent individualized cues in order to maintain balance (see Table 15-1).
vestibular rehabilitation improved performance on the Increased difficulty maintaining balance on tests 5 and 6 in
SOT to within normal limits, while subjects in the control older subjects, therefore, may reflect age-related changes
group did not change their SOT scores.21 In individuals in the vestibular system or the increased difficulty of those
with bilateral vestibular loss (BVL), improvements have tests.55,56 Wolfson and colleagues8 suggest that the poorer
been noted in functional limitations, as well as measures of performance of older persons on tests in which visual and
disability and balance confidence although no significant somatosensory feedback is altered is due to either biome-
changes were reported for the SOT.49 These findings indi- chanical factors or to changes in central processing of
cate that although patients with BVL improve following sensory information. Regardless, test results of patients
therapy, they continue to demonstrate significant physical who are older must be made taking the normal age-related
impairments.49 There is also some evidence that dynamic test scores into consideration.
 Dynamic Posturography 267

EQUILIBRIUM SCORES BY AGE

100

80 Figure 15-8. Anterior/posterior sway, as reflected by the

Equilibrium score

equilibrium score, is shown for each of the different

conditions of the sensory organization test for subjects of
60 different ages. The higher the equilibrium score, the more
stable the subjects. All age groups show an increase in
AP sway (indicated by lower equilibrium scores) as the
40 conditions become more difficult. Note that there is little
variation in stability in people age 20 to 69 years across
20 the different sensory organization test conditions
(identified as C1–C6). In people 70 years and older, a
decrement in postural stability is obvious primarily in
0 conditions 5 and 6 (C5 and C6) in which both visual and
somatosensory feedback are altered concurrently.
C1 C2 C3 C4 C5 C6
Sensory test conditions

20–29 30–59 60–69 70–85

Diagnosis Center of Gravity Alignment

Presently, the results of the sensory organization tests are The ability or inability to maintain balance may also be
not considered to be useful in the diagnosis of specific dis- affected by COG alignment prior to the toes-up or toes-
orders. This is because the results are variable even within down perturbation. Shifts in static alignment posteriorly
specific diagnostic groups. Furthermore, considerable would be likely to result in loss of balance with toes-up
overlap occurs in results among different diagnostic perturbations, whereas shifts anteriorly would result in
groups and even between normal and abnormal subjects in loss of balance with toes-down perturbations. Although
the older population.8 The sensitivity of the sensory loss of balance when the support surface is rotated toes-up
organization test in identifying vestibular disorders has may indicate retropulsion, it should be remembered that
been reported as between 45% and 95%, depending on patients afraid of falling backward may shift their center of
the clinical criteria used to identify vestibular dysfunc- mass forward and therefore may lose their balance during
tion.22,30,57 Goebel and Paige19 concluded that posturogra- toes-down perturbations.
phy testing did not distinguish between patients who did
or did not experience vertigo.
Subject Characteristics
Attempts have been made to improve the sensitivity of
dynamic posturography as a diagnostic tool by assessing Age, gender, and height all affect the long-latency
postural stability with the subject’s head in different posi- responses measured using surface electrode EMG.
tions. The rationale is that head position will affect Increasing age of the subject results in increased latency to
vestibular input if a unilateral vestibular deficit is present. onset and duration of the short-latency response and in
Neither head extension nor lateral tilt has improved increased integrated amplitude and duration of the long-
the sensitivity of dynamic posturography.58,59 Other work latency responses.61 Although Lawson and colleagues61
has examined the effect of horizontal head movement found subject height was correlated significantly with time
during the SOT. The results suggest that the addition of to onset, it accounted for a relatively small amount of the
the head movements increases the difficulty of condition 5 variance of the latencies (3% to 21%).
of the SOT and therefore the sensitivity of posturography
testing in identifying compensated peripheral vestibular
Initial Center of Gravity Alignment
lesions (Shepard, personal communication). It is also
possible that the sensitivity of dynamic posturography may It is clinically important to recognize that these latencies can
be increased if a measure other than peak-to-peak AP sway be altered if the subject leans either forward or backward.
were used; for example, measures such as sway velocity Leaning forward, for example, increases the length of the
may be more sensitive.60 gastrocnemius/soleus muscle group prior to the stretch
produced by the support surface movement. The added
Motor Control/Adaptation Tests: stretch imposed by rotating the support surface toes-up
elicits a short-latency response with a shorter time to onset.
Automatic Postural Responses Similarly, the latencies do not seem to be affected by head
Abnormalities in force development and the latency to position or vision.9 Other than by leaning forward or back-
onset of force development of the automatic responses can ward, it is not possible to voluntarily modify the time to
be due to pain, leg length differences, limitation in ankle onset of the automatic postural responses.62 Measurement
range of motion, and weakness as well as neurologic prob- of reactive torque can be used as a screening test. When it
lems. Subject age has only a minimal effect on responses to yields abnormal results, a combination of measurement of
translational perturbations.6 reactive force and EMG activity can be used to determine
268 NEUROTOLOGIC DIAGNOSIS

whether abnormalities in the automatic postural responses 15. Trueblood P, Hodson-Chennault N, McCubbin A, Youngclarke D:
are due to biomechanical or neurologic factors. Performance and impairment-based assessments among community-
dwelling elderly: Sensitivity and specificity. Issues on Aging 24:2–6,
2001.
16. Wallmann HW: Comparison of elderly non-fallers and fallers on
SUMMARY performance measures of functional reach, sensory organization,
and limits of stability. J Gerontol 56A:M580–583, 2001.
The use of force platforms has provided more detailed 17. Tinetti ME, Speechley M, Ginter SF: Risk factors for falls among
objective data in the assessment of postural control than that elderly persons living in the community. New Engl J Med
available through clinical examination alone. Current tech- 319:1701–1707, 1988.
nology enables us to measure a patient’s ability to use differ- 18. Asai M, et al: Evaluation of vestibular function by dynamic postur-
ent sensory cues for balance, to voluntarily weight shift, and ography and other equilibrium examinations. Acta Otolaryngol
(Stockh) 1504 (Suppl):120–124, 1993.
to react to external perturbations. Some of these tests can
19. Goebel JA, Paige GD: Dynamic posturography and caloric test
assist in diagnosis, such as measures of sway frequency results in patients with and without vertigo. Otolaryngol Head Neck
during quiet stance and EMG recordings of lower extrem- Surg 100:553–558, 1989.
ity muscle activity during automatic postural responses. Of 20. Furman JM: Role of posturography in the management of vestibu-
particular interest is the ability of dynamic posturography to lar patients. Otolaryngol Head Neck Surg 112:8–15, 1995.
identify individuals who are at risk for falling; an ability 21. Black FO, Angel CR, Pesznecker SC, Gianna C: Outcome analysis
that can lead to the initiation of appropriate intervention to of individualized vestibular rehabilitation protocols. Am J Otol
prevent falls. In addition, posturography is effective in iden- 21:543–551, 2000.
tifying performance abnormalities that suggest nonphysio- 22. Di Fabio RP: Meta-analysis of the sensitivity and specificity of plat-
logic balance problems. Dynamic posturography is a useful form posturography, Arch Head Neck Surg 122:150–156, 1996.
23. Keim RJ: Clinical comparisons of posturography and electronystag-
tool for establishing and monitoring treatment. Newly
mography. Laryngoscope 103:713–716, 1993.
developed testing protocols should enable us to quantify 24. Horak FB, Nashner LM, Diener HC: Postural strategies associated
postural stability during functional activities such as moving with somatosensory and vestibular loss. Exp Brain Res 82:167–177,
from sitting to stand or during ambulation. 1990.
25. Herdman SJ et al: Characteristics of postural stability in patients
with aminoglycoside toxicity. J Vestib Res 4:71–80, 1994.
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40. Fetter M, Zee DS, Proctor LR: Effect of lack of vision and of occip- 51. Rose DJ, Clark S: Can the control of bodily orientation be
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43. Shepard N, Telian SA, Smith-Wheelock M: Habituation and 53. Camicioli R, Panzer VP, Kaye J: Balance in the healthy elderly:
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44. Horak FB, Jones-Rycewicz C, Black FO, Shumway-Cook A: Effects 54. Cohen H, et al: Changes in sensory organization test scores with
of vestibular rehabilitation on dizziness and imbalance. Otolaryngol age. Age Ageing 25:39–44, 1996.
Head Neck Surg 106:175–180, 1992. 55. Baloh RW, Jacobson KM, Socotch TM: The effect of aging on
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46. Black FO, Nashner LM: Postural disturbances in patients with 57. Hamid MA, Hughes GB, Kinney SE: Specificity and sensitivity
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47. Di Girolamo S, et al: Postural control in benign paroxysmal posi- 58. Barin K, Seitz CM, Welling DB: Effect of head orientation on the
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48. Blatt PJ, et al: The effect of the canalith repositioning maneuver on 59. Chandra NS, Shepard NT: Clinical utility of lateral head tilt
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 Chapter
Vestibular Evoked Myogenic
Potentials
16 Outline

Steven D. Rauch, MD Introduction Measuring Vestibular Evoked

Discovery of Vestibular Myogenic Potentials
Evoked Myogenic Potentials Clinical Applications of
Basic Physiology of Vestibular Evoked Myogenic
Vestibular Evoked Myogenic Potentials
Potentials Future Directions

INTRODUCTION patients with benign paroxysmal positional vertigo, but

absent in patients with advanced Ménière’s disease and
Brief (0.1 msec) loud (>90 dB sound pressure level, SPL) Ménière’s patients having undergone a Cody tack proce-
monaural clicks or tone bursts produce a large (60 to dure.6 Based on these observations, Townsend and Cody
300 μV ) short-latency (8 msec) inhibitory potential in the proposed that the averaged inion response to acoustic
tonically contracted ipsilateral sternocleidomastoid stimulation was mediated by the saccule.6
muscle, known as vestibular evoked myogenic potentials
(VEMP). Considerable robust evidence supports the
contention that VEMP is a vestibulocolic reflex whose BASIC PHYSIOLOGY OF VESTIBULAR
afferent limb arises from acoustically responsive neurons EVOKED MYOGENIC POTENTIALS
in the saccule, with signals conducted centrally via the
inferior vestibular nerve. Thus the VEMP can be used as a Speculation about the origin of VEMP has been supported
test of otolith organ and peripheral vestibular function. by animal research. McCue and Guinan identified acousti-
Since it depends on both sound transmission through the cally responsive fibers in the cat vestibular nerve.7,8 Single-
middle ear and structural integrity of the saccule, it also unit recordings from the inferior vestibular nerve in these
has merit in diagnosis of superior semicircular canal dehis- animals revealed fibers with irregular background activity
cence syndrome and in Ménière’s syndrome (cochleosac- that phase-lock to low-frequency (800 Hz) tone bursts of
cular hydrops). 80 dB SPL and show increased firing rates with increasing
stimulus intensity. In these same fibers acoustic clicks
evoked action potentials with minimum latencies of
DISCOVERY OF VESTIBULAR EVOKED 1.0 msec. Fibers fell into two classes: with the shortest
MYOGENIC POTENTIALS latency either to compression (“push” fibers) or rarefaction
(“pull” fibers) clicks. The observation of preferred
Thirty-five years ago, when the science of averaged evoked response phases approximately 180 degrees apart was
response measurement was in its infancy, Bickford, Cody, interpreted to mean that fibers innervate hair cells having
and others first characterized the range of evoked opposite morphologic polarity, an arrangement found in
responses in human subjects.1–5 The postauricular response the saccule. Biocytin fiber labeling and tracing confirmed
was determined to be an acoustically evoked contraction, bipolar cell bodies in the inferior vestibular ganglion with
or “sonomotor” response, of the postauricular muscle. peripheral processes innervating saccular epithelium and
The integrity of the cochlea and cranial nerve VII were central processes going to vestibular nuclei and a region
required for this response to be present. In contrast, the ventromedial to the cochlear nucleus.
inion response, named for the posterior scalp location where
it was maximally recorded, was present in deaf patients but
absent in patients after vestibular neuronitis or vestibular MEASURING VESTIBULAR EVOKED
neurectomy. Though initially thought to arise from cortex, MYOGENIC POTENTIALS
the averaged inion response was eventually demonstrated
to originate from extracranial musculature.2 Furthermore, Short broadband clicks or tone bursts of 0.1-msec duration
the inion response was preserved in patients with semicir- delivered via headphones can be used as stimuli for VEMP
cular canal ablation due to streptomycin toxicity and in testing. The response is recorded electromyographically
270
 Vestibular Evoked Myogenic Potentials 271

(EMG) using surface electrodes over the ipsilateral stern- CLINICAL APPLICATIONS OF VESTIBULAR
ocleidomastoid muscle. The positive electrode is posi- EVOKED MYOGENIC POTENTIALS
tioned over the upper third of the muscle, and the negative
electrode is positioned over the muscle tendon just above Clinical utility of VEMP testing has been demonstrated in
the clavicle. Patients are seated upright and instructed to three areas: assessment of vestibular nerve function, diag-
turn their head forcefully away from the test ear (i.e., try to nosis of superior semicircular canal dehiscence syndrome,
push their chin over the contralateral shoulder). This tenses and evaluation of Ménière’s syndrome. Colebatch and
the ipsilateral sternocleidomastoid muscle, a necessity for Halmagyi first noted that the VEMP response was extin-
measuring the inhibitory VEMP response. Ongoing EMG guished following ipsilateral vestibular neurectomy and
activity is visually monitored on an oscilloscope to ensure speculated that the response may provide useful informa-
uniform muscle tension during testing, and patients are tion in assessment of patients with hearing and balance
instructed to relax their neck muscles between runs. The disorders.17 Murofushi and colleagues studied VEMP and
EMG recording is bandpass filtered and averaged as in its relation to vestibular neuritis and benign paroxysmal
evoked response audiometry. The resultant response con- positional vertigo (BPPV).18 They found the VEMP absent
sists of a biphasic wave with an initial positive peak (P1) at in 16 of 47 vestibular neuritis patients, none of whom went
12–13 msec latency and a subsequent negative peak (N1) at on to develop BPPV. In 10 of 47 patients with vestibular
22–23 msec latency (Fig. 16-1). neuritis, BPPV did develop and all 10 had intact VEMP.
A number of investigators have sought to characterize These findings indicate that absent VEMP in acute vesti-
the normal VEMP response.9–16 These studies have shown bular neuritis is indicative of inferior vestibular nerve
that the VEMP is more consistently detectable and has a involvement. Such patients lose innervation of the saccule
lower threshold for click than tone burst stimuli. The and posterior semicircular canal and therefore lose the
click-evoked VEMP has a normal threshold of 85 to 90 dB VEMP reflex and cannot develop BPPV. Acute vestibular
SPL. With tone bursts, there is a “tuning curve” showing neuritis patients with intact VEMP have involvement of
greatest sensitivity (i.e., lowest threshold) for frequencies their superior vestibular nerve. A significant proportion of
of 500 to 1000 Hz. Systematic variation of stimulus rate them go on to degeneration of the utricle, with subsequent
shows decreasing VEMP P1 latency with increasing rate. shedding of otoconia and symptomatic BPPV. In another
Above the 5-Hz stimulus rate, VEMP peak-to-peak ampli- study, Murofushi and colleagues showed that the VEMP is
tude decreases with increasing rate. Above the threshold, abnormal in 80% of acoustic neuroma patients, even in the
VEMP amplitude increases with stimulus level. Amplitude presence of normal calorics.19 As might be predicted, the
of the VEMP response is proportional to the mean level of test is particularly sensitive for inferior vestibular nerve
tonic muscle activation of the sternocleidomastoid during involvement.19–21
recording. The value of VEMP in diagnosis of superior canal dehis-
cence syndrome is due to the fact that the dehiscence creates a
“path of least resistance” that shunts acoustic energy through
the vestibular labyrinth rather than through the cochlea. This
yields three clinical effects: a pseudoconductive hearing loss,
40 a Tullio phenomenon of acoustically evoked vertigo, and a
lowered VEMP threshold. The VEMP threshold is typically
about 20 dB lower in superior canal dehiscence cases than in
normal subjects (70 dB vs. 95 dB).22–24
P1
20
All patients with classic Ménière’s syndrome have
cochleosaccular hydrops.25 Because saccular afferents give
rise to the VEMP response, it is logical to expect that
Amplitude (μV p-p)

altered motion mechanics of the distended saccule might

create an altered VEMP in Ménière’s patients. This has
0 been confirmed in several studies.26–32 De Waele and
coworkers studied click-evoked potentials in 59 Ménière’s
patients and found the neck response absent in 54%.26
Likewise, Murofushi and colleagues found the VEMP
response delayed or absent in 51% of Ménière’s subjects.30
:20 A few studies have also combined the VEMP with glycerol
or furosemide “dehydration testing” and shown alteration
of the VEMP response after administration of the osmotic
agent.31–33 Whether this refinement of the VEMP test sig-
N1
:40 nificantly enhances its sensitivity or specificity remains to
0 10 20 30 be seen.
Latency (ms)

Figure 16-1. Normal VEMP response. A typical VEMP response, evoked FUTURE DIRECTIONS
by a 250-Hz tone burst stimulus at 123 dB peak pressure (90 dB HL).
The response shows a positive peak, P1, at approximately 12 msec and
a negative peak, N1, at approximately 22 msec. Values measured include Notwithstanding existing demonstrations that the click-
peak-to-peak amplitude, P1 latency, and N1 latency. evoked and tone burst-evoked VEMP are altered in
272 NEUROTOLOGIC DIAGNOSIS

peripheral vestibulopathies, such as vestibular neuritis, 13. Welgampola MS, Colebatch JG: Characteristics of tone burst-
superior canal dehiscence syndrome, and Ménière’s evoked myogenic potentials in the sternocleidomastoid muscles.
syndrome, much work remains to be done to understand, Otol Neurotol 22:796, 2001.
14. Ochi K, Ohashi T, Nishino H: Variance of vestibular-evoked
characterize, and use the VEMP clinically. Specifically, the
myogenic potentials. Laryngoscope 111:522, 2001.
effects of stimulus rate and intensity on click-evoked 15. Cheng PW, Murofushi T: The effects of plateau time on vestibular-
response, the frequency-specific thresholds (“tuning evoked myogenic potentials triggered by tone bursts. Acta
curve”) of the tone burst-evoked response, and the modu- Otolaryngol 121:935, 2001.
lating effect of gravitational input to the saccule during 16. Cheng PW, Murofushi T: The effect of rise/fall time on vestibular-
testing have not been adequately defined for different evoked myogenic potential triggered by short tone bursts. Acta
disorders. The specific nature of these alterations will have Otolaryngol 121:696, 2001.
implications for biophysical models of the saccule. 17. Colebatch JG, Halmagyi GM: Vestibular evoked potentials in human
Correlation of VEMP results with other vestibular func- neck muscles before and after unilateral vestibular deafferentation.
tion tests, and especially with other otolith organ tests, Neurology 42:1635, 1992.
18. Murofushi T, Halmagyi GM, Yavor RA, Colebatch JG: Absent
such as subjective visual vertical (SVV) or off-vertical axis
vestibular evoked myogenic potentials in vestibular neurolabyrinthi-
rotation (OVAR), has not been systematically studied. tis. An indicator of inferior vestibular nerve involvement? Arch
Results of such investigations are likely to improve our Otolaryngol Head Neck Surg 122:845, 1996.
understanding of the physiology of the otolithic vestibular 19. Murofushi T, Matsuzaki M, Mizuno M: Vestibular evoked myogenic
organs as well as provide the refinements of the VEMP potentials in patients with acoustic neuromas. Arch Otolaryngol
test protocol that improve its diagnostic sensitivity and Head Neck Surg 124:509, 1998.
specificity. 20. Tsutsumi T, Tsunoda A, Noguchi Y, Komatsuzaki A: Prediction of
the nerves of origin of vestibular schwannomas with vestibular
evoked myogenic potentials. Am J Otol 21:712, 2000.
REFERENCES 21. Chen CW, Young YH, Wu CH: Vestibular neuritis: Three-
dimensional videonystagmography and vestibular evoked myogenic
1. Bickford RG, Jacobson JL, Cody DTR: Opportunities and pitfalls potential results. Acta Otolaryngol 120:845, 2000.
in the processing of neuroelectric data: Observations on averaged 22. Streubel SO, Cremer PD, Carey JP, et al: Vestibular-evoked
potentials recorded from the scalp in man. In Fifth IBM Medical myogenic potentials in the diagnosis of superior canal dehiscence
Symposium, 1963. syndrome. Acta Otolaryngol Suppl 545:41, 2001.
2. Bickford RG, Jacobson JL, Cody DTR: Nature of average evoked 23. Brantberg K, Bergenius J, Tribukait A: Vestibular-evoked myogenic
potentials to sound and other stimuli in man. Ann NY Acad Sci potentials in patients with dehiscence of the superior semicircular
112:204, 1964. canal. Acta Otolaryngol 119:633, 1999.
3. Cody DTR, Jacobson JL, Walker JC, Bickford RG: Average evoked 24. Ostrowski VB, Byskosh A, Hain TC: Tullio phenomenon with
myogenic and cortical potentials to sound in man. Ann Otol Rhinol dehiscence of the superior semicircular canal. Otol Neurotol 22:61,
Laryngol 73:763, 1964. 2001.
4. Jacobson JL, Cody DTR, Lambert EH, Bickford RG: Physiologic 25. Rauch SD, Merchant SN, Thedinger BA: Ménière’s syndrome and
properties of the post-auricular response (sonomotor) in man endolymphatic hydrops. Double-blind temporal bone study. Ann
[abstr]. Physiology 7:167, 1964. Otol Rhinol Laryngol 98:873, 1989.
5. Kiang NYS: An auditory physiologist’s view of Ménière’s syndrome. 26. de Waele C, Huy PT, Diard JP, et al: Saccular dysfunction in
In Second International Symposium on Ménière’s Disease. Ménière’s disease. Am J Otol 20:223, 1999.
Cambridge, MA, Kugler & Ghedini Publications, 1988. 27. Heide G, Freitag S, Wollenberg I, et al: Click evoked myogenic
6. Townsend GL, Cody DTR: The averaged inion response evoked by potentials in the differential diagnosis of acute vertigo. J Neurol
acoustic stimulation: Its relation to the saccule. Ann Otol Rhinol Neurosurg Psychiatry 66:787, 1999.
Laryngol 80:121, 1971. 28. Akin FW, Murnane OD: Vestibular evoked myogenic potentials:
7. McCue MP, Guinan JJ Jr: Influence of efferent stimulation on Preliminary report. J Am Acad Audiol 12:445, 2001.
acoustically responsive vestibular afferents in the cat. J Neurosci 29. Colebatch JG: Vestibular evoked potentials. Curr Opin Neurol
14:6071, 1994. 14:21, 2001.
8. McCue MP, Guinan JJ Jr: Acoustically responsive fibers in the 30. Murofushi T, Shimizu K, Takegoshi H, Cheng PW: Diagnostic
vestibular nerve of the cat. J Neurosci 14:6058, 1994. value of prolonged latencies in the vestibular evoked myogenic
9. Colebatch JG, Halmagyi GM, Skuse NF: Myogenic potentials Potential. Arch Otolaryngol Head Neck Surg 127:1069, 2001.
generated by a click-evoked vestibulocollic reflex. J Neurol 31. Murofushi T, Matsuzaki M, Takegoshi H: Glycerol affects vestibu-
Neurosurg Psychiatry 57:190, 1994. lar evoked myogenic potentials in Ménière’s disease. Auris Nasus
10. Bath AP, Harris N, Yardley MP: The vestibulo-collic reflex. Clin Larynx 28:205, 2001.
Otolaryngol 23:462, 1998. 32. Shojaku H, Takemori S, Kobayashi K, Watanabe Y: Clinical useful-
11. Wu CH, Young YH, Murofushi T: Tone burst-evoked myogenic ness of glycerol vestibular-evoked myogenic potentials: Preliminary
potentials in human neck flexor and extensor. Acta Otolaryngol report. Acta Otolaryngol Suppl 545:65, 2001.
119:741, 1999. 33. Seo T, Yoshida K, Shibano A, Sakagami M: A possible case of
12. Wu CH, Murofushi T: The effect of click repetition rate on vestibu- saccular endolymphatic hydrops. ORL J Otorhinolaryngol Relat
lar evoked myogenic potential. Acta Otolaryngol 119:29, 1999. Spec 61:215, 1999.
 Chapter
Central Auditory Processing Disorders
Assessment and Remediation

Outline 17
Introduction Intelligence, Cognition, and Wileen Chang, MS
Definition of Auditory Language
Robert W. Keith, PhD
Processing Medications
Prevalence of Auditory Auditory Processing Testing
Processing Disorders Children
Historical Perspective Adults
Behavioral Tests of Auditory Screening for Auditory
Processing Processing Disorders
Manner of Presentation A Multidisciplinary Approach
Monaural Measures Goals
Binaural Measures Test Battery Components
Dichotic Measures Test Interpretation
Anatomical Level Tested Remediation of Auditory
Electrophysiologic Tests Processing Disorders
Auditory Brainstem Response Auditory Processing Abilities
Auditory Middle-Latency in the Elderly
Response Auditory Processing Testing
The P300 in Hearing Aid Applications
Mismatch Negativity Future Directions
Other Late Auditory Evoked Functional Magnetic
Responses Resonance Imaging
Factors Affecting Auditory Brain Mapping and Scalp
Processing Test Results Topography
Subject’s Age Summary
Peripheral Hearing Loss

INTRODUCTION auditory processing disorders, auditory perceptual disorders, and

auditory language-learning disorders.1 The most recent
For many years clinicians have recognized, according to change of terminology from central auditory processing dis-
pure tone thresholds and other standard audiometric orders (CAPD) to auditory processing disorders (APD) was
tests, a population of patients whose ability to hear in made to avoid the implication of the exact site of lesion
everyday situations is poorer than expected. These patients and to emphasize the interaction of peripheral and central
may have hearing that is within normal limits to pure tones disorders and processes.2
but still have difficulty hearing in noisy situations, when
several persons are speaking at a time, or when in a rever-
berant room. Patients who have a chronic disease that
affects the central nervous system may have problems with
DEFINITION OF AUDITORY PROCESSING
comprehension of auditory information. In many cases, a
According to the American Speech-Language-Hearing
disorder of auditory processing has been identified. This
Association (ASHA) Task Force on Central Auditory
chapter was written for the neurotologist with two pur-
Processing, central auditory processes [auditory process-
poses in mind: to provide an understanding of the basics of
ing] are “auditory system mechanisms and processes
auditory processing testing and remediation and to discuss
responsible for the following behavioral phenomena:
the latest developments and issues in this ever-growing
field. Sound localization and lateralization
A note about terminology is in order. Until recently, Auditory discrimination
auditory processing disorders were referred to as central Auditory pattern recognition
273
274 NEUROLOGIC DIAGNOSIS

Temporal aspects of audition, including temporal resolu- that are distorted in some way to reduce the intelligibility
tion, temporal masking, temporal integration, and tem- of the message. The basic principle of sensitized speech
poral ordering testing is that the distorted message can be understood by
Auditory performance decrements with competing persons with normal hearing and a normal central auditory
acoustic signals system. When an auditory processing disorder is present,
Auditory performance decrements with degraded acoustic however, speech intelligibility will be poor. The construct
signals of sensitized speech testing is extremely powerful and is
the basis of all behavioral speech tests of central auditory
These mechanisms and processes are to apply to nonver-
function.
bal as well as verbal signals and to affect many areas of
The purpose of central auditory testing—initially to
function, including speech and language.”3 A central audi-
identify lesions of the brainstem and cortex—has changed
tory processing disorder [auditory processing disorder] “is
as a result of developments in radiology with techniques
an observed deficiency in one or more of the above-listed
such as magnetic resonance imaging. Currently, auditory
behaviors.”3
processing testing in children focuses on identifying prob-
To further define these terms, sound localization refers to
lem areas that affect academic performance. In adults the
a person’s ability to find the direction of a sound source.
focus is on determining how APD affects communication
Sound lateralization refers to a person’s ability to determine
and vocational achievement. In both populations, then, the
where inside the head a sound appears to be (e.g., on the
focus is on what Bergman and colleagues15 refer to as the
right side of the head, left side, or in the center). Auditory
“functional disorders of communication” or “functional
discrimination refers to one’s ability to determine if two
auditory performance deficits.”3
sounds are the same or different. Temporal resolution
describes the process in which timing cues are distin-
guished (e.g., a measure of how much time must be inserted BEHAVIORAL TESTS OF
between two tones for them to be perceived as two distinct
tones [gap detection]). Temporal masking refers to forward
AUDITORY PROCESSING
and backward masking. In this phenomenon, noise that is
The premise of behavioral testing of auditory processing
presented slightly before or after a stimulus can partially
lies in the concept of using sensitized speech measures to
mask or cover part of the stimulus. Temporal integration is
reduce extrinsic redundancy. Speech contains multiple
the increase in sound intensity required to hear a sound of
acoustic and linguistic cues, not all of which are necessary
shorter duration. So, for example, a tone of 200 millisec-
to understand the incoming message. For example, in the
onds will have a 10-dB lower threshold than a tone that
sentence “the cats are drinking milk,” it is not necessary to
lasts only 20 milliseconds. Finally, temporal ordering
hear the s at the end of “cats” to know that more than one
involves the ability to recognize the sequence of acoustic
cat is being discussed; the verb are signals the plural form.
stimuli as they occur in time.
Speech carries a multitude of other redundant linguistic
cues, such as tense and intonation.
In addition, the speech signal typically contains a greater
PREVALENCE OF AUDITORY amplitude and a wider range of frequencies than is neces-
PROCESSING DISORDERS sary for understanding. For instance, most people can eas-
ily understand quiet speech even though the frequency and
Prevalence of APD varies; there is no “gold standard” for amplitude spectrum is very different from normal conver-
measuring the prevalence of APD. Many children who sational speech. In addition, most persons can understand
have learning disabilities (prevalence of 4% to 5%) also have speech on the telephone, which has a limited frequency
APD.4,5 Chermak and Musiek6 estimate that APD occurs range compared to normal face-to-face communication. The
in 2% to 3% of all children, with a 2:1 male-to-female ratio. frequency range on a telephone is 300 to 3000 Hz, whereas
The literature presents the prevalence of auditory process- face-to-face communication has a range of 250 to 6000 Hz.
ing disorders in adults across a broad range, depending on The structure of the central auditory nervous system
the investigator and criterion used. The prevalence in (CANS) itself creates intrinsic redundancy. The CANS is
adults ranges from 0% to 75% (1% to 23% in Cooper & well documented as a complicated neural network of
Gates,7 19% in Gang,8 58% in Kricos et al,9 60% in ipsilateral and contralateral connections that originate
Rodriguiez et al,10 74% in Arnst,11 74% in Shirinian and and terminate at multiple points. Auditory information is
Arnst,12 and 75% in Stach et al13). conveyed via many neural pathways to the auditory cortex,
and the system is wired to be intrinsically redundant.
Therefore, if one neural pathway is damaged, the system
HISTORICAL PERSPECTIVE can often perform normally in ideal, quiet listening situa-
tions. The system with a lesion in the CANS can compen-
Early research of central auditory testing was conducted in sate, given the extrinsic redundancy that exists in this
the 1950s in Milan, Italy, by a group of otolaryngologists situation. However, if a damaged system with decreased
that included Bocca, Calearo, Antonelli, and Teatini.14 intrinsic redundancy is placed in an environment that has
Those early investigators recognized that routine audiomet- decreased extrinsic redundancy (e.g., hearing in background
ric tests do not identify lesions affecting the central hearing noise), the system is unable to compensate. The information
pathways. Special techniques, called sensitized speech tests, needed to understand the speech signal cannot reach the
were needed to identify those lesions. Sensitized speech auditory cortex and the person cannot understand the
measures use speech stimuli (syllables, words, or sentences) incoming speech. Most behavioral tests of central auditory
 Central Auditory Processing Disorders: Assessment and Remediation 275

processing decrease the extrinsic redundancy of the incom- ratio or “10dB S/N ratio.” Signal-to-noise ratios can be
ing signal to “tax” the central auditory nervous system. positive or negative, depending on whether the speech or
Despite the vast number of them, behavioral auditory noise is higher in intensity. Examples of this form of test
processing tests can be classified by two methods: the include the Auditory Figure Ground subtests of the
manner of stimulus presentation16 or the anatomic level SCAN–C17 and SCAN–A,18 the Speech Perception in Noise
being tested. In the first method of categorization, called (SPIN) test,21 and the QuickSIN test.22 A notable instrument
the manner of presentation, the tests are distinguished by that has withstood the test of time is the Synthetic Sentence
how the stimuli are presented: monaural, binaural, and Identification–Ipsilateral Competing Message (SSI-ICM)
dichotic. In monaural tests, a single stimulus or multiple test, developed by Jerger, Speaks, and Trammel.23
stimuli are presented to one ear. In binaural tests, stimuli
are presented to both ears. The third category, dichotic Frequency and Duration Pattern Recognition
testing, is a special kind of binaural test. During dichotic The frequency patterns test (FPT) includes two frequen-
testing, two different signals with equal onset and offset cies presented in six patterns of high and low. The patient
times are presented to the two ears simultaneously. This is asked to identify the tone pattern (e.g., high-high-low,
form of testing is separated out from other binaural tests low-high-low). The duration patterns test (DPT) presents
because of its importance in APD assessment. one frequency in six patterns of two durations (e.g.,
350 msec and 500 msec). The patient identifies the pattern
Manner of Presentation of the signal (e.g., short-long-short, long-long-short). The
FPT and the DPT are nonlinguistic (nonlanguage) tasks;
Behavioral AP tests are broadly classified as monaural, however, the response can be either linguistic (the patient
binaural, or dichotic according to the manner in which they labels the stimulus pattern) or nonlinguistic (the patient
are presented and the way in which the signal is configured. manipulates blocks to represent the stimulus pattern).
Recent research states that abnormalities in DPTs may
indicate the presence of a cortical lesion.24
Monaural Measures
Temporal Processing Disorders/Gap Detection Tests
Filtered Speech or Frequency-Altered Speech
Temporal processing disorders can be identified using gap
In this form of sensitized speech measure, the patient is
detection tests. In this method, two tones are presented
asked to repeat single-syllable words. These words, how-
with a variable time interval between the tones. The
ever, are low-pass filtered to reduce the amount of high-
patient reports whether one or two tones were heard. The
frequency information. Low-pass filtering is commonly
gap detection threshold is the shortest time gap in which
done using cut-off frequencies of 500, 750, or 1000 Hz
the patient perceived two tones. Patients with a normal
at either 18 dB or 32 dB per octave. Two current, norm-
referenced tests for filtered speech are the Filtered Words auditory system can identify time intervals as brief as
subtest of the SCAN–C Test for Auditory Processing 2 milliseconds between tones, with a normal average gap
detection threshold of approximately 10 milliseconds.
Disorders in Children–Revised17 and the same subtest in
When gap detection thresholds exceed 20 milliseconds,
the SCAN–A Test for Auditory Processing Disorders in
the individual is likely to have difficulty discriminating
Adolescents and Adults.18
speech sounds, and a temporal processing disorder is said
Time-Compressed Speech to exist. A current test of gap detection is the Random Gap
Detection Test (RGDT).25
In this test speech is compressed in a shorter time frame by
removing some segments of the speech signal and putting
the remaining segments back together. Beasley, Schwimmer, Binaural Measures
and Rintleman19 found that persons with normal auditory
perception understand speech with time compression rates Masking Level Differences
up to 50% but have difficulty with time compression of Masking level differences (MLDs) are tested to determine
60% or greater. An example of this test is the Time the presence of brainstem abnormalities based on a phe-
Compressed Sentence Test (TCST),20 which presents sen- nomenon called binaural release from masking. This
tence material at 40% and 60% time compression. This process is tied to the auditory system’s ability to detect
test is norm-referenced for children from 6 to 12 years old. timing differences between ears. Detecting timing cues
is actually the detection of phase differences between ears
Background Noise and is used in the localization of sounds, especially low-
Three terms—speech recognition in noise, auditory figure frequency ones.
ground, and speech in competition—describe the same basic The concept of binaural release from masking is as
task. The subject is asked to repeat words or sentences follows. Tones can be presented between ears which are in
spoken when background noise is present. The competing phase and out of phase with one another. In-phase tones
signal can be linguistic, ranging from a single speaker to a are presented first. A masking noise is introduced to just
multiple-speaker speech babble, or it can be nonspeech, cover the tone. If the tones are changed to be out of phase,
such as white noise or speech noise. The level of the the tone becomes audible again and is “released from
speech in relation to the competing signal is often masking.” Binaural release from masking is a result of brain-
described in terms of a signal-to-noise ratio. Thus, a stem processing at the level of the superior olivary com-
speech signal that is 10 dB higher in intensity than the plex.26 In addition, speech can be used instead of tones as
competing noise is described as a 10-dB signal-to-noise the target stimulus.
276 NEUROLOGIC DIAGNOSIS

In the MLD test, the MLD is the difference in intensity Abnormal dichotic test results are associated especially
needed for the tone to be just audible over the masking with lesions of the corpus callosum or auditory cortex.26
noise between the in-phase and out-of-phase conditions. Dichotic measures include the following:
For a 500-Hz tone, the MLD should be greater than 7 dB
Dichotic Consonant-Vowel (CV) test
with an average of approximately 12 dB.26 Wilson and col-
Dichotic Digits38
leagues27 found MLDs of approximately 13 dB for a 500-
Staggered Spondaic Word (SSW) test39
Hz tone in normal young adult listeners. MLDs lower
Competing Sentence Test40
than normal are consistent with lower brainstem dysfunc-
Dichotic Sentence Identification (DSI) test41
tion. A number of studies indicate that abnormal MLDs
Competing Words and Competing Sentences subtests of
are consistent with disorders of the brainstem.28–32 The
the SCAN–C Test for Auditory Processing Disorders
largest MLD effects are seen in the lower frequencies (300
in Children–Revised17 and SCAN–A Test for Auditory
to 600 Hz).33 The introduction of a prerecorded MLD test
Processing Disorders in Adolescents and Adults18
on compact disc by Wilson and colleagues27 simplifies the
procedure and makes it feasible for more clinics to
perform this test. Anatomic Level Tested
Localization Auditory processing tests can also be categorized accord-
Localization is the ability to identify the source of ing to the presumed anatomic level being assessed (see
sounds in the surrounding environment. Poor localiza- Table 17-1). The bottleneck principle, discussed in the
tion ability is associated with auditory brainstem disor- “Test Interpretation” section, should be considered as well.
ders26,34,35 and cortical disorders.26,35,36 Although tests
that use localization are common when investigating
hearing in infants behaviorally (visual reinforcement ELECTROPHYSIOLOGIC TESTS
audiometry), testing of localization for purposes of central
auditory disorders is not practiced in most centers. A The role of electrophysiologic testing has great promise in
promising strategy has been recently described by the auditory processing test battery. A large body of liter-
Koehnke and Besin’s 3-D (three-dimensional) auditory ature has emerged in the past decade in this arena. Elec-
test of localization, in which virtual reality techniques and trophysiologic tests discussed for use in APD assessment
digital signal processing are used to assess localization include the auditory brainstem response (ABR), the mid-
under headphones.37 dle-latency response (MLR), the P300, the mismatch neg-
ativity (MMN), and other late auditory evoked responses.
One reason to conduct electrophysiologic tests is to rule
Dichotic Measures out auditory neuropathy. This phenomenon is character-
ized by normal otoacoustic emissions, absent or abnormal
Dichotic testing is an extremely sensitive measure of audi-
ABR, and absent acoustic reflexes. The implication of
tory maturation and auditory nervous system function and
these findings is that persons with auditory neuropathy
dysfunction. During dichotic testing, different speech sig-
have normal cochlear outer hair cell function with abnor-
nals with equal onset and offset times are presented simul-
mal neural synchrony of cranial nerve VIII or abnormal
taneously to both ears. A number of speech stimuli are
cochlear inner hair cell function.42 The remediation efforts
used, including nonsense syllables, numbers (referred to as
for auditory neuropathy are significantly different from
“digits”), monosyllabic words, compound words or spon-
those for APD, and they include possible cochlear implan-
dees, sentences, and nonsense sentences. Test instructions
tation. Nevertheless, the requirement that all children
include both free recall (the subject replies with whatever
was heard in no given order) or directed ear (both stimuli
are repeated under instructions of “right ear first” or “left
ear first”). TABLE 17-1. Auditory Processing Tests
Dichotic tests of young subjects find a strong right ear
advantage (REA), that is, better scores in the right ear than Anatomic Level Type of Test
the left. The REA results from the direct relationship
Brainstem Masking level differences, lower brainstem
between the right ear and the dominant left language lesions
hemisphere. As children approach 12 to 14 years, the REA Binaural fusion of low- and high-pass filtered
disappears, which is a sign of auditory maturation. In speech
normal adults, a slight REA is often observed. However, Rapidly alternating speech
individuals with lesions of the auditory regions of the Localization
Lateralization
central nervous system (CNS) or those with APD show Cerebral cortex Dichotic tests
various response patterns including: Low-pass filtered word tests
Auditory figure ground, speech recognition
Deficits in left ear performance in noise
Poor overall performance Time-compressed speech
Enhanced right ear advantage Difficult monaural tasks
Switch from right ear advantage on a “directed right” con- Impaired localization
Reduced temporal processing
dition to a left ear advantage on “directed left” listening Nondominant hemisphere Frequency and duration pattern recognition
condition
 Central Auditory Processing Disorders: Assessment and Remediation 277

undergo electrophysiologic tests as part of an APD assess- disorder.57 The MLR obtained on that child was abnormal
ment remains controversial.2,43,44 with no repeatable patterns in the responses from either
Electrophysiologic testing does have significant limita- ear. Fifer and Sierra found a correspondence with abnormal
tions and considerations. First, although these are physio- performance on the SSW test and the MLR in a 7-year-old
logic responses, they are not truly objective because they with auditory processing disorder.58 Jerger and colleagues,
need to be interpreted by an examiner. In addition, sub- Fifer and Sierra, and Ozdamar and Kraus all postulated that
jects must often cooperate during testing. This may mean the MLR has potential for identifying and understanding
that subjects need to rest quietly during the test or need to central auditory processing disorders.57–59 This evoked
pay close attention to a task. Middle-latency and cortical response’s degree of success in the assessment of auditory
evoked potentials especially are affected by sleep states and processing disorders is yet to be established.
attention.
The P300
Auditory Brainstem Response
The P300 is a cognitive evoked potential that evaluates
The best known of the auditory evoked potentials, the attention and information processing. One of the late
ABR is a series of neurologic responses that are assumed to auditory evoked responses, it is also known as P36. It con-
reflect the sequence of activity of the auditory nerve and sists of one large peak that occurs approximately 300 mil-
nerve tracts and nuclei of the ascending auditory path- liseconds after an effective stimulus,54 hence the name P300.
way.45 These compound action potentials result from an To elicit the P300, an “oddball paradigm” is employed.
acoustic stimulus of a fast rise time (a click) and occur A series of stimuli are presented to the patient, with an
within the first 10 milliseconds following the stimulus. occasional different stimulus, or “oddball,” presented about
Because the ABR reflects pontine-mesencephalic trans- 20% of the time. The patient’s task is often to attend to the
mission of neural activity, it is a measure of central audi- oddball stimuli, often by counting them. The attention to
tory processing at the brainstem level. Early investigators the oddball stimuli causes the P300 to appear. The P300 is
reported abnormalities in the ABR in children with audi- greatly influenced by the subject’s attention, alerting, arousal,
tory processing and language-learning disorders.46–49 Stein and psychological state with small or delayed amplitude
and Kraus report various studies showing ABR abnormal- responses occurring when there is some abnormality of
ities in patients with confirmed hydrocephalus, autism, cognitive processing.60 As such it has been used to study
and Down syndrome.50 Lynn and colleagues report ABR attention deficit and auditory processing disorders in
abnormalities in patients with olivopontocerebellar degen- children. For example, Jirsa and Clontz found reduced
eration.51 Keith and Jacobson report ABR abnormalities amplitude of the P300 in a group of children with auditory
commonly observed in patients with multiple sclerosis.52 processing disorders.61 Jirsa also found that the P300
A newer application of the ABR in auditory processing decreased in latency and increased in amplitude after
is maximum-length sequences. (See Jirsa53 for further structured treatment in an APD group of children.62
information.) Since these early studies, a vast literature
has grown to document the validity and efficacy of ABR
testing in a wide range of populations.
Mismatch Negativity
The mismatch negativity is a late, endogenous evoked
Auditory Middle-Latency Response potential that occurs after 100 milliseconds and after the
P2 late cortical response. Kraus and colleagues studied the
The middle-latency components of the auditory evoked MMN in detail.63 They report that the MMN is associated
response occur after the ABR and within the first 100 with neurophysiologic processing during discrimination of
milliseconds following the presentation of an effective acoustic stimuli. They note that it is especially appealing
auditory stimulus.6 There are two major positive and neg- because it is not influenced by attention and does not require
ative peaks in the response, typically labeled Na, Pa, Nb, a behavioral response from the subject, even though it is
and Pb.54 The MLR is believed to have multiple genera- elicited with an oddball paradigm, as with the P300. It also
tors, including the temporal lobe or thalamocortical proj- is free of the confounding effects of language develop-
ects, the reticular formation, thalamus, and inferior ment, cognitive ability, and behavioral development. They
colliculus, as well as contributions outside of the central also indicate that the MMN is stable throughout the school
auditory nervous system.55 It is affected by the depth of years (ages 6-15 years) and provide MMN normative data
sleep, which may explain the variability found in the MLR for speech syllable stimuli. It is interesting to note that
of children. It is best obtained when awake.55 In regards to they found changes in the MMN that occurred with some
age effects, MLRs in infant and young children have dif- speech stimuli but that were not distinguished in conscious
ferent morphologies and latencies from those in adults. behavioral discrimination tasks. They suggest that the
Kraus and colleagues reported that detectability of the MMN may be related to preconscious discrimination ability.
MLR increased significantly as a function of age. Some data indicate that the MMN in normal, healthy
Detection of MLR Na components increased from 75% to subjects may not be quite as robust as described. For
90% as subjects’ age increased from 0 to 20 years. The example, Kurtzberg and colleagues, Dalebout and Stach,
detection of the Pa component increased from 40% to and Cunningham all found MMN to be absent in 25% to
90% during the same time frame.56 35% of normal children and adults.64–66 Other work
Jerger and colleagues published a case report of an with the MMN and auditory processing has been done by
11-year-old boy with a classic history of auditory processing Liasis and colleagues, Naatanen, Kraus and colleagues,
278 NEUROLOGIC DIAGNOSIS

Jansson-Verkasalo, Purdy and colleagues, Hugdahl and Staggered Spondaic Word (SSW ) test, which has corrections
colleagues, Bertoli and colleagues, and Schulte-Korne and for hearing sensitivity loss39,79
colleagues.67–74 Therefore, while MMN continues to be a
Competing sentences, MLR, and P300 are less likely
promising research tool for groups of subjects, its use in
to be affected by peripheral hearing loss.3 In addition, a
the assessment of individual subjects should be approached
wide range of nonlinguistic tests that use tones can be
with caution.
considered when attempting to identify an auditory
processing disorder in this population; they include
Other Late Auditory Evoked Responses Random Gap Detection, Median Plane Localization, dif-
Research is being conducted to investigate other late audi- ferential thresholds for frequency and intensity, and tone
tory evoked responses in the assessment of APDs. These decay tests.
responses occur after 80 to 100 milliseconds. Besides the
MMN and P300, other responses are the N1, P2, and N2. Intelligence, Cognition, and Language
Research related to APD populations include the work of
The effect of intelligence and cognitive ability is well
Jirsa and Clontz, who found that the N1 and P2 had
documented. Subjects’ performance will generally be
increased latencies in a group of children with APD.61
commensurate with their mental age and should be
Tonnquist-Uhlen found significant differences in N2 and
interpreted appropriately. Language ability is an important
P2 latencies in language-impaired children.75 Purdy and
factor as well because many auditory processing measures
colleagues found different P1 and P3 responses in learning-
are language based. For instance, vocabulary knowledge is
disabled children.71 Ponton and colleagues suggest that
late potentials can provide information about the essential for the recognition of words with reduced extrin-
maturation of the CANS.76 Hayes and colleagues also sic redundancy.
measured differences in P1 and N2 in children with learn- In addition, native language and language dialect can
ing problems, after a computer remediation program was have an impact on test results. It has been demonstrated
used.77 This also corresponded with a change in behavioral that normal adult subjects who are not native speakers of
performance measures. English typically have difficulty performing sensitized
speech tasks, even years after being immersed in the
English language.80,81 Native English speakers from other
FACTORS AFFECTING AUDITORY English-speaking countries also have difficulty taking
American-accented speech tests of auditory processing.
PROCESSING TEST RESULTS Marriage found that normally performing children in
Great Britain fell at the 16th percentile of performance on
Subject’s Age SCAN–C because they were unable to interpret some of
The age of the subject vastly affects the performance on the American-accented test items.82
auditory processing tests. The effects of age are based on
changes resulting from neural maturation, changes in the Medications
auditory nervous system in aging, and language level.
When referring a patient for APD assessment, the cor- The effect of medications on auditory processing tests
rected age based on language ability, and not just the is beginning to emerge in the field. Keith and Engineer
chronological age, should be considered. Electrophysio- found that children with attention deficit disorder (ADD)
logic tests also are affected by age. who were taking methylphenidate (Ritalin) had signif-
icantly improved auditory processing performance.83
Tillery and colleagues found auditory attention improved
Peripheral Hearing Loss with Ritalin in children with both APD and attention
Peripheral hearing loss, both conductive and sen- deficit hyperactivity disorder (ADHD), but auditory pro-
sorineural, is a significant factor in testing and interpreta- cessing abilities were unchanged.84 The effect of selective
tion of auditory processing. Patients with peripheral serotonin reuptake inhibitors (SSRIs) such as fluvoxamine
hearing loss cannot be tested reliably with most of the cen- and fluoxetine on auditory processing abilities needs
tral auditory measures that incorporate speech signals investigation, as shown by the case study presented by
because of cochlear distortion and asymmetrical hearing Gopal and colleagues.85 Chermak reviews this subject
loss. For example, the dichotic consonant-vowel (CV) test, briefly.86
masking level difference test, low-pass filtered speech
tasks, and time-compressed speech tasks are affected by
hearing loss. Fortunately, some tests have been researched AUDITORY PROCESSING TESTING
or adapted for testing subjects with peripheral hearing
loss. According to Stach,26 these tests include: Children
Dichotic Sentence Identification (DSI) test, which can be used Children younger than 5 years old are difficult to test with
with PTA of 50 dB or lower41 these special measures, and there are few normative tests
Synthetic Sentence Identification (SSI) test, which has norma- available. After the age of 6 years, children can be tested
tive data based on degree of hearing loss78 with relative ease using standardized tests. Nonverbal per-
Dichotic digits test, interpretation of which can be adjusted sons or persons with limited intelligence are not candi-
based on hearing loss present38 dates for testing. For further information, consult the
 Central Auditory Processing Disorders: Assessment and Remediation 279

guidelines for referring children for APD assessment formal screening tests.2 Examples of questionnaires include
published by a group of Houston audiologists.87 the Children’s Auditory Performance Scale (CHAPS) and
The focus of testing children’s auditory processing is to the Screening Instrument for Targeting Educational Risk
investigate a possible factor for poorer school perform- (SIFTER).96,97 An example of a formal screening test is the
ance, language delays, reading problems, learning difficul- Selective Auditory Attention Test (SAAT).98 A word of
ties, and behavior difficulties. The majority of children caution: Auditory processing tests designed for screening
referred for testing do not have specific identifiable brain should not be used to diagnose auditory processing disor-
lesions and many have completely normal neurologic ders, as has been done in the past.2 This results in an
examinations. The purpose of APD testing of children is overdiagnosis of auditory processing disorders.
to identify those who have an auditory processing disorder
that may underlie or contribute to a child’s poor social
skills, use of language, or academic performance.
A Multidisciplinary Approach
Children with auditory processing disorders often mis- The test battery used in auditory processing assessment
understand what is said, give inconsistent responses to needs to be part of a multidisciplinary approach. Essential
auditory stimuli, and frequently request that information members of this team are the audiologist and speech-
be repeated. These children have poor auditory attention, language pathologist. For assessment of children, teachers
have difficulty listening in the presence of background noise, and parents are also essential members of the team. This
and are easily distracted. They have difficulty with phonics team approach is recommended in two consensus state-
and speech sound discrimination and have poor auditory ments by specialists in central auditory processing.2,3
memory. Their speech and language skills, both receptive Other specialists, such as psychologists, also may be
and expressive, may be poor. These problems occur with- involved.
out hearing loss, but there might also be hearing loss.
The relationship of language acquisition and auditory
processing is complex. A vast body of literature addresses Goals
different theories about this relationship. In the normal The ASHA Task Force reveals that “the purpose of the
child, auditory processing abilities develop in a parallel or central auditory assessment is to determine the presence of
a reciprocal relationship with language abilities. Children a central auditory processing disorder and to describe its
with auditory processing disorders are a subset of children parameters.”3 Concerning children specifically, there is con-
with receptive and/or expressive language disorders. troversy as to whether the assessment should focus on delin-
In addition, issues of attention need to be considered. eating a deficit specific to the auditory realm, differentiating
APD can coexist with attention deficit hyperactivity disor- APD from other disorders such as language and learning
der or attention deficit disorder. The relationships among problems, or determining management strategies.2,43
all these disorders is not yet completely understood.88
Nevertheless, APD can be distinct clinically from ADHD.89
Test Battery Components
Adults The components of the APD test battery vary, based on
Auditory processing disorders in adults often manifest the model of auditory processing. The tests chosen are
themselves in everyday communication, either socially or especially important for assessment of children’s hearing
vocationally. Like children with APD, adults with APD have because they are still learning the basic components of lan-
more than normal difficulty in challenging listening situa- guage. Audiologists tend to approach APD testing with a
tions. They often report difficulty hearing in noisy environ- bottom-up approach, believing that language problems
ments, when speaking with an individual with a foreign stem from deficit(s) in basic auditory processes. Speech-
accent, or with someone who speaks very fast. APD in this language pathologists tend to approach auditory process-
population may be related to acquired etiologies; it has been ing with a top-down approach, believing that the auditory
documented with Parkinson’s disease, chronic alcoholism, processing difficulty is due to problems with higher-level
Alzheimer’s disease, stroke and head trauma, tumors, multi- influences, such as language, cognition, information pro-
ple sclerosis, and chemical exposure. APD also may be iden- cessing, and attention.
tified in previously undiagnosed learning-disabled adults.90–94 Not surprisingly, then, the essential auditory processing
As mentioned earlier, APD testing of adults can be use- test battery is highly variable among audiologists. The
ful in identifying lesions of the central auditory nervous American-Speech-Language-Hearing Association Task
system, although this is not the typical purpose today. Force on Central Auditory Processing consensus statement
APD testing can be used to track the recovery of auditory provides a workable guideline. For both adult and pediatric
processing skills95 and provide information on the impact populations, the test battery can include the following3:
of APD on everyday function. I. Case history
II. Nonstandard but systematic observation of
Screening for Auditory Processing auditory behavior
Disorders III. Audiologic test procedures
A. Behavioral techniques
Mostly, children are screened for APD. According to the 1. Measures of peripheral function
2000 Bruton Conference on APD, this can be done by a. Pure tone thresholds
observation of the child using questionnaires and/or b. Speech recognition
280 NEUROLOGIC DIAGNOSIS

c. Acoustic immittance measures TABLE 17-3. Recommended Minimal Test Battery

d. Otoacoustic emissions, when possible for Diagnosis of APDs in School-Age Children
2. Auditory processing tests
a. Temporal processes—ordering Behavioral measures Pure tone audiometry
Performance-intensity functions
discrimination, resolution (e.g., gap for word recognition
detection), and integration A dichotic task
b. Localization and lateralization Duration pattern sequence test
c. Low-redundancy monaural speech Temporal gap detection
Electroacoustic and Immittances
(time-compressed, filtered, electrophysiologic measures Otoacoustic emissions
interrupted, competing, etc.) Auditory brainstem response
d. Dichotic stimuli, including competing Middle latency response
nonsense syllables, digits, words, and
sentences Data from Jerger J, Musiek F: Report of the consensus on the diagnosis of auditory
processing disorders in school-aged children. Journal of the American Academy of
e. Binaural interaction procedures Audiologists 11:467, 2000.
B. Electrophysiologic procedures can also be used
IV. Speech-language pathology measures
In the ASHA statement, the test battery is not standard;
see Bellis,55 Masters, Stecker, and Katz,100 Hall and
instead, an individual approach to assessment and selection
Mueller,101 Musiek and Chermak,102 and Margolis.103
of tests is taken. This means that the tests that comprise
In test selection, Musiek and Chermak recommend the
the battery vary, depending on the individual and the
following considerations: availability of normative data,
observed problem areas. In addition, the tests chosen
test sensitivity and specificity, test reliability, ease of
should be appropriate for the age of the population. Keith
administration, comprehensive assessment, use of test data
suggests specific tests that relate to the ASHA recommen-
(guided by the use of the results), patient factors, and test
dations.1 These have been updated and are reprinted in
medium (e.g., compact disc, cassette).102 In addition, the
Table 17-2.
qualifications of the professional who will administer the
Another approach to CAP testing is the recommenda-
test(s), in auditory processing specifically, must be consid-
tion of a minimal test battery. An example of this was
ered because they vary greatly.104
suggested by the 2000 Bruton Conference Consensus
statement on APD in school-age children, as reproduced
in Table 17-3.2 This minimal test battery is not agreed on by Test Interpretation
all audiologists.43 Indeed, Emanuel found that none of the
There are a number of important basic principles in audi-
practicing audiologists surveyed used all of the tests in
tory processing test interpretation. The first, the bottleneck
the minimal test battery recommended by the Bruton
principle, states that lower auditory anatomic-level function
conference.99 For further examples of usable test batteries,
typically affects higher-level responses. Cranial nerve VIII
is often thought of as the bottleneck. A deficiency in a cor-
tically sensitive measurement may have been affected by a
TABLE 17-2. Auditory Processing Tests Related to ASHA
lesion lower in the central auditory processing pathway,
Test Battery Areas
such as in the cochlea, auditory nerve, or brainstem.
ASHA Test Battery Area Auditory Processing Tests Similarly, the subtlety principle states that “the more cen-
tral the lesion, the more subtle its impact will be.”105 For
Temporal processing, Auditory Fusion Test (Revised) example, a brainstem lesion can result in profound, rising
resolution and gap Random Gap Detection Test
detection to mild hearing loss to pure tones.106 On the other hand,
Frequency and Pitch Pattern Test temporal lobe lesions are not likely to affect hearing sensi-
temporal ordering Duration Patterns Test tivity to pure tones or word recognition in quiet surround-
Sound localization and Clinical localization of sounds through ings.26 There are exceptions to the subtlety principle, such
lateralization earphones or speakers
Median plane localization task
as in the case of bilateral temporal lobe lesions. These can
Low-redundancy Time Compressed Sentence Test cause “cortical deafness,” such as a seeming auditory agnosia
monaural speech Filtered Words test from SCAN–C or SCAN–A or profound hearing sensitivity loss.107–109
Auditory Figure Ground test from SCAN–C or A few other key principles also apply. Sensitized speech
SCAN–A tests show no dominance effect in normal adults; scores are
QuickSIN test, for older children
Dichotic stimuli Dichotic Digits Test equivalent for both ears. When a lesion of the auditory
Dichotic Words Test from SCAN–C or SCAN–A cortex is present, sensitized speech tests yield mild to mod-
Staggered Spondee Word Test erately reduced intelligibility scores in the ear contralateral
Competing Sentence Test from SCAN–C or to the lesion, although both ipsilateral and contralateral
SCAN–A
Binaural interaction Masking Level Differences
deficits are sometimes found.3 On the other hand, tempo-
Electrophysiologic Auditory Brainstem Response ral lobe lesions that extend deep toward the midline reveal
procedures Middle Latency Response a paradoxical ipsilateral ear lesion.110
Brainstem lesions affect the sensitized speech scores to a
ASHA, American Speech-Language-Hearing Association. greater extent than cortical lesions do. The reduced intel-
From Keith RW, Auditory processing disorders. In Roser R, Downs, M (eds.): Auditory
Disorders in School Children: Law, Identification, Remediation, 4th ed. New York, ligibility occurs on either the same or the opposite side of
Thieme Medical Publishers, 2004. the brainstem lesion, depending on the neural pathways
 Central Auditory Processing Disorders: Assessment and Remediation 281

involved. Scores are often reduced bilaterally when the 3. Compensatory strategies designed to teach the individual
lesion crosses the midline or through secondary effects how to overcome residual dysfunction and maximize
of pressure, even from remote lesions.111 In difficult mon- use of auditory information. These focus on improv-
aural tasks, with lower brainstem lesions, the performance ing learning and listening skills. They include teach-
is poorer usually ipsilateral to the lesion. With higher ing the person to be an active listener, increasing
brainstem lesions, performance can be poorer ipsilateral motivation, attribution training, whole body listening
and contralateral to the lesion.26 techniques, and metacognitive strategies.55
One recent trend in APD assessment is the development
Remediation of APD in children needs to take full
of the concept of a central auditory processing disorder
advantage of the neural plasticity of the central auditory
divided into subtypes of deficits. For example, Bellis and
nervous system.113,114 Neural maturation must also be
Ferre delineate auditory processing disorders into three
taken into account. The treatment plan for adults may
primary subprofiles and two secondary subtypes. The
focus more on management of the environment and
three primary subtypes are Auditory Decoding Deficit,
compensatory strategies and less on direct remediation
Prosodic Deficit, and Integration Deficit. The two sec-
training techniques. This makes sense because of the
ondary subtypes are Associative Deficit and Output
decreased neural plasticity in adulthood.
Organization.55
For more thorough and comprehensive sources of man-
As a second example, the subtypes of auditory processing
agement approaches and issues, consult Bellis,55 Masters,
deficits have been described by Masters, Stecker, and Katz
Stecker, and Katz,100 and Chermak.115 In addition, Musiek
in the Buffalo Model.100 This model uses four clusters of
describes three useful and practical management approaches
test results and behavioral characteristics, speech-language
that can be used as part of a comprehensive APD manage-
test results, and academic factors. The four clusters are
ment program.116
Decoding, Tolerance-Fading Memory, Integration, and
Of course, the existence of a strategy does not mean it is
Organization. Although these models of auditory process-
an effective strategy. In the area of auditory processing, a
ing have been popularized, there is no evidence to
great amount of research is needed to determine treatment
substantiate claims that the remediation proposed to be
effectiveness and outcome measures. Hayes and colleagues
associated with each model has an effective outcome.
did such a study in which children with learning problems,
including an auditory perceptual deficit, underwent a com-
puterized training program, Earobics.77 Not only did their
REMEDIATION OF AUDITORY performance improve in measures of auditory processing,
PROCESSING DISORDERS but changes in cortical potentials were also measured.
Other studies that report improved auditory abilities and
Different management strategies of auditory processing language function after formal training were conducted
disorders exist. Regardless of the management approach, it by Merzenich and colleagues, Tallal and colleagues, and
is important that the management approach be multidisci- Habib and colleagues.117–119
plinary. It also should be individualized based on the areas
of weakness or deficit identified in the auditory processing
assessment. AUDITORY PROCESSING ABILITIES
Additionally, it is important to be specific in the man-
agement approach; some professionals still believe that
IN THE ELDERLY
intervention strategies are not specific enough to warrant
In the 1990s special interest was focused on auditory pro-
auditory processing testing.112 An example of the possible
cessing abilities and the elderly population. The familiar
downfalls of a nonindividualized approach is the use of FM
concept of phonemic regression and central presbycusis was
assistive listening devices for school-age children. FM sys-
revisited. Recall that phonemic regression describes the
tems are not necessarily the best recommendation in all cases. It
phenomenon in which an elderly adult’s ability to under-
is possible that this reduction of background noise may not
stand words, often measured by word recognition scores,
allow the auditory skills to develop in those environments
is disproportionately poorer than would be expected based
with some individuals.55
on pure tone thresholds. This, indeed, was simply refer-
Strategies for remediation of APD fall into three major
ring to an auditory processing disorder becoming evident
categories:
with aging. It is often forgotten that Gaeth found the
1. Management of the environment, which includes strate- prevalence rate of phonemic regression in 1000 elderly
gies such as preferential seating, FM systems, sound individuals to be only 2.7%.120 Research suggests that
field systems, teaching suggestions (comprehension auditory processing disorders in the normal elderly may
checks, use of visual aids, etc.), classroom acoustics, not be the rule, but the exception, which is consistent with
and communication strategies. Gaeth’s early findings.
2. Remediation techniques designed to improve the per- A number of studies challenge the common assumption
son’s auditory processing skills. This includes training that auditory processing decreases with age in most or all
in auditory closure, speech in noise, dichotic listening, individuals. Hearing loss is often a confounding variable.
localization, prosody, and temporal patterning. It also Humes and Christopherson found that the threshold ele-
includes computer-assisted therapy with such soft- vation in sensorineural hearing loss was the primary factor
ware programs as Fast ForWord (Scientific Learning affecting the speech identification performance of elderly
Corp.) and Earobics (Cognitive Concepts). subjects, and not just age alone.121 To read other studies
282 NEUROLOGIC DIAGNOSIS

that challenge the common assumption that auditory poorer ear is disproportionately affected compared with
processing declines with aging, consult Surr,122 Grady123 the other ear. Using concepts of auditory neural plasticity,
Holmes, Kricos, and Kessler,124 Jerger and colleagues,125 then, it would be recommended to aid the poorer ear
Humes and colleagues,126 and Harris and Reitz.127 as soon as possible to preserve auditory processing in that
Thompson discusses several alternative hypotheses to ear. It should be noted that the concept of acquired
explain phonemic regression.128 They include experimen- suprathreshold asymmetry is still controversial and is not
tal artifacts that include failure to account for the fact that supported in all studies conducted.26
elderly persons are less willing to guess, prolonged reac- Last, late-onset auditory deprivation should also be consid-
tion time in this population, insufficient stimulus presenta- ered in hearing aid use. This can occur in monaural hearing
tion level, and the effects of decreased hearing sensitivity. aid fittings with bilateral, symmetric hearing loss. In some
In addition, she suggests that cognitive factors such as individuals, the unaided ear decreases in word recognition
changes in attention, declining memory, need for more ability, whereas the aided ear does not. However, the plastic-
practice, and social expectations (defined as the expectation ity of the auditory system becomes apparent as this negative
that the elderly person’s hearing is poorer than a normal effect is reversible if the other ear is aided soon enough.26
adult’s) are factors in tests of auditory processing.
These studies serve as a reminder to neurotologists and
audiologists who work with seniors that central auditory FUTURE DIRECTIONS
processing disorders in the elderly may not be a global
phenomenon, characteristic of all elderly. Further research is needed to collect and refine norms for
On the other hand, there still exists a strong argument many behavioral APD tests. More information needs to be
that auditory processing does decrease during the aging gathered on electrophysiologic tests, such as MMN, MLR,
process. Histologic and morphologic evidence still seem to and P300. Outcome measures and efficacy measures are
support this concept; age-related changes in the cochlea, needed to assess different remediation and treatment meth-
the auditory nerve, and the central auditory pathways at ods. There is a need for a “gold standard” definition of audi-
both the brainstem and temporal lobe levels have been tory processing, providing the basis for studies of sensitivity
described.129,130 Declined performance on behavioral audi- and specificity for different auditory processing tests. This
tory processing measures also are presented in the litera- will pave the way for improved models of assessment and
ture. Jerger and colleagues used a number of auditory management. In addition, the use of functional MRI and
processing disorder tests on 130 elderly subjects. They brain mapping and scalp topography show promise.
concluded that the speech discrimination problems of the
elderly cannot be explained on the basis of degree of
peripheral hearing loss or degree of cognitive decline.130 FUNCTIONAL MAGNETIC
Neils and colleagues,131 Von Wedel,132 Baran,133 and RESONANCE IMAGING
Willott134 also provide evidence that suggests that auditory
processing changes do occur with aging. An exciting advance in assessment of APD developed in
the early 1990s is functional imaging based on magnetic
resonance methods (fMRI). This technique allows visuali-
AUDITORY PROCESSING TESTING zation of brain activity resulting from increases in regional
IN HEARING AID APPLICATIONS cerebral blood flow associated with processing of sensory
information. Through fMRI, auditory neuroscience will
Interestingly, auditory processing tests to help determine be able to investigate aspects of auditory nervous system
hearing aid success has been discussed more recently. organization, attention, memory, and other factors in
Givens, Arnold, and Hume found statistically significant ways that were unimaginable several years ago. Cacace,
correlations between certain auditory processing tests and Tasciyan, and Cousins summarize that this new research
hearing aid satisfaction. They suggest that a full battery frontier provides insights into fundamental properties of
with auditory processing tests may be helpful.135 Studies by human sensory, motor, and cognitive functions in both
Chmiel and Jerger and by Stach and colleagues further normal and pathologic states. They state that the appeal of
investigate this application.136,137 this technique is “based on its noninvasive nature, tempo-
Auditory processing tests may also be helpful in deter- ral and spatial resolution, suitability for studying humans,
mining when to recommend binaural versus monaural and its potential for wide-range future availability.”141 See
hearing aids. This is related to a phenomenon called bilat- the article by Cacace and colleagues for an excellent tutorial
eral interference. Some people with APD find that their on this subject.141 Other researchers looking at fMRI and
ability to perform binaurally is actually poorer than the auditory processing are Suzuki and colleagues,142 Poldrack
best monaural performance. This has been seen in some and colleagues,143 Seifritz and colleagues,144 Sevostianov and
elderly individuals and in a multiple sclerosis patient.138,139 colleagues,145 Novitski and colleagues,146 Engelien and
An interesting case study of an elderly patient who per- colleagues,147 and Hall and colleagues.148
formed better with monaural hearing aid use was pub-
lished by Chmiel and colleagues.140
Another interesting concept applicable to hearing aid use
Brain Mapping and Scalp Topography
is acquired suprathreshold asymmetry. Evidence is suggesting Scalp topography of auditory evoked potentials with color
that when an individual develops an asymmetry caused by imaging techniques provide a scheme for easy visualization
a peripheral hearing loss, the auditory processing in the of the voltage distribution of evoked potentials at key
 Central Auditory Processing Disorders: Assessment and Remediation 283

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 Chapter
Objective Measures
of Auditory Function
Outline 18
Introduction Acoustic Neuroma Diagnosis Paul R. Kileny, PhD
Otoacoustic Emissions with the Auditory Brainstem
Response Bruce M. Edwards, AuD
Electrocochleography
Measurement Criteria for
Auditory Brainstem Response
Diagnostic Auditory
Detection of Hearing Loss
Brainstem Response
Using the Auditory Brainstem
Response Case Studies
Estimating Amplification Middle Latency Responses
Benefit: Electrophysiologic Auditory Potentials in
Procedures Cochlear Implant Surgery

INTRODUCTION response; other electrophysiologic applications involve the

subcortical and cortical auditory regions. Methods for the
Beginning with the 1939 discovery of human auditory electrophysiologic assessment of auditory system activation
evoked potentials by Pauline Davis1 there has been by electrical stimulation including cochlear implants have
remarkable progress in the clinical application and effec- been developed and refined, allowing one to record
tiveness of electrophysiologic and other objective measures preoperative and postimplant electrically evoked auditory
of auditory function. These developments have been brainstem or middle latency potentials. All of these may be
prompted in part by distinct technological changes since accomplished by noninvasive or minimally invasive stimu-
the advent of the first electronic response averager, devised lation and recording techniques. This chapter reviews
by G. D. Dawson in 1952. It consisted of a revolving principles and practices of auditory neurodiagnostic tests
commutator charging condensers, resulting in a total of in current clinical use.
124 time points. The advent of digital averagers brought a
veritable explosion of productivity in the area of clinical
auditory neurophysiology marked by significant events OTOACOUSTIC EMISSIONS
such as the first human scalp–recorded auditory brainstem
response (ABR) by Jewett, Romano, and Williston.2 Otoacoustic emissions (OAEs) are sounds produced
Over the years, clinical auditory neurophysiology has actively by the human ear as part of the normal hearing
contributed to both diagnostic and surgical monitoring process and were first described by Kemp.3 The active
applications. Electrophysiologic measures are now used nonlinear mechanism of outer hair cell (OHC) motility
for both diagnosis and enhancement and support of amplifies the motion of the cochlear partition 100- to
sophisticated microsurgical interventions in the temporal 1000-fold and, as a byproduct, produces various forms of
bone, subtemporal skull base, and posterior fossa. In the OAEs.4 Because OAEs are acoustic byproducts of the
diagnostic arena, it is possible to evaluate the function and inner ear, they are often referred to as “cochlear echoes.”
the integrity of the auditory pathway from end-organ There are two primary types of OAE: spontaneous
receptor to cerebral cortex. Evoked otoacoustic emissions OAEs (SOAEs) are present even in the absence of an
provide information regarding the status of cochlear outer exogenous stimulation of the ear; evoked OAEs (EOAEs)
hair cells. Electrophysiologic measures provide us with occur in response to the presentation of an acoustic stimulus
information about functional characteristics of outer hair to the ear.5 Evoked OAEs may be further divided into the
cells via the cochlear microphonic as well as the status of categories of transiently evoked OAEs (TEOAEs), which
the cochlea in presumed Ménière’s disease using electro- are elicited by an acoustic transient such as a click or tone
cochleography. Also, the cochlear nerve and brainstem burst, stimulus frequency OAEs (SFOAEs), which are
auditory pathway for neurodiagnostic or hearing threshold elicited by a single continuous pure tone, and distortion
applications is assessed via the auditory brainstem product OAEs (DPOAEs), which are generated by two
287
288 NEUROTOLOGIC DIAGNOSIS

continuous pure tones separated by a specific frequency mass resulting from middle ear effusion or increased stiffness
difference.5 Evoked OAEs can be detected in most ears caused by eustachian tube dysfunction may adversely affect
with normal hearing and are reduced or absent in ears an OAE. Thus, even in cases in which cochlear function is
affected by cochlear disorders.5 normal, attenuation resulting from mass or stiffness effects
The test procedure for obtaining OAEs requires little could render OAEs unmeasurable. Significant for neonatal
subject preparation and relatively brief examination periods, hearing loss detection, Doyle and colleagues have shown14
and it is performed in a relatively straightforward manner. that the obstruction of the external ear canal by debris/
During testing, a probe that contains both a miniature vernix was significantly related to more hearing screening
loudspeaker and a microphone is sealed into the ear canal. referrals using OAEs. The majority of the infants in the
The loudspeaker delivers the stimulus to the ear canal study, however, did pass an ABR hearing screening. The
while the microphone samples the output (emission) for discrepancy between results of hearing screening by
approximately 20 ms following stimulus presentation. The DPOAE and ABR was further demonstrated by Barker
signal from the microphone is then amplified and averaged and colleagues15 who screened a population of 569 new-
in order to enhance the signal-to-noise ratio. borns using ABR and DPOAEs. All infants passed the ABR
Signals used to generate TEOAEs consist of clicks or hearing screening. Since no universally accepted standards
tone bursts. Transient OAEs in response to click stimuli exist for a DPOAE hearing screening pass, several pass cri-
consist of a delayed, nonlinear, frequency-filtered echo of teria based on response replication and/or presence of a
the stimulus.3 Healthy ears typically demonstrate several DPOAE at 2000 Hz were applied post hoc. With the most
regions of strong response for TEOAEs between 0.4 and stringent pass criteria for DPOAE, only 64.4% of ears
6 kHz and between 0.5 and 8 kHz for DPOAEs.5–7 The passed, whereas with the least stringent criteria, 88.9%
latency of TEOAEs is typically 5 to 20 ms in humans and passed. This represents a discrepancy in the pass rate
tends to decrease as frequency increases, supporting a between ABR and DPOAE of 11% to 35% when the ABR
cochlear origin of TEOAEs.5 is considered the gold standard. None of the infants
Signals used to generate DPOAEs consist of two stimulus enrolled in this study carried risk factors for hearing loss,
tones, separated in frequency, presented at 55 to 85 dB and long-term follow-up did not identify any delayed-
SPL. Nonlinear cochlear processes are responsible for the onset hearing loss. Koivunen and colleagues16 investigated
emission of responses at frequencies that are not present in the effects of the physical properties such as the weight and
the two-tone input. The output requires averaging to fluid viscosity of middle ear effusion on emissions and tym-
measure DPOAEs at specific frequencies. The most panogram configuration. These authors demonstrated that
prominent DPOAE occurs at the cubic difference frequency 7% of ears with normal tympanogram findings and 46% of
described by the expression “2F1-F2,” in which F1 repre- ears with abnormal tympanograms yielded reduced or
sents the lower frequency stimulus and F2 the higher absent emissions. A significant correlation was found
frequency primary tone.5,8,9 Distortion product OAEs are among the mean weight of the effusion, the reproducibility
low in amplitude, usually about 60 dB lower than the levels of emissions, and the tympanogram configuration. Fifty-
of the eliciting primary tones. seven percent of ears with mucoid effusion and 26% with
Otoacoustic emissions have shown promise as occupa- nonmucoid effusion had no emissions recorded. Koivunen
tional audiologic test tools not only because they can be and colleagues asserted that the effects of middle ear func-
obtained and measured in a relatively straightforward tion on the ability to record an otoacoustic emission are
manner, but also because they have considerable potential not related specifically to tympanogram configuration.
for assessing the role of OHC dysfunction in hearing Figure 18-1 shows side-by-side recordings of distortion-
impairment.5,7 OAEs specifically test the micromechanical product (“A”) transient-evoked (“B”) otoacoustic emis-
activity of OHCs, that is, the auditory receptors most sions from the same ear of a normal hearing young female.
sensitive to the damaging influence of noise.5 Additionally, These two modes of eliciting an OAE provide analogous
OAE measures demonstrate excellent intrasubject test/ information but require stimulus paradigms that result in
retest reliability,5,10,11 as well as stability over several years different displays. For the TEOAE, the emission is pre-
for any one ear.3,12 sented in the frequency domain with added information
An additional advantage is that OAEs test discrete regarding magnitudes at discrete frequencies and repro-
frequency-specific regions of the cochlea, thereby ducibility. For the DPOAE, the emission is presented in an
enabling one to clearly denote differences between areas of audiogram form (hence, “DP-gram”) that plots emission
normal and abnormal function and also to accurately track intensity as a function of the F2 frequency. In general, the
dynamic changes in outer hair cell–based disease such as distortion product method results in a better frequency
noise-induced hearing loss. Factors known to cause sen- resolution for higher frequencies. Clinical applications for
sorineural hearing loss may reduce or abolish OAEs. otoacoustic emissions may be divided into two areas:
Studies have shown that acoustic overstimulation that estimation of auditory thresholds and site of lesion differ-
results in a temporary threshold shift reduces OAEs.5,13 ential diagnosis. In terms of auditory threshold estimation,
Several variables affect the presence and magnitude of otoacoustic emissions cannot be used to determine
OAEs including middle and outer ear disorders, environ- specific thresholds, only to infer threshold ranges.
mental and biologic noise levels, the number of averaged Generally, when otoacoustic emissions are present, one
sweeps, and primary tone characteristics (in DPOAE). can infer the presence of auditory thresholds no poorer
Because both the forward and reverse transmission of than approximately 30 to 35 dB HL (hearing level);
acoustic energy are necessary for the documentation of an analyzing individual band reproducibility and signal-to-
OAE, external and middle ear conditions such as increased noise ratios of those bands will aid in understanding the
 Objective Measures of Auditory Function 289

significance of “fragmented responses.”17 In terms of F2:F1=1.218 F1=65.0dB spl F2=55.0db spl

differential diagnosis, the otoacoustic emissions may be DP-gram
used in cases of confirmed vestibular schwannoma to make
inferences regarding cochlear reserve, possibly using this
information to decide on the feasibility of a hearing
preservation procedure. For instance, in a case of a diag-
nosed cerebellopontine (CP) angle mass, mild to moderate 20
hearing loss with otoacoustic emissions may indicate a
purely neural hearing loss with cochlear blood supply (and
hence cochlear function) spared. Intuitively, this type of a
clinical picture may be compatible with a good prognosis
for hearing preservation. Conversely, absence of otoa- dBspl 10
coustic emissions along with an abnormal ABR in the pres-
ence of only a mild hearing loss may indicate cochlear
involvement. In extreme situations of severe to profound
hearing loss, a very abnormal ABR but intact emissions
accurately predicted hearing recovery to normal in a case 0
of a very large CP angle meningioma that extended into
the internal auditory canal (IAC).18
In addition to comparing two modes of obtaining and
displaying evoked otoacoustic emissions, Figure 18-1 also
indicates the sensitivity of this measurement tool for inner
800 1K 2K 3K 4K 5K6K 8K10K
ear pathology. Each version of this subject’s OAEs is char-
acterized by a reduction of the OAE output (signal-to-noise A Hz (F2)
ratio) at approximately 3 kHz in spite of normal audiometric Stimulus @0dB 20 RESPONSE FFT RESPONSE 23.0dB
thresholds from 0.5 to 4 kHz (including the interoctave .3Pa +
WAVE REPRO 99%
OCT RPR% SNRdB
frequencies) in this young subject. Significantly, her history 1.0 1.5 2.0 3.9 4.0 kH NOISE INPUT
0 32.6dB
includes several years of playing in a university marching 99 99 99 99 99 % REJECTION AT
− 24 24 29 25 23 dB 46.7dB
band and orchestra without consistent use of appropriate −.3Pa 20 STIMULUS 78 dB pk A+B MEAN 22.9dB
noise attenuators. The “dips,” or notches, in each OAE dB MEAN STIMULUS
A−B DIFF −0.6dB
4ms 0 kHz 6 STABILITY 96%
record could be an early indication of noise-induced damage.
Response Waveform
Another application of otoacoustic emissions is in the 60 Stim = 78.2dB
diagnosis of so-called auditory neuropathy/auditory dys-
synchrony. These patients have hearing losses that range 30
+0.5 mPa
from moderate to profound and have reduced or absent (28 dB)
speech recognition and absent ABRs with normal or near
normal otoacoustic emissions. These patients retain their
cochlear microphonic, which indicates functioning outer
hair cells. For those patients who benefit from cochlear
implantation and exhibit auditory thresholds and speech
recognition scores similar to other cochlear implant recip-
ients, the diagnosis of “neuropathy” is problematic. These
patients also exhibit electrically evoked auditory potentials
in the absence of acoustically evoked responses. While this
manifestation is compatible with some form of neural dys-
synchrony, the overall clinical picture may be more compat-
0 ms 10 ms 20 ms
ible with inner hair cell dysfunction or a deficit of afferent
transduction. Hence one observes physiologic responses B
associated with outer hair cell function and effective Figure 18-1. A, Distortion product and B, transient evoked otoacoustic
electrical stimulation associated with hearing. emissions from a young female with normal hearing thresholds measured at
The following case documents such a clinical scenario. octave and interoctaves (0.25 to 8 kHz). History is significant for repeated
A female patient was diagnosed with severe to profound noise exposure during orchestral practice and marching band performances.
Note the 3-kHz emission notch in each display.
sensory neural hearing loss at 10 months of age. Earlier,
she had failed her initial newborn ABR hearing screening
and follow-up testing. Further diagnostic evaluation to be within normal limits (Fig. 18-3), which indicated,
resulted in the following: Auditory brainstem responses along with the presence of cochlear microphonics, the
were absent with the exception of polarity-inverting presence of appropriately functional outer hair cells. Her
responses to rarefaction and condensation clicks and tone preimplant audiogram is shown in Figure 18-4. Prior to
bursts within a latency range compatible with the cochlear implantation, electrically evoked auditory brainstem
microphonic, as illustrated in Figure 18-2. This prompted responses (EABRs) were obtained. They consisted of a large
an attempt to obtain otoacoustic emissions. The patient’s wave III and a smaller amplitude wave V (Fig. 18-5). No
distortion product otoacoustic emissions were interpreted such components were present with acoustic stimulation.
290 NEUROTOLOGIC DIAGNOSIS

Click ABR: Right Ear Preoperative Pure Tone Thresholds

0

Hearing level in dB (ANSI-96)

95 alt. 10
CM 20
30
95 rev. 40
50
CM 60
75 rev. 70
80
90
55 rev. 100
110
Figure 18-2. Auditory brainstem responses from the right ear of a
10-month-old patient with a severe to profound hearing loss as documented 250 500 1K 2K 4K 8K
following behavioral audiometric testing. Observe the cochlear microphonic
responses in the middle two traces (95 rev. and 75 rev.) obtained by Frequency in Hz
recording ABRs using positive polarity clicks; the polarity is reversed, and
negative polarity clicks are used in the subsequent recording at 95 and then Figure 18-4. Preimplantation audiogram of a patient with a severe to
at 75 dB nHL. The cochlear microphonic is absent after further attenuation profound sensorineural hearing loss, cochlear microphonics, absent auditory
of the stimulus level (55 rev.). brainstem responses, and distortion product otoacoustic emissions. Right
ear implantation was successful.

Consequently, the EABR results indicated that electrical

stimulation was more effective than acoustic stimulation in Although this type of recording results in a very large ampli-
synchronously activating the auditory pathway for this tude response, it is an invasive method not well accepted by
patient. She received a cochlear implant at age 2. Using the a substantial proportion of patients. Noninvasive methods
cochlear implant, detection threshold levels in the 35 to are available (i.e., a gold foil “Tiptrode,” or Coats’ “Leaf”
40 dB HL range were established (Fig. 18-6), which com- electrode) but may be less efficient in providing an inter-
pared favorably with her preimplant audiometric studies. pretable response or may be uncomfortable for the patient.
Another noninvasive recording device uses a soft
hydrogel-tipped electrode placed against the lateral
ELECTROCOCHLEOGRAPHY tympanic membrane surface under direct visual control
(“TM-ECHochGtrode,” manufactured by BioLogic
The term electrocochleography refers to the recording of Systems Corp.). This electrode can provide consistent, satis-
acoustically evoked neuroelectric events generated by the factory resolution of the cochlear microphonic, summating
cochlea and the auditory nerve. Early cochlear-produced potential, and action potential. Although response ampli-
potentials and auditory nerve action potentials constitute tudes obtained with the hydrogel device are reduced when
the electrocochleographic response. compared to those obtained with a transtympanic needle
Electrocochleographic measurements may be obtained electrode, the noninvasive, comfortable nature of this
using several recording techniques. The original method recording paradigm obviates the need for a physician’s
of electrocochleographic recording involves placing a involvement in electrode placement without sacrificing
transtympanic needle electrode on the promontory. test sensitivity. Following placement, the impedance of the
electrode is measured to ascertain appropriate positioning.
The electrode is held in place with a standard, foam insert
dB transducer tip, and in our experience it is tolerated well by
60 L1
L2 patients as young as 10 and 12 years of age.
DP
40 NF

20 + III

v @4.5 msec. 800

0 uA
.25 uV III

−20 600
v uA
0.25 0.5 1.0 2.0 4.0 8.0 kHz .25 uV
Distortion-product otoacoustic emissions −
Figure 18-3. Distortion product otoacoustic emissions (see Fig. 18-2), EABR: Right Ear
and severe to profound hearing loss from the right ear of the patient with
cochlear microphonic responses in the right ear. Response strength (signal- Figure 18-5. Preimplantation electrically evoked auditory brainstem
to-noise ratio) ranges from 8 to 24 dB. DP, distortion product emission; responses from a young patient with auditory nerve dys-synchrony (see
NF, noise floor. Figs. 18-2 through 18-4).
 Objective Measures of Auditory Function 291

CI Detection Skills AP amp

ECoG
Base SP amp
0
Hearing level in dB (ANSI-96)

10
ABR v
20
30
C C
40 C C C CM
50
60
70
80 ECoG/ABR recording
90 Sensitivity and Sweep Time/Division
100 ECoG: 1.24 uV 1.0 msec
110 ABR : 1.24 uV 1.0 msec
CM : 0.31 uV 1.0 msec

250 500 1K 2K 4K 8K Figure 18-7. Two-channel recording consisting of electrocochleographic

and auditory brainstem responses (top two traces); the lowermost tracing is
Frequency in Hz
the cochlear microphonic response to a tone burst stimulus with no dis-
cernible summating potential.
Figure 18-6. Postactivation implanted sound-field pure tone thresholds
from a 2-year-old patient with auditory nerve dys-synchrony (see Figs. 18-2
through 18-5).
mechanical characteristics of the basilar membrane and
Electrocochleography consists of the following contributes to the increased amplitude of the SP considered
components: to be diagnostic of endolymphatic hydrops.19
In order to reduce interpatient variability, the ratio
1. The cochlear microphonic (CM), an alternating
between the amplitude of the SP and the AP (SP/AP ratio)
current (AC) potential that closely resembles the wave-
is employed instead of measuring the absolute amplitude
form of the acoustic stimulus and reflects changes in
of the SP.20 Owing to the increase of the SP amplitude
the resistance of the outer hair cells during stimulation.
associated with endolymphatic hydrops, patients are
To obtain a cochlear microphonic, click or tonal stim-
expected to exhibit larger SP/AP ratios. In a study of subjects
uli must be delivered in a constant polarity fashion.
with normal hearing for age,21 SP/AP amplitude ratios
2. The summating potential (SP), a direct current (DC)
recorded extratympanically ranged from 0.04 to 0.59. Other
potential that follows the stimulus envelope, appearing
studies have found similar values of the ratio in normal-
as a baseline shift of the recorded cochlear micro-
hearing patients. Using transtympanic recordings, Gibson
phonic. It arises from DC intracellular potentials
and colleagues22 calculated SP/AP ratios that ranged from
generated by hair cells. To resolve the SP better, stim-
10% to 63%. However, the sensitivity of this measurement
uli must be delivered in an alternating polarity fashion;
appears limited because an overlap exists between SP/AP
otherwise, individually obtained condensation and rar-
ratios of patients with (nonhydropic) cochlear hearing loss
efaction responses are summed to cancel out the
and patients with classic symptoms of endolymphatic
cochlear microphonic.
hydrops. Coats and colleagues23 found that 44% of
3. The eighth nerve action potential (AP) is the equivalent
Ménière’s ears tested fell under the 95% upper limits of
to wave I of the ABR, reflecting the summed activity
normal ears. This translates into a sensitivity of only 56%,
of synchronously firing cochlear nerve fibers.
reflecting the fluctuant nature of hydropic conditions.
We recommend the following recording technique: prior Increased amplitude of the SP/AP ratio is not limited to
to placement of the tympanic membrane surface electrode, hydropic conditions. Marangos and colleagues24 reported
self-adhering surface electrodes are placed in the midline of increased SP/AP amplitude ratios in patients with CP
the forehead just below the hairline, and on each mastoid. angle tumors. Therefore, caution should be exercised to
This allows one to simultaneously record an electro- avoid the missed diagnosis of CP angle tumors that may be
cochleogram (ECoG) from the ear with the tympanic associated with increased SP amplitude. A normal SP/AP
membrane (TM) electrode as well as an ABR wave V from amplitude ratio does not rule out endolymphatic hydrops
the contralateral side. Clicks of alternating or constant and an increased ratio should be considered a supportive,
polarity and tone burst stimuli are presented at an intensity but a nonpathognomonic finding of hydrops.
of 85 dB nHL or greater if the patient has a substantial The following clinical criteria for electrocochleography
hearing loss. One or two kilohertz (kHz) tone bursts have a are used in our clinic: SP/AP ratio exceeding a value of
5-millisecond rise time and a 10-millisecond plateau. 0.40 with click stimuli; summating potential amplitude for
Figure 18-7 shows a click-evoked ECoG with well-defined tone burst stimulation of 2 microvolts or more. The N1
SP and AP components (top trace), a contralaterally recorded (or AP) component condensation-versus-rarefaction click
ABR with the wave V marked, and a tone burst ECoG latency difference has not been used systematically in
consisting of a cochlear microphonic with no discernible SP. our clinic.25 If it is used, a difference greater than
Electrocochleography is used most as a neurotologic 0.38 milliseconds (condensation latency is greater than
diagnostic aid in identifying cochlear hydropic conditions rarefaction latency) is considered abnormal. The electro-
associated with Ménière’s disease and other cochleopathies. cochleography criteria are based on the following clinical
It is thought that the presence of hydrops alters the assumptions: In the presence of hydrops, a distended scala
292 NEUROTOLOGIC DIAGNOSIS

media results in an increase of the negative SP amplitude

AP amp
and in a possible increase in cochlear microphonic and
cochlear nerve AP thresholds. Additionally, in more
advanced disease the amplitude of the AP may be reduced. SP amp
The increase in the amplitude of the negative SP alone or
in combination with a decrease in AP amplitude is the LE: 0.3
underlying cause for the increased SP/AP amplitude ratio Base
AP amp
for clicks. With tone burst stimuli, an increase in SP
amplitude appears as a shift of the cochlear microphonic
baseline, which indicates an increase in SP amplitude. SP amp
A 42-year-old woman came to our clinic with a 5-year
history of episodic vertigo, progressive right ear hearing
RE: 0.6
loss that fluctuated, and right-sided tinnitus and aural Base
pressure. Figure 18-8 illustrates her audiogram character-
ized by normal hearing in the left ear and a moderate, low-
frequency sensorineural hearing loss in the right ear with
minimally reduced word recognition scores. She under- ECoG: SP/AP<Rt. side
went an electrocochleographic evaluation. Both clicks and Figure 18-9. Electrocochleographic responses from a 42-year-old woman
1000-Hz tone bursts were used as stimuli. As illustrated in with unilateral hearing loss (see Fig. 18-8). The summating potential (SP) to
Figure 18-9, she presented with a normal SP/AP ratio of action potential (AP) amplitude ratio is beyond the normal limit of 0.4 when
measured from the right ear.
0.3 in her left, nonsymptomatic ear and an elevated SP/AP
ratio of 0.6 in the symptomatic right ear. Also, as illus-
trated in Figure 18-10, her tone burst electrocochleogra- Electrocochleography may also be used as an objective
phy was characterized by a prominent SP with amplitude indicator of treatment efficacy. This is illustrated by the
of approximately 2 microvolts in her right ear (top trace) following case involving a 55-year-old patient with a several-
as opposed to a barely measurable SP with the same stim- year history of left-sided Ménière’s disease. Over the years,
ulus in the left ear (lower trace). The increased SP ratio on he had been treated conservatively with low-sodium diet
the right side as well as the large amplitude SP obtained and diuretics; however, he continued to have spontaneous
with tone burst stimulation helped confirm a diagnosis of vertiginous episodes and fluctuating low-frequency hearing
Ménière’s disease in her right, symptomatic ear. Notably, loss. He was seen in our clinic, where he received a pressure
the caloric test results obtained during the patient’s equalization tube placed in the left tympanic membrane in
vestibular evaluation showed a reduced caloric response in preparation for treatment with the Meniett device
the right ear compared to the left but in absolute terms still (Medtronic Xomed). This device is recommended to alle-
within normal limits. Consequently, the interpretation was viate symptoms of Ménière’s disease and it delivers brief
“paretic lesion in the right ear or an irritative lesion in the pressure pulses through a tympanometry-like ear tip placed
left ear.” The presence of abnormal electrocochleography into the ear canal. For some patients this type of treatment,
in conjunction with right ear symptoms helped determine which is recommended 3 times a day for 5 minutes, results
the laterality of the disease. in both subjective and objective changes.26 Figure 18-11
illustrates pre- and post-treatment click-evoked electro-
cochleography obtained within a 4-month interval. The
0 figure illustrates a normalization of the SP/AP ratio
10 from a value of 0.7 to a value of 0.34. It is of note that the
dB (ANSI S 3.6, 1996)

20
30
40
50 RE
60 SP
70
80
90 LE
SRT %
RE 30 92
LE 05 100
1.2 uV
250 500 1,000 2,000 4,000 8,000 2 msec
Frequency in hertz (Hz)
ECoG: CM on large SP, RE
Figure 18-8. Audiogram of a 42-year-old woman with right ear hearing loss,
tinnitus, and aural pressure. Normal pure tone thresholds are present in the Figure 18-10. Tone burst-evoked electrocochleography reveals a prominent
left ear and a moderate lower frequency hearing loss in the right ear; speech summating potential from right ear responses (top trace); combined with an
audiometrics are compatible with the pure tone information. SP/AP ration of 0.6, it helped to confirm Ménière’s disease.
 Objective Measures of Auditory Function 293

AP amp Janetta28 localize the neural generators of ABR wave peaks I

SP amp
through V to the auditory pathway between the cochlear
Base
nerve and the nucleus of the lateral lemniscus in the mid-
Pre: 0.7 brain. Waves I and II are generated by activity at the distal
AP amp and proximal cochlear nerves, respectively. The presence
SP amp of two action potentials originating from activity within
Base the same cranial nerve is attributed to a transition in nerve
Post: 0.34 fiber covering from the central neuroglial cells to the
peripheral Schwann cell endoneurium at the segment of
ECoG: pre- v. post-treatment the auditory nerve nearest the porus acusticus. Near-field
recordings enhance both waveform peaks, as seen in
Figure 18-11. Electrocochleography results from a patient treated with
a Meniett device (Medtronic Xomed) for Ménière’s disease. Note the
electrocochleography.
increased amplitude of the action potential (AP) in the post-treatment Activity in the cochlear nucleus and in the superior olivary
condition. A delay in the absolute latencies of responses in the lower trace is complex is represented by ABR waveform peaks III and IV,
due to a pressure equalization tube in the left tympanic membrane. respectively. Moller and Janetta28 reported that waveform
peak V reflects activity in the lateral lemniscus. Neural
activity in the area of the inferior colliculus corresponds
amplitude of the AP is increased in the post-treatment temporally with the post-wave V negativity recorded on
waveform. The post-treatment latency is slightly delayed the scalp. Waveform peaks IV through VI are highly complex
with respect to the treatment latency owing to the pres- and probably reflect multiple neural generator activity.
ence of the PE tube. Acoustic stimuli used to evoke the ABR include wideband
clicks and tone bursts and are delivered via insert or supra-
aural earphones or a bone-conduction transducer. Clicks
AUDITORY BRAINSTEM RESPONSE are brief rectangular pulses of constant or alternated polarity,
while tonal stimuli may be characterized as sinusoidal
The ABR is the averaged surface-recorded activity from signals with brief rise, fall, and plateau durations. To be
multiple-source neural generators in the peripheral and effective in evoking a response, the intensity level of the
lower central auditory nervous system and represents the acoustic stimuli must lie within a patient’s dynamic range.
synchronous discharge activity of onset-sensitive single Therefore, patients with severe to profound hearing
units from first- through sixth-order neurons (Fig. 18-12). losses are less likely to have an ABR. In order to ensure
The high-intensity ABR is characterized by five or more that the highest-quality ABRs are recorded, stimulating
waves, the positive peaks of which are conventionally and recording parameters are carefully adjusted for the
labeled with Roman numerals.2,27 Studies by Moller and patient’s hearing levels (Table 18-1). Therefore, audiologic

Primary
auditory Medial
cortex geniculate
body Probable ABR Generators:
Wave I Distal auditory nerve
Wave II Proximal auditory nerve
Wave III Cochlear nucleus
Wave IV Superior olivary complex
VI Inferior Wave V Lateral lemniscus
colliculus Wave VI Inferior colliculus
Dorsal V
cochlear Nucleus I III
nucleus of lateral
lemniscus IV
V
Ventral II
VI
cochlear III IV
nucleus
II

I
Superior
Trapezoid body olivary
nucleus
Figure 18-12. Probable auditory brainstem response generators and associated waveform peaks. [Adapted with permission from Olsen WO: Special auditory
tests. In Jacobson JT, Northern JL (eds.): Diagnostic Audiology. Austin, TX: Pro-ed, 1991, p 38.]
294 NEUROTOLOGIC DIAGNOSIS

TABLE 18-1. Selected ABR Parameters for Neurodiagnostic

and Hearing Estimation Investigations
Neurodiagnostic Hearing Estimation

Stimulus type* Click, 1-kHz tone burst Click; 0.5 to 2-kHz

tone burst 20–250 Hz
Stimulus rate† 21.1/sec 31.1/sec
Stimulus rise, fall time‡ Click: NA; tone: 2-0-2 Click: NA; tone: 2-0-2
Number of sweeps 2000–3000 1200–4000
Intensity (or range) 75–95 dB nHL 05–95 dB nHL
Stimulus delivery§ Insert earphone Insert, supra-aural,
bone-conduction
transducers 20–1000 Hz
Bandpass settings (Hz) 100–3000 20/30–3000 Hz
Amplification × 100 k × 100 k
Analysis duration 15 msec 20–25 msec
v
III
*Alternating polarity used for neurodiagnostic testing to reduce spread of stimulus
artifact into recording; single polarity clicks useful to visualize cochlear microphonic in I
auditory neuropathy/auditory dys-synchrony.
†
Rate, number of averages increased in studies of the effects of demyelinating disease.
20–3000 Hz
‡
Rate lowered for bone conduction measurements to reduce vibrotactile spread of
stimulus. Ramping for 2 kHz tonal stimuli changes to 2-1-2.
§
Appropriate transducer is selected for routine testing or for patients with atretic ears and 0.31 uV
the like.
1.5 msec

assessments should be conducted before neurodiagnostic

ABR testing. Figure 18-13. ABR waveforms reflect alterations in bandpass filter settings.
The ABR is a far-field representation of responses along Note the slow-wave component of the ABR in the uppermost ABR tracings,
upon which wave peaks ride; second, observe improved clarity of waveform
the auditory pathway. The term far-field indicates that peaks once the high-frequency cutoff reaches or exceeds 1000 Hz, confirm-
recording electrodes do not directly contact anatomic gen- ing ABR dependence on relatively low-frequency energy.
erators. There are at least two deleterious effects of recording
electrical potentials from the scalp. First, far-field recordings
are less robust, partly due to the distance between generator amplifier gain.29 The capacity for common mode signal
site(s) and recording site. Second, other sources of electrical rejection depends largely on preparation, that is, the
noise may obscure the ABR. Such “competing” electrical physical layout of the test area in relation to devices
signals may have electroencephalographic, electrocardiac, that generate electrical fields, the shielding of the
or electromyographic sources, or they may originate from measurement channel(s), and the quality of compo-
electrical devices in or proximal to the test location or nents such as leads used to record responses.
from an essential medical monitoring device such as a 3. Signal averaging, which is important for measurement
pulse oximeter. Unless properly controlled and canceled, of low-amplitude, repetitive responses time-locked
the competing electrical potentials can easily diminishing with a precise trigger source (synchronized response
ABR waveform quality. summing); the amplitude of unsynchronized noise
Optimizing the electrode sites via thorough cleansing diminishes with successive averaging, decreasing by
and gentle abrasion techniques is crucial. So, too, properly the square root of the number of sweeps resulting in
selected recording parameters enhance the ABR recording. a signal-to-noise ratio above unity. Larger response
For example, the ABR consists of energy in a specific band. amplitudes are obtained with greater stimulus intensity
Bandwidth filters set to record responses in the approximate and generally require fewer averages. Approximately
frequency range 20 to 3000 Hz provide a high-quality 1500 to 2500 samples typically produce adequate
recording that includes all waveform peaks (Fig. 18-13). In signal-to-noise ratios. Figure 18-14 demonstrates the
the figure, note that relatively smaller changes are evident improvement in ABR waveform morphology that can
after opening bandpass settings beyond 20 to 1000 Hz, be expected when additional sweeps are included in
attesting to the dependence of the ABR on energy at or the averaging process.
below 1000 Hz.
Investigators have used four-channel recordings to more
Several technological tools exist that allow an examiner to
accurately identify individual components of the ABR in
extract electrophysiologic target responses from competing
patients who have intracranial injuries30 or acoustic nerve
noise. These include the following:
tumors.31 In the latter report, the investigators used
1. Differential amplification, which functions by reject- Tiptrode ear canal reference electrodes and reported that of
ing voltages with equal or common amplitude and the four recording choices, the ipsilateral record afforded
phase at positive and negative inputs, referenced to the best neurodiagnostic information. Presumably, this
ground; then, the remaining difference in voltage at reflected the somewhat “nearer-field” recording of ABR
those two inputs is amplified. This process is known responses, adding to the amplitude of individual com-
as common mode rejection. ponents and leading to improved signal-to-noise ratios.
2. The ratio of common mode noise rejected, specified A four-channel ABR was obtained at 80 dB nHL from a nor-
in decibels; larger decibel ratings indicate better mal-hearing subject in order to demonstrate the capacity for
 Objective Measures of Auditory Function 295

contralateral channel, and the enhancements of peaks III

and V in the horizontal and vertical channels, respectively.
The amplitude of waveform peak V in the vertical channel
is more than four times that recorded in the horizontal
channel owing to the presumed orientation of the respective
v dipole vector for wave peak V. The authors have found
125 clicks that appropriate control of the recording montage is very
useful in neurodiagnostic ABR measurements, particularly in
the case of patients with moderate to severe high-frequency
sensorineural hearing losses.
III v
In summary, the ABR reflects activity from multiple
500 clicks generators along the auditory pathway in response to various
acoustic stimuli. Stimulus and recording parameters should
be optimized to provide a record of the neurophysiologic
function of the auditory nerve based on the results of a
v concomitant audiologic assessment. Importantly, ABR wave-
III
I 2,000 clicks form morphology is affected by mass lesions on or near the
auditory nerve. Neurologic lesions that are manifestations
of demyelinating disease also affect ABR recordings by
0.31 uV desynchronizing spike propagation along the myelinated
auditory pathway. Thus, the ABR can be a good neurophys-
1.5 msec
iologic indicator of auditory nerve and auditory brainstem
functional integrity.
Figure 18-14. ABR signal-to-noise ratio increases and morphology improves as
sweeps are added to the averaged response. Note that wave V may be seen with
as few as 125 clicks presented. In neurodiagnostic ABR evaluation, additional DETECTION OF HEARING LOSS USING
averaging is required to facilitate wave peak identification (2000 clicks). THE AUDITORY BRAINSTEM RESPONSE
enhancing individual components of the neurodiagnostic Newborns and infants are incapable of participating in
ABR, leading to more precise measurements and reporting behavioral hearing evaluations to the extent that detailed
(Fig. 18-15). The recording employed ipsilateral, contralat- ear-specific information cannot be obtained until children
eral, “horizontal,” and “vertical” references simulta- are 2 to 4 years old.32 Given a mandate that calls for early
neously; note the absence of waveform peak I in the identification of congenital or early-onset hearing loss by
several months of age,33 the ABR becomes an ever more
important part of the collection of clinical instruments that
audiologists use to estimate the magnitude and type of
III v
hearing loss in children. ABR has similar value in the esti-
I
mation of peripheral hearing sensitivity in noncompliant,
Cz-A2 (ipsilateral)
II IV older patients.
Attenuated stimulus levels produce ABRs with
decreased amplitude and prolonged absolute latencies.
Figure 18-16 demonstrates that ABR wave V typically has
the largest amplitude and is more easily identified as stim-
Cz-A1 (contralateral)
ulus levels diminish, making wave V the most useful wave-
form component for estimating ABR thresholds. By
convention, in the clinical setting ABR recordings are
replicated to ensure proper identification of waveform
A1-A2 (horizontal) components. Manufacturers of electrophysiology equipment
offer software that computes correlation coefficients as
statistical representations of replicability, and single-point
F ratios (Fsp) can be measured to assist in describing the
variances of two ABR samples. Making use of such statistical
Cz-C2 (vertical)
measures helps to enhance clinical descriptors (“good,”
“fair,” or “poor” waveform morphology) typically used in
0.31 uV
reporting ABR results.
The ABR as a carefully used hearing screening instrument
1.5 msec
in the well-baby unit or in the neonatal intensive care unit
can be valuable using either automated, default protocols
or operator-controlled parameters. Delivering low-intensity
Figure 18-15. Four-channel ABR recorded at 80 dB nHL from a normal-hear-
ing female using reference electrode at ipsilateral and contralateral earlobes
stimuli monaurally, it aids in the eventual detection of uni-
and at the second cervical vertebra; note differences in amplitude and lateral and bilateral mild or greater hearing losses.34
absolute latency of waveform peaks throughout this four-channel recording. Relative to other measures such as otoacoustic emissions,
296 NEUROTOLOGIC DIAGNOSIS

Alternating click 500 Hz toneburst as well as the desire to more closely approximate the behav-
v v ioral audiogram for precise amplification fitting. Lower-
I III (70) (55) frequency hearing estimates via the click ABR are less
predictable.41 So-called ramped tonal stimuli have longer
v v
(20) (45) temporal characteristics (on and off times as well as plateau
duration) and reflect the activity of fewer neural fibers.42
v v
(10) (35)
The morphology of the tonal ABR waveform is dissimilar
to click-evoked responses, reflecting fewer contributing
(05) (25) neural elements and a more apical orientation in its gener-
ation along the basilar membrane. Absolute latencies of
0.31 uV tonal ABRs are prolonged and amplitudes may be reduced
2.0 msec
(see Fig. 18-16). Extended averaging will result in improved
Auditory brainstem responses morphologic characteristics such as improved signal-to-
noise ratios and more distinct waveform peaks while pro-
Figure 18-16. Grand averages of multiple recordings of a right ear ABR
using click (left panel ) or 500-Hz tone burst (right panel ) auditory stimuli.
viding averaged results that are better suited to threshold
The latencies of the responses to tonal stimuli are prolonged relative to the determination.
click ABR responses, and tonal amplitudes are reduced as well. As alluded to earlier, the impetus to establish universal
hearing screening and provide appropriate, comprehensive
habilitation propels the desire to record frequency-specific
the technique has higher sensitivity and associated costs, ABRs. Appropriately programmed amplification will be fit
requires a more sophisticated and experienced operator, to newly identified hearing impaired infants. There are
and limits screening statements to higher-frequency hearing. numerous methodologies for tonal ABR evaluation and
“Refer” results mandate rescreening with ABR or otoa- Hyde43 summarized many of them. For example, a spectrally
coustic emissions. Based on the outcome, diagnostic evoked constrained transient stimulus with a nominal center fre-
potential testing may be needed. quency is delivered to the test ear; masking may be used in
Click-evoked ABR threshold testing continues to be a the contralateral ear. It is useful to know how much side
common procedure, despite the significant limitations asso- band energy is present above and below the center fre-
ciated with use of transient stimuli.35 Investigators continue quency. Nonlinear gating functions (e.g., Blackman, cosine
to search for protocols that produce threshold results that square) help to attenuate side band energy characterized
simulate the “speech-frequency band,” that is, 0.5 to 2 kHz by approximately 30 dB of attenuation within one octave
of the audiogram. Retrospectively, click threshold results from the nominal center frequency (Fig. 18-17). However,
have been found to correlate best with high-frequency differences in results obtained using various gating strategies
thresholds near 2000 Hz.36–38 These findings are partially may be less than expected. Purdy and Abbas44 reported
attributable to changes in the frequency and amplitude 2-kHz and 4-kHz tone burst ABR thresholds exceeded
characteristics of broadband, rapid-onset stimuli that are behaviorally elicited thresholds by 10 to 13 dB using either
delivered to the diminutive, pliable infant ear canal via linear or Blackman gating. This investigation emphasized
an insert transducer through 26 centimeters of flexible, the importance of setting appropriate filter bandwidths
polyethylene tubing. when using tone burst stimuli; that is, appropriate low-
Gorga and colleagues39 compared click-evoked ABR frequency weighting must be a recording parameter choice
threshold and latency characteristics to pure tone audio- when using tone burst stimuli with a center frequency
metric findings in normal-hearing (N = 22) and sen- below 1000 Hz.
sorineural hearing impaired subjects (N = 194). The latter
group was composed of 125 people with high-frequency
configurations of hearing loss, while the remaining 69
people had flat hearing loss. These investigators reported
that when comparing ABR thresholds to audiometric data,
agreements between those two indices were highest when
audiometric test frequencies were 2 kHz and 4 kHz (r = 0.75 2.031 kHz
and 0.73, respectively). Correlations to pure tone thresholds
at 1 kHz and 8 kHz were poorer (0.65 and 0.6, respectively).
Behavioral thresholds at frequencies below 1 kHz were not
analyzed in this report. A normal threshold ABR result,
based on the use of click stimuli, should be carefully
reported suggesting that (a) normal hearing exists in the
approximate frequency range of 1 to 4 kHz in the test ear
or that (b) an island of normal hearing resides in that same
frequency range.40
While broadband click stimuli are used to perform ABR 31.25 Hz 3.156 kHz 6.281 kHz
during hearing screening and in subsequent hearing
Figure 18-17. Spectral waveform of a Blackman-gated tone burst with a
threshold estimation, tonal stimuli are used with ever center frequency equal to 2031 Hz used in ABR frequency-specific estimates
greater regularity. This is due to the recognition of certain of hearing sensitivity. Sideband energy peaks were −28 dB relative to peak
inherent limitations associated with the use of click stimuli energy at 2031 Hz.
 Objective Measures of Auditory Function 297

The efficiency with which tonal ABR thresholds predict that aim to develop an objective clinical technique to
behavioral audiometric thresholds continues to be scruti- gauge aided benefit better in very young patients.
nized. Stapells45 performed a meta-analysis of the literature Many investigations have analyzed the use of the ABR as
concerning air conducted tone-evoked ABR testing in an objective measure of amplification benefit for infants
children and adults. Thirty-two investigations were vis-à-vis the absolute latency of ABR wave V referenced to
reviewed, representing the results from 1203 subjects normal listeners.47 Although transient clicks have been
including 388 subjects with sensorineural hearing loss. He shown to have a role, tonal stimulus artifacts contaminate
reported that tonal ABR thresholds in normal listeners evoked responses,48 and an inability to describe changes in
ranged from 10 to 20 dB nHL. In the group of hearing- evoking stimuli by amplification has presented challenges.
impaired subjects, tonal thresholds were 5 to 15 dB higher Further, the failure of click-evoked ABR to adequately
than behavioral thresholds in adults and were ± 10 dB than define lower-frequency gain49 and demonstrate the utility
behavioral thresholds in infants. The use of the tone- of compression circuits in hearing aids50,51 has curbed
evoked ABR was strongly encouraged. In a retrospective investigational interest.
study that compared behavioral pure tone and electro- Despite these hurdles, objective techniques continue to
physiologic thresholds, Edwards and colleagues46 reported be examined to determine their role in assessing aided
that a combination of click, 0.5 kHz, and 1.0 kHz frequency benefit. For example, Purdy and Kelly52 reported that the
tone burst thresholds, when averaged and given one of cortical auditory evoked potential (CAEP)53 might be
four data set assignments reflecting average thresholds effective during hearing aid assessments by using speech
from normal to severe, compared favorably to similarly stimuli. Until approximately 7 years of age, a large, late P1
ranked behavioral assignments. They reported that despite response dominates the CAEP and may help to demonstrate
a 100% incidence of recurring otitis media, a combination the benefits of amplification in youngsters reported by
of air- and bone-conducted ABR testing produced results Rapin and Graziani54 and Gravel and colleagues.55 With
with good predictive value for identifying both type and inherently higher face validity than tonal stimuli, longer
magnitude of hearing loss. Notably, the data were skewed duration speech stimuli (cumulative durations of 30 to 75 ms,
toward moderate and greater degrees of hearing loss, onset duration longer than 10 ms) might also better assess
reflecting the common hearing status of multiply involved the utility of compression circuitry, broadening the scope
children with CHARGE syndrome. of hearing aid assessment56 and may help to moderate several
Several salient points must be considered when comparing of the technical difficulties mentioned earlier such as stim-
electrophysiologic and behavioral test results. They ulus ringing and an inability to demonstrate input-output
include the following: characteristics of an amplification device.
Auditory steady-state responses (ASSRs) are elicited by
1. Significant differences in calibration methodologies
amplitude-modulated tones that are common in infants
for electrophysiologic and audiometric tonal stimuli
and unaffected by sleep.57 Multiple tones can be presented
2. Discrepancies between ABR stimulus intensity as
simultaneously to each ear for threshold testing, while
“set” on test equipment versus the actual output
amplitude-modulated tones transduced through free-field
measured in the ear canal (particularly in younger
speakers resist distortion, making them ideal stimuli for
patients with small volume ear canals), which can lead
assessing aided hearing. Picton and colleagues58 sought out
to underestimation of actual ABR stimulus intensity
aided threshold responses using ASSRs in a group of 35
3. The possibility of fluctuating or progressive hearing
older children with hearing impairment. One goal of the
loss, as in patients with large vestibular aqueduct
study was to compare ASSRs and behavioral thresholds in
syndrome or those with a genetic predisposition for
developmentally advanced children in order to be able to
progressive hearing loss
estimate the predictive ability of ASSR results for very young
4. Spectral differences between electrophysiologic
children and others who would not be able to offer behav-
stimuli, particularly brief, broadband clicks, and audio-
ioral responses. The investigators discovered that
metric thresholds38
amplitude-modulated ASSR stimuli provided more fre-
quency specificity than ABR click or tonal stimuli, and
reported physiological-to-behavioral differences of 13 to
17 decibels (+/− 8 db) at 0.5, 1.0, and 2.0 kHz for the group
ESTIMATING AMPLIFICATION BENEFIT: of aided, cooperative children. Picton’s group suggested
ELECTROPHYSIOLOGIC PROCEDURES that responses to such amplitude and frequency-
modulated stimuli might better evaluate aided speech
The early provision of appropriately fitted amplification is perception processes while determining both audibility
a worthy goal toward which hearing professionals strive. and discrimination ability.57
Unfortunately, until newborns and infant children achieve
developmental levels that allow one to obtain reliable and
valid behavioral test results, “appropriately fitted amplifi- ACOUSTIC NEUROMA DIAGNOSIS WITH
cation” is an objective reached via a combination of care THE AUDITORY BRAINSTEM RESPONSE
provider observation and subjective scaling measures.
Prescriptive fitting measures based on electrophysiologic Mass lesions of the retrocochlear pathway are thought to
data are helpful for managing multiple amplification char- produce ABR abnormalities through pressure on, displace-
acteristics but do not functionally describe the effect of the ment of, or attenuation of the auditory nerve or auditory
intervention on hearing sensitivity. Thus, efforts continue brainstem. Depending on its volume and location, a mass
298 NEUROTOLOGIC DIAGNOSIS

in proximity to retrocochlear auditory structures may atten- When wave I is not attainable, the absolute latencies of
uate, delay, or abolish certain ABR waveform components. wave V should be determined bilaterally, and interaural
This model for ABR interpretation may be applicable in differences (ILD-V) calculated. Hearing impairment,
cases where tumor involvement with the auditory pathway whether conductive, cochlear, or retrocochlear, prolongs
is discrete and when preexisting hearing thresholds are wave V latency.
normal. However, these principles frequently may not In the presence of a hearing loss, ILD-V is interpreted
apply because of preexisting pathology leading to extensive with consideration given to the magnitude of the hearing
interplay between brainstem components in processing loss at 4 kHz. Appropriate adjustment of wave V latency
auditory stimuli.59,60 Therefore, use of the ABR for diagnos- diminished the false-positive rate from 24% in the uncor-
tic purposes mandates consideration of other supporting rected condition, to 8% of a group of 266 patients with
audiologic information. unilateral sensorineural hearing loss. In a group of 94 con-
A good example is provided by the absence of an ABR in firmed cases of acoustic neuroma, the same correction for
an ear with a severe hearing loss. If an inadequate stimulus hearing loss at 4 kHz produced a false-negative rate of 2.3%
level is used to generate electrophysiologic responses, test (3 patients).61 Rosenhamer and colleagues62 recommend an
results may be misinterpreted inappropriately and elevate adjustment of 0.1 ms/10 dB increment in hearing threshold
one’s index of suspicion for an eighth nerve or brainstem above 30 dB at 4 kHz.
lesion. Clearly, the ABR should be evaluated with suitable The audiometric configuration has been shown to influ-
attention paid to the patient’s hearing levels at the time of ence the I–V interpeak latency. Keith and Greville59 found
the test. Accordingly, cochlear dysfunction can often be increased I–V interpeak latencies in patients with notched
compensated to enhance the accuracy in the ABR-directed high-frequency hearing loss in the absence of CP angle
assessment of the auditory pathway. lesions. This probably reflects the greater role assumed by
Differential diagnosis based on the ABR involves a high-frequency generators in producing wave I relative to
strategy that considers several characteristics of evoked those responsible for wave V. The I–III interpeak latency
waveforms. This “hierarchy of analysis” assesses the overall is influenced to a lesser extent by cochlear hearing loss.
configuration of the response and its composing waves in Moreover, the most reliable ABR manifestation of an
the context of the hearing status. acoustic tumor appears to be an increase in the I–III
The first step in the analysis is to determine the presence interpeak latency on the affected side.63,64 This interval is
or absence of an ABR evoked by an appropriate stimulus. therefore recommended for neurotologic diagnostic appli-
For instance, in the presence of severe to profound hearing cations whenever these peaks are available.
impairment at frequencies exceeding 500 Hz, morpholog- When the lack of definition of the ABR obtained with
ically defined responses to 75 dB nHL clicks are not clicks prevents measurement of interpeak latencies, narrow-
anticipated. band tonal stimuli may take advantage of lower thresholds
The second level of ABR analysis verifies the presence of at specific frequencies. To use lower thresholds at 1000 Hz
all major composite peaks and their replicability. If the in evoking the ABR, 1000-Hz tone pips can supplement
recorded waveforms are of sufficient technical quality, the the click-evoked ABR. Suggested parameters for 1000-Hz
following characteristics apply: tone pips include gating with a nonlinear function
(Blackman) using a 1-ms rise-fall time and a very brief
1. Wave V should stand out as the most robust of the
plateau (100 ms).
ABR components in normal-hearing subjects and the
In selected cases, Telian and Kileny65 found the use of
most resilient component in patients with cochlear
1000-Hz tone pips helpful in circumventing the effects of
pathology, with threshold preserved at or near behav-
elevated thresholds in the 2000 to 4000 Hz range on the
ioral threshold levels.
click-evoked ABR. Of 17 patients with surgically confirmed
2. Wave I is less robust and its morphology fails to
acoustic neuromas, 15 of which presented with sloping
resolve at stimulus levels below 40 dB SL. An absent
high-frequency SHL, reliable evidence of retrocochlear
or poorly resolved wave I (with waves III and V pres-
involvement could be made from the click-evoked ABR in
ent) with moderate to severe sensorineural hearing
only 5 cases based on abnormal interpeak latencies and
loss carries little implication for retrocochlear function;
ILD-V. In two patients, wave V was the only replicable and
however, the absence of waves III or V, or both, with
identifiable component for both clicks and 1000-Hz tone
a robust and well-defined wave I is highly sugges-
pips, and the diagnosis of retrocochlear involvement.
tive of auditory brainstem impairment. Absence of
Some of these were cases where click responses were
components beyond wave I can occur in cases
absent and the diagnosis was based on the significant pro-
of acoustic neuroma with or without significant
longation of wave V latency for tone pips. In other cases,
hearing loss.
despite the fact that the ILD-V for clicks normalized after
The third level of ABR interpretation measures the correcting for hearing loss at 4000 Hz as recommended by
latencies of waveform peaks and intervals between peaks, Selters and Brackmann,61 the ILD-V for tone pips was
provided the morphology of the response permits. I–III significantly prolonged in spite of symmetric hearing
and III–V interpeak latencies are measured and compared sensitivity at 1000 Hz.
with normative data. Normative data are plotted as a fre- Recently, the auditory brainstem response has come
quency distribution that incorporates standard deviation under scrutiny for the detection of small acoustic neuromas;
intervals. I–III and III–V latencies are classified as normal that is, sensitivity has been reported to range from 63% to
if the values fall within the 95% confidence interval for 93%. A recent study66 reported on 25 patients with surgi-
mean latencies. cally proven small acoustic neuromas measuring 1 cm or less.
 Objective Measures of Auditory Function 299

The ABR was abnormal in 92% of patients in this series. Our Mangham69 investigated the performance of ABR with
data shows that when using optimal technique including the and without sinusoidal harmonic acceleration testing. The
combination of click- and tone-evoked ABR, the ABR sensi- study included 74 patients with acoustic tumors and
tivity for small acoustic neuromas can be increased to a clin- 78 controls. ABR testing outperformed harmonic acceler-
ically acceptable 90+%. Like other diagnostic tests, the ABR ation alone or in combination with the ABR and proved
is only as good as the operator and the interpreter. This is to be more cost-effective than a protocol that included
also true for imaging studies with a theoretical sensitivity both ABR and sinusoidal harmonic acceleration. When
approximating 100%; however, poor imaging quality or the Selters and Brackmann61 criterion for ABR positivity
interpretation error can alter this high sensitivity. (ILD = V > 0.2 msec) were applied, the sensitivity of the
A novel approach to diagnosing small acoustic neuromas ABR testing alone was 94% and its specificity was 79%. In
with the ABR was developed by Don and colleagues.67 a hypothetical case with a posterior probability for an
These investigators coined the concept of the “stacked acoustic tumor of 0.01, an ILD-V of 0.2 msec increases
derived-band ABR.” The diagnostic criterion here is the the probability of an acoustic neuroma to 0.047. The
amplitude of a reconstructed auditory brainstem response probability of a tumor increases monotonically until the
from the sum of click-evoked ABRs obtained with different ILD-V reaches a value of 0.7 ms, the point at which
ipsilateral high-pass filtered noise. By embedding clicks in there is little increase in the posterior probability for a
high-pass filter noise with different cut-off frequencies, tumor.
ABRs are generated that represent different, specific fre- Based on data collected in normal subjects and confirmed
quency regions along the basilar membrane. Responses cases of acoustic neuroma in the Audiology Clinic at the
within this set have different latencies dictated by place of University of Michigan Medical Center, criteria for a
stimulation along basal and more apical basilar membrane. positive test result are as follows:
Those obtained from the more apical regions have a
I–III > 2.3 msec; III–V > 2.1 msec;
longer latency than those obtained from the basal region.
I–V > 4.4 msec; ILD-V > 0.4 msec;
Averaged responses are realigned and summed to obtain a
ILD-V (1-kHz tone burst) > 0.60 msec.
reconstructed grand average. Don and colleagues found
that the amplitude of the reconstructed ABR was sensitive For several years, the authors have evaluated the neuro-
to the presence of small acoustic neuromas; that is, it was diagnostic applications of tonal or frequency-specific ABR.
reduced when compared to normal ears with no acoustic Previously, we investigated the feasibility of using 1-kHz
neuroma or to the contralateral ear of a patient with a uni- tonal ABR in normal-hearing subjects and in patients with
lateral acoustic neuroma. These investigators surmise that high-frequency hearing loss beyond 1 kHz.
summing the ABRs obtained from different regions along A comparison of wave V latencies between these two
the basilar membrane provides the total neural-synchronous groups indicated an absence of statistically significant
response to stimulation. Amplitude reduction most likely differences for 1-kHz stimuli, indicating the utility of this
reflects the reduction in the number of stimulable neural stimulus for neurodiagnostic applications. The mean
elements in an ear with an acoustic neuroma. This technique latency for the normal group was 6.35 ms compared with
is not in widespread use, although the software is available 6.45 for those with high-frequency hearing loss. That is,
on at least one commercial-evoked potential instrument. the latency of 1 kHz was not affected by the presence of
high-frequency hearing loss. The mean latency for clicks
Measurement Criteria for Diagnostic was 5.6 ms for normals and 5.9 ms for high-frequency
losses, which was statistically significant.
Auditory Brainstem Response We then compared wave V latencies to 1-kHz tonal
The diagnostic sensitivity and specificity of absolute and stimuli between two audiometrically matched groups, one
interpeak latency measures depends on how normal limits with cochlear hearing loss and the other with confirmed
are specified. For example, “normal” defined by wave latency acoustic neuromas. As expected, patients with acoustic
+/− one standard deviation of the mean (derived from a pop- neuromas had significantly prolonged wave V latencies
ulation of normal subjects) will produce few missed cases when compared with their audiometrically matched
(high sensitivity) and a larger number of “false-positive” cochlear hearing loss counterparts. Patients with cochlear
findings (low selectivity). losses had a mean latency of 6.7 ms, while the acoustic
Thomsen and colleagues68 analyzed the effects of the neuroma patients had a mean latency of 7.6 ms, representing
criteria choice on diagnostic outcome. ILD-V values in a statistically significant difference.65
27 patients with surgically confirmed acoustic neuromas Gorga and colleagues70 also reported reliability in
were compared with ILD-V values in 70 patients with ABRs to tone bursts covering a wide range of frequencies
Ménière’s disease. A criterion of ILD-V more than 1.0 ms and levels in normal subjects. They found the flexibility
for ABR positivity produced no false-positives and a 15% offered by tonal stimuli to be helpful in evaluating subjects
false-negative rate (i.e., confirmed tumor cases classified as with various configurations of hearing loss. Fowler
nontumor). When ILD-V criteria were restricted to 0.5 ms, and Mikami71 in a retrospective analysis of patients
there was an increase in the false-positive rate to 11% and with asymmetrical cochlear losses reported a high
a reduction of the false-negative rate to 4% (only one correlation between ears for wave V latency evoked with
tumor case classified as nontumor). Further restriction of 1-kHz tone bursts. She further suggested that 1-kHz
the ILD-V criterion to 0.3 ms left the false-negative rate tone bursts can supplement interpretation of click-
at 4% but raised the false-positive rate to 23%, clearly an evoked ABR in patients with significant high-frequency
effect that can make the ABR test results misleading. hearing loss.
300 NEUROTOLOGIC DIAGNOSIS

Case Studies 0

1: A 54-year-old male presented to our clinic with primary 10

complaints of tinnitus and unilateral progressive hearing

dB (ANSI S 3.6, 1996)

20
loss. The audiogram showed normal hearing in the left ear 30
and a mild sloping to severe to profound sensorineural loss
40
in the right ear (Fig. 18-18A).
Traditional click-evoked ABR yielded a robust normal 50
waveform for the left ear with readily identifiable waves. 60
An expectedly poor response was obtained for the right ear
70
(Fig. 18-18B). A 1-kHz tonal ABR was able to elicit a
response with a better morphology. Had only click studies 80
been performed, we could not have ruled out the effects 90
SRT %
of hearing loss. The data from the 1-kHz ABR furthered RE 35 36
the diagnosis of a retrocochlear lesion since the effect of LE 10 100
hearing loss at this frequency was negligible (Fig. 18-18C).
Subsequent to our evaluation, a magnetic resonance imag- 250 500 1,000 2,000 4,000 8,000
ing (MRI) was performed, which confirmed the presence A Frequency in hertz (Hz)
of a 1.5-cm acoustic neuroma. The patient underwent
tumor resection with pathology, which further confirmed III v
a vestibular schwannoma. I
2: A middle-aged woman self-referred to Otolaryngology Lt
and Audiology with complaints of chronic, increasing
right ear tinnitus, and bilateral hearing loss greatest in the
right ear. She had no complaints of otalgia, dizziness, or
facial muscle weakness. Previously, her primary care physi- I
cian had obtained a temporal bone MRI; the radiologist’s
Rt
report was negative for neoplasm in either internal audi-
tory canal or cerebellopontine angle. On the day of her
otology clinic visit, she was worked in for audiologic
assessment and ABR. These results, portrayed in Figure
18-19A–C, indicate a slightly asymmetric mild to moderate 15 ms
sensorineural hearing loss greatest in the right ear. Word B Click ABR, RE vestibular schwannoma
recognition scores are 88% and 68% for the left and right
ears, respectively (see Fig. 18-19A). The ABR results were 75 dB nHL
dramatic: Normal interpeak and absolute latencies were cal-
culated for the left ear, and for the right ear, the wave I–III, 6.72
III–V, and I–V interpeak latencies are far outside our clinic’s v
normative values; the right ear waveform morphology fol-
lowing click stimuli was very poorly formed, while responses
to 1-kHz stimuli are marginally better (see Fig. 18-19B–C).
This patient eventually underwent planned hearing preser-
vation surgery for a 2-cm vestibular schwannoma.
Left Right
C 1 kHz ABR, RE vestibular schwannoma
MIDDLE LATENCY RESPONSES
Figure 18-18. A, Preoperative audiogram of a 54-year-old man with a
right-sided 1.5-centimeter vestibular schwannoma. B, Preoperative click ABR
The most useful component of the auditory evoked from a 54-year-old man with a right-sided vestibular schwannoma. Interpeak
response in the diagnosis of auditory cortical involvement latencies are normal for the unaffected left ear (top trace), while the
is the middle latency auditory evoked response (MLR). waveform morphology for the right ear is poorly formed after wave I (bottom
The most prominent and robust component of this trace). C, Preoperative 1-kHz tone burst ABR from the same 54-year-old man
with a 1.5-centimeter vestibular schwannoma. Averaged responses for the
response is a scalp-positive peak with a midpoint latency of left ear are repeatable and within normal clinical values, while for the right
25 to 35 ms in neurologically normal adults. This compo- ear the response is poorly formed.
nent is widely distributed over the scalp but is most promi-
nent over frontocentral regions. There is some evidence
that this component is at least in part generated by the central deafness (with indication of an intact auditory
auditory cortex because it is attenuated or diminished in periphery), the MLR may be absent or substantially reduced
cases of temporal bone lesions.38,72 In patients with unilateral in amplitude bilaterally as well as at midline electrodes.73
lesions of the auditory cortex, the Pa component of the Improvements in the configuration of the MLR generally
MLR is greatly reduced in amplitude or absent over the coincide with improvement in hearing abilities in such
affected hemisphere. In those rare cases with bilateral cases evolving from a return of appropriate hearing sensi-
hemorrhagic temporal lobe infarcts manifesting as true tivity to slow, gradual improvements in speech recognition
 Objective Measures of Auditory Function 301

0 Preoperative electrical testing typically consists of electrical

10 stimulation applied to the promontory or round window
niche with an electrode placed transtympanically or under
dB (ANSI S 3.6, 1996)

20 direct vision through a tympanotomy incision or tympa-

30 nomeatal flap. Response to stimulation can be assessed with
40 behavioral techniques such as an adaptive procedure. Adult
patients who have had experience with acoustic stimulation
50
are easily assessed with behavioral techniques. The inclusion
60 of congenitally deaf adults and infants in the prospective
70 implantable patient population has created the need for
80 nonbehavioral techniques of determining the presence of
responses of the auditory system to electrical stimulation.
90 Both electric ABRs and electric middle latency
SRT %
RE 30 68 responses have been used as indicators of the electrical
LE 15 88 responsiveness.75 Miyamoto and Brown76 have successfully
obtained electric ABRs in the operative setting following
250 500 1,000 2,000 4,000 8,000 implantation with the 3M/House single-channel device.
A Frequency in hertz (Hz) Rectangular biphasic pulses were applied to the implanted
electrode through a modified external coil placed over the
III receiver coil following the closure of the incision. This
I approach to confirming the electrical excitability of the
I V-LE click
III V-RE click auditory system is limited by the necessity to conduct the
test after the surgical procedure is completed.
Electrically evoked ABRs may be obtained both with
I V-RE 1kHz I III V-LE 1kHz toneburst
preperioperative transtympanic stimulation77 as well as
toneburst postimplant by stimulating selected electrodes of the
cochlear implant. The transtympanically evoked EABR is
0.16 uV typically obtained in the operating room while the patient
1.5 msec is under general anesthesia and with neuromuscular block-
ade. Muscle paralysis reduces the likelihood of an artifactual
NeuroDx ABR myogenic responses that may either contaminate the EABR
B C or masquerade as an EABR. Stimuli are delivered by a
needle electrode placed transtympanically on the cochlear
Figure 18-19. A, Preoperative audiogram of a female with chief complaints promontory. A custom-designed battery-operated stimulator
of right ear tinnitus, hearing loss, and no benefit from right ear amplification.
B-C, Neurodiagnostic ABRs; in the left panel, right ear grand averages of
activated by a trigger pulse from an evoked potential system
more than 10k clicks and 1-kHz tone bursts; interpeak and absolute latencies was used to generate the necessary stimuli. This stimulator
are far beyond two standard deviations of clinical normative values; left ear is capable of delivering biphasic pulses with an output limit
responses (right panel) are normal for clicks and tones. of 999μ amps. These biphasic stimulus pulses have a typical
duration of 200μ seconds per phase and we record the
presumably in association with the absorption of blood EABR with a contralateral earlobe or mastoid reference.
and reductions in the intracranial pressure. We recommend that EABRs be obtained on pediatric
An intact auditory periphery coupled to an interrupted patients who fulfill the following criteria:
central nervous system (CNS) pathway or a severely dam- 1. Confirmed temporal bone malformation
aged auditory cortex will result in a complete absence of 2. Uncertain preoperative audiometric threshold due to
functional hearing. the patient’s young age or developmental status
3. Preoperative audiometric thresholds exceeding the
AUDITORY POTENTIALS IN COCHLEAR limits of the audiometer
IMPLANT SURGERY Figure 18-20 illustrates EABRs obtained perioperatively
from three patients aged 18 months, 14 months, and
The advent and expanded application of the cochlear 13 months. The responses resemble an acoustically evoked
implant has introduced the need for an objective assessment ABR with several differences. First, latency of wave V
of auditory pathway response to electrical stimulation par- ranges from 4 to 4.5 milliseconds, which is at least 1 to 1.5
ticularly in young patients. It is advantageous to have the milliseconds earlier than wave V latency obtained at high
ability to determine the electrical excitability of auditory stimulus intensities. Second, it is difficult to resolve the
neural elements before committing an ear to implantation. early components of the response (waves I and II) because
Along with other preoperative data, this information of the presence of a large stimulus artifact derived from
serves as a basis for counseling and helps avoid implantation electrical stimulation. In order to minimize contamination
in a nonexcitable ear. Some cochlear implant clinicians by the stimulus artifact, the initial 2 milliseconds of the
perform preoperative electrical promontory testing in recorded trace were digitally blanked; therefore, neither
adults as a guide for selecting the ear to be implanted pro- artifactual nor physiologic electrical activity is discernible
vided other preoperative measures indicate candidacy.74 within this initial time.
302 NEUROTOLOGIC DIAGNOSIS

18 months could be tracked down to a threshold of 600 microamps as

+ III
v illustrated in this figure. No attempt was made to obtain
500 uA
responses at lower levels. In this case the electric ABR
.25 uV responses helped us select the left ear for implantation based
− on lower perioperative electric thresholds.
Another important application of perioperative transtym-
+ 14 months III v panic stimulation is in cases of congenital temporal bone
400 uA malformations such as common cavity deformities, and an
v apparent absence of IAC or a very narrow IAC. The follow-
ing case illustrates this application. Figure 18-22 illustrates
.25 uV a computed tomography (CT) from a 31/2-year-old patient
500 uA
who was a cochlear implant candidate based on audiologic
− criteria. Imaging studies helped identify the presence of
13 months bilateral common cavity deformities with a wide IAC on
+ III v the left side and an apparent absence of IAC on the right
side. Transtympanic electrical stimulation helped deter-
500 uA
mine that indeed the right ear was most likely devoid of a
v cochlear nerve based on an absent response with electrical
600 uA stimulation (Fig. 18-23, bottom trace). The top trace illustrates
.25 uV well-defined electric ABR obtained with stimulation of the
− left ear, which was subsequently selected for implantation
with effective cochlear implant use.
Latency 1.0 ms/division The electrically evoked auditory brainstem response
Figure 18-20. Preoperative electrically evoked auditory brainstem responses may also be used following implantation to facilitate pro-
from three patients. Absolute latencies of waves III and V are earlier than gramming, particularly in young children. Instead of deliv-
responses obtained using acoustic stimuli delivered through earphones. ering a stimulus transtympanically to the promontory and
attempting to record a response, following implantation
Figure 18-21 is an illustration of the application of the the cochlear implant and its programming equipment may
transtympanic electric ABR technique to select an ear be interfaced with evoked potential instrumentation and
for implantation. These responses were obtained from a responses may be recorded with selective activation of
21/2-year-old with symmetrical, bilateral severe to profound electrodes or electrode pairs. Several studies have shown
sensorineural hearing loss. With right ear stimulation (top the efficacy and usefulness of this technique.78–80 In general,
set of traces), responses could be obtained only at 900 mir- EABR thresholds are closer to actual, behavioral comfort
croamps. While these responses indicated the presence of levels than to thresholds but their presence can be helpful
excitable auditory neural elements, our prior experience to set stimulation parameters. The practical disadvantage
indicates that effective implant performance coincides of the EABR applied in such a manner is that particularly
with transtympanic electric ABR thresholds of 600 with young children it would be necessary to obtain it
microamps or less. With left ear stimulation, responses under sedation because the EABR is very vulnerable for

EABR: 2.5-Year-Old Boy

with Congenital Deafness

+ v RE
900 uA

III
v

LE
v 700 uA
III

650
v

600
−

Latency 1 msec/div
Figure 18-21. Electric auditory brainstem responses from the right ear (RE) Figure 18-22. Computed tomography image of a 3-year-old cochlear implant
and the left ear (LE) of a patient who underwent a successful left ear cochlear candidate showing bilateral common cavity defects; the internal auditory
implantation. canal is widened on the left side, while the IAC is absent on the right side.
 Objective Measures of Auditory Function 303

+ III v Neural Response Telemetry

II
4 180
4 183
LE
4 186
4 189
RE
4 192
4 195
4 195
.50 uV 127 uV

2 msec
0.0 0.5 1.0 1.5 2.0
− Time (msec)

EABR @ 600 uA Figure 18-24. Neural response telemetry responses from a 7-year-old boy.
Responses were used to estimate programming levels for this difficult-to-test
Figure 18-23. Transtympanic electrocochleography from a 3-year-old boy youngster. A threshold of 186 clinical units was established for electrode 4.
undergoing cochlear implant workup. Note the absence of a response from
the right ear (IAC absent on CT).

They found no significant differences between EAP and

contamination by movement and myogenic artifacts. The EABR threshold levels; therefore, these two techniques
alternatives are the measurement of electric auditory may be used interchangeably in adult populations. It is still
potentials (EAPs) recorded via telemetry procedures, preferable, however, to use the EAP in children who may
hence the term neural response telemetry, or NRT. These necessitate sedation to obtain an EABR.
measurements use the two-way telemetry (currently com-
mercially available for only Cochlear Corporation/Nucleus
implants and Advanced Bionics implants). This can be ACKNOWLEDGMENTS
accomplished by using one pair of electrodes to deliver the
stimulus and a nearby pair to record the response that is We would like to acknowledge the contributions of John
returned via back-telemetry. The response recorded by elec- K. Niparko, MD, and Karin E. Young, MA, who helped
trodes designated as recording electrodes of the implants write the first version of this chapter in 1994. Also, we
array are transmitted back transcutaneously to the speech would like to recognize and thank Mrs. Janice LaPointe,
processor interface. With certain additional manipulations, secretary to the senior author, who helped prepare the
these responses are averaged much like an evoked potential, manuscript.
displayed on the computer screen, stored, or printed for the
record. This technique does not require surface recording
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 Chapter
Functional Imaging of Auditory
Cortical Activity
19 Outline

Manuel Don, PhD Introduction Spatiotemporal Source Functional Imaging with

Functional Imaging of Modeling: Technical Magnetic Resonance Imaging
Curtis W. Ponton, PhD Background and General
Neuroelectrical and Aspects
Neuromagnetic Scalp Activity Advantages and Principles
Background and Principles Disadvantages of Blood Oxygenation Level–
Electric Fields Spatiotemporal Source Dependent Contrast
Magnetic Fields Modeling Imaging
The Need for Multichannel Clinical Applications of Dipole Blood Perfusion Imaging
Recordings Source Analyses Using Vascular Contrast
Electrical Multichannel Positron Emission Agents
Recordings Tomography Blood Perfusion Imaging
Magnetic Multichannel Background and General Using Inversion Recovery
Recordings Principles Methods
Brain Maps Advantages and Auditory Studies Using
Technical Aspects Disadvantages of Positron Functional Magnetic
Kinds of Information that Emission Tomography Resonance Imaging
Maps Provide Clinical Applications Advantages and
Advantages and Cochlear Implant Disadvantages of Functional
Disadvantages of Stimulation Magnetic Resonance Imaging
Topographic Maps Tinnitus Studies with Clinical Applications and
Clinical Applications of Positron Emission Combining Imaging
Maps Tomography Techniques
Dipole Source Modeling Summary
Early Dipole Source
Localization Methods:
Single- and Moving Dipole
Models

INTRODUCTION Previously, we focused on functional imaging with

evoked electrical and magnetic potentials recorded at the
In the version of this chapter included in the previous surface of the head by means of topographic mapping
edition of this book, we identified emerging clinical issues (“brain-mapping”) and spatiotemporal source modeling
and fundamental questions in the study and evaluation of (STSM) techniques. Although our major emphases in the
the auditory system concerned with (1) identifying the previous edition were electromagnetic approaches, we also
anatomic sites where various aspects of auditory process- touched on functional imaging with positron emission
ing occur in the brain, (2) the temporal nature of the tomography (PET) and the then newly emerging attempts
processing, (3) whether such processing can be measured to image functionally with magnetic resonance imaging
objectively, and (4) how such measurements change with (fMRI). Since the publication of this chapter over 10 years
various kinds of pathology. Answers to these issues and ago, significant advances have taken place in all of these
questions are critical prerequisites in understanding the technologies. Much more research has focused on the
origin and extent of hearing disorders, which in turn may potential clinical applications of these techniques. In par-
be helpful in assessing and guiding rehabilitation ticular, the research and application of fMRI has experi-
processes. enced tremendous growth. Numerous published studies
306
 Functional Imaging of Auditory Cortical Activity 307

have attempted to identify and characterize neural activity and magnetic fields associated with neural activation
in cortical areas of the brain while processing simple and following auditory-sensory stimulation. However, it is
complex (e.g., speech) auditory stimuli. In this chapter, we important to acknowledge that some neural activity pro-
now expand our review of the fMRI work in addition to duces local current paths that are contained close to the
updating the information on other brain imaging tech- generator and may not generate the far-field electric and
niques. Again, for each of the various methods we present magnetic fields that extend to and are recordable from
a brief description of the technical aspects, the kinds of the scalp.
information obtained, their advantages and disadvantages, It is generally accepted that the far-field scalp-recorded
and the current and future clinical applications in evaluat- brain activity primarily represents excitatory postsynaptic
ing the auditory system. The technical complexities potentials (EPSPs) produced by pyramidal cells that are
and vast literature on the development and application uniformly organized perpendicular to the cortical surface.
of these methods preclude a comprehensive review of either It is likely that this far-field activity represents the
the technical aspects or application results. Our intention synchronous EPSPs of tens of thousands to millions of
in this revised chapter, despite its brevity, is that this review cortical pyramidal cells. This far-field activity produces
will provide an effective overview of the basic principles intrinsically related electric and magnetic fields at the
of these techniques, their current and potential value, scalp. A simplistic view of this relationship is to consider
and the limitations of the clinical evaluation of auditory activation of a small segment of neural tissue, as schemat-
function. ically shown in Figure 19-1. This activation can be repre-
We emphasize at the outset that the techniques sented in a short length of current flow. The direction of
described in this chapter are physiologically based and are this small current flow is shown by the arrow and, in this
concerned with characterizing the distribution, location, example, is oriented tangential to the surface of the head.
and temporal variations in amplitude of electric, magnetic, This is often described as an equivalent current dipole.
and metabolic activity from auditory-evoked sources of Current flows out of the head of the arrow (+ pole) and
neural activity in the cortex. Ten years ago, clinical appli- flows into the tail of the arrow (−pole), producing both an
cation of these techniques for assessing auditory function electric and magnetic field. The electric field (Fig. 19-1A)
was limited, but we suggested that with continued devel- is perpendicular to the magnetic field (Fig. 19-1B).
opment and evolution, these techniques would prove to be Temporal variations in the current flow result in temporal
very valuable in the assessment of cortically mediated variations in both the electric and magnetic fields. The
auditory function. During these last 10 years or so, ample advantage of brain-generated electrical potentials and
evidence has emerged to support this suggestion. magnetic fields is the sensitivity to spontaneous and
induced changes in the functional brain state coupled with
extremely high (submillisecond) temporal resolution.4
Although there are differences in recording these fields,
FUNCTIONAL IMAGING OF both electrical and magnetic responses should, in general,
NEUROELECTRICAL AND provide similar information because they are intrinsically
NEUROMAGNETIC SCALP ACTIVITY related phenomena resulting from current flow due to
ionic movement in the underlying tissue.
Before embarking on a discussion of functional imaging
of electrical and magnetic activity, we review briefly some
of the principles and technical aspects of these kinds of Electric Fields
activity. Such a simple review should help the reader In the past, most auditory evoked response studies
understand these imaging techniques. Also, our focus will measured the voltage (electrical potential) between two
be on the middle and late auditory evoked potential activ- electrodes on the scalp. One electrode was usually placed
ity because they originate in subcortical areas including
the thalamus and neocortical areas including primary and
secondary (including association) auditory cortices.

Background and Principles

We recall from basic neurophysiology that neural stimula-
tion results in changes in permeability of neural membrane
tissues to various ions. These changes in permeability cre-
ate net imbalances in the local concentrations of negative
and positive charges as ions move in response to concen-
tration and electrical gradients. For thorough reviews of
the complexities of the relationship between intracellular
and extracellular currents generated by ionic movement
and the corresponding electric and magnetic fields, the
reader is referred to Nunez,1 Scherg,2 and Williamson and
Kaufman3 for rigorous but readable explanations of these A B
important principles. The point of departure for us is that Figure 19-1. Current dipoles and resulting electric (A) and magnetic (B)
from the scalp surface, we can record electrical potentials fields.
308 NEUROTOLOGIC DIAGNOSIS

at the vertex and the other (reference) at some other smearing and spreading of the magnetoencephalograph
location such as the mastoid or earlobe. Because the (MEG) is extremely limited. Furthermore, the sensitivity
magnitude of stimulus evoked, time-locked neural activity of MEG drops off approximately twice as fast as a function
is very small (orders of magnitude smaller) relative to the of the angle (θ) of the sensor to the source as the sensitiv-
background electrical activity, response averaging tech- ity of EEG. Consequently, sources of pure tangential
niques are required to average the nonstimulus-locked orientation are much more accurately localized by MEG
component of the electroencephalograph (EEG). The than EEG.12 However, sources of current in the brain that
resultant averaged responses, or voltage waveforms, are are radially (perpendicularly) oriented to the surface are
assumed to represent electrical activity from neural struc- not detectable magnetically. Moreover, because of the
tures at the brainstem, thalamic, or cortical levels depend- more rapid drop in sensitivity, magnetic fields from
ing on the recording parameters of sampling rate, filtering, deep brain structures are typically too weak to be detected
and amplification. The data of interest have been the at the scalp surface. Thus, studies that make use of
latency and amplitude of component peaks in these aver- magnetic recordings are predominately focused only on
aged waveforms. The most important limitation associated surface cortical activity. However, MEG resolution con-
with averaged evoked scalp-recorded electrical potentials tinues to improve with the advent of technology that
is that the waveform from any given location on the scalp decreases the distance between the detector and the head
represents compounded electrical activity evoked by the and by improvements in signal-to-noise ratios.12 Other
stimulus. Given the possibility that more than one area of than extremely deep or radially oriented sources, a
the brain contributes to the activity, it is not possible to magnetic counterpart to any EEG activity can always be
separate the contributions from differential recordings measured.
between a single pair of electrodes. That is, the evoked Both MEG and EEG have advantages and disadvan-
response waveform from a differentially recorded pair of tages. Some debate still persists about which is best for a
electrodes is basically the linear summation of all volume- given application. Since MEG more accurately locates
conducted electrical activity originating from different sources oriented tangentially and EEG is more accurate
structures and areas of the brain. for radial sources, the techniques can be complimentary.12
Furthermore, the waveform recorded depends not only Williamson and colleagues13 and Hari11 provide clear
on the pattern of activity of the sources, but also on the succinct reviews of the different advantages of electrical
location, distance, and orientation of these sources relative and magnetic recordings and stress that a combination of
to the recording electrodes. It is possible that peak activity both kinds of recordings will provide the best and most
observed at the surface for a given electrode pair occurs at complete information about underlying neural activity.
a time when none of the contributing sources shows peak Aside from the theoretical issues, practical considerations
activity. The frequently used method of simply measuring may be just as important in determining which technique
the latencies and amplitudes of peaks and valleys as direct is more suitable for a specific clinical application. For
evidence of the time and magnitude of specific neural example, MEG recordings require that a patient’s head
events is often inappropriate. Such simple recordings remains essentially stationary (in the same position
cannot provide unambiguous information about the local beneath a set of sensors imbedded in a helmet) for the
origin of brain activity, nor the true temporal nature of the duration of a recording. Because EEG electrodes are fixed
underlying activity pattern(s). Nevertheless, we can still to scalp with a water-soluble conductive gel or paste, some
record and use these measures for diagnostic purposes as movement is possible. Consequently, for young children,
long as we do not assume they represent the true activity or for individuals with uncontrollable tremor (e.g., those
patterns of the underlying sources. with Parkinson’s disease), EEG-based recording may be
more practical. Conversely, the setup and acquisition time
Magnetic Fields to obtain good-quality (high signal-to-noise ratio) record-
ings can be much shorter for MEG data. Additionally, the
The recording of the magnetic fields associated with equipment and maintenance costs for multichannel mag-
cortical currents requires special technical considerations netic field recordings (i.e., SQUID devices) are far greater
as well as a magnetically shielded environment to avoid (orders of magnitude) than that for electrical recordings
artifact contamination from extraneous sources. Several (i.e., EEG systems). Thus, controversy remains about
studies5–11 have described recording methodologies for whether MEG provides sufficient additional information
these minute magnetic fields using magnetic sensors and and advantages to justify the cost.
SQUID (superconducting quantum interference device)
magnetometers. Just as variations in voltage can be plotted The Need for Multichannel Recordings
over time, so can the corresponding variations in magnetic
flux. Thus, magnetic recordings show “peaks” and Single-channel recordings provide limited information
“troughs” of magnetic flux amplitude over time. about how the compounded or net electrical or magnetic
Some of the issues noted earlier for electrical evoked activity at a single location on the scalp varies over time.
potentials also apply for evoked magnetic fields except for This is usually appropriate and sufficient when the need
the issue of a reference; magnetic recordings are refer- for information regarding the location(s), activity, or the
ence-free. Unlike electric fields, magnetic fields recorded distribution of the sources is unnecessary for the analyses
at the surface are nearly undistorted by the skull and other and if the requisite information can be observed in that
tissue. Compared with the EEG, which is volume- single-channel recording. However, as Lehmann4 points
conducted through fluids, tissue, and bone to the scalp, out, the electrical potential at any point on the scalp is an
 Functional Imaging of Auditory Cortical Activity 309

ambiguous value since it is only defined in relation to the are not uncommon. In general, the more channels and,
electrical potential at another point. In the following sections therefore, the closer the spacing between electrodes, the
we discuss the principles and techniques of multichannel better the resolution in characterizing the distribution
recordings and advantages for functional imaging. and in computing the estimated loci of underlying sources
at the brain surface. The upper limit of the number of
Electrical Multichannel Recordings electrodes to use remains a practical and theoretical issue.
Typically, evoked responses from sources deep in the
In order to assess the loci of sources that contribute to the brain (e.g., the brainstem) are recorded with very few
surface evoked electrical activity, recordings from multiple channels because that activity tends to be widely distrib-
locations on the scalp are required. Figure 19-2 (top) shows uted at the surface of the head. Although it has been shown
typical location of 32 electrodes according to the standard that auditory brainstem responses (ABRs) can also be
10–20 system14 and the associated potential waveforms analyzed with spatial information,15,16 multichannel
recorded from those locations. Today, sophisticated recordings to describe the spatial distribution of the
systems permitting the recording, display, and analyses electrical activity are applied mainly to potentials gener-
of 256 channels (electrodes) of electrical potential data ated by the cortical areas of the brain. When recording

Figure 19-2. (Top) The scalp distri-

bution for cortical activity evoked by
monaural stimulation to the left ear.
The major peaks of the auditory
evoked potentials are marked in the
inset. (Bottom) On the left, a voltage
distribution for N100 of the auditory
evoked potentials is shown for the
activity shown at top of this figure.
In center, the scalp voltage distribution
is shown for the P150 potential. The
voltage distribution for a left median
nerve somatosensory N54 is shown
on the right. (See Color Plate 1)
310 NEUROTOLOGIC DIAGNOSIS

from many locations on the scalp, as in typical EEG and enhanced by color or gray-scale representation of the
for describing the scalp surface potential distribution, the distribution of surface activity, became a popular tool
recording at each location must be made, by definition of for studying electrical brain activity during the 1980s.
a voltage potential, with reference to some other locus on (For general reviews, see Lehmann et al.,18 Picton et al.,23
the scalp or body. The issue of the reference electrode is an and other studies.24–26)
important one that can affect interpretation.17 A typical Now these color or gray-scale representations of the
reference is the mastoid of one ear. Many studies have distribution of surface activity are giving way to the use of
been conducted with the two electrodes on the mastoids or equipotential maps1 to avoid bias by the selection of the
earlobes linked together for a reference in an effort to color scale and also to emphasize the shape of the voltage
minimize certain electrical artifacts of nonneural origin. or CSD distribution rather than the peak areas.
However, linking electrodes creates an inherent problem
in that it modifies the electrical potential distribution over
Technical Aspects
the whole scalp by imposing the same potential on both
ears. In essence, linking electrodes, although not affecting The principles for constructing a map are similar for
the generators, may distort the recorded electric fields by electrical or magnetic activity. The example we discuss is
providing an electric “short” between these two loca- for electrical activity, that is, voltage maps. At any given
tions.17 Furthermore, the undistorted field cannot be instant, that is, latency, the voltage at each of the record-
recovered. Whether such distortions are significant for ing sites can be presented visually by colors or pseudo gray
typical recording conditions is controversial, but it is best scales.20,27 For example, we can specify that the voltage
to avoid this problem by not recording the activity using range of ±100 μV can be presented by the two major
linked mastoid or earlobe electrodes. A recommended colors, red and blue. The darkest shade of red represents
approach now adopted by many laboratories is to compute the maximum positive value of +100 μV. The less positive
reference-free data by using an average reference, which is the voltage value, the lighter the shade of red. Zero and
simply the average of potentials recorded at each electrode nearly zero values will be white. When the voltage
at all times subtracted from each individual electrode.17,18 becomes negative, the value is represented by shades of
Typically, we are interested in examining changes in the blue. The more negative the value, the darker the blue.
evoked responses across the scalp, which are easier to Similarly, when color use is inappropriate, a computed
detect when activity common to all scalp locations (in pseudo gray-scale map of the activity can be used, with the
essence, a constant, which may be very large relative to the dithered gray pattern representing negative and black
remaining activity) is removed from the data. representing positive potentials. Since the recorded activ-
ity is only at the specified electrode locations, a map of the
Magnetic Multichannel Recordings whole surface of the head requires much interpolation.
There are various schemes of interpolation. Thus, if the
Similar to electrical recordings, the assessment of the loci value at one location was 40 μV and 60 μV at an adjacent
of sources that contribute to the surface-recorded evoked electrode, then the area between these electrodes would
magnetic activity also requires recordings from multiple show, depending on the kind of interpolation, a gradient
locations on the scalp. Although in the early 1980s only of increasing darkness of the red or gray colors, that
single-channel magnetometers were available, SQUIDs represents the increasing positivity from +40 to +60 μV.
containing more than 120 channels are now the standard. Obviously, the more electrodes and closer spacing, the
The main reason for the increase in channels is the same more accurate the interpolation.
as for electrical studies: to improve the resolution for In the earlier edition of this chapter, we provided a
isolating the loci of the source of activity. detailed example of the use of the gray-scale method that
will not be repeated here. Instead, we now briefly review
Brain Maps equipotential voltage or CSD maps because they provide
better information about the distribution of electrical or
In brain mapping, the emphasis is no longer on analysis magnetic activity.
of waveforms recorded at selected scalp sites but rather Figure 19-2 (bottom, left) shows the grand mean wave-
on analysis of the spatial potential distribution over the forms evoked by a brief click-train recorded from various
scalp at selected times. Thus, spatial analysis by means locations on the scalp and an equipotential map of the
of multichannel recordings is necessary because it trans- activity. In this figure, the equipotential maps are shown
forms the potential differences between electrodes into for latencies of 100 msec at the maximum of the N1 com-
reference-independent values, which can provide descrip- ponent. For the 100-msec N1 component map, there is a
tions of activity across the scalp. clearly asymmetrical representation of the activity with a
In early work, Vaughan and Ritter19 and a number of strong negative/positive reversal over the right scalp, con-
laboratories analyzed data from multichannel electrical tralateral to the stimulus left ear. These results are consis-
recordings. They demonstrated the use of methods and tent with those reported by Borg and colleagues,28 who
mathematical algorithms for converting activity from mul- found that on isovoltage maps, the focus of the N1 audi-
tiple electrode sites into a topographic map, the so-called tory potential is slightly contralateral to the stimulated ear
brain map, that approximates an almost continuous plot of for most subjects.
evoked potential amplitudes or current source densities In Figure 19-2 (bottom, center), the distribution at a later
(CSDs) across the scalp.20–22 These topographic maps, time (158 msec) is shown corresponding to the maximum
 Functional Imaging of Auditory Cortical Activity 311

of the P2 wave. The distribution map for the P2 component Advantages and Disadvantages
at 158 msec is much more symmetrical with a large peak at of Topographic Maps
the midline. In a similar fashion, for each sampled instant
The basic advantages of maps are (1) they are easy to
of time, an equipotential brain map can be generated.
generate; (2) they provide a quick view of the surface dis-
Thus, if the waveforms were composed of 500 data points
tribution of voltages, magnetic flux, or CSD; and (3) they
sampled at 1-msec intervals, 500 equipotential brain maps
can show how these surface distributions change over a
could be generated. Each 1-msec map can be displayed
short period after stimulus onset.
consecutively to illustrate how the distributions on the
Maps also have several disadvantages. First, and most
scalp change over time. Also, less time-specific maps can
notable is that the maps are only two-dimensional; they
be created by calculating a representative potential over an
simply characterize the amplitude distributions of the
epoch of time (i.e., several sampled points) instead of the
summed source activities projected to the surface of the
value at one instant. Grandori and coworkers9 and Kraus
scalp at a given instant. Although the analyses of such topo-
and McGee29 have performed extensive map analyses on
graphic maps can provide useful information, they cannot
auditory middle-latency potentials in normal-hearing
be used for assessing the cortical location or fine temporal
individuals.
activity of the neuroelectrical generators in the brain that
As mentioned earlier, another form of the electric field,
produce the topography. Simply visualizing the color or
CSD, can be also be mapped.30 (CSD is the second deriv-
gray-scale, the equipotential or CSD maps of the voltage
ative of the spatial voltage field.) Maps can also be gener-
distribution do not allow us to evaluate the various possi-
ated to show the distribution of the magnetic flux over the
ble sources. Furthermore, these surface maps provide little
surface of the head. More recently, infrared radiation has
information regarding the cortical depth of the sources.
been used to identify cortically activated areas.31 Mapping
For example, with a montage of 20 electrodes evenly
in essence is simply a graphical representation of the
distributed over the scalp, it can be shown that for a given
distribution of some form of activity, usually at a given
instant, auditory and somatosensory stimulation generate
instant, at the surface of the head. Sophisticated maps can
the same spatial maxima (similar location) in surface
be generated with realistic head models obtained from
maps over the hemisphere contralateral to the side of
MRI data and dense arrays of electrodes as demonstrated
stimulation. Thus, it would be difficult to differentiate the
by Gevins and colleagues.32
cortical origins of such activity patterns because of the
similarity between the two-dimensional maps. Further-
Kinds of Information that Maps Provide more, it has been shown that a surface generator localized
in one hemispheric fissure can produce a surface field with
Significant changes in the maps or in the nature and
an apparent locus in the other hemisphere.36 Thus, the use
location of estimated sources may provide significant
of surface distributions as a tool for assessing laterality of
information regarding auditory processing. The kinds of
function may be misleading and could result in serious
information sought in the analyses of these brain maps are:
misinterpretation and diagnosis. Thus, one should be
(1) Do specific maps or changes in the maps relate to
cautious with the use of two-dimensional brain maps to
auditory processing? (2) How do maps differ between the
identify sources of electrical activity.
normal-hearing population and a hearing-impaired popu-
A second disadvantage of maps is the need for extensive
lation? (3) What are the location(s) of the neural tissues
interpolation. The appearance of the maps is highly
within the brain responsible for generating a particular
affected by the method of interpolation.26 Nonlinear
scalp map2?
interpolation or spatial filtering can result in map topogra-
One can produce average maps for both a single subject
phies with peaks and troughs at locations where electrodes
and across subjects. Changes in the maps are evaluated
were not located.4 Finally, different baselines or references
visually and statistically. A real, statistically measurable
produce maps with different appearances. Some of the
change33,34 in the map or distribution from one stimulus
problems of map interpretation are presented by Scherg
condition to the next is evidence that the sources underly-
and von Cramon.37 A useful method of interpolation for
ing the activity have changed. Thus, differences in the
equipotential and CSD maps is the spherical spline
maps signal different underlying sources and may be used
method described by Pascual-Marqui.38
in well-controlled studies to delineate pathology. There
are several types of measures of topographic maps. For
Clinical Applications of Maps
example, Duffy35 has applied significance probability map-
ping (SPM) and grid sector analysis (GSA) to assess Despite the disadvantages noted, maps initially seemed to
whether the maps are similar to maps of a reference group. have some promise as a clinical tool in certain medical dis-
Global field power is a measure of the hilliness of the scalp ciplines. Consequently, they have been applied to studies
potential distribution or the spatial variance.18 Weaknesses of epilepsy, cortical infarcts, tumors, emotional distur-
of statistical maps are the assumptions of normality and bance and dementia, headache, learning disabilities, and
independence of the data. For example, Grandori and other neurologic diseases.24,35 Kraus and McGee29 sug-
colleagues9 found that map differences that could be visu- gested that there could be some clinical utility in brain
ally detected between right and left ear stimulation could maps of cortical auditory potentials, particularly in patients
not be verified using z statistics. Likewise, Kraus and with cortical lesions in the temporal lobes. However, clini-
McGee29 had difficulties in using the z score to determine cal application of topographic maps for auditory evaluation
abnormalities. has yet to be clearly demonstrated. Although some
312 NEUROTOLOGIC DIAGNOSIS

approaches can statistically distinguish one map from

another, Wong26 suggests pessimistically that it is unlikely
that useful statistical techniques that can quantify a map
as normal or abnormal will be widely available in the
near future. Furthermore, given the limitations of two-
dimensional information, such maps have given way to
three-dimensional imaging techniques. The following
sections review the various techniques for providing activity
information in three dimensions.

Dipole Source Modeling

A major drawback of electric or magnetic field maps is
their inability to provide definitive information about the
sources in the brain that produce the maps or distribu- A
tions. This is the classic “inverse problem” in electric field
theory, which is to calculate the electrical sources within a
volume conductor (i.e., the brain) given the empirical
potential field on the surface. This inverse problem has no
unique solution because a given potential field (map) can
be produced by any number of source configurations.1,17,39
Although one cannot solve the inverse problem, a number
of studies have attempted to get around it by taking the
“forward problem” approach. The forward problem in
electric field theory as applied to human evoked potentials
involves the calculation of the potential field distribution
on the surface of the head when the sources and their loca-
tions in three dimensions, the geometry of the head, and
the conductivities of the various compartments of the head
are given, assumed, or known.39,40 One can then compare
the modeled distribution with the recorded distribution
and estimate the goodness of fit for the source configura- B
tion and activity. Some models simplify the calculations by
assuming certain properties and conductivities for the
various compartments (e.g., skin, skull, cerebral spinal
fluid [CSF], and brain tissue) of the head. Such simplifica-
tions often yield results that are sufficiently accurate for
certain conditions and assumptions.
In the preceding discussion of the inverse and forward
problems, we have referred to “sources” that generate the
potential field. Source analysis is an examination of the
reciprocal inverse problem in which the goal is to deter-
mine the location and configuration of generators within
the head that produced the observed potentials on the
scalp.17,41 In laminarly structured cortex where most neu-
rons have a common orientation that is perpendicular to
the cortical surface, synchronous neuronal activity can be
modeled by current dipoles.42 Figure 19-3 is a schematic
diagram adapted from Scherg2 showing activation of various C
small segments of a cortical fold. Because of the columnar Figure 19-3. Schematic of an equivalent dipole with radial (A), tangential
organization, current sources (+) and sinks (−) are dis- (B), and oblique (C) orientation relative to the surface of the head. Each
placed perpendicular to the cortical surface. Thus, if the equivalent dipole represents the sum of a number of activated elements shown
segment of activated cortex lies on the surface of the brain in the shaded area. (Modified from Scherg M: Fundamentals of dipole source
analysis. In Grandori F, Hoke M, Romani GL [eds.]: Auditory evoked magnetic
(Fig. 19-3, top) or is parallel to the lateral convexity, the fields and electrical potentials. Adv Audiol, vol 6, Basel, Karger, 1990.)
associated dipole is radial. If the activated segment lies in
the depths of the fissure (Fig. 19-3, middle), the associated
dipole is tangential. An oblique dipole results from activa-
tion of the banks of the fissure (Fig. 19-3, bottom). For most because their field provides an equivalent description of
applications we use the extended definition of equivalent the compound activity of all neuronal elements in their
dipole to represent the dipole whose electric field best vicinity that are oriented parallel to the dipole axis. Note
approximates summated fields of a number of closely spaced in Figure 19-3 that a single radial and a single tangential
sources and sinks.2 These dipoles are called equivalent equivalent dipole provide a good approximation of the
 Functional Imaging of Auditory Cortical Activity 313

compound activity of all cortical segments on one side and the data based on the density of the clustering of the indi-
in the vicinity of the right side of the cortical fold. Even vidual dipole fits (or both). Thus, a cluster with a large
the oblique activity can be represented by the radial and spatial extent that changes systematically as function of
tangential dipoles. time point to a generator configuration consisting of more
than one time-varying source. Alternatively, a cluster with
locations that change nonsystemically (randomly) over a
Early Dipole Source Localization Methods:
specified time interval may provide an indication of the
Single- and Moving Dipole Models
reliability of the source location based on the spatial extent
Early dipole localization methods tried to account for the (or volume) of the cluster of single dipoles.
instantaneous spatial distribution of the scalp potential,
magnetic field, or CSD at a fixed time (see Wood39 for a
Spatiotemporal Source Modeling:
good review). These methods involve the use of a physical
Technical Aspects
model of signal propagation in the head to compute the
expected surface topography usually associated with a The dipole solution cannot provide an unambiguous
current dipole source having arbitrary parameters. For statement about sources because there is no unique
electrical potentials, six parameters are usually required to solution to the inverse problem, and each potential distri-
specify a source (three for position, two for orientation, and bution may be generated by many simultaneously
one for strength). For magnetic recordings, five parameters activated processes.18 However, Scherg15 and Scherg and
are required to specify the source (three for location, one von Cramon16 created a different viewpoint and asked
for strength, and only one for orientation since MEG is whether a combined spatiotemporal approach would not
sensitive to only tangentially oriented sources). The posi- greatly enhance the validity of dipole source analyses.
tion, orientation, and intensity of the source are iteratively They demonstrated that with the use of a precise defini-
adjusted to reproduce maximally the target topography.43 tion of the equivalent of a model dipole in conjunction
Usually, interpretation is restricted to latencies at which a with reasonable spatial constraints (hemispheric symmetry
single equivalent dipole source accounts well for the data. etc.), the source problem can be reduced so that a unique
These early methods restricted analysis to a single equiva- solution likely exists for a certain hypothesis.2 The princi-
lent dipole because the number of independent parameters ples of this approach are (1) use available information from
underlying a single instantaneous scalp map is only less or anatomy and physiology to construct an electrical model
equal to the number of recording channels. The use of a of the head, (2) put forward different hypotheses of the
single source keeps the number of parameters small relative origin of an evoked potential by placing equivalent model
to the number of data values, which is an essential prereq- sources within all structures known or assumed to respond
uisite for reliable estimates in the presence of recording to a certain stimulus, and (3) attempt to explain the
noise.43 Hence, for a given instant, not much more than a complete evoked potential data set over space and time by
single equivalent dipole, which already has six coordinates, such a model. The solution can then be tested and com-
can be extracted with confidence.44 pared with competitive hypotheses.2 Thus, spatiotemporal
Instantaneous single equivalent dipole solutions have dipole modeling is fundamentally a hypothesis-driven
some problems. When a part of the brain becomes technique for examining the origins of cortical activity.
activated while a previous part is still active, instantaneous Spatiotemporal source modeling as developed by
single-dipole solutions often describe virtual sources Scherg15 and Scherg and von Cramon16,45 is an approach
remote from both actual sources. In other words, the loca- to brain source localization that accounts for the whole
tion of this equivalent dipole does not necessarily coincide sequence of scalp topographies by a few equivalent dipole
with the loci of the activated brain structures if multiple sources having fixed positions and orientations but a
sources instead of a single source underlie the actual scalp varying strength over time. STSM solutions provide the
map39,43; rather the solution may represent the “center of locations, the orientations, and the strengths of activity
gravity” for the distributed activity at that instant. For over time of equivalent dipoles that could explain the
cortically mediated neural activity, it is quite likely that measured spatiotemporal data. Although equivalent
more than one distinct source contributes to the scalp dipoles can now be computed in several ways, Figure 19-4
activity at any given instant. Certainly for the auditory summarizes the STSM approach developed by Scherg.15
system, it is well documented that bilateral cortical activity Although the figures are schematically shown in two
exists even to monaural stimulation. Consequently, a dimensions, the process must be visualized in three dimen-
single-dipole or moving dipole model of such activity will sions. Recall that the activity recorded from any given
frequently generate a source located along the midline of electrode site on the surface of the head is the sum of all
the head, which clearly represents a physiologically the active sources. This is illustrated in Figure 19-4A
implausible solution. In such cases, single-dipole or mov- for four sources (two pairs of bilateral sources). The
ing dipole models are poor representations based on their amount of contribution from any source to that electrode
physiologic plausibility.43 This does not rule out the value site depends on the conductivity of the medium, the dis-
of single- or moving dipole solutions under all conditions. tance, the orientation, and the strength of the activity. The
For example, if a single-dipole model is used to describe a activity recorded at each of the four electrode sites relative
generator with an established single underlying source to the reference at the top of the head (Cz) is the sum of
over the period of its activation, the clustering of the these four equivalent dipole sources. The bipolar voltage
single-dipole sources can provide information about (1) the waveform recordings shown in Figure 19-4B are simply
validity of the single generator model or (2) the quality of the difference in activity between the reference and the
314 NEUROTOLOGIC DIAGNOSIS

Figure 19-4. Schematic summary of the STSM approach. A, Voltage at any point on the surface of the head is the sum of active sources in the head. The
amount of contribution from any source to that electrodes depends on the conductivity of the medium, the distance, the orientation, and the strength of the
activity. B, Bipolar derivations with Cz as reference. C, Surface waveforms and source waveforms. (Modified from Scherg M: Fundamentals of dipole source
analysis. In Grandori F, Hoke M, Romani GL [eds.]: Auditory evoked magnetic fields and electrical potentials. Adv Audiol, vol 6. Basel, Karger, 1990.)

recording electrode sites. As shown in Figure 19-4C the source is different owing to these parameters of the dipole
four equivalent dipole sources that are active in the brain activity. Note that even though the source activity is
have a simple time-varying source waveform. Thus, the relatively simple, the summed activity as shown by the
sum at each electrode is different as shown by the surface bipolar derivation can be more complex because of three-
waveforms because the relative contribution from each dimensional summation of the source activity.
 Functional Imaging of Auditory Cortical Activity 315

Each electrode site has an associated equation for the finite element models are becoming more widespread.
summed voltage activity. For a given distance and orienta- Application of these models may be particularly appropri-
tion, and a head model for which size and conductivities of ate for assessing the auditory system. Although a spherical
the various compartments (brain, CSF, skull, and skin) are shell model conforms reasonably well to the geometry of
known or assumed, the source activities are computed by occipital cortex, it is much less appropriate for temporal
an iterative procedure, by means of matrix algebra. These cortex. Both boundary and finite element models conform
computations produce a modeled set of waveforms corre- to the natural shape of volume conductor compartments
sponding to the actual location of electrodes on the scalp. (skull, CSF, and brain). Consequently, these volume con-
These modeled waveforms are then compared with the ductors serve to minimize the localization errors inherent
recorded data in a statistical least-squares procedure. The in applying a volume conductor model that does not
iterative procedure is completed when the best fit, which conform to the shape of the brain. Details of dipole
is the smallest residual variance for a given solution, is modeling based on these volume conductors are beyond
achieved. In essence, the procedure attempts to construct the discussion of this chapter. However, note that, as is
a set of dipoles whose location, orientation, and strength true with scalp voltage mapping, the dipole analysis can be
over time will add at the surface of the modeled head and improved by generating more realistic head models
come close to matching the data recorded from the subject. obtained from individual anatomic MRI data (e.g., Teale
The following is an example of this process: et al. and Fuchs et al.),46–48 as seen in Figure 19-5 (middle
Figure 19-5 shows the scalp waveforms (top, left), dipole and bottom right.
source location (top, right), and source waveforms (bottom, With current available commercial software, the local-
left) for the auditory evoked potential data previously ization accuracy of the STSM approach for electrical
shown in Figure 19-2. This solution was obtained with an potentials approaches about 1 cm, but is highly dependent
approximated three-shell head model. Computationally, on the signal-to-noise ratio in the data. More accurate
the few sources are fitted simultaneously to all data across localization with the use of dipole modeling is possible
space and over time. This fitting over both space and time with magnetic fields,49 but with the limitation that radially
has the effect of increasing the reliability of the model- oriented activity cannot be characterized. However, con-
ing.43 A best fit solution is shown for a bilateral set of siderable continuing work seeks to improve accuracy
regional dipoles, which are a set of three dipoles having a and speed of dipole localization estimations through the
common location but orthogonal orientations. Therefore, use of sophisticated algorithms.46,50–55 For example, by
the total number of dipoles for a pair of bilateral regional generating precalculated matrices, Fuchs and cowork-
dipoles is six. The computed source waveforms for each of ers47,48 have provided the capacity to use more realistic
the six dipoles is shown for the best fit solution (Fig. 19-5, boundary and finite element models in near real-time
bottom, left. It can be seen that all three pairs of dipoles in operations. These improvements are necessary if evoked
each set of regional dipoles show significant activity. The electrical potentials and magnetic fields are used to esti-
tangential dipoles contain the typically observed N1–P2 mate sources of neural activity. Modeling electric or mag-
complex, indicating a predominate site of origin on the netic fields produces comparable results.56 The focus is
superior surface of the temporal lobe. The second pair of now more on the determination of the temporal properties
dipole sources shows activity consistent with the T com- of the neural activity and only their general potential loca-
plex. The T complex represents a set of peaks and troughs tions rather than accurate specific loci. Instead, accurate
that are generated along with the larger N1–P2 complex. localization and temporal characterization of the neural
The dipoles associated with this activity have a radial ori- activity can be obtained by combining dipole modeling
entation, indicating a site of generation predominately on or current density reconstruction with other metabolic
the lateral surface of the temporal lobe, likely reflecting (PET or single-photon emission-computed tomography,
activation of secondary, parabelt areas of auditory cortex. SPECT) or hemodynamic (fMRI) techniques discussed later
The third set of dipole waveforms contains two major in this chapter.
peaks that correspond in latency to the middle latency
response peaks Pa and Pb. It is interesting that the orien-
tation of these sources is along the sagittal plane, orthogo- Advantages and Disadvantages
nal to the tangential orientation of the of Spatiotemporal Source Modeling
N1–P2 peaks. The origin of the regional dipoles localized
In summary, Achim and colleagues43 noted the following
to the area of superior temporal cortex of the head model,
advantages of the STSM approach:
which is consistent with the expectation of auditory
processing. The statistical best fit approach indicates that 1. Compared with two-dimensional surface color or
more than 95% of the variance in the original scalp gray-scale maps, localizing the origin of distributed
recordings is accounted for by the modeled waveforms brain activity is more adequately resolved by fitting
over the response time epoch. a number of sources simultaneously from a number
Many complex issues are involved in the modeling of consecutive scalp topographies. Much of the
process, including the assumptions of the nature of the power of STSM arises from its capitalization on both
head model. Initially, most analyses relied on simple spher- spatial and temporal information. The temporal
ical, multishell head models because more realistic models aspect is the important distinction from earlier dipole
were too computationally intensive. However, with the localization models.
widespread availability of high-speed computing in personal 2. For phasic neuroelectric activity, STSM is typically
computers, use of more realistic boundary element and more plausible physiologically than the alternative
316 NEUROTOLOGIC DIAGNOSIS

interpretation of a moving dipole, which models time- Even more valuable is the possibility that we may be
varying topographies as the displacement of a unique able to determine if different channels of cochlear implant
focus of activity whose position, orientation, and inten- stimulation are reflected tonotopically in auditory cortex
sity vary across time and often successfully accounts as revealed by the loci of the best fitting regional diploes.
only for a fraction of the observed topographies. Evoked magnetic fields produced by acoustic stimulation
3. STSM is more parsimonious than the moving single- have demonstrated tonotopic organization of auditory
source model, requiring fewer parameters to account cortex.67–69 An example of using STSM in evaluating
for a complete spatiotemporal data matrix. cochlear implant patients from our work65 is shown in
4. It has been shown that large localization errors can Figure 19-6. At the time of these recordings, the subject
occur with source analysis techniques for a given was an 8-year-old child implanted with the 22-channel
time, depending on the type of head model.57 These Nucleus Cochlear Corp. cochlear implant. The stimuli
errors are reduced by performing the fitting over consisted of short bursts of biphasic current pulses spaced
many time points instead of one, as is the case with 2 msec apart and presented at a burst rate of one per
STSM. Nonetheless, the complexities of source second. Electrode pairs were activated at three locations in
analyses require careful interpretation. the cochlea: near the basal end of the array (electrodes 2
and 6), adjacent to this basal location (electrodes 6 and 10),
The major disadvantages of this technique are its com-
and at the apical end of the array (electrodes 18 and 22). The
plexities and the need to use models and assumptions that
locus of the regional dipole source solution for electrical
are imperfect. Furthermore, for electrical activity, with
stimulation of each of the three cochlear regions is shown
current commercially available software, localization
in Figure 19-6. For all three stimulus conditions, the locus
accuracy is limited to about 1 cm depending on the head
of the regional dipole best fit solutions was consistent with
model and various other assumptions. Current research
activation of auditory cortex. Furthermore, as seen in the
demonstrates several ways to improve the technique when
sagittal view of the model, the loci for the three different
used alone. Nonetheless, even with the currently com-
areas of cochlear stimulation were organized such that the
mercially available software, one can, through cautious
most basal stimulation was posterior and the most apical
and careful application, use these techniques to provide
stimulation was most anterior along the supratemporal
information about auditory processing not available
plane of auditory cortex. This organization is consistent
otherwise.
with a tonotopic arrangement of going from high frequency
to low frequency found in the magnetic studies with
Clinical Applications of Dipole acoustic stimulation.
Source Analyses The shift in the loci is significant and consistent with
magnetic studies.67–69 For this individual, we are confident
Although the STSM or dipole source localization tech- that the shifts are not accounted for by simple variability of
niques have proved useful in clinical studies aimed at local- the solutions. However, it is important to point out that,
izing epileptic spike activity58–63 and cerebral tumors,64 although differences in source location as a function of site
clinical application of STSM alone has yet to become rou- of stimulation within the cochlea have been obtained in
tine in the assessment of auditory problems. many implanted adults, the patterns do not consistently
Clinical application of dipole source-modeling tech- match previously observed tonotopic maps. This inconsis-
niques to problems related to hearing require studies of tency might reflect variability unrelated to the site of stim-
processing in normal auditory systems. During the previ- ulation. Alternatively, these variable patterns of spatial
ous decade, numerous studies have focused on such representation may reflect reorganizational differences
processing laying the groundwork for comparisons related between individuals with varying causes of deafness. Much
to clinical issues. In their early work, Scherg and von work remains to determine whether this approach is viable
Cramon37 showed that the STSM analysis may have clinical means for assessing multichannel cochlear implant stimu-
value in patients with cortical lesions affecting the auditory lation to ascertain the degree of separation and overlap in
system. They demonstrated varying types of abnormalities activating different neural channels.
in the dipole source waveforms associated with lesions of Most of the studies to date have been demonstrations
primary auditory cortex, acoustic radiations, and auditory of the feasibility of the technique and its application to var-
association cortex. ious types of evoked potential activity related to auditory
We attempted to use the source localization technique processing such as the mismatch negativity (MMN) poten-
with cochlear implant patients, particularly younger chil- tial70 and P300.71 Other studies focused on the localization
dren, to determine (1) the extent that responses (behav- of evoked potentials related to processing various sounds
ioral and physiologic) are auditory only and (2) if the including speech.72–74 Because the accuracy of source local-
different channels of stimulation activate different neural ization using dipole modeling alone is limited, much of the
subpopulations in the periphery.65 Because electric current current research is now focused on using a combination
stimulation can potentially activate any nearby neural of dipole and other imaging techniques. As discussed later,
pathway, often other neural structures (vestibular and sen- combining dipole source analyses with metabolic or fMRI
sorimotor) may be stimulated. Such nonauditory evoked techniques may provide a powerful approach for studying
potentials have been observed.66 Our preliminary findings the function of brain structures related to hearing. The
suggest that this technique may be very useful in identify- dipole source analyses estimates the neural activity with
ing auditory and somatosensory contributions to evoked good temporal resolution, and the other imaging tech-
electrical activity from implant stimulation. niques provide good source localizations.
Functional Imaging of Auditory Cortical Activity 317

Continued
318 NEUROTOLOGIC DIAGNOSIS

Figure 19-5. (Upper left): Grand mean scalp-recorded cortical activity evoked by left ear stimulation from a group of young adults. (Lower left): Dipole wave-
forms for each component of regional sources location in homologous left and right hemisphere locations. The sagittal sources contain the middle latency peaks
Pa and Pb, contralateral (upper) and ipsilateral (lower) to the stimulation ear. The radial source waveforms contain the T complex components Ta and Tb. The
tangential source waveforms contain the classic P1, N1, and P2 components. (Upper right): Location of the regional dipole sources superimposed on a schematic
diagram of the head and brain. (Middle right): Source solutions superimposed on an average MRI (from the Montreal Neurological Institute). The sources are
localized to the surface of the superior temporal gyrus. (Lower right): Source solutions superimposed on a structural MRI from and individual subject showing
the location of activity relative to distinct anatomical landmarks. (See Color Plate 2.)

POSITRON EMISSION TOMOGRAPHY metabolism. Tracers such as 18F-dopa, 11C-raclopride, and

11
C-SCH23390 may be used to assess function in
Background and General Principles dopaminergic systems. Other tracers may be used to target
specifically function of monoamine oxidase, benzodiazepine,
Positron emission tomography (PET) is an imaging tech- or opiate receptors.75,77
nique that delineates the magnitude of metabolic activity PET studies generate three-dimensional representations
in the brain. PET is used to measure blood flow, oxygen with an effective resolution of better than 2 cm, so compar-
and glucose metabolism, amino acid metabolism, tissue isons of metabolic activity between adjacent cortical regions
acid–base balance, membrane transport, and receptor– are possible.75,78 However, analysis of functional organization
ligand interactions in the human body.75 The measure- within a region is limited because most subcortical and cor-
ment of metabolism is indirect since PET devices detect tical structures such as auditory cortex have dimensions equal
concentrations of positron-emitting isotopes that have to or less than 2 cm. Attempts to resolve detail of less than
been injected into the bloodstream. These isotopes or 2 cm produce a partial volume effect in which gray and white
radionuclides become concentrated in areas of the body matter of the brain are blended in the PET image. Errors in
where metabolic demand is high. The nucleus of the PET data introduced by the partial volume effect can be
radionuclide contains an excess positive charge, which minimized through correcting PET79 or by performing
diminishes in one of two ways. Negatively charged elec- baseline PET studies for comparison.75 Baseline studies are
trons orbiting the nucleus may be captured or the nucleus also important for establishing local background metabolic
may emit a positron. A positron emitted from the nucleus rates, which vary from one part of the brain to another in
quickly combines with an electron in a process known as both nonhuman species and in humans.75,80
annihilation. During annihilation, the masses of the elec- Although the spatial resolution of PET limits the study
tron and positron convert to electromagnetic radiation in of functional organization within auditory cortex, the
the form of two gamma rays of equal intensity that are temporal resolution of PET studies also places limits on
emitted 180 degrees to each other.76 Positron emission is stimulation paradigms. For example, transitional changes
registered by the PET imaging system only when annihi- on the order of 20 to 200 msec in a speech segments are
lation photons traveling in opposite directions activate sufficient to allow discrimination between phonemes.
coincidence detectors simultaneously.77 By adjusting the However, changes in cortical regional blood flow and
location of the coincidence detectors, concentration patterns metabolism follow a much longer time course. According
for photon emission can be generated for the whole body to Mazziotta and Phelps,75 30 to 40 minutes may be
or for a specific organ of interest such as the brain. required for metabolic activity to achieve a stimulus-
dependent steady-state necessary for PET imaging with
Advantages and Disadvantages deoxyglucose. Thus, it is likely that cortical activation
patterns represented in PET data not only reflect local
of Positron Emission Tomography activation of sensory cortices but also activations associ-
PET images can provide extensive information on func- ated with manipulations of task demands and expectations
tional neurochemical activity in the brain. Radionuclides that may vary from one experimental condition to another.
such as proton-rich isotopes of carbon, nitrogen, or oxygen PET activations can be obtained with 15O-labeled
are used as tracers in PET studies of blood flow or oxygen compounds, which require less than 60 seconds to obtain

Figure 19-6. The loci for three stimulus conditions that differed in which implant electrodes were activated. Stimulation of the basalmost electrodes produces
the most posterior source location; stimulation of the apicalmost implant electrodes produces the most anterior source location.
 Functional Imaging of Auditory Cortical Activity 319

sufficient flow information during stimulation. However, hemisphere. Three months after implant surgery, the areas
even 60-second epochs are too long to examine local of low metabolic activity and the asymmetry between left
neural responses to the microstructure of speech. and right hemisphere metabolic activity were no longer
One additional limitation for PET imaging results from apparent. PET images obtained while the patient listened
the use of radioactive tracers. Although these tracers clear the to recorded speech showed increased levels of metabolic
body quite rapidly, the number of times an individual may be activity in the left parietal cortex. According to Ito and
safely exposed to these elements is limited. Consequently, colleagues,78 the increased metabolism found in auditory
repeated PET imaging of a single individual over a short cortex extended to auditory association cortex, perhaps
interval (weeks) is not possible. Moreover, the use of radioac- indicating that the neural activity evoked by the implant
tive isotopes necessary for PET studies essentially precludes had been perceived as speech. Although this conclusion
the use of this to assess central auditory function in children. may be somewhat premature, PET imaging provided evi-
dence of changes in local patterns of cortical metabolism
Clinical Applications following implantation and demonstrated that regions of
the brain normally associated with auditory function were
PET studies may not be useful for examining rapid changes activated by implant stimulation.
in neural activity in response to transient acoustic stimula- Many additional PET or SPECT studies during the pre-
tion, but global studies of auditory function and brain vious decade have examined the distribution of activated
organization are possible with PET. Early PET or SPECT brain areas to stimulation with a cochlear implant. For the
studies have been conducted with a variety of acoustic stim- most part, the basic findings are similar and demonstrate
uli, including noise, tones, words, stories, and music.81–91 that electrical stimulation of the auditory pathway results in
An early study of auditory function using PET performed activation of areas seen with normal acoustic stimulation or
by Reivich and coworkers81 reported that monaurally consistent with behavioral responses to the stimuli98–105 as
presented stories produced a 20% to 25% increase in local well as for evaluating the effectiveness of the implant106–113
cerebral metabolism throughout the right temporal lobe or for assessing neuroplasticity resulting from deafness or
regardless of the ear of stimulation. Other studies have use of the cochlear implant.114–120
found lateralized patterns of activation dependent on the The exploration of central auditory function in normal-
manner of presentation or the content of the presented hearing children will likely remain limited due to the neces-
material. Results of Greenberg and colleagues85 showed that sity of using radioactive isotopes. However for deaf children
the local cerebral metabolism rate for glucose was 7% and adults, the use of PET or SPECT imaging is more justi-
higher in the temporal lobe on the side contralateral to the fiable if such data can add significantly to preoperative deci-
stimulated ear. Mazziotta and coworkers88 used PET to sions regarding the appropriateness of cochlear implantation
study cerebral activation patterns to verbal and nonverbal as a therapeutic treatment. Recent data reported by Roland
acoustic stimulation. Although verbal discourse increased and coworkers112 examined SPECT activations to auditory
metabolism in left hemisphere structures including the thal- stimulation before and after cochlear implantation in three
amus and frontal cortex, the pattern of metabolic asymme- adults with pure-tone average audiograms of 90 dB or greater
try for nonverbal stimuli was dependent on the processing bilaterally. Results of the study showed that despite having
strategy used by the subject. Metabolic activity was greater relatively similar hearing losses across subjects, significant
in the left than in the right hemisphere for musically trained differences in patterns of cortical activation were observed
individuals or individuals who used visual imagery to between ears. Such results might provide important insights
process the nonverbal stimuli. In contrast, metabolic activ- about which side should be implanted. For adults and
ity was greater in the right than the left temporal lobe in postlingually deafened individuals, behavioral testing can
subjects who did not use visual imagery or who lacked an often provide sufficient information for such decisions.
extensive musical background. During the past decade However, for young children or prelinguistically deafened
numerous additional studies have been aimed at localizing individuals, PET studies of cortical activation patterns pro-
brain areas devoted to these various aspects of auditory vide a preoperative method of assessing objectively which ear
function and to the processing of speech stimuli.92–97 would provide the best postoperative activation of cortex.
PET imaging might also be used to determine the extent
Cochlear Implant Stimulation of damage and preserved auditory function following trau-
matic or ischemic brain injury.75 PET data may be useful for
PET has also been used to assess cortical neural activation delineating deficits associated with damage to primary audi-
produced by electrically stimulating nerve fibers with a tory receiving areas from those associated with damage to
cochlear implant array. In an early PET study, Ito and higher-order speech reception areas in temporoparietal cor-
colleagues78 studied preimplantation and postimplantation tex. PET studies might also provide insight on the origins of
cortical activity in a 38-year-old man who had suffered so-called central auditory processing disorders.121 Atypical
from profound hearing loss at age 11/2 years following cortical metabolism patterns might exist in those individuals
treatment with streptomycin. PET images obtained as a affected by central auditory processing disorders.
baseline before implantation showed broadly distributed
areas of low metabolic activity in the left middle-frontal,
Tinnitus Studies with Positron
posterotemporal, and parietal cortices. The parietal and
Emission Tomography
temporal lobe, as well as Heschl’s gyrus in the right hemi-
sphere, showed little metabolic activity, although activity Several studies have explored PET imaging as a technique
levels were somewhat higher in the right than in the left for objective detection and identification of origin (i.e.,
320 NEUROTOLOGIC DIAGNOSIS

peripheral or central) for tinnitus. PET studies may provide brain with better temporal and spatial resolution than
general information regarding activity and its locus. PET techniques. The new functional imaging MRI (fMRI)
Whether the source of the tinnitus lies in the auditory method relies on changes in the blood supply to the brain
periphery or in central structures of the auditory pathway, that accompany sensory stimulation or changes in cogni-
auditory cortex might show evidence of chronic activation tive state. An excellent review of the early work with this
by a change in metabolic activity. For example, it has been technique is provided by Tank and colleagues.134 Following
suggested that tinnitus associated with unilateral activation this early work, numerous fMRI studies have been con-
of cortex is an indication of a central origin since a periph- ducted of many aspects of auditory function, which we will
eral origin should have bilateral representation.122 Studies briefly review later. Other recent reviews of studies that
comparing cortical metabolic patterns from patients with use fMRI to investigate the auditory system can be found
tinnitus and those without have been performed. The results in Huckins and coworkers,135 Cacace and colleagues,136
of Arnold and colleagues123 and Wang and coworkers124 Seifritz and coworkers, and Bernal and Altman.137,138
using 18F-deoxyglucose (FDG)-PET studies on patients Currently, three basic methods are used to image func-
with disabling chronic tinnitus showed increased metabolic tionally with MRI. Two of the three methods are noninva-
activity mostly in the left primary auditory cortex compared sive approaches, and the third uses exogenous vascular
with nontinnitus subjects. PET studies have evaluated those contrast agents.
patients whose tinnitus can be altered in loudness by orofa-
cial movements125 or by eye movements.126 Studies during
Blood Oxygenation Level–Dependent
habitual tinnitus and when the tinnitus has been suppressed
Contrast Imaging
in the same patient have also been studied.128–130 In addition,
individuals whose tinnitus is triggered by consuming certain Blood oxygenation level–dependent (BOLD) contrast
foods or drinks such as caffeine might be appropriate for imaging is based on the magnetic properties of hemoglo-
repeated studies comparing PET images obtained before bin. For example, because deoxyhemoglobin (hemoglobin
and after ingesting the tinnitus-inducing foods or beverages. without a bound oxygen molecule) is paramagnetic, a blood
Many of these studies also suggest that other brain areas may vessel containing deoxyhemoglobin placed in a magnetic
be involved in the response to emotional responses to the field will alter the field in its vicinity. The greater the
adverse percept of tinnitus (e.g., Mirz et al.).131 amount of deoxyhemoglobin, the greater the local distortion
Johnsrude and colleagues132 recently published a review of the magnetic field surrounding the blood vessel. This
of the use of PET for functionally imaging the auditory distortion surrounding the blood vessel can, in turn, affect
system. However, its poor temporal resolution, its need for the magnetic resonance images of nearby water protons.
radioisotopes, its invasiveness, and its high cost have Thus, the changes in the hemoglobin that are present in
limited its clinical utility. For many applications, it may be low concentrations are difficult to monitor directly by
replaced in the future by fMRI. Although, PET may still MRI. However, these changes affect the signal character-
have the major role in imaging cortical activity to electri- istics of water molecules that are easier to measure since
cal stimulation when prostheses with metal, such as the water molecules are 100,000-fold higher in concentration.
cochlear implant, are used. Ogawa and colleagues139 showed that at high magnetic
fields, blood vessels could be imaged, and the images of the
blood vessels were affected by induced changes in cerebral
FUNCTIONAL IMAGING WITH MAGNETIC blood flow and oxygen utilization.
RESONANCE IMAGING
Blood Perfusion Imaging Using Vascular
Background and General Principles Contrast Agents
A technical description of MRI is not presented here. The For the commonly used magnetic field strength in clinical
reader is referred to the brief review by Andrew.133 In MRI systems, the signal changes observed by the BOLD
essence, MRI involves imaging in a slice of the head, the contrast technique are only a few percent. One can obtain
distribution of protons that have been selectively excited significantly larger changes in signal intensity, ranging from
(i.e., in resonance) by applying a magnetic field gradient. 50% to 100%, by intravenous injection of an exogenous
In its most basic application, MRI does not use ionizing paramagnetic contrast agent. These perfusion-based maps
radiation and is noninvasive. However, contrast improve- have excellent spatial resolution. Furthermore, maps can be
ment can be achieved by intravenous injection of a para- calibrated to provide quantitative changes in cerebral blood
magnetic solution such as gadolinium diethylenetriamine flow and cerebral blood volume. Belliveau and cowork-
pentaacetic acid (Gd-DTPA). Most MRIs are maps of the ers,140,141 using Gd-DTPA, first reported perfusion-based
proton nuclear magnetic resonance (NMR) signals from maps with a focus on cerebral blood volume changes accom-
water and fat in the tissues but images of blood flow and panying stimulation of the visual system.
diffusion can also be obtained.133 Currently, the spatial
resolution of MRI, below 1 mm, is far superior to that of Blood Perfusion Imaging Using Inversion
other neuroimaging techniques. Recovery Methods
The early application of MRI provided mainly anatomic
imaging technique devoid of dynamic functional informa- Kwong and coworkers142 demonstrated that the perfusion
tion. However, during the past 15 years, a variant of MRI of blood in brain areas can be measured noninvasively with
was developed to provide functional maps of the human a method called inversion recovery (IR). This method
 Functional Imaging of Auditory Cortical Activity 321

depletes the concentration of MRI-visible water protons in is shorter than the hemodynamic response function for
a brain region and measures water protons that enter the each stimulus item, data collected with boxcar designs are
region through blood flow, providing a direct measure- interpreted as a brain state- (task-induced) dependent
ment of flow without the use of exogenous contrast agents. measure. The disadvantage of boxcar designs is that the
Improvement in resolution can also be achieved by acoustic noise of the imaging sequence is concurrent with
increasing the strength of the magnet. In the past, typical the fMRI stimulation, which may significantly affect the
clinical systems had a magnet strength of 1.5 T (teslas); arousal and attention. In addition, the acoustic noise of
now it is much more common to find systems with magnet the imaging sequence will act as a mask for experiments
strengths of 3 to 4 T, with the occasional research lab having using auditory stimulation.
more high-powered magnets of 7 T.
The use of fMRI to study auditory neural function is Advantages and Disadvantages
based on the fact that changes in neural activity are accom- of Event-Related Designs
panied by changes in energy metabolism. Tank and In an event-related paradigm, stimulus presentation is
colleagues134 discuss several lines of evidence that support asynchronous with fMRI acquisition sequences. One
the notion that increased metabolic rate is correlated in disadvantage of event-related design experiments is their
many mammalian species, including humans, with an somewhat lower level of cortical activation (compared with
increase in blood flow that can be controlled locally.143–146 boxcar designs), thus resulting in lower statistical power.
In addition to the variety of methods that have evolved Lower levels of cortical activation lead to longer fMRI
for acquiring fMRI, two major stimulus presentation/ acquisition times. One advantage of event-related or
experimental design paradigms have been adopted for use sparse designs is that responses to single stimulus type can
in most fMRI experiments: the so-called box or block be characterized by averaging activation across multiple
designs and event-related, or sparse stimulation, designs. stimulus presentations.The data are more easily inter-
A number of excellent reviews have been written describ- pretable relative to specific types of stimulus events. As
ing the benefits and drawbacks of these techniques. Briefly, such, the fMRI data recorded during event-related
boxcar designs are experimental sequences in which stim- sequences are much more comparable to evoked (or event-
ulation is simultaneous with (occurs at the same time as) related) potentials. Another major advantage of event-related
the imaging sequence. Event-related, or sparse, designs paradigms is that since stimulus presentation precedes
are those in which a series of stimuli are presented during each scanning sequence, the arousal and attentional effects
a period prior to the onset of the MR scanning sequence. produced by the high noise levels of the imaging sequence
The justification for this approach is that for BOLD stud- are not superimposed on cortical activations produced by
ies, a buildup time of approximately 4 seconds is needed the stimulus events.
for the response to reach its peak. For auditory studies, this
is an advantageous over the boxcar design because experi-
mental acoustic stimulation can be separated from the arti- Auditory Studies Using Functional Magnetic
factual acoustic stimulation produced by the scanning Resonance Imaging
sequence. It is now well established for many auditory Cortical Areas Involved in Basic Processing
processes that psychophysical data obtained in the pres- of Auditory Stimuli
ence of high levels of background masking noise do not
always match those for stimuli presented in quiet. For Functional imaging techniques have been trying to answer
example, Shtyrov and coworkers147 demonstrated that for the fundamental question of where in the cortex certain
speech-evoked MEG responses, the degree of lateralized types of auditory processing take place. The assumption is
cortical activity evoked by the presentation of a deviant that with simple acoustic stimuli such as tones, one acti-
stimulus (MMN) changes dramatically between no-noise vated area must be primary auditory cortex. Examples are
and background noise conditions. Thus, with no back- studies trying to identify areas involved in basic processing
ground noise, speech-evoked MMN dipole activity was for simple tones to verify tonotopic organization at cortical
strongly lateralized to the left hemisphere. However, in levels or effects of parametric changes in the stimuli.149–162
the presence of background white noise, the magnitude Although a number of these studies suggest that tonotopic
of the left hemisphere response decreased, while activity in organization can be seen, the fMRI studies of Talavage and
the right hemisphere increased. These results, combined colleagues154 and Schonwiesner and coworkers163 suggest
with psychophysical studies of the effects of background that multiple frequency-dependent activation sites exist
noise on auditory perceptual processes, would suggest that and that it is difficult to demonstrate a single primary
the event-related or sparse experimental paradigm would tonotopic organization. Another basic processing issue is
be preferable for fMRI studies of central auditory where and how the brain is activated in response to simple
processes. A brief review of the advantages and disadvan- monaural and binaural stimuli.164–168
tages of these two techniques as described by Horwitz and
Cortical Development, Maturation, and Plasticity
colleagues148 is outlined in the following sections.
In the study of activation and processing of simple auditory
Advantages and Disadvantages of Boxcar Designs input, understanding the time course of the development
As one advantage, boxcar design experiments are typically and maturation of such processing is very valuable. Such
able to measure higher levels of cortical activation, result- knowledge is vital to understanding not only pathology but
ing in greater statistical power. This in turn leads to faster also the plasticity of a compromised auditory system. It has
fMRI acquisition times. Because the interstimulus interval been demonstrated that fMRI studies can be carried out in
322 NEUROTOLOGIC DIAGNOSIS

children169 as well as in infants and neonates170 and could effect of attention186,187 and involuntary attention switch-
provide insight to cortical development and maturation ing188,189 in the processing of sounds. Other issues related
when compared with studies in adults. Understanding to the processing of speech and language are differences in
development and maturation of cortical processes helps us activation between words and nonwords or speech and
to understand changes due to deafness and the related nonspeech,190–193 listening comprehension,194–196 semantic
issues of reorganization and brain plasticity. For example, processing,196 sex differences in laterality of language com-
Tschopp and colleagues171 and Bilecen and coworkers172 prehension,196,198 identifying where speech parameters are
used fMRI to study activation of auditory cortical areas in processed in the brain,199,200 and specific sensitivity to
unilaterally deaf patients, and Suzuki and colleagues173 vocal sounds.201 Because of the complexities involved in
showed that cortical patterns change very quickly in speech and language processes, interpretations of the
patients who suffered sudden hearing losses. Studies in activations observed in fMRI studies are often difficult and
totally deaf patients who subsequently received cochlear do not always parallel findings with direct cortical stimula-
implants may provide clues about brain plasticity and how tion.202 The popularity of language studies and fMRI was
it may be affected by deprivation and the reintroduction of recently emphasized by a special journal issue devoted to
auditory stimulation. “Functional Brain Imaging of Language” (Human Brain
Mapping, vol. 18, 2003).
Cross-modal Activation in Primary Auditory Cortex
Tinnitus
One of the more controversial issues related to deafness
and plasticity is whether reorganization subsequent to We already discussed attempts to detect the presence of
deafness is such that stimulation in the visual modality tinnitus with the PET imaging methods. Functional MRI
produces activation in primary auditory cortex (PAC). has been similarly used to identify objectively the presence
Although ample fMRI evidence demonstrates that visual of certain kinds of tinnitus and the locations in the
stimulation associated with communication (e.g., lip reading) auditory system that might be involved. Thus far, only
can activate auditory cortical areas,174–178 as well as evidence certain forms of tinnitus have been amenable to study
that activity increases in auditory areas of the temporal with fMRI.203–206 Studying with fMRI the neural activity
lobe of deaf subjects performing visual tasks or stimulated associated with the presence or onset of tinnitus is
visually,176,179–181 it is unclear that such visual stimuli particularly difficult because of the high noise levels
activate the PAC. Some claim activation of PAC with produced by the scanner. Attempts to overcome this inher-
visual stimuli alone.176,180,181 Others claim from their fMRI ent disadvantage of fMRI are discussed in the following
analyses that activation occurs in nonprimary auditory section.
areas but not in primary auditory cortex.119,178 Animal
work in congenitally deaf cats by Kral and colleagues182
also demonstrated that there was no evidence for cross- Advantages and Disadvantages
modal reorganization of primary auditory cortex. In other of Functional Magnetic Resonance
words, primary auditory cortex remains specific to audi- Imaging
tory stimuli. A problem that leads to this controversy is the
identification of primary auditory cortex from the MR The obvious advantage of those fMRI techniques that
scans. Such identification can be difficult. More cytoarchi- image without exogenous contrast agents is their noninva-
tectonic studies are needed to develop an accurate siveness. Unlike PET and SPECT, MRI has no known
anatomic reference system.183,184 toxicity issues and many repetitions of experiments on
individual subjects are possible.
Cochlear Implant Assessment However, perfusion-based fMRI imaging techniques
Assessing cortical plasticity may lead to an understanding that use intravenous injections of paramagnetic solutions
of performance differences with a cochlear implant. to improve the contrast suffer the same drawbacks of
Although a number of PET studies of cochlear implant invasiveness and toxicity that limit the number of scans
patients have been done, little has been done with fMRI on a single patient. Also, only a single map is produced
because of the metal content in implants (discussed later). by imaging during the transit of a contrast agent, and
Truy107 and Giraud and colleagues119 reviewed the use of var- the time course of the hemodynamic changes cannot be
ious neurofunctional imaging techniques including fMRI to measured.
study cochlear implant patients and cortical plasticity and A major disadvantage for auditory studies is that fairly
noted their advantages and disadvantages. high levels of noise are generated by MRI units, which
makes it difficult to conduct auditory studies.188,207 A
Speech and Language Studies detailed specification of the spectral characteristics of
During the previous 10 years numerous fMRI studies have the noise from the scanner can be found in Ravicz and
tried to determine the cortical areas involved in speech colleagues.207 Several studies have addressed the noise
perception and discrimination as well as areas important issue. McJury and Shellock208 discuss in their review (1) the
for language processing. A review of these studies is not various types of acoustic noise produced during the oper-
possible here. We simply provide a few examples of the ation of MRI systems, (2) the characteristics of the acoustic
kinds of studies that are being conducted. Studies of noise, and (3) information regarding noise control tech-
speech processing under dichotic and diotic conditions185 niques. As described previously, it may be preferable for
suggested differences in areas activated that may be due to fMRI-based studies of central auditory processing to use
attention factors. A number of studies investigated the those experimental designs that rely on the physiologic
 Functional Imaging of Auditory Cortical Activity 323

delays between the onset or the end of stimulation, and the and clinical application of functional imaging techniques
corresponding hemodynamic response can be used to min- related to auditory evaluation are now emerging. Although
imize the MRI noise in acoustic stimulation studies.137,209–214 a review of clinical application is not possible, we can exam-
Alternatively, developing effective methods to attenuate ine some of the assumptions about the potential value of
or cancel the noise generated by the MRI systems215 or use these imaging techniques. Many of the possible clinical
of a loudness-matching formula to reduce the effects uses for auditory evaluation can be seen from the various
of scanner noise on the activation measures should be topics we have just reviewed. In addition, it has been shown
considered.211 that functional imaging with MRI can be useful in mapping
Another major disadvantage for auditory investigations epileptic foci and studying patients with psychiatric and
is that the use of MRI with cochlear implants is con- neurologic disorders.121,233 We briefly mentioned that
traindicated because of the possible torquing that can many of these metabolic and blood flow neuroimaging
result when applying a magnetic field to metal containing studies have directed their attention to determining the
ferrous material.216 However, Lazeyras and colleagues217 anatomic location of important language areas and map-
claim that fMRI scans can be safely obtained in patients ping areas involved in higher cognitive processing.
with a cochlear implant with methodologic changes and
careful techniques. Alwatban and coworkers218 and Schmidt
and colleagues219 demonstrated methods for electrically SUMMARY
stimulating the auditory system in deaf subjects and also
studying them with fMRI in order to assess the patient’s Functional imaging of electrical, magnetic, and metabolic
suitability for a cochlear implant. activity of the brain in response to sensory stimulation is
a rapidly evolving area of investigation. Each of the
Clinical Applications and Combining techniques can provide different views of brain activity,
and each has its own advantages and disadvantages. In
Imaging Techniques general the neuroimaging methodologies can be catego-
Because each of the imaging techniques has advantages rized into those that have high temporal resolution (EEG
and disadvantages, which technique is appropriate depends and MEG) and those that have high spatial resolution
on the type of patient and the information desired. It is (PET, SPECT, and fMRI). For investigations of central
obvious that if it were possible to gather information from auditory processing, particularly those involved with
more than one technique, better information could be speech, some advantage might be gained by acquiring the
obtained than from any single technique alone. The prob- high temporal resolution of EEG and high spatial resolution
lem is that these imaging techniques are expensive and of fMRI simultaneously. This technologically challenging
require facilities that are not always widely available. approach will likely become a focus of much development
Nonetheless, the value of information that a combination and investigation over the next few years. Although the
of techniques can provide for clinical application is great, clinical value and applications of these techniques have not
and we believe such combination studies will be more been clearly defined, the demonstration of their enormous
common as issues of cost and availability are resolved. The potential for helping us understand the nature and location
main advantage of fMRI and PET studies is their ability to of sensory deficits is emerging. Realization of this poten-
localize sources of presumed activity with fairly good tial will take some time, but the information provided by
accuracy. However, their main disadvantage is that they functional imaging techniques should be valuable in
provide poor temporal information, especially PET diagnosis and treatment of auditory-impaired patients.
images. Localization of neural activity with dipole source
analyses of electrical and magnetic surface recordings is
less precise, but these methods provide good temporal
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 PLATE 1

Figure 19-2.Top, The scalp distribution for cortical activity evoked by monaural stimulation to the leftear. The major peaks of the auditory evoked potentials are
marked in the inset. Bottom, On the left, a voltage distribution for N,oo of the auditory evoked potentials is shown for the activity shown at top of thisfigure. In
center, the scalp voltage distribution is shown for the P150 potential. The voltage distribution for a left median nerve somatosensory N54 is shown onthe right.
 PLATE 2

Figure 19·5. Upper left, Grand mean scalp-recorded cortical activity evoked by leftear stimulation from a group of young adults. Lower left,
Dipole waveforms for each component of regional sources location in homologous leftand righthemisphere locations. The sagittal sources contain
the middle latency peaks Pa and Pb, contralateral (uppe!') and ipsilateral (lowe!') to the stimulation ear. The radial source waveforms contain the
T complex components Ta and Tb. The tangential source waveforms contain the classic P" N,. and P2 components. Upper righI, Location of the
regional dipole sources superimposed on a schematic diagram of the head and brain. Middle right, Source solutions superimposed on an average
MRI (from the Montreal Neurological Institute). The sources are localized to the surface of the superior temporal gyrus. Lower righI, Source
solutions superimposed on a structural MRI from and individual subject showing the location of activity relative to distinct anatomical landmarks.
 Chapter
Imaging of the Labyrinth

Outline 20
Magnetic Resonance Perilymphatic Fistula Alexander S. Mark, MD
Imaging Techniques for the Labyrinthine Neoplasms
Labyrinth Labyrinthine Schwannomas
Labyrinthine Lesions Other Tumors Involving the
Congenital Malformations of Labyrinth
the Inner Ear Postoperative Changes
Labyrinthine Hemorrhage Endolymphatic Hydrops
Labyrinthitis Conclusion
Contrast Enhancement of the
Labyrinth

U ntil recently, the only appropriate imaging modality

for diseases affecting the temporal bone was high-
resolution computed tomography (HRCT). Although this
spontaneous hyperintensities inside the labyrinth, which
can be caused by fat (lipoma), blood (trauma, cholesterol
granuloma, vascular malformation), tumor (schwannomas),
technique is obviously still important and in fact relied on or a high protein concentration of the intralabyrinthine
by most centers for imaging many temporal bone diseases, fluid (in case of acoustic schwannomas). In the coronal
the advent of magnetic resonance (MR) contrast agents plane, fat-suppressed, T1-weighted spin-echo images
has clearly expanded the role of MR imaging (MRI) in this should be used to eliminate the high signal intensity of
region.1 Recent technical innovations in fast imaging and the bone marrow, often present in the walls and especially
high-resolution techniques have finally made MRI appro- in the roof of the IAC. These images can also be used to
priate for many of these conditions, and in some cases exclude a lipoma or to differentiate lesions from the fat
uniquely so. This chapter discusses the role of MRI in the used to close the surgical access route.
evaluation of the labyrinthine pathology.2 Today, heavily T2-weighted gradient-echo or fast spin-
echo 3DFT images4 are mandatory if the labyrinth has
to be evaluated in detail. These images must be very thin,
MAGNETIC RESONANCE IMAGING 0.5 to 0.7 mm, and must provide high contrast between
TECHNIQUES FOR THE LABYRINTH the cerebrospinal fluid, intralabyrinthine fluid, nerves, and
bone. This sequence is mainly used to check the three
The labyrinth is always imaged together with the internal branches of the vestibulocochlear nerve and the facial nerve
auditory canal (IAC) and cerebellopontine angle. MRI of in the IAC and to verify possible loss of intralabyrinthine
the labyrinth should include high-resolution pre- and post- fluid due to the presence of fibrosis or a tumor.5 Three-
contrast T1-weighted images in the axial plane and post- dimensional reconstructions, multiplanar reconstructions,
contrast T1-weighted images in the coronal projection. and virtual images6 of the fluid-containing membranous
Conventional spin-echo 3-mm-thick T1-weighted images labyrinth can be obtained with these images,7 which are
(14–16 field of view, 192 × 256 matrix, and four excitations used more and more frequently prior to cochlear implanta-
on a 1.5-T imager) provide good images of the labyrinth. tion.8 However, one must bear in mind these sequences are
Nevertheless, today more and more thinner 2-mm spin- prone to magnetic susceptibility artifacts.9
echo or even 1-mm 3-D Fourier transform (3DFT) gradi-
ent-echo T1-weighted images are used.3 These images
demonstrate the different turns of the cochlea, the LABYRINTHINE LESIONS
vestibule, semicircular canals, and, in many cases, the endo-
lymphatic sac in even more detail. Even the nerves and In the past, the labyrinth was almost exclusively imaged with
vessels inside the IAC and cerebellopontine angle become HRCT. CT still has its value for the evaluation of congeni-
visible on the 1-mm-thick images. Precontrast T1-weighted tal SNHL although modern MR sequences can depict most
images are necessary to differentiate enhancement from of the pathology seen on CT and is even able to detect
331
332 NEURORADIOLOGY

congenital malformations that remain invisible on CT.

Recently, because of a number of technical advances coupled
with the availability of intravenous contrast agents, a num-
ber of inflammatory and neoplastic lesions of the labyrinth
diagnosed previously only at autopsy or at surgery can be
imaged. This section describes some of the labyrinthine
diseases that can be diagnosed by imaging modalities and
emphasizes the respective strengths of HRCT and MRI.

CONGENITAL MALFORMATIONS
OF THE INNER EAR
Congenital malformations of the cochlea and vestibular
system are frequently found in patients with sensorineural
hearing loss (SNHL) and vertigo.10 These malformations
can be detected on CT but patients presenting with SNHL
or vertigo are today best first examined on MRI.11 Figure 20-1. Labyrinthine hemorrhage. Eleven-year-old girl with leukemia
Therefore the MRI technique must include thin and sudden total right-sided SNHL. Fine horizontal nystagmus to the left on
left lateral gaze. Temporal bone specimen demonstrates hemorrhage in the
T2-weighted gradient-echo images (3DFT-constructive cochlea and vestibule. (From Schuknecht HF: Hemolabyrinth. In Schuknecht
interference in steady state, CISS) or fast spin-echo images HF [ed.]: Pathology of the Ear, 2nd ed. Philadelphia, Lea and Febiger, 1993, pp
because this pathology can be overlooked on the other MRI 303–306, with permission.)
sequences. The most frequent congenital malformation is a
large vestibular aqueduct (CT) or large vestibular duct and
sac12,13 (MRI). The patients present with SNHL, often trig-
gered by minor trauma, and vertigo and loss of equilibrium. and results in deafness.17 The most important imaging
The vestibular aqueduct or sac is considered too large when signs are (1) absence of a bony barrier between the cochlea
its diameter is larger than 1.5 mm or when it is larger than and fundus of the IAC; (2) enlargement of the labyrinthine
the diameter of the posterior semicircular canal or duct. segment of the facial nerve canal; (3) convex angle anteri-
Associated enlargement of the scala vestibuli/scala media in orly between labyrinthine and tympanic segment of the
comparison with the scala tympani is often present in these facial nerve canal; (4) large vestibular aqueduct/duct and
patients and can only be detected on MRI.14 sac; and (5) cochlear dysplasia.
Semicircular canals or ducts with an abnormal shape,
increased or decreased diameter, or that are partially
absent can be detected on CT and on T2-weighted LABYRINTHINE HEMORRHAGE
gradient-echo images. The most frequent malformation is,
however, a saccular semicircular canal confluent with an In the absence of trauma, labyrinthine hemorrhage18 is a
enlarged vestibule. The term LCVD (lateral semicircular rare cause of SNHL and vertigo.19 It can occur in patients
canal-vestibule dysplasia) is used when this occurs as a sole with coagulopathies, leukemia20 (Figs. 20-1 and 20-2), after
radiographically detectable anomaly. Cochlear malforma-
tions are often associated with severe congenital SNHL.15
Aplasia of the complete temporal bone, aplasia of the
cochlea, common cavity formation (cochlea and vestibule
form one cavity), dysplasia (severe malformation of the
cochlea) and hypoplasia of the cochlea (cochlea is small,
number of turns can be reduced), and less severe malfor-
mations (Mondini’s malformation) can all be detected on
CT and MRI.16 However, some subtle signs can be seen
only on MRI. For instance, the inter- and intrascalar
defects inside the cochlea, described by Mondini, and the
absence of a normal separation between scala tympani and
vestibuli can be recognized only on MR.
Abnormal connections can exist between the subarach-
noid spaces and the perilymphatic space in patients with
congenital inner ear malformations. In these patients the
pressure of the cerebrospinal fluid is transmitted to the
cochlea and causes a perilymphatic hydrops. These patients
can present with recurrent meningitis, progressive fluctu-
ating hearing loss, tinnitus, and/or vertigo. When these Figure 20-2. Elderly man with chronic myelocytic leukemia and bilateral
patients are operated on (e.g., stapedectomy), the intra- SNHL. Coronal precontrast T1-weighted images demonstrate high signal in
labyrinthine fluid gushes out of the cochlea (gusher ear) the cochleas (arrows).
 Imaging of the Labyrinth 333

A B
Figure 20-3. Cochlear hemorrhage secondary to an surgically proven intracanalicular arteriovenous malformation. A, Coronal nonenhanced T1-weighted MRI
shows high signal (arrow) presumed to represent methemoglobin in the cochlea. B, Coronal T1-weighted MRI through the IAC shows high signal within it
(arrowheads).

fistulization of an adjacent lesion (e.g., hemangioma, arte- high signal intensity in the labyrinth consistent with sub-
riovenous malformation, Fig. 20-3), cholesterol granuloma, acute hemorrhage.25 Theoretically, acute hemorrhage
or carcinoma of the endolymphatic sac21 (Fig. 20-4), or should be diagnosed on T2-weighted images as a very low
secondary to trauma with or without an associated fracture. intensity signal, but we have not encountered such cases in
Viral labyrinthitis may also be hemorrhagic22 (Fig. 20-5). our experience. Realistically, most patients will be studied
Labyrinthine hemorrhage cannot be demonstrated by CT. at the subacute stage.
However, it can be suspected when a fracture of the tem- If the bleeding was severe enough, the mixture of intra-
poral bone23 is identified passing through the labyrinth.24 labyrinthine fluid and blood will eventually become a clot or
MRI is uniquely suited to the demonstration of show soft tissue/fibrotic characteristics. This can be recog-
labyrinthine hemorrhage. Precontrast studies demonstrate nized on the 3DFT, gradient-echo, T2-weighted images as

A B
Figure 20-4. Hemorrhagic low-grade adenocarcinoma of the endolymphatic sac within the medial temporal bone fistulizes to the membranous labyrinth with
subacute blood in vestibule. A, Axial CT image of the left temporal bone at the level of the vestibule (arrow) shows the adenomatous tumor (curved arrow) as an
area of scalloping along the medial surface of the temporal bone. B, T1-weighted axial MRI at the same level as A reveals the high-signal tumor (curved arrow)
with high signal within the vestibular membranous labyrinth (arrowhead), presumed to represent methemoglobin. (From Mark, et al: MRI of sensory neural
hearing loss: More than the eye? AJNR 14:37–45, 1993, with permission.)
334 NEURORADIOLOGY

LABYRINTHITIS
The term labyrinthitis describes any inflammatory process
of the membranous labyrinth. It is most often due to
viruses26–28 such as rubella29 (Fig. 20-6), mumps30 (Fig. 20-7),
herpes zoster,31 measles,32 or Lassa fever,33 but it may be
secondary to pyogenic bacterial infections (Figs. 20-8 and
20-9) or syphilis34 (Fig. 20-10). The hallmark of labyrinthi-
tis on MRI is demonstration of enhancement of the cochlea
or vestibule on the postcontrast study.35 Labyrinthitis is
the most frequent cause of labyrinthine enhancement.
The intralabyrinthine fluid, mixed with gadolinium which
leaked through the ruptured blood-labyrinth barrier, is
only mildly hyperintense when the labyrinthitis is viral in
origin.
Bacterial labyrinthitis36 and especially labyrinthitis fol-
lowing pneumococcal labyrinthitis is often hemorrhagic
Figure 20-5. Acute hemorrhagic viral labyrinthitis. Thirty-year-old woman and results very quickly in fibrous obliteration of the intra-
with acute SNHL on the right and vertigo during the course of a viral illness. labyrinthine fluid spaces. In these patients high signal
Axial unenhanced T1-weighted image reveals high signal intensity in the right
cochlea and vestibule consistent with subacute hemorrhage. (Courtesy of intensity can be seen in the labyrinth on the unenhanced
Dr. D Schellinger, Washington, DC) T1-weighted images (when hemorrhagic), intral-
abyrinthine enhancement can be seen on the postcontrast
study, and the high-signal-intensity intralabyrinthine fluid
is replaced by fibrous tissue. Calcification can occur very
a region where the high signal intensity of the intra- quickly, even during the first 2 weeks following the infec-
labyrinthine fluid is replaced by low-signal-intensity material. tion, and can eventually lead to complete labyrinthitis
When a fracture is present, the loss of the high-signal- ossificans. Calcified obliteration cannot be distinguished
intensity intralabyrinthine fluid can also be caused by on MRI; only CT can identify the calcified areas.
leaking of the fluid into the middle ear cavity. The empty However, fibrous obliteration will remain unnoticed on
space inside the labyrinth is then very quickly obliterated CT. Therefore, MRI and CT are complementary in the
by clot and fibrous tissue formation. A less well-known study of patients with labyrinthitis. The detection of
cause of labyrinthine hemorrhage and subsequent obliter- calcifications or fibrous obliteration inside the membra-
ation of the intralabyrinthine fluid spaces is surgery. Stapes nous labyrinth is, of course, essential in the preoperative
surgery can result in intralabyrinthine bleeding. The assessment of cochlear implant candidates. As mentioned
drilling performed during middle or posterior fossa earlier, only a combined CT-MRI evaluation provides the
approach to treat acoustic schwannoma can also result in surgeon with all the necessary information. Moreover,
subtle intralabyrinthine bleeding (concussion) and can unlike CT, MRI is often capable of showing whether a
eventually cause complete obliteration of the intra- single scala is still open and can be used for cochlear
labyrinthine fluid spaces. implantation.

A B
Figure 20-6. Rubella labyrinthitis. Axial (A) and coronal (B) contrast-enhanced images demonstrate enhancement of the membranous labyrinth and cochlea.
The diagnosis was confirmed by serology.
 Imaging of the Labyrinth 335

A B
Figure 20-7. Mumps labyrinthitis. Young child with bilateral SNHL and vertigo 3 weeks following mumps orchitis. A, Axial T1-weighted postcontrast image
demonstrates intense enhancement of the cochlea and membranous labyrinth. B, Late sequelae of measles labyrinthitis from another patient who had severe
SNHL since age 4 years following measles infection. The study shows severe atrophy of the organ of Corti and endolymphatic hydrops. (From Schuknecht HF:
Viral infection. In Schuknecht HF [ed.]: Pathology of the Ear, 2nd ed. Philadelphia, Lea and Febiger, 1993 pp 235–244, with permission.)

A B

Figure 20-8. Bacterial labyrinthitis. Middle-aged man with left middle ear infection, acute hearing
loss, and facial nerve paralysis. Pre (A) and post (B) gadolinium-enhanced, axial T1-weighted
images demonstrate enhancement of the left cochlea and vestibule endolymphatic sac and IAC.
Note the cerebellar abscess. CT (C) demonstrates bony erosions in the temporal bone.
(Courtesy of Dr. Jean Prere, Toulouse, France)

C
336 NEURORADIOLOGY

endolymphatic hydrops. Necrosis of the membranous

labyrinth and, if the patient survives, healing with new
bone formation (labyrinthitis ossificans) develop in the
later stages.
In the preantibiotic era, syphilis37 was a major cause of
SNHL. The disease could be acquired perinatally, result-
ing in congenital hearing loss, or in adult life. The pathol-
ogy includes a meningoneurolabyrinthitis in the early
stages of congenital syphilis and in the acute meningitides
of the secondary and tertiary stage, and temporal bone
osteitis in the late congenital forms and in tertiary syphilis.
The chronic lesions are identical regardless of the acquisi-
tion mode and are characterized by endolymphatic
hydrops and degeneration of the sensory and neural
structures.38
Immune-mediated inner ear disease may be isolated
or seen in the context of a systemic autoimmune disease.
Figure 20-9. Bacterial labyrinthitis. Middle-aged man with right middle Primary autoimmune labyrinthitis is a relatively new cause
ear infection, acute hearing loss, and facial nerve paralysis. Coronal of SNHL.39 The diagnosis is based on a positive lympho-
gadolinium-enhanced, axial T1-weighted image demonstrates enhancement cyte transformation test to inner ear preparation and a
of the right cochlea and vestibule (arrow) consistent with extension of the
infection to the labyrinth. positive response to steroid treatment.
Systemic autoimmune disorders that may affect the
inner ear include Cogan’s syndrome, polyarteritis nodosa,40
Wegner’s granulomatosis, and relapsing polychondritis.
Bacterial labyrinthitis can result either from extension Cogan’s syndrome is an autoimmune disease characterized
to the labyrinth of a middle ear infection (otogenic suppu- by interstitial keratitis and hearing loss in Venereal Disease
rative labyrinthitis), in which case the infection usually Research Laboratory (VDRL)-negative patients. The dis-
penetrates the labyrinth through the oval window, or after ease responds to steroids. Enhancement of the cochlea and
meningitis, in which case it is usually bilateral (meningo- vestibule as well as obliteration of the membranous labyrinth
coccal bacterial labyrinthitis). Otogenic suppurative has recently been reported in autoimmune labyrinthitis and
labyrinthitis is characterized pathologically in the acute in patients with Cogan’s syndrome41 (Fig. 20-11). Relapsing
phase by a polymorphonuclear infiltrate in the perilym- polychondritis is an autoimmune disease characterized by
phatic space followed by a fine fibrillar precipitate and multiple episodes of cartilage inflammation, in particular,

A B
Figure 20-10. Syphilitic labyrinthitis. A 30-year-old man with decreased hearing and facial palsy on the right. A, Coronal T1-weighted, gadolinium-diethylenetri-
amine pentaacetic acid (Gd-DTPA)-enhanced images. Enhancement of the right cochlea and of the right facial nerve (arrow). The left cochlea and facial nerve
are normal. B, Congenital syphilis. Progressive bilateral hearing loss since age 18 years, progressing over 10 years. Extensive microgummata are noted in the
pericochlear bone (arrowhead). A large gumma is noted in the internal auditory canal (IAC) in the place vacated by degenerated vestibular and cochlear nerves
(arrow). There is marked endolymphatic hydrops (asterisks) and advanced atrophy of all structures in the IAC. (From Schuknecht HF: Infections of the inner ear.
In Schuknecht HF [ed.]: Pathology of the Ear, 2nd ed. Philadelphia, Lea and Febiger, 1993, pp 247-253, with permission.)
 Imaging of the Labyrinth 337

A B

C D
Figure 20-11. Cogan’s syndrome. A, Precontrast and, B, postcontrast axial T1-weighted images demonstrate enhancement of the right cochlea (arrow) and
vestibule (arrowhead). C, A 0.7 mm high-resolution T2-weighted image demonstrates obliteration of the normal fluid in the cochlea and vestibule. D, HRCT
demonstrates ossification in the basal turn of the cochlea. (From Casselman JW, Mojoor MHJM, Albers FW: MR of the inner ear in patients with Cogan
syndrome. AJNR 15:131–136, 1994, with permission.)

of the earlobe. The condition may be associated with contrast medium in the setting of only moderate SNHL.
hearing loss and vertigo. We have recently demonstrated This study demonstrated marked enhancement of the
labyrinthine enhancement in this entity (Fig. 20-12). Finally, cochlea and vestibule. Our anecdotal observation suggests
intralabyrinthine enhancement can also be seen in cases of that the use of higher doses may increase the sensitivity
tuberculosis and sarcoidosis, and can even occur after for such abnormalities. Thus, similar to enhancement in
gamma-knife treatment in the vicinity of the labyrinth. the meninges, there is a threshold effect (Fig. 20-13),
with only the most severe inflammatory processes produc-
ing labyrinthine enhancement.43 The resolution of the
CONTRAST ENHANCEMENT enhancement may parallel resolution of the patient’s
OF THE LABYRINTH symptoms42 (Fig. 20-14), or, if the inflammatory process
has resulted in permanent damage to the labyrinthine
Study of the functional correlation between labyrinthine membrane, the enhancement may resolve but the patient’s
enhancement and objective and subjective cochlear and symptoms persist indefinitely. Enhancement may also
vestibular symptoms reveals that the enhancement is a recur if the inflammatory process is reactivated, even in
highly specific finding of labyrinthine pathology.42 Indeed, patients who have been deaf for years.
all patients with enhancement of the cochlea or vestibule In a subset of patients with SNHL, we have demon-
have cochlear or vestibular findings, both subjectively and strated segmental enhancement of different turns of the
objectively. Furthermore, these symptoms and signs are cochlea.44 In certain patients the level of enhancement
severe when the standard dose of contrast medium correlates with the frequency range of the hearing loss; that
(0.1 mmol/kg) was used. We have recently used a triple-dose is, enhancement of the basal turn of the cochlea results in
338 NEURORADIOLOGY

A B
Figure 20-12. Relapsing polychondritis. Thirty-year-old man with sudden SNHL and a history of recurrent pain and inflammation in the ear lobe. Axial
(A) and coronal (B) postcontrast T1-weighted images demonstrate marked enhancement of the cochlea and vestibule and faint enhancement of the IAC.

high-frequency hearing loss (Fig. 20-15), and enhancement inner ear and the middle ear typically involving injury to
of the apical turn results in low-frequency hearing loss the membranes of the oval window, round window, or
(Fig. 20-16). This correlation is not always present because both.46 This condition is one of the many causes of sudden
certain patients with isolated enhancement of the basal hearing loss and vertigo. It is a difficult condition to diag-
turn will have complete hearing loss over all frequencies. nose even at surgery because the leakage of perilymph may
The remarkable degree of correlation between high- be intermittent and such small amounts of fluid are
resolution-enhanced MRI and clinical examination in involved that its direct observation may be difficult. The
many cases should prompt further investigations using condition is associated with either direct trauma to the ear
MRI in this highly specialized anatomic region. or barotrauma. Experimental studies in guinea pigs have
shown that barotrauma can induce ruptures of the round
window and oval window membranes and intralabyrinthine
PERILYMPHATIC FISTULA hemorrhage, which predominates in the basal turn of
the cochlea,47 where the round window opens. We have
Perilymphatic fistula45 is a controversial condition defined seen three patients with perilymphatic fistulae suspected
as an abnormal communication between perilymph of the clinically or surgically proven in whom labyrinthine

A B
Figure 20-13. Selective enhancement of the cochlea. Viral labyrinthitis, 70-year-old woman with severe right-sided hearing loss and vertigo but only minimally
abnormal electronystagmograph. A, T1-weighted, Gd-DTPA-enhanced image. Enhancement of the cochlea (solid arrow) but not the vestibule (open arrow)
on the right side. No enhancement of the asymptomatic side. B, The enhancement and her symptoms resolved 6 months later. (From Seltzer S and Mark AS:
Contrast enhancement of the labyrinth on MR scans in patients with sudden hearing loss and vertigo: Evidence of labyrinthine disease. AJNR 12:13–16, 1991,
with permission.)
 Imaging of the Labyrinth 339

A B

Figure 20-14. Viral labyrinthitis. A, Abnormal cochlear and vestibular

function right ear; initial study. T1-weighted, Gd-DTPA-enhanced image.
Enhancement of the right cochlea (solid arrow) and vestibule (open arrow).
No enhancement is seen on the contralateral side. B, One month after initial
study, at which time the patient had some improvement in hearing and slight
improvement on ENG testing. T1-weighted, Gd-DTPA-enhanced image. There
is persistent labyrinthine enhancement. C, Five months after initial study, at
which time the patient had marked improvement in hearing and resolution of
vestibular symptoms. Axial T1-weighted, Gd-DTPA-enhanced image.
The previously noted enhancement of the right cochlea and vestibule is no
longer present. (From Seltzer S and Mark AS: Contrast enhancement of the
labyrinth on MR scans in patients with sudden hearing loss and vertigo:
Evidence of labyrinthine disease. AJNR 12:13–16, 1991, with permission.)

enhancement was present (Fig. 20-17). As suggested in the and be clinically indistinguishable from Ménière’s disease.51
experimental studies, the enhancement predominated in the In fact, in the past these lesions were mostly diagnosed dur-
basal turn of the cochlea but was also seen in the vestibule ing destructive labyrinthectomy for intractable “Ménière’s
in some patients. Some of these patients improved following disease.” In the past, the diagnosis on CT could be made
surgical patching of the oval window. only in the later stages when bony expansion of the cochlea
or vestibule had occurred. Now these lesions can be easily
diagnosed using contrast-enhanced MRI,52 which demon-
LABYRINTHINE NEOPLASMS strates a markedly enhancing mass in the cochlea (Fig. 20-
19) or vestibule (Fig. 20-20).
The major differential diagnosis of labyrinthine schwan-
Labyrinthine Schwannomas noma is labyrinthitis. Schwannomas usually enhance much
Labyrinthine schwannomas48 are the most common benign more intensely, the enhancement persists over many
neoplasms of the labyrinth.49 They are histologically identical months, and the lesions may expand, contrary to labyrinthi-
to their counterparts in the IAC. Isolated intralabyrinthine tis, where the enhancement resolves over several months
schwannomas are reported to be more common in the with or without resolution of the patient’s symptoms.
cochlea (Fig. 20-18) (based on the European experience), but In patients with labyrinthine schwannomas, the high-
in our experience they are more common in the vestibule.50 signal-intensity intralabyrinthine fluid is replaced by the
In patients with neurofibromatosis they are more frequent hypointense tumor on the submillimetric T2-weighted
in the vestibular system. Schwannomas in the vestibule spin-echo or gradient-echo images. On these very detailed
originate in the fibers of the vestibular nerves. Branches of images it is sometimes even possible to depict in which
these nerves reach the ampullae of the semicircular canals scala the schwannoma is located. On the contrary, the
(superior vestibular nerve reaches the superior and lateral fluid retains its high signal intensity in the early stages
semicircular canal, the inferior vestibular nerve reaches the of labyrinthitis. T2-weighted images are important, espe-
posterior semicircular canal), and therefore larger schwanno- cially since two nonenhancing intralabyrinthine schwanno-
mas will eventually grow into these ampullae. Labyrinthine mas have been recently reported.53 Schwannomas also
schwannomas can present with SNHL or vertigo (or both) have slightly higher signal intensity than the surrounding
340 NEURORADIOLOGY

b
c
a
a

A B

C D
Figure 20-15. Selective enhancement of the basal turn of the cochlea. A 35-year-old woman with left-sided high-frequency hearing loss. Precontrast (A), and
postcontrast, gadolinium-enhanced (B) axial T1-weighted images demonstrate enhancement of the basal turn (b) of the cochlea and vestibule (c). Notice also the
enhancement of the endolymphatic sac bilaterally (a). Postcontrast, gadolinium-enhanced, consecutive coronal T1-weighted images (C, D). Notice enhancement
of the basal turn but not of the apical turn of the left cochlea, correlating with the patient’s high-frequency hearing loss. (From Mark AS and Fitzgerald D:
Segmental enhancement of different turns of the cochlea on Gd-enhanced MRI: Correlation with frequency of hearing loss and possible sign of perilymphatic
fistula. AJNR 14:991–996, 1993, with permission.)

intralabyrinthine fluid on the unenhanced T1-weighted the adult or rhabdomyosarcoma of the temporal bone in
images. This is another sign that can be used to differenti- the child may extend into the labyrinth. Metastasis may
ate intralabyrinthine schwannomas from labyrinthitis. extend perineurally along the cochlear nerve and penetrate
Moreover, in patients with intralabyrinthine schwannomas the cochlea (Figs. 20-22 and 20-23).
most frequently only one compartment (cochlea or Endolymphatic sac tumors (ELSTs) are rare, low-grade
vestibule/ semicircular canals) is involved, whereas in malignant neoplasms of the temporal bone, which may
labyrinthitis both compartments are more frequently be hemorrhagic54 and invade the vestibule and cochlea.
involved. Isolated reports suggest a possible association between
Patients with labyrinthine schwannomas have stable or ELSTs, which are extremely rare in the general popula-
progressively worsening symptoms. Vestibular schwannomas tion, and von Hippel-Lindau disease (VHL). In a recent
may be associated with intracanalicular and cerebellopon- large series, MRI revealed evidence of 15 ELSTs in 13
tine angle schwannomas in patients with neurofibromatosis (11%) of 121 patients with VHL, but in none of the 253
(Fig. 20-21). patients without evidence of VHL.55
Middle ear cholesteatomas in the later stages may also
Other Tumors Involving the invade the inner ear (Fig. 20-24), but the patient’s history
and the CT findings are usually obvious.
Labyrinth Other lesions growing or invading the membranous
Malignant neoplasms of the cochlea are exceptional. labyrinth include lipomas, histiocytosis X,56 cholesterol
Squamous cell carcinoma or adenoid cystic carcinoma in granulomas, granulation tissue, and pachymeningitis, among
 Imaging of the Labyrinth 341

A B

C D
Figure 20-16. Forty-year-old man with low-frequency SNHL on the right. A, Axial, precontrast, T1-weighted image is normal. B, Postcontrast, axial, T1-weighted
image demonstrates a small focus of enhancement in the apical turn of the cochlea (arrow). C, Coronal, postcontrast, T1-weighted image through the anterior
aspect of the cochlea demonstrates enhancement of the right apical turn of the cochlea (arrowhead) and normal apical turn of the left cochlea (open arrow).
D, Coronal, postcontrast, T1-weighted image through the basal aspect of the cochlea is normal. (From Mark AS, Fitzgerald D: Segmental enhancement of
different turns of the cochlea on Gd-enhanced MRI: Correlation with the frequency of hearing loss and a possible sign of perilymphatic fistula. AJNR
14:991–996, 1993, with permission.)

others. Once these lesions invade the labyrinth, most of them

will cause intralabyrinthine enhancement, visible on the
postcontrast T1-weighted images. Only lipomas and choles-
terol granulomas will not enhance and have spontaneous
hyperintensities on the unenhanced T1-weighted images.
All the previously mentioned lesions cause loss of high-
signal-intensity intralabyrinthine fluid on the T2-weighted
gradient-echo or fast spin-echo images.

POSTOPERATIVE CHANGES
Enhancement of the vestibule may be seen in patients who
have undergone destructive vestibulectomies for incurable
Ménière’s disease. In this case, an enhancing “mass” may
be seen in the vestibule communicating with the mastoid.
Clinical correlation is necessary not to confuse this find-
Figure 20-17. Perilymphatic fistula. Thirty-year-old man with sudden SNHL
after lifting heavy weights at the gym. Coronal, postcontrast, T1-weighted
ing with extension of middle ear infection into the
image demonstrates enhancement of the cochlea (arrow). The patient’s vestibule. Postoperative enhancement of the labyrinth
symptoms improved following surgical patching of the oval window. may also be seen in patients who have undergone surgery
342 NEURORADIOLOGY

A A

B B

C C
Figure 20-18. Presumed left cochlear schwannoma. Fifty-year-old man with Figure 20-19. Left cochlear schwannoma. Axial T1-weighted (A) precontrast
slowly progressive high-frequency SNHL. A, Axial T1-weighted image and (B) postcontrast images demonstrate an enhancing lesion filling the left
demonstrates a 1-mm enhancing mass in the basal turn of the cochlea cochlea. C, Pathologic specimen from another patient demonstrates an
(arrowhead). The lesion remained unchanged over 3 years while the patient’s intracochlear schwannoma. (Courtesy of Dr. H Schuknecht, Boston, MA.)
symptoms slowly progressed. B, Coronal, three-dimensional, T2-weighted
images demonstrate a filling defect matching the enhancing lesion.
C, Pathologic specimen from another patient demonstrates a 1-mm
intracochlear schwannoma. (Courtesy of Dr. H Schuknecht, Boston, MA.)
 Imaging of the Labyrinth 343

A A

B B
Figure 20-21. Twenty-three-year-old man with neurofibromatosis type II.
A, Temporal bone specimen. Simultaneous schwannoma in the right IAC
and a 2 × 2.5-mm vestibular schwannoma is present between the footplate
of the stapes and the lateral wall of the saccule. (Courtesy of HF Schuknecht,
Boston, MA.) B, Presumed left vestibular schwannoma (short arrow) and
intracanalicular schwannoma (long arrow) in another patient with left-sided
SNHL and vertigo and no history of neurofibromatosis type II. (Courtesy of
D Brown, Washington, DC.)

in the IAC or cerebellopontine angle cistern for acoustic

schwannomas or meningiomas. The enhancement is not
usually clinically relevant because these patients have lost
their hearing from their original tumor or the surgery.
However, this finding may be significant in a patient with
a small intracanalicular tumor in whom a hearing-sparing
procedure was attempted, that is, “chemical labyrinthitis”
C from perioperative extension of hemorrhage from the
IAC into the cochlea or vestibule. This finding, rather
Figure 20-20. Right vestibular schwannoma in a patient with a 1-year history than direct injury to the cochlear nerve at the time of
of vertigo and hearing loss. A, Axial and, B, coronal T1-weighted images
show globular enhancement of the right vestibule (arrow). The long-standing
surgery, may explain some of the surgical failures in these
history and the focal enhancement suggest schwannoma rather than cases.
labyrinthitis. C, Pathologic specimen from another patient demonstrates an Membranous labyrinth fibrosis may also occur when
intravestibular schwannoma. (Courtesy of Dr. H Schuknecht, Boston, MA.) surgery is performed in the vicinity of the membranous
labyrinth. Postoperative intralabyrinthine hemorrhage
in case of stapes surgery or surgery in the region of the
 A B
Figure 20-22. Metastasis to the IAC and cochlea. Middle-aged woman with transient facial palsy 6 months prior to the scan interpreted clinically as Bell’s palsy.
Now has new facial palsy and hearing loss. A, CT shows an enlarged acoustic canal. B,T1-weighted image with contrast confirms an intracanalicular mass
extending into the cochlea.

A B

C D
Figure 20-23. Metastatic lung carcinoma to the left IAC and left cochlea. A, Axial, T1-weighted precontrast and B, postcontrast images demonstrate an
enhancing mass filling the left IAC and extending into the left cochlea (arrow), consistent with leptomeningeal tumor spread extending into the patient’s cochlea.
C, Coronal image shows the associated parenchymal metastasis. (Courtesy of Dr. C Truwit, Minneapolis, Minn.) D, Metastatic adenocarcinoma of the breast in a
75-year-old patient who presented with acute hearing loss and facial palsy. (Courtesy of Dr. H Schuknecht, Boston, MA.)
 Imaging of the Labyrinth 345

vertigo and hearing loss and intractable vertiginous symp-

toms requiring hospitalization. The clinicopathologic
correlation is complicated further by the discovery of
labyrinthine hydrops at autopsy in patients with no
reported symptoms of vertigo during their lifetime. The
concept of Ménière’s disease being the consequence of a
viral infection with a predilection for the endolymphatic
sac is appealing in the sense that it may explain both the
histologic findings and the patient’s clinical symptoms.
Until recently, imaging of patients with Ménière’s disease
has been disappointing.62 CT and MRI were primarily used
to exclude other conditions such as acoustic neuroma,
which may mimic Ménière’s disease. The endolymphatic
sac can be seen on HRCT63,64 and MRI, and there is a
statistically lower rate of visualization of the vestibular
aqueduct and endolymphatic sac in patients with Ménière’s
disease than in asymptomatic controls.65–67
Figure 20-24. Cholesteatoma fistulizing into the labyrinth. Coronal, We recently encountered a series of patients with symp-
postcontrast, T1-weighted image demonstrates a nonenhancing mass in the toms compatible with Ménière’s disease in whom MRI
middle ear with a peripheral rim of enhancement. Notice enhancement of the demonstrated enhancement of the endolymphatic sac68
labyrinth. (Fig. 20-25). Similar to enhancement of the cochlea and
vestibule, enhancement of the endolymphatic sac is consis-
geniculate ganglion of the facial nerve can also result in tent with an inflammatory process in this location,69 such
subsequent complete obliteration of the intralabyrinthine as a viral infection,70 and may correlate with the acute
fluid spaces. This can also explain occasional poor postsur- stage of the disease. It is possible that in later stages the
gical results in some patients. enhancement resolves and the fibrotic sac may not be seen
at all on MRI in the later stages of the disease.
Direct visualization of Reissner’s membrane on ultra-
ENDOLYMPHATIC HYDROPS high-field MRI (above 2T) is a hopeful new development
that should allow direct diagnosis of endolymphatic
Endolymphatic hydrops57 is defined pathologically as hydrops in the future.71
dilatation of the endolymphatic spaces. Extensive experi- Otosclerosis is a condition of unknown origin in which
mental evidence suggests that endolymphatic hydrops is the normal endochondral bone is replaced by foci of
the result of a functional failure of the endolymphatic sac to spongy, vascular, irregular new bone that is less dense.72
resorb the endolymph,58 resulting in dilatation of the These spongy decalcified foci in the later stages become
endolymphatic spaces with or without rupture of Reissner’s less vascular and more solid. The condition is bilateral in
membrane and communication of the endolymph and the most patients and often symmetrical. There is a 2-to-1
perilymph. female predominance, and the disease usually appears in
Schuknecht and Gulya59 classified endolymphatic hydrops the second or third decade of life. Otosclerosis is classified
in congenital, acquired, and idiopathic forms. Any congenital into two major clinical categories. The fenestral type of
malformation can result ultimately in endolymphatic otosclerosis involves the lateral wall of the labyrinth,
hydrops. Among the best known is the large vestibular aque- including the promontory, facial nerve canal, and both
duct syndrome, in which a markedly dilated endolymphatic the oval and round window niche. The involvement of
sac and vestibular aqueduct are associated with other inner the oval window results in fixation of the footplate of the
ear malformations and congenital SNHL and vertigo. Any of stapes and conductive hearing loss. Retrofenestral otoscle-
the inflammatory or traumatic lesions mentioned earlier may rosis occurs when the process of demineralization involves
have labyrinthine hydrops as the end result. the otic capsule itself. These changes in the bone may
Among the idiopathic forms of labyrinthine hydrops, affect the spiral ligament at the surface of the membranous
Ménière’s disease is the best known. This condition is labyrinth and result in SNHL; thus, a patient with otoscle-
clinically characterized by fluctuating SNHL with or rosis may have a combined conductive and sensorineural
without vertigo and tinnitus. It is most often unilateral hearing loss depending on the relative distribution and
and, when bilateral, it is usually asynchronous. Ample labo- severity of the disease. CT is the imaging modality of
ratory evidence suggest that Ménière’s disease is caused by a choice for diagnosing otosclerosis.73 Depending on the
functional failure of the endolymphatic sac to resorb the location of the foci of demineralization along the cochlea,
endolymph. Electromicroscopy study of biopsies of the specific frequency ranges may be affected more than oth-
endolymphatic sac60,61 in patients with Ménière’s have ers.74 The lesions visualized on CT can sometimes be seen
revealed a wide spectrum of findings from a near normal as enhancing lesions on MRI35 (Fig. 20-26). This finding
sac to an inflammatory reaction to fibrosis and complete probably reflects the leakage of gadolinium in the highly
atrophy and obliteration of the endolymphatic sac. This vascular spongiotic bone during the early stages of the
spectrum of histologic findings explains the great disease. In the later stages of the disease, when the spongi-
heterogeneity of the clinical findings in these patients from otic bone is replaced by dense bone, the enhancement
mild forms with occasional episodes of vertigo to severe disappears.
 A B
Figure 20-25. Probable Ménière’s disease. Fifty-year-old woman with sudden onset SNHL and vertigo. Hearing improved after 4 days. The patient had a similar
episode 5 years earlier. A, Axial, T1-weighted, precontrast MRI is normal. B, Axial, enhanced fat-saturated, T1-weighted MRI reveals enhancement of the left
endolymphatic sac.

A B

C D
Figure 20-26. Cochlear otosclerosis: Enhanced axial (A) and coronal (B) T1-weighted images of the left temporal bone in a patient with the clinical and CT
diagnosis of cochlear otosclerosis shows foci of enhancement within the bony labyrinth surrounding the cochlea. CT (C) shows the typical findings of
otosclerosis. Pathologic specimen (D) shows a focus of otosclerosis anterior to the oval window. (From Schuknecht HF: Hemolabyrinth. In Schukenecht HF
[ed.]: Pathology of the Ear, 2nd ed. Philadelphia, Lea and Febiger, 1993, pp 303–306, (with permission.)
 Imaging of the Labyrinth 347

Paget’s disease and osteopetrosis are best evaluated with 14. Davidson HC, Harnsberger HR, Lemmerling MM, et al: MR
CT, and MRI has little to add. evaluation of vestibulocochlear anomalies associated with large
However, in patients with fibrous dysplasia, MRI may endolymphatic duct and sac. Am J Neuroradiol 20:1435–1441,
1999.
be helpful.75 Enlarged dense bone with a “ground glass”
15. Jackler RK, Luxford WM, House WF: Congenital malformations
appearance is seen in fibrous dysplasia, and the bony of the inner ear: A classification based on embryogenesis.
changes can narrow the IAC or can encase the aqueducts Laryngoscope 97:2–14, 1987.
or membranous labyrinth. The bone abnormalities in 16. Casselman JW, Kuhweide R, Ampe W, et al: Inner ear malforma-
fibrous dysplasia vary considerably,76 but high signal inten- tions in patients with sensorineural hearing loss: detection with
sity on T2-weighted spin-echo images and precontrast gradient-echo (3DFT-CISS) MR imaging. Neuroradiology
T1-weighted images and strong enhancement on the post- 38:278–286, 1996.
contrast images (isointense or hyperintense compared with 17. Phelps PD, Reardon W, Pembrey M: X-linked deafness, stapes
fat) indicate active or progressive fibrous dysplasia. gushers and a distinctive defect of the inner ear. Neuroradiology
33:326–330, 1991.
18. Schuknecht HF: Hemolabyrinth. In Schuknecht HF (ed.): Pathology
CONCLUSION of the Ear, 2nd ed. Philadelphia, Lea and Febiger, 1993
pp 303–306.
The availability of intravenous contrast agents sensitive to 19. Kumar A, Maudelonde C, Mafee M: Unilateral sensorineural hearing
loss: Analysis of 200 consecutive cases. Laryngoscope 96:14–18, 1986.
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20. Sando I, Egami T: Inner ear hemorrhage and endolymphatic
riers coupled with high-resolution imaging have hydrops in a leukemic patient with sudden hearing loss. Ann Otol
significantly expanded the potential role of MRI in the Rhinol Laryngol 86:518–524, 1977.
evaluation of the membranous labyrinth. Although many of 21. Ouallet JC, Marsot-Dupuch K, Van Effenterre R, et al: Papillary
the findings described in this chapter are still of uncertain adenoma of endolymphatic sac origin: A temporal bone tumor in von
significance in terms of patient management, the potential Hippel-Lindau disease. Case report. J Neurosurg 87(3):445–449,
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23. Swartz JD, Swartz NG, Korsvik H, et al: Computerized tomo-
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52. Mafee MF, Lachenauer CS, Kumar A, et al: CT and MR imaging of therapeutic options for viral labyrinthitis. Ann N Y Acad Sci
Intralabyrinthine schwannoma: report of two cases and review of 830:306–313, 1997.
the literature. Radiology 1990;174:395–400, 1999. 71. Koizuka I, Seo R, Kubo T, et al: High-resolution MRI of the human
53. Zbar RI, Megerian CA, Khan A, Rubinstein JT: Invisible culprit: cochlea. Acta Otolaryngol Suppl 520 Pt 2:256–257, 1995.
Intralabyrinthine schwannomas that do not appear on enhanced 72. Wiet RJ, Rasian W, Shambugh GE: Otosclerosis 1981 to 1985, our
magnetic resonance imaging. Ann Otol Rhinol Laryngol four year review and current perspective. Am J Otol 7:221–228, 1986.
106(9):739–742, 1997. 73. Blakley BW, Hilger PA, Taylor S, Hilger J: Computed tomography
54. Mukherji SK, Albernaz VS, Lo WW, et al: Papillary endolymphatic in the diagnosis of cochlear otosclerosis. Otolaryngol Head Neck
sac tumors: CT, MR imaging, and angiographic findings in 20 Surg 94:434–438, 1986.
patients. Radiology 202(3):801–808, 1997. 74. Swartz JD, Mandell DW, Berman SE, et al: Cochlear otosclerosis
55. Manski TJ, Heffner DK, Glenn GM, et al: Endolymphatic sac (otospongiosis): CT analysis with audiometric correlation.
tumors. A source of morbid hearing loss in von Hippel-Lindau Radiology 155:147–150, 1985.
disease. JAMA 277(18):1461–1466, 1997. 75. Moreau S, Bourdon N, Goullet de Rugy M, et al: Temporal fibrous
56. Claros P, Claros A Jr, Claros A, Gilea I: Labyrinth involvement in dysplasia with labyrinthine involvement. Apropos of a case and
Langerhan’s cell histiocytosis. Acta Otorhinolaryngol Esp 50(7): review of the literature. Ann Otolaryngol Chir Cervicofac
549–552, 1999. 114(4):140–143, 1997.
57. Schuknecht HF: Pathophysiology of endolymphatic hydrops. Arch 76. Casselman JW, De Jonge I, Neyt L, et al: MRI in craniofacial
Oto-Rhino-Laryngol 212:253–262, 1976. fibrous dysplasia. Neuroradiology 35:234–237, 1993.
 Chapter
Imaging of the Cerebellopontine Angle

Outline 21
Technical Considerations Nonvestibular Posterior William W. M. Lo, MD
Classifications and Incidence Fossa Schwannomas
Michael M. Hovsepian, MD
of Cerebellopontine Angle Vascular Lesions
Tumors Extradural Lesions
Vestibular Schwannoma Intra-axial Tumors
Meningioma and Simulants Intracanalicular Lesions
Epidermoid and Other Cysts Conclusion

TECHNICAL CONSIDERATIONS brain tissue against CSF, noncontrast, heavily T2-weighted,

submillimeter thin-section images have been recom-
Modern imaging techniques for the cerebellopontine mended for low-cost screening for acoustic tumors.11 Such
angle (CPA) and internal auditory canal (IAC) consist images may be obtained by fast spin-echo (FSE) or by
principally of magnetic resonance imaging (MRI) and gradient-echo technique (constructive interference steady
computed tomography (CT). Angiography is occasionally state, or CISS). Normal structures as demonstrated by CISS
employed when evaluating vascular lesions.1 images are illustrated in Figure 21-1.4–7 However, gadolin-
Because of its superior soft tissue contrast, multiplanar ium chelates as paramagnetic contrast agents administered
capability, and lack of ionizing radiation, MRI holds a intravenously, markedly enhance the signal intensity of
substantial advantage over CT in imaging the CPA.2 most tumors, as well as inflammatory lesions on T1WI,
Furthermore, with paramagnetic contrast enhancement, and aid in characterization and differential diagnosis of
MRI has become the unquestioned method of choice for lesions. Thus, contrast-enhanced T1WI is nearly always
visualization of small acoustic tumors.3 The frequent used for detection or evaluation of CPA and IAC tumors,
untoward reactions to intravenous (IV) iodinated contrast in a comprehensive study.3,12–15 Normal T1WI are illus-
material for CT are obviated. Furthermore, recently trated in Figure 21-2.16,17
developed heavily T2-weighted, submillimeter thin- Although T2WI add little to the detection of extra-axial
section, spin-echo or gradient-echo images exquisitely tumors, they are useful in assisting characterization of
outline cisternal nerves and vessels better than gas CT- tumors (e.g., in meningioma, lipoma, peritumoral cysts,
cisternography, and the otic labyrinth as well as or better peritumoral edema, hemorrhage, etc.). They are also more
than high-resolution CT.4–7 This chapter therefore focuses sensitive than T1WI for detection of intra-axial lesions
primarily on MRI. (inside the brain) that can produce acoustic symptoms,
CT remains useful in special situations, for example, such as occur in multiple sclerosis, infarct, and edema, as
when MRI is not available, when patients are too claustro- well as in hemosiderin deposition in superficial siderosis.18
phobic or too large to be accommodated in the scanner, Thus, a comprehensive study of the CPA would typi-
when visualization of calcium or bone changes is impor- cally include T1WI in thin sections through the posterior
tant,8 or when acute hemorrhage is in question.9,10 fossa and IAC before and after the administration of
Although a detailed discussion of the technical aspects gadolinium chelates, and T2WI in thicker sections to
of MRI is beyond the scope of this chapter, a general survey the brain.
understanding of the capabilities and limitation of the Under some circumstances, modified or additional
technique will greatly assist the clinician in effectively techniques may be employed. For example, in neurofibro-
using MRI for investigation of the CPA or the IAC. matosis 2 (NF2),19,20 in which multiple intracranial schwan-
Although not all CPA symptoms are caused by tumors, nomas and meningiomas, and spinal schwannomas,
the principal concern raised is usually the presence or meningiomas, and ependymomas are often present, post-
absence of a tumor. Because most of the tumors in the contrast T1-weighted surveys that include the entire head
CPA are intradural extra-axial (outside the brain) and and spine may be desirable.19,21–22 When vascular lesions
partly outlined by cerebrospinal fluid (CSF) and because such as aneurysm, arteriovenous malformation (AVM), or
T2-weighted images (T2WI) superbly outline nerves and vertebrobasilar dolichoectasia (VBD) are encountered or
349
350 NEURORADIOLOGY

C 4

V P
1

C 5
L
a P
sc v
IV

3
sc F
2
B
IV

A B

C P
sc
mp
a IV
C IAC
v P ce ce

C D
Figure 21-1. Normal structures in IAC on CISS images (A-C). A, CISS axial 0.8 mm through the superior aspect of the IAC demonstrating the parallel course of
the facial nerve (1) anterior to the superior vestibular nerve (3). B, inferior aspect of the IAC where the divergent relationship or Y-shaped configuration of the
cochlear nerve (4) anterior to the inferior vestibular nerve (5) is depicted. C, a prominent AICA loop is seen within the proximal IAC. D, T2W axial FSE 5.5 mm
of posterior fossa. 1, facial nerve; 2, vestibulocochlear nerve; 3, superior vestibular nerve; 4, cochlear nerve; 5, inferior vestibular nerve; IV, fourth ventricle;
a, AICA; B, basilar artery; C, cochlea; ce, cerebellar hemisphere; F, flocculus; L, lateral recess of the fourth ventricle; mp, middle cerebellar peduncle; P, pons;
sc, semicircular canals; v, vestibule.

suspected, MR angiography may be added (Fig. 21-3).23 isointense or mildly hypointense on precontrast images.
When confirmation of lipoma or fat, including operatively Furthermore, multiple sclerosis (Fig. 21-4) or superficial
placed fat, is desired, a fat suppression technique may be siderosis (Fig. 21-5) may be completely missed, should
invoked.24 either be present. A fat-suppressed postcontrast sequence
Obviously, the desire for completeness and quality must is generally necessary for evaluation of postoperative
be balanced against the constraints of time, cost, through- recurrence.3 A precontrast T1-weighted sequence is nec-
put, and patient tolerance. For practical purposes, a essary for evaluation of paragangliomas, which may
comprehensive study probably should not exceed half an become nearly isointense with bone marrow on postcon-
hour per patient. A noncontrast, heavily T2-weighted, trast images (Fig. 21-6). Thus, each institution or facility
thin-section survey specifically used for screening for must devise protocols best suited to its own needs or
acoustic tumors may be accomplished in less than 15 minutes practice and adapt to new technical developments that
at considerably lower cost. Such a study, however, carries emerge. Our current protocol is offered as an example in
the disadvantage of not being able to differentiate lipomas Table 21-1.
or melanotic melanoma,25 which are hyperintense on Although one study showed that 5-mm sections com-
preconstrast T1WI, from schwannomas, which are pared favorably with 3-mm sections in detection of
 Imaging of the Cerebellopontine Angle 351

A B

C D
Figure 21-2. Normal structures in CPA. (A–H), Postcontrast T1WI (Gd-T1WI) overlapping 3-mm sections centered every 1.8 mm. A, Midpons. Dominant
structure is pons itself (P) surrounded by prepontine cistern anteriorly, CPA cisterns bilaterally, and fourth ventricle (IV ) posteriorly, and connected to cerebellar
hemispheres (CH) posterolaterally by middle cerebellar peduncles (mp). Trigeminal nerves traverse CPA cistern to enter Meckel cave (mc in B–E) inferior to
attachment of tentorium cerebelli (TC). Basilar artery (B) ascends anterior to pons. B, Mid-lower pons. Contrast-enhanced choroid plexus (ch) is seen on roof of
fourth ventricle (IV). Lateral recess (I) of the fourth ventricle leads toward foramen Luschka (black arrow in D). Meckel cave (mc) filled with CSF lies adjacent to
contrast-enhanced cavernous sinus (CS). C, Lower pons. Facial (7) and acoustic (8) nerves traverse cistern toward IAC in close relationship to loop of anterior
inferior cerebellar artery (a). Cochlear nuclei are located immediately anterior to lateral recess (I). Rostral ends of cerebellar tonsils (t) are seen flanking caudal
end of inferior vermis (vr). Inferior petrosal sinus (IP) communicates with cavernous sinus (CS). Petrous apex (pa) is filled with hyperintense fatty marrow.
D and E, Pontomedullary junction. Belly of pons (P) extends far anteriorly beyond medulla (M). Posterior to medulla is foramen of Majendie (white arrow)
opening to vallecula (long white arrow) between the tonsils (t). Lateral recess is flanked by inferior cerebellar peduncle (ip) anteriorly and contrast-enhanced
choroid plexus (ch) posteriorly. The latter protrudes into CPA cistern through foramen of Luschka (short black arrow) posterior to acoustic nerve (8) and inferior
to flocculus (f in C).
Continued

acoustic tumors,26 most facilities use the thinnest sections Images in a second orthogonal plane should be
practicable for imaging of the IAC whenever permitted obtained when a tumor is encountered20 to demonstrate
by the capability of their equipment, most commonly the relationship of tumor to the tentorium and the jugular
2- to 3-mm sections,3,27 because intracanalicular tumors fossa, and when volumetric measurements are desired.
are often only a few millimeters in diameter and may Gadolinium contrast agent should be routinely used in
be suboptimally visualized or even obscured by partial comprehensive studies because it markedly improves
volume effect in thicker sections. The interslice gap also visualization of small tumors, permits identification of
differs, from varying degrees of overlap up to perhaps residual or recurrent tumor, and adds precision to the
20% gaps. A minimum qualitative standard, which perhaps delineation of tumor in the IAC (Fig. 21-7).3 There are
should be insisted on, is that the facioacoustic nerves only a few contraindications to its use, and side effects
through their cisternal and canalicular portions be rarely occur. Furthermore, gadolinium chelate enhance-
recognizable bilaterally, either on T1WI or T2WI (see ment confirms labyrinthitis28 and reveals nondestructive
Figs. 21-1 and 21-2). An unfocused study of the brain intralabyrinthine schwannomas.29,30
with 5-mm or thicker sections is inadequate for imaging Numerous studies have been performed to identify the
the IAC. potential biologic effects of MRI, but none of them have
352 NEURORADIOLOGY

E F

G H
Figure 21-2, cont’d. Facial nerve (7 ) and superior vestibular division of acoustic nerve (8) extend into labyrinthine facial nerve canal (7l ) and vestibule (v), respec-
tively, in D; and cochlear and inferior vestibular divisions of acoustic nerve (8), respectively, into cochlea (c) and vestibule (v) in E. Geniculate ganglion (7g) and
tympanic segment (7t) of facial nerve show normal contrast enhancement. Abducens nerve (6) crosses cistern to enter cavernous sinus (CS). Mastoid segment
(7m) of facial nerve is at times paralleled by a fatty collection posteriorly (also in F, G, and H) F and G, Upper medulla. Glossopharyngeal and vagus nerves (9–10)
extending from lateral medulla toward jugular foramen are difficult to separate from each other. Greater superficial petrosal nerve (gsp) extends from geniculate
ganglion (7g in E) anteromedially on floor of middle fossa. Cranial opening of cochlear aqueduct (ca) closely overlies pars nervosa of jugular foramen (not well
shown). H, Lower medulla. Spinal accessary nerve (11) ascending toward jugular foramen is also difficult to distinguish from glossopharyngeal and vagus (9–10
in F and G). Rootlets of hypoglossal nerve extend from preolivary sulcus anteriorly toward hypoglossal canal inferior to jugular tubercle (jt), which is separated
from petrous apex (pa) by petro-occipital fissure (pof). Posterior inferior cerebellar artery (p) arises from vertebral artery (V). Artifact from flow is seen streaking
between sigmoid sinuses (S ). Carotid artery (C), jugular vein (J ), tympanic cavity (T ), and external auditory canal (E ) are all signal-free.

A B
Figure 21-3. Vertebrobasilar dolichoectasia. A, Axial Gd-T1WI. Tortuous left vertebrobasilar artery (long arrow) crosses left to right anterior to pons. Small arterial
branch (open arrow) coursing toward left CPA probably represents left AICA. Note normal enhancement of geniculate ganglion and proximal tympanic facial nerve and
posterior fossa veins (small arrows). Serration across cerebellum between sigmoid sinuses is caused by pulsating flow of blood in sigmoid sinuses. B, Coronal MR
angiography. 3-D time-of-flight technique, maximum intensity projection. Same vertebrobasilar artery (long arrow) and probable left AICA (open arrow) as in A. Superior
cerebellar and posterior cerebral arteries and right posterior inferior cerebellar artery (small arrows) are also seen. No contrast injection is necessary for MRA.
 Imaging of the Cerebellopontine Angle 353

A B
Figure 21-4. Multiple sclerosis. A, T1WI. Subtle pontine lesion (arrowhead) shows easily overlooked minimal hypointensity. B, T2WI. Hyperintensity of lesion is
obvious.

A B
Figure 21-5. Superficial siderosis. Patient has bilateral progressive sensorineural hearing loss several years after surgical resection of left inferior frontal
arteriovenous malformation. A, T1WI. No abnormality is apparent. B, T2WI. Thin layer of hypointensity from pial and subpial deposition of hemosiderin is
visible on pons, cerebellum, and acoustic nerves (arrows). (Compare with Fig. 21-1). Thin layer of hypointensity is also present on inferior surfaces of cerebral
hemisphere (not illustrated). Hypointensity of dentate nuclei may be physiologic.

A B
Figure 21-6. Jugular paraganglioma (glomus jugulare tumor) with PF extension. A, T1WI. B, Gd-T1WI. Note loss of natural contrast between tumor and clivus
marrow after Gd-DTPA and importance of precontrast images to serve as baseline. Tumor circumferentially narrows intrapetrous carotid (open arrow) and
extends to protympanum (short arrow) to surround cochlea (arrow). Note dural tails (long thin arrows) and arterial branch (arrowhead) supplying tumor.
(Compare with Fig. 21-28).
354 NEURORADIOLOGY

TABLE 21-1. Sample Magnetic Resonance Protocol for CLASSIFICATIONS AND INCIDENCE OF
Comprehensive Study of Cerebellopontine Angle/Internal CEREBELLOPONTINE ANGLE TUMORS
Auditory Canal
Approximately 10% of intracranial tumors originate in the
Axial survey of brain: T2WI, 5.5-mm thickness
Axial posterior fossa detail: T1WI precontrast, 2.0-mm thickness
CPA.38 Most of them arise from the cranial nerve sheath,
Axial submillimeter posterior fossa detail: CISS, 0.8-mm thickness the meninges, the blood vessels, and the congenital rests
Axial survey of brain: DWI, 5.0-mm thickness located in the extra-axial compartment. Some arise from
Axial posterior fossa detail: T1WI post-Gd FS 2.0-mm thickness the petrous bone or the jugular foramen and are extradural
Coronal posterior fossa detail: T1WI post-Gd FS, 2.0-mm thickness in origin but intrude into the CPA. A few are exophytic
If postoperative patient: Pre-Gd T1WI, FS, 2.0-mm thickness
For NF2: include post-Gd T1WI axial and coronal whole brain, 5.5-mm growths of intra-axial lesions arising from the brain.
thickness Lesions in the CPA are extremely diverse. Provided in
Table 21-2 for reference are the lesion types and numbers
CISS, constructive interference steady state; DWI, diffusion-weighted images; FS, fat- from three major series.39–41 The Brackmann series repre-
suppressed; Gd, gadolinium chelate; NF2, neurofibromatosis 2; T1WI, T1-weighted images;
T2WI, T2-weighted images.
sents material from a neurotologic practice, excluding
paragangliomas.
Although the percentages differ, all three series show
acoustic or vestibular schwannoma (VS), as by far the most
common, comprising some 60% to 90% of all CPA
determined any significant hazards.31,32 More directly lesions. The three series also agree that the distant second,
related to otologic interest is acoustic noise produced by third, and fourth most common tumors by narrow margins
the activation and deactivation of the gradient magnetic are meningioma, congenital intradural epidermoid tumor
filed.33,34 Reversible hearing loss may be induced by such or cyst, and nonacoustic posterior fossa schwannomas,
noises.35 Disposable ear plugs or other noise reduction respectively. These four common tumor types account for
devices should be routinely used.31 about 75% to 98% of all CPA mass lesions.
Certain prosthetic implants and metallic materials are Beyond the four most common tumors, the types of
associated with potential hazards. Examples are cardiac mass lesions in the CPA are extremely diverse and numer-
pacemakers, ferromagnetic cerebrovascular aneurysm ous (see Table 21-2). The Revilla series of 205 CPA lesions
clips, and intraocular ferromagnetic foreign bodies.31 includes 1 primary melanoma, 1 paraganglioma, and 13
High-field MRI is strictly contraindicated for patients cerebellar and petrous bone tumors infiltrating the CPA.40
with cochlear implants,31,36 although low-field scanners The Brackmann series of 1354 CPA tumors includes
may be safe. Stapes prostheses are safe for MRI with the 7 arachnoid cysts, 4 hemangiomas, 1 hemangioblastoma,
exception of the Richards-McGee platinum-stainless steel 2 astrocytomas, 2 medulloblastomas, 3 metastatic
piston manufactured in a relatively small quantity and only tumors, 2 dermoids, 2 lipomas, 1 malignant teratoma, and
for a brief period after mid-1987, using C17NI4 stainless 1 chondrosarcoma.39 The series of 455 CPA lesions of
steel instead of the more common 316L stainless steel.37 Valavanis41 includes among primary tumors, 1 melanoma
Eyelid springs used for patients with facial nerve palsy and 3 hemangiomas; among secondary tumors, 47 para-
have shown deflection in vitro but no significant ill effects gangliomas, 1 ceruminoma, 2 chondrosarcoma, 8 chor-
in vivo. doma, and 6 extensions of cerebellar and petrous bone

A B
Figure 21-7. Intracanalicular vestibular schwannoma. A, T1WI. Typical small tumor isointense with brain without enlargement of IAC (arrow). Such a tumor may
be isointense with CSF and not apparent on T2WI. B, Gd-T1WI. Extent of tumor (filling fundus of IAC) is more fully and precisely demonstrated postcontrast.
(Compare with Figs. 21-30, 21-42, 21-43, 21-44, 21-46, and 21-47.)
 Imaging of the Cerebellopontine Angle 355

TABLE 21-2. Classification and Frequency of CPA Lesions

Revilla (1947) Brackmann (1980) Valavanis (1987)
No. % No. % No. %

Primary Tumors of the CPA

Acoustic schwannoma 154 75.1 1236 91.3 275 60.5
Meningioma 13 6.3 42 3.1 31 6.8
Epidermoid 13 6.3 32 2.4 17 3.7
Arachnoid cyst — — 7 0.5 9 2.0
Schwannoma of the fifth, seventh, ninth, tenth, and eleventh nerves 10 4.9 19 1.4 18 4.0
Primary melanoma 1 0.5 — — 1 0.2
Hemangioma — — 4 0.3 3 0.7
Lipoma, dermoid, teratoma — — 5 0.4 — —
Secondary Tumors of the CPA
Paraganglioma 1 0.5 — — 47 0.3
Ceruminoma — — — — 1 0.2
Chondroma-chondrosarcoma — — 1 0.1 2 0.4
Chordoma — — — — 8 1.8
Extension of cerebellar and petrous bone tumors 13 6.4 5 0.4 6 1.3
Metastases — — 3 0.2 12 2.6
Vascular Lesions
Aneurysm — — — — 4 0.9
Arteriovenous malformation — — — — 4 0.9
Vertebrobasilar dolichoectasia — — — — 17 3.7

From Lo WWM: Tumors of the temporal bone and the cerebellopontine angle. In Som PM, Bergeron RT (eds.): Head and Neck Imaging, 2nd ed, St. Louis, Mosby-Year Book, 1991.

tumors; among vascular lesions, 4 aneurysms, 4 AVMs, appear as a rounded mass centered at the porus (Fig. 21-9).
and 17 VBDs; and 12 metastases. Other rare lesions not As VSs enlarge they often assume an ovoid configuration
listed may also appear as mass lesions in the CPA, for with their long axis parallel to the posterior petrous wall
example, lymphoma,42 hypertrophic pachymeningitis,43 (Fig. 21-10). Intracanalicular VSs initially appear as small
syphilis, sarcoidosis,44,45 rhabdoid tumor,46 and so forth. (See
also Chapter 49, Rare Tumors of the Cerebellopontine
Angle.) TABLE 21-3. Imaging Differential Diagnosis of CPA Lesions
Such a long list of possibilities makes differential diag- I. Extra-axial Lesions II. Extradural Lesions
nosis difficult. To simplify discussion in this chapter, the A. Vestibular schwannoma A. Bone lesions
CPA lesions are grouped into eight categories (Table 21-3). B. Meningioma and simulants 1. Cysts, e.g.,
Five extra-axial groups: (1) vestibular schwannoma, (2) Leptomeningeal metastases cholesterol cyst
Primary meningeal lymphoma epidermoid cyst
meningioma and simulants, (3) epidermoid and other Primary meningeal melanoma mucocele
cysts (arachnoid, cysticercal, dermoid, etc.), (4) non- Meningeal sarcoidosis 2. Tumors, e.g.,
vestibular posterior fossa (PF) schwannomas (V, VII, IX, Hypertrophic pachymeningitis chordoma
X, XI, XII), and (5) vascular lesions (VBD, aneurysm, C. Epidermoid and other cysts chondroma
AVM, superficial siderosis, etc.); two extradural groups: Arachnoid cyst chondrosarcoma
Cysticercal cyst giant cell tumor
(6) bone lesions (benign or malignant, primary or metasta- Epithelial cyst myeloma
tic) and (7) paraganglioma; and finally an intra-axial group Neuroenteric cyst metastases
including astrocytoma, ependymoma, papilloma, heman- Craniopharyngioma xanthoma
gioblastoma, metastasis, lymphoma, and so on. Such a Lipoma B. Paraganglioma
D. Nonvestibular PF schwannomas (glomus jugulare tumor)
categorization does not follow traditional classifications V, VII, IX, X, XI, XII III. Intra-axial Lesions
based on cell origin but is more conducive to differential E. Vascular lesions A. Brainstem tumor
diagnosis based on location and appearance of the lesions VBD Astrocytoma
as revealed by imaging. (See also Chapter 49, Rare Tumors Berry aneurysm Lymphoma
of the Cerebellopontine Angle.) Intracanalicular lesions Giant aneurysm Hemangioma
Arteriovenous malformation B. Cerebellar tumor
with a slightly different differential diagnosis are also Superficial siderosis Astrocytoma
discussed. Hemangioblastoma
Metastases
Lymphoma
VESTIBULAR SCHWANNOMA Hemangioma
Medulloblastoma
C. Fourth ventricular tumor
Commonly but incorrectly termed acoustic neuromas,19,20,38 Ependymoma
VSs are by far the most common tumor in the CPA and Choroid plexus
the IAC.39–41 Most characteristically they arise in the IAC papilloma
and enlarge into the CPA, with a rounded mass in the CPA D. Nontumorous
and a cone-shaped stem in the IAC enlarging the porus Infarct
Multiple sclerosis
acusticus (Fig. 21-8). Some tumors arise in the CPA and
356 NEURORADIOLOGY

A B
Figure 21-8. Typical large IAC-CPA VS. Smoothly marginated tumor mushrooms out of IAC into CPA, causing funnel-shaped widening of the IAC and forming
an extra-axial mass deforming the pons. A, T1WI. Tumor is nearly homogeneous, mildly hypointense to brain, and hyperintense to CSF. A vessel is seen trapped
between the tumor and pons (arrow). B, Gd-T1WI. Marked contrast enhancement is typical of VSs. Intratumoral cystic components (arrow) are much more
obvious than precontrast.

A B
Figure 21-9. Medium-sized cisternal VS. Tumor is extra-axial, smoothly marginated, rounded, and centered to porus acusticus. A, T1WI. Tumor is mildly
hypointense to brain, hyperintense to CSF, and slightly granular in texture. B, Gd-T1WI. Tumor shows marked nearly homogeneous enhancement postcontrast.
(Compare with Fig. 21-27.)

A B
Figure 21-10. Giant cisternal VS. Tumor is extra-axial, smoothly marginated, ovoid, centered over porus acusticus, and deforming pons, cerebellum, and fourth
ventricle. A, T1WI. Tumor is mildly hypointense to brain and hyperintense of CSF and nearly homogeneous except for cystic component (arrowhead). Vessels
are seen between tumor and brain (arrows). B, Gd-T1WI. Tumor shows marked contrast enhancement except for cystic component. Giant tumors are often
entirely extracanalicular as in this case.
 Imaging of the Cerebellopontine Angle 357

A B
Figure 21-11. Vestibular schwannoma with dural tail. A, T1WI. B, Gd-T1WI. Otherwise typical appearing IAC-CPA vestibular schwannoma shows enhancing dural
tail (arrow) extending to posterior petrous surface. This finding was present in only 1 of 100 VSs in an unpublished series.

rounded masses and then become sausage-shaped as they on T2WI (see Figs. 21-7 through 21-12). As a group, they
grow to fill the canal (see Fig. 21-7). At times, intra- enhance far more than any other benign extra-axial tumor,
canalicular VSs may be lobulated or globular and focally but sufficient overlap occurs among tumors of different
erode the canal. types so that the degree of enhancement alone cannot
Schwannomas are typically isointense or mildly always be relied on to differentiate the type of tumor.47
hypointense to brain on T1WI, enhance markedly on The enhancement may or may not be homogeneous
gadolinium, and are between brain and CSF in intensity because microcyctic and macrocystic components within

A B

Figure 21-12. NF2. A, T1WI. B, Gd-T1WI. C, Sagittal Gd-T1WI. Patient

has bilateral VSs (vertical arrows), bilateral trigeminal schwannomas
(horizontal arrows), left facial schwannoma (open arrow), and left
posterior fossa, falx, and parasagittal meningiomas (oblique arrows).
Note also occlusion of left lateral sinus (blank arrow) and dural “tails”
(long thin arrows).

C
358 NEURORADIOLOGY

the tumor are common in schwannomas, reflecting the Funnel-shaped enlargement of the IAC is common in
presence of Antoni type B tissue (see Figs. 21-8 and VSs and rarely seen in other lesions (see Figs. 21-8 and
21-10).1,38,48,49 Initially, nonenhancing microcystic compo- 21-11).41,54 The incidence of hydrocephalus roughly corre-
nents on a short sequence may attain enhancement in time lates with tumor size. One report noted hydrocephalus in
as equilibration of contrast material in extracellular space 17 of 44 patients in whom a tumor of 3 cm or larger was
takes place.1 present.62 Rarely, a large VS compressing the brain may
Schwannomas may also be accompanied by one or more cause peritumoral edema.41
overlying arachnoid cysts (Fig. 21-13), and at times be CT and MRI have been extremely useful in studying the
dominated by one.50 Calcification is rarely present in natural history of VS. Many such studies have been pub-
schwannomas.41,49,51–54 lished.63–73 Their methodologies may vary, but the results
Rarely, intratumoral hemorrhage may cause focal hyper- appear to concur that most tumors are stable or slowly
intensity or hypointensity depending on the age of the growing (of the order of 2 mm or less a year) but some
hemorrhage.55–58 Even more rarely, subarachnoid hemor- grow as much as 1 cm or more a year. These results appear
rhage may be the presenting symptom of a large VS.59,60 to correlate with those revealed by monoclonal antibody
However, acute subarachnoid hemorrhage may not be studies.74 To establish the growth rate of a tumor, an initial
apparent on MRI even when obvious on CT.10 CT is follow-up study in perhaps 6 months may be done. If the
therefore indicated when the signs and symptoms suggest tumor is found to be stable or very slow growing, subse-
subarachnoid hemorrhage.14 quent follow-up studies then may be repeated at 1- to
A dural “tail” often observed in meningiomas (Figs. 21-12, 2-year intervals.
21-14, and 21-15), on rare occasions may be seen associ- In postoperative studies for residual or recurrent tumor,
ated with a VS (see Fig. 21-11).61 precontrast and postcontrast studies at matching levels are

A B

C D
Figure 21-13. VS with arachnoid cysts. Tumor is extra-axial, slightly lobulated, centered over porus acusticus, and lies predominantly in CPA cistern with an
overlying arachnoid cyst as large as the tumor itself laterally and a smaller arachnoid cyst medially. A, T1WI. Tumor is mildly hypointense to brain; arachnoid
cysts (arrows) are isointense to CSF. B, Gd-T1WI. Tumor shows marked contrast enhancement, and arachnoid cysts (arrows) show no enhancement. C, T2WI.
Tumor is slightly hypointense to CSF and slightly granular in texture. Arachnoid cysts (arrows) are isointense to CSF and homogeneous. D, Coronal Gd-T1WI.
Tumor extends superiorly to undersurface of tentorium (down arrow) and inferiorly over contrast-enhanced sigmoid sinus (up arrow) medial to enhanced high
jugular bulb (open arrow).
 Imaging of the Cerebellopontine Angle 359

A B

C D
Figure 21-14. CPA meningioma with classic features. A, T1WI. B, Gd-T1WI. C, T2WI. D, Coronal Gd-T1WI. Tumor is an extra-axial, hemispherical mass with its
broad base against the posterior petrous wall, obtuse bone tumor angle, underlying focal hyperostosis (open arrow), central vascular pedicle (long thin arrow),
and transincisural (arrowheads) and transtentorial (paired white arrows) middle fossa extensions. Tentorium is indicated by black arrows. Central hypointensity
is consistent with fibrosis and calcification. Note dural tails (tandem arrowheads) in B.

A B
Figure 21-15. En-plaque meningioma with transpetrous tumor in posterior and middle fossas. A, T1WI. B, Gd-T1WI. Tumor (arrows) is isointense and
inconspicuous precontrast, but markedly hyperintense postcontrast. Note dural tail over clivus (arrowhead), tumor filling right Meckel’s cave in contrast to
unfilled left Meckel’s cave (open arrow), and underlying focal hyperostosis (small arrows). Note also tentorial attachment (curved arrows).
(Courtesy of James J. Hodge, MD)
360 NEURORADIOLOGY

important for differentiation of surgically placed fat from neurofibromatosis), established by the National Institute
tumor.75 Fat suppression technique should be used.24 After of Health (NIH) Consensus Development Conference as
hearing-conservation techniques have been performed to separate disorders, represents a significant advance in the
remove small VSs, enhancement of varying degrees at the understanding and management of these disorders.19
operative site is usually present.76 Serial follow-up studies Although both disorders are autosomal-dominant and may
are necessary to establish the presence or absence of be inherited or acquired by mutation, they are associated
tumors.77 with defects in different chromosomes.81,82 Because both
After stereotactic radiosurgery, one series shows VSs disorders may have central nervous system (CNS) involve-
often shrank (22%) but more commonly remained stable ment, the terms peripheral and central neurofibromatosis
in size (73%) and rarely continued to grow (4%).78 The should be discarded.83 It is important to be aware of their
corresponding numbers for untreated tumors were 3%, differences so that the MRI examination may be appropri-
59%, and 38%, respectively.78 The majority (79%) of ately tailored to the disorders.83,84
tumors after radiosurgery showed loss of central enhance- The diagnostic criteria for NF1 may be found in
ment, which sometimes returned (Fig. 21-16). Some 5 to Chapter 46. The criteria for NF2 include (1) bilateral
15 months after treatment, 9% developed hyperintensity eighth nerve masses seen with appropriate imaging
on T2WI in the adjacent pons and the cerebellar peduncle techniques, such as CT or MRI (see Fig. 21-12) or (2) a
with associated contrast enhancement on T1WI sugges- first-degree relative with NF2 and either a unilateral
tive of breakdown in the blood-brain barrier. Some of eighth nerve mass or two of the following: neurofibroma,
these changes resolved after months and were not neces- meningioma, glioma, schwannoma, or juvenile posterior
sarily associated with neurologic symptoms. Similarly, subcapsular lenticular opacity.19
contrast enhancement was observed in the trigeminal Besides bilateral VSs, NF2 patients are at risk for
nerve in some of the patients. Up to 10% of the patients schwannomas of other cranial and spinal nerves, and
developed hydrocephalus months after radiosurgery and intracranial and spinal meningiomas, often multiple (see
required ventriculoperiotoneal shunts.78–80 Some tumors Fig. 21-12).21,83 Members of some kindreds also develop
continued to grow and required reradiation or eventually ependymomas.22 Choroid plexus calcification is com-
surgical resection.79 mon.85 NF2 patients, however, are not at risk for optic
The distinction of neurofibromatosis 1 (NF1) (von gliomas, focal cerebral hamartomas, and many other
Recklinghausen’s disease) from NF2 (bilateral acoustic stigmata common in NF1.83

A B

Figure 21-16. VS after stereotactic radiosurgery. A, T1WI. Hypointensity

in adjacent pons consistent with edema (arrow). B, Gd-T1WI. Central
nonenhancement (curved arrow) consistent with cystic component or loss
of enhancement seen in majority of VSs after stereotactic radiosurgery.
Pontine enhancement (arrow) consistent with breakdown of blood-brain
barrier seen in a small percentage of patients. C, T2WI. Hyperintensity in
middle cerebellar peduncle and adjacent pons and cerebellum consistent
with edema (arrows). (Courtesy of Barry D. Pressman, MD)

C
 Imaging of the Cerebellopontine Angle 361

MENINGIOMA AND SIMULANTS Meningiomas often calcify on CT (25%).41,94 On MRI,

calcification appears hypointense on both T1 and T2WI
In the CPA, meningioma is a distant second to VS in inci- (see Fig. 21-14), although hyperintense calcification has
dence.39,40,86 It is most often the lesion difficult to differ- also been reported.95 MRI is less sensitive to calcification
entiate from VS.41,52,86,87 (See Chapter 47.) than CT and may not detect faint calcifications.
Meningiomas in the CPA most commonly arise from Underlying hyperostosis is infrequently seen but strongly
the posterior petrous surface (Fig. 21-17). Like VSs they diagnostic when present (see Figs. 21-14 and 21-15).41 The
are extra-axial, but unlike VSs they are usually eccentric IAC is rarely if ever enlarged.
to the porus (see Fig. 21-14). Also unlike VSs, menin- Cystic foci may be present in the tumor but appear
giomas frequently herniate into the middle cranial fossa, much less commonly in meningiomas that in VSs.52
(see Figs. 21-14 and 21-17).41 They may grow into the Peritumoral edema is more commonly associated with
middle fossa through the tentorium or the temporal bone meningiomas than with VSs. Meningeal blood supply in
(see Figs. 21-15 and 21-17).41,87 the form of an arborizing signal void is highly characteris-
Most characteristically, meningiomas are sessile and tic if present. Marginal vessels and surrounding CSF cleft
hemispherical in configuration, with their broad base may be seen but are nonspecific.96
against the petrous bone (see Fig. 21-14). They show Dural thickening surrounding meningiomas, best seen
obtuse bone tumor angles (see Fig. 21-14) in contrast with gadolinium enhancement (see Figs. 21-12, 21-14, and
to VSs, which are typically spherical or ovoid and show 21-15)97 has been variously termed meningeal sign, dural
acute bone tumor angles (see Figs. 21-8 through 21-13 and tail, and flare sign.98–100 Initially found to correspond to
21-16).41 Less commonly, meningiomas are flat or plaque- tumoral extension within or around the dura,97,99 the dural
like (en plaque) (see Fig. 21-15), and rarely pedunculated thickening in many subsequent cases has been found to
and nearly rounded.38 The en plaque meningiomas are contain only connective tissue, hypervascularity, and no
notably prone to cause deep infiltration of the petrous tumor.101 Hence, to establish the histopathology in a peri-
bone (see Fig. 21-15).38 The surface of meningiomas is tumoral meningeal thickening, biopsy is necessary. In most
usually smooth or slightly lobulated. cases, the thickening represents reactive rather than neo-
On MRI, like VSs, meningiomas are isointense or slightly plastic changes.102
hypointense on T1WI but, unlike VSs, they vary from Dural thickening has been found in 52% to 72% of the
hyperintense to hypointense on T2WI (see Fig. 21-14).8 meningiomas on postcontrast MRI.98–100 It has also been
(Hypointensity on T2WI may be due to calcification, found, although much less frequently, in nonmenin-
fibrous tissue, melanotic elements, hemosiderin, fat, etc.)58 giomas, including oligodendroglioma, schwannoma (see
Gentry and colleagues8 found that when the intensity of Fig. 21-11),61,100 glioblastoma, metastases, and other
the CPA mass was equal to or less than that of gray matter tumors (see Figs. 21-6, 21-18, 21-19, and, later in this
on T2WI, meninigioma was the most likely diagnosis. chapter, Fig. 21-35).102 Thus, peritumoral dural thickening
The variability in signal intensity of meningiomas on is strongly suggestive but not diagnostic of meningioma.
T2WI appears to reflect the histopathologic diversity of Aoki and coworkers98 found dural thickening and
meningiomas. Tumors significantly hypointense to brain enhancement extending into the IAC in two of four CPA
cortex tend to be composed primarily of fibroblastic or meningiomas that simulated the stem of a VS.
transitional elements, whereas those significantly hyperin- Several rare neoplastic and inflammatory diseases
tense tend to be composed primarily of syncytial involving the meninges may simulate meningiomas on
(meningothelial) or highly vascular elements.38,88,89 CT or MRI. Among the neoplasms are loculated lep-
Generally, however, accurate prediction of histology by tomeningeal metastasis (meningeal carcinomatosis)
imaging is not possible,90,91 and tumor aggressiveness and
recurrence rate does not necessarily correlate with histol-
ogy.92 Metabolic rate as revealed by positron emission
tomography (PET) may be a better prognosticator of
tumor aggressiveness and likelihood of recurrence.93

Figure 21-18. Loculated and diffuse meningeal metastases from carcinoma

Figure 21-17. Diagrammatic representation of locations of 19 meningiomas of the prostate. Gd-T1WI, Loculated metastases are present in both IACs
producing CPA symptoms (left and right sides combined). (From House JW (arrows) and diffuse metastasis (long thin arrows) similar to dural “tail.”
and O’Connor AF [eds.]: Handbook of Neurotological Diagnosis, New York, Differential diagnosis: meningeal lymphoma, melanoma, sarcoidosis,
1987, Marcel Dekker, Inc, p 290, by courtesy of Marcel Dekker, Inc.) tuberculosis, syphilis, idiopathic pachymeningitis.
362 NEURORADIOLOGY

A B

C D
Figure 21-19. Idiopathic hypertrophic pachymeningitis. A, Sagittal T1WI. B, T2WI. C, Gd-T1WI. D, Coronal Gd-T1WI. Mass (black arrows) is extra-axial,
dural-based on clivus and posterior petrous surface, slightly inhomogeneous and hypointense on T1WI, A, and inhomogeneous in intensity of T2WI, B, with
mild inhomogeneous enhancement postcontrast, C and D, except for dural tails (white arrow) where enhancement is more intense. The patient is a 50-year-old
woman who had rubbery hypovascular prepontine mass at transtemporal exploration and well-formed granulomas and chronic inflammation of histopathologic
examination. No organisms were found on stains and cultures. (Courtesy of Robert K. Jackler, MD.)

(Figs. 21-18 and 21-20),103–105 primary meningeal lym- the middle cranial fossa. Their shapes are thus quite vari-
phoma,42,106 and primary malignant melanoma.41,107,108 able. They tend to burrow into the surface crevices of the
Among the inflammatory diseases are meningeal sarcoido- brain and possess a fine surface irregularity reminiscent of
sis,44,109 tuberculosis, syphilis, and idiopathic hypertrophic that of cauliflower.110 The petrous apex may be eroded.41,111
cranial pachymeningitis (see Fig. 21-19).43 All of the pre- On CT they are well known to be isodense with CSF.8
ceding conditions may appear as diffuse dural thickening But, rarely they may be hyperdense (see Fig. 21-22).112–114
simulating en plaque meningiomas or localized dural-based On MRI they are slightly hyperintense to CSF on T1WI
masses simulating sessile meningiomas. However, they are and isointense on T2WI in the vast majority of
not expected to have underlying hyperostosis, intratu- cases.8,110,115,116 But, rarely, they show reversed signal inten-
moral calcification, or discernible arborizing meningeal sities and are hyperintense on T1WI and hypointense on
arterial feeders. T2WI (“white epidermoids”) (see Fig. 21-22).117,118
They often show fine internal strands and at times a thin
capsule of brain intensity.116 They may surround rather
EPIDERMOID AND OTHER CYSTS than displace the cisternal arteries.116 Small punctate calci-
fications are infrequently seen in the periphery.119
Congenital intradural epidermoid tumors or cysts are the Epidermoid cysts are nonenhancing (see Fig. 21-12).119
third most common mass lesion in the CPA (Figs. 21-21 Association of an enhancing component should arouse the
and 21-22).39,41 suspicion of a squamous carcinoma arising from an epider-
They may be anterolateral or posterolatral to the brain- moid cyst.120,121
stem. They tend to expand where the physical resistance is A number of other cysts may simulate epidermoid cysts
low, often extending into the prepontine and suprasellar in the CPA. They are all nonenhancing extra-axial masses
cisterns and “dumbbell” into the contralateral cistern or of nearly CSF attenuation (on CT) and intensity (on
 Imaging of the Cerebellopontine Angle 363

A B
Figure 21-20. Loculated leptomeningeal metastasis simulating meningioma. Patient had right hearing loss for only 2 weeks, an unusually short duration of
symptoms for a meningioma, and had previously had a malignant melanoma removed from her trunk. Metastatic melanoma was surgically confirmed. A, Gd-
T1WI. Hemispherical homogeneously enhancing extra-axial mass eccentric to porus acusticus with extension into IAC, entirely consistent with a meningioma.
B, Coronal Gd-T1WI. Subtle symmetric additional metastases within foramen magnum are seen (arrows). (Courtesy of Peter W. Joyce, MD.)

A B

C D
Figure 21-21. Intradural congenital epidermoid cyst (tumor). A, T1WI. B, Gd-T1WI. C, T2WI. D, Coronal Gd-T1WI. Irregular extra-axial mass displaces pons
and insinuates toward fourth ventricle through widened lateral recess (arrowheads). Tumor is slightly hyperintense to CSF on T1WI, A, nonenhancing postcon-
trast, B, and nearly isointense to CSF on T2WI, C, and shows fine internal inhomogeneity and fine surface irregularity (A, B, and C). Note herniation (arrows in
D) through tentorial incisura displacing midbrain.
364 NEURORADIOLOGY

A B

Figure 21-22. Intradural “white” congenital epidermoid. A, Noncontrast CT.

B, T1WI. C, T2WI. This very rare “white” epidermoid in the right CPA
deforming the medulla is hyperdense of CT, A, hyperintense of T1WI, B, and
hypointense on T2WI, C, in complete reversal to the relatively common and
more typical “black” epidermoid in the preceding figure. The MR intensities
of a “white” epidermoid are similar to those of lipoma (see Figs. 21-25 and
21-44); the CT hyperdensity, however, is in contrast to the hypodensity
characteristic of lipoma or fat. (Courtesy of Robert K. Jackler, MD.)

MRI)—hypointense on T1WI and hyperintense on on T1WI, but T2WI demonstrate the surrounding
T2WI. Lipoma is also considered at this time because it is parenchymal reaction to greater advantage.129 Coexistent
nonenhancing, although its x-ray attenuation and MR sig- parenchymal, ventricular, or additional cisternal cysts,
nal intensities of fat are distinctive from those of most when present, strongly support the diagnosis.
cysts.122,123 Very rare congenital cysts that may be encountered in
Arachnoid cysts in the CPA are usually large masses and, the CPA include epithelial cysts,130–133 neurenteric cysts,134
like epidermoid cysts, hypointense on T1WI and hyperin- and craniopharyngioma.17,135 Although their CT and MR
tense on T2WI (Fig. 21-23).124,125 (See Chapter 55, images have been illustrated, generalization of their find-
Neurotologic Aspects of Posterior Fossa Arachnoid ings is difficult on the basis of the very few cases reported.
Cysts.) But unlike epidermoid cysts, their surfaces are Some of them show CT attenuation and MR intensities
smooth and their contents homogeneous. They displace atypical of uncomplicated cysts.132,134,135
rather than surround the arteries in the cistern. An attempt In contrast to most CPA tumors and cysts, lipomas are
to differentiate the two lesions on the basis of imaging is hyperintense on T1WI and hypointense on T2WI and
worthwhile, since the symptoms of arachnoid cysts may be parallel the signal intensity of orbital and subcutaneous fat
controlled by diuretics alone.126 Diffusion-weighted and (Fig. 21-25).122,136–140 They show no contrast enhance-
fluid-attenuated MR sequences may help in differentiating ment, and their hyperintensities on T1WI are diminished
the two lesions when routine spine-echo studies are incon- by fat suppression sequences.24 Without pregadolinium
clusive.127 images for comparison, their inherent hyperintensity on
Cysticercosis should be considered in endemic areas. T1WI will not be recognized when only postgadolinium
Cisternal cysticercal cysts are also of CSF attenuation and T1WI are obtained; nor will their characteristic short T2
intensity, but are usually smaller than arachnoid cysts and values be appreciated without adequate T2WI. Because
often detected only by the presence of focal cisternal conservative management for lipomas may be advis-
widening (Fig. 21-24).128 Unlike parenchymal and ventric- able,122,136,137,139,141–143 diagnosis on the basis of imaging
ular cysticercal cysts, which are separate from one another, findings is of considerable importance. Besides the charac-
cisternal cysts are racemose, a few centimeters in diame- teristic MRI intensities, the negative Hounsfield values of
ters, and lack a scolex.128 The majority are detectable only lipomas on CT are also diagnostic.42,123,141
 Imaging of the Cerebellopontine Angle 365

A Figure 21-24. CPA cysticercal cysts. T1WI. Bilateral cisternal cysts (arrows)
isointense with CSF indent pons and slightly bow left facioacoustic nerves
(curved arrow).

C
Figure 21-23. CPA arachnoid cyst. A, T1WI. B, T2WI. C, Postcontrast CT.
Cyst is isointense with CSF on MRI, A and B, and isodense with CSF on CT,
C, and nonenhancing, similar to a typical epidermoid but is distinguishable
from the latter by being smooth surfaced and homogeneous. Note notching
on surface by basilar artery in A and B. B
Figure 21-25. CPA lipoma. A, T1WI. B, T2WI. Note characteristic hyperinten-
sity on T1WI (arrow in A) and hypointensity on T2WI (arrow in B) in reverse
of CSF. See also Fig. 21-44.
366 NEURORADIOLOGY

NONVESTIBULAR POSTERIOR Facial schwannomas are, in most cases, indistinguish-

FOSSA SCHWANNOMAS able from VSs on CT or MRI when they arise in the CPA
or the IAC (Fig. 21-27).1,138,151 When they arise in the CPA
Schwannomas arising from PF cranial nerves other than or the IAC, they tend to show vestibulocochlear symptoms
the vestibular are rare.38,44 They resemble VSs in appear- and may be indistinguishable from VSs clinically as
ance but differ from them in location.41,144 Not infre- well,151–153 unless a cisternal facial schwannoma lies clearly
quently, facial and intracranial jugular foramen anterior to the course of the acoustic nerve.
schwannomas are associated with symptoms relating pri- Schwannomas of the glossopharyngeal, vagus, and
marily to the eighth nerve. Careful assessment of their spinal accessory nerves (jugular foramen schwannomas)
relationship to the cranial foramina is important so that may be predominantly intracranial (type A), predomi-
the correct diagnosis can be made and inappropriate use of nantly in the skull base (type B), or predominantly
the translabyrinthine approach avoided.145 extracranial (type C).154 Type A tumors tend to present
Among the PF schwannomas, trigeminal schwannoma with eighth nerve and cerebellar signs and symptoms, and
is a distant second to VS in frequency of occurrence.144 type B and C tumors tend to present with palsies of the
Trigeminal schwannomas may arise intradurally from ninth, tenth, or eleventh cranial nerves.154–157 Thus type A
the nerve root in the CPA and the Meckel cave or extradu- tumors mainly need to be differentiated from VS and type
rally from the gasserian ganglion in the middle cranial B tumors from paraganglioma (glomus jugulare tumor),
fossa (Fig. 21-26).146–149 They often dumbbell into the meningioma, and other tumors that may involve the jugu-
posterior and middle fossae through the porus trigemi- lar foramen (Fig. 21-28). (See also Chapter 61.) On CT
nus.86,147–149 The foramen ovale or foramen rotundum the jugular foramen enlarged by a schwannoma shows a
(or both) may be enlarged. They tend to be larger than smooth rounded margin.1 On MRI, the prominent ser-
the average VS,149 and more often contain cystic pentine arborizing signal voids common in large paragan-
components.41,150 gliomas are seldom present,158 and on angiography the

A B

C D
Figure 21-26. Cystic trigeminal schwannoma. A, T1WI. B, Gd-T1WI. C, PDWI. D, T2WI. Bulk of tumor lies in posterior fossa with a small middle fossa
component enlarging left Meckel’s cave (arrow). Note similarity of tumor to arachnoid cyst (Fig. 21-19) on noncontrast images (A, C, and D). Tumor is nearly
of CSF intensity of T1WI, A, because of predominance of intratumoral cystic components, and more obvious in B postcontrast, but also subtly suggested in
A and C.
 Imaging of the Cerebellopontine Angle 367

A B
Figure 21-27. CPA facial schwannoma. A, T1WI. B, Gd-T1WI. Isointense rounded extraaxial tumor centered at porus acusticus, A, intensely enhancing
postcontrast, B, indistinguishable from VS (see Fig. 21-9).

tumors are less vascular than paragangliomas but more so VBD, or elongation and dilatation of the vertebrobasi-
than meningiomas.154,155,159 (See also Chapters 22 and 61.) lar arteries, is probably the vascular lesion most commonly
When the pars nervosa of the jugular canal is selectively associated with compressive symptoms of the PF cranial
expanded, a glossopharyngeal schwannoma can be recog- nerves (Figs. 21-3 and 21-29).164 The basilar artery may
nized. When the entire jugular foramen is diffusely and be considered ectatic if its diameter is more than 4.5 mm
enlarged, however, differentiation among the jugular fora- (see Fig. 21-29) and elongated if it deviates beyond the
men schwannomas is not possible by imaging.1 lateral margin of the clivus (see Fig. 21-3) or the dorsum
Rarely a hypoglossal schwannoma may also appear as a sellae or if it bifurcates above the plane of the suprasellar
mass in the CPA. Its identity can be traced if the hypoglos- cistern.165
sal canal is smoothly and selectively enlarged.160–162 When Patients with VBD may or may not be symptomatic.166
the bone erosion incorporates the adjacent jugular fora- The incidence of cranial nerve compressive symptoms, how-
men, identification of precise origin of the tumor is then ever, appears to correlate with the degree of tortuosity.167
no longer possible.160 A symptomatic patient with a tortuous basilar artery
of normal caliber is more likely to have involvement of
a single cranial nerve (see Fig. 21-3); conversely, one with a
VASCULAR LESIONS dilated and tortuous artery is likely to have multiple com-
pressive or ischemic neurologic deficits or hydrocephalus
Vascular lesions in the CPA are rare, but a number of them (see Fig. 21-29).164
may clinically mimic neoplasms and should be considered In most cases the actual compression of a cranial nerve is
in the differential diagnosis on imaging.163 exerted by the superior cerebellar artery on the trigeminal,

A B
Figure 21-28. Jugular foramen schwannoma. A, T1WI. B, Gd-T1WI. Patient has NF2. Tumor is slightly lobulated and located partly in posterior fossa, deforming
medulla and cerebellum, and partly in jugular foramen. It is mildly hypointense to brain, A, and intensely enhancing postcontrast, B. Vascularity is more promi-
nent in this tumor than in a typical schwannoma, raising the question of a paraganglioma (see Fig. 21-6). Note signal from slowly flowing blood in left sigmoid
sinus enhancing postcontrast.
368 NEURORADIOLOGY

A B
Figure 21-29. Vertebrobasilar dolichoectasia. A, Sagittal T1WI. Dilated and tortuous basilar artery (curved arrow) shows peripheral laminar hyperintensity due
to very slow flow or thrombi (or both) and central moderate intensities due to moderately slow flow within the patent lumen. Normal flow void is seen in the
undilated proximal and distal arteries (straight arrows). B, Gradient echo image. Flowing blood appears hyperintense on such images. Basilar artery (curved
arrows) shows marked fusiform dilatation and marked tortuosity. Signal intensities in such dilated arteries are often complex due to presence of thrombi of vary-
ing are and flow of varying velocity. Similar complex intensity patterns may be also found in giant aneurysms, although the latter lesions are rounded or ovoid
rather than fusiform. (Courtesy of William P. Dillon, MD.)

the anterior inferior cerebellar artery (AICA) on the facial With future improvements MR angiography may become
or vestibulocochlear, or the posterior inferior cerebellar a useful adjunct (see Fig. 21-3).23
artery (PICA) on the glossopharyngeal. Hence, vascular For preoperative diagnosis of neurovascular cross-
cross-compression by a branch of the vertebrobasilar compression, some centers use CT or MRI only to exclude
artery may occur without the vertebrobasilar itself neces- other causes of symptoms,168,176 whereas others use, in
sarily being substantially dilated or tortuous. In fact, the addition, gas-CT cisternography for positive identification
offending vessel may at times be a vein instead of an artery.168 of the offending vessel before surgical microvascular
Furthermore, vessel-nerve contact or even vascular grooving decompression (Fig. 21-30).9,177 The point of contact may
of the nerve does not necessarily mean disease.169 be in the cistern, the porus, or the canal and not necessar-
Positive identification of the offending vessel by imag- ily limited to the canal as described in some reports.169,177
ing is difficult. Angiographic localization, which visualizes Concerns about postprocedural morbidity,178 even with
the vessel but not the nerve, is indirect and invasive.170,171 25-gauge rather than the “standard” 22-gauge spinal nee-
CT with IV contrast shows the vertebrobasilar arteries dles,179 have discouraged continued use of the gas-CT cis-
and the brainstem but not adequately the branches of ternogram in favor of the MR cisternogram with fast spin
the vertebrobasilar or the cranial nerves in question.172 echo or CISS (see Fig. 21-1).4,5,11
MRI offers improved resolution of the structures, but expe- Aneurysms of the vertebrobasilar system comprise about
rience with MRI in this application is as yet limited.173–175 10% of intracranial aneuryms.180 The common locations

Figure 21-31. AICA berry aneurysm. Selective vertebral angiogram. Patient

had subarachnoid hemorrhage and hearing loss. Aneurysm (arrow) shows
Figure 21-30. AICA loop in IAC (also see Fig 21-1). High-resolution gas-CT nipple-like configuration suggestive of recent bleeding. (Reprinted from
cisternogram. Loop on AICA is marked with curved arrow; facial nerve, short Lo WWM: Tumors of the cerebellopontine angle. In Som PM, Bergeron RT
arrow; acoustic nerve, long arrow. [eds.]: Head and Neck Imaging, 2nd ed. St. Louis, Mosby-Year Book, 1991.)
 Imaging of the Cerebellopontine Angle 369

A B
Figure 21-32. Giant PICA aneurysm. A, Precontrast. B, Postcontrast CT. Aneurysm at PICA origin is partially thrombosed and slightly hyperdense to brain pre-
contrast, A, and shows nonenhancing thrombus (open arrow) and enhancing lumen (long arrow) and outer rim (short arrow) postcontrast,
B. (Courtesy of Duane E. Blickenstaff, MD.)

are the basilar bifurcation, the basilar trunk, the vertebral Dilated enhancing vessels may be seen in the CPA on CT
artery, and the PICA. Berry aneurysms usually present and serpentine hypointense loops on MRI.41,189
with subarachnoid hemorrhage (SAH) (Fig. 21-31), Superficial siderosis (SS), or pial siderosis of the
whereas giant aneurysms (those exceeding 2.5 cm) usually acoustic nerves, is not a vascular lesion in itself but the
present instead as mass lesions (Fig. 21-32).181 result of chronic subarachnoid hemorrhage, often of
AICA aneurysms, representing only 1% of intracranial venous or capillary origin such as from an occult ependy-
aneurysms, are quite rare.182 In the past, AICA aneurysms moma.191 It is rare, but has been recognized with increas-
have often been operated on with the erroneous diagnosis ing frequency with greater awareness and the increasing
of acoustic tumor.182,183 A review of 22 reported cases availability of high-field MRI. It should be considered in
revealed that 16 had acoustic and 14 had facial nerve symp- the differential diagnosis of CPA lesions since the affected
toms and signs. Most had headaches, nausea, and vomit- patients commonly complain of bilateral progressive sen-
ing, and 13 had documented SAH.182 Most were in the sorineural hearing loss and ataxia (see Fig. 21-5).18,191,192
5- to 7-mm range, although two exceeded 15 mm. Although SS is characterized by intracellular and extracellular dep-
VSs may on rare occasions present with SAH, they tend to osition of hemosiderin in the leptomeninges and subpial
be large, not small tumors.59,60 tissue of the brain, spinal cord, and cranial nerves. The
Berry aneurysms appear as signal voids on MRI and acoustic nerve with its long glial-lined segment appears
enhancing lesions on CT. Angiography is diagnostic (see especially vulnerable. The characteristic hypointensity
Fig. 21-31). of pial and subpial tissue and the cranial nerves is seen
Giant aneurysms are usually partially thrombosed.41,181 only on T2WI on high-field MRI and gradient-echo
A partially thrombosed aneurysm appears on MRI with a imaging.18,192
signal void in the patent lumen surrounded by layers of
thrombi of varying signal intensities and sometimes a
low-intensity outer rim (see Fig. 21-29).184–187 Signal loss
from pulsating CSF around the basilar artery may mimic
the signal void of an aneurysm.188 MR angiogram or
contrast-enhanced CT would show the true size of the
basilar artery. On CT a partially thrombosed aneurysm
shows an enhancing outer rim with an isoattenuating
nonenhancing mural thrombus surrounding an enhanc-
ing lumen (see Fig. 21-32), superficially resembling
a partially enhancing cystic schwannoma.1,41,181,189 A
thrombosed aneurysm is filled with a nonenhancing
thrombus, and an unthrombosed one contains only the
enhancing lumen.41
AVMs in the CPA are exceedingly rare (Fig. 21-33).
Although they are generally intracerebral and cause
primarily intracerebral hemorrhage, totally extracerebral
AVMs, which are predisposed to primary subarachnoid Figure 21-33. CPA arteriovenous malformation. Selective vertebral
bleeding, may be seen in the CPA.189 One or more cerebral angiogram. Principal feeder appears to be right AICA. (Courtesy of Livia G.
aneurysms coexist with AVMs in about 20% of cases.190 Solti-Bohman, MD.)
370 NEURORADIOLOGY

EXTRADURAL LESIONS INTRA-AXIAL TUMORS

Bone lesions and paragangliomas are extradural lesions and Intra-axial tumors arise from the brain and a detailed dis-
are detailed in Chapter 22, Imaging of the Lateral Skull cussion is beyond the scope of this chapter. Some of them
Base. Here they are briefly discussed only as a reminder that produce exophytic masses in the CPA and must be consid-
they may intrude into the CPA.1 Bone lesions in the petrous ered in the differential diagnosis.
apex include cystic lesions such as cholesterol granuloma Intra-axial PF tumors arise from the brainstem, the
(cholesterol cyst) (Fig. 21-34), congenital intrapetrous cerebellum, or the fourth ventricle. Tumors of the brain-
epidermoid cyst, and petrous apex mucocele193; solid tumors stem are mainly astrocytomas that occur in children or
such as chordoma, chondroma, chondrosarcoma (Fig. 21-35), young adults (Fig. 21-36).195–197 Exophytic growths are
giant cell tumor, myeloma, metastases, xanthoma,194 and so common. Tumors in the cerebellum may arise from the
on; and intrapetrous carotid aneurysm. Papillary endolym- vermis or the hemispheres. The vermian tumors are prin-
phatic sac tumors, which may also protrude into the cipally medulloblastomas in childhood, now classified as
CPA, are discussed in Chapter 23, Imaging of the Facial primitive neuroectodermal tumors (PNETs).196,198,199 The
Nerve. The more aggressive of the extradural tumors may hemispheric tumors include astrocytomas,196 usually of the
at times transgress the dura and form an intradural mass pilocystic variety in young adults, hemangioblastomas in
(see Fig. 21-35). The same may be said for paragangliomas middle-aged individuals,200 and metastases.196 Any of the
from the jugular foramen (see Fig. 21-6). The associated three may be cystic or solid.96 Lymphoma of the brain is
bone changes of an apparently intradural mass may reveal its seen with increasing frequency in recent years, particularly
true origin. among immunosuppressed patients (Fig. 21-37).196,201

A B

C D
Figure 21-34. Triloculated cholesterol granuloma (cholesterol cyst) of petrous apex. Huge extra-axial mass partly in posterior and partly in middle fossa.
A, T1WI shows markedly hyperintense contents in two of the loculations but a mixture of hyperintensities and hypointensities in the third. B, T2WI shows
markedly hyperintense contents in two of the loculations but markedly hypointense contents in the third. Note increased thickness of hypointensity in capsule
as compared to A. C, Postcontrast CT shows isodense contents and thin opaque capsules, in part formed by remodelled bone. D, Coronal HRCT shows
extradural intrapetrous origin of mass, which has expanded into posterior and middle fossas (arrowheads). Note partitions between loculations (short arrow)
and erosion of cochlea and semicircular canal (open arrows).
 Imaging of the Cerebellopontine Angle 371

A B
Figure 21-35. Petrous apex chondrosarcoma. A and B, Gd-T1WI. Highly conspicuous markedly enhancing intradural component (arrowhead) of tumor in CPA
indenting pons represents merely “tip-of-iceberg” of the much larger but less conspicuous inhomogeneously enhancing extradural intrapetrous tumor extending
into posterior fossa (twin arrows), middle ear (arrow), and Meckel’s cave (crossed arrow). Tumor also extends below skull base (black arrow). Note dural tail
(long thin arrow).

Although any intra-axial tumor may grow into the CPA, In the IAC as in the CPA, tumors other than VSs are
tumors from the fourth ventricle are particularly prone to uncommon, but because therapeutic implications for some
do so.202 They are ependymomas (Fig. 21-38)203,204 and of the lesions are significantly different from those of VSs,
choroids plexus papillomas (Fig. 21-39).205–208 Both of each of the lesions should be carefully considered and if
these tumors often contain granular calcifications. possible preoperatively identified. In general, few intra-
Although extra-axial tumors are more common in the canalicular schwannomas, either vestibulocochlear or
CPA in adults and older teens,209 exophytic intra-axial facial, are associated with signs of facial nerve involvement.
tumors are more common in childhood.199 Presence of such signs in a patient with an intracanalicular
Nonneoplastic brain lesions such as multiple sclerosis tumor should be a clinicoradiologic clue that arouses
(see Fig. 21-4)210–211 and infarct (Fig. 21-40)210,212 also suspicion of a nonschwannomatous tumor.216
enter into the differential diagnosis, as do AVMs,213 cav-
ernous angiomas,214,215 developmental venous anomaly 1. Vestibular schwannomas again constitute about 90%
(venous angiomas), and capillary telangiectasia.214 of the tumors.48,179,216
2. Facial schwannomas are rare and usually indistin-
guishable from VSs preoperatively.1,152,153
INTRACANICULAR LESIONS 3. Meningiomas have been said to cause facial palsy
more often than VSs but rarely have they been fully
Intracanalicular lesions of the IAC carry a slightly different documented.217,218 They may be accompanied by
differential diagnosis from lesions of the CPA (Table 21-4). hyperostosis or dural tail.

A B
Figure 21-36. Pontine astrocytoma. A, PDWI. B, T2WI. Intra-axial mass is mildly to moderately hyperintense and poorly marginated from pons and cerebellum
(short arrows) and deforms fourth ventricle. Exophytic growth of tumor fills CPA cistern (open arrows). (Courtesy of Anton N. Hasso, MD.)
372 NEURORADIOLOGY

A B

Figure 21-37. Primary cerebellar lymphoma. A, Gd-T1WI. B, PDMI.

C, T2WI. Moderately enhancing intraaxial tumor in region of flocculus
(arrow) mildly hyperintense on PDWI, B, and T2WI, C, with peritumoral
edema (small arrows) not apparent on Gd-T1WI, A. Differential diagnosis:
solid astrocytoma, hemangioblastoma, and metastasis.

A B
Figure 21-38. CPA ependymoma. A, T1WI. B, T2WI. Exophytic tumor from foramen of Luschka, widening lateral recess and displacing medulla (short arrow)
and fourth ventricle (arrow) from left cerebellum (open arrow). As in other exophytic intra-axial tumors (Fig. 21-36), brain tumor margins are less distinct than
in extra-axial tumors. (Compare with Fig. 21-39.)
 Imaging of the Cerebellopontine Angle 373

A B
Figure 21-39. CPA choroid plexus papilloma. A, T1WI. B, T2WI. Tumor from foramen Luschka widening lateral recess, and displacing medulla (short arrow)
and fourth ventricle (arrow) from right cerebellum (open arrow). Tumor is mildly hypointense on T1WI, A, and mildly hyperintense on T2WI, B. Because the
choroid plexus is extra-axial, brain tumor margins of papilloma are better defined than in ependymoma (see Fig. 21-38) (Courtesy of Val M. Runge, MD.)

4. Intracanalicular vascular tumors (hemangioma/vas- 6. Lipochoristomas (lipomas) contain adipose and

cular malformation) are probably a distant second other ectopic mature mesenchymal tissues, such as
to VSs in incidences in the IAC.219–222 They tend to smooth muscle, in varying proportions, with fat
cause a greater degree of nerve deficits and are more usually predominating. Fat shows distinctive MR
commonly accompanied by facial nerve symptoms signal intensities, being markedly hyperintense
than VSs of comparable size.216,221,223–225 Some of on T1WI and moderately hypointense on T2WI
them contain intratumoral bone spicules discernible (Fig. 21-44)142,230 and can be confirmed by precon-
on high-resolution CT with bone algorithm trast fat-suppressed T1WI.24,139
(Fig. 21-41)226,227; some may be associated with honey- 7. Melanotic melanomas are also hyperintense on
comb changes of the adjacent bone (see Fig. 21-41).221 T1WI and hypointense on T2WI, but amelanotic
On MRI, some are isointense or hyperintense to CSF melanomas do not follow such a pattern (see Figs.
on T2WI and a few are moderately hyperintense on 21-20 and 21-43).58,108,231
T1WI, but often they are indistinguishable from 8. Lymphoma in the IAC may involve the lep-
schwannomas, especially when precontrast T1WI and tomeninges.232
adequate T2WI are lacking (Fig. 21-42).220,222 9. Glioma of the acoustic nerve is an extreme rarity.233
5. Intracanalicular metastases may be suspected from a 10. Osteomas of the IAC are also rare and are better
short duration of symptoms, facial weakness, a known demonstrated on CT than on MRI (Fig. 21-45).
history of malignancy, and a rapid growth rate on Osteomas containing purely cortical bone are
serial studies.1,228,229 Not infrequently they are bilat- hypointense on all sequences; those containing fatty
eral (Figs. 21-18 and 21-43). marrow simulate lipomas in intensities.

TABLE 21-4. Intracanalicular Lesions

Neoplastic
Vestibular schwannoma
Facial schwannoma
Meningioma
Hemangioma
Metastasis
Melanoma
Lymphoma
Glioma
Osteoma
Nonneoplastic
Lipochoristomas (lipomas)
AICA loop
AICA aneurysm
Figure 21-40. AICA infarct. T2WI. Nonexpansile hyperintense right ponto- Meningitis
cerebellar lesion (open arrow) in territory of anterior inferior cerebellar artery Neuritis
hardly discernible on T1WI (not illustrated). (Compare with Fig. 21-4.) Note Hamartoma
also hyperintensity from slowly flowing blood in tortuous basilar artery
(arrow). AICA, anterior inferior cerebellar artery.
374 NEURORADIOLOGY

A B

C D

Figure 21-41. IAC hemangioma A, T1WI. B, Gd-T1WI. C, T2WI. D, and E,

HRCT. Tumor (white arrow) extending slightly anterointeriorly beyond IAC is
nearly isointense on T1WI, A, strongly enhancing postcontrast, B, and
hyperintense on T2WI C, similar to schwannomas. HRCT reveals
characteristic intratumoral bone spicule (black arrow) in D and “honeycomb”
bone erosion (black arrow) of the floor of IAC in E. Some hemangiomas
however do not show the characteristic bone changes (see Fig. 21-37).
(Courtesy of Malcolm D. Graham, MD.)

Hamartoma of the acoustic nerve has also been thus advised for very small lesions to verify persistence of
reported.216,234 Other nonneoplastic IAC lesions include symptoms or tumor growth.244,245
(1) AICA loop in the IAC (see Figs. 21-30 and 21-1),169,177,235
which may at times simulate a tumor,236 (2) AICA aneurysm
as previously discussed (see Fig. 21-31),182,183 (3) meningeal CONCLUSION
inflammation and adhesion (Fig. 21-46),237,238 and (4) neuri-
tis of the facial or acoustic nerves (Fig. 21-47).239–243 One The variety of tumors and other lesions that may arise in
report described four cases of vestibulocochlear neuritis with the CPA and the IAC are indeed enormous. However, the
hearing loss, positive auditory brainstem response, and MRI common extra-axial types, which are well over 90% of
finding of focal nerve enhancement indistinguishable from the lesions, are quite consistent in their appearance on
small intracanalicular VSs.244 A period of observation was imaging. These include VS, meningioma, epidermoid and
 Imaging of the Cerebellopontine Angle 375

Figure 21-42. IAC hemangioma/vascular malformation. Gd-T1WI. Tumor is

markedly hyperintense postcontrast and indistinguishable from IAC schwan-
nomas. Compare with Figs. 21-7 and 21-41.

A B

Figure 21-43. Bilateral IAC metastases from melanoma. A, T1WI. B, Gd-T1WI.

C, T2WI. Tumors are isointense on T1WI, mildly enhancing of Gd-T1WI. One
is isointense with gray matter and one with white matter on T2WI. Patient
had bilateral rapidly progressive hearing loss and facial palsies.

C
376 NEURORADIOLOGY

A B
Figure 21-44. IAC lipoma. A, Gd-T1WI. B, T2WI. On Gd-T1WI alone, hyperintense tumor is indistinguishable from a schwannoma or hemangioma
(see Figs. 21-7 and 21-42). Hypointensity of tumor (arrow) on T2WI, however, suggests fat. See also Fig. 21-25. (Courtesy of Kenneth L. Kidd, MD.)

A B
Figure 21-45. IAC osteoma. A, Coronal CT. Osteoma (arrow) consisting entirely of cortical bone arising from anterosuperior wall of porus acusticus caused
sensorineural hearing loss relieved by resection. B, Gd-T1WI. Tumor (arrow) is hypointense in all sequences and nonenhancing postcontrast. A marrow-
containing osteoma would have shown central hyperintensity on T1WI similar to marrow in petrous apices. (Courtesy of Derald E. Brackmann, MD.)

A B
Figure 21-46. Chronic inflammation. A, T1WI. B, Gd-T1WI. Small isointense soft tissue in fundus of IAC (arrowhead) enhancing postcontrast (arrow),
indistinguishable from small VS except for perhaps presence of a small dural tail (small arrow). Compare with Figs. 21-7 and 21-47. Patient had progressive
left sensorineural hearing loss of 3-year duration. Mass in fundus of left IAC adherent to dura and involving acoustic nerve was completely removed. Pathologic
diagnosis: nongranulomatous active chronic nonspecific inflammation. (Courtesy of Robert D. Sostrin, MD.)
 Imaging of the Cerebellopontine Angle 377

A B

Figure 21-47. Focal cochlear neuritis. A, T1WI. B, Gd-T1WI. Globular

thickening of acoustic nerve (arrow) with marked postcontrast
enhancement (arrow) indistinguished from intracanalicular VS
(see Fig. 21-7). Patient had progressive right sensorineural hearing loss
of 1-year duration and abnormal acoustic brainstem reflex. C, Gd-T1WI,
obtained 10 weeks after A and B. Considerable decrease in thickening
and enhancement since initial study, B, with now only residual
enhancement in cochlear nerve. Lack of clinical improvement lead to
exploration by middle fossa approach, which found no tumor.
(Courtesy of Michael J. O’Leary, MD.)

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23:250–253, 1994. 240. Daniels DL, Czervionke LF, Millen SJ: MR findings in the Ramsay
224. Shelton C, Brackmann DE, Lo WW, Carberry JN: Intratemporal Hunt syndrome. Am J Neuroradiol 9:609, 1988.
facial nerve hemangiomas. Otolaryngol Head Neck Surg 241. Korzec K, Sobol SM, Kubal W, et al: Gadolinium-enhanced
104:116–121, 1991. magnetic resonance imaging of the facial nerve in herpes zoster
225. Sundaresan N, Eller T, Ciric I: Hemangiomas of the internal audi- oticus and Bell’s palsy: Clinical implications. Am J Otol
tory canal. Surg Neurol 6:119–121, 1976. 12:163–168, 1991.
226. Atlas MD, Fagan PA, Turner J: Calcification of internal auditory 242. Osumi A, Tien RD: MR findings in a patient with Ramsay-Hunt
canal tumors. Ann Otol Rhinol Laryngol 101:620–622, 1992. syndrome. J Comput Assist Tomogr 14:991–993, 1990.
227. Gavilan J, Nistal M, Gavilan C, Calvo M: Ossifying hemangioma 243. Tien RD: Inflammatory disease of the cranial nerves.
of the temporal bone. Arch Otolaryngol Head Neck Surg Neuroimaging Clin North Am 1:89, 1991.
116:965–967, 1990. 244. Han MH, Jabour BA, Andrews JC, et al: Nonneoplastic enhancing
228. Jung TT, Jun BH, Shea D, Paparella MM: Primary and secondary lesions mimicking intracanalicular acoustic neuroma on gadolin-
tumors of the facial nerve. A temporal bone study. Arch ium-enhanced MR images. Radiology 179:795–796, 1991.
Otolaryngol Head Neck Surg 112:1269–1273, 1986. 245. Arriaga MA, Carrier D, Houston GD: False-positive magnetic res-
229. Nelson DR, Dolan KD: Cerebellopontine angle metastatic lung onance imaging of small internal auditory canal tumors: A clinical,
carcinoma resembling an acoustic neuroma. Ann Otol Rhinol radiologic, and pathologic correlation study. Otolaryngol Head
Laryngol 100:685–686, 1991. Neck Surg 113:61–70, 1995.
 Chapter
Imaging of the Lateral Skull Base

Outline 22
Technical Considerations Benign Vascular Tumors Other Lesions Involving the Grace Fan, MD
Computed Tomography Meningiomas Jugular and Carotid Area
Hugh D. Curtin, MD
Magnetic Resonance Imaging Endolymphatic Sac Tumors Middle Ear and Mastoid
Pathology Fifth Nerve Sheath Tumor Inflammatory Middle Ear
Petrous Apex and Cavernous Sinus Disease
Cholesterol Cysts or Hemangiomas Tumors of the Middle Ear
Granulomas Direct Extension from External Auditory Canal
Epidermoids Nasopharyngeal and Keratosis Obturans
Mucoceles Infratemporal Lesions External Auditory Canal
Pseudolesions of the Petrous Metastasis and Other Cholesteatoma
Apex Solid Lesions Exostosis and Osteoma
Petrous Apicitis Superior Semicircular Canal Malignant Lesions of the
Aneurysms Dehiscence External Canal
Chordomas and Jugular and Carotid Region Infection
Chondrosarcomas Paragangliomas Malignant External Otitis
Other Lesions Nerve Sheath Tumors Summary
Fibrous Dysplasia Aberrant Carotid Arteries

T he lateral skull base is not a precisely defined region.

This terminology has recently evolved in the discipline
of skull base surgery to describe the region coinciding
This chapter separates the temporal bone into four
major regions: the petrous apex, the jugular and carotid
region, the middle ear, and the external auditory canal
roughly with the medial temporal bone. In this context, (EAC). The internal auditory canal would represent a fifth
the other regions are the anterior skull base and the central major area but this is discussed in a separate chapter along
skull base. The anterior skull base is predominantly the with the cerebellopontine angle cistern. The seventh nerve
floor of the anterior cranial fossa and subjacent nasal cavity, has a tortuous course through the entire temporal bone
upper ethmoid sinuses, and orbits. Central skull base refers and must be considered in the differential diagnosis in
to the region close to the sphenoid bone and includes the many regions.
cavernous sinus, sella, and parts of the basiocciput as well
as the sphenoid bone itself along with the various foramina
transmitting the vascular and neural structures. TECHNICAL CONSIDERATIONS
This chapter emphasizes the petrous apex and medial
temporal bone but also includes some description of the Computed tomography (CT) and magnetic resonance
pathology in contiguous regions more appropriately imaging (MRI) are used in evaluation of the skull base.
assigned to the central skull base. Lesions of the middle ear Individual radiologists have certain preferences in some
and external auditory canal are briefly discussed. The regions, but one modality may be clearly superior in certain
proximity of the cavernous sinus and clivus to the temporal situations.
bone makes them appropriate for inclusion in a discussion High-resolution CT scanning is usually preferred as the
of the lateral skull base. The differential diagnoses of lesions initial imaging study for the evaluation of most temporal
in these areas are closely related and pathology can certainly bone disease other than that in the internal auditory canal.
cross from one part of the skull base to the next. CT offers the greatest structural definition of current
A large number of diagnostic possibilities must be con- imaging modalities with the advantage of demonstrating
sidered when a lesion is detected in the temporal bone or thin bony septations and fine bony anatomy to localize and
lateral skull base. The diagnosis can be limited considerably characterize disease.
depending on the precise location or apparent site of the Air, thin plates of cortical bone, septations in the mas-
lesion’s origin. A tumor arising in one location may have a toids, and the otic capsule all have a similar appearance on
diagnosis completely different from that of a lesion arising MRI. All appear black or as a signal void and little structure
in another location only millimeters away. is appreciated. MRI, however, has the ability to distinguish
383
384 NEURORADIOLOGY

subtle differences in soft tissues. In some cases, the signal signal may fail, mimicking an enhancing lesion.1 Other
characteristics can strongly suggest a certain diagnosis. A artifacts may obscure important anatomy.
gadolinium-enhanced MRI is also considered the most Other current MRI techniques such as magnetic reso-
sensitive study for the evaluation of possible internal audi- nance angiography (MRA) and magnetic resonance spec-
tory canal pathology, particularly for acoustic neuromas troscopy (MRS) may also aid in the diagnosis. MRA should
(vestibular schwannomas). be performed if vascular lesions such as aneurysm or
anatomical vascular variations are questioned. MRS may
Computed Tomography help further characterize a malignant lesion.
Diffusion-weighted images (DWI) do not give good
High-resolution axial thin section CT is usually performed anatomic detail but may give information regarding
to visualize the extent of bone involvement in lateral skull molecular motion or Brownian movement within a lesion.
base lesions. Care should be taken to ensure that any exten- Lesions with similar imaging characteristics on routine MRI
sion above or below the skull base is included in the scanned sequences can sometimes be distinguished. For instance,
area. To ensure maximal bone detail, bone algorithms should epidermoids are bright on diffusion-weighted images while
be performed on the data. a cerebrospinal fluid (CSF)-containing structure tends to
Reformatted coronal images can be generated from the be dark.
axial images. These images can give excellent information
on the relationship of structures. Until recently, direct scan-
ning has had a higher resolution and was required if bone PATHOLOGY
erosions in a plane other than the axial were to be detected.
The recent introduction of multidetector CT scanners To aid differential diagnosis, the lateral skull base is divided
has further improved image quality by improving spacial in four regions: petrous apex, jugular/carotid area, middle
resolution. The images are obtained with very thin sections ear, and external canal. Although there is some overlap, the
(as thin as 0.5 mm) allowing for less partial volume artifact. lesions that arise in each of these regions are fairly distinct so
The cross-sectional data can be postprocessed or reformat- the regions are discussed separately in the following sections.
ted into multiple planes, most commonly axial and coronal. Although regional divisions are important, some lesions
Occasionally, additional planes such at various obliquities such as metastasis, multiple myeloma, and soft tissue sar-
are helpful in assessing certain pathologies and complex comas may involve any portion of the petrous bone.
anatomies. Multislice multidetector CT has not only allowed
finer slice imaging but also accelerates data acquisition times,
thus decreasing motion-related artifacts and radiation risk. PETROUS APEX
Currently, at our institution, we do not do direct coronal
scanning. The petrous bone is a simple block of bone covered by dura
The middle ear, mastoid, and external auditory canal are and frequently penetrated by air cells from the middle ear or
often evaluated without intravenous contrast. In evaluation mastoid. The bone is separated from the greater wing of the
of the petrous apex and the carotid/jugular area, contrast sphenoid by the petrosphenoidal fissure and from the clivus
is often helpful and is routinely used. Bolus injection is by the petroclival or petro-occipital synchondrosis. Lesions
important for evaluating lesions involving the jugular in the petrous apex typically are related to the bone, the dura,
fossa, particularly differentiating an occluded jugular vein or the air cell system with its associated modified respiratory
from tumor. With multidetector machines, CT angiograms epithelium. Many lesions involve the apex secondarily.
(CTA) and CT venograms (CTV ) can be useful in detecting
arterial and venous pathologies such as aneurysms and
venous sinus thrombosis. Cholesterol Cysts or Granulomas
The petrous apex cholesterol cyst, or granuloma, consists
Magnetic Resonance Imaging of variable amount of granulation tissue and fluid in what
is considered an expanded air cell of a pneumatized petrous
On MRI scans through the skull base, spin echo images are apex. The cholesterol cyst is most likely the end point of a
still the usual images used. For small lesions, the thinnest continuum of pathology beginning with a simple obstructive
cuts possible should be performed. Unenhanced T1- effusion and ending with an expanded air cell that contains
weighted images are best for demonstrating the fat planes fibrosis, granulation tissue, fluid, and blood breakdown
beneath the skull base. Postcontrast images are essential products. The narrow drainage path of an apex air cell may
for evaluating intracranial extension and certain pathologies. be compromised by a minor infection or simple mucosal
Routine T2-weighted images do not provide anatomic edema related to pressure changes in the middle ear. Fluid
detail but are often helpful in narrowing the differential may accumulate, giving an effusion. At some time in the
diagnosis. Very high resolution T2-weighted images are used evolution of the lesion small hemorrhages may occur from
as pseudocisternograms and give excellent detail regarding the wall (Fig. 22-1). The blood breakdown products are
the anatomy of the IAC. poorly absorbed from the closed cavity and contribute to
Fat suppression on the enhanced images may be helpful the characteristic findings on CT and particularly MRI.
in evaluating lesions that extend beyond the petrous bone On CT scans, the cholesterol cyst is an expansile lesion at
into the extracranial tissues. Caution is necessary, however, the petrous apex. The bone is smoothly remodeled similar to
when evaluating near air-containing structures, such as a mucocele (Fig. 22-1A). Indeed, the findings of an apex cho-
nasopharynx and sphenoid sinus. The suppression of fat lesterol cyst have similarities to a hemorrhagic mucocele in
 Imaging of the Lateral Skull Base 385

the paranasal sinuses. Typically, the cyst has similar density to

the brain (Fig. 22-2A), denser than usually seen in an epider-
moid. Sometimes the wall of the cholesterol cyst enhances
but no enhancement occurs in the lumen of the cyst.
MRI demonstrates a characteristic bright signal on a
T1-weighted sequence (Fig. 22-2B). The signal on a
T2-weighted signal is predominantly bright but may have
a mixture of high and low signals (Fig. 22-2D). Areas of very
dark signal are also characteristic and most likely represent
hemosiderin, a breakdown product of blood.2,3
A cholesterol cyst of the petrous apex shares some char-
acteristics with the cholesterol granuloma of the middle
ear. The cholesterol granuloma of the middle ear contains
cholesterol clefts and granulation tissue but does not tend
to cause cystic expansion.4
Imaging not only suggests the diagnosis but can also
determine the relationship of the lesion to the carotid
artery and to the labyrinth and internal auditory canal.
A Computed tomography can usually define the air cell tract
that originally led to the air cell that is now expanded.

Epidermoids
Epidermoids are less common than previously thought,
yet they represent a major differential consideration for
expansile masses at the petrous apex. There is a wall of
stratified squamous epithelium and a central mass of keratin.
Desquamation of the cells from the wall of these lesions
is responsible for their slowly progressive expansion and
resultant bony remodeling. Although the wall may enhance,
the central keratin mass does not.
In the petrous apex, an epidermoid can show expansion of
bone that is very similar to a cholesterol granuloma. In our
experience, the epidermoid may appear to follow lines of
least resistance and expand above or below the otic labyrinth
and at times may reach the middle ear. The CT density tends
to be slightly lower than that of a cholesterol granuloma
but differentiation of the two entities is easier with MRI.
B Epidermoids usually have a low T1 signal and a high T2 sig-
nal (Fig. 22-3), distinguishing them from cholesterol cysts,
which have a high T1 signal.3,5 The T1-weighted sequence
is the key consideration. Almost all epidermoids are high
signal on T1-weighted images; epidermoids are typically low
signal on the T1-weighted sequence.
Epidermoids may occur intracranially6; the most common
location is in the cerebellopontine angle cistern. Of note,
though rare intracranial epidermoids have been reported
to have a bright T1 signal, this phenomenon is distinctly
unusual particularly in the skull base.
The imaging differentiation of cholesterol cyst and
epidermoids is clinically relevant. To prevent recurrence, the
walls of epidermoid tumors must be completely resected
or exteriorized. This may entail extensive surgery.7,8 This
surgery may not be necessary for cholesterol granulomas.

Figure 22-1. Hemorrhage in a cholesterol cyst. A, Axial CT in bone algorithm

demonstrates an expansile mass in the left petrous apex (black arrows)
partly surrounding the petrous carotid artery (black arrowhead). B, Axial
C T2-weighted image shows a fluid-fluid level in the mass (white arrow). Note
the fluid in the mastoids (white arrowhead). The lesion is bright on axial
T1-weighted view. This high signal represents blood breakdown products,
not enhancement from gadolinium (C).
386 NEURORADIOLOGY

A B

C D
Figure 22-2. Cholesterol cyst, or granuloma. A, Axial nonenhanced CT shows an expansile mass at the right petrous apex with soft tissue density (black
arrowhead). B, Axial T1-weighted MRI without contrast. The mass demonstrates bright signal (white arrow). C, The lesion does not enhance on the
postgadolinium fat-saturated T1-weighted image (double arrows). D, T2-weighted image demonstrates mixed signal. The low signal (white arrowhead) is
probably a result of the hemorrhagic contents.

Many surgeons treat cholesterol granulomas by a drainage T2 signal with peripheral enhancement of the lining
procedure and do not attempt to resect the walls of the mass.9 mucosa.10 Because mucoceles also arise in obstructed air
cells, they may be part of the same spectrum of disease
as cholesterol cysts or granulomas. Mucoceles in other
Mucoceles sinuses have variable signals depending on their protein
True simple mucoceles of apical petrous cells are rare but content, so theoretically they might be very bright on
have been described. Such lesions have low T1 and bright T1-weighted images and difficult to distinguish from
 Imaging of the Lateral Skull Base 387

A A

B
Figure 22-4. Normal fat of the petrous apex. A, Noncontrast T1-weighted
B image shows asymmetry of the signal at the petrous apex. On the right, the
petrous apex is pneumatized. On the left, medullary fat at the petrous apex
Figure 22-3. Epidermoid. A, Axial T1-weighted MRI demonstrates an has high signal (white arrow). B, CT scan at approximately the same level.
expansile low signal right petrous apex lesion (arrow). B, The lesion Compare the pneumatized right petrous apex with the medullary bone in the
(arrowhead) has high signal on T2-weighted image. left petrous apex (black arrow).

cholesterol granulomas. Mucoceles, like epidermoids and and pneumatization of the contralateral side, T1-weighted
cholesterol cysts, do not enhance centrally and therefore MRI images show a high signal in the nonpneumatized
are distinguished from more solid tumors, which do have bone. The high signal represents medullary fat (Fig. 22-4A).
central enhancement. Chordomas, chondrosarcomas, The air in the pneumatized bone gives a signal void typical
metastasis, plasmacytomas, and pituitary adenomas of air. T2-weighted images reveal the normal drop-off
enhance to some degree throughout their mass. in signal from the medullary fat and exclude cholesterol
granuloma. On fast spin echo images, this fading of the
Pseudolesions of the fat signal is less dramatic. In such cases, fat suppression
Petrous Apex sequences with T1 images can be used to eliminate the
signal from fat and clarify the situation. CT can also
Several pseudolesions can be confused with cholesterol differentiate these two entities.
granuloma or epidermoid. For example, if there is Fluid or mucus in apical air cells is more challenging.
nonpneumatized medullary bone at one petrous apex Mucus, depending on its protein concentration, has highly
388 NEURORADIOLOGY

variable signal characteristics that could mimic cholesterol

granuloma. In such cases, CT is revealing. If there is
preservation of septae between the opacified air cells and
no expansion, a cholesterol cyst or mucocele is excluded
(Fig. 22-5). If obstruction persists, however, breakdown or
expansion of air cells may occur and a mucocele or choles-
terol cyst may develop. Hemorrhage into the obstructed
air cell may set up the foreign body giant cell reaction
characteristic of cholesterol cyst or granuloma. Obstructed
air cells, mucocele, and cholesterol granuloma may repre-
sent a continuous spectrum of pathology. An alternative
to immediate surgery is to follow these patients with CT
or MRI.
Rarely, a pocket of arachnoid extends into the petrous
apex, usually from the region of Meckel’s cave (Fig. 22-6).
These CSF-filled pockets can be difficult to differentiate
Figure 22-5. Fluid in apical air cells. CT scan demonstrates opacification of from an epidermoid. Coronal and sagittal T2-weighted
the right petrous apex (arrow). Note the preservation of the septae, excluding imaging are often useful planes for demonstrating the
cholesterol granuloma and mucocele from the differential. connection to the CSF space. In ambiguous cases, a CT
with intrathecal contrast confirms these findings.

B C
Figure 22-6. Bilateral meningoceles of the petrous apex. A, Sequential high-resolution axial T2-weighted images demonstrate high signal in each petrous apex
(arrows) extending from Meckel’s cave (arrowheads) with corresponding high-resolution coronal T2- and T1-weighted images (B and C ).
 Imaging of the Lateral Skull Base 389

A B
Figure 22-7. Petrous apicitis presenting with cranial nerve six palsy. A, Axial T1-weighted image with contrast and fat saturation demonstrates abnormal focal
enhancement at the right petrous apex with dural enhancement extending along the clivus in the region of Dorello’s canal (arrowhead), right cerebellopontine
angle, and right internal auditory canal (white arrows). B, Axial CT bone algorithm shows fluid in the inferior right petrous apex but no definite bone destruction
(black arrow).

Petrous Apicitis bone has the same signal as the adjacent air in the
tympanic cavity. (See also the section on Aberrant Carotid
Petrous apicitis is a destructive infection involving the Arteries.)
petrous apex. Facial pain, sixth nerve palsy, and ipsilateral
ear drainage is a clinical triad described by Gradenigo in Chordomas and Chondrosarcomas
patients with petrous apicitis (Fig. 22-7). CT will show air
cell opacification (Fig. 22-7B) and sometimes bone break- Chordomas and chondrosarcomas share many imaging
down. The dura may enhance (Fig. 22-7A) and epidural features and are therefore considered together. These
abscess can develop as the infection progresses. MRI will lesions arise medial to the apex but can extend into the
show the enhancement of the apex extending to the dura temporal bone as they enlarge. Chordomas are more often
and toward the gasserian ganglion in Meckel’s cave. midline and arise from notochordal remnants in the
basiocciput and basisphenoid (Fig. 22-9). Conversely, chon-
drosarcomas usually arise from cartilage in cranial base
Aneurysms synchondroses. Most chondrosarcomas in the lateral skull
Aneurysms of the petrous segment of the carotid artery are base region arise off midline at the petroclival synchon-
rare.11 Because of their location they may grow quite large drosis (Figs. 22-10 and 22-11). They may also arise from
before compressing vital structures and producing symp- the smaller synchondroses in the spheno-occipital separa-
toms. When these aneurysms erode into the middle ear tion, nasal septum, paranasal sinuses, and the more anterior
cavity, they are particularly dangerous. The turbulent flow skull base.12–14
within the aneurysms produces a variable MRI signal that Both tumors are bright on T2-weighted images. This is
can be very confusing (Fig. 22-8A), particularly if flow- important because several mimics lack this intense T2 signal.
sensitive MRI is not performed. In other cases, much of For example, metastasis, multiple myeloma, and invasive
the aneurysm can be filled with thrombus. CTA and MRA prolactinoma may all mimic the CT and T1-weighted
are currently the most sensitive imaging modalities for MRI appearance of a chordoma. However, on T2-weighted
assessing aneurysms. images, these lesions generally do not have a bright
Clinically, aneurysms can mimic a middle ear mass such T2 signal (Fig. 22-12D).15 The distinction is important
as a glomus tumor. In these cases, CT is helpful because it because chordoma and chondrosarcoma may be managed
can show the remodeling or erosion of the wall of the by a major skull base resection and radiation, whereas the
petrous carotid canal (Fig. 22-8B). This thin wall of bone other lesions can be managed by biopsy and radiation or
is invisible on most MR images because dense cortical medical therapy.13,14,16
390 NEURORADIOLOGY

A
B

C
Figure 22-8. Petrous carotid aneurysm. A, Axial noncontrast T1-weighted MRI. A mass at the left petrous apex extending into the middle ear has mixed areas of
high and low signal (outlined arrows). The patient was taken to surgery with the thought that this middle ear mass represented a cholesteatoma or cholesterol
granuloma. At surgery it was observed that the mass was pulsatile and additional studies were obtained. B, Axial CT scan bone algorithm. The left carotid canal
is enlarged (arrows). Note the normal lateral bony wall of the right carotid (curved arrow). C, AP view from a left common carotid angiogram. A multilobulated
aneurysm (arrows) is present that involves the proximal aspect of the petrous segment of the internal carotid artery. The variable signal within the aneurysm is
due to flow rate variations within the lumen.
 Imaging of the Lateral Skull Base 391

C
Figure 22-9. Chordoma. A, Axial postcontrast CT shows a large enhancing mass in the central skull base. The mass invades both cavernous sinuses (straight
arrows) and also extends to involve the petrous apex bilaterally (curved arrows). B, The bone algorithm at the same level as A. There is erosion of the petrous
apex bilaterally (curved arrows) and also bilateral mastoid effusions (open arrows). C, Slightly higher cut shows small spicules of bone in the center of the mass
(arrowheads). These most likely are remnants of preexisting bone rather than matrix mineralization.
392 NEURORADIOLOGY

B
A

C D
Figure 22-10. Skull base chondrosarcoma. A, Axial T2-weighted image shows a very high signal expansile mass in the right petroclival synchondrosis extending
into the right petrous apex (black arrow). B-C, Coronal T1-weighted images without and with contrast demonstrates enhancement of the lesion (white arrows).
D, Bone algorithm axial CT demonstrates central chondroid matrix within the mass that is eroding the bone at the synchondrosis (arrowhead).
 Imaging of the Lateral Skull Base 393

A
Figure 22-11. Chondrosarcoma. A, Coronal CT bone algorithm shows the dense chondroid mineralization in this chondrosarcoma (straight arrows). This lesion
arose at the petroclival synchondrosis. Note the normal synchondrosis on the left (curved arrow). B, T2-weighted MRI. The mineralized portion of the tumor has
low T2 signal (arrows). The nonmineralized portions of the chondrosarcoma are bright (outlined arrows) on T2.

Both chordomas and chondrosarcomas may calcify. In however, occasionally parts of the fibrous dysplasia have a
one study, 7 of 26 (27%) chordomas and 7 of 16 (44%) high T2 signal (Fig. 22-13D).17
chondrosarcomas contained calcifications. Many times Computerized tomography can be definitive if it reveals
the mineralization or bone and calcium in a chordoma rep- the dense “ground glass” characteristic of this lesion (Fig. 22-
resent remnants of bone largely destroyed by the tumor 13E–F ). However, fibrous dysplasia and other benign
(Fig. 22-9C). Large fragments may exist. Chondrosarcoma fibroosseous lesions are extremely variable in appearance
calcifications are variable and may be large and clumped radiologically (Fig. 22-14) and may be difficult to exclude
(see Figs. 22-10D and 22-11A) and are often easily visualized from a list of differential diagnoses. This is particularly
on MRI as a region of very low signal on all imaging true in lesions where the fibrous elements dominate.
sequences (Fig. 22-11B). Some chondrosarcomas, however,
show no obvious mineralization. Both chordomas and Benign Vascular Tumors
chondrosarcomas enhance moderately to intensely after
Benign vascular tumors, or ossifying hemangiomas, can
contrast (Fig. 22-10B and C). The enhancement is often
arise in the petrous apex near the geniculate ganglion. The
easier to appreciate on MRI.
lesions often have indistinct margins and may have intratu-
The position of the lesion is a major determinant in
moral bone spicules, which can be seen on high-resolution
differentiating chordoma from chondrosarcoma. Chordoma
CT (Fig. 22-15). The intratumoral bone has led to the
is almost exclusively a midline lesion; chondrosarcomas,
term ossifying hemangioma. Although the bulk of the tumor
although they occur occasionally in the midline, are more
lies outside the facial nerve canal, expansion of the canal is
commonly located off midline in the area of the synchondrosis
common. Occasionally, the lesions are well circumscribed
separating the central skull base from the petrous apex.
and lack internal bone spicules. These well-demarcated
hemangiomas are hard to differentiate from a facial nerve
Other Lesions sheath tumor. In most cases, however, the internal spicules
Fibrous Dysplasia and ill-defined bony margins suggest the correct diagno-
sis.18 Meningiomas can have a similar appearance.
Fibrous dysplasia can present a serious diagnostic challenge
with MRI. Elements in the dysplastic bone are metabolically Meningiomas
active and enhance after contrast. On enhanced MRI
scans, fibrous dysplasia may look like an enhancing skull base Intracranial or dural processes may involve the petrous
neoplasm (Fig. 22-13A–C). Most often it is hypointense on apex by remodeling or invading through the dural covering.
T2-weighted images because of the bone matrix within it; Petroclival and cavernous sinus meningiomas commonly
394 NEURORADIOLOGY

C D
Figure 22-12. Multiple myeloma. A, Axial CT shows a large destructive lesion of the basiocciput (arrows). B, Coronal T1-weighted MR shows the mass to be
isointense with brain (arrows). C, Postcontrast MRI at the same level as B shows intense uniform enhancement of the mass (arrows). D, T2-weighted axial
MRI. The mass in the basiocciput is intermediate in signal (arrows). It extends into the prevertebral space and displaces the longus coli muscle anteriorly
(open arrow). The lack of bright T2 signal helps differentiate this lesion from chordoma and chondrosarcoma.
 Imaging of the Lateral Skull Base 395

A B

C D
Figure 22-13. Fibrous dysplasia. A, Axial T1-weighted MRI shows a low signal mass involving the left temporal bone, left pterygoid bones, and left temporal
mandibular joint (bracket). B-C, Axial and coronal T1-weighted with contrast. The lesion demonstrates irregular enhancement (bracket). D, Axial T2-weighted
image shows mixed areas of high and low signal (bracket). Continued
396 NEURORADIOLOGY

E
Figure 22-13. Cont’d, E-F, Axial and coronal CT in bone algorithm show the characteristic “ground glass” appearance of fibrous dysplasia (arrows). Note the
sparing of the otic capsule (arrowheads).

involve the petrous apex. Lesions may involve the posterior from meningiomas because they almost never calcify, rarely
or superior surface of the bone. The margins usually taper have enhancing dural tails, and are usually higher in signal
to the surface of the bone at an obtuse angle. The tumor and less homogeneous on T2-weighted images (Fig. 22-17).
can cause remodeling of the bone, hyperostosis, or enhance- Meningiomas may have moderate signal intensity on
ment of the marrow cavity (Fig. 22-16). This may be best T2-weighted images, but they are seldom as bright as
appreciated with fat-suppressed postcontrast images. The neuromas.21,22 Hemangiomas involving the cavernous sinus
most common scenario is to have a meningioma growing are rare, but when they are large they can erode the petrous
along the petrous apex without apparent bone change. apex. These lesions are indistinguishable from meningiomas
Occasionally, cavernous sinus tumors spread into the by CT and on angiography they can show “puddling” of
petrous bone along the carotid canal. contrast, which can be confused with meningioma. MRI
makes the distinction because hemangiomas are extremely
Endolymphatic Sac Tumors bright on T2-weighted images.23 Differentiation of a cav-
ernous sinus hemangioma from a nerve sheath tumor may
Tumors thought to arise from the endolymphatic sac give the be more difficult.
appearance of a locally destructive lesion in the bone just
posterior to the labyrinth along the medial aspect of the Direct Extension from Nasopharyngeal
posterior semicircular canal.19,20 This location is very charac- and Infratemporal Lesions
teristic and corresponds to the position of the endolymphatic
sac and vestibular aqueduct. The papillary cystadenomatous Malignancy arising in the nasopharynx or infratemporal
lesion frequently contains hemorrhagic foci as well as cystic fossa can grow into the lateral skull base. Although any
areas. The cysts appear as bright areas on T2-weighted location can be involved, the petroclival synchondrosis and
images and the hemorrhagic areas can have a bright signal on contiguous foramen lacerum are particularly prone to inva-
T1-weighted images and dark areas on T1- and T2-weighted sion especially from nasopharynx carcinomas (Figs. 22-18
images, reflecting the appearance of various blood breakdown and 22-19). The petroclival and petrosphenoidal fissures
products in the tumors. The lesions are usually more cystic are close to the fossa of Rosenmüller, where these neo-
and more focally invasive than meningiomas that can also plasms tend to arise. Extension beyond the fissures brings
occur in this area. These lesions can occur in patients with the tumor to the cavernous sinus.
von Hippel-Lindau disease in whom they can be bilateral. In most cases either CT or MRI suffices. CT better
demonstrates the cortical bone destruction (see Fig. 22-18)
and can visualize fairly gross involvement of the cavernous
Fifth Nerve Sheath Tumor and Cavernous
sinus. MRI visualizes the actual tumor within the bone and
Sinus Hemangiomas
is considered by most to be more precise in showing cav-
Trigeminal nerve sheath tumors (trigeminal neuromas) may ernous sinus invasion (see Fig. 22-19) and more sensitive in
smoothly remodel the petrous apex. They are differentiated demonstrating involvement of the petroclival synchondrosis.
 Imaging of the Lateral Skull Base 397

A B

C D
Figure 22-14. Benign fibroosseous lesion. Thirty-year-old woman with a 2-year history of facial paralysis. A, Axial CT bone algorithm shows an expansile
lesion of the left petrous apex (arrows). B, Cut slightly lower than (A) shows erosion in the region of the geniculate ganglion (arrow). C, Coronal bone algorithm
shows the lesion (arrows) that erodes the labyrinthine and tympanic segment of the facial nerve canal (arrowheads). D, Cut slightly posterior to (C ), shows
erosion of the tegmen tympani (arrowheads) by this lesion. The tegmen is intact on the right (open arrow). At surgery, this proved to be a benign fibroosseous
lesion.

MRI. They enhance on either CT or MRI. The appearance

Metastasis and Other Solid Lesions
overlaps with that of metastasis. Because they enhance, they
The petrous apex is a bone with a medullary space and so are not confused with cholesterol cyst or epidermoid.
metastasis to the apex can occur. Metastasis results in a Langerhans’ cell histiocytosis can involve the mastoid
destructive mass. The center part enhances to some extent region and middle ear but can also involve the petrous
and gives a solid appearance rather than the “cystic” apex. The lesion is frequently described as “punched out”
nonenhancing appearance of the epidermoid or the choles- with a sharp margin and without sclerosis but occasionally
terol cyst. In an adult, an enhancing destructive mass of the the margin can be more sclerotic. On MRI, the lesion is
apex suggests a metastasis or meningioma. seen as a solid mass often with loss of the cortex. The sig-
Plasmacytomas can arise in any bone, including the nal is usually described as high on T2-weighted sequences
petrous apex. The lesions tend to be fairly homogenous on but this is variable. The lesion enhances on either CT
CT. They are relatively dark on T2-weighted images on or MRI.
Figure 22-15. Ossifying hemangioma. Twenty-eight-year-old woman with a long-
standing right facial weakness. Two bone algorithms from an axial CT scan.
Abnormal bone appears along the anterior surface of the petrous ridge. There are
small interruptions in the cortical bone (arrowheads). There is expansion of the
labyrinthine segment of the facial nerve canal (wavy arrow). The bony spicules in
the lesion produce a honeycomb appearance.

A
B

Figure 22-16. Meningioma invading the petrous apex. A, Coronal

postcontrast CT shows an enhancing lesion along the left petrous apex
(outlined arrows) with extension of the enhancing tissue into the left
internal auditory canal (curved arrow). Compare to the normal right
internal auditory canal (open arrow), which contains low-density CSF.
B, Bone algorithm at the same level as (A) shows slight irregularity of the
superior cortex of the petrous apex (arrows). Compare this to the normal
dense bone on the right side (open arrow). C, Postcontrast MRI confirms
abnormal enhancement in the left internal auditory canal. Enhancement
deep to the cortex of the petrous ridge confirms involvement of the
marrow cavity (small straight arrows).
Continued

C
 Imaging of the Lateral Skull Base 399

D E
Figure 22-16. Cont’d, D, Axial postcontrast MRI shows tumor on both the anterior and posterior surfaces of the petrous bone (large straight arrows). There is
enhancement within the petrous apex itself (small straight arrows). Abnormal enhancement extends across the midline of the clivus (curved arrow). A “tail” of
tumor extends along the wall of the left transverse sinus (arrowheads) but does not occlude the sinus. E, Sagittal postcontrast MRI shows the enhancing tissue
in the internal auditory canal (straight white arrow). In this plane the abnormal enhancement deep to the cortex of the petrous ridge is again apparent
(wavy white arrow). “Dural tails” are seen extending from the tumor into the middle cranial fossa (open arrow), the posterior cranial fossa (straight black
arrow), and along the tentorium (curved black arrow).

Superior Semicircular Canal Dehiscence Coronal CT images demonstrate a defect in the superior
curve of the superior semicircular canal.24 The reformatting
Superior semicircular canal dehiscence is covered in the
capabilities of multidetector give excellent images in any
chapter on the labyrinth but is mentioned briefly here
plane. A 45-degree oblique (Stenver’s plane) image passing
because it does involve the bone over the labyrinth. Several
perpendicular to the arc of the superior semicircular canal
recent reports relate symptoms of sound (Tullio’s phenome-
often show the dehiscence best.
non) or pressure-induced (Hennebert’s sign) vertigo or nys-
tagmus to a third “mobile” window in the bony labyrinth.
Normally, the labyrinth is a closed hydraulic system. The JUGULAR AND CAROTID REGION
oval and round windows are the only two movable openings
in the system. As the acoustic energy is transmitted via the The jugular foramen and vertical portion of the carotid
ossicles to the oval window, the footplate of the stapes artery canal are grouped together because differential
vibrates slightly. Fluid is not compressible and so a compen- diagnoses of lesions affecting these areas overlap.
satory motion must occur somewhere in the system if there is The carotid canal is anterior to the jugular fossa. Both
to be movement of the fluid or propagation of the vibration. the artery and the vein are separated from the middle ear
There is subtle motion of the perilymph of the cochlea as the by very thin but very important cortical plates of bone.
round window membrane moves outward in response to the Anatomically, the jugular fossa is divided into the
inward movement of the footplate. Normally, there is no sig- smaller medial pars nervosa and the larger lateral pars vas-
nificant movement of the fluids in the semicircular canal. cularis (Fig. 22-21B). Cranial nerves IX, X, and XI pass
Each is a closed system with no external opening. If there is along the medial part of the jugular fossa. The more lateral
a dehiscence of the bony canal, however, subtle movement pars vascularis contains the jugular vein.
can occur and this compresses the endolymph. Motion The size of the pars vascularis may vary greatly according
within the endolymph is interpreted as dizziness. Most such to the variable size of the jugular vein. The bony wall
“third windows” are related to fistulas into the labyrinth separating the jugular bulb from the middle ear is very thin
resulting from cholesteatoma and surgical interventions. or may even be absent in the case of dehiscent jugular fossa
An important cause that is potentially treatable is dehis- (Fig. 22-21A). The vascular part of the jugular fossa is
cence of the superior semicircular canal roof (Fig. 22-20). smoothly marginated (see Fig. 22-21B). Evaluation of
The etiology of the dehiscence is not exactly known. These these bony walls is best achieved with CT.
patients can undergo surgical packing of the dehiscent area, The MRI appearance of the jugular fossa varies con-
which often provides symptomatic relief.24,25 siderably. Signal of the flowing venous blood depends on
 the speed and turbulence of flow in the jugular bulb. The
appearance depends on the size of the vein, the configuration
of the jugular bulb, and the phase in the cardiac cycle.
As a result, the signal from the jugular fossa can range
from a flow void to a very bright signal on both T1- and
T2-weighted images. The results of MRI contrast
enhancement are also unpredictable because of this
variable flow.
A typical scenario for confusion occurs in assessing the
patient with intermediate signal in the jugular fossa on
unenhanced study who has enhancement on a postcon-
trast exam (Fig. 22-22). The question is whether this rep-
resents a normal vein with slow flow, clot within the
vein, or an enhancing glomus jugulare tumor. It may be
possible to make the distinction on flow-sensitive MRI or
MRA. If the flow in a patent vein is demonstrated, there is
no tumor or thrombosis. If flow is not definitely identified,
however, the problem may remain. Slow flow is difficult
to exclude. CT and particularly CT venography may be
helpful in this regard. If a bolus of contrast is given, then
the vein should opacify even if flow is very slow. Jugular
A thrombosis might confuse the issue because organized
thrombus has been shown to enhance in some cases (see
Fig. 22-22).

Paragangliomas
Paragangliomas arise from the glomus formations found in
many places in the temporal bone, particularly in the
adventitia of the dome of the jugular bulb and in the
mucosa covering the cochlear promontory and along
branches of Arnold’s nerve between the descending facial
nerve and the jugular foramen.26
A glomus tumor (paraganglioma) arising on the cochlear
promontory and limited to the middle ear cavity is called a
glomus tympanicum and usually gives a conductive hearing
loss due to impingement on the oval window or ossicles
(Fig. 22-23). A red mass is seen through the tympanic
membrane. The plate of bone representing the lateral wall
of the jugular foramen is intact in a glomus tympanicum.
This important landmark is best demonstrated and evalu-
B ated on CT.
Tumors along the wall of the jugular foramen erode the
normally smooth walls of the jugular foramen (Fig. 22-24A).
They may extend into the middle ear and produce a mass
in the hypotympanum. Indeed, such a tumor, called
glomus jugulare or glomus jugulotympanicum, commonly
presents because of problems related to the middle ear
component of the tumor. Once again the difference
between a glomus tympanicum and glomus jugulare (jugu-
lotympanicum) is determined by CT. Erosion of the plate
of bone at the lateral aspect of the jugular fossa indicates
that indeed the tumor is a glomus jugulare. If this plate is
intact, then the lesion is limited to the middle ear and is a
glomus tympanicum.

Figure 22-17. Trigeminal nerve sheath tumor (arrowheads). A, Axial

T2-weighted MRI shows a high signal mass within the left Meckel’s cave, caus-
C ing remodeling of the left petrous apex. B-C, Axial and high-resolution coronal
T1-weighted image with contrast. The enhancing mass also involves the left
cavernous sinus and prepontine cistern along the course of cranial nerve V.
 Imaging of the Lateral Skull Base 401

B
A

C
Figure 22-18. Nasopharyngeal cancer invading the skull base. A, Axial CT shows effacement of the left fossa of Rosenmüller (thick straight arrow). Compare
this with the normal right side (thin straight arrows). The prevertebral space is enlarged on the left (open arrow) and the left parapharyngeal space appears
to be infiltrated rather than displaced (curved arrow). B, More superior cut shows abnormal enhancement along the petrous apex and posterior aspect of the
left cavernous sinus (arrows). Meckel’s cave on the left has been replaced by enhancing tissue but the right side (curved arrow) appears normal. C, Bone
algorithm at the same level as (B) shows destruction of the cortex as well as the marrow space of the left petrous apex (arrows).
402 NEURORADIOLOGY

A B

C
Figure 22-19. MRI of nasopharyngeal cancer invading the skull. A-C, Sequential axial T1-weighted MRI with contrast. There is a large mass (arrowheads) in the
nasopharynx extending into the left nasal cavity and into the left cavernous sinus. Note the narrowing of the left carotid flow void (arrow). D, Coronal
postcontrast T1 shows tumor (arrowheads) extending through skull base.

Paragangliomas also arise from the ganglia of the vagus Paragangliomas are easily detected on MRI. They
nerve immediately inferior to the skull base (Fig. 22-25). enhance intensely, reflecting high vascularity. In larger
This tumor is called a glomus vagale. The glomus vagale lesions, there are flow voids that indicate large tumor vessels
can enlarge to involve the skull base or extend into the detected on standard spin echo or flow-sensitive MRI
posterior fossa. Such tumor extension tends to follow the (see Figs. 22-24D and 22-25D) giving a “salt-and-pepper”
pars nervosa (medial jugular foramen). The lateral wall of appearance to the lesion. Flow voids in a lesion in this
the jugular fossa is usually intact. area suggest a paraganglioma. Occasionally, large vessels
Paragangliomas can be multiple, so once one lesion is in a meningioma or vascular metastasis (from thyroid or
found the imaging study is usually extended to the level of renal cancers) create confusion with paraganglioma. On
the bifurcation of the carotid to search for carotid body CT, tumor vessels usually cannot be resolved from adja-
tumors as well as glomus vagale tumors.27 cent enhancing tumor stroma. If the lesion is very small,
 Imaging of the Lateral Skull Base 403

B
Figure 22-21. Dehiscent jugular bulb. A, Axial CT bone algorithm shows
absence of the bony wall between the jugular fossa and the middle ear
(arrow). B, Normal comparison. Note the smaller pars nervosa (arrowhead)
and more lateral pars vascularis (double arrows).
C
Figure 22-20. Superior semicircular canal dehiscence in a patient with
sound-induced vertigo. A, Coronal CT bone algorithm shows a defect in the
roof of the superior semicircular canal (arrowhead). B, Stenvers’ plane near
the same level as (A), perpendicular to the arc of the semicircular canal
confirms this (arrowhead). C, Pöschl plane, parallel to the superior
semicircular canal, shows a good portion of the roof is dehiscent
(arrowheads).
404 NEURORADIOLOGY

A B

Figure 22-22. Venous sinus thrombosis. A, Axial T1-weighted image.

There is intermediate signal in the right jugular fossa and right sigmoid
sinus (straight arrows). Compare this with the flow void in the left
jugular fossa (curved arrow). Also of interest is the small amount of fat
located lateral to the jugular bulb on each side (white arrows). A small
amount of medullary bone is frequently found lateral to the jugular fossa.
B, Postcontrast MRI. There is enhancement in the right jugular bulb and
right sigmoid sinus (straight arrows). It is uncertain from these images
whether the jugular is patent. Enhancement can be seen due to slower
turbulent flow or due to an organized thrombus with enhancement.
A glomus jugulare tumor may also enhance. C, Contrasted CT shows
less opacification of the right jugular and sigmoid (straight arrows) than
the normal left jugular (curved arrow). Bone algorithms confirmed that
there was no erosion of the right jugular fossa and therefore glomus
tumor is unlikely. This represents organized thrombus in the right jugular
and sigmoid. It is apparent from (B) that organized thrombus can
enhance somewhat. CT with bolus injection of contrast will clarify
ambiguous cases such as this one; there is greater enhancement of
the patent lumen (curved arrow) than the thrombus (straight arrows).
Dynamic scanning is often required to make this distinction.

C
 Imaging of the Lateral Skull Base 405

C
Figure 22-23. Glomus tympanicum tumor causing secondary obstruction. A-B, Axial and coronal CT bone algorithm demonstrates an abnormal soft tissue
mass in the left middle ear at the cochlear promontory (arrowheads). Note the fluid in the left mastoid air cells (asterisk). C-D, On axial and coronal gadolinium-
enhanced T1-weighted MRI, the mass intensely enhances (arrow).

intratumoral vessels may not be visualized by imaging.

This is particularly true of the paragangliomas arising at
Nerve Sheath Tumors
the cochlear promontory (glomus tympanicum). Nerve sheath tumors also occur in the jugular fossa. As
Although almost all paragangliomas are detectable on schwannomas of cranial nerve IX, X, or XI enlarge, they
MRI, CT is usually used for the initial evaluation because erode or expand the medial part of the jugular foramen.
of the importance of lateral plate of the jugular foramen The lateral plate of the pars vascularis is usually spared
in separating a glomus tympanicum from a glomus jugu- (Fig. 22-26A and B). The margin of the expanded foramen
lare. That landmark is poorly seen with MRI and so its is usually smooth, unlike the more irregular margin of a
integrity is difficult to assess. Once the diagnosis of glo- paraganglioma.
mus jugulare is made, however, MRI can provide valuable MRI features that suggest a nerve sheath tumor include
information regarding potential intracranial extension high T2 signal, involvement of the medial jugular foramen,
and the patency of the jugular vein and sigmoid sinus. smoothly marginated bone remodeling, and cystic change
MRI visualizes tumor growing into the vein and sinus (Fig. 22-26C and D).28,29 In some cases the cystic change in
as well. the tumor is so extensive that it mimics an arachnoid cyst
406 NEURORADIOLOGY

A B

C D
Figure 22-24. Glomus jugulare. A, Axial CT bone algorithm shows expansion and permeative destruction of the walls of the right jugular fossa (black arrows).
Compare this to the normal left jugular fossa (double arrows). B-C, Axial CT without and with contrast shows intense enhancement of the mass (black arrows).
D, MRI at approximately the same level. Axial T2-weighted image shows multiple small flow voids within the mass (arrowhead). Continued

or epidermoid tumor.30 Nerve sheath tumors lack flow plate of bone separating the artery from the tympanic cavity
voids and have fairly abrupt margins with surrounding (Fig. 22-27A and B). The anomalous artery itself is a soft
meninges. tissue density mass. It enters the tympanic cavity through
an enlarged tympanic canaliculus and courses through the
middle ear cavity next to the cochlea (Fig. 22-27C and D).
Aberrant Carotid Arteries If there is a persistent stapedial artery associated with
Normally, the vertical portion of the petrous carotid artery the aberrant carotid, the tympanic segment of the facial
is covered by a thin plate or wall of bone separating it from nerve canal may be enlarged. The stapedial artery courses
the tympanic cavity.31 Absence of this plate of bone indicates through this part of the facial nerve canal to enter the cranial
an anomalous vessel. As with the plate of the jugular fora- cavity and form the middle meningeal artery. The foramen
men, CT is the method of choice for visualizing the thin spinosum is absent in this instance.
 Imaging of the Lateral Skull Base 407

E F
Figure 22-24. Cont’d, E-F, Axial T1-weighted image without and with contrast shows intense enhancement.

An aberrant carotid artery should be excluded in every or enlargement of the canal (Fig. 22-28) or enhancement of
imaging study of the temporal bone but particularly when the medullary cavity surrounding the canal.
a red mass is seen behind the tympanic membrane. CT can Involvement of the hypoglossal nerve is clinically indi-
differentiate an aberrant carotid artery from a glomus tym- cated by unilateral atrophy of the intrinsic and extrinsic
panicum or jugulare. The differential depends on demon- muscles of the tongue. The imaging correlate of atrophy is
stration of the presence or absence of the lateral plates of fatty infiltration of one-half of the tongue, which is visible
the jugular and carotid canals. on CT or MR (Fig. 22-29C). During acute muscle atrophy,
there may be enhancement of the muscle before fatty
Other Lesions Involving the Jugular replacement is apparent. Similar findings are observed with
atrophy of the muscles of mastication when the trigeminal
and Carotid Area nerve is involved with tumor.
Meningiomas are rare in the jugular fossa. They probably
arise from arachnoid cap cells that are in the sheaths that MIDDLE EAR AND MASTOID
surround the cranial nerves as they exit the skull.32,33
Although they may be difficult to differentiate from more Inflammatory Middle Ear Disease
common paragangliomas, calcification, hyperostosis, and
enhancing dural rims (dural tail) may suggest the correct The majority of middle ear disorders are inflammatory and
diagnosis. The destruction or demineralization may be less related to eustachian tube dysfunction. CT is preferred to
obvious than in paraganglioma. MRI in most cases because of its superior demonstration
Chondrosarcomas and chordomas are seldom confused of the ossicles, bony labyrinth, tegmen tympani, facial
with lesions of the jugular fossa because they are centered nerve canal, and the septations within the mastoid air cells;
more medially. However, it is very important to evaluate structures often affected by middle ear pathology.
the involvement of the jugular fossa in these lesions. This Acute and chronic otitis media may result in opacification
is particularly true in large lesions, which can involve the of the middle ear. Fluid, mucosal thickening, and granulation
jugular fossa bilaterally. The lower cranial nerves are at tissue are usually indistinguishable on CT. These inflam-
risk during the surgical approach to these lesions. matory responses are also difficult to differentiate on MRI;
The hypoglossal canal is located just inferior and medial all tend to be intermediate in signal on T1-weighted
to the jugular fossa and is frequently involved with processes images and bright on T2-weighted images. Gadolinium
that occur there. It is well demonstrated in both the axial may enhance mucosal thickening or granulation tissue but
and coronal plane and by CT or MRI. Enhancement within obstructed fluid will not be enhanced.
the hypoglossal canal is frequently seen as a normal finding Cholesteatomas tend to occur in the upper tympanic
and should not be confused with pathology. Abnormality membrane and grow into Prussak’s space and the upper
can be established only if there is an obvious mass, erosion, middle ear (Fig. 22-30). These secondary cholesteatomas
408 NEURORADIOLOGY

A B

C D
Figure 22-25. Glomus vagale. A, Postcontrast CT shows an enhancing mass (m) splaying the high cervical internal carotid artery (straight arrow) and the
jugular vein (curved arrow). The mass enhances intensely, almost as much as the vessels. B, Higher cut at the level of the jugular foramen. The tumor has not
reached this high. The pars nervosa (arrow) is relatively lucent, indicating that there is no tumor spread to this area. The pars vascularis (open arrow) enhances,
but this is due to the jugular vein, not enhancing tumor. C, Bone algorithm CT at the same level as (B). The cortical margins of the jugular fossa (arrows) are
sharp and smooth. There is no demineralization or erosion to suggest a glomus jugulare tumor involvement of the pars vascularis. D, T1-weighted MRI at
approximately the same level as (A). The mass (m) splays the cervical internal carotid artery (straight arrow) and jugular vein (curved arrow). Note the flow void
in this mass (outlined arrow), which indicates that the mass is highly vascular.

are associated with chronic ear disease dating to childhood single image slice (Fig. 22-31). Reading subtle erosions of
and usually the mastoid air cell system is poorly developed. the horizontal semicircular canal in the vertical plane can
If a cholesteatoma is suspected, CT is the study of be difficult because an oblique slice through the anterior
choice. Erosion of the scutum and tegmen tympani are curve of the canal can suggest a false defect. The facial
best demonstrated by coronal CT (Fig. 22-30B). Erosion nerve canal can also be eroded.
of the horizontal semicircular canal is best assessed in the Primary epidermoid tumors (congenital or primary
axial CT because the entire lateral margin can be seen in a cholesteatoma) occur in the petrous apex, but they occa-
 Imaging of the Lateral Skull Base 409

A
B

C D
Figure 22-26. Tenth nerve sheath tumor. A, Axial enhanced CT shows a ring enhancing lesion (large arrows) extending from the right jugular foramen into the
cerebellopontine angle cistern. Incidentally, note the enhancing choroid plexus in the left foramen of Luschka (small arrow). B, Bone algorithm image
demonstrates expansion of the pars nervosa of the right jugular foramen (arrows). C, T1-weighted MRI. The mass (straight arrow) has regions of intermediate
and low T1 signal. There is an arachnoid cyst lateral to the mass (curved arrow). D, T2-weighted MRI. The mass shows regions of low and high T2 signal. The
bright areas in the tumor (straight arrow) represent areas of cystic degeneration or necrosis. The arachnoid cyst (curved arrow) adjacent to the cisternal portion
of the tumor is also bright on T2.

sionally arise in the middle ear as well. These are thought extra-axial collections and meningeal enhancement may be
to result from the growth of a congenital rest of squamous obscured by artifact from the adjacent bone on CT scans.
epithelium. They are not related to chronic ear infections Septic thrombophlebitis may occlude the sigmoid sinus.
and the mastoid air cells may be well pneumatized. Venous sinus thrombosis may be demonstrated by either
Intracranial complications of mastoiditis and MRI or CT. The CT demonstration of clot requires bolus
cholesteatomas require careful imaging. Epidural, subdural, injection of contrast (Figs. 22-22 and 22-32). The intralu-
and brain abscesses are best evaluated with MRI. Small minal thrombus will appear as a filling defect in the lumen
410 NEURORADIOLOGY

A B

C D
Figure 22-27. Aberrant carotid artery. Thirty-seven-year-old woman with a pulsatile mass behind her right ear drum. A, Axial CT bone algorithm shows absence
of the lateral bony wall of the carotid canal (outlined arrow), which is intact on the left (curved arrow). B, Slightly more inferior cut shows more bulbous
protrusion of the right internal carotid artery into the middle ear (single outlined arrow). Again, note the intact bony wall of the left carotid canal (double outlined
arrows). C, Coronal bone algorithm demonstrates the normal carotid canal on the left (curved arrow). On the right, the petrous carotid artery courses into the
middle ear (outlined arrow). D, Slightly more anterior coronal image demonstrates the relationship of the aberrant carotid artery (outlined arrow) to the cochlea
and ossicles. Again, note the normal lateral wall of the left carotid canal (curved arrow).

of the vein. The MRI demonstration of clot is more has been removed a herniation can occur through the
complicated; flow artifacts on standard spin echo weakened area.
sequences often give a false-positive impression of clot CT can suggest a defect in the tegmen and is better than
within the sinus and jugular bulb. MRI at demonstrating the thin cortical plate of bone
Herniation of brain or meninges through a defect in (see Figs. 22-30 and 22-33B and C ). However, since the
the tegmen can present as a conductive hearing loss and bone is very thin, a partial volume effect may average the
a mass in the middle ear or mastoid. Such a defect may bone with contiguous soft tissue and suggest a defect
represent a congenital dehiscence. A cholesteatoma may where there is none. Small defects can also be missed.
erode or thin the tegmen and once the cholesteatoma Therefore, both the radiologist and the surgeon must be
Figure 22-28. Schwannoma, jugular foramen. A, Axial T1-weighted image shows an enhancing mass (arrowheads) originally thought to arise in the right hypoglos-
sal canal. Note enhancement of the normal left hypoglossal canal (double arrows). B, Coronal CT bone algorithm demonstrates that the lesion extends through the
jugular foramen (arrow) rather than the hypoglossal canal. The hypoglossal canal (double arrows) is normal. The jugular tubercle is eroded (arrowhead).

Figure 22-29. Metastatic paraganglioma with hypoglossal nerve atrophy.

A, Sagittal T1-weighted MRI shows a large mass in the left jugular fossa.
The mass extends inferiorly within or adjacent to the jugular vein
(outlined arrows). B, Axial T1-weighted MRI. There is a mass in the
poststyloid parapharyngeal space (outlined arrows) just posterolateral to
the left internal carotid artery (curved arrow). C, Section slightly inferior
to (B) shows fatty infiltration of the left half of the tongue (arrows). Also
note the abnormally enlarged left spinal accessory nodes (curved arrow).
This paraganglioma had metastasized to cervical nodes. Metastatic
paragangliomas do occur but are uncommon.

C
412 NEURORADIOLOGY

A B
Figure 22-30. Cholesteatoma. A-B, Axial and coronal CT bone algorithm shows and expansile mass involving the upper middle ear cavity (asterisk). Coronal
view better demonstrates involvement of Prussak’s space and epitympanum, causing bony erosion of the scutum (arrowhead) and tegmen tympani (double
arrows).

A
Figure 22-31. Cholesteatoma eroding horizontal semicircular canal. A, Axial CT bone window shows abnormal soft tissue in the left middle ear and mastoid
antrum (outlined arrow). This cholesteatoma erodes the horizontal semicircular canal (arrowheads). B, Two images from an axial CT bone algorithm of a differ-
ent patient than shown in (A). There is a soft tissue mass in the left middle ear eroding the left horizontal semicircular canal (open arrow). Compare this to the
normal bony margin of the right horizontal semicircular canal (outlined arrow).
 Imaging of the Lateral Skull Base 413

A B
Figure 22-32. Jugular vein thrombosis. A, Postcontrast CT shows normal enhancement of the left jugular vein (open arrow) and of both carotid arteries
(arrowheads). The right jugular vein (curved arrow) does not exhibit enhancement. B, Higher cuts in the same patient show a lack of enhancement in the lumen
of the right sigmoid sinus (straight arrow). The smaller left sigmoid sinus (open arrow) enhances normally.

A B
Figure 22-33. Cholesteatoma with erosion of the tegmen tympani. A, Axial bone algorithm CT shows a mass eroding into the carotid canal (large straight
arrow). B, Coronal view shows erosion of the tegmen tympani (arrowheads).

Continued
414 NEURORADIOLOGY

C D

E F
Figure 22-33. Cont’d, C, Soft tissue window at the same level as (B). It was not possible to determine by CT if the brain herniated into the defect (arrowheads).
D, T2-weighted axial MRI shows the mass (white arrows) to be of high signal. E, Postcontrast axial T1-weighted image shows peripheral enhancement of the
mass (white arrows). F, Coronal postcontrast MRI shows peripheral enhancement (arrowheads). The center of the mass (outlined arrow) does not enhance.
Unlike CT, MRI is able demonstrate that no brain tissue has herniated into the tegmen defect.

aware that assessment of the tegmen by even high-resolution Tumors of the Middle Ear
CT has its limitations.
MRI can be very helpful in these situations. Even Tumors that involve the middle ear are uncommon.
though the thin cortical bone of the tegmen is not seen, Paragangliomas (glomus tympanicum) arise at the
the status of the inferior surface of the brain is well defined. cochlear promontory and have already been discussed.
The coronal image can indicate if the brain is clearly These tumors must be differentiated from aberrant carotid
separated from the area in question or, alternatively, artery and glomus jugulare tumors, any of which can present
protrudes down into the defect (Fig. 22-33F). as a mass in the middle ear.
 Imaging of the Lateral Skull Base 415

Malignant tumors in the middle ear are extremely rare

and include squamous carcinomas, adenocarcinomas, and
adenoid cystic carcinomas. These lesions are usually
accompanied by considerable bone destruction. Otherwise,
imaging findings are not specific. They are difficult to
differentiate from metastasis or locally invasive tumors
such as rhabdomyosarcoma or lymphoma.
Histiocytosis X also may occur as a destructive lesion in
the petrous bone and must be differentiated from malignan-
cies or inflammatory pathology by biopsy.34 The margin of
the lesion is frequently sharp. Signal on MRI can vary.
Fibroosseous lesions may involve the middle ear but are
usually better defined and less infiltrative than malignancies.
A
EXTERNAL AUDITORY CANAL
Keratosis Obturans
Keratosis obturans gives a gradual smooth bony widening
of the external auditory canal filled with soft tissue density
on CT (Fig. 22-34). They are more commonly bilateral
and occur in younger patients. They often present with
acute severe pain and uncommonly with otorrhea.

External Auditory Canal Cholesteatoma

Cholesteatoma involvement of external auditory canal is
rare, as opposed to the more common cholesteatoma of
the middle ear. Cholesteatomas of the EAC can be congen-
ital,35 spontaneous, or secondary to infection, trauma, or
surgery.36 They are often confused with keratosis obturans.
EAC cholesteatomas tend to occur in older patients and
has a milder presentation of chronic pain and otorrhea. The
occurrence is more commonly unilateral. CT demonstrates
soft tissue density often along the canal floor, sparing the
tympanic membrane. Unlike the smooth bony widening of
B
keratosis obturans, EAC cholesteatomas demonstrate focal
erosions along the canal (Fig. 22-35).37 Figure 22-34. Keratosis obturans. A-B, Axial and coronal CT bone algorithm
shows soft tissue density in the external auditory canal causing smooth grad-
ual widening (arrowheads).
Exostosis and Osteoma
Two benign lesions associated with bony overgrowth are
exostosis and osteoma. Exostoses (Fig. 22-36) are much Tumors of the external canal may spread along paths of
more common and are often bilateral. They are considered least resistance—medially into the middle ear or laterally
to be induced by cold water swimming. They arise in the into the cartilaginous portion of the external canal. From
most medial aspect of the osseus canal adjacent to the here they can spread inferiorly beneath the skull base or
tympanic membrane. They are broad based and very anteriorly into the parotid gland.
dense. Osteomas (Fig. 22-37) tend to be unilateral, arise Such soft tissue extension can be demonstrated with CT
more laterally, and are rounder or more focal. or MRI (Fig. 22-39). Of particular importance is the stylo-
mastoid foramen. Replacement of the fat beneath the sty-
lomastoid foramen can be demonstrated with CT or MRI
Malignant Lesions of if thin sections are used. In general, CT can be used as the
the External Canal first examination because of its demonstration of bone ero-
sion. If extension beneath the skull base is inadequately
Malignant lesions of the external canal are diagnosed by demonstrated, MRI should be performed.
biopsy, but imaging is used to determine if the lesion is When the tumor extends across the middle ear, the bony
resectable. Squamous cell carcinoma is most common but labyrinth and the lateral plates of the carotid canal and
basal cell carcinomas, minor salivary gland tumors (for jugular fossa again become important landmarks if a surgical
example, adenoid cystic carcinoma), and spread from resection is planned.
malignant parotid tumors also occur. Erosion of the bony Occasionally, severe radiation osteonecrosis produces bone
external canal is best demonstrated by CT (Fig. 22-38). destruction, which mimics a malignancy of the temporal
416 NEURORADIOLOGY

B
Figure 22-35. EAC cholesteatoma. A-B, Axial and coronal CT bone algorithm
demonstrates a soft tissue density (arrowheads) in the right external auditory
canal causing focal bony erosions (arrows).

B
Figure 22-37. EAC osteoma. A-B, Axial and coronal CT bone algorithm
shows a focal ossification protruding into the left external auditory canal
from the inferior wall (arrowhead). It is partially obstructing the canal.

bone (Fig. 22-40). The history of radiation and biopsies

negative for malignancy suggests the correct diagnosis.

INFECTION
Malignant External Otitis
Malignant external otitis (MEO) (necrotizing external otitis)
can mimic carcinoma. At imaging, the appearance may be
very similar with erosion of the bony canal and extension
into the soft tissues beneath the skull base. Although MEO
can erode into the middle ear and mastoid, this disease
Figure 22-36. EAC exostosis. Axial CT bone algorithm demonstrates bony preferentially extends inferiorly at the junction of the bony
overgrowth into both external auditory canals causing narrowing (arrowheads). and cartilaginous canals to involve the soft tissues beneath
 Imaging of the Lateral Skull Base 417

B
Figure 22-39. Squamous cell carcinoma of the external auditory canal.
A, T1-weighted MRI shows an abnormal mass involving the left temporal
bone (arrow). B, Postcontrast MRI at the same level as (A). There is marked
B enhancement of the mucosa of the middle ear cavity (white arrow). There is
also more modest enhancement of the tumor (black arrow).
Figure 22-38. Basal cell carcinoma of the external auditory canal (EAC).
A, Enhanced CT shows soft tissue filling the left external auditory canal
(arrows). B, Bone algorithm at the same level shows erosion of the posterior
(straight arrow) as well as the anterior (curved arrow) walls of the EAC. The Differentiation of MEO from a malignant neoplasm of the
lesion also extends through the tympanic membrane into the middle ear. external canal is usually not possible based on imaging. The
Note the handle of the malleus and the incus (arrowhead).
distinction is made on clinical grounds. MEO is almost
exclusively a disease of diabetic patients. Biopsy will be neg-
the external auditory canal. From here the disease can ative for neoplasm and pseudomonas can be cultured.
spread medially beneath the skull base to involve the cranial
nerves. The seventh nerve is involved as it exits the
stylomastoid foramen. Further extension involves the SUMMARY
nerves of the jugular foramen and cranial nerve XII.
Extreme cases of MEO spread across the midline and Imaging is used to detect and to stage lesions of the lateral
eventually involve the bone of the petrous apex and clivus. skull base. Although opinions vary greatly, in most cases
Newer antibiotics have significantly diminished the high-resolution CT (particularly multislice CT) is preferred
morbidity and mortality of this disease. because of the ability to visualize the fine bony anatomy,
418 NEURORADIOLOGY

13. Meyers SP, et al: Chondrosarcomas of the skull base: MR imaging

features. Radiology 184:103–108, 1992.
14. Meyers SP, et al: Chordomas of the skull base: MR features. Am J
Neuroradiol 13:1627–1636, 1992.
15. Libshitz HI, et al: Multiple myeloma: Appearance at MR imaging.
Radiology 182:833–837, 1992.
16. Oot RF, et al: The role of MR and CT in evaluating clival chordomas
and chondrosarcomas. Am J Neuroradiol 9:715–723, 1988.
17. Utz JA, et al: MR appearance of fibrous dysplasia. J Comput Assist
Tomogr 13(5):845–851, 1989.
18. Curtin HD, Jensen JE, Barnes L Jr, May M: “Ossifying” hemangiomas
of the temporal bone: Evaluation with CT. Radiology 164:831–835,
1987.
19. Lo W: Endolymphatic sac tumor: More than a curiosity. Am J
Neuroradiol 14:1322–1323, 1993.
20. Mukherji SK, et al: Papillary endolymphatic sac tumors: CT, MR
imaging, and angiographic findings in 20 patients. Radiology
202(3):801–808, 1997.
21. Hirsch WL, Hryshko FG: Comparison of MR imaging, CT, and
angiography in the evaluation of the enlarged cavernous sinus.
Am J Neuroradiol 9:907–915, 1988.
22. Yuh WTC, et al: MR imaging of primary tumors of trigeminal
nerve and Meckel’s cave. Am J Neuroradiol 9:665–670, 1988.
23. Linskey ME, Sekhar LN: Cavernous sinus hemangiomas: A series, a
review, and a hypothesis. Neurosurg 30:101–108, 1992.
Figure 22-40. Focal radiation necrosis of the skull base. Axial CT bone
algorithm shows destruction of the posterior wall of the right external 24. Minor LB, et al: Sound- and/or pressure-induced vertigo due to
auditory canal (straight arrow). There is marked sclerosis of the squamosal bone dehiscence of the superior semicircular canal. Arch Otolaryngol
portion of the occipital bone adjacent to the mastoid (curved arrow). The Head Neck Surg 124:249–258, 1998.
cystic changes in the mandibular condyles (arrowheads) are of uncertain 25. Mong A, et al: Sound- and pressure-induced vertigo associated with
etiology. dehiscence of the roof of the superior semicircular canal. Am J
Neuroradiol 20:1973–1975, 1999.
26. Lo WWM, Solti-Bohman LG, lambert PR: High-resolution CT in
which is very important in evaluating the region of the the evaluation of glomus tumors of the temporal bone. Radiology
temporal bone. 150:737–742, 1984.
27. Arriaga MA, Lo WW, Brachman DE: Magnetic resonance angiogra-
phy of synchronous bilateral carotid body paraganglia and bilateral
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28. Graham MD, LaRouere MJ, Kartush JM: Jugular foramen schwan-
1. Anzai Y, Lufkin RB, Jabour BA, Hanafee WN: Fat suppression failure nomas: Diagnosis and suggestions for surgical management. Skull
artifacts simulating pathology on frequency-selective fat-suppression Base Surg 1(1):34–38, 1991.
MR images of the head and neck. Am J Neuroradiol 13:879–884, 29. Saski T, Takakura K: Twelve cases of jugular foramen neurinoma.
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2. Gherini S: Resident’s page. Arch Otolaryngol Head Neck Surg 30. Kawamura Y, SZE G: Totally cystic schwannoma of the tenth cranial
112:674–677, 1986. nerve mimicking an epidermoid. Am J Neuroradiol 13:1333–1334,
3. Rosenberg RA, et al: Cholesteatoma vs. cholesterol granuloma of 1992.
the petrous apex. Otolaryngol Head Neck Surg 94:322–327, 1986. 31. McElveen JT Jr, Lo WW, Gabri TH, Nigri P: Aberrant internal
4. Martin N, et al: Cholesterol granulomas of the middle ear cavities: carotid artery: Classic findings on computed tomography. Otolaryngol
MR imaging. Radiology 172:521–525, 1989. Head Neck Surg 94:616–621, 1986.
5 Clifton AG, Phelps PD, Brookes GB: Cholesterol granuloma of the 32. Geoffray A, Lee Y-Y, Jing B-S, Wallace S: Extracranial meningiomas
petrous apex: Case reports. Br J Radiology 63:724–726, 1990. of the head and neck. Am J Neuroradiol 5:599–604, 1984.
6. Horowitz BL, Chari MV, James R, Bryan RN: MR of intracranial 33. Malony TB, Brackman DE, LO WW: Meningiomas of the jugular
epidermoid tumors: Correlation of in vivo imaging with in vitro 13C foramen. Otolaryngol Head Neck Surg 106:128–136, 1992.
spectroscopy. Am J Neuroradiol 11:299–302, 1990. 34. Cunningham MJ, Curtin HD, Butkiewicz BL: Histiocytosis X of
7. Pyle GM, Wiet RJ: Petrous apex cholesteatoma: Exteriorization vs. the temporal bone: CT findings. J Comput Assist Tomogr 12(1):
subtotal petrosectomy with obliteration. Skull Base Surg 1(2): 70–74, 1988.
97–105, 1991. 35. Quantin L, et al: Congenital cholesteatoma of external auditory
8. Yanagihara N, Nakamura K, Hatakeyama T: Surgical management canal. Int J Pediatr Otorhinolaryngol 62(2):175–179, 2002.
of petrous apex cholesteatoma: A therapeutic scheme. Skull Base 36. Vrabee JT, et al: External canal cholesteatoma. Am J Otol 21(5):
Surg 2(1):22–27, 1992. 608–614, 2000.
9. Feghali JG, Kantrowitz AB: Periaqueductal approach to cholesterol 37. Malcolm PN, et al: CT appearance of external ear cholesteatoma.
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10. Larson TL, Wong ML: Primary mucocele of the petrous apex: MR
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 Chapter
Imaging of the Facial Nerve

Outline 23
Technique Carcinomas Sujana S. Chandrasekhar, MD
Congenital Anomalies Rare Tumors
Antonio De la Cruz, MD
Normal Variants Trauma
Congenital Ear Deformities Inflammatory Disease William W. M. Lo, MD
Tumors Intrinsic Inflammation Fred F. Telischi, MD
Schwannomas Extrinsic Inflammation
Vascular Tumors Hemifacial Spasm
Epidermoid Cysts Summary
Cholesterol Cysts

I maging of the facial nerve has evolved into a precise

procedure that employs both high-resolution computer-
ized tomography (HRCT) and magnetic resonance imag-
at the posterosuperior region of the tympanum, subtends
an angle of 95 to 125 degrees and results in a nearly verti-
cal descent of the nerve. The vertical (or mastoid) portion
ing (MRI). It has gone from the era of plain films, followed of the facial nerve canal descends 13 mm to the stylomas-
by conventional polytomography,1,2 popularized in the toid foramen. The extratemporal facial nerve, as it
1960s, through cisternographic tomography,3 performed emerges from the stylomastoid foramen, runs anteriorly in
primarily through the mid-1970s, to the present standards the substance of the parotid gland and divides into two
of HRCT and MRI.4–9 The advantages of CT over the primary branches: the temporofacial, or superior, division
techniques in use previously are (1) high-contrast resolu- and the cervicofacial, or inferior, division. These two
tion; (2) simultaneous display of densities of air, soft tissue, divisions in turn elaborate main branches and break up
and bone; (3) ease of examination; and (4) half of the into a plexus to supply the facial muscles.
radiation dose of polytomography. The advantages of MRI Accurate clinical history and physical examination
include (1) easy multiplanar projection without patient are necessary when choosing the imaging modality that
repositioning, (2) superior soft tissue resolution, and (3) lack will best evaluate facial nerve lesions. Different sites of
of exposure to ionizing radiation. Facial nerve imaging is neural injury must be imaged differently. MRI and HRCT
today accomplished by using MRI with gadolinium dieth- often yield complementary information and at times both
ylenetriamine pentaacetic acid (DTPA) enhancement and are required for optimal demonstration of facial nerve
HRCT, either jointly or alone. pathology.
The facial nerve has a complex, multiplanar course, both MRI is the method of choice when (1) the site of
intracranially and extracranially (Figs. 23-1, 23-2, and involvement is clinically unlocalized because it is the only
23-3).10–12 The intracranial portion extends from the imaging modality that demonstrates the facial nerve
brainstem to the internal auditory canal (IAC), for a length comprehensively from the pons to the parotid gland; (2) the
of 23 to 24 mm, and includes the premeatal segment, site of lesion is clinically localized to either the intracranial
which lies in the cerebellopontine angle (CPA). The or the extratemporal portion of the nerve because it pro-
intratemporal portion is subdivided into three segments. vides excellent soft tissue contrast; or (3) the onset of
A length of 5 to 12 mm (average = 10 mm) passes through symptoms is acute because, with gadolinium enhancement,
the IAC and then passes anteriorly and slightly inferiorly MRI is capable of showing changes of inflammation not
in its labyrinthine segment for 3 to 5 mm to reach the seen on CT.13–15
geniculate fossa. The nerve has its first surgical genu at the Thin-section HRCT that makes use of a bone or edge-
geniculate ganglion, where it turns at an acute angle of enhanced algorithm renders exquisite bony detail. It is the
approximately 75 degrees to run posteriorly and slightly preferred initial imaging modality when a lesion is clini-
laterally and from which emerges anteromedially the cally localized in the middle ear or mastoid and is the
greater superficial petrosal nerve. The tympanic portion of method of choice in cases of temporal bone trauma.16–18
the facial canal is straight, 10 to 12 mm in length, and, in CT with a standard soft tissue algorithm with and without
65% of cases, covered by a thin bony lamella over its exter- an intravenous iodinated contrast medium may be used to
nal wall. The mastoid, or second surgical, genu occurring evaluate the CPA and the parotid gland, but results are

419
420 NEURORADIOLOGY

A B

C D
Figure 23-1. Normal HRCT anatomy of the facial nerve-axial views, left ear. A, Arrowheads demonstrate IAC segment, labyrinthine segment, and geniculate
ganglion. Note Bill’s bar (vertical crest) separating the facial and superior vestibular nerves. B, Arrowheads demonstrate the tympanic segment. C, The mastoid
segment (arrowhead) lies at about 3 o’clock to the jugular fossa. D, Facial nerve (arrowhead) sitting in fat as it exits the stylomastoid foramen.

inferior to MRI in soft tissue contrast, and without covering the pons to the parotid gland, before and after
intrathecal gas injection this modality does not exclude intravenous injection of a paramagnetic contrast agent.
small IAC tumors.3 This is used only as a secondary option Sagittal or oblique sagittal images can be helpful in
when MRI is not available or when the patient cannot be displaying lesions in the facial nerve canal (FNC) (see
imaged on the MR scanner, for example, if the patient is Fig. 23-3E) and do not require patient repositioning.9,14,19,20
too claustrophobic or too large. Segments of the nerve in the facial canal enhance in the
majority of normal subjects after the administration of
intravenous gadolinium.21 This enhancement is due to the
TECHNIQUE presence of a perineural vascular plexus in the FNC and
may be asymmetrical in normal individuals. Compared
The technical considerations for MRI of the facial nerve with the findings in Bell’s palsy or Ramsay Hunt
are nearly identical to those for MRI of the CPA and the syndrome, the enhancement in normal subjects is less
IAC. These considerations are fully discussed in detail in intense and does not extend into the premeatal segment of
Chapter 21, Imaging the Cerebellopontine Angle, and are the nerve in the IAC (see Figs. 23-3A, B).
not repeated here. When necessary, similar techniques are HRCT for facial nerve evaluation is done in contiguous
extended to cover the course of the extratemporal facial thin sections, no thicker than 2 mm, with a bone or edge-
nerve through the parotid gland see (Fig. 23-3F). enhanced algorithm for maximal spatial resolution.4,22
For detection and demonstration of facial nerve lesions, Transverse sections of the temporal bone are obtained at
a well-focused MRI is indispensable because many of these either a 0- or 30-degree plane with respect to the infra-
are only a few millimeters in size. The technique employs orbital-meatal line. Scanning in either plane avoids direct
imaging in transverse and coronal planes, with contiguous radiation to the ocular lenses. The 30-degree plane is
or overlapping thin sections of 3 mm each in thickness, additionally advantageous in that it lies nearly parallel to
 Imaging of the Facial Nerve 421

A B

C D
Figure 23-2. Normal HRCT anatomy of the facial nerve-coronal views, left ear. A, Geniculate fossa (arrow). Note semicanal of tensor tympani (arrowhead).
B, The labyrinthine and proximal tympanic segments (arrowheads) lie superior to the cochlear capsule, across from the malleus. C, The tympanic segment
(arrowhead) is seen as it lies under the lateral semicircular canal, medial to the short process of the incus, and superolateral to the oval window niche.
D, Mastoid segment (arrow), medial to the mastoid process, exiting the temporal bone at the stylomastoid foramen.

the tympanic or horizontal segment of the FNC and compromises surgical access may be seen on HRCT and
thereby avoids sectioning of this segment in a cross- should be recognized (Fig. 23-4A).29 The bony wall of the
sectional or “salami” fashion.23 Additional images may be FNC may be developmentally dehiscent in 35% to 55% of
obtained in a modified coronal plane (by tilting the gantry) the population, most commonly in the midtympanic
with the patient either supine or prone. With multirow- segment over the oval window niche.26–28,30,31 The most
detector CT, which is now commonly available, coronal common tympanic segment aberrations that may be
and sagittal images can now be reformatted from axially encountered in surgery are: a course over the oval window;
acquired data with ease and with little loss of resolution. bifurcation proximal to the oval window; a course
posteriorly either between the oval and round windows or
inferior to the round window; a course through the
CONGENITAL ANOMALIES stapedial arch; a course along the superior aspect of the
lateral semicircular canal; or a course from the geniculate
ganglion straight downward over the promontory.27
Normal Variants Imaging in the coronal plane is most helpful in excluding
The labyrinthine FNC may originate from the midportion an aberrant tympanic segment.6
rather than the fundus of the IAC.24 The geniculate fossae The anterior portion of the tympanic FNC may be
may vary in size, although there is generally symmetry enlarged by a persistent stapedial artery in its course from
between the right and left sides.17 The most common the tympanic cavity to the middle cranial fossa to termi-
variations in the course of the FNC involve the distal nate as the middle meningeal artery.32,33 Most individuals
portion of the nerve.25–28 A “drooping,” or protruding, with this finding have few or no symptoms, and such a
tympanic segment that overlies the oval window and nonpathologic enlargement must not be mistaken for a
422 NEURORADIOLOGY

A B

C D

E F
Figure 23-3. Normal MRI of the left facial nerve-T1-weighted images. A, Axial, precontrast: arrows show normal geniculate ganglion and tympanic segment.
B, Axial, postcontrast: same structures. C, Axial, precontrast: mastoid segment (arrowhead). D, Axial, postcontrast: same structure. E, Sagittal, precontrast:
mastoid segment (arrow). F, Axial, precontrast: facial nerve (arrow) entering the substance of the parotid gland, posterolateral to the retromandibular vein
(arrowhead).

tumor. A persistent stapedial artery can be suspected, even these cases. The marrow of the styloid process may mimic
when the artery itself is too small to be visible on CT, in the mastoid segment of the facial nerve (see Fig. 23-4B) on
the absence of the ipsilateral foramen spinosum (Fig. 23-5).32 HRCT; a distinction between the two structures can be
HRCT is diagnostic. MR angiography may be used for made by following the course of the facial nerve on serial
confirmation; conventional angiography is not indicated in images.
 Imaging of the Facial Nerve 423

Congenital Ear Deformities

A high incidence of aberrance of the tympanic segment of
the facial nerve is seen in patients with other congenital
middle ear abnormalities and should be sought.34 The
vertical segment may be displaced anteriorly. The motor
facial nerve may be congenitally absent, as in Möbius’
syndrome or aplasia of the facial motor nucleus, in which
the FNC is very small because it needs to accommodate
only sensory and parasympathetic fibers (see Fig. 23-5C).35
Abnormal enlargement of the geniculate fossa should be
considered in the evaluation of spontaneous CSF otorrhea,
as this condition has been described.36

TUMORS
Although most neoplasms are extrinsic and involve the
A facial nerve only secondarily, facial nerve schwannomas
and hemangiomas arise from facial nerve structures. The
more common extrinsic tumors affecting the facial nerve
are epidermoids, cholesterol granulomas, jugulotympanic
paragangliomas, and squamous cell carcinomas. Rarer
extrinsic tumors are primary fallopian canal paragangliomas,
papillary adenomatous endolymphatic sac tumors, metas-
tases, histiocytosis X, embryonal rhabdomyosarcoma, and
choristoma.

Schwannomas
Facial nerve schwannomas (FNSs) may involve any segment
of the nerve or may involve more than one segment, not
always in continuity. They are often sausage-shaped,
expanding long segments of the FNC. Latack and col-
leagues37 have represented eight examples of FNS in dia-
grammatic form (Fig. 23-6). The clinical presentation and
imaging findings depend on the segment(s) of the nerve
B involved. Because they involve the nerve by compression
rather than invasion, facial palsy is generally a late finding.
Intratemporal-segment schwannomas demonstrate facial
nerve symptomatology earlier than do those at the CPA or
the IAC. On MRI, FNSs are heterogeneous lesions
hypointense to brain on T1-weighted images (T1WI),
isointense on proton-density, and hyperintense on T2-
weighted images (T2WI) (Fig. 23-7). These tumors enhance
briskly with gadolinium (Figs. 23-7B and 23-8). They are
isodense to brain with enhancement after iodinated contrast
on CT; however, tumors within the IAC or bony FNC
can be missed; therefore, MRI is preferable for identifying
small lesions.38,39 Lesions involving the distal tympanic and
mastoid segments image more characteristically than do
those in the perigeniculate, IAC, and parotid portions.
An imaging distinction between facial and vestibular
schwannomas in the CPA or the IAC is nearly impossible
C to make (see Fig. 23-7), although histologically they
Figure 23-4. Congenital variant: protruding tympanic segment–coronal appear quite different.40 Certain imaging “clues” may aid
HRCT, left ear. A, Tympanic segment of facial nerve (arrowhead) covers the in differentiating these lesions. Anterosuperior erosion of
oval window. B, Mastoid segment of facial nerve (arrow) should not be the IAC or erosion of the labyrinthine FNC on HRCT has
confused with the marrow of the styloid process (arrowhead). Both
anomalies are associated with external auditory canal atresias. C, Lateral been suggested as a diagnostic clue, but it is not reliable.41
subcutaneous exit of the mastoid segment of the facial nerve, a rare but Eccentric placement of the tumor in the IAC may help in
highly treacherous anomaly of the facial nerve canal. making a preoperative diagnosis of facial schwannoma.42
424 NEURORADIOLOGY

A B

C1 C2
Figure 23-5. A and B, Congenital variant: persistent stapedial artery. A, Coronal HRCT, left ear: Arrowhead points to enlarged proximal tympanic segment of FNC
caused by persistent stapedial artery. B, Axial CT of skull base: Arrowhead at normal foramen spinosum on right, immediately posterolateral to the foramen
ovale. This structure is absent on the side of the persistent stapedial artery. (Courtesy of David F. Sobel, MD) C, Congenital variant: hypoplastic FNC in a child
with congenital facial palsy. (left, abnormal; right, normal)

There may be more than one component: one in the

IAC/posterior cranial fossa and one in the middle cranial
fossa connected via a narrow waist through the laby-
rinthine FNC (see Fig. 23-8). The dumbbell-shaped FNS
from the posterior to the middle cranial fossa in the mid-
petrous region is highly characteristic. Large geniculate
ganglion schwannomas may be mistaken for meningiomas,
gliomas, or temporal lobe metastases. Coronal images are
helpful in demonstrating the extradural origin of schwan-
nomas; also smooth enlargement of the FNC favors the
diagnosis of FNS (Fig. 23-9). Tumors arising from the
tympanic segment may cause conductive hearing loss as
the only symptom (Fig. 23-10). A pathognomonic finding
is an enhancing enlargement of varying thickness along a
significant length of the nerve (Figs. 23-11 and 23-12).37,38
During radiography of proximal tympanic segment
schwannomas, one should not be misled by a persistent
stapedial artery or developmental dehiscence of the FNC,
Figure 23-6. Eight types of FNS. The shaded areas represent segments of
the nerve involved by tumor. Most FNSs involve long segments of the nerve.
as discussed previously.
(Reproduced with permission from Latack JT, et al: Facial nerve neuromas. Differential diagnosis for geniculate ganglion lesions
Radiologic evaluation. Radiology 149:731–739, 1983.) includes vascular tumors such as hemangiomas, epidermoid
 Imaging of the Facial Nerve 425

A A

B B
Figure 23-8. FNS in posterior and middle cranial fossae. A, Precontrast
T1WI axial MRI. B, Postcontrast T1WI axial MRI.

borders of epidermoid cysts are extremely sharp (see

Figs. 23-18A, and 23-20A). Hemangiomas are heteroge-
neously hyperintense on MRI and enhance strongly with
gadolinium-DTPA (Figs. 23-15 and 23-16). Epidermoid
cysts are isodense or hypodense on CT and are nonen-
hancing after contrast administration (see Figs. 23-19B
and 23-20B). On MRI, epidermoid cysts are hypointense
on T1WI and hyperintense on T2WI (see Figs. 23-18B, C
and 23-19C, D), and they do not enhance with gadolinium
(see Fig. 23-20D). The CT and MRI features of a menin-
C gioma at the geniculate ganglion resemble those in the CPA.
Figure 23-7. Axial MRI of an FNS. A, The tumor (arrow) is heterogeneous
and mildly hypointense to brain on T1WI, precontrast. B, The mass enhances Vascular Tumors
briskly with gadolinium–DPTA on postcontrast T1WI. C, On T2WI, the mass
is mildly hyperintense to brain. Intratemporal vascular tumors include hemangiomas,
composed of thin-walled vascular spaces, and vascular mal-
formations, composed of thick-walled vascular spaces lined
with a layer of epithelium surrounded by fibroblasts and
cysts, and meningiomas. Distinguishing among these collagen. The two lesions may coexist in a single mass.
lesions can be done with MRI and HRCT, based on the The most common site of occurrence is the geniculate
sharpness of their borders and on enhancement character- ganglion, followed by the IAC and then the mastoid genu.
istics. On HRCT, the borders of hemangiomas are not They are usually less than 1 cm in diameter. The nerve is
sharp (Figs. 23-13 and 23-14), the borders of schwanno- involved by invasion and these tumors cause hemifacial
mas are moderately sharp (see Fig. 23-12B), and the spasm and facial palsy early. If located in the IAC, they
426 NEURORADIOLOGY

A A

B B
Figure 23-9. Geniculate ganglion schwannoma, left. Presenting complaint: Figure 23-10. Tympanic FNS, left. A, Axial HRCT. Arrowhead points to soft
conductive hearing loss. A, Axial HRCT. Arrowhead points to small soft tissue mass in middle ear, medial to the ossicles, lying along the tympanic
tissue mass between cochlear promontory and ossicles. B, Coronal T1WI FNC. B, Axial T1WI, postcontrast MR. Arrowhead shows enhancing mass
MRI. Arrowhead to small component of tumor corresponds to soft tissue in along tympanic FN.
the middle ear seen on CT. The large component protruding into the temporal
lobe was clinically silent.

also cause a greater degree of sensorineural hearing loss Many of these tumors are similar to schwannomas in
than would be expected based solely on size.43 Early detec- signal intensity on T1WI and T2WI, but some are
tion may allow complete removal with preservation of most hyperintense than typical schwannomas on T2WI
facial nerve function, avoiding facial nerve resection and (Fig. 23-17).46,47
grafting.44
Intratumoral bone spicules may be seen (see Fig. 23-13). Epidermoid Cysts
This bone formation is a reaction to the hemangioma
itself.45 Labyrinthine and geniculate ganglion lesions show Petrous apex epidermoid cysts attain considerable size
subtle CT findings that include irregular and indistinct before involving the facial and acoustic nerves in the CPA
bone margins and reticular or “honeycomb” bone (see or IAC. More common facial nerve involvement is seen
Fig. 23-14). Geniculate ganglion vascular tumors seen with congenital epidermoid cysts of the supralabyrinthine
with MRI demonstrate nonhomogeneous intensities, region of the temporal bone.48 From this point of origin
which are the MRI correlate of the “honeycomb” seen on they readily erode the proximal FNC and can either reach
CT (see Fig. 23-15). They are difficult to distinguish from around the superior semicircular canal and extend medi-
schwannomas when they occur at the mastoid genu. Their ally superior to the IAC or laterally into the epitympanum,
enhancement with contrast is not helpful on CT because or they can erode the cochlea or superior semicircular
density changes in such small lesions interspersed among canal, which causes fistulization. CT demonstrates an
bone are difficult to discern. HRCT with gas cisternog- expansile lesion-eroding bone, with sharp bone margins.
raphy is usually required for lesions of the IAC, but MRI Calcifications may be seen. T1WI MRI demonstrates low
with gadolinium-DTPA enhancement demonstrates these to intermediate signal, and T2WI shows high signal inten-
lesions well and is preferred over CT (see Fig. 23-16). sity (Figs. 23-18 and 23-19).
 Imaging of the Facial Nerve 427

Carcinomas
Survival in patients with squamous cell carcinoma of the
temporal bone is related directly to the depth and extent of
tumor involvement.49 Physical examination is unreliable,
because the medial external auditory canal and tympanic
membrane are visible in only 50% of patients.50 Plain film
radiographs and tomograms are likewise inadequate.
HRCT, however, is very accurate in assessing the depth
and extent of tumor invasion.51 The technique uses a
standardized protocol of bone and soft tissue algorithms
with thin slices in both axial and coronal planes. Facial
nerve involvement in these tumors occurs as a result of
tumor extension through the fissures of Santorini into the
extratemporal facial nerve, or in the middle ear/mastoid.
Adenoid cystic carcinoma causes facial nerve palsy directly
as it spreads along the perineurium. Both MR and HRCT
A are used in imaging this tumor.

Rare Tumors
Fewer than 20 cases of paraganglioma of the facial canal
(glomus faciale) without involvement of the jugular bulb
have been reported in the literature.52–58 Two more cases
have been diagnosed at our institution. Arnold’s nerve, the
auricular branch of the vagus nerve, passes via one or two
mastoid canaliculi from the jugular bulb to the facial canal
and ascends in the vertical portion of the FNC.59
Paraganglia (glomus bodies) can be found along Arnold’s
nerve within the vertical FNC. HRCT demonstrates
expansion of the vertical FNC (Fig. 23-21A) and, with
larger tumors, may show destruction in the mastoid
(Fig. 23-21B). To demonstrate that the jugular foramen is
B not involved, catheter or MR venography is helpful.
Figure 23-11. FNS–sagittal T1WI MRI. Note multifocal lesions from the
Jugulotympanic paragangliomas may grow to affect the
geniculate ganglion to the stylomastoid foramen (arrowheads). Compare facial nerve secondarily, which is demonstrated on imaging
this to the normal sagittal view seen in Figure 23-3E. A, Precontrast. of the tumor.
B, Postcontrast. Other tumors of the temporal bone secondarily affecting
the facial nerve are endolymphatic sac tumors (ELST),
metastatic lesions, Langerhans’ cell histiocytosis, embry-
onal rhabdomyosarcomas, and non-neoplastic choristomas.
Acquired epidermoid cysts of the temporal bone may Papillary adenomatous tumors of endolymphatic sac origin
also cause facial nerve symptomatology. Radiologically, (ELST) are rare, locally invasive, and often extend into the
they are similar to congenital epidermoid cysts except that medial mastoid to cause facial palsy (Fig. 23-22).60 Bilateral
they originate from the middle ear and mastoid and may ELSTs have been found in patients with von Hippel-
extend around the bony labyrinth to the petrous apex. A Lindau disease.61 Of metastatic lesions to the temporal
common location of FN involvement is in the geniculate bone, 34% present with facial nerve palsy.62 The primary
ganglion region. Changes of chronic inflammation are tumors are usually in the prostate, breast, or kidney. CT
seen in the middle ear and mastoid (Fig. 23-20). demonstrates bony destruction with tumor encroachment
on the FNC; MR with gadolinium-DTPA is useful in
Cholesterol Cysts equivocal cases.63
Langerhans’ cell histiocytosis causing facial palsy has
Cholesterol granulomas form from obstruction of been reported in 15 cases.39 The pathophysiology is
drainage of petrous apical air cells, followed by repetitive histiocytic infiltration of the temporal bone leading to
cycles of hemorrhage. They may cause irritation and initi- compression of the nerve within the eroded fallopian
ate a foreign body reaction from their cholesterol crystals. canal. CT shows an expansile soft tissue mass with bony
They grow silently in the petrous apex until they exert labyrinthine and ossicular erosion. Embryonal rhabdomy-
pressure on cranial nerve V, VI, VII, VIII, IX, X, XI, or osarcoma, an early childhood malignancy, involves the tem-
XII. These lesions are best imaged by combining HRCT poral bone in 7% of cases. Of 12 cases reported by Wiatrak
and MRI. CT shows a sharply marginated, expansile and Pensak,64 6 had seventh cranial nerve paralysis as a
lesion, without calcifications. MRI demonstrates high presenting manifestation, and all of these 6 patients had
signal intensity on both T1WI and T2WI. middle ear tumors. The usual path of spread of
428 NEURORADIOLOGY

A B

C D
Figure 23-12. FNS, left, extending from the IAC through the descending (mastoid) segment. A, Axial HRCT. Arrowheads at FNS in geniculate and tympanic
segments. B, Coronal HRCT. Tumor in mastoid segment (arrowhead). C, Axial T1WI, postcontrast MRI. Tumor in IAC, geniculate and tympanic segments
(arrowheads). D, Sagittal T1WI, postcontrast MRI. Tumor in tympanic and mastoid segments (arrowheads).

Figure 23-13. Hemangioma–axial HRCT, left side. Demonstrates intratumoral Figure 23-14. Hemangioma–axial HRCT, right side. Note irregular bony
bone (arrowhead) within IAC hemangioma. margins (arrow), honeycombing, and larger bone spicules (arrowhead).
 Imaging of the Facial Nerve 429

Figure 23-15. Hemangioma of geniculate ganglion–axial T1WI, postcontrast

MRI, right. Heterogeneous hyperintensity of the hemangioma (arrowheads)
corresponds to the honeycomb appearance seen on HRCT (see Fig. 23-14).

Figure 23-16. Hemangioma of IAC–axial T1WI, postcontrast MRI, left. Note

intense enhancement with gadolinium (arrows). This lesion cannot be
differentiated radiologically from schwannoma. The enhancement seen at the
geniculate ganglion (arrowhead) was not tumor at surgery.

C
Figure 23-18. Suprageniculate congenital epidermoid cyst, left ear, axial
projections. A, HRCT. Arrow demonstrates sharp margin of bony erosion.
Note involvement of the ampullated end of the superior semicircular canal
(arrowhead). B, This lesion has intermediate signal intensity on T1WI MRI.
C, The same lesion has high signal intensity on T2WI MRI.

Figure 23-17. Hemangioma–axial T2WI MRI, right. Note hyperintensity of

tumor on T2WI in IAC and CPA, distinguishing it from the typical
schwannoma.
430 NEURORADIOLOGY

A B

C D
Figure 23-19. Petrous apex congenital epidermoid cyst, left ear, axial projections. A, HRCT with bone algorithm. The large lesion is expanding the petrous apex
(arrows). B, CT with soft tissue algorithm, postcontrast. The mass is isodense or mildly hypodense to brain and nonenhancing (arrows). C, T1WI MRI.
The mass is mildly hypointense to brain with an isointense capsule (arrows). D, T2WI MRI. The mass is markedly hyperintense.

rhabdomyosarcoma of the middle ear cleft is by invasion localization with HRCT is vital because the surgical
and destruction of the FNC with infiltration of the facial approach to decompression varies with the exact site of
nerve, extension to the IAC, and from there on to the facial nerve injury.67 Gadolinium-enhanced MRI has been
leptomeninges. The imaging modality of choice in these advocated for identifying focal enhancement as a method
cases is HRCT because it assesses bony destruction and for localizing traumatic injury to the facial nerve.68
can evaluate response to therapy. Middle ear salivary gland Classically, temporal bone fractures have been divided
choristomas, which are tumors composed of normal cells into two types: longitudinal (70% to 90%) and transverse
not normally found at the site of occurrence, usually affect (10% to 30%), defined by the orientation of the fracture
the tympanic segment of the facial nerve and the ossicles.65 relative to the long axis of the petrous bone. Ten percent
to 20% of longitudinal fractures result in facial nerve palsy,
which is usually delayed in onset and incomplete. The
TRAUMA fracture line is oriented along the long axis of the tempo-
ral bone and, in palsy cases transgresses the nerve in the
Specific thin-section HRCT is necessary in the radiologic perigeniculate region (Figs. 23-23A, B). Facial paralysis
evaluation of temporal bone trauma, because approxi- occurs in 50% of transverse fractures, and is more fre-
mately 60% of temporal bone fractures are not apparent quently of immediate onset and complete. The facial nerve
on routine head CT examinations.66 It is preferable to is usually involved in the labyrinthine or tympanic seg-
obtain both axial and coronal sections; however, if the ment (Fig. 23-24). More recent literature indicates that a
status of the patient’s cervical spine precludes positioning large percentage of temporal bone fractures are “mixed,”
for direct coronal images, coronal reconstructions from in that the fracture line is both along and across the long
direct axial images can suffice.6 Accurate preoperative axis of the petrous bone. Audiometric data associated with
 Imaging of the Facial Nerve 431

A B

C D
Figure 23-20. Acquired epidermoid cyst of the temporal bone, right ear. A, Axial HRCT shows a sharply and smoothly marginated lobular mass extending from
the middle ear cavity, anterior to the cochlea to expand the petrous apex, eroding portions of the cochlear capsule. B, Axial CT with soft tissue algorithm shows
the mass to be mildly hypodense to brain. The patient’s facial weakness was due to erosion in the geniculate ganglion region (arrow). C, Axial T1WI MRI shows
that the mass is mildly hypointense, with a thin isointense capsule (arrowheads), similar to that seen in Figure 23-19, C. D, Coronal T1WI MRI, postcontrast.
The cholesteatomatous material shows no enhancement; there is enhancement of tissue in the middle ear and surrounding the capsule (arrowheads) as a result
of reactive inflammation.

differently oriented fracture lines are available.69 Other nerve in these individuals.74–77 The pathologic enhance-
large series have looked at fractures as either otic capsule ment seen on gadolinium-enhanced MRI is much more
“sparing” or “involving,” with capsule-involving fractures intense than seen in normal subjects, usually involves the
having a higher incidence of facial palsy.70 perigeniculate and labyrinthine segments, and can extend
into the premeatal segment (Fig. 23-25). These findings
are consistent with the theory of meatal nerve entrapment
INFLAMMATORY DISEASE popularized by Fisch and Esslen.78 Nerve enhancement
may persist 4 months or longer following the onset of
paralysis. No difference is seen radiographically between
Intrinsic Inflammation acute and chronic cases, and there is no prognostic signifi-
Bell’s palsy, or idiopathic isolated peripheral facial palsy, cance attributable to the presence or the degree of facial
represents 50% to 85% of all cases of facial nerve palsy.71 nerve enhancement in patients with viral inflammatory
The majority of cases have a typical clinical presentation facial paralysis.79 Enhancement with enlargement of the
and do not require imaging; however, in 15% there is an nerve suggests tumor rather than inflammation.
atypical presentation or a prolonged course.72,73 In these Herpes zoster oticus, or Ramsay Hunt syndrome, man-
cases, gadolinium-enhanced MRI is useful and can help the ifests as auricular vesicles, ear pain, and facial paralysis.
clinician avoid missing a CPA/IAC tumor. The presumed Abnormal gadolinium enhancement of the facial nerve is
accumulation of gadolinium in areas of inflammation and seen, similar to that seen in Bell’s palsy. If the inflammation
disruption of vessel integrity has provided the basis for spreads to involve the eighth nerve and membranous
evaluation by means of this modality.14 A number of stud- labyrinth, variable enhancement of these structures is also
ies have demonstrated significant enhancement of the facial noted on MRI.75,80,81
432 NEURORADIOLOGY

B
Figure 23-21. Facial canal paraganglioma (glomus faciale), left ear, axial
HRCT. A, Expansion of vertical FNC (arrowhead). B, Arrows show extension
of tumor beyond FNC to adjacent mastoid and external auditory canal,
encroaching on the jugular fossa (arrowhead).

Lyme disease is a treponemal multisystemic infection

B
that is transmitted by a deer tick (Ixodes dammini). Ten Figure 23-22. Papillary adenomatous tumor of the endolymphatic sac,
percent of all patients with Lyme disease and 50% of those left ear, axial projections. A, HRCT. The tumor is destroying bone in the
retrolabyrinthine region with extension to the medial mastoid (arrowheads)
patients with central nervous system infection will have at the area of the mastoid facial nerve genu. B, T1WI MRI. This tumor
unilateral or bilateral facial nerve palsies.82 Enhancement (arrowheads) is heterogeneous, containing hypointense, isointense and in
of the facial nerve on MRI is seen and is identical to that particular, hyperintense foci, precontrast.
seen with herpes zoster oticus and Bell’s palsy.

Extrinsic Inflammation stylomastoid foramen.88 Nuclear medicine evaluation with

Acute otitis media, chronic otomastoiditis, and cho- technetium scanning to detect the extent of skull base
lesteatoma have been associated with facial paralysis. osteomyelitis and gallium scanning for early detection of
Cholesteatoma is present in more than half of the cases of recurrence are invaluable in this disease. Facial nerve
chronic otitis media and facial palsy.83 Imaging is indicated imaging per se is not indicated in these cases; however, CT
in patients with facial palsy and chronic otomastoiditis or and MRI are helpful in assessing the extent of disease
cholesteatoma and is directed toward preoperative surgical because they can demonstrate evidence of inflammatory
planning. HRCT is the imaging modality of choice and soft tissue changes around the stylomastoid foramen
because it can clearly identify areas of the fallopian canal and mastoid segments of the facial nerve.89
violated by surrounding inflammatory soft tissue.84 Other
temporal bone infections secondarily causing facial nerve
palsy include mucormycosis, tuberculosis, and syphilis.85–87 HEMIFACIAL SPASM
Malignant (necrotizing) otitis externa, a skull base
osteomyelitis, can be complicated by facial palsy through Hemifacial spasm (Fig. 23-26) is a hyperactive facial nerve
spread of infection via the fissures of Santorini in the dysfunction characterized by painless paroxysmal spasms
external auditory canal, which involves the nerve at the of the ipsilateral mimetic musculature. It is frequently the
 Imaging of the Facial Nerve 433

A A

B B
Figure 23-23. A, Longitudinal temporal bone fracture, left ear, axial HRCT. Figure 23-25. Bell’s palsy, left, postcontrast T1WI MRI. A, Axial. Arrowheads
Comminuted longitudinal fracture (arrows), with large fragment (arrowhead) show marked enhancement in the premeatal segment in the fundus of the
involving the geniculate fossa, and extension of the fracture laterally through IAC, the geniculate ganglion, and the tympanic segment. Compare this to the
the EAC (twin arrows). B, Longitudinal temporal bone fracture, left ear, axial mild to moderate enhancement seen on the asymptomatic right side.
HRCT. This is a similar but more subtle comminuted fracture compared with B, Coronal. Arrowheads demonstrate marked enhancement of the premeatal
the fracture in A. The fracture lines involve the geniculate fossa and extend segment and the geniculate ganglion. The opposite (normal) side
laterally through the mastoid cortex (arrowheads). Note blood in the mastoid demonstrates mild enhancement in the geniculate ganglion only (line).
cavity.

Figure 23-24. Transverse temporal bone fracture, left ear, axial HRCT. This
patient presented with a complete ipsilateral sensorineural hearing loss and
abrupt-onset facial paralysis. The fracture line courses through the ampullary Figure 23-26. Hemifacial spasm. This heavily T2-weighted CISS image
limb of the lateral semicircular canal (arrowhead), transecting the underlying illustrates the neurovascular cross-compression that can be seen in
tympanic segment of the facial nerve. hemifacial spasm.
434 NEURORADIOLOGY

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Otolaryngol Head Neck Surg 102(2):101–105, 1990. 79. Sartoretti-Schefer S, Brandle P, Wichmann W, Valavanis A:
53. Dutcher PO, Brackmann DE: Glomus tumor of the facial canal: A Intensity of MR contrast enhancement does not correspond to clin-
case report. Arch Otol Head Neck Surg 112:986–987, 1986. ical and electroneurographic findings in acute inflammatory facial
54. Waldron MNH, Flood LM, Clifford K: A primary glomus tumor of nerve palsy. AJNR 17:1229–1236, 1996.
the facial nerve canal. J Laryngol Otol 116:156–158, 2002. 80. Daniels DL, Czervionke LF, Millen SJ: MR findings in the Ramsay-
55. Mafee MF, Raofi B, Kumar A, Muscato C: Glomus faciale, glomus Hunt syndrome. AJNR 9:609, 1988.
jugulare, glomus tympanicum, glomus vagale, carotid body tumors, 81. Osumi A, Tien RD: MR findings in a patient with Ramsay-Hunt
and simulating lesions. Role of MR imaging. Radiol Clin N Am syndrome. J Comput Assist Tomogr 14(6):991–993, 1990.
38(5):1059–1076, 2000. 82. Clark JR, et al: Facial paralysis in Lyme disease. Laryngoscope
56. Kania RE, et al: Primary facial canal paraganglioma. Am J 95:1341–1345, 1985.
Otolaryngol 20(5):318–322, 1999. 83. Takahashi H, et al: Analysis of 50 cases of facial palsy due to otitis
57. Petrus LV, Lo WMM: Primary paraganglioma of the facial nerve media. Arch Otol 241:163–168, 1985.
canal. AJNR 17:171–174, 1996. 84. Valavanis A, Kubik S, Schubiger O: High resolution CT of the nor-
58. Magliulo G, et al: Multiple familial facial flomus: case report and review mal and abnormal fallopian canal. AJNR 4(3):748–751, 1983.
of the literature. Ann Otol Rhinol Laryngol 112(3):287–292, 2003. 85. Gussen R, Canalis RF: Mucormycosis of the temporal bone. Ann
59. Guild SK: The glomus jugulare, a nonchromaffin paraganglion in Otol 91:27–32, 1982.
man. Am Otol Rhinol Laryngol 62:1045–1071, 1953. 86. Verduijn PG, Bleeker JD: Secondary syphilis of the facial nerve.
60. Lo WWM, et al: Endolymphatic sac tumors: Radiology diagnosis. Arch Otol 108:382–384, 1982.
Radiology 189:199–204, 1993. 87. Windle-Taylor PC, Bailey CM: Tuberculous otitis media:
61. Poe DS, Tarlov EC, Thomas CB, Kveton JF: Aggressive papillary A series of 22 patients. Laryngoscope 90:1039–1044, 1980.
tumors of temporal bone. Otolaryngol Head Neck Surg 108:80–86, 88. Chandler JR, Grobman L, Quencer R, Serafini A: Osteomyelitis of
1993. the base of the skull. Laryngoscope 96(3):245–251, 1986.
62. Maddox HE: Metastatic tumors of the temporal bone. Ann Otol 89. Rubin J, Curtin HD, Yu VL, Kamerer DB: Malignant external oti-
76:149–165, 1967. tis: Utility of CT in diagnosis and follow-up. Radiology
63. Angeli SI, Luxford WM, Lo WW: Magnetic resonance imaging in the 174:391–394, 1990.
evaluation of Langherhan’s cell histiocytosis of the temporal bone: 90. Nagaseki YN, et al: Oblique sagittal magnetic resonance imaging
Case report. Otolaryngol Head Neck Surg 114(1):120–124, Jan 1996. visualizing vascular compression of the trigeminal of facial nerve.
64. Wiatrak BJ, Pensak ML: Rhabdomyosarcoma of the ear and tempo- J Neurosurg 77:379–386, 1992.
ral bone. Laryngoscope 99:1188–1192, 1989. 91. Pamir MN, et al: The aid of computerized tomography in hemifa-
65. Bottrill ID, Chawla OP, Ramsay AD: Salivary gland choristoma of cial spasm. J Neuroradiol 19:293–300, 1992.
the middle ear. J Laryngol Otol 106(7):630–632, 1992. 92. Tash RR, et al: Hemifacial spasms caused by a tortuous vertebral
66. Holland BA, Brant-Zawadzki M: High resolution CT-temporal artery: MR demonstration. J Comput Assist Tomogr 12(3):492–494,
bone trauma. AJNR 5:291–295, 1984. 1988.
67. Gentry LR: Temporal bone trauma-current perspectives for 93. Girard N, et al: Three-dimensional MRI of hemifacial spasm with
diagnostic evaluation. Neuroimag Clin N Am 1(2):319–340, 1991. surgical correlation. Neuroradiology 39:46-51, 1997.
 Chapter
Diagnostic and Therapeutic
Angiography
24 Outline

Christopher F. Dowd, MD Introduction Fistulas

Techniques Extracranial Arteriovenous
Van V. Halbach, MD
Arteriography Fistulas
Randall T. Higashida, MD Embolization Atherosclerosis
Major Artery Occlusion Fibromuscular Dysplasia
Intraoperative Angiography Normal Variants
Venography Tumors
Disease Processes Jugulotympanic Glomus
Vascular Tumors
Aneurysms Meningiomas
Arteriovenous Schwannomas
Malformations Miscellaneous Tumors
Dural Arteriovenous Conclusion

INTRODUCTION tailor the study. A full and informed consent is obtained

from the patient including an explanation of the indica-
Radiologic evaluation of patients who present with tions for the angiogram, the procedure itself, and risks.
symptoms or signs suggesting neurotologic disease usually The majority of cerebral angiograms are performed via
commences with performance of plain-film radiography, a transfemoral artery approach.1 The patient is placed in
computed tomography (CT), or magnetic resonance the supine position on the fluoroscopy table, a peripheral
imaging (MRI). In selected circumstances, this evaluation intravenous (IV) line is established, and mild IV sedation
can be enhanced by performing angiography to visualize may be administered. The skin over the femoral artery
the circulation of the head, neck, and brain optimally. is prepped and draped in a sterile fashion, and 1% lido-
Moreover, endovascular therapy (therapeutic angiography, caine is administered as a local anesthetic. A hollow punc-
embolization) has emerged as an accepted and valuable ture needle is placed into the common femoral artery,
therapeutic option in treating many vascular conditions of through which a soft-tipped guidewire is directed retro-
the skull base and brain. The role of angiography and grade into the aorta. The puncture needle is removed, and
endovascular therapy in the evaluation and treatment of the angiographic catheter is advanced over the guidewire
pathologic conditions producing pulsatile tinnitus, otalgia, into the aorta. The catheter and guidewire combination
otorrhagia, hearing loss, vertigo, and lower cranial nerve may be advanced cephalad under fluoroscopic guidance
palsies, including angiographic techniques and indications to select one of the great vessels arising from the aortic
for diagnostic and therapeutic angiography, will be arch, thus gaining access to the circulation of the neck
presented in this chapter. and head.
Once in position, iodinated contrast is injected through
the catheter while radiographic films are exposed, either
TECHNIQUES directly (“cut film” technique) or by computerized digital
subtraction. Injection of multiple arteries in multiple
Arteriography projections is often necessary. Finally, the catheter is
removed, and direct pressure is placed over the femoral
It is important to review the pertinent history, both from puncture site for 15 minutes. The patient is instructed to
the referring physician and from the patient, to document remain supine with the leg used for the puncture straight
the necessity of the angiogram and to elicit any history of for 6 hours, under observation.
allergies. Review of all prior radiographic studies including Alternatively, access to the arterial circulation may be
CT or MRI scans is important to delineate the diagnostic achieved via axillary or brachial artery approach, using
goals of the angiogram. Assessment of peripheral pulses similar techniques. Rarely, direct puncture of the common
and a neurologic examination are necessary to properly carotid artery is performed.2
436
 Diagnostic and Therapeutic Angiography 437

Embolization (99mTc-HMPAO) perfusion imaging,7–9 or provocative test

occlusion by artificially lowering systemic blood pressure
Devascularization of a tumor, arteriovenous malformation during test occlusion,10 but the role of these tests is not
(AVM), or arteriovenous fistula (AVF) requires placement fully defined. In Higashida’s series of cavernous internal
of embolic material into the affected artery (embolization) carotid aneurysms treated by detachable balloon occlu-
while maintaining patency of the normal surrounding sion,4 10% of patients developed new neurologic deficits
vessels. Diagnostic angiography is performed and assessed despite tolerance of the test occlusion, although the major-
initially, and an embolization plan is determined. A longer, ity of these deficits were transient and were treated
softer, more slender embolization catheter (usually 2–3 successfully by volume expansion or antiplatelet therapy.
French) is placed coaxially through the diagnostic guiding Test occlusion of the smaller-caliber distal carotid circula-
catheter and navigated to the site for embolization. tion or vertebral artery may also be achieved using a
Systemic anticoagulation is used if the catheter enters the nondetachable balloon catheter system; however, this pre-
intracranial circulation to prevent thrombus formation cludes use of the double-lumen catheter measurement of
along the catheters and to avoid the risk of distal emboliza- distal pressures.
tion to normal arteries. Once in position, superselective Permanent occlusion is performed by simultaneously
arteriography is performed to search for normal arteries placing detachable balloons into the internal carotid in
that must be preserved. A provocative injection of Amytal tandem, in order to ensure against deflation of one bal-
Sodium (amobarbital sodium), a short-acting barbiturate, loon. Platinum coils can also be used, but are often used in
may also be used to detect supply to the central nervous combination with a balloon, because coil use alone may
system and retina. A positive test consists of production allow thrombus formation while some antegrade flow
a reversible neurologic deficit. Two percent cardiac persists, risking distal embolization and stroke. Vigorous
lidocaine is used to detect supply to cranial nerves. A IV fluid administration for volume expansion and strict
negative test does not guarantee safety of embolization. If limitation of activity, usually for a period of 3 days, to allow
embolization is deemed safe, selection of the embolic adequate cerebral perfusion is important to limit the
agent is made based on the nature of the pathology, size possibility of delayed ischemia or infarction. These
of the vessels to be treated, and potential risks. Embolic balloons are filled with radiopaque contrast material, so
agents include particulate material (polyvinyl alcohol they can be visualized on serial plain skull radiographs,
[PVA], Gelfoam particles, and acrylic microspheres), thus ensuring continued adequate positioning and guard-
detachable silicone or latex balloons, liquid adhesives ing against deflation or distal migration.
(N-butyl cyanoacrylate), platinum or coils, custom-cut silk
suture, and ethanol. Embolization of cerebral aneurysms
requires placement of platinum coils directly into the Intraoperative Angiography
aneurysm with the goal of preserving flow in the parent The neuroradiologist is asked to perform diagnostic cere-
artery. The patient is monitored carefully for neurologic bral angiography in the operating theater to assist in
changes during the embolization. Control angiography is surgical procedures with increasing frequency.11 Neurosur-
performed after embolization to document the adequacy geons in particular rely on excellent quality angiographic
of the procedure. images obtained with a portable digital subtraction C-arm
unit to evaluate the location of a vascular lesion such as
an AVMs or to confirm proper aneurysm clip placement.
Major Artery Occlusion This portable technique has application to skull base
Large or fusiform aneurysms, arterial dissections causing surgery as well, in evaluating aneurysms, AVMs, dural
thrombus formation, and malignant skull base or neck AVFs, and patency of major arteries. The technique is
tumors3 may require permanent occlusion of the internal similar to conventional angiography, using a transfemoral
carotid or vertebral artery as definitive therapy or as a arterial approach. It is helpful to place a femoral arterial
presurgical adjunct. Prior to permanent occlusion, a test introducer sheath at the beginning of the operation,
occlusion of the artery in question is necessary to which can be slowly perfused with saline during surgery.
determine whether the collateral supply to the brain is This sheath can be accessed for angiography at any
adequate to avoid ischemia or infarction. A common site desired time.
for test occlusion is the origin of the affected internal
carotid artery (ICA). After systemically anticoagulating the
patient, a double-lumen test occlusion catheter with a
Venography
nondetachable balloon can be positioned in the proximal Evaluation of skull base tumors or conditions that cause
internal carotid.4 Under constant neurologic surveillance, pulsatile tinnitus may require performance of a cerebral or
the balloon is inflated to occlude the artery, and arterial jugular venogram. This is also the access route of choice
back-pressures can be measured through the catheter for endovascular treatment of some dural AVFs. This can
lumen distal to the inflated balloon. The test occlusion be performed safely via puncture of a femoral vein, with
is performed for 30 minutes. Neurologic tolerance of the navigation of the catheter through the vena cava to the
test occlusion without new deficit and adequate pressure internal jugular vein. Vigilance must be maintained to
measurements are essential for predicting tolerance of avoid cardiac arrhythmia production by stimulation of the
a permanent occlusion. Some authors advocate the addi- right atrial or ventricular wall during catheterization, an
tion of cerebral blood flow evaluation using stable xenon uncommon complication. The catheter can be placed at
CT5,6 or technetium hexamethylpropyleneamine oxime any location in the venous system and a venogram
438 NEURORADIOLOGY

obtained. Smaller catheters are required for intracranial Traumatic pseudoaneurysms occur as a result of pene-
use to limit the risk of venous sinus perforation. Pressure trating injuries (knife or missile wounds) or fractures of
measurements can also be performed to evaluate the the skull base. The cervical portions of the carotid arteries
hemodynamics at the site of a lesion, such as a meningioma are free, but become fixed as they enter the petrous bone,
invading the transverse sinus.12,13 With patient cooperation, creating candidate sites for deceleration, hyperextension,
provocative measures using Valsalva’s maneuver, lateral or rotational injury. These pseudoaneurysms are associ-
head turning, or flexion and extension may assist in re- ated with epistaxis,17,18 active hemorrhage per os, cranial
creating or temporarily obliterating subjective pulsatile tin- nerve palsies from mechanical compression, otorrhagia
nitus, and venography can be performed in those positions. (petrous segment of ICA),19 and traumatic extracranial
AVFs (vide infra), in particular carotid-cavernous or verte-
bral artery fistulas. A pseudoaneurysm may form as a result
DISEASE PROCESSES of thrombosis of an AVF or may rupture in a delayed fashion
to form a fistula.
Vascular CT scanning has a 90% sensitivity for detecting
aneurysmal SAH within 24 hours, but is much less sensitive
Aneurysms
in identifying the aneurysm. Larger aneurysms can be seen
An aneurysm is an abnormal focal arterial dilitation.13 as focal, contrast-enhancing areas adjacent to the parent
Aneurysms can be classified in a number of ways. vessel. They may exhibit mural calcification, circumferen-
Morphologically, aneurysms can be termed saccular, tial layers of internal thrombus that may not enhance, or
fusiform, dissecting, or giant. Pathologic differentiation is adjacent mass effect. Giant aneurysms may erode the
made between true aneurysms, which are composed of petrous or sphenoid bones, creating a smooth contour.
normal arterial tissue layers with a defect in the media,14 MRI may demonstrate the aneurysm as a focal area of flow-
and false aneurysms, or pseudoaneurysms, which are related signal void in the expected zones around the circle
bounded only by adjacent bone, soft tissue, or even clot of Willis. Inhomogeneity of signal within the aneurysm
formed as a result of previous aneurysm rupture or vascular may represent turbulent flow or partial thrombosis. MRI
injury. Etiologically, aneurysms are classified as congenital, detects calcification in the aneurysm wall poorly.
traumatic, atherosclerotic, mycotic, or dissecting.13 These Angiography is the most effective method for identify-
categorizations overlap: for example, congenital aneurysms ing cerebral aneurysms. A thorough angiographic study is
are true aneurysms, whereas traumatic or mycotic essential and includes examination of both internal carotid
aneurysms are pseudoaneurysms. and vertebral arteries. Identification of aneurysms arising
The majority of aneurysms are located intracranially. from the PICA origins may be accomplished by contrast
Common sites for congenital (or “berry”) aneurysms are in injection of one vertebral artery, as long as reflux down the
the regions of the anterior communicating artery, middle contralateral vertebral artery demonstrates its PICA ori-
cerebral artery trifurcation, supraclinoid ICA, basilar gin. Common carotid compression during injection of the
artery, and at the origin of the posterior inferior cerebellar contralateral ICA may be necessary to opacify the anterior
artery (PICA). A small percentage may arise in locations communicating artery, the most common site for congen-
that can produce otologic symptoms, including lower cra- ital aneurysms and for aneurysms overlooked on initial
nial nerve palsies, otorrhagia, localized pain, and dizziness. angiography.
This is especially true of traumatic pseudoaneurysms, Formerly, the treatment of choice for congenital
which commonly occur at the skull base. intracranial aneurysms was craniotomy and surgical clip-
The prevalence of congenital aneurysms is estimated ping. This may be precluded in giant or heavily calcified
from autopsy studies at 2%;13 this estimate varies consider- aneurysms, those with a wide or absent neck, in those
ably among these studies. Many of these individuals are occurring in locations difficult to access surgically, or in
never symptomatic. Unfortunately, there is no effective, patients with severe underlying medical conditions.20–22
noninvasive screening measure for detecting aneurysms. As This is especially true of aneurysms located in the petrous
a result, the most common presentation is subarachnoid or cavernous segments of the ICA, sites more likely to
hemorrhage (SAH), which can produce catastrophic symp- produce otologic symptoms.4,23,24 Endovascular therapy
toms ranging from severe headache and nuchal rigidity for aneurysms was introduced by Serbinenko in 1974,25
to coma and death. Secondary complications include and the first large series were reported in the early
aneurysm rerupture, most likely to occur within the 30 days 1980s26,27 using latex balloons. Higashida and colleagues
following the initial hemorrhage,15,16 and vasospasm, which subsequently reported the endovascular treatment of 215
arises in 20% to 30% of aneurysmal SAH cases. Unruptured aneurysms using a detachable silicone balloon as the
aneurysms can present with local mass effect, headache or embolic agent,22 as well as treatment of cavernous carotid4
pain, and ischemic neurologic events resulting from throm- and vertebrobasilar28 aneurysms. Fibered pushable coils
boemboli arising within a partially thrombosed aneurysm. were used in the late 1980s and early 1990s,29 but
A distinction must be made between aneurysms arising in a were supplanted by the detachable platinum microcoil.
subarachnoid location and those arising extracranially (e.g., These were developed and introduced in 199230,31 and
petrous or cavernous portion of ICA), as the latter are at remain the current endovascular embolic agent of choice
considerably reduced risk of SAH. Associated conditions for aneurysm therapy with parent artery preservation.
include polycystic kidney disease, coarctation of the aorta, These detachable coils use a monopolar current to permit
fibromuscular hyperplasia, and AVMs.13 Congenital atraumatic coil detachment within the aneurysm. The goal
aneurysms are multiple in 20% of cases. of endovascular therapy is to exclude the aneurysm from
 Diagnostic and Therapeutic Angiography 439

the circulation while preserving flow in its parent artery32 aneurysms.43 This congenital condition can be seen at any
by placing the embolic device within the aneurysm. This age, but symptoms arise most commonly in the third
is precluded in fusiform or wide-necked aneurysms, decade.44 Intraparenchymal hemorrhage represents the most
which permit migration of the embolic device into the parent catastrophic form of presentation, may be accompanied by
arterial lumen. In such cases, permanent occlusion of the intraventricular or subarachnoid hemorrhage, and carries
parent artery, if tolerated by the patient as predicted by test a 10% mortality rate and 30% morbidity rate. The risk
occlusion, can provide effective aneurysm thrombosis.4,33,34 of hemorrhage is estimated at 1% to 3% per year, but each
The most widely used embolization device for treat- hemorrhage augments this risk.44,45 Other common
ment of fusiform aneurysms of the extracranial carotid presenting symptoms are seizures and headaches. AVMs
artery has been the detachable balloon.35 Carotid test located in the occipital lobe have a particular association
occlusion is followed by permanent occlusion using two with migraine headaches. Progressive neurologic deterio-
balloons in tandem. The balloon is loaded onto a micro- ration, seen in a minority of patients in the absence of
catheter and is directed from the femoral artery into the hemorrhage, is thought to result from either venous
affected vessel. It is then inflated and detached within the hypertension or “steal” of blood supply to the AVM from
artery. Halbach and coworkers have used these techniques normal brain tissue.
to treat six aneurysms of the petrous portion of the ICA23 Rarely, posterior fossa AVMs can present with neuroto-
(Fig. 24-1), a location in which direct operative exposure logic symptoms, including vertigo, diminished hearing,
is difficult. Presenting symptoms included hearing loss, trigeminal neuralgia, and hemifacial spasmic46 (Fig. 24-3).
vertigo, pulsatile tinnitus, trigeminal neuralgia, and head- Pulsatile tinnitus is distinctly unusual. These symptoms
ache. All aneurysms were cured, documented angiograph- are often related to the venous drainage pattern of the
ically. Only one minor complication (amaurosis fugax) AVM rather than to the location of the AVM nidus itself.
arose in this series. Despite the uncommon occurrence of As a result of long-standing high flow and elevated pres-
petrous aneurysms,36–39 they may present emergently with sure, AVM draining veins may become enlarged, tortuous,
otorrhagia spontaneously19 or after biopsy.40 Few petrous restricted, or thrombosed and may impinge on cranial
aneurysms have been reported in the literature, 27% of nerves as they exit the brainstem.
which present with hemorrhagic rupture, equally divided CT scanning will delineate the AVM as a serpiginous
between otorrhagia and epistaxis.23 Larger aneurysms tangle of contrast-enhancing tubular structures, represent-
arising from the vertebrobasilar system can also produce ing the AVM nidus. Routine spin-echo MRI sequences will
cranial nerve deficits secondary to mass effect and can be show a similar pattern, with signal dropout, or “flow void”
treated in similar fashion.28 within the AVM due to fast-flowing blood. Newer flow-
Trauma is the most frequent cause of aneurysms involv- sensitive MRI sequences will demonstrate the AVM as
ing the cervical and petrous segments of the ICA, external high signal, confirming the presence of flow within the
carotid artery, and extracranial vertebral artery41 (Fig. 24-2). lesion. Enlarged feeding arteries and draining veins enter
These are technically pseudoaneuryms and are treated by and exit this nidus. The relationship of the AVM to adja-
a different protocol. In the acute setting, the walls of these cent normal structures is more easily identified on MRI
pseudoaneurysms are formed of fresh thrombus of insuffi- because of improved differentiation of soft tissue struc-
cient strength to contain a balloon or other embolic tures and lack of artifacts in the posterior fossa normally
devices. Direct embolization of the pseudoaneurysm is seen on CT. Acute hemorrhage is better evaluated with
contraindicated, and parent vessel occlusion is required to CT, and subacute/chronic hemorrhage on MRI.
prevent life-threatening epistaxis or massive pseudoan- Angiography remains essential to confirm the diagnosis,
eurysm formation. Exception to this rule can be made search for risk factors for hemorrhage, and plan therapy.
when the aneurysm is sufficiently surrounded by bony Feeding arteries are often multiple and enlarged due to
structures (e.g., foramen transversarium of the cervical increased flow,47 and each must be demonstrated angio-
spine) to hold these embolic materials in position. In the graphically. Primary supply is derived from pial arteries
chronic setting, the fibrosis of the pseudoaneurysm wall (e.g., anterior, middle, or posterior cerebral artery
has taken place, which may allow direct embolization with branches), but dural branches may be recruited secondar-
parent artery preservation. ily and are thought to have the capacity to produce
The risks of endovascular aneurysm therapy have been headache by affecting the highly innervated dura. The
well-documented and include aneurysm rupture during angioarchitecture of the nidus is seen only on angiography,
embolization, thromboembolic phenomenon, stroke due and aneurysms arising from feeding arteries or within
to intolerance of major vessel occlusion, and transient cra- the nidus can be delineated. Irregular, restricted patterns
nial nerve deficits from mass effect. The risk of the pro- of venous drainage may represent increased risk of
posed embolization procedure must be tailored to the risk hemorrhage, by increasing pressure within the AVM
of the underlying condition to the patient. nidus.
The treatment of choice is complete surgical resection.
Arteriovenous Malformations This cannot always be achieved with acceptable morbidity
rates, and surgeons have devised pretherapeutic grading
An AVM is an abnormal network of arteriovenous connec- systems to evaluate such risks.48 Alternatively, stereotactic
tions without the normal intervening capillary bed. It can radiosurgery can provide effective therapy for smaller AVMs
be found throughout the body and is a common vascular with unacceptable surgical risk. In either case, embolization
malformation in the central nervous system.42 It is discov- undertaken as prior adjunctive therapy can improve the
ered with one-seventh the frequency of intracranial efficacy of the primary treatment.49 The surgeon is assisted
440 NEURORADIOLOGY

A B

Figure 24-1. Fusiform petrous internal carotid artery aneurysm in a 14-year-old girl
with a pulsatile retrotympanic mass and severe unilateral headaches. A, Transaxial
noncontrast CT scan shows expansion of the petrous portion of the right carotid
canal by a fusiform internal carotid aneurysm with erosion of the petrous bone
(arrow). B, Transaxial long TR (repetition time)/TE (echo time) MRI scan
(TR 2800/TE 80), rostral to (A), shows expansion of the petrous carotid canal by the
aneurysm with inhomogeneous signal (arrow). This mixed signal represents
turbulent flow within this portion of the aneurysm and possibly some surrounding
thrombus. Lateral (C), and anteroposterior (D) angiographic views, right internal
carotid artery injection confirm the presence of an irregular, partially thrombosed
fusiform aneurysm extending from the distal cervical segment to the proximal
cavernous segment of the internal carotid artery.
Continued

C
 Diagnostic and Therapeutic Angiography 441

Figure 24-1, cont’d. E, Plain skull film, lateral view, shows two oval
embolization balloons filled with radiopaque metrizamide. These balloons
have been placed into the IAC proximal and distal to the aneurysm to provide
occlusion of the artery and aneurysm.

by improved visibility and reduced operative blood loss (PVA particles),53 liquid adhesives54,55(N-butyl cyanoacry-
and operating room time,50 and the radiotherapist by late), ethanol, and acrylic spheres. In AVMs with large
diminished flow in a smaller target.51 Occasionally, fistulous connections, embolic platinum coils,56 silk suture
embolization alone is curative or provides palliation in segments, or even detachable balloons57 can be deposited
large AVMs that produce neurologic deficits related to at the fistula site.
cerebral steal phenomenon or effects of abnormal venous Complications of endovascular AVM therapy include
drainage.46 AVM rupture, perforation of a feeding artery,58 and stroke
The first AVM embolization was performed by direct from inadvertent embolization of normal arteries. Improved
catheterization of the common carotid artery and deposi- catheter technology and advances in angiographic imaging
tion of embolic spheres that flowed preferentially to the capabilities can reduce these risks, but do not substitute for
AVM.52 Presently, the embolization procedure uses a the skill and judgment of the experienced interventional
No. 2 French microcatheter, which can be superselectively neuroradiologist.
navigated into an AVM feeding artery. These micro-
catheters are of two general types: steerable or flow-
Dural Arteriovenous Fistulas
directed. A general anesthetic is used most often to
eliminate patient motion during the delicate embolization, A dural arteriovenous fistula (DAVF) is an acquired artery-
but in some circumstances the patient may be treated to-vein shunt in the dura mater without an intervening
under IV sedation alone, allowing the possibility of selec- malformation or nidus. This usually occurs along one of
tive tolerance testing using Amytal Sodium. Embolic the dural venous sinuses draining the brain. It differs from
materials in common use include particulate emboli an AVM in location (dural rather than intraparenchymal),
442 NEURORADIOLOGY

C
Figure 24-2. Traumatic internal carotid artery pseudoaneurysm in a 62-year-
old man presented emergently with active arterial bleeding from the mouth,
hoarseness, and tongue and palatal deviation. He had undergone attempted
transoral biopsy of a calcified retropharyngeal mass 2 days earlier and had a
remote childhood history of tonsillectomy without complication. Lateral (A),
and anteroposterior (B) angiographic views of a left internal carotid artery
injection, show a giant, bilobed pseudoaneurysm of the cervical segment of
the internal carotid artery projecting anteromedially toward the oropharynx.
The anteroposterior view was obtained during manual compression of the
contralateral (right) common carotid artery to assess patency of the anterior
communicating artery and cross-flow between the hemispheres, important
information in consideration of carotid occlusion as treatment for the false
aneurysm. C, Left internal carotid artery injection, high-magnification antero-
posterior angiographic view, shows the pseudoaneurysm originating from a D
tonsillar loop of the internal carotid artery (arrows). D, Plain skull film, lateral
view, after balloon occlusion of the left internal carotid artery, shows two
contrast-filled detachable silicone balloons (black arrows) placed proximal to
the heavily calcified pseudoaneurysm (white arrows).
 Diagnostic and Therapeutic Angiography 443

A B
Figure 24-3. Cerebellar AVM in a 58-year-old man presenting with right hemifacial spasm, pulsatile tinnitus, and intermittent dizziness. A, Coronal MRI scan
(TR 600/TE 20) shows an AVM nidus (arrow) in the right cerebellar hemisphere, along with feeding arteries and draining veins (foci of signal void). B, Transaxial
MRI scan (TR 2800/TE 80) shows vessels in the cerebellopontine angles (open black arrows) abutting the internal auditory canals (white arrows). The AVM
nidus is not present on this image.
Continued

cause (acquired rather than congenital),59 morphology direction. This drainage route may become inadequate if
(lack of AVM nidus), and arterial supply (dural rather than the arterialized inflow overwhelms the drainage capabili-
pial). The majority of these lesions arise spontaneously, ties of the sinus or if venous stenosis or restriction devel-
although there are associations with trauma60 and a history ops. In this instance, venous outflow may be reversed and
of venous sinus thrombosis, infection, and hormonal drain to the contralateral transverse sinus, or retrogade
changes.41 The specific genesis of the condition is unclear, into cortical/parenchymal veins. This type of aberrant
although it is speculated that small arteriovenous connec- venous drainage places the patient at significant risk for
tions arise in the wall of a thrombosed dural sinus, which cerebral hemorrhage or infarction, which may be the ini-
progress to form the DAVF. Alternatively, venous sinus tial symptom, especially if stenoses or varices develop in
thrombosis is a known sequela of DAVFs,61 raising the these cortical veins (Figs. 24-4 and 24-5). The character of
question of which pathologic state, thrombosis or arteri- the pulsatile tinnitus may change, becoming softer or even
ovenous shunting, precedes the other. Djindjian62 classi- disappearing. Such a phenomenon may herald the devel-
fied DAVFs according to pattern of venous drainage and opment of cortical venous drainage as the dominant sinus
presented the first large series of patients treated with undergoes thrombosis.41 As experience with this phenom-
embolization therapy. enon has accrued, indications for urgent therapy have been
DAVFs occur in certain locations with some frequency, identified,74,75 including hemorrhage, cortical venous
including the transverse sigmoid sinus, cavernous sinus drainage, visual loss, and raised intraocular pressure.
(also termed indirect carotid cavernous fistulas),63,64 tento- DAVFs involving the cavernous sinus variably produce
rium, ethmoidal groove,65 vein of Galen area,66,67 superior pulsatile tinnitus, proptosis, chemosis, orbital pain, oph-
sagittal sinus, marginal sinus (foramen magnum), and pet- thalmoplegia (cranial nerves III, IV, VI), decreased visual
rosal sinuses.68 Symptoms depend heavily on location and acuity (cranial nerve II), and raised intraocular pressure.
routes of venous drainage,69 with the exception of pulsatile Most patients present to an ophthalmologist, but if the
tinnitus,70–72 which is seen in the majority of DAVFs, espe- superior ophthalmic vein is occluded, the patient may
cially if the venous drainage from the fistula involves a experience only pulsatile tinnitus without ophthalmologic
petrosal sinus. A bruit is classically auscultated by the physi- symptoms. DAVFs involving the transverse, sigmoid, and
cian and characterized as loud, harsh, and of variable high petrosal sinuses can present more insidiously. Patients
pitch. A small subpopulation of infants73 and children gen- with these types of DAVFs typically experience pulsatile
erally exhibit more arteriovenous shunting than their adult tinnitus without a vascular tympanic mass on otoscopy76,77
counterparts and may also experience high-output conges- and sometimes headache, otalgia, or lower cranial nerve
tive heart failure, cortical atrophy, and a poorer prognosis.41 deficits (Fig. 24-6), but lack of more specific symp-
The major characteristic of a DAVF that directs its toms often hinders the diagnosis. In Halbach’s series of
therapy is the pattern of venous drainage.62 This also has 28 patients with transverse or sigmoid sinus DAVFs, 18
a direct bearing on symptomatology. A DAVF may drain presented with pulsatile tinnitus and another 8 with
exclusively into the affected venous sinus in an antegrade intracerebral, subarachnoid, or subdural hemorrhage.78
444 NEURORADIOLOGY

C D

Figure 24-3, cont’d. Early arterial (C) and venous (D) angiographic phases of
a left vertebral artery injection, anteroposterior views, show the right
cerebellar hemisphere AVM supplied primarily by the enlarged right AICA
(C, open arrow). Several large serpiginous draining veins traverse the
cerebellum (D). E, Arterial angiographic phase, left vertebral artery injection,
Townes view, after embolization of the AVM with polyvinyl alcohol particles.
Note absent opacification of the previously seen AICA. Residual AVM is
supplied by the right superior cerebellar artery (SCA). The patient’s
hemifacial spasm, pulsatile tinnitus, and dizziness abated completely.

DAVFs involving the ethmoidal groove, tentorium, and vein an entirely normal magnetic resonance appearance.79
of Galen often present catastrophically with hemorrhage Patients who have developed veno-occlusive changes
because development of cortical venous drainage fre- show dilated vessels representing cortical venous drainage,
quently precedes development of other symptoms. without a focal parenchymal AVM nidus, differentiating
Cross-sectional imaging can assist in the diagnosis DAVFs from AVMs. Major sinus thrombosis may also
of a DAVF, but CT and MRI should not be used as a screen- be evident. Complications of veno-occlusive disease,
ing measure because of their relative lack of sensitivity. such as hemorrhage or infarction, are well demonstrated
DAVFs without veno-occlusive disease may demonstrate on MRI.
 Diagnostic and Therapeutic Angiography 445

C D
Figure 24-4. Complex transverse sinus DAVF, treated with particulate embolization and surgery, in a 68-year-old woman presenting with cerebellar hemorrhage
with several-month history of dizziness and nausea with acute worsening, new left facial numbness and mild weakness, and gait instability with falling to the
left. A, Gadolinium–DTPA-enhanced transaxial MRI scan (TR 600/TE 20), performed after symptom onset but before acute worsening, shows left cerebellar
hemisphere swelling and enhancement, with several foci of signal void representing abnormal vessels. No discreet arteriovenous malformation nidus is seen.
B, Transaxial MRI scan (TR 2800/TE 80), performed in the same plane as (A) several days after abrupt symptom worsening, shows a new left cerebellar
hemorrhage. A central dark area (deoxyhemoglobin) is surrounded by high-signal edema. C, Left internal carotid artery injection, anteroposterior view, venous
angiographic phase, shows absent normal venous drainage to the left transverse sinus with opacification of the right transverse sinus (arrows) only. Arterial (D)
and magnified venous (E) angiographic phases of a left external carotid injection, lateral views, show a transverse sinus DAVF supplied by several transmastoid
perforating branches (D, small arrows) of the occipital artery and by posterior division of the middle meningeal artery (D, curved arrow). These feeding arteries
were catheterized superselectively and embolized.
Continued
446 NEURORADIOLOGY

E F

G H

Figure 24-4, cont’d. The isolated segment of transverse sinus (open arrows)
drains only to multiple cerebellar veins (E) and demonstrates no normal
antegrade venous drainage. F, Left vertebral artery injection, lateral
angiographic view, also shows the DAVF (open arrows) supplied by posterior
meningeal artery (curved arrow). G, Selective left posterior meningeal artery
(black curved arrow) injection, lateral angiographic view, opacifies the
affected isolated left transverse sinus (large open arrows). Note contrast
reflux into left vertebral artery (curved open arrows). The microcatheter was
navigated to a more distal position in the posterior meningeal artery prior to
embolization to avoid reflux of embolic material into the vertebral artery. Left
vertebral artery (H) and left external carotid artery (I) injections, lateral
angiographic views, after embolization of occipital, middle meningeal, and
posterior meningeal artery supply, show no residual DAVF. The patient
subsequently underwent craniotomy and surgical occlusion of the affected
transverse sinus to remove the possibility of future recanalization of the
DAVF. She has recovered fully from her hemorrhage.

I
 Diagnostic and Therapeutic Angiography 447

A B
Figure 24-5. Foramen magnum DAVF, treated by liquid adhesive embolization in a 30-year-old man presenting with acute onset of severe headache and nausea
followed by coma. A, Noncontrast transaxial CT scan shows a large acute left cerebellar hematoma with midline shift and rupture into the displaced fourth
ventricle (arrow). B, Left vertebral artery injection, lateral angiographic view, shows faint opacification of a pseudoaneurysm (curved open arrow) supplied by a
muscular branch of the vertebral artery (black arrow).
Continued

Subselective angiography is necessary for diagnosis and a period not to exceed 30 seconds, up to three times per
should be performed even when CT or MRI is normal hour. This results in static blood flow at the fistula site due
when a DAVF is suspected clinically. This will allow con- to the combination of reduced inflow and outflow. This
firmation of the exact location of the DAVF, visualization maneuver is contraindicated with atherosclerotic carotid
of all feeding arteries, assessment of the venous drainage bifurcation disease, cortical venous drainage, high-flow fis-
including sinus occlusion and cortical venous outflow, and tulas, DAVF-associated visual loss or elevated intraocular
examination of patency of important dural-pial artery pressure, or in children.
anastomoses. Because dural arteries provide arterial input Just as DAVFs may regress spontaneously, progression
and can originate from many sources, the angiogram can produce veno-occlusive changes and cortical venous
should specifically include injection of the internal carotid drainage resulting in cerebral hemorrhage or infarction,
(meningohypophyseal and inferolateral trunks), external underscoring the dynamic nature of this process. Endo-
carotid, vertebral (posterior meningeal and muscular vascular therapy has become the treatment of choice in
branches), ascending pharyngeal, occipital, and middle DAVFs to prevent such sequelae. Transarterial approaches
meningeal arteries.41 Supply may be bilateral: depending allow navigation of microcatheters through feeding arter-
on expected shunt location, the appropriate contralateral ies as close to the fistula site as possible. The goal of
arteries must be examined (i.e., both vertebral arteries in a embolization is to obliterate the fistula site, since proximal
torcular DAVF; both middle meningeal arteries in a supe- feeding artery occlusion will not cause thrombosis of the
rior sagittal sinus DAVF.) DAVF, but will encourage collateral supply to the fistula
In considering therapeutic options, it is useful to and will preclude future use of the embolized artery as a
remember that DAVFs are dynamic lesions. A DAVF may potential route for embolization. Embolic material that
be considered a benign disease in the absence of veno- traverses the shunt and produces only venous occlusion
occlusive disease, visual loss, or elevated intraocular pres- causes redirection of venous outflow and possible aggrava-
sure. Under such conditions, conservative therapy is tion of cortical venous flow without reducing arterialized
indicated. A small percentage of DAVFs undergo sponta- inflow. Liquid adhesive agents (N-butyl cyanoacrylate) are
neous regression without therapy or following diagnostic ideal when there is minimal risk of embolizing normal
angiography. dural arteries because they allow less chance of recanaliza-
Assisted thrombosis of such benign fistulas can also be tion. However, particulate agents (PVA particles) are tech-
achieved using carotid–jugular compression therapy, espe- nically easier to use and may be selected when increased
cially in cavernous sinus DAVFs.80 The patient uses the risk of normal artery embolization is present, despite the
contralateral fingertips to manually compress the common greater possibility of recanalization. Preembolization
carotid artery and internal jugular vein simultaneously for provocative testing with 2% cardiac lidocaine may help
448 NEURORADIOLOGY

C D

Figure 24-5, cont’d. C, Left external carotid injection, lateral angiographic

view, shows a DAVF at the foramen magnum supplied by the ascending
pharyngeal artery (closed arrows). The pseudoaneurysm opacifies (curved
open arrow) and is the likely source of the hemorrhage. D, Superselective left
ascending pharyngeal artery (straight black arrows) injection, lateral
angiographic view, shows the fistula site at the foramen magnum supplied by
branches of the neuromeningeal division of the ascending pharyngeal artery.
Restricted early venous drainage to the cerebellum is seen (straight open
arrowhead), along with the pseudoaneurysm (curved open arrow). Note
opacification of the odontoid artery (curved black arrow) which can
anastomose with the vertebral artery. To avoid reflux of embolic material into
this artery and possible brainstem or posterior fossa stroke, the
microcatheter in the ascending pharyngeal artery was advanced to the fistula
site, and liquid adhesive embolization was performed. E, Postembolization
left external carotid injection, lateral angiographic projection, shows no
residual DAVF or pseudoaneurysm.

determine the embolization risk in a particular artery and pressure and aggravate symptoms. Cavernous sinus
assist the choice of embolic agent. Often, a series of staged DAVFs lend themselves particularly well to this tech-
embolizations will permit access to certain feeding arteries nique.63 From a transfemoral venipuncture, a microcatheter
that were initially too small to permit catheter passage for system is navigated through the internal jugular vein and
embolization, by allowing them to enlarge. The severity of inferior petrosal sinus (IPS) to the cavernous sinus.
veno-occlusive changes will direct whether conservative or Embolic materials in frequent use include platinum coils56
aggressive management is pursued. and silk suture. Frequently, the IPS will permit catheter
Despite the best efforts at transarterial embolization, passage even if it fails to opacify on preembolization
some DAVFs may remain patent. Others may have no angiography. Other transvenous routes to the cavernous
adequate arterial access because of prior embolization or sinus include external jugular to angular to superior
surgical ligation of feeding arteries. Transarterial ophthalmic vein, and from the contralateral cavernous
embolization may be hazardous in still others because of sinus across the sellar veins. Transverse sigmoid sinus
crucial territory supply from adjacent arteries. In these DAVFs have also been treated successfully using the trans-
instances, transvenous catheterization and embolization venous approach.78,81 Embolization of the diseased sinus
may provide safe occlusion at the fistula site. Embolization itself is achieved by placement of a series of platinum or
of veins away from the fistula site will only raise venous steel coils to occlude the fistula. A normal sinus with
 Diagnostic and Therapeutic Angiography 449

Figure 24-6. Inferior petrosal sinus DAVF, treated by balloon and coil
embolization in a 47-year-old man with a 5-year history of tongue weakness
and hemiatrophy and pulsatile tinnitus. He subsequently developed
hoarseness and palatal deviation. A, Contrast-enhanced transaxial CT scan
shows right tongue hemiatrophy and low density fatty replacement (arrows)
with deviation of the oral cavity to the affected side. B, Right common
carotid artery injection, lateral angiographic view, shows an inferior petrosal
sinus DAVF supplied by a markedly enlarged ascending pharyngeal artery
with drainage through a varix to the internal jugular vein (open curved
arrow). The fistula site is identified (long straight arrow). C, Selective right
ascending pharyngeal artery injection, lateral magnified angiographic view,
shows the fistula more clearly. A detachable silicone balloon was
flow-directed through the ascending pharyngeal artery and was detached at
the fistula site.
Continued

C
450 NEURORADIOLOGY

F
Figure 24-6, cont’d. D, Postembolization right common carotid artery injection, lateral angiographic view, shows the detachable embolization balloon (outlined
by arrows) and no residual fistula supply from the ascending pharyngeal artery. E, Right vertebral artery injection, lateral angiographic view, shows residual sup-
ply to the fistula from a cervical muscular branch (long straight arrows) with faint opacification of the internal jugular vein (open curved arrow). A microcatheter
was navigated through this muscular branch to the varix at the fistula site, and platinum coil embolization of the fistula site and feeding muscular branch was
performed. F, Postembolization right vertebral artery injection, lateral angiographic view, shows multiple platinum coils in the varix at the fistula site (large
arrow) and in the feeding muscular branch (small arrow), without residual arteriovenous shunting.
 Diagnostic and Therapeutic Angiography 451

antegrade flow, without cortical venous reflux, should not decompress the cavernous sinus. Trauma is by far the most
be considered for this technique, as this type of DAVF is common cause. Because the cavernous segment of the ICA
low-risk and other sinus drainage routes may be inade- is fixed by dura at the skull base, it is susceptible to injury
quate for normal venous drainage, if the affected sinus is from skull base fracture.84 Nontraumatic CCFs result from
closed. ruptured cavernous carotid aneurysms or may occur spon-
Surgical obliteration of the DAVF may be necessary taneously in association with fibromuscular dysplasia,
when neither transarterial nor transvenous embolization Ehlers-Danlos syndrome,85 or neurofibromatosis.41
can be performed. This is particularly true in ethmoidal As with DAVFs, symptoms depend on routes of venous
DAVFs65 occurring along the floor of the anterior cranial drainage, but pulsatile tinnitus is present in the overwhelm-
fossa, which present with frontal lobe hemorrhage or ing majority of patients. One can often auscultate a bruit
subarachnoid hemorrhage. Other DAVFs are termed over the temporal bone, mastoid region, or eye. Retrograde
“complex”82,83 because they require a combination of drainage through an enlarged superior ophthalmic vein may
endovascular and surgical techniques for cure. This com- produce proptosis, chemosis, orbital pain, ophthalmoplegia,
bined approach is reserved for DAVFs likely to produce trigeminal pain or numbness, visual loss, and raised intraoc-
hemorrhage or neurologic deficits from veno-occlusive ular pressure to variable degrees depending on patency of
disease and has been effective in transverse/sigmoid and other venous outflow pathways. Retrograde drainage
deep venous DAVFs. through the sphenoparietal sinus to cortical veins places the
After embolization, certain clinical sequelae are patient at risk for intracerebral or subarachnoid hemorrhage
expected. They include transient headache, disappearance or infarction. The contralateral eye may become involved
of pulsatile tinnitus, and transient ophthalmoplegia in cav- if venous drainage crosses the sella to pressurize the con-
ernous sinus DAVFs. True endovascular complications are tralateral cavernous sinus. Drainage along the petrous bone
uncommon and include stroke or cranial nerve deficits (inferior and superior petrosal sinuses) most often produces
from inadvertent embolization of crucial normal arteries pulsatile tinnitus.
or occlusion of normal venous drainage patterns, hemor- The diagnosis of CCF is made clinically and confirmed
rhage from occlusion of normal veins or perforation of angiographically, but cross-sectional imaging may assist the
subarachnoid veins or dural sinuses, and visual loss from evaluation of these patients. CT is best suited to demon-
iatrogenic restriction of the superior ophthalmic vein strate skull base fractures, especially using bone reconstruc-
without closure of the DAVF. Due to the great number tion algorithms. CT or MRI may reveal dilatation of the
of skull base collateral pathways, complexity of vascular cavernous sinus, proptosis, enlargement of the superior
anatomy, and variety of technical materials available, such ophthalmic vein, cortical venous drainage, or infarction or
surgical complications can be limited only by training and hemorrhage in the brain.
experience. Angiography is necessary to delineate the CCF and its
venous drainage pathways. The angiographer must be
Extracranial Arteriovenous Fistulas vigilant in identifying trauma-related injuries to other
arteries, such as dissection, pseudoaneurysm formation, or
Acquired arteriovenous fistulas involving direct major a second fistula. Depending on the clinical scenario, both
artery-to-vein shunts may also occur in expected locations in internal and external carotid arteries should be studied
and around the skull base, not involving dura. Characteristic angiographically. Specific angiographic maneuvers use
types include direct carotid–cavernous, vertebral, and scalp manual compression of the ipsilateral common carotid
arteriovenous fistulas. Most of these fistulas result from artery while injecting the vertebral artery (Huber’s maneu-
direct traumatic injury to the affected artery and subse- ver)86 or ipsilateral ICA (Mehringer’s maneuver)87 to aid in
quent fistula formation with an adjacent vein. Although identifying the exact site of the fistula in the cavernous
symptoms differ with location, the classical presentation carotid. High flow necessitates a fast filming rate.
includes pulsatile tinnitus and an objective bruit. Surgical therapies have been supplanted by transarterial
balloon embolization, the treatment of choice.88–90 From a
Direct Carotid–Cavernous Fistulas transfemoral approach, a detachable balloon is directed
Direct carotid–cavernous fistulas (CCFs) represent through the ICA to the fistula site. Fistula flow allows
acquired communications between the cavernous portion entry of the balloon through the defect in the ICA into the
of the ICA and its surrounding cavernous venous sinus. cavernous sinus, where it is inflated and detached to close
A tear in the ICA causes arterialized inflow into the cav- the CCF and preserve patency in the ICA91 (Fig. 24-7).
ernous sinus, which must direct this high pressure to other This procedure has achieved closure of the CCF in almost
draining veins. This entity differs from the cavernous sinus all cases, with a residual ICA patency rate of 90%.84 A
dural AVF (indirect carotid–cavernous fistula) in that the pseudoaneurysm may develop at the site of injury after
latter is composed of numerous small shunts in the wall of embolization, which rarely requires additional therapy due
the cavernous sinus from small dural internal or external to production of cranial nerve palsies (III, IV, V1, or VI).
carotid branches, although similar symptoms may result. Embolic or ischemic complications are unusual, but can be
Common venous drainage pathways from the cavernous caused by premature detachment and distal migration of a
sinus include inferior and superior petrosal sinuses, supe- deflated balloon or intolerance of carotid occlusion. Care
rior and inferior ophthalmic veins, pterygoid venous must be taken to avoid occlusion of the ICA proximal to
plexus, sphenoparietal sinus (to cerebral veins), and con- the fistula site, as this will increase retrograde arterial steal
tralateral cavernous sinus across the sella. Several of these to the fistula from the supraclinoid ICA and preclude
venous routes must drain in a retrograde direction to further endovascular therapy.
452 NEURORADIOLOGY

A B

C D
Figure 24-7. Direct CCF in a 30-year-old man with pulsatile tinnitus and mild unilateral proptosis and chemosis. A, Left internal carotid artery (solid curved
arrows) injection, lateral angiographic view, shows a direct CCF with arteriovenous shunting across the fistula site (long arrow) and early opacification of the
cavernous sinus (large open arrowhead). Retrograde venous drainage opacifies the enlarged superior ophthalmic vein (open curved arrows) and cortical veins
(small solid arrows), placing this patient at risk for visual decline and cerebral hemorrhage. B, Left IAC injection, lateral angiographic view, with ipsilateral
common carotid artery manual compression proximal to the catheter tip (Mehringer’s maneuver87) defines the fistula site (long arrow) more clearly. Early filling
of the cavernous sinus (open arrow) and its venous drainage pathways is seen. C, Plain skull film, lateral view, during balloon embolization. The detachable
balloon is inflated with contrast, and is not yet detached from its catheter. D, Postembolization left ICA injection, lateral angiographic view, shows no residual
fistula. The balloon has been detached within the cavernous sinus allowing patency of the ICA. A small residual pseudoaneurysm (arrow) demarcates the
previous fistula site.

Vertebral Fistulas
to treatment, as retrograde arterial steal distally in the
Vertebral fistulas represent acquired abnormal arteriove- affected vertebral artery may not allow its opacification
nous shunting from the extracranial vertebral artery to from ipsilateral proximal vertebral artery injection.
adjacent veins. Penetrating trauma, especially knife and As with CCFs, transarterial balloon embolization has
gunshot wounds, is the most common cause by far. become the primary therapy.91–94 One or more detachable
Clinical symptoms and signs include pulsatile tinnitus balloons can be navigated through the vertebral artery tear
(especially with more distal lesions), expanding hematoma, into the receiving vein and inflated to close the fistula
neck pain, progressive vertebrobasilar ischemia from arte- (Fig. 24-8). The angiographer must avoid producing a
rial steal, and various cerebral and spinal cord neurologic normal perfusion pressure breakthrough (NPPB) phe-
deficits associated with venous hypertension, mechanical nomenon as a result of the treatment. Abrupt restoration
compression, or subarachnoid hemorrhage. of cerebral blood flow immediately after closure of a high-
Angiography will define the exact site of the fistula and flow vertebral fistula of long duration with arterial steal
route of venous drainage. Arterial steal can be confirmed, if can overwhelm the ability of the cerebral vasculature to
present, by injection of the contralateral vertebral artery compensate, as it may have lost its autoregulatory capacity.
and observation for retrograde opacification of the affected This could theoretically result in intracerebral hemor-
vertebral artery from the vertebrobasilar junction to the fis- rhage or malignant cerebral edema.95 Gradual occlusion of
tula site. Complete transection of the vertebral artery with the fistula using staged procedures will limit such cata-
retraction of the severed stumps is difficult to assess prior strophic complications.
 Diagnostic and Therapeutic Angiography 453

Scalp Arteriovenous Fistulas

Scalp AVFs are often associated with a large varix (cirsoid
aneurysm). Most often traumatic, abnormal connections
from superficial temporal, occipital, and posterior auricular
branches of the external carotid artery to dilated, irregular
scalp veins may produce loud pulsatile tinnitus, cosmetic
deformity, headache, or scalp necrosis.96 Surgical methods
of treatment required extensive excision, risking significant
operative blood loss and recurrence of the fistula from col-
lateral supply, which limited the effectiveness of this form of
therapy. Endovascular approaches have been used as surgi-
cal adjuncts and alone as definitive therapy. After superse-
lective bilateral arteriography has delineated the fistula site
and pattern of venous drainage, transarterial, transvenous,
or direct varix puncture with embolization of the fistula site
can be curative. Selection of embolic material depends on
proximity of the catheter to the exact fistula site, caliber of
vessels, rate of flow, and location. Liquid adhesive agents are
A B the most permanent, but care must be taken to avoid scalp
necrosis from occlusion of normal arteries. Platinum and
steel coils, PVA particles, silk suture, absolute alcohol, and
detachable balloons have also been used.

Atherosclerosis
Atherosclerosis is a major cause of morbidity and death in
developed countries. It is the major cause of arterial occlusive
disease (thrombosis and embolism), which is responsible for
80% of cerebral strokes.97 It frequently involves the common
carotid artery bifurcation, ICA origin and siphon, vertebral
artery origin, and basilar trunk. Formation of atheromatous
plaque is accompanied by gradual stenosis, thrombotic
occlusion, calcification, ulceration, and embolism. Tortuosity
and dilatation can be associated findings as well, common in
the basilar artery (dolichoectasia), which can produce
trigeminal neuralgia or hemifacial spasm.98 Although
patients present classically with episodes of cerebral ischemia
or infarction, many patients demonstrate an audible bruit
over the affected artery. Rarely, this is perceived by the
patient as pulsatile tinnitus.
Carotid duplex examination, which includes ultrasound
visualization of the carotid bifurcation and Doppler meas-
urement of blood velocity, is an effective noninvasive
screening tool. Although advances in magnetic resonance
angiography (MRA) and computerized tomographic angiog-
C raphy (CTA) have improved spatial resolution and have
allowed better estimation of the degree of stenosis caused by
Figure 24-8. Vertebral fistula in a 23-year-old man with pulsatile tinnitus
after a shotgun wound to the left neck. A, Left vertebral artery injection, a given lesion, conventional angiography remains the
anteroposterior angiographic view, shows a high-flow vertebral fistula standard for evaluation of atherosclerotic carotid and verte-
with multiple draining veins. Antegrade flow in the left vertebral artery bral arterial occlusive disease. Antiplatelet medications and
(curved open arrows) is seen proximal to the fistula site. A shrapnel endarterectomy remain treatment staples, although transar-
fragment (black arrow) is shown for orientation. B, Right vertebral artery
injection, anteroposterior angiographic view, shows antegrade flow in the
terial balloon angioplasty99–102 and carotid stenting103–106
right vertebral artery (black curved arrow) with angiographic steal seen as have emerged as alternative treatments for clinically and
retrograde flow in the distal left vertebral artery (open curved arrow) to hemodynamically significant atherosclerotic lesions. These
the fistula site (large black arrow). The shrapnel fragment is again shown endovascular treatments are especially helpful in more distal
(smallblack arrow). C, Postembolization left vertebral artery injection, surgically inaccessible locations, in patients who have under-
high-magnification anteroposterior angiographic view, shows antegrade flow
in the artery (long arrow) without residual arteriovenous shunting. A single gone prior neck irradiation, and in recurrent stenoses.
balloon was detached across the fistula site, now demarcated by a small
residual pseudoaneurysm (large arrow) adjacent to the shrapnel fragment Fibromuscular Dysplasia
(small arrow).
Fibromuscular dysplasia (FMD), also called fibromuscular
hyperplasia or fibromuscular disease, is an idiopathic
454 NEURORADIOLOGY

stenotic condition of large arteries97 most often seen in encourage further investigation and may provide a prom-
middle-aged women. Stenosis develops from overgrowth ising primary therapy.
of muscular and fibrous tissue in the arterial wall.
Originally identified in renal arteries, the cervical portions
of the internal carotid and vertebral arteries are common Normal Variants
disease sites. Symptomatic FMD most often presents Aberrant Petrous Internal Carotid Artery
as cerebrovascular insufficiency, but pulsatile tinnitus has
been reported.107,108 Patients with FMD are prone to arte- An aberrant petrous ICA is a rare anatomic variant
rial dissection, AVFs,109 and aneurysm formation. Indeed, wherein the petrous portion of the ICA can take an anom-
we have encountered a middle-aged woman, previously alous course through the middle ear cavity and may pres-
treated with carotid occlusion for a cavernous segment ent with pulsatile tinnitus or conductive hearing loss as a
ICA aneurysm, who later presented with pulsatile tinnitus retrotympanic mass, simulating a glomus tympanicum
attributed to FMD in the contralateral cervical ICA tumor.111–114 During embryogenesis, the dorsal and ventral
(Fig. 24-9). aortas are connected by a series of four arches. Further
Angiography is necessary for the diagnosis and classi- modification occurs both by anastomosis and by arterial
cally demonstrates a long-segment “string-of-beads” regression. Abnormal development of the third aortic arch
appearance, with variable stenoses. Endarterectomy or can result in agenesis of the cervical segment of the ICA.
surgical revascularization has been the mainstay of therapy Collateral supply is derived from a primitive ascending
in symptomatic FMD, but successful reports of balloon pharyngeal artery that courses through the tympanic cav-
angioplasty100,110 and stent placement in selected cases ity. This artery has been labeled the “aberrant” ICA.113,115
Prior to the advent of CT, angiography was necessary
to avoid the potential catastrophic consequences of per-
forming surgery or biopsy of the suspected lesion, which
could result in stroke or exsanguinating hemorrhage.
Angiographically, the aberrant ICA ascends in a more lat-
eral position than usual (Fig. 24-10) and takes a sharp turn
anteriorly within the middle ear. Currently, this diagnosis
is made on transaxial and coronal CT scans, which show
absence of the normal vertical segment of the carotid
canal, lack of a bony covering at the lateral aspect of the
horizontal petrous carotid canal, and enlargement and
ectasia of this canal. A rounded soft tissue mass in the
medial aspect of the middle ear is continuous with the
petrous carotid canal.112 MRI appears less sensitive than
CT in the detection of this condition,76,77 although MRA
may be diagnostic.
Persistent Stapedial Artery
A persistent stapedial artery is a rare variant in which the
usual embryonic regression of the proximal stapedial
artery fails to occur. Initially a continuation of the hyoid
branch of the ICA, the stapedial artery becomes annexed
by the developing external carotid system and regresses
proximally at the level of the stapes. The distal remnant of
the stapedial artery corresponds to the middle meningeal
artery. If this regression fails to occur, the stapedial artery
remains as a branch of the petrous segment of the ICA
coursing through the stapes and turning anterosuperiorly
to become the middle meningeal artery.113,114
Aberrant Jugular Bulb
A high, or aberrant, jugular bulb represents exposure of
the bulb to the middle ear cavity due to a congenital or
acquired dehiscence of the normal bony jugular plate
(Fig. 24-11). This condition can variably produce conduc-
tive hearing loss and presents as a bluish middle ear
mass.116 CT has supplanted angiography as the method of
diagnosis, exhibiting a defect in the anterolateral aspect of
Figure 24-9. FMD in a 58-year-old woman with pulsatile tinnitus. Left the jugular foramen allowing protrusion of the jugular
common carotid artery injection, anteroposterior angiographic view, shows bulb into the middle ear cavity.76,117 Smooth, regular ero-
alternating areas of dilitation and stenosis (“string-of-beads” appearance) in
the cervical segment of the internal carotid artery (arrows) indicative of FMD.
sion of the jugular foramen permits differentiation of this
No other cause for pulsatile tinnitus was found. condition from glomus tumor.112 As with an aberrant
 Diagnostic and Therapeutic Angiography 455

Figure 24-11. Aberrant jugular bulb. Left internal jugular venogram,

anteroposterior projection, shows absence of a portion of the bony jugular
plate allowing the jugular bulb to protrude into the middle ear cavity
superiorly (arrows). (Case courtesy of William P. Dillon, M.D.)

A petrous ICA, radiographic evaluation prior to surgery will

avoid the potential for massive bleeding.76,112,116 Pulsatile
tinnitus secondary to enlarged jugular bulb (“megabulb”)
without bony or other vascular abnormalities has also been
described.118
Mechanical Compression of the Jugular Vein
Mechanical compression of the jugular vein has been seen
angiographically with ipsilateral head turning, thought to
result from compression of the adjacent sternocleido-
mastoid,116 or with contralateral head turning, thought to
result from compression of a transverse process. Although
this phenomenon has been seen in patients presenting
with subjective pulsatile tinnitus, it has also been seen in
normal individuals, and the clinical consequences of this
observed phenomenon are unclear.

Tumors
Jugulotympanic Glomus Tumors
Glomus tumors (paragangliomas, chemodectomas) are
highly vascular, slow-growing, generally benign tumors
arising from paraganglionic glomic tissue. This tissue is
composed of cells that have the capacity to detect chemi-
cal changes, such as alterations in oxygen and carbon
dioxide concentration and pH changes, in arterial blood.
These cells are derivatives of nonchromaffin paraganglions
of neuroectodermal origin and have secretory capacity as
well (catecholamines, serotonin).
Glomus tumors can be found at any adult age and have
a female predilection.119–122 The most common sites are
the temporal bone (jugular and tympanic), carotid body,
and vagus nerve.123,124 They are also seen with increased
B frequency at higher altitudes.
Figure 24-10. Aberrant pertous internal carotid artery. Longstanding pulsatile Five percent of glomus tumors can secrete vasoactive
tinnitus. A, Transaxial CT scan shows a rounded soft tissue mass representing hormones. Patients with episodic hypertension, diaphore-
the internal carotid artery in the medial aspect of the left middle ear cavity sis, headache, flushing, anxiety, or palpitations may harbor
(arrows) continuous with its slender petrous segment anteromedially. B, Left glomus tumors that produce catecholamines or serotonin.
common carotid artery injection, anteroposterior angiographic view, shows
the unusual lateral course (arrow) and sharp angulation of the aberrant ICA Hypertensive crises may be sporadic or precipitated by
within the middle ear cavity. (Case courtesy of William P. Dillon, M.D.) massage, surgical manipulation, or angiography.125 Analysis
456 NEURORADIOLOGY

of these functional tumors may yield elevated serum, another.129 When evaluating a glomus tumor, angiography
urine, or tumor values of catecholamines, norepinephrine, must include injection of ascending pharyngeal, occipital,
or homovanillic acid. Patients considered for angiography posterior auricular, middle meningeal, and internal maxil-
or embolization should undergo screening for urine lary branches of the external carotid artery. Internal carotid
vanillylmandelic acid (VMA) or 5-hydroxyindoleacetic acid and vertebral arteries also give rise to dural branches that
(5-HIAA), breakdown products of the vasoactive substances. can supply the tumor. Tumors invading intradurally may
Prophylactic alpha blockade (phentolamine, phenoxy- parasitize pial supply including anterior and posterior
benzamine) should precede angiography in patients with inferior cerebellar arteries.41 Occasionally, angiography
evidence of elevated catecholamines. Antihypertensive will reveal an unsuspected additional glomus tumor. The
agents (nitroprusside,126 labetalol) should be readily avail- ascending pharyngeal artery (particularly its inferior
able during the procedure. Additionally, posttherapy tympanic branch132) nearly always supplies jugulotympanic
hypotension can develop due to baseline circulatory glomus tumors, as it gives off branches that supply normal
volume constriction coupled with a precipitous drop in structures in these locations. As such, it is postulated that
circulating catecholamines. bilateral ascending pharyngeal artery injections can
Presenting clinical symptoms depend on tumor loca- effectively diagnose all jugulotympanic glomus tumors.41
tion.127 Glomus jugulare tumors present with the jugular The stylomastoid artery, which normally supplies the
foramen syndrome consisting of palsies of cranial nerves descending portion of the facial nerve, can arise from
IX–XI (difficulty speaking or swallowing, hoarseness, the occipital, posterior meningeal, or posterior division of
trapezius and sternocleidomastoid weakness). Retro- the middle meningeal arteries and can supply glomus tumors
auricular pain may be noted, but subtle pulsatile tinnitus extending posterolaterally. Tumors extending superiorly
may be overlooked initially. With tumor growth, tongue will involve the middle meningeal artery.
deviation (involvement of cranial nerve XII), jugular bulb Embolization is performed as a preoperative adjunct to
occlusion by the tumor mass, or vertigo and hearing loss limit surgical blood loss (Figs. 24-12 and 24-13). Its effi-
may ensue. Very large tumors may produce cerebellar cacy has been demonstrated by many authors.41,133,134
compression or raised intracranial pressure. Glomus tym- Supraselective catheterization of a feeding artery is fol-
panicum tumors classically present with unilateral pulsatile lowed by high-resolution arteriography. Functional testing
tinnitus, which may be accompanied by conductive hear- of cranial nerves with 2% cardiac lidocaine (10–20 mg)
ing loss or peripheral facial nerve palsy (occurring acutely may be helpful. PVA particles 300 μm or larger can satu-
in 30% of cases128). Situated on the cochlear promontory, rate the tumor bed and generally avoid cranial nerve
the tumor may appear as a purple-red mass behind the deficits. Vigilance will allow detection of anastomoses with
tympanic membrane on otoscopy and produce otorrhagia. intracranial arteries, such as connections between the
Medial invasion to the inner ear can produce vertigo and occipital artery or odontoid branch of ascending pharyn-
sensorineural deafness. Posterior invasion can produce geal artery with the vertebral artery. Particular care is
lower cranial nerve deficits, as with a primary glomus necessary to preserve the neuromeningeal branch of the
jugulare tumor. Finally, these tumors may be multifocal or ascending pharyngeal artery (cranial nerves IX–XI) and
multicompartmental and can be seen clinically, pathologi- the stylomastoid artery (facial nerve). Embolization of pial
cally, and angiographically.129 supply is difficult to achieve safely.41
Initial diagnostic radiologic evaluation should consist of Among the limited complications arising from the large
CT or MRI. The benefit of CT lies in its ability to evalu- number of embolization procedures performed to treat
ate bone erosion with optimal resolution.76,77,130 Glomus glomus tumors are transient facial nerve palsy, extravasa-
jugulare tumors erode the jugular foramen initially, tion of contrast related to high-pressure injection of the
whereas glomus tympanicum tumors appear as a tuft of embolic agent, and palsies involving cranial nerves IX–XI.
enhancing tissue eroding the cochlear promontory.112 A These last are related particularly to liquid adhesive
characteristic feature of glomus tumors is the pattern of embolization of the neuromeningeal branch of the ascend-
simultaneous local extension along canals and vessels.131 ing pharyngeal artery.41
MRI offers the ease of multiplanar imaging and can evalu-
ate differences among soft tissue structures well, but is less Meningiomas
effective evaluating subtle bony changes.
Diagnostic angiography remains an effective method of Meningiomas are common benign extraaxial tumors of the
evaluating glomus tumors preoperatively and assessing meninges covering the brain.135 These tumors are thought
arterial supply and ability to carry out preoperative to have arisen from cells that form arachnoid villi, which
embolization, degree of vascularity, encasement of major serve to reabsorb cerebrospinal fluid from the cerebral cis-
arteries, degree of arteriovenous shunting, presence of terns into the venous sinuses. As such these tumors are
major venous sinus occlusion by tumor, multicompart- found in locations where the arachnoid villi are most plen-
mentalization or multifocality of tumor, confirmation of tiful, along the dura lining the venous sinuses of the brain
the expected diagnosis, and exclusion of other vascular and skull base.
skull base processes mimicking glomus tumors. Classical Specific presenting symptoms depend on tumor loca-
angiographic features include enlargement of feeding tion and size. Common locations include parasagittal and
arteries, intense tumor stain, and arteriovenous shunting. lateral cerebral convexity (most common sites), sphenoid
These tumors may be supplied by a single enlarged artery wing, petrous ridge, cerebellopontine angle (CPA), teno-
or by multiple feeders, depending on tumor size and rium, foramen magnum, orbit, cavernous sinus, or rarely
number of compartments, which can be separate from one in sites without dural attachments (intraventricular, sylvian
 Diagnostic and Therapeutic Angiography 457

Figure 24-12. Glomus jugulare tumor in a 47-year-old man with

pulsatile tinnitus. A, Transaxial MRI scan (TR 750/TE35) with
gadolinium-DTPA enhancement, shows an enhancing mass in the left
jugular foramen (arrow). Transaxial (B) and coronal (C) CT scans,
windowed to optimize visualization of bone, show enlargement of the
jugular foramen with erosion of its lateral bony margins (closed
arrows). The tissue mass has permeated bone and extends into the
middle ear (C, white arrow).
Continued

fissure). Because arachnoid cell rests may be found in the A number of histologic subtypes have been described,138
jugular foramen, internal auditory canal, geniculate gan- including syncytial, transitional, fibroblastic, angioblastic,
glion area, and along the lesser and greater superficial and malignant varieties, depending on the predominant
petrosal nerves,136 meningiomas arising from these cells cell type.139 There is a correlation between incidence of
may present with neurotologic symptoms, including meningioma and a history of prior irradiation, with a
conductive hearing loss (temporal bone, middle ear), sen- latent period of 5 to 25 years.140
sorineural hearing loss and vestibular symptoms (internal CT and MRI have supplanted plain skull radiography in
auditory canal, simulating an acoustic neuroma), tinnitus, the initial diagnostic evaluation of meningiomas. CT scan-
and facial nerve palsy (CPA), or hoarseness, cough, dys- ning will show a well-circumscribed extraaxial mass rela-
phagia, difficulty speaking and handling secretions, and tively isodense or hyperdense compared with normal brain
trapezius weakness (jugular foramen).137 tissue on noncontrast images; these enhance brightly with
458 NEURORADIOLOGY

Figure 24-12, cont’d. D, Left external carotid artery (ECA) injection, lateral
angiographic view, shows a highly vascular mass in the jugular foramen
region, characteristic of a glomus tumor. Supply is derived from ascending
pharyngeal (open curved arrow), posterior auricular (large closed curved
arrow), and occipital transmastoid perforating branch (small closed curved
arrow) arteries. Early retrograde opacification of the sigmoid sinus (long
straight arrow) indicates arteriovenous shunting through the tumor.
E, Superselective left ascending pharyngeal artery (posterior branch)
injection, lateral angiographic view, shows dense tumor blush. This was
followed by provocative testing and particulate embolization. F, Left external
carotid artery injection, lateral angiographic view performed after
embolization of all three ECA feeding arteries, shows no residual tumor
opacification. The tumor was successfully resected the following day.

administration of IV contrast.131 MRI scanning with admin- each as a supply source because a global common carotid or
istration of gadolinium–DTPA allows more facile tumor even external carotid injection may visualize these arteries
evaluation in multiple planes, which is especially helpful inadequately. Dural arteries from the internal carotid
for evaluating the dural attachment of the tumor and (meningohypophyseal trunk, inferolateral trunk, ethmoidal
patency of dural sinuses. branches of ophthalmic artery) and vertebral (posterior
Meningiomas are typically vascular tumors, as would be meningeal) arteries may also supply the tumor. As a menin-
expected of tumors arising from the vascular dura. gioma grows, it parasitizes pial branches, which supply small
Additionally, meningiomas receive their blood supply pri- twiglike branches to the periphery of the tumor. Another
marily from dural arteries, especially from external carotid characteristic feature of meningiomas is the angiographic
branches.141 Depending on tumor location, arterial supply is staining pattern: uniform radial arrangement of tiny tumor
derived predominately from middle meningeal, accessory vessels in a well-defined round tumor. Opacification begins
meningeal, ascending pharyngeal, or occipital transmastoid in the arterial phase, augments, and persists into the venous
perforating branches of the external carotid artery and may phase without washout (Fig. 24-14).
be bilateral, especially in a midline tumor. Superselective Cerebral venography has a limited role in the evaluation
catheterization of these branches is important for excluding of meningiomas. Confirmation or exclusion of dural sinus
 Diagnostic and Therapeutic Angiography 459

A B

C D
Figure 24-13. Glomus jugulare tumor in a 53-year old woman with loud pulsatile tinnitus and headaches. She underwent staged preoperative particulate
embolization followed by complete surgical resection. A, Transaxial MRI scan (TR 600/TE 20) with gadolinium–DTPA enhancement, shows subtle increased
signal in the left jugular bulb (arrow). B, Transaxial contrast-enhanced CT scan confirms the presence of an enhancing mass in the left jugular bulb (arrow).
Transaxial (C) and coronal (D) CT scans, windowed to optimize visualization of bone, show enlargement of the left jugular foramen and erosion of the lateral
cortex (white arrows).
Continued

patency, which may be questionable on other imaging by venography is superior to that of arteriography. Finally,
studies, can be made. This assessment is important for the venous pressure gradients across a sinus partially obstructed
surgeon because the tumor and occluded adjacent sinus by a meningioma can be measured,12 and sinus test occlu-
can be resected without danger of venous infarction, sion performed to assess tolerance of surgical resection of
whereas a patent sinus should be preserved. This is espe- the tumor and adjacent sinus.
cially true of the dominant (usually the right) transverse The goal of therapy for meningiomas is complete erad-
sinus and posterior two-thirds of the superior sagittal ication of the tumor. This is best achieved by complete
sinus. Delineation of the exact site of sinus tumor invasion surgical resection, when possible. Not all meningiomas are
460 NEURORADIOLOGY

G
Figure 24-13, cont’d. E, Left ECA injection, lateral angiographic view, shows
a highly vascular ill-defined mass (black arrow) in the region of the jugular
foramen, characteristic of a glomus tumor. Arteriovenous shunting
to the sigmoid sinus (small open arrows) and internal jugular vein (open
curved arrow) is seen. Superselective catheterization of: occipital (F) posterior
auricular (G) and middle meningeal (H) arteries prior to embolization, lateral H
angiographic views, shows dramatic tumor blush and AV shunting.
Continued

vascular, and some authors have questioned the benefit of Advances in technology, including improved spatial
preoperative embolization in meningiomas with feeding resolution of digital subtraction “road-mapping” angio-
arteries easily accessible to the surgeon.142 However, pre- graphic systems and development of softer steerable or
operative devascularization of the microvascular tumor flow-directed microcatheters, have provided the angiogra-
bed by embolization143,144 provides the following advan- pher with safer supraselective access to tumor vascularity.
tages: diminution of surgical blood loss and operative time, However, experience with endovascular techniques is nec-
improvement of visibility for the surgeon, allowing the essary to avoid the many pitfalls associated with these
surgeon to amputate a portion of the tumor devascularized procedures. Prior to embolization, the patient is given cor-
by embolization, and control of arterial flow in surgically ticosteroids to reduce the immediate risk of tumor
inaccessible tumor feeders (especially at the skull base). swelling after embolization, and a sublingual calcium
 Diagnostic and Therapeutic Angiography 461

channel blocker or topical nitropaste (or both) to reduce

the incidence of arterial spasm, sometimes encountered
during catheterization of external carotid branches.
Arteries of the skull base supplying meningiomas may
also supply critical normal structures or provide collaterals
to the intracranial circulation. The angiographer must be
aware of this and carry out effective evaluation to protect
against this prior to embolization. The ascending pharyn-
geal artery, often providing supply to meningiomas of the
skull base, gives off a neuromeningeal division supplying
cranial nerves IX–XI and sometimes XII. It also gives rise
to the odontoid artery, which anastomoses with the verte-
bral artery. Inadvertent embolization could result in ipsi-
lateral vocal cord paralysis, inability to adequately handle
oral secretions, palatal or tongue deviation, and stroke
involving the brainstem or posterior fossa. The occipital
artery also anastomoses with the vertebral artery as it
enters the foramen magnum, which may be impossible to
visualize without superselective angiography. The middle
meningeal artery can anastomose with the cavernous por-
tion of the ICA via the inferolateral trunk or can give rise
to a meningolacrimal artery, which traverses the sphenoid
bone through the canal of Hyrtl to supply the retina. This
vessel may provide the entire retinal supply or a portion
I thereof. Inadvertent embolization could result in central
retinal artery embolism and monocular blindness. The sty-
lomastoid artery supplying the peripheral facial nerve can
arise from the occipital, posterior auricular, or middle
meningeal arteries. The accessory meningeal artery can
supply cranial nerves III, IV, and VI. The distal internal
maxillary artery can anastomose with the ICA via the
artery of foramen rotundum or vidian artery.
Several techniques have been developed to reduce com-
plications of inadvertent embolization. Once the micro-
catheter has been navigated into the artery to be
embolized, it is directed as close to the tumor as possible
without causing spasm or complete flow arrest, to avoid
potential normal branches arising more proximally.
Supraselective angiography using high resolution is per-
formed to visualize normal arteries or collaterals to the
vertebral or internal carotid arteries. Supraselective
angiography of the middle meningeal artery requires
J centering the angiographic film over the orbit, specifically
to exclude the presence of a meningolacrimal artery.
Provocative testing by injecting 2% cardiac lidocaine
(10 to 20 mg) may result in temporary cranial nerve deficit
revealing unsuspected supply via the artery considered for
embolization, requiring more distal placement of the
microcatheter before embolization or withdrawal of the
catheter from that artery without embolization. Selection
of the appropriate embolic agent depends on the goal of
embolization. Because embolization is a preoperative
adjunct in this setting, safe embolization without the need
for a permanent embolic agent is best achieved with the

Figure 24-13, cont’d. I, Left vertebral artery injection, lateral angiographic

view, shows tumor opacification from several branches including the
posterior meningeal artery (arrow). J, Left posterior meningeal artery
injection, lateral angiographic view, shows abundant tumor supply, embolized
with particles. The catheter tip is marked (arrow). K, Left PICA injection,
lateral angiographic view, shows tumor supply from small branches.
K Embolization is precluded because of supply to normal distal PICA (arrow).
462 NEURORADIOLOGY

A B

C D
Figure 24-14. Recurrent clivus meningioma in a 35-year-old man with a remote childhood history of a brain tumor treated by radiation. He has undergone prior
craniotomy for resection of multiple meningiomas. He now presents with hearing loss, generalized weakness, and gait instability. He underwent preoperative
particulate embolization followed by surgical debulking of the tumor. A, Transaxial contrast-enhanced CT scan shows a vascular mass on the clivus displacing
the brainstem posteriorly. B, Transaxial MRI scan (TR 2500/TE 40) shows the high-signal clival mass invading the left porus acousticus and encasing the
displaced left vertebral artery (arrow). C, Sagittal MRI scan (TR 600/TE 20) with gadolinium–DTPA enhancement shows posterior displacement of the brainstem
and encased basilar artery (arrows) by the enhancing extraaxial clival mass. D, Coronal MRI scan (TR 600/TE 20) with gadolinium–DTPA enhancement shows
the mass abutting the internal auditory canals (arrows).
Continued
 Diagnostic and Therapeutic Angiography 463

G H
Figure 24-14, cont’d. E, Right vertebral artery injection, lateral angiographic view, shows marked posterior displacement of the basilar artery (arrows) by the
mass and mild diminished caliber of its inferior portion consistent with tumor encasement. F, Right ICA injection, lateral angiographic view, shows tumor supply
from the meningohypophyseal trunk (arrow). The relatively small tumor supply, difficult catheterization, and risk of reflux of embolic material into the ICA do not
warrant an attempt at embolization of this branch. G, Right ECA injection, lateral angiographic view, shows abundant tumor blush supplied by the ascending
pharyngeal artery (arrow). H, Superselective right ascending pharyngeal artery injection, lateral angiographic view prior to embolization, shows tumor supply
and reflux of contrast via the odontoid artery to opacify the right vertebral artery (arrows). Extreme care during embolization must be taken to avoid high
pressure injections which could reflux embolic material in the same manner.
464 NEURORADIOLOGY

use of particulate agents. The smallest available PVA par- hearing loss due to cochlear nerve compression. Although
ticles (measuring 50 to 200 μm), Gelfoam powder, or small most acoustic schwannomas arise in the vestibular nerve
acrylic spheres will penetrate well into the tumor bed, but sheath, vertigo, disequilibrium, and dizziness are less com-
risk permeating normal branches of similar size that are mon. Similarly, the facial nerve, which shares the internal
too small to resolve well on angiography, particularly at auditory canal with its cochlear and vestibular eighth nerve
the base of the skull where the dense petrous bone will counterparts, is affected infrequently,151,152 possibly
hinder optimal radiography. Large particles may result in because motor fibers are less sensitive to local effects of
proximal occlusion of the artery without adequate tumor compression than sensory fibers. Tumor enlargement into
penetration. Therefore, an intermediate size particle (250 the CPA and posterior fossa can compress the cerebellum
to 500 μm) may achieve the desired result with less risk producing ataxia, compress the brainstem or exiting cra-
to small normal branches. Liquid adhesive agents (e.g., nial nerves (most commonly the trigeminal nerve), or
N-butyl cyanoacrylate) need not be used in this setting, result in obstructive hydrocephalus or raised intracranial
as their permanence is unnecessary and they will easily pressure.110 Schwannomas arising in the trigeminal nerve
permeate small normal branches below the resolution sheath present with facial paresthesias and hypesthesia, but
capacity of current angiographic systems. Vigilance must may become quite large in the absence of such symp-
be maintained to avoid reflux of embolic material into nor- toms.120 Schwannomas of cranial nerves IX to XI can pro-
mal proximal branches by overly vigorous embolization. duce the jugular foramen syndrome (difficulty speaking and
Pial meningioma supply is generally not embolized preop- swallowing, hoarseness, and trapezius and sternocleidomas-
eratively, as pial branches provide only a small percentage toid paralysis) due to the intimate anatomic arrangement of
of tumor vascularity, and the risk of embolization is greater these three cranial nerves.
than that of dural artery embolization. A postembolization CT scanning demonstrates an extraaxial, well-circum-
control angiogram is performed to document adequate scribed tumor eroding the involved canal and may enhance
results. variably with IV contrast administration. More recently,
Despite the many potential pitfalls of meningioma MRI has supplanted CT in the primary evaluation of
embolization, the complication rate is very small in expe- schwannomas, especially acoustic schwannomas, because
rienced hands.41,142,145,146 Berenstein reports 3 permanent of superior intrinsic soft tissue contrast differences, lack
(monocular blindness, stroke) and 5 transient (facial nerve) of artifacts produced on CT by density differences at
neurologic deficits in 185 patients.41 Two cases of sub- air-bone or soft tissue-bone interfaces, and ease of multi-
arachnoid hemorrhage have been encountered.41,145 planar image acquisition. Small intracanalicular acoustic
Trismus, resulting from internal maxillary artery branch schwannomas can be detected easily on MRI and are
occlusion, was more prevalent prior to the introduction of best evaluated on gadolinium–DTPA-enhanced short TR
microcatheters.142 (repetition-time) images obtained in both transaxial and
coronal planes.
Several angiographic features of schwannomas assist in
Schwannomas
differentiating them from meningiomas, which have a sim-
Schwannomas, 90% of which occur in the CPA, are benign ilar angiographic appearance. Schwannomas have been
extraaxial tumors arising from the cranial nerve sheaths, described as hypervascular in up to 68% of cases,41 espe-
which are formed of Schwann cells.112,139 Usually solitary, cially in larger tumors or in the rare childhood case,153 but
multiple schwannomas are characteristic of neurofibro- feeding arteries are generally of normal or minimally
matosis, and bilateral acoustic schwannomas are the hall- enlarged caliber, and tumor stain, when present, is less
mark of the central form of neurofibromatosis, or NF2.147,148 dense than that of a meningioma.154,155 No arteriovenous
Sensory cranial nerves are overwhelmingly involved. shunting occurs, but a network of capsular veins may
These tumors are generally seen in middle-aged individu- encircle the tumor. The most suggestive angiographic
als and have a predilection for females. Association with finding is the presence of multiple small puddles of con-
head and neck irradiation during childhood has been pos- trast that persist into the venous phase.156 Arterial supply
tulated.149 can be predicted from tumor location and may arise from
The so-called acoustic schwannoma is by far the most external carotid branches or from the anterior (AICA) or
common site of tumor origin. Ninety percent of these posterior (PICA) inferior cerebellar arteries in cases of
tumors arise in the superior division of the intracanalicular acoustic schwannomas.155
vestibular nerve. The trigeminal nerve is the next most fre- Preoperative embolization has been shown to be effica-
quent site of origin.112 Schwannomas in other locations are cious in treating vascular schwannomas153,156 by reducing
most often manifestations of neurofibromatosis. The facial tumor blood supply and easing surgical resection, as with
nerve, although infrequently a tumor site, is the most com- meningiomas. Embolization techniques are also similar. Use
monly affected motor nerve.139 of intermediate-sized PVA particles (300 μm) in selected
Generally, schwannomas are firm, encapsulated tumors branches of the external carotid artery can effect adequate
that may contain cysts. As the tumor grows, it may become tumor devascularization while safely avoiding cranial nerve
lobulated, increase in vascularity,150 or develop arachnoid deficits, especially if undertaken after provocative lidocaine
adhesions that may result in arachnoid cysts.151 testing. Pial artery embolization should be reserved for very
Clinical presentation depends on the size and site of ori- large vascular schwannomas, as the risk of producing neuro-
gin of the tumor. Acoustic schwannomas initially present logic deficit from embolization of the PICA (Wallenberg’s
with tinnitus and progressive, high-frequency neurosensory syndrome) or AICA (vertigo, diminished hearing) is
 Diagnostic and Therapeutic Angiography 465

considerably greater than with external carotid branch CONCLUSION

embolization. Although no large body of experience with
embolization of schwannomas has been compiled, smaller Diagnostic angiography plays an essential role in the eval-
series suggest minimal risk in experienced hands.156 uation of vascular abnormalities and tumors presenting to
the skull base surgeon. Additionally, embolization of these
abnormalities has become an accepted form of therapy,
Miscellaneous Tumors broadening the treatment options for both the surgeon
Malignant Skull Base Tumors and the patient. Further technical developments and
experience will permit an expanded role of endovascular
Endovascular therapy can provide palliation or adjunctive therapy by well-trained individuals who have mastered
therapy for surgery in vascular primary or secondary endovascular techniques and who are aware of their capa-
malignant skull base tumors. Angiography will assess the bilities and limitations.
vascularity of the mass, and particulate embolization will
permit tumor necrosis, decreased mass effect,41 and
reduced arterial inflow. As with other vascular tumors, this
will allow safer surgical resection or biopsy with reduced REFERENCES
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bleeding and diminish pain.41 Properly sized particulate
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 Chapter
Auditory Neuropathy, Sarcoidosis,
Siderosis, and Idiopathic
Pachymeningitis

Outline 25
Auditory Neuropathy Histopathology History and Physical Exam Angela D. Martin, MD
Introduction Pathophysiology Audiology
Colin L. W. Driscoll, MD
Incidence Clinical Presentation CSF Findings
Etiology Evaluation Imaging
Pathophysiology Audiology Treatment
Clinical Presentation Diagnostic Tests Outcomes
Audiometric Findings Cerebrospinal Fluid Findings Idiopathic Hypertrophic
Peripheral Neuropathy Imaging Pachymeningitis
Vestibular Function Treatment Introduction
Evaluation Outcomes Incidence and Etiology
Medical Evaluation Superficial Siderosis of the Histopathology
Audiology Evaluation Central Nervous System Clinical Presentation
Treatment Options Introduction Evaluation
Future Directions Incidence Imaging
Sarcoidosis Etiology Treatment
Introduction Pathophysiology Outcomes
Incidence Pathology
Etiology Clinical Presentation

AUDITORY NEUROPATHY AN. Although the overall number of patients with AN in

the general population appears small, one in nine infants
Introduction found to have a permanent hearing deficit met the criteria
for AN.3 Park and Lee found that 6% of patients with
Auditory neuropathy (AN) is a term used to describe patients bilateral severe to profound hearing loss had present oto-
with a hearing disorder characterized by (1) a bilateral pure acoustic emissions.9 Among patients with AN, there
tone sensorineural hearing loss (SNHL); (2) absent or appears to be no gender preference.10 The identification of
severely abnormal auditory brainstem responses (ABR) AN in older children and adults is complicated by the fact
beginning at wave I, suggesting impairment of function of that the OAEs are sometimes lost and therefore the disor-
afferent neural transmission; (3) preserved otoacoustic der cannot be distinguished from other types of SNHL.
emissions (OAEs) and cochlear microphonics (CMs),
suggesting normal cochlear outer hair cell function; and
(4) normal imaging studies (Table 25-1).1–5 Although AN Etiology
has only been recently described, the condition is not The causes of AN are currently being investigated and
new.6–8 AN was difficult to recognize in the past because appear to be diverse. In approximately 50% of patients
tests to distinguish disorders of the cochlear receptors from AN has no defined cause. Genetic factors have been iden-
those of the auditory nerve were not routinely performed. tified and appear to account for the disorder in ≈40% of
patients with AN. Other associated causes, including
Incidence toxic-metabolic, infectious, and immunologic factors that
account for ≈10% of patients.10 In infants AN has been
Data regarding the incidence of AN in children is associated with neonatal hyperbilirubinemia,11,12 hypoxia,
gradually accumulating due to widespread institution of congenital infection, and prematurity.3,13 It may occur as
infant hearing screening programs. There are no data for part of a generalized metabolic, toxic, or inflammatory
adults. In a study from Australia the incidence of AN neuropathy, as seen with diabetes,14 uremia,15 or exposures
presenting in infancy was found to be 0.23% of the general to cisplatin, which appears to selectively damage inner hair
population. Of the 5199 infants who underwent screening, cells.16 AN has been diagnosed in patients with Friedreich’s
109 had an abnormal ABR (2.09%). Of these, 12 had ataxia,17 in patients with a hereditary motor and sensory
present OAEs or CMs, consistent with the diagnosis of neuropathy (HMSN)18–20 and Charcot-Marie-Tooth
471
472 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 25-1. Main Features of Auditory Neuropathy discrepancy may be secondary to the more widespread use
Clinical Findings
of OAEs and ABRs in the evaluation of hearing loss in
infants and children than in adults. Furthermore, ≈20% of
Difficulty understanding speech, particularly in background noise the children with AN currently being followed have been
Normal physical exam, except for hearing loss found to lose their OAEs over time. AN in adult patients
Audiometric Findings who have subsequently lost their OAEs would therefore
be underdiagnosed.10
Bilateral pure tone sensorineural hearing loss Infants with AN usually present when abnormal ABRs
Preserved otoacoustic emissions and cochlear microphonic
Absent or severely abnormal ABR
and preserved OAEs are found during routine infant
Impaired word recognition score out of proportion to degree of hearing loss screening. In older children and adults, the clinical pres-
entation is typically that of a gradual hearing loss. These
Imaging Findings
patients report extreme difficulty understanding speech,
Normal CT and MRI especially when using the telephone or in noisy environ-
ments. Many are dependent on lip reading. Some patients
ABR, auditory brainstem response; CT, computed tomography; MRI, magnetic report fluctuations in hearing over time. It is not uncommon
resonance imaging. for them to be accused of malingering or for their hearing
disorder to be mistaken for a behavioral problem. It can be
disease,21 or as an isolated and sporadic event.22 A genetic confusing for older children and young adults and the sur-
mutation of the PMP22 gene in Charcot-Marie-Tooth rounding friends and family because the hearing can be
disease,23 as well as a mutation mapped to 8q24 in some quite satisfactory in quite environments but very poor in
Bulgarian and Italian Gypsy families with AN have been other settings.
identified.19
Audiometric Findings
Pathophysiology
Hearing loss ranges from mild to profound, and there is no
The site of the pathology causing the findings of absent characteristic audiometric pattern. Patients with AN often
ABRs and preserved OAEs and CMs in AN has yet to be have difficulty providing consistent responses during
discovered. It has been suggested that the disorder may testing and demonstrate test-retest variability. Starr and
occur at the level of the inner hair cells, the synapse colleagues reported that 31% have a hearing loss of 35 dB
between the inner hair cells and the eighth nerve, the gan- or less, 39% have between a 35- and 70-dB loss, and
glion neurons, the nerve fibers, or any combination of 30% have a greater than 70-dB loss. Thresholds remain
these.4 Along the auditory nerve, the site of pathology may constant over time in ≈40% of patients, fluctuate in 30%,
be the myelin sheath or the neuron (axon and dendrite).10 and worsen in ≈15%.10 Impaired word discrimination is
Other authors have hypothesized that the normal synchro- disproportionate to pure tone loss. The audiogram reveals
nous activity of the auditory nerve is disrupted, which may a flat configuration in 41%, an upsloping pattern consis-
be secondary to a demyelinating process, leading to tem- tent with a low-frequency loss in 29%, an irregular “saw
poral and speech-processing deficits, without necessarily tooth” pattern in 9%, a U-shaped pattern in 5%, tent-
affecting the amplification function of the inner ear.4,24,25 shaped loss in 5%, and a downsloping pattern in 11%
An increase in body temperature has been associated with (Fig. 25-1).10
marked worsening of hearing in some patients with AN.26 ABRs are either absent or severely abnormal in all cases
Starr noted that heat sensitivity is common among patients (Fig. 25-2). A few patients with preserved components
with multiple sclerosis and that this worsening in hearing (wave V with or without wave III) have been identified
in patients with AN may represent a conduction block sec- when the stimulus rate was slowed.10 In these cases, wave
ondary to a myelin disorder.10 Chinchillas with carbo- V was of prolonged latency and decreased amplitude, and
platin-induced lesions of the inner hair cells (IHCs) and wave III was of abnormal morphology. The differences in
type I neurons demonstrated similar characteristics to ABRs suggest that the loss of neural synchrony is variable
patients with AN.27 Temporal bone findings in patients among patients with AN secondary to different causal and
with Friedreich’s ataxia revealed a pronounced loss of physiologic factors.10 Stapedial reflexes are absent in all
nerve fibers and spiral ganglion cells, increasing from base but a few patients with AN. Normal distortion product
to apex, with preservation of the outer hair cells.28 and transient evoked otoacoustic emissions (DPOAE,
Hyperbilirubinemia has been implicated but because this TEOAEs) or CMs are present at initial examination.
is a common occurrence after birth it is difficult to know if Increased amplitude of CMs has been observed in patients
there is a causal relationship. with AN who are younger than 10 years compared with
normal subjects.1,19 In one study increased amplitude of
Clinical Presentation CMs was observed in 50% of patients.10 The significance
of this finding is currently unknown. There have also been
AN has been diagnosed in all ages from newborns to reports of loss of OAEs on future testing with preservation
adults. A study of 67 patients with AN by Starr and of CMs,2,11 with a 20% incidence reported in a recent
colleagues found that children under the age of 10 years study.10 The reason for this finding is also currently
account for the majority of the population with AN unknown, but may represent a primary disorder of the
(≈75%), whereas adolescents and adults account for the outer hair cells (OHCs) or damage to the OHCs from
minority (≈25%). They suggest that the reason for the hearing aid use or middle ear disorders.
 Auditory Neuropathy, Sarcoidosis, Siderosis, and Idiopathic Pachymeningitis 473

Auditory Neuropathy a generalized neuropathic process that expresses itself as

:10
patients get older.
0
10 Vestibular Function
20
Patients typically have no vestibular symptoms. Abnormal
30
caloric tests have been identified in asymptomatic patients
dB hearing level

40
with AN who tended to be older and have a concomitant
50 peripheral neuropathy.29 There have also been a few
60 reports of abnormal vestibular function tests in older
70 patients with AN who had vestibular symptoms, but no
80 evidence of a peripheral neuropathy.30 This may represent
90 Word Recognition a neuropathy of the vestibular nerves as part of a general-
100 R=60% ized neuropathic process or as an isolated eighth nerve
L masked BC L unmasked AC L =60%
110 R masked BC R unmasked AC MLV@40 SL process.
120
125 250 500 1,000 2,000 4,000 8,000
1,500 3,000 6,000 Evaluation
Medical Evaluation
Figure 25-1. Audiogram from an adult patient with bilateral auditory
neuropathy. Note the characteristic marked variation in thresholds at different Because too little is known about the pathophysiology of
frequencies, saw-toothed pattern. This variation makes testing her difficult
and when younger she was thought to be malingering. Also note, despite
AN, the evaluation is largely the same as that for patients
good pure tone thresholds her word recognition scores are poor. with other types of SNHL. Regardless of other testing
(e.g., syphilis, autoimmune tests), in all adults with AN we
recommend a magnetic resonance imaging (MRI) scan and
consultation with a neurologist in order to identify any
Peripheral Neuropathy
concomitant peripheral neuropathy or other associated
Usually at the time of presentation, patients are otherwise neurologic disorder. In addition to a complete neurologic
neurologically normal. However, Starr and colleagues exam, patients may undergo nerve conduction studies
identified a peripheral neuropathy in a significant number looking for an absence or slowing of nerve conduction
of patients with AN. They found no evidence of a periph- velocities as well as a diminished amplitude of the com-
eral neuropathy in children younger than 5 years, whereas pound action potential. In patients for whom there is a
80% of patients examined after age 15 years showed both high suspicion of a peripheral neuropathy, a sural nerve
clinical and nerve conduction evidence of a peripheral biopsy is recommended to confirm the diagnosis.
neuropathy.10 Larger population-based studies will be Our current philosophy when evaluating a child with
needed to clarify the relationship between AN and other hearing loss is to be thorough in our efforts to determine the
peripheral neuropathies. AN may occur alone or as part of cause and to search for evidence of a syndromic disorder.

Accepted: LD05 Fsp :180.00 :100.00 :200.00 :100.00 Cursor 1L: 4.80 Diff 5.54 ms
Rejected: 0 Cursor 2L: :0.74 Diff 0.04 uV

Stimulus artifact
Rarefaction clicks

Figure 25-2. ABR obtained with clicks

presented at 90-dB hearing loss to the 7
right ear of the same patient presented Cochlear microphonics
in Figure 25-1. The ABR demonstrates 15
the presence of a phase reversing 11
cochlear microphonic and no other
identifiable waveforms. The absence of a
repeatable waveform beyond the cochlea
is suggestive of neural dyssynchrony.

Stimulus artifact
Condensation clicks
Nicolet
0.15 uV 1.0 msec
l
0 10
msec
474 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

The core medical team in our practice consists of an oto- patients with AN.31,32 A recent review at our institution of
laryngologist, geneticist, ophthalmologist, and pediatrician. 10 children with AN compared with a matched group with
Evaluation by a pediatric neurologist has not been a routine hearing loss from other causes showed no difference in
part of our evaluation because of the rarity of a peripheral performance after cochlear implantation (unpublished
neuropathy at a young age but is considered on an individual data). Evoked intraoperative and postoperative potentials
basis. Because these children may develop other neu- (EABR) and electrical compound action potentials
ropathies later in life, a neurology appointment at some (ECAP) demonstrate the ability of the cochlear implant to
point seems reasonable. Laboratory work typically consists restore neural synchrony. We have had similar favorable
of an ECG, thyroid function test, urinalysis, glucose, and an results in adults.
MRI or computed tomography (CT) scan of the head.
Genetic screening for abnormalities in the Connexin-26 gene Future Directions
is encouraged and performed in most cases. Our evaluation
procedure continues to evolve, and with advances in genetic The following factors vary among patients with AN: cause,
screening over the next several years we will continue to alter age of onset, presence or absence of a peripheral neuropa-
our routine to minimize the number of tests obtained. thy, degree of hearing loss, differences in physiological
measures of auditory function (ABRs, OAEs/CMs), and
differences in treatment outcomes. As more is learned
Audiology Evaluation
about AN, it will become more evident whether this is
Accurate audiometric testing is critical to making the diag- truly a single disorder or many different ones that share a
nosis, and the knowledge and abilities of an experienced few common features. Routine use of nerve conduction
audiologist are invaluable. In addition to standard audio- studies in patients with AN will help to identify the rate of
metric tests and age-appropriate speech perception tests, a peripheral nerve disorder in this population. Genetic
otoacoustic emissions are obtained and followed over time. studies may identify a common link in hereditary cases of
Evoked potentials always include an ABR in which we AN. Long-term outcomes of AN patients with cochlear
record phase-reversing clicks or tone bursts in order to implants will shed light on the effectiveness of this treatment.
identify the cochlear microphonic. Middle (MLR) and late Our understanding of AN is evolving, with many ques-
(LLR) latency responses may also be recorded. For adults, tions still to be answered.
the Hearing In Noise sentence Testing (HINT) is quite
beneficial in delineating the difficulty that patients have in
different listening situations. SARCOIDOSIS
Lastly, although most patients are asymptomatic with
regard to vestibular function, abnormalities of vestibular Introduction
caloric stimulation have been identified. Therefore, it may
be appropriate for patients to undergo vestibular testing to Sarcoidosis is a chronic systemic granulomatous disease of
identify baseline function. unknown origin. It is characterized by the presence of
noncaseating granulomas that can affect any organ system
of the body. Although it most commonly affects the pul-
Treatment Options monary, ocular, dermatologic, and lymphatic systems, the
Treatment options for children with AN include intensive central nervous system (CNS) may also be affected.33 CNS
speech and language therapy, hearing aids, or cochlear symptoms include hearing loss or vertigo (or both). Other
implantation. From the time that AN was first reported in otolaryngologic manifestations of sarcoidosis include
the literature, clinicians have questioned whether it was involvement of the salivary gland (uveoparotid fever), the
wise to consider amplification with hearing aids or larynx (most often supraglottic), nasal cavity and nasophar-
cochlear implants,3,11,17,18,22 There was concern that ampli- ynx (mucous membrane lesions, septal perforation), and
fication would cause further injury to the cochlea and that neck (cervical adenopathy).34,35
cochlear implants would not work because the hearing loss
was due to a problem with the nerve. In an effort to not Incidence
injure the outer hair cells, hearing aids were often fitted
using a low-gain and wide-dynamic-range compression The overall incidence of sarcoidosis is 40 per 100,000.36
strategy. The hearing aids were usually tolerated, but Neurosarcoidosis occurs is approximately 5% to 10% of
because the gain was low they seldom provided any bene- cases.37,38 The cranial nerve (CN) most commonly affected
fit. The trend now is to fit the hearing aids to the behav- is the facial nerve, presenting with unilateral or bilateral
ioral audiogram according to accepted rules and assess facial paralysis with a good prognosis for spontaneous
auditory skill development. Most children will tolerate the recovery.37,39–41 Lesions of the optic, trigeminal, and
aids but many will not demonstrate adequate progress in vestibulocochlear nerves are fairly common. Symptoms
acquisition of speech and language skills. For those who do include optic neuritis/atrophy (CN II) and unilateral
show progress, amplification is the treatment of choice. sensory loss of the face (CN V).41,42 Sarcoidosis of the
Adults with mild or moderate losses often reject hearing eighth nerve presenting with hearing loss or vertigo is
aids, stating that “the sound is louder but I still can’t under- often associated with other cranial neuropathies. Isolated
stand the words.” It is likely that the children who fail to eighth nerve involvement is rare.35 Whereas the overall
progress with hearing aids are having the same problem. incidence of hearing loss among cases of sarcoidosis is
Despite some early reports of poor outcomes, cochlear ≈0.5%,43 in cases of neurosarcoidosis it occurs in 10% to
implantation has now been shown to be a viable option for 20% of cases.36 Cranial nerves less commonly involved
 Auditory Neuropathy, Sarcoidosis, Siderosis, and Idiopathic Pachymeningitis 475

may cause symptoms of dysphagia and hoarseness (IX, X), In neurosarcoidosis, a predilection for the basal lep-
anosmia (I), and disturbances of ocular movements tomeninges is evident and often presents as granulomatous
(III, IV, VI).42 meningitis affecting the hypothalamus, third ventricle,
pituitary, and cranial nerves. Less commonly, neurosar-
coidosis presents as a mass lesion. Sarcoid granulomas
Etiology occurring at the cerebellopontine angle (CPA) have been
Despite advances in the understanding of sarcoidosis, a reported.35,46–53 In one of these cases, the CPA lesion was
specific cause has not been identified. Human leukocyte the only clinical finding, and the sarcoid granuloma was
antigen (HLA) studies show a higher prevalence of the mistaken for a meningioma and treated surgically.47
disease among first-generation relatives of patients with
sarcoidosis, suggesting a genetic factor.44 The current the- Clinical Presentation
ory suggests that a combination of environmental factors
and a genetically susceptible individual is most likely The clinical presentation of hearing loss with sarcoidosis
responsible for the induction of the disease.36 is quite variable. Often involvement of the eighth nerve
occurs with other symptoms or cranial neuropathies,
including uveitis, hilar adenopathy, and facial paralysis.35,54
Histopathology Isolated cases of hearing loss have been reported as the
The typical histopathologic features of sarcoidosis include presenting symptom of sarcoidosis.35,47,55 The hearing loss
noncaseating granulomas consisting of epithelioid cells may be fluctuating55,56 or of sudden onset.35,53,54,57 Other
surrounded by mature lymphocytes (Fig. 25-3). Other cells symptoms include tinnitus, vertigo, or disequilibrium with
that are often present include giant cells, both Langerhans’ a positive Romberg test and hypoactive calorics.53,54
and foreign body types. The inflammatory process is associ- Depending on the site of the lesion(s), the hearing loss
ated with an increase in activated T cells and macrophages, may be unilateral or bilateral. Typically the hearing loss is
initiating an immune response with the release of inter- sensorineural, although cases of a conductive loss have
feron-γ, interleukin-2, other cytokines, and proinflamma- been reported secondary to nasopharyngeal granulomas
tory factors.36 The diagnosis of tuberculosis is excluded by obstructing the eustachian tube.52 Systemic symptoms
the absence of central caseation and acid-fast bacilli.45 include fever, malaise, weight loss, and night sweats. The
age of presentation of neurosarcoidosis is typically young
Pathophysiology adulthood between ages 30 and 44 years,37,39–41,58 although
there have been reports in children.59
Autopsy findings of the temporal bone in a patient with The differential diagnosis of hearing loss in the setting of
sarcoidosis and neurosensory deafness revealed a striking neurosarcoidosis includes syphilis, multiple sclerosis,
perivascular lymphocytic infiltration of the eighth nerve, Cogan’s syndrome, Vogt-Kyoanagi-Harada disease, endo-
resulting in myelin and axonal degeneration. Within the lymphatic hydrops, other granulomatous diseases including
inner ear, degeneration was evident in the cochlear and tuberculosis and Lyme disease, CPA tumors, and AIDS.42,56
labyrinthine neuroepithelium and stria vascularis.45 It has
been hypothesized that the neurosensory deafness and Evaluation
vestibular dysfunction in sarcoidosis begins as a reversible
neuropathy. With the persistence of the inflammatory In patients presenting with a unilateral or asymmetric
response, fibrotic changes occur, resulting in irreversible fluctuating or sudden-onset hearing loss, the diagnosis of
tissue damage.36,46 sarcoidosis should be included in the differential diagnosis.

Figure 25-3. In tumefactive sarcoidosis, the disease

presents as a dural-based meningioma-like mass.
Histologically, the typical feature is the presence of
numerous nonnecrotizing granulomas, composed of
epithelioid histiocytes and multinucleated giant cells.
A, Hematoxylin-eosin stain at low power; B, High power
view.

A B
476 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

Initial work-up includes a thorough history with a detailed TABLE 25-2. Laboratory Findings Supportive of the
review of systems, inquiring about fatigue, weight loss, Diagnosis of Sarcoidosis
changes in vision, and so on. Physical examination should
include a general exam, including assessment of the ACE ↑
WBCs ↓
skin, as well as complete otolaryngologic and neurologic Hemoglobin ↓
evaluations. Facial nerve function should be documented. Platelets ↓
Due to the high incidence of associated ocular findings, BUN and creatinine ↑
most often uveitis, patients who are suspected of having Serum calcium ↑
sarcoidosis should undergo ophthalmologic evaluation. Liver function tests ↑
ESR ↑
ACE, angiotensin I-converting enzyme ; BUN, blood urea nitrogen; ESR, erythrocyte
Audiology sedimentation rate; WBCs, white blood cells.

Audiometric testing includes pure tone audiometry, word

recognition, stapedial reflexes (usually absent), tympanom-
etry, and ABR (often absent or abnormal). If patients have clinical outcome.63 Increased immunoglobulin G (IgG)
associated vestibular symptoms, electronystagmography index and oligoclonal bands have been reported, suggesting
should be performed. that intrathecal immunoglobulin synthesis is increased.39,41
Elevated CD4:CD8 ratios of CSF lymphocytes have
Diagnostic Tests been reported,64 as have elevations in lysozyme and
β-2-microglobulin.42
The criteria for the diagnosis of neurosarcoidosis include a
clinical picture compatible with the disease, typical radio-
logic findings, and histologic evidence of noncaseating gran- Imaging
ulomas. Plain film chest radiograph is performed to search MRI with gadolinium is the imaging study of choice. The
for hilar adenopathy and pulmonary infiltrates, which are granulomatous lesions will enhance on T1 images with
present in ≈90% of patients at some time during the course gadolinium. MRIs performed without contrast may miss
of their disease.38 Biopsy specimens may be obtained from the diagnosis of sarcoidosis.49 Lesions are usually well
any involved tissue in the body. If pulmonary involvement is defined, slightly hyperdense, and homogenously enhanc-
evident, the diagnosis may be obtained by transbronchial or ing.42 Some lesions are quite large (Fig. 25-4), whereas
mediastinoscopic biopsy or bronchoalveolar lavage (BAL).36 others may be very subtle. MRI is also helpful for moni-
Fine-needle aspiration can give an accurate diagnosis when toring the response of CNS lesions to treatment.51 A lack
taken from involved lymph nodes or salivary glands.60 If no of vascularity of sarcoid granulomas is seen on angiogra-
specific lesions are identified, a random lip biopsy of minor phy.47 CT scanning is typically less sensitive but may reveal
salivary glands may confirm the diagnosis in 40% to 50% of a large mass as shown in Figure 25-4.
patients with hilar adenopathy.61 Gallium-67 scanning can identify sites of inflammation
Serologic testing, although nonspecific, should be and may be useful in identifying asymptomatic lesions that
obtained to support the diagnosis of sarcoidosis. Tests can be accessed for directed biopsy. Although the test can
include CBC (leukopenia, anemia, thrombocytopenia), be positive in any inflammatory or neoplastic lesions, the
electrolytes (elevated blood urea nitrogen [BUN] and cre- identification of pulmonary lesions is relatively specific for
atinine), serum calcium (hypercalcemia), liver function sarcoidosis.65
tests (elevated AST, ALT, Alk Phos), sedimentation rate
(elevated), and angiotensin I-converting enzyme (ACE,
elevated) (Table 25-2). ACE levels are often elevated in
Treatment
sarcoidosis and thought to be specific for this disease, but Systemic steroids are the cornerstone of treatment for sar-
increased levels are also seen in patients with leprosy, coidosis and neurosarcoidosis. Typically larger doses of
Gaucher’s disease, liver disease, diabetes mellitus, hyper- steroids are used with neurosarcoidosis, that is, 60 to 80 mg
thyroidism, systemic infection, and malignancy.61,62 methylprednisolone daily.42 Dosages should be tapered
Purified protein derivative (PPD) and appropriate skin carefully. In patients in whom corticosteroids may be con-
tests should be performed to rule out anergy, which occurs traindicated, other agents including methotrexate, aza-
in ≈25% of patients. thioprine, cyclosporine, chloroquine, hydroxychloroquine,
radiation, and other immunosuppressive drugs have been
Cerebrospinal Fluid Findings used.66 In cases of acute hydrocephalus, expanding mass
lesions, and progressively worsening neurologic deficit
Cerebrospinal fluid (CSF) findings in neurosarcoidosis secondary to increased intracranial pressure unresponsive
are nonspecific. However, up to 80% of patients with to medical treatment, surgical intervention is recom-
neurosarcoidosis show some CSF abnormalities.37 Abnor- mended for decompression.38,42
malities include mononuclear pleocytosis, increased protein,
elevated CSF pressure and low glucose levels. Increased CSF
ACE occurs in ≈50% of patients with neurosarcoidosis.
Outcomes
Levels tend to fall with treatment and correlate with the The hearing loss often improves with the initiation
activity of the disease42; however, Ferriby and coworkers of steroids. However, it may also be relapsing or chroni-
found no correlation between blood or CSF ACE and cally progressing. The prognosis for patients with
 Auditory Neuropathy, Sarcoidosis, Siderosis, and Idiopathic Pachymeningitis 477

A B

Figure 25-4. Axial (A) and coronal (B) T1-weighted MRI scans with
gadolinium demonstrate an enhancing petroclival lesion that was initially felt
to be a large meningioma. Axial CT scan (C) with contrast shows the same
homogeneously enhancing, noncalcified lesion.

neurosarcoidosis is poorer than for patients with sarcoido- past the diagnosis was officially made only at autopsy,67
sis without neurologic involvement. Patients with cranial whereas today the diagnosis is almost always made with
neuropathies and aseptic meningitis tend to do better, with MRI. The cardinal clinical features of superficial siderosis
a greater than 90% recovery or improvement compared are progressive SNHL and cerebellar ataxia.68
with those with other neurologic manifestations, especially
parenchymal disease, who tend to have a prolonged course
with significant morbidity.63 The mortality rate of neuro- Incidence
sarcoidosis is between 5% and 15%.40,41,64 The incidence of superficial siderosis of the CNS is
unknown. A review article by Fearnley and colleagues in
1995 revealed that only 87 cases have been reported in the
SUPERFICIAL SIDEROSIS OF THE world literature.68 With the advent of MRI, the diagnosis
CENTRAL NERVOUS SYSTEM can be made more readily and even detect presymptomatic
cases. In one series, MRI findings consistent with the diag-
Introduction nosis of superficial siderosis were found in 0.15% of 8843
consecutive MR studies. Eighty-five percent of these
Superficial siderosis of the CNS is a rare, but potentially patients reported no symptoms.71 Superficial siderosis can
fatal, cause of SNHL.67 The disorder is caused by deposi- occur in any age group, with age of onset ranging between
tion of hemosiderin in the CNS secondary to recurrent or 14 and 77 years. Males are typically more commonly
persistent bleeding into the subarachnoid space.68–70 In the affected than females (3:1).68
478 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

Etiology Clinical Presentation

The cause of superficial siderosis of the CNS is persistent Prior to the onset of symptoms there is reported to be a
or recurrent bleeding into the subarachnoid space, leading presymptomatic phase, in which superficial siderosis is
to a deposition of hemosiderin in the CNS. In a review present, but not sufficient to cause symptoms. This phase
series of 63 patients, the bleeding site was identified in ranges from 4 months to 30 years, with a mean of 15 years.68
54% of cases, whereas in 46% of patients the source of Clinically superficial siderosis of the CNS presents as a
bleeding remained unknown.68 In the cases in which the distinct syndrome characterized by progressive SNHL
site of bleeding was identified, the source was found to be (95%), cerebellar ataxia (88%), and pyramidal signs (76%).
due to dural pathology (CSF cavity lesion or cervical root The pyramidal signs range from mild symptoms, such as
lesion) in 47% of patients; a vascular tumor (ependymoma, hyperreflexia, to severe symptoms of paraparesis and quadri-
oligodendroglioma, and astrocytoma) in 35%; and a vas- paresis. Other symptoms include dementia (24%), bladder
cular abnormality (arteriovenous malformation or disturbance (24%), anosmia (17%), anisocoria (10%), and
aneurysm) in 18% of patients.68 Systemic iron overloaded sensory signs (13%) (Table 25-3).68
conditions, such as hemachromatosis, do not typically lead The most common feature of superficial siderosis is
to iron excess in the CNS due to the blood-brain barrier bilateral progressive SNHL, with the high frequencies
for iron.72 being more severely affected.68 The hearing loss may be
asymmetric and is typically retrocochlear, supported by
absence of stapedial reflexes and abnormal brainstem
Pathophysiology evoked potentials.68 Takasaki and coworkers suggest that
In superficial siderosis of the CNS, hemosiderin deposi- there may also be damage to the cochlea due to the eleva-
tion is primarily seen in areas bathed by circulating CSF, tion of the detective threshold of CM and no response on
including the cerebellum, brainstem, and eighth nerve. DPOAE in one patient.80 It is possible that damage to the
Chronic exposure of blood to the CSF leads to the break- organ of Corti could occur by way of a patent cochlear
down of hemoglobin into ferritin and hemosiderin, which aqueduct.81 One case of a sudden bilateral profound hear-
accumulates in the microglia.73 Immunohistochemical ing loss occurring at the time of a subarachnoid hemor-
staining has shown that selective siderosis of the cerebel- rhage has been reported.82
lum and eighth nerve is due to the biosynthesis of ferritin Vestibular function has been evaluated and reported in
in the microglia of these tissues.74 It has been postulated only a few patients with superficial siderosis. In all of the
that ferritin synthesis is neuroprotective by binding the patients evaluated, the vestibulo-ocular reflex is absent or
iron released into the CSF by the red cells and that tissue diminished.77,83 Symptoms of vertigo and unsteadiness
damage occurs only after this reserve has been exhausted.75 reported by patients probably have a combination of
A characteristic finding of superficial siderosis involving vestibular and cerebellar components.
the cranial nerves is preferential staining to the proximal
(glial) segments versus the distal (Schwann cell) seg- History and Physical Exam
ments.74 The eighth nerve, unlike the adjacent facial nerve,
retains its glial sheath up to the internal auditory canal Patients presenting with SNHL with or without ataxia
(IAC). This long glial segment makes the eighth nerve should undergo a complete history and physical exam,
particularly susceptible, resulting in a greater chance of including a neurologic evaluation. Questions related
hemosiderin deposition and chance of axonal damage. In to history of head trauma recently or in the past,
addition, the location of the eighth nerve in the pontine headaches, change in sense of smell or vision, and
cistern exposes the nerve not only to a large pool of CSF, symptoms of imbalance should be included. During the
but also a greater flow of CSF.68 Cranial nerve I is also otolaryngologic exam, the patient’s sense of smell should
affected for similar reasons, and it is speculated that anos- be tested.
mia is underreported in association with siderosis.68
Audiology
Pathology Audiometric testing includes pure tone audiometry, word
Gross pathology of superficial siderosis reveals character- recognition, and stapedial reflexes. Further testing may
istic light-brown staining of diffusely thickened and include ABRs or OAEs (or both). Vestibular testing
fibrotic leptomeninges.76 The eighth nerve, and to a lesser should be considered if patients report imbalance or
extent, cranial nerves I and II, are typically darkly pig- vertigo.
mented secondary to a dense accumulation of hemosiderin
often associated with demyelination and atrophy.74
Hemosiderin deposition in the tissues, revealed by staining TABLE 25-3. Key Clinical Features of Superficial Siderosis
with Prussian blue, is associated with demyelination, neu- Progressive sensorineural hearing loss (95%)
ronal loss, reactive gliosis, and the appearance of intra- Cerebellar ataxia (88%)
cellular rounded eosinophilic ovoid bodies.77,78 Ovoid Pyramidal signs (hyperreflexia, paraparesis, quadriparesis) (76%)
bodies represent degenerated axonal swellings caused by Dementia (24%)
Bladder disturbance (24%)
heme-iron complexes, which catalyze lipid peroxidase Anosmia (17%)
reactions, resulting in a local oxidative effect and neuroax- Anisocoria (10%)
onal dystrophy.79
 Auditory Neuropathy, Sarcoidosis, Siderosis, and Idiopathic Pachymeningitis 479

Cerebrospinal Fluid Findings

The main CSF findings are hemorrhage and xanthochro-
mia. Other features include elevated iron, red blood cell,
and ferritin levels, as well as the presence of erythrophages
and siderophages.68 A review of CSF findings in 48 patients
with superficial siderosis revealed hemorrhage in 20 patients
and xanthochromia in 16. In a small percentage of patients,
the CSF may be normal. In these cases it may be necessary
to repeat the CSF examination.68

Imaging
A suggestive clinical picture and CSF findings, along with
diagnostic MRI findings can confirm the diagnosis of
superficial siderosis of the CNS. MRI findings are pathog-
nomonic for superficial siderosis and MRI is currently
the gold standard for diagnosis, preventing the need for
biopsy (Table 25-4). T1-weighted images appear normal.
T2-weighted images reveal a characteristic marginal
hypointensity of the brainstem, cerebrum, cerebellum, and
eighth nerve (Fig. 25-5A, B). The hypointensity is due to
the paramagnetic effect of iron, which leads to the induc-
tion of local heterogeneous magnetic field gradients with
A
shortened relaxation times, promoting signal voids in the
MRI.68,84 CT is not useful for the diagnosis of superficial
siderosis,85 although it may show atrophy of the cerebrum
and cerebellum.
When an MRI of the head does not localize a site of
bleeding intracranially, further evaluation should include
MRI of the spine in search of a spinal cord lesion. If nega-
tive, magnetic resonance angiography (MRA) or conven-
tional angiography may be performed to exclude a vascular
lesion.69

Treatment
Treatment of superficial siderosis consists of identification
and surgical control or endovascular treatment of sus-
pected bleeding sites.67,68 There is currently no evidence
that chelating agents, such as deferoxamine, or antioxi-
dants, such as vitamin E, affect the progression of the
disorder.68
The hearing loss is typically managed with hearing aids.
Cochlear implant use has been successful in one reported
case in a patient with a bilateral profound hearing loss who
no longer benefited from hearing aids.81

Outcome
B
Superficial siderosis is a chronic illness. Once diagnosed,
patients may become bed-bound secondary to cerebellar Figure 25-5. Superficial siderosis. Axial T2-weighted MRI scans revealing
characteristic marginal hypointensity around the brainstem (A) and
ataxia or a myelopathic syndrome. Even after surgical cerebellum (B) due to the paramagnetic effect of deposited iron.
intervention to stop the bleeding, it may still take several
years before the effectiveness of surgery is known. Also, it

TABLE 25-4. Key MRI Findings in Superficial Siderosis is currently unknown whether the disease continues to
progress after the bleeding has been stopped. In most
T1-weighted images: Appear normal
T2-weighted images: Marginal hypointensity of brainstem, cerebrum,
cases, the disease is ultimately fatal, although it may
cerebellum progress slowly over several decades. The mean survival of
reported cases is 11 years.68
480 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

IDIOPATHIC HYPERTROPHIC (less than 60 mm H2O) that occurs without an inciting

PACHYMENINGITIS event, such as trauma or lumbar puncture. The clinical
course of SIH, unlike IHCP, is typically benign.93
Introduction
First described by Naffziger and Stern in 1949, idiopathic
Histopathology
hypertrophic pachymeningitis (IHCP) is a rare fibrosing Gross pathology of IHCP reveals an immensely thickened
inflammatory process characterized by marked thickening and fibrotic dura. Histologic features are characterized by
of the dura.86 The site of dural involvement can be subdi- a chronic nonspecific inflammatory infiltrate of lympho-
vided into intracranial, spinal, and craniospinal, with the cytes, plasma cells, and histiocytes (Fig. 25-6).89,91
intracranial form being rarer than the spinal form. The Granulomas may or may not be present.88 Chronic infec-
most common intracranial symptoms are headache, cranial tious and neoplastic processes are absent. It has been
nerve palsies, and ataxia. Presenting symptoms may theorized that the symptoms of headache and cranial
include hearing loss and tinnitus or vertigo. IHCP is neuropathies are secondary to nerve encasement and
a diagnosis of exclusion, since other clinical entities can ischemia due to the chronic inflammation and fibrosis of
produce thickening of the meninges. The diagnosis is the dura.88-90 Fibrosis may also cause occlusion of the venous
made with biopsy and supported with characteristic MRI sinuses.94
findings.
Clinical Presentation
Incidence and Etiology The clinical presentation of IHCP is extremely variable
The incidence and cause of IHCP are currently unknown. and depends on the site of involvement of the dura. The
Early reports of pachymeningitis were typically attributed most common symptoms are a subacute or chronic local-
to syphilis or tuberculosis. Today, however, most reported ized headache and single or multiple cranial neuropathies.
cases are idiopathic.87 The age at presentation in reported A review of 33 cases in the literature by Parney revealed
cases ranges from 20 to 78 years, with a mean age of that the most commonly affected cranial nerve is the
51 years. The incidence is equal in males and females.87,88 eighth followed by the second cranial nerve.87 Symptoms
The three main known causes of IHCP are sarcoidosis, include asymmetrical SNHL, tinnitus, and vertigo. The
tuberculosis, and syphilis.89–91 Other infectious causes hearing loss may be sudden in onset.95 Symptoms also
include fungi and viruses, including human T-cell lym- include ataxia. In a review of their series, Hatano and
phoma virus-1 (HTLV-1).92 Autoimmune causes include colleagues divided IHCP into two main sites of involve-
rheumatoid arthritis, Wegener’s granulomatosis, polyar- ment: (1) cavernous sinus to superior orbital fissure
teritis nodosa, and multifocal fibrosclerosis.91 Neoplastic involvement, affecting cranial nerves III, IV, V, and VI,
processes include lymphoma, plasmacytoma, meningioma, and (2) falcotentorial to posterior fossa dural involvement,
and metastatic prostate cancer.89 IHCP has also been asso- involving cranial nerves V, VII, VIII, IX, and X.89 IHCP
ciated with spontaneous intracranial hypotension93 and has also been associated with the Tolosa-Hunt syndrome
dialysis.90 Spontaneous intracranial hypotension (SIH) is a (painful ophthalmoplegia), optic neuropathy, and diabetes
rare syndrome associated with low intracranial pressure insipidus.89

Pathology

Giant cell

Intense
inflammation Figure 25-6. Histopathology slide showing a
chronic nonspecific inflammatory infiltrate of
lymphocytes, plasma cells, and histiocytes.

Granuloma &
Necrosis
 Auditory Neuropathy, Sarcoidosis, Siderosis, and Idiopathic Pachymeningitis 481

Evaluation
To make the diagnosis of IHCP, known causes of pachy-
meningitis must be ruled out (Table 25-5). Appropriate
work-up includes plain film chest radiograph, PPD skin
test, and CSF serology and culture. Serologic tests include
reactive protein reagent (RPR), ACE, rheumatoid factor
(RF), antinuclear antibody (ANA), and antineutrophil
cytoplasmic antibodies (C-ANCA). Nonspecific findings
in patients with IHCP include an elevated erythrocyte sed-
imentation rate (ESR) in the majority of patients, as well as
an elevated CSF protein.87 Dural biopsy is necessary to
exclude known causes of pachymeningitis and obtain the
diagnosis of IHCP. In patients in whom tuberculosis is sus-
pected, but routine tests are negative, use of polymerase
chain reaction (PCR) on CSF or biopsy specimen may be
helpful.91

Imaging
MRI with contrast is necessary to support the diagnosis.
IHCP lesions appear isointense or hypointense relative to
brain on T1-weighted images and hypointense with or
without a thin margin of hyperintensity on T2-weighted
images. Lesions show intense dural enhancement with
gadolinium (Fig. 25-7A, B).89,96 Lesions that are more A
localized may mimic a meningioma.97 Screening studies,
such as noncontrast fast-spin echo T2-weighted images
used for acoustic tumors, may miss the diagnosis.95 CT with
and without contrast often reveals thickening of the dura.94

Treatment
Management of IHCP involves corticosteroid therapy,
which has been effective in relieving symptoms and halting
the progression of the disease.90,91 Symptoms may recur or
progress, however, despite treatment.88,89 Hatano and col-
leagues89 and Bang and coworkers93 reported that linear
lesions, which have diffuse enhancement of the meninges,
might have a better response to corticosteroids than nodu-
lar lesions, which have a localized enhancement and thick-
ening of the meninges. High-dose pulse steroid therapy
may help to reduce side effects that occur with daily
steroid administration.89 Immunosuppressive agents, such
as azathioprine, used mainly to taper corticosteroids, have
shown early promising results, but long-term follow-up is
still needed.91 Radiotherapy has not been proven to be effec-
tive.89,91 Surgical excision is necessary to make the diagnosis B
of IHCP. In certain circumstances, such as involvement of Figure 25-7. Gadolinium-enhanced coronal (A) and axial (B) T1-weighted
the optic canal and superior orbital fissure, surgical decom- MRI scans depicting the intense dural enhancement and thickening seen with
pression may be necessary to help alleviate symptoms.88,89 pachymeningitis.

TABLE 25-5. Known Causes of Pachymeningitis In cases with a positive PPD, but negative histologic exam
Infectious Tuberculosis, syphilis, fungal, HTLV-1
and cultures for tuberculosis (TB), a trial of anti-TB med-
Autoimmune Rheumatoid arthritis, Wegener’s granulomatosis, ications may be warranted.87
polyarteritis nodosa, multifocal fibrosclerosis
Neoplastic Lymphoma, plasmacytoma, meningioma, metastatic
prostate cancer Outcomes
Other Sarcoidosis, spontaneous intracranial hypotension,
dialysis Although the number of reported cases of IHCP has
recently increased with the advent of MRI, there is still
HTLV-1, human T-cell lymphoma virus type I. much to learn with regard to cause, incidence, treatment,
482 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

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 Chapter
Vestibular Neuritis
26 Outline

Joel A. Goebel, MD, FACS Introduction Diagnosis

Historical Background Treatment
Gerard Gianoli, BSE, MD
Pathophysiology Prognosis
Clinical Features Future Directions

INTRODUCTION studied 85 cases and postulated a relationship between VN

and paroxysmal positional nystagmus.5
Vestibular neuritis (VN) is a clinical diagnosis made in In 1956, a landmark article appeared by Lindsay and
cases presenting with severe vertigo, nausea, and vomiting Hemenway describing seven cases of acute vertigo without
in the absence of significant hearing loss or central nervous hearing loss and the accompanying histopathologic
system signs. Throughout the years, numerous names have findings.6 In all seven cases, severe positional vertigo
been used for this clinical picture, including epidemic ver- developed after the initial prolonged attack and varying
tigo, neurolabyrinthitis epidemica, acute labyrinthitis, degrees of superior vestibular nerve, lateral and superior
vestibular paralysis, and vestibular neuronitis. As the name canal ampulla, and utricle damage was found with sparing
implies, VN is thought to be caused by an inflammatory of the inferior vestibular nerve and posterior canal
condition of the vestibular nerve, although the exact cause ampulla. Although they postulated vascular occlusion of
of the inflammation remains speculative. Even though the the anterior vestibular artery as the probable cause in
clinical picture can be variable, certain key features in the one case, no direct evidence of occlusion was noted and a
patient history and, to a lesser extent, the examination and viral cause was included in their differential diagnosis.
laboratory findings makes this diagnosis possible. Schuknecht (1962) studied these cases and four additional
In the following sections, we will explore the historical patients and postulated that the positional vertigo was
background of VN and the evolution of thought regarding caused by loosened otoconia from the damaged utricle
its pathophysiology and then discuss the main features of stimulating the intact posterior canal ampulla.7 From
the history, examination and laboratory findings. We will these two papers, it was suspected that, regardless of
then present current therapeutic options based on recent cause, V N was a selective degenerative process that spared
evidence regarding anatomic considerations and probable the inferior vestibular nerve, posterior canal ampulla, and
viral causes. Emphasis is placed on controversial issues saccule.
such as the exact nature of viral involvement, single versus In 1981, Schuknecht and Kitamura described temporal
recurrent attacks, and the cause of selective superior versus bone findings in patients with VN.8 In certain cases, selec-
inferior vestibular nerve involvement. tive superior vestibular nerve atrophy was seen without
end-organ degeneration. In other cases, however, both
neural and end-organ atrophy were found (Fig. 26-1). No
HISTORICAL BACKGROUND evidence of arteriolar thrombus or intralabyrinthine hem-
orrhage was seen. They concluded that VN preferentially
The first case of what might today be called VN was damaged the superior vestibular nerve and corresponding
reported in the literature in 1909 by Ruttin.1 In 1952, Dix end-organs without offering a plausible explanation for
and Hallpike reported 100 cases with either single or mul- this selectivity. Furthermore, a viral cause was suspected in
tiple attacks of vertigo without hearing loss and com- this disorder, but no definitive direct evidence was noted
mented that canal paresis with caloric irrigation was on histopathologic examination.
unilateral in 47% and bilateral in 53% of the cases. They The presence of a latent viral infection in VN had been
mentioned that all symptoms ceased within a few years suspected for many years before recent electron micro-
after diagnosis.2 Harrison (1962) studied 67 patients and scopic techniques and polymerase chain reaction (PCR)
noted recurrent attacks up to seven years later in 29 amplification became available. As noted earlier, Schuknecht
patients.3 Lumio and Aho (1965) followed 27 patients for and Kitamura felt that the lack of vascular injury in their
at least 6 months and noted that all patients showed specimens and a similarity in labyrinthine and neural
complete recovery or only mild unsteadiness.4 Boffi (1965) injury in three of their cases to a case of herpes zoster
484
 Vestibular Neuritis 485

affects the superior vestibular nerve and related labyrin-

thine receptors.

PATHOPHYSIOLOGY
Total atrophy
of ampullary Since the diagnosis of vestibular neuritis is clinical rather
nerve fibers Atrophy of crista than pathologic, the pathophysiology is speculative.
Lindsay and Hemenway thought the explanation for the
vertigo without hearing loss in their seven patients was
occlusion of the anterior vestibular artery, which supplies
the superior and lateral semicircular canal ampullae, utric-
ular macula, and the superior vestibular nerve itself. Later,
however, Schucknecht hypothesized that the insult was
Normal ampullary most likely viral due to the pattern of hair cell loss and
Normal crista nerve fibers fibrosis and the lack of any arterial or venous occlu-
sion seen on temporal bone microscopic examination.
Figure 26-1. Photomicrographs through sections of the superior vestibular Subsequent reports have supported the presence of viral
nerve and lateral semicircular canal ampulla in a patient with right vestibular particles in Scarpa’s ganglion in temporal bones of patients
neuronitis. A, Right ear shows severe atrophic changes in both the nerve and with and without a clinical history of VN but have failed
crista ampullaris. B, Left ear demonstrates normal nerve and end-organ to definitively prove that these viral particles are the
architecture. (Reprinted with permission from Schuknecht HF, Kitamura K.
Vestibular neuronitis. Ann Otol Rhinol Laryngol 78(Suppl):1–19, 1981.) cause of the clinical picture rather than a coincidental
bystander. There is, however, enough compelling immuno-
histochemical evidence in support of viral ganglionitis
oticus described by Zajtchuk and colleagues was suggestive (especially HSV-1) as the cause of VN to make it the
for a viral cause.9 Friedman and House described an abun- leading hypothesis.
dance of lipofuscin inclusion bodies in Scarpa’s ganglion Two puzzling observations about VN require further
cells in a case of clinical VN and felt that this may repre- investigation—that is, (1) why the superior vestibular nerve
sent a “wear and tear” phenomenon following a viral infec- and its end-organs are more often affected than the inferior
tion.10 In similar fashion, Baloh and coworkers described vestibular nerve, posterior canal, and saccule and (2) why
Scarpa’s ganglion cell loss in a patient with clinical vestibu- the amount of histologic injury varies widely from case to
lar neuritis and felt the changes were consistent with viral case. One theory states that VN is caused by a selective
infection even though electron microscopy or immuno- viral ganglionitis that only affects superior vestibular nerve
histochemistry failed to demonstrate evidence of viral cells.15 However, because no anatomic barrier exists within
particles.11 However, Furata and colleagues reported 6 of the ganglion to prevent viral spread between cells, this
10 temporal bones of patients with VN had herpes simplex explanation seems unrealistic Arbusow and coworkers pro-
virus (HSV) particles identified by PCR.12 Arbusow and posed a dual innervation of the posterior canal ampullae via
coworkers studied evidence of HSV-1 infection in both separate bony channels to explain sparing of posterior canal
Scarpa’a ganglion and the geniculate ganglion and found function. Recently, Goebel and colleagues and Gianoli and
widespread distribution of the viral elements throughout coworkers proposed anatomic differences in the length,
both ganglia. According to their study, serologic evidence trabeculation, and arteriolar channels between the superior
of primary exposure by HSV-1 can be found in more and inferior vestibular nerve bony paths to explain selective
than 80% of the adult population and has been identi- superior nerve and end-organ injury.16 Both studies con-
fied in Scarpa’s ganglion in 60% of temporal bone speci- firmed a longer, narrower, more trabeculated bony path for
mens by PCR.13 Historically, the evidence seems to the superior vestibular nerve compared with either the
support a viral etiology for VN although by the strictest inferior vestibular or singular nerves in normal temporal
definition a cause and effect relationship has not been bones (Fig. 26-2). They hypothesized that VN causes neu-
established. ral edema and subsequent entrapment and possible
As noted in the histopathologic studies of VN, a ischemia of the superior more than inferior nerve and end-
predilection for superior vestibular nerve or related end- organ structures. This theory also accounts for milder cases
organ structures is fascinating. Even the early observations with more complete recovery of function (no permanent
of Schuknecht and Kitamura that benign positional ver- ischemic changes) and more severe cases with loss of
tigo frequently occurs following VN suggests that poste- canal and otolith function. It must be noted, however, that
rior semicircular canal function is intact on the involved no study to date has documented definitive evidence of
side. Indeed, Fetter and colleagues used multiple-axis rota- vascular compromise.
tional measurements of the vestibulo-ocular reflex (VOR)
in patients with a clinical history of VN to show that
ipsilateral posterior canal function was intact while lateral CLINICAL FEATURES
and anterior canal function on the same side were vari-
ably reduced.14 In some instances, however, either all Typically, vestibular neuritis begins with an abrupt onset of
canal function or, rarely, only posterior canal function vertigo accompanied by nausea and vomiting. In some
is affected. In most cases, however, it appears that VN instances, the onset of the attack is less dramatic with an
486 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

of the initial vertiginous episode is typically hours up to a

day in duration.
Although the onset of VN is more predictable, the
chronic course of the disease is more variable. In most
cases, the initial episode will resolve, and the patient expe-
riences dysequilibrium while ambulating and momentary
dizziness with rapid head turns lasting up to 3 months
after the initial attack. However, some patients experience
repeated episodes of severe vertigo much like the initial
episode although the intensity and duration is usually less
than the first spell. One theory for the recurrent episodes
proposed by Gacek and Gacek is reactivation of a latent
viral ganglionitis secondary to another viral infection or
stress.15 In all instances, the episodes of vertigo diminish or
disappear but the residual dysequilibrium persists to a
greater or lesser extent. The variability in recovery is due
A to a combination of the extent of end-organ damage and
the ability of the central nervous system to compensate for
the loss of peripheral function. If end-organ damage is
minimal, persistent dysequilibrium is unlikely. However,
significant loss of ipsilateral semicircular canal and utricu-
lar function frequently leads to lingering postural instabil-
ity and disorientation with rapid head movements.
A fascinating observation is the apparent association of
benign positional vertigo (BPV) following VN in a per-
centage of cases. This observation was first made by
Schucknecht who hypothesized that utricular damage from
VN caused loosening of otoconia, which then migrated to
the posterior semicircular canal and stimulated the intact
posterior canal ampulla.7 Gacek and Gacek proposed an
alternative theory of recurrent viral ganglionitis to explain
the positional spells.15 In any event, BPV following neuritis
is common and is treated with the same canalith reposi-
tioning maneuvers used for idiopathic BPV.
B
Figure 26-2. Photomicrographs of sections through the labyrinth and
internal auditory canal in a normal temporal bone specimen. A, Superior DIAGNOSIS
vestibular nerve and canal. A denotes lateral semicircular canal crista,
B superior vestibular nerve, C arteriole of superior vestibular nerve, and The diagnosis of VN is made by a typical history and
D reticulated bony canal. Note the length and degree of bony trabeculations.
B, Singular nerve and canal. A marks the singular nerve, B the reticulations in exclusion of other causes of sudden loss of unilateral
the canal, C the arteriole within the canal, and D posterior canal ampulla. vestibular input. At times, the diagnosis of VN is difficult
Note the shorter course and looser trabeculation compared with part A. because many other recurrent vestibular pathologies can
(Reprinted with permission from Goebel J, O’Mara W, Gianoli G. Anatomic mimic VN at their onset. For example, the initial episode
considerations in vestibular neuritis. Otol Neurotol 22:512–518, 2001.)
of Ménière’s disease, perilymphatic fistula, or vestibular
migraine can all be indistinguishable from VN if there are
no auditory findings with the first episode. Over time,
antecedent period of vague dizziness and nausea. Many however, these entities can usually be identified by the
times the initial episode awakens the patient at night or is natural course and progression of the disease. In general,
first noticed when they get out of bed. The vertigo may VN is typically a single severe episode of vertigo without
wax and wane but is present in all head positions. Most involvement of the auditory system, whereas the other
patients feel better lying flat and still, although some pre- entities tend to be recurrent vestibulopathies and may have
fer to sit upright during the episodes. In all cases, head auditory involvement at some point as the disease pro-
movement exacerbates the vertigo and nausea. Sometimes gresses. However, some cases of VN involve recurrent
there is a history of upper respiratory infection or even bouts of vertigo and can only be distinguished from other
influenza preceding the attack, but this is not a predictable causes by the lack of hearing loss or any central nervous
historical finding. What is remarkable, however, is the system signs or symptoms after a thorough investigation.
absence of auditory or central nervous system signs and The typical history of VN includes the abrupt onset of
symptoms. In a minority of cases, unilateral tinnitus may severe rotary vertigo associated with nausea, vomiting, and
be present and audiometry may document a high-fre- diaphoresis. There are typically no auditory symptoms to
quency hearing loss. There is no loss of consciousness, localize the lesion. There may be a history of a prior cold
memory loss, or motor or sensory deficits that might be or upper respiratory infection in the days or weeks prior
seen in brainstem ischemia or infarction. The time course to the onset of the acute vertigo. During the attack, the
 Vestibular Neuritis 487

patient prefers to sit or lie perfectly still to minimize nausea. BPPV. The conventional treatment of acute-onset VN is
There should be no neurologic symptoms, such as blurred supportive care—antiemetics, hydration, and judicious use
or double vision, dysarthria, dysphagia, or alterations in con- of vestibular-suppressant medications. In mild cases,
sciousness. Vomiting is common and may be severe enough meclizine 25 mg PO tid is sufficient, whereas severe cases
to require hospitalization and intravenous fluids. Very often may benefit more from diazepam either orally or par-
the patient will be convinced that he is having a stroke or a enterally to suppress vertigo and nausea. Inpatient admis-
heart attack, precipitating a visit to the emergency room. sion may be justified in some cases due to the severity of
The length of the initial vertigo spell is usually a few hours vomiting and dehydration. Although vestibular suppres-
with a lingering disequilibrium for days to weeks. During sants may benefit the patient during the acute phase
the recovery phase, the patient usually notes symptoms of the disease, long-term use of these medications may
brought on mainly by quick head movements, particularly to actually delay central compensation by masking ongoing
the affected side. The patient may feel off balance for several symptoms. Consequently, tapering of vestibular suppres-
months after the incident and in some cases may have symp- sants should be done as soon as possible after the onset of
toms persist for years. Additionally, it is not uncommon for VN—usually within a week. There is also some evidence
patients to develop BPPV after a bout of VN. that early use of corticosteroids in VN may reduce the
Physical examination during the acute phase of VN will intensity and duration of the vertigo and may actually
demonstrate a brisk horizontal-rotary nystagmus with the improve overall recovery of function.17 Finally, since VN
fast phase beating to the uninvolved side, implying is felt to be viral in origin, there is a theoretical basis for
involvement of semicircular canals in both the horizontal using antiviral agents early in the disease process although
and vertical planes. Removal of fixation by using Frenzel no studies have confirmed their efficacy.
lenses intensifies the nystagmus. An otherwise normal Chronic treatment of VN should start soon after the
neurologic exam and the ability to stand unassisted with- diagnosis is made. Vestibular rehabilitation therapy with or
out lateropulsion is important in distinguishing VN from without assistance of a therapist should begin once the
an acute cerebellar hemorrhage or infarct. Imaging studies patient has been stabilized to help speed central compensa-
are usually normal, but high-resolution MRI with gadolin- tion. Exercises that reinforce the vestibulo-ocular reflex and
ium may show enhancement of the eighth cranial nerve. ambulation should be encouraged. Vestibular-suppressant
Oculographic studies are usually not indicated during the medications should be tapered to prevent symptom masking
initial episode but may demonstrate either unilateral or during central compensation. Most patients will note signif-
bilateral caloric reduction and a lingering nystagmus with- icant improvement in their symptoms within the first sev-
out fixation. If the extent of vestibular injury is substantial, eral weeks. However, some symptoms may persist for many
the patient may exhibit refixation saccades on unilateral months and in some severe cases indefinitely. Persistent
head thrust toward the affected ear even months to years symptoms may include disequilibrium with fast head
following the initial episode. movement, particularly when turning to the affected side.
In most cases, the patient with VN experiences a single As noted earlier, the appearance of BPPV following the
episode of vertigo lasting up to a day and recovers com- initial episode of VN is not uncommon. Treatment of
pletely over a few weeks. Some cases with documented concomitant BPPV is probably best delayed until the
severe vestibular loss may experience poor compensation patient has resolved the most severe symptoms of VN.
and lingering dysequilibrium. Finally, in a few cases of Canalith repositioning with the Epley or Semont maneu-
suspected VN the vertigo attacks recur although usually vers usually suffice as treatment. Treatment of concomi-
in diminishing intensity. tant BPPV is mandatory to enhance the patient’s chances
The key features of VN and common vestibular disor- for full central compensation.
ders in the differential diagnosis are listed in Table 26-1. Once satisfactory central compensation has occurred,
some patients may exhibit “decompensation.” Typically
when patients are fatigued or under physical or emotional
TREATMENT stress they may exhibit an exacerbation of movement-
induced disequilibrium. This will resolve when the fatigue
Medical management of VN can be divided into acute treat- or physical/emotional stress has resolved. Vestibular exer-
ment, chronic treatment, and treatment of concomitant cises may mitigate these symptoms. Vestibular suppressants

TABLE 26-1. Comparison of Vestibular Neuritis with Other Common Labyrinthine Disorders
Vestibular Neuritis Labyrinthitis Ménière’s Disease BPPV Acoustic Neuroma

Onset Abrupt Abrupt Variable Abrupt Slow

Duration Hours Hours Minutes Seconds Days
Intensity Severe Severe Variable Variable Mild
Hearing loss None Severe Variable None Variable
Recurrence Possible None Yes Yes Possible
Treatment Suppressants Suppressants Suppressants CRP Surgery
Steroids Steroids Diet, diuretic Observation
Gamma RT

BPPV, benign paroxysmal positioning vertigo; CRP, Canalith Repositioning Procedure; RT, Radiation Therapy.
488 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

usually do not help and may exacerbate these symptoms. 2. Dix M, Hallpike C: The pathology, symptomatology and diagnosis
A Dix-Hallpike exam should be performed during these of certain disorders of the vestibular system. Ann Otol 61:987–1016,
episodes to ensure these symptoms are not secondary 1952.
3. Harrison M: Epidemic vertigo-vestibular neuronitis: A clinical
to BPPV.
study. Brain 85:613–620, 1962.
4. Lumio J, Aho J: Vestibular neuronitis. Ann Otol Rhinol Laryngol
74:264–270. 1965.
PROGNOSIS 5. Boffi A: Positional nystagmus and vertigo in vestibular neuronitis.
Laryngoscope 75:484–490, 1965.
In most cases, VN is a benign self-limited process with an 6. Lindsay JR, Hemenway WG: Postural vertigo due to unilateral
excellent prognosis once the patient recovers from the ini- partial vestibular loss. Ann Otol 65:692–708, 1956.
tial attack. Recovery of balance is generally complete, and 7. Schuknecht HF: Positional vertigo: Clinical and experimental
alteration of lifestyle is not necessary. In some cases, how- observations. Trans Am Acad Opthalmol Otolaryngol 66:319–331,
ever, lingering disequilibrium is disturbing and requires 1962.
8. Schuknecht HF, Kitamura K: Vestibular neuronitis. Ann Otol
ongoing exercise therapy and modification of daily activi-
Rhinol Laryngol 78(Suppl):1–19, 1981.
ties. If BPPV develops, it may be recurrent, and reposition- 9. Zajtchuk JT, Matz GJ, Lindsay JR: Temporal bone pathology in
ing maneuvers may be needed from time to time. Finally, herpes oticus. Ann Otol Rhinol Laryngol 81:331–339, 1972.
in a few instances, recurrent vertigo attacks develop and 10. Friedmann I, House W: Vestibular neuronitis—Electron microscopy
require suppressant therapy. of Scarpa’s ganglion. J Laryngol Otol 94:877–883, 1980.
11. Baloh RW, Lopez I, Ishiyama A, et al: Vestibular neuritis: Clinical-
pathologic correlation. Otolaryngol Head Neck Surg 114:586–592,
FUTURE DIRECTIONS 1996.
12. Furata Y, Takasu T, Fukada S, et al: Latent herpes simplex virus
As the cause and pathophysiology of VN becomes more type I in human vestibular ganglia. Acta Otolaryngol (Stockh) 519
(Suppl):93–96, 1995.
clearly known, interventional therapy will be aimed at
13. Arbusow V, Schulz P, Strupp M, et al: Distribution of herpes simplex
reducing the ultimate amount of injury to the vestibular virus type I in human geniculate ganglia; Implications for vestibular
nerve and end-organ. Clinical trials are necessary to deter- neuritis. Ann Neurol 46:416–419, 1999.
mine the utility of corticosteroid and antiviral therapy 14. Fetter M, Dichgans J: Vestibular neuritis spares the inferior division
early in the course of the disease. Specific virus identifica- of the vestibular nerve. Brain 119:755–763, 1996.
tion in Scarpa’s ganglion and end-organ tissues in cases of 15. Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann
VN will enhance our understanding of whether direct cel- Otol Rhinol Laryngol 111:103–114, 2002.
lular injury or indirect neural and end-organ damage sec- 16. Goebel J, O’Mara W, Gianoli G: Anatomic considerations in
ondary to edema and ischemia is the mechanism of injury. vestibular neuritis. Otol Neurotol 22:512–518, 2001.
17. Kitahara T, Okumura S, Takeda N, et al: Effects of steroid therapy
on long-term canal prognosis and activity in the daily life of
vestibular neuronitis patients. Nippon Jibiinkoka Gakkai Kaiho 104:
REFERENCES 1059–106, 2001.

1. Ruttin B: Zur Differentialdiagnose der Labyrinth-u.

Hornervekrankungen. Z Ohrenheilkd 57:327–331, 1909.
 Chapter
Otologic and Neurotologic
Sequelae of Meningitis

Outline 27
Introduction Other Neurologic Alexis H. Jackman, MD
Epidemiology Abnormalities
David R. Edelstein, MD
Microbiology Testing
Pathophysiology and Treatment
Histopathology Conclusion
Signs and Symptoms

INTRODUCTION EPIDEMIOLOGY
Meningitis is a major cause of sensorineural hearing loss in The development and widespread use of H. influenzae type b
both the pediatric and adult populations. Despite recent vaccine has greatly altered epidemiologic patterns
advancements in its prevention, diagnosis, and treatment, of meningitis. Consequently, the epidemiology of post-
it is still associated with significant neurologic morbidi- meningitic hearing loss reflects this change, yet its impact
ties and mortality. Meningitis remains a major cause of remains. Wolff and Brown noted in a 1987 study that
sensorineural hearing loss.1–3 The effect of meningitis on 9% of children enrolled in special education programs
hearing is primarily a direct effect of infection in the inner suffered from hearing loss–associated meningitis.3
ear, but compromise of any structures along the auditory Presently, meningitis-associated hearing loss is a common
pathway of the central nervous system may also play a role. indication for cochlear implantation.7
The importance of understanding the disease process is Several types of meningitis exist and the probability of
critical to the neurotologist since cochlear implantation has developing a sensorineural hearing loss can often be pre-
assumed a prominent role in the treatment of postmeningitic dicted based the etiology of the disease. Hearing loss is
sensorineural hearing loss.4 most often attributed to the bacterial form of the disease.
Although the incidence of bacterial meningitis has Furthermore, the probability of developing a sensorineural
significantly decreased since the implementation of conju- hearing loss has been shown to differ among bacterial
gate Haemophilus influenzae type b vaccine, other forms of organisms, Streptococcus pneumoniae having the highest
bacterial meningitis are still prevalent and are associated reported incidence of hearing loss.8 Although fungal menin-
with high rates of deafness. Rates of hearing loss have been gitis rarely occurs, it has been reported to have as high as
reported in up to 40% of children with meningitis.2,5,6 43% chance of causing significant hearing loss; whereas,
Also, as the number of immunocompromised individuals viral meningitis, the most common form of meningitis, is
continues to increase, deafness associated with viral and associated with a low rate of hearing loss.9–11
fungal meningitis are increasing in prevalence. The reported incidence of hearing loss associated with
The influence of meningitis on speech and language are bacterial meningitis has varied over the past 40 years. A
amplified in prelingually deafened children. A major prob- major retrospective study in 1978 by Nadol reported that
lem associated with postmeningitic hearing loss is the diffi- 6% of the 547 participants exhibited hearing loss after
culty of identifying the condition in a young child. Optimum meningitis.11 Whereas, Rosenhall and Kankkunen in 1981
diagnosis and treatment of meningitis continues to change reported 30% of the 270 participants developed hearing
with medical advancements. Once meningitis is diagnosed, loss after meningitis.12 A recent meta-analysis of 45 studies
the choice of antibiotics becomes a critical decision for with a total of 4920 cases of pediatric meningitis reported
the physician and family. In addition, the adjunctive use hearing loss in 11% of patients, with a severe to profound
of steroids continues to be hotly debated. Identification of sensorineural hearing loss of 5%.13 Other studies have
hearing loss can lead to earlier intervention, such as hearing reported the percentage of significant hearing loss due
aid selection and cochlear implantation. Since the degree of to meningitis to be as low as 6% and as high as 40%
cochlear pathology at the time of surgery has surgical and (Table 27-1). This variation in incidence has been attributed
prognostic implications for patients who receive cochlear to several factors such as biases in the data collection, sample
implants, early coordination with a cochlear implant team is size, geographic location, and screening for effects of
essential if there is a profound bilateral hearing loss. ototoxic medication.
489
490 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 27-1. Studies of Incidence of Hearing Loss following Meningitis

Date Author* Cases Hearing Loss (%)

1962 Kresky1 155 6

1969 Sproles76 33 12
1976 Feigin20 50 6
1977 Lindenberg57 82 18
1977 Jones77 47 6
1978 Nadol11 547 6 (12% bacterial, 4% fungal, 0% viral)
1978 Raivio 131 22
1979 Keane19 100 6
1979 Habib91 775 6
1979 Nylen78 83 18
1980 Berlow74 47 11
1981 Finitzo-Hieber6 86 37
1981 Kotagal79 41 12
1981 Rosenhall12 270 30
1982 Feldman80 44 17
1983 Munoz81 70 31
1984 Dodge53 185 10
1984 Guiscafre41 236 16 (5% chronic)
1984 Kaplan82 37 11
1984 Vienny48 51 21 (10% chronic)
1984 MacDonald62 34 15
1985 Borkowski46 94 18
1985 Baldwin5 20 40
1985 Lin83 58 33
1986 Edwards84 86 8
1988 Lebel59 176 26
1988 Dawson86 145 10
1988 Smyth87 15 17
1989 Lebel & McCracken88 333 14
1990 Pomeroy et al89 191 10
1990 Schaad et al70 114 10
1990 Snedeker91 113 11
1990 Taylor et al92 97 8

Hearing loss can be defined only among meningitis Another reason for possible underreporting of meningitis-
survivors. Despite advances in treatment, there is still a sig- related hearing loss is unidentified unilateral hearing loss.
nificant incidence of mortality. A study from Bowman Gray The incidence of unilateral and bilateral meningitis has also
showed the death rate to be 12% in patients with acute varied in several studies. Henneford and Lindsay reported
meningitis and 31% in a smaller group with chronic a 5% incidence of bilateral hearing loss versus Nadol’s
meningitis.14 In 1995, the case fatality rate for bacterial reporting a 77% incidence of bilateral hearing loss.11,17
meningitis in the United States ranged from 6% for This loss often remains undetected unless the affected ear
H. influenzae to 21% for S. pneumoniae (Table 27-2).15 In or the contralateral ear undergoes additional otologic insult
contrast, a recent Canadian study of acute bacterial menin- that necessitates hearing testing.
gitis in adults in 2000 reported a mortality rate of 18%. In The effect of the patient’s age on the incidence of
this study, the highest meningitis-related mortality was meningitis-associated hearing loss is also debated. Twenty-
seen with Listeria monocytogenes of 40% followed by a rate one percent of children older than 2.5 years exhibited a
24% with S. pneumoniae.16 There is a strong possibility that sensorineural hearing loss compared with only 5% of chil-
this subgroup would have experienced a high incidence of dren younger than 2.5 years.11 Similarly, Vernon reported a
hearing loss and other neurologic sequelae if these patients high incidence of multiple neurologic sequelae in addition
had survived. to deafness among children younger than 18 months old

TABLE 27-2. Causes of 248 Cases of Bacterial Meningitis in 1995 and Overall Cases Fatality Rate According to Organism
Organism No. Cases Reported Percentage of Total Incidence Case Fatality Rate (%)

H. influenzae 18 7 0.2 6
S. pneumoniae 117 47 1.1 21
N. meningitides 62 25 0.6 3
Group B streptococcus 31 12 0.3 7
L. monocytogenes 20 8 0.2 15

From Schuchat A, et al: Bacterial meningitis in the United States in 1995. N Engl J Med 337:970, 1997.
 Otologic and Neurotologic Sequelae of Meningitis 491

who contracted meningitis.2 However, Ozdamar, Kraus, organism, making it now the fourth most common cause
and Stein found a lack of statistical significance to age or of meningitis in adults.25 Its prevalence among patients
prematurity on the probability of developing a hearing loss who have deficits in cell-related immunity, such as in
after meningitis.18 patients with human immune deficiency syndrome or hema-
There is some question as to the correlation of sex with tologic abnormalities, has been noted.26,27 As the number of
the incidence of hearing loss. Keane and colleagues, for immunocompromised individuals increases, more cases of
example, reported a male preponderance of 1.4 to 1 in the viral and fungal meningitis and meningitis-related hearing
younger than 1 age group.19 Similarly, in Vernon’s classic loss are being reported. Postviral meningitis–associated
study boys outnumber the girls 82 to 32.2 Feigin and hearing loss, although not as common as bacterial-associated
colleagues also reported a male-to-female ratio of 62% to hearing loss, does occur. The neurotropic nature of viruses
38%.20 In contrast, however, Nadol, Ozdamar, and others such as herpes simplex and human immunodeficiency virus
have not confirmed this sex distribution, nor has any other (HIV) are well known and their presence in the cochlea
researcher proposed a convincing explanation for such a and the eighth cranial nerve has been demonstrated.28
sex-related pattern of hearing loss.11,21

MICROBIOLOGY PATHOPHYSIOLOGY AND

HISTOPATHOLOGY
Meningitis may be caused by many bacterial and fungal
organisms as well as by several viral strains. Historically, The most prevalent etiology of hearing loss associated
meningitis was a disease of infancy and childhood and with meningitis results from an inflammatory labyrinthitis
was most commonly due to bacterial organisms such as initiated by an infectious pathogen via the cochlear aqueduct.
H. influenzae and S. pneumoniae. Other well-known causes The inflammatory infiltrate is then replaced by fibrous
of bacterial meningitis include Neisseria meningitidis, tissue and cellular debris, and subsequently, neoossification
L. monocytogenes, Staphylococcus aureus, and group B strep- within the cochlea occurs. The end result, termed cochlear
tococcus. The relative importance of different pathogens ossificans or labyrinthitis ossificans, is the pathological hall-
among various age groups continues to be seen in popula- mark of meningitis-related sensorineural hearing loss.
tion studies, but the predominance of various organisms Several authors have reported on histopathologic
within these groups has changed in the recent past. changes in the temporal bone after meningitis. Schuknecht
Twenty years ago, H. influenzae type b (HiB) meningitis presented seven cases of pneumococcal meningitis that
developed in 1 in 200 children younger than 5 years and caused a variety of pathologic findings including widespread
accounted for 70% of bacterial meningitis in this age inflammation of the pneumatized spaces of the temporal
group.22 In December 1987, HiB conjugate vaccines were bone, large pacchionian bodies in the posterior cranial
licensed for routine use. Its widespread use in preschool- fossa extending into the mastoid, and a suppurative
age children has lead to dramatic declines in diseases labyrinthitis with pus in the cochlear aqueduct and
caused by HiB, reportedly up to 94%, and the hope for vestibule.29 Igarashi described destruction of the stria vas-
eradication of the disease due to HiB now seems an attain- cularis and massive hemorrhage in the cochlear duct. He
able goal.23 Consequently, infants and children, the group postulated that primary bacterial endolymphatic involve-
HiB most affected, are no longer the age groups most ment could occur not only in suppurative labyrinthitis but
commonly associated with meningitis and meningitis- also in the serous form via destruction of local vessels. He
related hearing loss. highlighted the presence of large amounts of inflammatory
In a multistate surveillance study of bacterial meningitis cells along all the nerves of the internal auditory canal.
in 1995, the median age of patients with bacterial menin- Inflammation was noted in the spiral ganglion cells, the
gitis had risen from 15 months in 1986 to 25 years, and loose perivascular tissue, the modiolus, and directly in the
S. pneumoniae replaced H. influenzae as the most common endolymphatic space via Reissner’s membrane or the base-
pathogen. The most prevalent pathogen in neonatal menin- ment membrane.30,31
gitis remained Streptococcus agalactiae (group B streptococ- Keithley and Harris demonstrated the sequential cellular
cus). However, in infants 1 to 23 months old, S. pneumoniae changes in the cochlea in response to a viral pathogen in
and N. meningitidis have replaced H. influenzae as the animal models. Lymphocytes, macrophages, and polymor-
predominant organism in this age group, accounting for phonuclear cells and other inflammatory cells entered the
45% and 31% of cases, respectively. N. meningitidis has also cochlea and caused variable degrees of structural damage,
replaced H. influenzae as the most common pathogen in the although hair cells were identified. Later changes in the
2 to 18 years age group and N. meningitidis was reported cochlea included fibrotic tissue, blood vessels, and ectopic
to cause of 59% cases in this age group. In the over 19 age bone, which was shown to persist even after the viral
group, S. pneumoniae was the most common bacteria particles were cleared.32 Similar cellular changes have been
(62% of cases).15 It is also important to consider less com- seen in response to bacterial meningitis in an animal
mon causes of meningitis, which may have a regional or model using S. pneumoniae. Evidence for bacterial spread
seasonal occurrence such as Lyme neuroborreliosis.24 via the cochlear aqueduct in meningitis was also demon-
Neuroborreliosis presenting as encephalitis or meningitis strated as the most intense inflammatory response and
is more common in the European form of this disease. greatest amount of ossification occurred in the scala tym-
The incidence of L. monocytogenes is increasing in inci- pani of the basal turn of the cochlea, where the cochlear
dence with up to 12.5% of adult cases caused by this aqueduct joins the cochlea.33 Temporal bone studies using
492 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

electron microscopy and immunohistochemistry of HIV

were preformed by Roland and colleagues. Fibrotic
changes in the spiral lamina, basilar membrane, and external
spiral ligament were demonstrated as well as budding viral
particles.28
Other causes of hearing loss can occur anywhere along
the neural peripheral and central auditory pathway. Septic
emboli can be transmitted via the vertebrobasilar system
and arrest end organ blood flow to the cochlea. Leichenger
reported on a case of deafness in the presence of meningo-
coccemia without evidence of meningitis, demonstrating
the potential effect of septicemia on the cochlea.34,35 Also,
there may be a local neuritis of the eighth cranial nerve as
it runs in the internal auditory canal with an inflammatory
infiltrate interrupting neuronal impulse transmission.
Hearing loss from central auditory pathway dysfunction
can result from local edema or leukocytic infiltration in the Figure 27-1. Temporal bone specimen of a patient with meningitis shows an
auditory pathway or cortex. Brainstem dysfunction following inflammatory infiltrate in the scala vestibuli and scala media especially
meningitis is a known cause of multiple neurologic disor- in the basal turn.
ders associated with meningitis and is postulated to result
from increased intracranial pressure or hydrocephalus. 48 hours, although delayed hearing loss can occur.40,41 It
The pressure in the ventricles may promote prolongation has been theorized that the reason for the initial hearing
of waves I to V on auditory brainstem response (ABR) test- loss may be local inflammation or immediate vasospasm.
ing. Additionally, seizures associated with meningeal irri- Reports of long-term or delayed hearing loss following
tation and fever and associated hypoxia can also predispose meningitis may be due to either slow disruption of cochlear
these patients to hearing loss. hair cells or degeneration of the brainstem.42
Another possible route of spread for meningitis-related
hearing loss is from the middle ear following otitis media
via the round or oval window depending on which site had SIGNS AND SYMPTOMS
the predominant degree of inflammatory infiltrate.36,37
Children with congenital malformations of the inner ear, Physicians are faced with three diagnostic pictures involving
such as Mondini’s dysplasia, may be predisposed to meningi- meningitis. First is the patient with otitis media who devel-
tis following middle ear infection. Congenital abnormalities ops lethargy, headaches, nausea, and severe otalgia. In this
of the inner ear may be associated with cerebrospinal fluid case, the physician is already attuned to the many possibili-
leakage by pathologic interconnections via the internal ties of hearing loss. Second are the patients with meningitis
auditory canal, the cochlear aqueduct, the oval window, or who need a complete otolaryngologic workup to determine
the round window.38,39 the cause or source of infection. Third is the child with
Meningitis is a known complication of temporal bone meningitis with a nonotologic cause or no known cause
fractures. The callus formation at the fracture site is not who needs a thorough hearing and age-appropriate vestibu-
replaced by bone and provides infectious pathogens a path- lar evaluation and follow-up.
way to the central nervous system (CNS). Once in the Children with otitis media should be monitored for the
CNS, pathogenic spread to the cochlea can occur via the development of not only mastoiditis but also such other
cochlear aqueduct or via bony defects between the CNS
and the inner ear, resulting in an inflammatory response
and sensorineural hearing loss.
Three cases from the Temporal Bone Collection of the
House Ear Clinic help to demonstrate the effects of bacte-
rial meningitis on the inner ear. The first case involved a
young adult who developed meningitis as a result of a skull
fracture. He presented with mastoiditis in one ear, which
spread to the contralateral inner ear via the CNS as a result
of meningitis. Figures 27-1 through 27-4 demonstrate the
purulent accumulation in the cochlea and stria vascularis.
The second case was of a young woman who died of a brain
abscess as a complication of chronic otitis media. Figure 27-5
shows the contralateral ear and cellular infiltration of the
internal auditory canal and scala media. The third case
involved a 66-year-old man who also died from meningitis.
Figures 27-6 and 27-7 show pus cells in the ganglion tissue
and nervous infiltration by inflammatory cells.
Figure 27-2. Photomicrograph is taken at 55 power near the round window at
The timing and degree of labyrinthitis ossificans are the exit of the cochlear aqueduct showing pus cells filling the aqueduct and
unpredictable and vary from case to case. Auditory involve- extending into the basal turn of the cochlea. (From Schuchat A, et al: Bacterial
ment has been reported to occur usually in the first 24 to meningitis in the United States in 1995. N Engl J Med 337:970, 1997.)
 Otologic and Neurotologic Sequelae of Meningitis 493

Figure 27-3. A larger view of the anterior basal turn showing pus in the two Figure 27-5. Pus in the internal auditory canal. There are some fibrotic
scalae. (From Gary N, Powers N, Todd JK: Clinical identification and changes and inflammatory cells in the scala media.
comparative prognosis of high-risk patients with H. influenzae meningitis.
Am J Dis Child 143:307, 1989.)

middle ear disease. Ozdamar, Kraus, and Stein found that

intracranial complications as meningitis, brain abscess, 64% of patients with meningitis had normal or borderline
otic hydrocephalus, lateral sinus thrombosis, and subdural hearing, 16% had a conductive loss, and 22% had a sen-
abscess. The common symptoms of meningitis include sorineural hearing loss.18 Predictably, conductive hearing
stiff neck, abnormal vision (blurring and diplopia), tremor, loss was largely related to the presence of otitis media.
ataxia, and seizures. Common signs that should be investi- A correlation analysis revealed the presence of a sen-
gated include papilledema, dysmetria, hemianopsia, sorineural hearing loss to be statistically related to both the
abnormal eye movements, abnormal Romberg and gait, pathogen involved and a hospitalization longer than 14 days.
and other neurologic abnormalities.43 Similarly, Borkowski and colleagues reported on a group
In a paper from the Children’s Hospital of Denver, a of 94 children with meningitis in which 44% had normal
system called the Herson-Todd scoring method was hearing, 18% had a sensorineural hearing loss, 17% had a
devised to predict hearing loss in certain high-risk patients conductive hearing loss, 11% had mixed losses, 9% had
with meningitis due to H. influenzae (see Table 27-3). The retrocochlear pathology, and 1% were identified as other
criteria included coma, hypothermia, seizures, shock, age, or unknown.46
cerebrospinal fluid (CSF) white blood cell count, hemo- Fluctuating and delayed hearing loss have both been
globin CSF glucose, and symptoms lasting more than described by Rosenhall and Kankkunen.12 In a series of
3 days. Outcome parameters included cognitive, motor, 327 patients followed for 3 years, Trolle found no cases of
clinical, speech, hearing, and visual factors.44,45 All of these fluctuating hearing.47 However, in a series of 236 patients
factors should be documented in the patient’s record. followed for 6 months, Guiscafre and colleagues found
The most common type of hearing loss following 28 patients with fluctuations in their sensorineural hearing
meningitis is a sensorineural loss, although a conductive loss.41 Vienny and colleagues also found in their series that
component may be present initially due to concurrent 68% of the patients had normal hearing, 22% had transient

Figure 27-6. Pus in Rosenthal’s canal and in the perilymph of the scala
Figure 27-4. High-power view of the organ of Corti demonstrating its vestibuli. The inflammatory cells are scattered among the ganglion cells and
disintegration as well as some changes in the stria vascularis. in the adjacent tissue.
494 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

ataxia. One of the challenges facing the clinician is to iden-

tify these problems systematically in order to better focus
on treatment and rehabilitation.
Historically the number of serious neurologic problems
experienced after recovery from meningitis was large.
In Trolle’s study from 1920 to 1945, he identified a
prechemotherapy rate of 54% (41% of these neurologic
sequelae were severe), which dropped to 50% after the early
introduction of sulfonamides and penicillin (17% severe).47
Similarly, in studies from the late 1940s and early 1950s,
Crook, Smith, and others identified a 12% to 19% incidence
of serious neurologic sequelae.51,52 In 1963, Dodge and
Swartz presented a series in which 44% of the patients
with H. influenzae meningitis experienced seizures, 12%
went into profound coma, and 18% developed ocular
movement dysfunction, and some died from cerebral
Figure 27-7. This auditory nerve has been invaded by many purulent cells.
edema.53 Nadol reported that 21% of meningitis survivors
had at least one nonotologic neurologic complication.11
Seizures are a common problem in patients who have
changes, and only 10% had early and persistent hearing meningitis with rates of up to 31%. Seizures included both
loss.48 Similar findings have been recorded by several generalized and focal and several patients experienced
other authors.18 Rosenhall and Kankkunen reported cases prolonged episodes of status epilepticus.53
of delayed hearing loss after a normal hearing interval Ataxia and other symptoms of vestibular dysfunction
between 6 and 12 months.12 have also been described as a both short- and long-term
Several configurations of hearing loss have been sequelae of meningitis. Farmer in 1945 reported on unilat-
reported. In Brookhauser’s series, 53% of the children eral and bilateral vestibular involvement in children with
with meningitis had a sensorineural hearing loss, of which meningococcal meningitis.54 Schwartz reported several
83% had a bilateral profound hearing loss, 14% had a children who had ataxia before treatment and two who
moderate hearing loss, and 3% had a mild hearing loss. In developed ataxia without other vestibular abnormalities.55
the better hearing ear, there was fairly even distribution of The ataxia was most likely cerebellar. Some of these patients
sharply sloping flat, through-shaped, and rising hearing.49 could have also developed ataxia due to use of streptomycin.
In Vernon’s classic work on prematurity and deafness, he In one series, eight children with postmeningitic ataxia were
compared the various causes of deafness and found meningi- reported. Of the seven children who were tested, electronys-
tis to result in the largest average level of hearing loss (93 dB) tagmography was abnormal in three, and all of the children
compared with such other causes as genetics (88 dB), prema- had a gradual improvement in their ataxia.56 Lindberg and
turity (83 dB), rubella (82 dB), and kernicterus (76 dB).2 colleagues reported that 12% of the 82 children in their
study developed temporary ataxia.57
Several other cranial neuropathies have been reported.
OTHER NEUROLOGIC ABNORMALITIES Dodge and Swartz best described the many focal signs of
cerebral dysfunction. Among the 147 cases in their study
Before the introduction of antibiotics, up to 60% of the were 3 cases of dysphagia, 8 cases of disconjugate gaze,
children with meningitis developed either brain damage or 3 cases of visual defects, 10 episodes of hemiparesis, and
some other form of serious neurologic dysfunction.1 Since 6 cases of paraplegia. Many of these complications may be
the 1950s, the incidence of neurologic sequelae after due to multiple factors including heightened intracranial
meningitis has ranged from 10% to 30%.50 The major pressure, generalized cerebral swelling, and purulent
neurologic sequelae include retardation, seizures, and material in the ventricles and subarachnoid space.53
Meningitis is also a leading cause of brain damage in
children. In early studies, major neurologic sequelae were
TABLE 27-3. Scoring System for Prediction of Morbidity reported to affect between 15% and 71% of meningitis
in H. Influenzae Meningitis patients. The percentage of deafness associated with other
Factor at Admission Points major neurologic problems was reported by Vernon to be as
high as 28%. These associated problems included cerebral
Severe coma 3 palsy, aphasia, mental retardation, and emotional distur-
Hypothermia 2 bances. The prevalence of multiple disturbances was as
Seizures 2
Shock 1
high as 38%. He reported that children younger than 1 year
Age <12 months 1 were most susceptible to these sequelae and that 35% of
CSF white blood cell count <1000 × 10/L 1 postmeningitic deaf children had an IQ level lower than 90.2
Hemoglobin <110 g/L 1 Sell and colleagues in 1971 attempted to study two groups
CSF glucose <1.1 mmol/L 0.5 of children: one with meningitis and a second matched pair
Symptoms persisting >3 days 0.5
or a near-age sibling. They found that based on several test
From Gary N, Powers N, Todd JK: Clinical identification and comparative prognosis of methods, the postmeningitic child had a greater chance of
high-risk patients with H. influenzae meningitis. Am J Dis Child 143:307, 1989. having a low IQ and other psychological sequelae.58
 Otologic and Neurotologic Sequelae of Meningitis 495

TESTING recommended that ABR tests be performed either when

the child is recovering or at least 1 week following the
Patients with meningitis usually undergo many tests during beginning of the antibiotic therapy.62
their hospital stay. The normal workup includes a physical One limitation of traditional click-stimulus ABR is an
examination, lumbar puncture, multiple blood tests, and a inability to identify hearing loss in the low- or middle-range
basic neurologic and infectious disease review. In a recent frequencies. In 1988, Brookhauser, Auslander, and Meskan
study of adult bacterial meningitis in 100 patients, Huessein highlighted this conflict. They noted that postmeningitic
and colleagues found almost all patients (97%) presented hearing loss could have a “wide array of audiometric con-
with fever higher than 37.7°C, 87% of patients had nuchal figurations,” not all of which could be easily outlined by
rigidity, and 51% had a decreased level of consciousness.16 ABR.49 Frequency-specific ABR and pure tone audiograms
Radiographs and magnetic resonance imaging (MRI) may become critical in these patients. They also emphasized
help to identify the source of infection and possible the importance of the audiologist’s impressions regarding
intracranial complications. However, computed tomography the test reliability in determining the type of test and repeti-
(CT) scans do not yield additional information useful in tion of testing necessary per patient. Newer techniques
prognosticating the outcome of the disease.59 using otoacoustic emission testing may also be helpful with
Hearing tests should be performed as soon as the patient the young or uncooperative child or infant.
has been stabilized. Unfortunately, audiograms are often If the patient has been identified as a potential cochlear
delayed to end of the hospitalization because of the needs implant candidate, additional radiographic testing is usually
of these sick children in the intensive care unit. Follow-up requested. Although high-resolution computed tomography
audiograms are just as important as the initial studies. Tests (HRCT) is traditionally used in cochlear implantation, a
should be performed promptly if there is a questionable high-resolution fast spin-echo T2-weighted MRI scan of
hearing loss. After hospital discharge, hearing tests should the temporal bone has been shown to be advantageous in
be repeated every 3 to 6 months until hearing has stabilized postmeningitic patients for its ability to detect cochlear
because both delayed deterioration and recovery of hearing fibrosis, which can be undetected by HRCT.63 Therefore,
are possible.12 a temporal bone MRI is often part of the preoperative
One challenge of otologists is assessing the neonatal or workup in postmeningitic patients.
infant patient with meningitis who needs a hearing evalua-
tion. Although traditional cribigrams and play audiometry
offer good screening tools, they are rough tests and do not TREATMENT
localize the side of loss and can miss significant fluctuations
in hearing. In 1971, Jewett and Williston suggested the use Children with meningitis may present with either a mild
of ABR testing as a major advance in testing young children febrile illness with neck stiffness or a profound illness with
or patients with serious neurologic damage who would not seizures, coma, and disseminated intravascular coagulation.
comply with the usual audiometric protocols.60 Thresholds Both groups need aggressive treatment and intensive care
in the higher frequencies are similar in the traditional click- monitoring after the diagnosis is made. Since the introduc-
specific ABR. In these tests, wave 1 may be used to monitor tion of antibiotics, the principal debate regarding the treat-
the integrity of the auditory nerve with the remaining ment of meningitis has concerned the choice of antibiotics
waves monitoring the brainstem auditory pathway. Absolute and the possible use of steroids in diminishing complications.
latencies, interwave latencies, and latency shifts can be Fluid management and frequent neurologic evaluations are
used to identify cochlear pathology, hypoxic encephalopathy, also essential.
intracranial hemorrhages, demyelination, and other brain- The first priority in the treatment of meningitis is the
stem abnormalities.61,62 initiation of antimicrobial therapy, which usually begins
Several authors have used ABR tests to monitor hearing with empiric therapy until Gram stain and culture results
loss in their patients with meningitis. In 1981, Finitzo- are available. Decisions regarding empiric therapy are
Hieber, Simhardi, and Hieber demonstrated the importance based on probable types of organisms and their known
of using ABR by identifying 14% more children suffering patterns of antibacterial resistance as well as on factors that
from unilateral hearing loss following meningitis than affect the bactericidal activity of an antibiotic in the
would have been identified by standard audiometric tech- cerebrospinal fluid. Optimal antibiotic therapy requires
niques.6 Similarly, by using ABR, Ozdamar, Kraus, and that the drug have a bactericidal effect in the cerebrospinal
Stein were able to identify hearing abnormalities in 37% fluid because specific antibody and complement factors are
of children included in the 1983 study. Of this group, 15% frequently absent in this immunologically deficient site.
had conductive hearing loss and 22% had sensorineural Major factors that influence bactericidal activity in the
hearing loss (10% had brainstem neuropathology).18 In CSF include degree of CNS penetration, concentration in
1984, Vienny and colleagues studied 51 children prospec- the CNS, and the antibiotic’s intrinsic activity. The advan-
tively with ABR; 69% had normal recordings, 22% tages of third-generation cephalosporins include their
showed transient abnormalities, and 9% had persistent increased antibacterial activity, increased CSF penetration,
auditory pathology.48 MacDonald and Feinstein in 1984 and expanded spectrum against β-lactamase organisms and
found a 62% agreement between standard conditioned gram-negative enteric bacilli as well as a reduced toxicity
orienting response testing (COR) and ABR. They con- compared with chloramphenicol and aminoglycosides.
cluded that ABR was more effective than COR for testing The age of the patient as well the health status and
infants younger than 6 months, children with significant immunization records of the patient will direct the clinician
handicaps, and patients with unilateral hearing loss. They toward the most likely organisms. For example, for a
496 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

nonimmunized 3-year-old child, antibiotic coverage who received steroids. Unfortunately, hearing was not
should be obtained for H. influenzae, N. meningitidis, and monitored as an outcome parameter. Eden and Cummings
S. pneumoniae. In the case of a 50-year-old patient receiving in 1978 and Berlow and colleagues in 1980 reported the
cytotoxic chemotherapy for leukemia, treatment should possibility of reversing the hearing loss of patients with
include coverage for Listeria and gram-negative organisms meningitis if they are treated with steroids.73,74 The best
as well as for S. pneumoniae. study of this subject was undertaken by Leben and colleagues
After identification of the probable causative organism, in 1988 when two double-blind placebo-controlled trials
knowledge of current patterns of antimicrobial resistance is in children with bacterial meningitis were performed. In
critical. A worldwide increase in antimicrobial resistance one study cefuroxime was used and in the second ceftriaxone
strains of S. pneumoniae has been documented. Resistance was used and both were combined with either a placebo or
of S. pneumoniae is mediated by alterations in penicillin- steroid. Lebel and colleagues found that the patients who
binding proteins involved in the synthesis of bacterial cell were treated with steroids had less moderate or severe
walls.64 In a 10-month surveillance study of S. pneumoniae bilateral hearing loss than the placebo group. Fifteen percent
in Atlanta, Georgia, in 1994, 25% of patients with invasive of the patients in the placebo group had bilateral sen-
pneumococcal infection were resistant to penicillin and sorineural hearing loss compared with only 3% of the
9% of those were also resistant to cefotaxime.65 Presently, recipients of dexamethosone.59 Gary, Powers, and Todd in
S. pneumoniae remains sensitive to vancomycin, which is 1989 reported that children with high Henson-Todd
the recommended therapy with presumed antibiotic resist- scores who were given steroids had a better outcome than
ance S. pneumoniae. If H. influenzae is suspected, the high those who did not receive steroids.14
prevalence of β-lactamase-resistant strains require empiric Once culture and sensitivity results are available, thera-
treatment with a third-generation cephalosporin such as peutic treatment can be tailored to these results, but it is
cefotaxime. Fortunately, most strains of N. meningitidis are also essential to try to identify the underlying cause of the
sensitive to ampicillin, although isolates with penicillin- meningitis. The otolaryngologist should not lose sight of
binding proteins have been identified in the United States, his or her role in identifying middle ear effusions or other
Europe, and South Africa.66–68 In these cases, a second- or possible otologic causes. In many patients, particularly
third-generation cephalosporin can be used. children, the underlying cause may be an upper respiratory
The interval between the first signs of meningitis and infection or a middle ear infection. Rapid drainage and cul-
the beginning of antibiotic therapy may affect the clinical turing of these sources will help both to relieve the inciting
and audiologic outcomes. Nadol reported that for children infection and to identify the pertinent organisms and their
who suffered no hearing loss, the average time to treatment sensitivities. Patients with mastoiditis should undergo a
was 32 hours compared with 47 hours for those who sus- complete mastoidectomy once antibiotics have been started
tained a hearing loss.11 Others have confirmed his result, and the patient is considered stable. In some individuals,
including Vienny and colleagues, who found that most HRCT scanning of the temporal bone may detect a congen-
hearing loss associated with meningitis occurs early in the ital cochlear abnormality or a traumatic break in the bony
course of the disease.48,69 A recent study compared the barriers between the cerebrospinal space and the environ-
audiologic outcomes of cefuroxime and ceftriaxone in ment. Unfortunately, the otologic cause of meningitis often
order to elucidate if the time to CSF sterilization had any goes unrecognized. Gower and McGuirt found, for example,
effects on hearing. The group, which received ceftriaxone, that only 22% of patients with a CNS complication of ear
which is known to more rapidly sterilize CSF, was found to disease had a complete otologic evaluation.75
have a 17% less frequent moderate to profound hearing
loss than the cefuroxime group.70 However, Dodge and
colleagues pointed out in 1984 that it can be difficult to CONCLUSION
determine the time when meningitis begins.69 Although
early antibiotic intervention is a priority in the treatment Meningitis remains a serious cause of hearing loss and
of any infection, the literature on the relationship of the other neurologic disorders. Advances in the antibiotic
timing of treatment of meningitis with long-term results development over the last 40 years have diminished the
remains controversial. incidence of the disease and lessened the chance of death.
Adjuncts to antibiotic treatment of meningitis have been Over the last 15 years, the greatest advance in reducing the
a focus of widespread study and speculation. In Dodge and prevalence of meningitis has come from the new vaccines.
Swartz’s landmark work in 1963, they suggested the use of Nevertheless, the incidence of temporary and permanent
high-dose corticosteroids to decrease the high CSF pressure hearing loss remains high in these patients, and cochlear
associated with meningitis.53 Other actions of steroids in implantation remains the treatment of choice for many
meningitis include decreasing brain edema, decreasing patients with severe to profound hearing loss.
prostaglandin concentrations, and inhibiting arachidonic Otologists often observe meningitis as a result of otitis
acid formation. It may also reduce the concentration of media. Early recognition of signs of meningismus and
lactate and protein and increase glucose in the CSF. prompt intervention with antibiotics and steroids may
Several case reports of glucocorticoid therapy were pre- alleviate or lessen long-term neurologic sequelae. Every
sented with good results. In 1969, two independent studies patient should have a full otolaryngologic and audiologic
by DeLemos and Haggerty and Belsey, Hoffpauir, and evaluation in addition to medical and neurologic workups.
Smith failed to show beneficial effects of steroids on the Close follow-up collaboration among the otologist,
outcome of meningitis.71,72 In this study the incidence of implant team, and medical teams provides the best care and
long-term neurologic effects was high among the patients outcome in patients with meningitis-related hearing loss.
 Otologic and Neurotologic Sequelae of Meningitis 497

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9. Adair CV, Gauld RL, Smadel JE: Aseptic meningitis, a disease of 38. Ohlms LA, et al: Recurrent meningitis and Mondini dysplasia. Arch
diverse etiology: Clinical and etiologic studies of 854 cases. Ann Int Otolaryngol Head Neck Surg 116:608, 1990.
Med 39:675, 1953. 39. Parisier SC, Birken E: Recurrent meningitis secondary to idiopathic
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11. Nadol JB Jr: Hearing loss as a sequela of meningitis. Laryngoscope Report of 337 cases of deafness due to cerebrospinal meningitis.
88:739, 1978. Chinese Med J 81:127, 1962.
12. Rosenhall U, Kankkunen A: Hearing alterations following meningitis: 41. Guiscafre H, et al: Reversible hearing loss after meningitis:
2. Variable hearing. Ear Hear 2:170, 1981. Prospective assessment using auditory evoked responses. Ann Otol
13. Baraff LJ, Lee SI, Schriger DL: Outcomes of bacterial meningitis in Rhinol Laryngol 93:229, 1984.
children: A meta-analysis. Pediatr Infect Dis J 12:389, 1993. 42. Silkes ED, Chabot J: Progressive hearing loss following Haemophilus
14. Gary N, Powers N, Todd JK: Clinical identification and comparative influenzae meningitis. Int J Ped Oto 9:249, 1985.
prognosis of high-risk patients with Haemophilus influenzae meningitis. 43. Powell KR: Meningitis. In Hoekelman RA, et al (eds.): Primary
Am J Dis Child 143:307, 1989. Pediatric Care, 2nd ed. St. Louis, Mosby Year Book, 1992, p 1352.
15. Schachat A, Robinson K, Wenger JD, et al: Bacterial meningitis in 44. Gantz B, McCabe B, Tyler R: Use of cochlear implants in obstructed
the United States in 1995. N Engl J Med 337:970, 1997. and obliterated cochleas. Otolaryngol Head Neck Surg 98:72, 1988.
16. Hussein AS, Shafran SD: Acute bacterial meningitis in adults: 45. Herson VC, Todd JK: Prediction of morbidity in hemophilus influenzae
A 12-year review. Medicine 79:360, 2000. meningitis. Pediatrics 59:35, 1977.
17. Henneford GE, Lindsay JR: Deaf-mutism due to meningogenic 46. Borkowski WJ, et al: Cerebrospinal fluid parameters and auditory
labyrinthus. Laryngoscope 78:251, 1968. brainstem responses following meningitis. Pediatr Neurol 1:134, 1985.
18. Ozdamar O, Kraus N, Stein L: Auditory brainstem responses in 47. Trolle E: Defective hearing after meningococcal meningitis. Acta
infants recovering from bacterial meningitis. Arch Otolaryngol Otolaryngol 38:384, 1950.
109:13, 1983. 48. Vienny H, et al: Early diagnosis and evolution of deafness in childhood
19. Keane WM, et al: Meningitis and hearing loss in children. Arch bacterial meningitis: A study using brainstem auditory evoked
Otolaryngol 105:39, 1979. potentials. Pediatrics 73:579, 1984.
20. Feigin RD, et al: Prospective evaluation of treatment of hemophilus 49. Brookhauser PE, Auslander MC, Meskan ME: The pattern and
influenzae meningitis. J Pediatr 88:542, 1976. stability of postmeningitic deafness. Laryngoscope 98:940, 1988.
21. Ozdamar O, Kraus N: Auditory brainstem response in infants 50. Hutchison PA, Kovacs MC: The sequelae of acute purulent menin-
recovering from bacterial meningitis: Neurologic assessment. Arch gitis in childhood. Can Med Ass J 89:158,1963.
Neurol 40:499, 1983. 51. Crook WG, Clanton R, Hodes HL: Hemophilus influenzae meningitis.
22. Cochi SL, Broome CV, Hightower AW: Immunization of US chil- Pediatrics 4:643, 1949.
dren with Hemophilus influenzae type B polysaccharide vaccine: 52. Smith ES: Purulent meningitis in infants and children: A review of
A cost-effectiveness model of strategy assessment. JAMA 253:251, 409 cases. J Pediatr 45:425, 1954.
1985. 53. Dodge PR, Swartz MN: Bacterial meningitis: A review of selected
23. Adams WG, Deaver KA, Cochi SL, et al: Decline of childhood aspects II. Special neurologic problems, postmeningitis complica-
Haemophilus influenzae type b (Hib) disease in the HiB vaccine era. tions and clinicopathological correlations. N Engl J Med 272:954,
JAMA 269:221, 1993. 1963.
24. Christen HJ: Lyme neuroborreliosis in children. Ann Med 28:235, 54. Farmer TW: Neurologic complications during meningococcic menin-
1996. gitis treated with sulfonamide drugs. Arch Int Med 76:201, 1945.
25. Schwartz B, Robinson ZK, Wegner JD, et al: Bacterial meningitis in 55. Schwartz JF: Ataxia in bacterial meningitis. Neurology 22:1071, 1972.
the United Stated in 1995. N Engl J Med 337:970, 1997. 56. Kaplan SL, et al: Ataxia and deafness in children due to bacterial
26. Lorber B: Listeriosis. Clin Infect Dis 24:1, 1997. meningitis. Pediatrics 68:8, 1981.
27. Mylonakis E, Hohmann EL, Calderwood SB: Central nervous 57. Lindenberg J, et al: Long-term outcome of hemophilus influenzae
system infection with Listeria monocytogenes: 33 years’ experience at meningitis related to antibiotic treatment. Pediatrics 60:1, 1977.
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58. Sell SHW, et al: Psychological sequelae to bacterial meningitis: Two 75. Gower D, McGuirt WF: Intracranial complications of acute and
controlled studies. Pediatrics 49:212, 1972. chronic infectious ear disease: A problem still with us. Laryngoscope
59. Lebel MH, et al: Dexamethasone therapy for bacterial meningitis 93:1028, 1983.
results of double-blind, placebo-controlled trials. N Engl J Med 76. Sproles ET, et al: Meningitis due to Hemophilus influenzae: Long-
319:964, 1988. term sequelae. J Pediatr 75:782, 1969.
60. Jewett DL, Williston JS: Auditory-evoked far fields averaged from 77. Jones FE, Hanson DR: H. influenzae meningitis treated with ampi-
scalp of humans. Brain 94:681, 1971. cillin or chloramphenicol, and subsequent hearing loss. Develop
61. Jerger J: Prediction of sensorineural hearing level from the brain Med Child Neurol 19:593, 1977.
stem evoked response. Arch Otolaryngol 104:456, 1978. 78. Nylen O, Rosenhall U: Hemophilus influenzae meningitis and hearing.
62. MacDonald JT, Feinstein S: Hearing loss following Hemophilus Int J Pediatr Oto 1:97, 1979.
influenzae meningitis in infancy: Diagnosis by evoked response 79. Kotagal S, et al: Auditory evoked potentials in bacterial meningitis.
audiometry. Arch Neurol 41:1058, 1984. Arch Neurol 38:693, 1981.
63. Arriaga MA, Carrier D: MRI and clinical decisions in cochlear 80. Feldman WE, et al: Relation of concentrations of Haemophilus
implantation. Am J Otol 17:547, 1996. influenzae type b in cerebrospinal fluid to late sequelae of patients
64. Coffey TJ, Daniels M, McDougal LK, et al: Genetic analysis of with meningitis. J Pediatr 100:209, 1982.
clinical isolates of Streptococcus pneumoniae with high-level resistance to 81. Munoz O, et al: Hearing loss after Hemophilus influenzae meningitis:
expanded-spectrum cephalosporins. Antimicrob Agents Chemother Follow-up study with auditory brainstem potentials. Ann Otol
39:1306, 1995. Rhinol Laryngol 92:272, 1983.
65. Hofmann J, Cetron MS, Farley MM, et al: The prevalence of drug- 82. Kaplan SL, et al: Onset of hearing loss in children with bacterial
resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 333:481, meningitis. Pediatrics 73:575, 1984.
1995. 83. Lin TY, et al: Seven days of ceftriaxone therapy is as effective
66. Van Esso D, Fontanals D, Uriz S, et al: Neisseria meningitides strains as ten days’ treatment for bacterial meningitis. JAMA 253:3559,
with decreased susceptibility to penicillin. Pediatr Infect Dis J 6:438, 1985.
1987. 84. Edwards MS, Baker CJ: Complications and sequelae of meningo-
67. Seaz-Nieto JA, Lujan R, Berron S, et al: Epidemiology and molecular coccal infections in children. J Pediatr 99:540, 1981.
basis of penicillin-resistant Neisseria meningitides in Spain: A 5-year 85. Lebel MH, et al: Magnetic resonance imaging and dexamethasone
history (1985–1989). Clin Infect Dis 14:394, 1992. therapy for bacterial meningitis. Am J Dis Child 143:301, 1989.
68. Woods CR, Smith AL, Wasilauskas BL, et al: Invasive disease 86. Dawson KP, Abott GD, Mogridge N: Bacterial meningitis in child-
caused by Neisseria meningitides relatively resistant to penicillin in hood: A 13-year review. NZ Med J 107:758, 1988.
North Carolina. J Infect Dis 170:453, 1994. 87. Smyth V, et al: Audiological management in the recovery phase of
69. Dodge PR, et al: Prospective evaluation of hearing impairment as a bacterial meningitis. Int J Pediatr 75:782, 1969.
sequelae of cute bacterial meningitis. N Engl J Med 311:869, 1984. 88. Lebel MH, McCracken GH: Delayed cerebrospinal fluid sterilization
70. Schaad UB, Suter S, Gianella-Borradori A, et al: A comparison of and adverse outcome of bacterial meningitis in infants and children.
ceftriaxone and cefuroxime for the treatment of bacterial meningitis Pediatrics 83:16, 1989.
in children. N Engl J Med 322:141, 1990. 89. Pomeroy SL, Homes SJ, Dodge PR, Feigin RD: Seizures and other
71. Belsey MA, Hoffpauir CW, Smith MHD: Dexamethasone in the neurologic sequelae of bacterial meningitis in children. N Engl J
treatment of acute bacterial meningitis: The effect of study design Med 323:1651, 1990.
on the interpretation of results. Pediatrics 44:503, 1969. 90. Habib RB, et al: Hearing impairment in meningococcal meningitis.
72. DeLemos RA, Haggerty RJ: Corticosteroids as an adjunct to treat- Scand J Infect Dis 11:121, 1979.
ment in bacterial meningitis: A controlled clinical trial. Pediatrics 91. Snedeker JD, Kaplan SL, Dodge PR, et al: Subdural effusion and its
44:30, 1969. relationship with neurologic sequelae of bacterial meningitis in
73. Eden AR, Cummings FR: Sudden bilateral hearing loss and meningi- infancy: A prospective study. Pediatrics 86(2):163, 1990.
tis in adults. J Otolaryngol 7:304, 1978. 92. Taylor HG, Mills EL, Ciampi A, et al: The sequelae of haemophilus
74. Berlow SJ, et al: Bacterial meningitis and sensorineural hearing loss: influenzae meningitis in school-age children. N Engl J Med 323(24):
A prospective investigation. Laryngoscope 90:1445, 1980. 1657, 1990.
 Chapter
Demyelinating Diseases

Outline 28
Introduction Auditory Evoked Responses Edwin M. Monsell, MD, PhD
Epidemiology Facial Weakness
Pathology and Speech Disorders in Multiple
Pathophysiology of Multiple Sclerosis
Sclerosis Visual Evoked Potentials
Clinical Features Other Ophthalmologic
Internuclear Manifestations
Ophthalmoplegia Other Cranial Nerves
Vestibular Manifestations Radiologic Imaging of
of Multiple Sclerosis Multiple Sclerosis
Auditory Manifestations Formal Diagnosis
of Multiple Sclerosis Management
Acoustic Reflex

INTRODUCTION a parent or child. MS is primarily a disease of persons of

northern European racial background. It is seen least often
This review will focus on multiple sclerosis (MS), the most in Asians and native African blacks and with intermediate
common demyelinating disorder and the one most often frequency in African Americans.1,3
encountered by the otolarygologist, neurotologist, and audi- The prevalence increases geographically as latitude
ologist (Table 28-1). MS is a disorder whose demyelinating increases. In the United States, the 37th parallel seems
effects on the central nervous system (CNS) are dissemi- to be a divider between a zone of higher prevalence
nated in space and time in 85% to 90% of patients on pre- (50 to 150/100,000) to the north and a zone of lower
sentation. Because the brainstem is commonly affected, prevalence (10/100,000) to the south.3 (In the United
otologists and neurotologists are often called on to assist States the 37th parallel is approximately described by a line
in various ways in the diagnosis and management of MS. connecting the cities of San Francisco, St. Louis, and
MS may be suspected on the basis of findings from Washington, D.C.)
routine evaluation of dizziness, hearing loss, or cranial There seems to be an increase in relative risk for those
nerve symptoms. A patient may be referred to help deter- who moved north, but the magnitude of this increase
mine whether early or mild brainstem findings on exami- appears less than the corresponding decrease found in
nation or testing support the diagnosis of MS in those who moved south. The greatest reduction in risk
combination with other findings. A question may arise occurs among those who moved south before the age of
whether a new symptom in a patient with an established 9 years. Some reduction occurs among those who moved
diagnosis of MS is due to the disease or to an unrelated, south between the ages of 15 and 19 years (Table 28-2).3,4
peripheral cause. Otologists and neurotologists may be
asked to treat dysequilibrium, facial palsy, hemifacial
spasm, or another symptom, and to provide rehabilitation PATHOLOGY AND PATHOPHYSIOLOGY
of hearing loss. OF MULTIPLE SCLEROSIS
The literature on the pathogenesis of MS is voluminous,
EPIDEMIOLOGY contradictory, and controversial. Theories of genetic, viral,
autoimmune, and multifactorial causation have been pro-
The female to male preponderance of definite MS is 1.5 to posed.5 Interruption of the blood-brain barrier has been
2:1.1,2 The onset is typically from ages 20 to 40. Onset invoked as an important early event in the causal sequence,
before puberty is rare. The prevalence of familial MS is as has inflammation.6
approximately 17%, though much less in first-degree rela- Because of its high lipid content, normal myelin is
tives. It is more common to have an affected sibling than hydrophobic. However, the breakdown products in active
499
500 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 28-1. Classification of Demyelinating Diseases MS can occur in any part of the CNS, most lesions are
in the white matter, producing sensory, cerebellar, and
I. Primary diseases of myelin upper motor neuron effects (weakness, hypertonia, and
A. Multiple sclerosis
B. Devic’s disease
hyperreflexia). The cerebrum, spinal cord, and ocular
C. Schilder’s disease pathways are commonly affected. There is a predilection for
D. Balo’s sclerosis periventricular regions. The presence of “silent” (subclini-
II. “Allergic” group (perivenous encephalomyelitis) cal) disease, variations in methods of clinical observation,
A. Postviral and variations in the performance and interpretation of
B. Postvaccinal
C. Antirabies immunization tests cause differing rates of abnormal findings in reported
D. Acute hemorrhagic leucoencephalitis series.
III. Infections
A. Subacute sclerosing panencephalitis (measles virus)
B. Progressive multifocal leucoencephalitis (papova virus)
IV. Toxic/Metabolic
CLINICAL FEATURES
A. Carbon monoxide, postanoxic
B. Diphtheria toxin MS is a chronic, relapsing disorder of youth and middle
C. Lead life. The clinical course is variable and difficult to predict,
D. Organic mercury ranging from “benign,” almost asymptomatic, MS to
E. Triethyl tin
F. Edema “malignant,” fulminant MS. Neurologic deficits may be
G. Methotrexate sudden in onset, slowly progressive, or subclinical.
V. Nutritional Most MS patients experience early remissions and
A. Vitamin B12 deficiency relapses, subsequently deteriorating into a chronic pro-
B. Marchifava-Bignami syndrome
C. Central pontine myelinolysis
gressive course with advancing disability.9–11 More than
VI. Heredofamilial system degenerations 70% of younger patients present with a series of relapses
A. Familial spastic paraplegia and remissions associated with complete or relative
B. Hereditary ataxias recovery following each early episode (relapsing-remitting
C. Leber’s disease MS). Increasing deficits are seen in many patients with
From Hallpike JF: Clinical aspects of multiple sclerosis. In Hallpike JF, Adams CWM,
repeated episodes. As many as 80% to 90% will eventually
Tourtellotte WW (eds.): Multiple Sclerosis: Pathology, Diagnosis, and Management. develop a progressive course (secondary progressive MS).
Baltimore, Williams & Wilkins, 1983. Other patients with MS (more commonly older male
patients) demonstrate a chronic, progressive course
from the onset (primary progressive MS). This pattern is
MS lesions become hydrophilic, resulting in increased associated with early disability and a poor prognosis
signal brightness on T2-weighted magnetic resonance (Table 28-3).
images (MRI). An acute MS plaque provokes a healing The severity of the clinical course can be roughly esti-
response that results in varying degrees of remyelination mated at presentation (Table 28-4). Approximately 20% of
and gliosis (scarring). patients follow a benign course.11,12 The benign course is
MS exerts its primary effect by disrupting the myelin typical of the youngest patients.13 Life span and physical
sheath, which functions normally to increase the rate of activity may be normal. If the first symptoms of MS are
transmission of action potentials in nerve axons. Tempo- followed by 5 or more years of remission, the course is
rary conduction blockade may occur in demyelinated more likely to continue to be benign.12,13
fibers when rates of stimulation exceed the refractory A malignant course is seen in 5% to 10% of patients and
period of axons. Action potentials in groups of fibers may usually occurs in younger patients.10 Many severe relapses
lose the synchrony of firing, possibly accounting for the occur during the first year, followed by early chronic,
abnormality of auditory brainstem responses in MS. progressive deterioration. Patients are severely disabled or
Axonal dysfunction, damage, or transection may also be dead within a few years of the first symptoms. Cerebral
present.7 The effects of MS lesions may be accentuated by and cerebellar symptoms dominate, though effects are
increased body temperature.6 Evidence that MS is height- widespread. Progressive cerebellar ataxia and intention
ened by trauma is generally discounted.8
The number and loci of lesions vary considerably among
patients, causing variable patterns of findings. Though
TABLE 28-3. Effect of Degree of Disability on Survival
TABLE 28-2. High-Risk Factors in Multiple Sclerosis Disability % Dying within 10 Years

Racial background Caucasian, North European, British Isles Walks unaided 7

Sex Female Walks with one stick 21
Age 20 to 40 years Walks with two sticks 34
Residence before age 15 years Above 37th parallel Can just stand 49
Family history of MS Sibs > parents > others Able to sit 64
Bedridden 84
MS, multiple sclerosis.
From Paty DW, Poser CM: Clinical symptoms and signs of multiple sclerosis. From Hyllested K: Lethality, duration and mortality of disseminated sclerosis in
In Poser CM (ed.): The Diagnosis of multiple Sclerosis. New York, Thieme-Stratton, 1984. Denmark. Acta Psychiatr Neurol Scand 36:553–563, 1961.
502 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

A B

C D
Figure 28-2. Axial MRI scans from a 29-year-old man. He presented with a 1-year history of constant lightheadedness and motion intolerance increasing as the
day goes on. His past history included an episode of transient visual loss in the left eye and an episode of tingling of the left leg. Physical examination revealed
spontaneous left-beating nystagmus that was accentuated on left lateral gaze, rigidity of the right upper and lower extremities, and hyperreflexia in the right
ankle. Arrows indicate MS plaques. A, Cerebral cortex with ovoid periventricular lesion (T2 image). B and C, Brainstem with lesion in deep cerebellar nuclei
(T2 images). D, T1 image with gadolinium enhancement showing a small plaque in the brainstem, representing an active MS lesion. Used with the permission
of the author.

and vague dizziness, are common in MS (see Table 28-5 Completely normal electronystagmography has been
and Fig. 28-2).20–22 Acute vertigo is an initial complaint in reported in no more than 12% of cases.23,24 The most com-
only 3% to 7% of MS cases.16,22 Dysequilibrium is proba- mon findings are abnormal visually induced eye movements
bly due to abnormalities in cerebellar, spinal cord, somato- (saccade test, smooth pursuit test, optokinetic nystagmus
sensory, and motor control mechanisms as well as vestibular test), positional nystagmus, and hyperactive caloric
function. responses.17,20
 Demyelinating Diseases 503

Although MS lesions of the peripheral vestibular appa-

ratus have not been reported, unilateral caloric weakness
occurs in approximately 7% of patients, presumably due to
plaques encroaching on the vestibular nuclei. Hyperexcitable
caloric responses have been noted in up to 44% of indi-
viduals with MS, apparently due to a loss of cerebellar
suppressant activity on caloric responses.20,23–25 Failure of
fixation suppression has been reported in up to 47% of MS
patients.20,23 Both hyperexcitablity and failure of fixation
suppression are related to MS lesions in cerebellar path-
ways. “Dysrhythmia” of caloric responses in 8% to 34% of
MS individuals is an artifact that arises from recording from
both eyes simultaneously when INO is present.20,23 As a
form of INO, it is a reliable indicator of MS.22
Pathologic nystagmus has been reported in 18% to
63% of cases, most commonly horizontal gaze nystag-
mus, reflecting the frequent occurrence of cerebellar
involvement in MS.26 Vertical nystagmus is not uncom-
mon, but rarely occurs apart from the horizontal form.
Pendular nystagmus is a severe cerebellar sign and is Figure 28-3. T2-weighted axial MRI scan from a 31-year-old man presenting
prevalent in approximately 4% of MS patients late in with sudden sensorineural hearing loss. There were no other clinical findings
corroborating the diagnosis of MS, but the CSF demonstrated an elevated
their disease.27 Monocular nystagmus should suggest the IgG index and oligoclonal bands. The arrow indicates an MS plaque in the
diagnosis of MS. low pons anterior to the fourth ventricle on the side opposite the sudden
Abnormal saccade latency, velocity, and accuracy have hearing loss. Used with the permission of the author.
been reported in 30% to 95% of patients.28,29 Optokinetic
nystagmus may be disrupted or asymmetrical, and abnor-
mality of smooth pursuit has been reported in 40% to 78%
of MS patients.20,30 Smooth pursuit is usually normal in tone slope in acute or chronic hearing loss associated with
pure peripheral vestibular disorders. When the smooth MS has emerged.20,21
pursuit mechanism is not functioning, tracking is saccadic. Standard clinical speech audiometry (speech reception
Saccadic tracking may occur from the effects of sedative threshold and word recognition) reveals few abnormalities
medication, inadequate alerting during testing, fatigue, in MS.17,20,40 Poor speech discrimination scores relative to
age, or poor visual acuity. pure tone thresholds may be consistent with a CNS lesion
Rotational testing of the vestibulo-ocular reflex and (or acoustic neuroma); however, reported rates in MS are
dynamic posturography have been used only infrequently typically low, 3% to 7%.20
in MS. There is evidence that posturography may be more Although results of traditional audiometric tests are usu-
sensitive than electronystagmography in detecting extra- ally normal in MS, tests requiring response to a sustained
vestibular abnormalities in posture control mechanisms stimulus, discrimination of speech in noise, and binaural
and may serve as a useful guide for balance therapy, though masking tests are commonly abnormal.20 Abnormal word
further study is necessary.31,32 recognition in a noisy environment has been reported in
14% to 36% of cases.17,20,41 Recent evidence has suggested
that some MS patients have a reduced ability to detect
AUDITORY MANIFESTATIONS OF small shifts in tone frequency, but retain the ability to
MULTIPLE SCLEROSIS detect small differences in intensity.42 Additional audio-
metric measures that have been found to be abnormal in
Hearing loss and tinnitus are not common complaints in MS MS include the synthetic sentence identification test, some
(see Table 28-5). There is no evidence that the prevalence of of the dichotic speech tests (staggered spondaic word test,
hearing loss is different from the rate in the general popu- dichotic sentence identification test, dichotic digits test),
lation.33 It has been reported that MS can cause sudden the rapid alternating speech perception test, and low-pass
sensorineural hearing loss, though apparently does so filtered speech.33
rarely (Fig. 28-3).33–37 Sudden sensorineural hearing loss
due to MS has retrocochlear features and has a good prog-
nosis for recovery.34 The presence of abnormal auditory ACOUSTIC REFLEX
brainstem responses38 or normal evoked otoacoustic emis-
sions may identify a central cause of the loss.39 In the normal acoustic reflex, the stapedius muscle
Reports of insidious, chronic sensorineural hearing loss contracts bilaterally when a loud tone is presented to the
in MS vary widely, and not many studies were controlled ear. The afferent limb of the reflex involves the auditory
for age or sex. One report indicated that 59% of MS nerve and the ventral cochlear nucleus, which in turn
patients had hearing loss compared with 27% in a control stimulates the medial superior olivary nucleus bilaterally.
group, though this high an incidence has not been con- The efferent limb reaches the facial motor nuclei bilat-
firmed in other studies.40 No consistent pattern of pure erally; these send motor twigs to the stapedius muscles
504 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

bilaterally. Ipsilateral stimulation is more effective than MS patients.54,56 Some effects of stimulus rate may depend
contralateral, and binaural stimulation is more effective on the polarity of the click stimulus.57
than monaural. The middle latency response (MLR) occurs approxi-
Several measurements of the acoustic reflex may be mately 30 msec after the onset of the stimulus, and the late
made. In standard clinical testing, the reflex thresholds are vertex response (LVR) consists of two peaks occurring nor-
recorded through an impedance bridge or otoadmittance mally at 90 and 180 msec, respectively, after the stimulus.
meter. Adaptation, or “decay” of the acoustic reflex is Abnormal MLRs and LVRs have been reported in brain-
defined as the loss of half or more of the reflex amplitude stem lesions, central auditory processing disorder, devel-
within the first 5 seconds of a 10-second stimulation opmental dysphasia, acoustic neuroma, and some central
period at 10 dB above the reflex threshold. Adaptation is disorders.58–60 These late potentials are less likely to be
normal at high frequencies, but abnormal at 500 or 1000 Hz. abnormal in MS than is the ABR, though there is evidence
Positive acoustic reflex decay occurs in retrocochlear dis- that the addition of the MLR, but not the LVR, to the
orders such as acoustic neuroma. ABR can increase the diagnostic yield in MS.61 Direct
Between 13% and 69% of MS patients have been comparisons of multimodality evoked potentials have
reported to display abnormal results for acoustic reflex found that visual evoked responses (VERs) are more
thresholds elicited by pure tone stimuli.43–45 Bilaterally sensitive (66%) for definite MS, followed by somatosen-
absent acoustic reflexes have been noted in 20% of MS sory evoked responses (23%), followed by ABR (18%).62,63
cases.46 In one review of 40 MS patients, elevated or absent Multimodality testing is more sensitive than any modality
reflex thresholds were found in all subjects with hearing alone, over 85%. The diagnostic yield of evoked potentials
loss.47 Reflex amplitude and, to a lesser extent, latency meas- drops when they are needed most, that is, in probable and
ures were more sensitive markers for MS (75%) than thresh- possible MS.64 Due to the many clinical and technical vari-
old measures (23%) in 122 subjects with MS48; however, ables, evoked potential testing has not become established
measures of acoustic reflex rise time and latency of onset are in clinical settings to follow the progress of MS or its
apparently not sensitive enough to detect otherwise asymp- response to treatment.
tomatic MS.49 These studies demonstrate that subclinical
abnormalities are variably present in the brainstem of MS
patients. Suprathreshold measures of the acoustic reflex have FACIAL WEAKNESS
not become established for routine clinical use in MS.
Facial weakness is infrequently a presenting symptom of
MS.15,65 Given that MS is a central nervous system disease,
AUDITORY EVOKED RESPONSES it may be assumed that facial motor pathology in MS is
due to upper or lower motor neuron disease within the
The detection of subclinical disease in the brainstem by CNS. The location of the lesion is usually the brainstem.65
evoked potential testing can be valuable in the diagnosis Approximately 15% of individuals with MS eventually
of MS. The auditory brainstem response (ABR) is elicited develop some degree of facial weakness (see Table 28-5).
by the application of acoustic click stimuli to the ear The most common manifestation is mild paresis in the
and recorded as far-field responses from the scalp within lower division of the face. The appearance of facial weak-
the first 10 to 15 msec of the stimulus onset.50 It is ness in a patient with established MS should not be
now assumed that the generators of waves I and II reflect assumed to be due to the MS, because of the high general
cochlear and auditory nerve activity and that waves III to incidence of idiopathic facial palsy (Bell’s palsy) and other
VI arise from several sites within the central auditory causes of facial paralysis. For example, in the author’s expe-
pathways.51 The asynchronous firing of impulses through rience, bilateral acoustic neuromas were found by MRI in
the auditory brainstem in MS would be expected to result a patient with established MS who developed unilateral
in abnormal ABR. facial weakness.
The ABR has been found to be abnormal in up to 83% Hemifacial spasm has also been reported in MS and is
of cases of MS.52,53 Clinically manifest and even clinically associated with the presence of a plaque involving the ipsi-
silent MS plaques may yield alterations in ABR waves I to lateral facial nucleus.66 Facial myokymia, which may occur
V, such as prolonged interwave latencies, higher amplitude in any or all divisions of the facial nerve, consists of flick-
of earlier than later waves in the response, absent waves, ering and undulation of the facial muscles. It is caused by
and poor replicability.17,52–54 Nevertheless, the ABR has not rhythmic discharge in individual muscle fascicles and sin-
been accepted as a means of demonstrating “dissemination in gle motor units rather than entire muscle groups. Facial
space” under new diagnostic criteria (see Table 28-9).13 myokymia is more often associated with MS than is hemi-
Latency values may show a bimodal distribution, with facial spasm.66,67 The two entities may be distinguished by
modes associated with either normal latency or markedly electromyography and may coexist rarely.66
abnormal latency in the range of 4 or more standard devi-
ations above normal values.53 One interpretation of this
finding is that neural conduction through the auditory SPEECH DISORDERS IN MULTIPLE
brainstem may be normal if there is no lesion, but even a SCLEROSIS
small lesion can cause a marked impairment of conduc-
tion.53 Latency increases may be more indicative of MS Dysarthria, one of the symptoms comprising Charcot’s
than changes in wave amplitude.55 It is unclear whether triad (dysarthria, intention tremor, and nystagmus), may be
increases in stimulus rate can enhance latency changes in caused by paresis or incoordination of speech musculature.68
 Demyelinating Diseases 505

The triad is classic in MS, but rarely occurs early in the motor division of the trigeminal nerve in MS; however,
disease.9 Dysarthria should be distinguished from disorders when it occurs in a young person, it may be the first symp-
of higher centers, such as apraxia of speech and aphasia.69 tom of MS.
Darley documented 59% of MS individuals with normal
speech, 28% with abnormal speech of minimal severity,
and 13% with abnormal speech of greater severity. The RADIOLOGIC IMAGING OF MULTIPLE
various speech deviations included impaired loudness con- SCLEROSIS
trol and harshness (77%), defective articulation (46%),
impaired emphasis (39%), impaired pitch control (37%), T2-weighted MRI is currently the most sensitive imaging
hypernasality (24%), inappropriate pitch level (24%), and modality for the detection of MS plaques in the brainstem,
breathiness (22%). These defects are presumed to be due whereas fluid-attenuated inversion recovery (FLAIR)
to the effects of MS plaques on the lower cranial nerve sequences are more sensitive for lesions in the cerebral
nuclei and motor control pathways. Lesions of the hemispheres. The sensitivity and specificity of MRI in MS
supranuclear corticobulbar tracts are associated with vary in different series with stage of disease, technique, and
pseudobulbar palsy.70 test interpretation. Additional variables include the
regional pattern of dissemination of the disease, the dura-
tion of disease, the age of plaques, and the region of the
VISUAL EVOKED POTENTIALS CNS being studied by MRI. Sensitivity and specificity
may be enhanced with the addition of T1-weighted
This sensory evoked potential modality can detect both sequences.80 Gadolinium contrast material can cross the
clinically apparent and subclinical damage to the optic broken blood-brain barrier of active MS lesions, resulting
nerve, tract, and radiations.71,72 Abnormal visual evoked in enhancement within the plaque.80–82
potential (VEP) findings have been reported in 57% to Sensitivity and specificity are less in subtentorial regions
100% of MS patients.71–73 The number of clinically silent than in supratentorial regions, particularly when clinically
lesions disclosed by VEP is considerable, ranging from 8% probable and possible MS are considered. In one study
to 24% of MS cases.72,73 Thus, VEPs are more sensitive MRI was 60% sensitive in infratentorial regions in clini-
indicators of MS than is the ABR and remain abnormal in cally definite MS and 33% in clinically probable MS,
more than 90% of cases. whereas the corresponding results for supratentorial
regions were 97% and 82%, respectively.80
The most common associations of lesions with high
OTHER OPHTHALMOLOGIC signal intensity on T2-weighted MRI are with normal aging
MANIFESTATIONS and with white matter ischemic lesions.82 The prevalence
of nonspecific incidental white matter changes is as high as
Visual disturbances have been reported in 55% to 77% of 20% among healthy individuals, higher among hyperten-
MS patients.74,75 Optic neuritis, often presenting as a cen- sives, and from 30% to 100% in demented persons.80
tral scotoma, is the most common visual manifestation of Lesions that enhance on T2-weighted sequences may also
MS. Scotomata may evolve over hours to days into a visual be found in neurosarcoidosis, Lyme disease, granulomatous
defect of any size, including complete blindness. Usually angiitis of the CNS, connective tissue disorders, subcortical
the scotomata resolve over a few weeks or months with a atherosclerotic encephalopathy, vasculitides, acute dissemi-
minimal residual visual deficit, though effects are perma- nated encephalomyelitis, subacute sclerosing panencephali-
nent in some cases. tis, autoimmune disease, central pontine myelinolysis,
Optic neuritis affects red and green color perception and vitamin B12 deficiency, tumors and tumor-like lesions, and
occurs to varying degrees in 31% to 55% of MS cases.72,74,75 other demyelinating and dysmyelinating diseases.82,83 Many
Swelling of the optic disc may occur if a demyelinating of the bright lesions in these disorders can be distinguished
lesion is located anteriorly. Other ophthalmologic manifes- from lesions due to MS. Superatentorial MS lesions are
tations of MS include: anisocoria, Horner’s syndrome, ocu- characteristically wider in the transverse diameter than the
lomotor defects, and abnormalities of visual psychophysical coronal diameter due to the orientation of fiber tracts.
tests. Vascular lesions do not characteristically have this ovoid
shape. Although T2-weighted bright lesions may be low in
specificity as isolated findings, they are quite specific for
OTHER CRANIAL NERVES MS in the context of clinical findings and abnormal CSF
studies. This specificity is further enhanced if lesions are
Loss of taste and dysgeusia have been reported in 8% to periventricular.80–82 Lesions in infratentorial regions or the
17% of MS cases.76,77 Changes in smell, which are more corpus callosum are worrisome.
difficult to assess, have been reported in up to 68%.78 The extent of MS lesions seen on MRI does not corre-
Facial numbness is an initial complaint in 2% to 3% of spond well to the duration or clinical severity of MS. The
individuals with MS.15,76 Hyperpathia may precede majority of lesions identified on MRI are not associated
hypoesthesia. Isolated persistent facial numbness is with symptoms. Meaningful comparisons between the
unlikely to be due to MS. Trigeminal neuralgia is rare in sensitivity of MRI and other laboratory investigations are
MS, occurring in only 1% to 2% of patients.15,16 Among difficult to make because of the number of variables
patients with trigeminal neuralgia the incidence of MS is involved, though with current technology MRI appears to
approximately 3%.79 It is rare to observe paralysis of the be more sensitive than evoked potential testing.84–86
506 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 28-6. Differential Diagnosis of Multiple Sclerosis TABLE 28-7. Rose Criteria for the Clinical Diagnosis
of Multiple Sclerosis, 1976
I. Diseases causing multiple lesions
A. SLE I. Clinically definite multiple sclerosis
B. Primary Sjögren’s syndrome A. Relapsing and remitting course with at least two bouts separated by
C. Polyarteritis nodosa no less than one month; or
D. AIDS B. Slow or stepwise progressive course extending over at least
E. Acute disseminated encephalomyelitis 6 months.
F. Lyme disease C. Documented neurologic signs attributable to more than one site of
G. Cerebrovascular disease predominantly white matter central nervous system pathology.
II. Systematised diseases D. Onset of symptoms usually between ages of 10 and 50.
A. Hereditary spinocerebellar ataxia E. No better neurologic explanation.
B. Subacute combined degeneration of the spinal cord II. Probable multiple sclerosis
C. Leukodystrophy A. History of relapsing and remitting symptoms but without
III. Single lesions of the CNS with a relapsing/remitting course documentation of signs and presenting with only one neurologic
A. Intracranial meningioma during pregnancy sign commonly asscociated with multiple sclerosis, or
B. Glioma of brainstem B. A documented single bout of symptoms with signs of mulifocal white
C. Extramedullary tumors in region of foramen magnum matter disease with good recovery and followed by variable
D. Primary cerebral lymphoma symptoms and signs.
E. Arteriovenous malformations involving brainstem C. No better neurologic explanation.
F. Tumors involving spinal cord III. Possible multiple sclerosis
IV. Single lesions with a progressive course A. History of relapsing and remitting symptoms without documentation
A. Cervical spondylotic myelopathy of signs, or
B. The chiari malformation B. Objective neurologic signs insufficient to establish more than one site
V. Monosymptomatic presentation: Note: 45% of MS patients of central nervous system white matter pathology.
A. Visual failure, i.e., optic neuritis C. No better neurologic explanation.
B. Diplopia, i.e., internuclear ophthalmoplegia
C. Vertigo: Note: as an initial symptom of MS, this is indistinguishable From Rose AS, Ellison GW, Myers LW, Tourtellotte WW: Criteria for the clinical diagnosis
from an episode of vestibular neuronitis; however, the course is of multiple sclerosis. Neurology 26:20–22, 1976.
generally shorter with MS.
D. Sensory symptoms
VI. Nonorganic Symptoms
Two immunomodulators are well established in the treat-
AIDS, acquired immunodeficiency syndrome; CNS, central nervous system;
MS, multiple sclerosis; SLE, systemic lupus erythematosus. ment of MS, glatiramer acetate,90 and interferon beta-1.91
From Matthews WB, Compston A, Allen IV, Matyn CN: McAlpine’s Multiple Sclerosis, In clinical trials most other agents were not demonstrated
2nd ed. New York, Churchill Livingstone, 1991.
to be effective, or toxicity was unacceptable.
The diagnosis of MS and overall management should be
the responsibility of a trained and experienced physician,
FORMAL DIAGNOSIS who will usually be a neurologist. Otolarygologists and
neurotologists have important supporting roles in patient
MS remains a clinical diagnosis and has an extensive dif- evaluation and treatment. The management of balance
ferential diagnosis (Table 28-6).76,87 Although the diag- disorders may require vestibular testing, counseling, and
nosis of MS may be clear on presentation, in mild or rehabilitation. Hearing evaluation and rehabilitation,
uncertain cases, years may be required to establish it. The including the use of amplification, may be appropriate.
variable natural history of MS has made necessary the Reasonable physical activities such as walking to help
development of diagnostic criteria for clinical and research maintain balance function are recommended along with
purposes consistent with the dynamics of the disease precautions to avoid falls. Muscle strengthening may
(Tables 28-7 through 28-9). Bladder hypertonia, bowel or improve gait and balance function, but weak muscles
sexual dysfunction, and the hot bath test can be used to can be strained by overuse. Stretching exercises are often
support the diagnosis on clinical grounds.88 Recently,
more emphasis has been placed on the use of MRI and lab-
oratory tests in diagnosis (see Table 28-9). TABLE 28-8. Clinically Definite MS—Schumacher Criteria,
CSF immunologic studies are abnormal in up to 90% of 1965
cases. No single CSF study is confirmatory of MS. These
studies are of less clinical value than evoked potentials or 1. Neurologic examination reveals objective abnormalities of CNS function.
imaging.87 In one study at least one component of a test 2. Examination or history indicates involvement of two or more parts of CNS.
3. CNS disease predominantly reflects white matter involvement.
battery consisting of visual evoked potentials, somatosen- 4. Involvement of CNS follows one or two patterns.
sory evoked potentials, and CSF studies was positive in a. Two or more episodes, each lasting at least 24 hours and a month or
100% of definite, 95% of probable, and 80% of possible more apart
MS cases.1 b. Slow or stepwise progression of signs and symptoms over at least
6 months.
5. Patient 10–50 years old at onset.
6. Signs and symptoms cannot be explained better by an other disease
MANAGEMENT process.

The rate of publication on the medical treatment of MS CNS, central nervous system; MS, multiple sclerosis.
From Schumacher GA, Beebe G, Kibler RE, et al: Problems of experimental trials of ther-
has tripled since the first edition of this book.89 apy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of
Corticosteroids are often used to treat acute relapses. therapy in multiple sclerosis. Ann N Y Acad Sci 12:552–568, 1965.
 Demyelinating Diseases 507

TABLE 28-9. Diagnostic Criteria, International Panel, McDonald, 2001

Clinical Presentation Additional Data Needed for MS Diagnosis

Two or more attacks; objective clinical None

evidence of two or more lesions
Two or more attacks; objective Dissemination in space, demonstrated by MRI
clinical evidence of one lesion or
Two or more MRI-detected lesions consistent with MS plus
positive CSF
or
Await further clinical attack implicating a different site
One attack; objective clinical evidence Dissemination in time, demonstrated by MRI
of two or more lesions or
Second clinical attack
One attack; objective clinical evidence Dissemination in space, demonstrated by MRI
of one lesion (monosymptomatic or
presentation; clinically isolated Two or more MRI-detected lesions consistent with MS plus
syndrome) positive CSF
and
Dissemination in time, demonstrated by MRI
or
Second clinical attack
Insidious neurologic progression Positive CSF
suggestive of MS and
Dissemination in space, demonstrated by (1) Nine or more
T2-weighted lesions in brain or (2) two or more lesions
in spinal cord, or (3) four to eight brain plus one spinal cord
lesion
or
Abnormal VEP associated with four to eight brain lesions,
or with fewer than four brain lesions plus one spinal cord
lesion demonstrated by MRI
and
Dissemination in time, demonstrated by MRI
or
Continued progression for 1 year

CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis; VEP, visual evoked potential.
See original source for qualifications, footnote, and explanatory material. From McDonald W, Compston A, Edan G, et al: Recommended
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50:121–127, 2001.

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 Chapter
Migraine
29 Outline

Lee A. Harker, MD Introduction Motion Sickness

Etiology and Pathogenesis Auditory Symptoms
Migraine and Neuro-otologic Migraine Types Associated
Disorders with Neurotologic Symptoms
Benign Paroxysmal Positional Migraine with Aura
Vertigo Basilar Migraine
Benign Recurrent Vertigo Migraine Aura without
Ménière’s Disease Headache
Familial Episodic Ataxia Management
Transient Ischemic Attacks Management of Headaches
Stroke Management of Vestibular
Neurotologic Symptoms Symptoms
Vertigo Summary

INTRODUCTION ETIOLOGY AND PATHOGENESIS

Migraine affects 28 million Americans, approximately Migraine is not caused by a primary vascular event as had
18% of women and 6% of men. After puberty the preva- been previously thought.4 It is best understood as a
lence is much higher in women than men, is highest primary disorder of the brain, a form of neurovascular
between ages 30 and 45 years in both sexes, and varies headache in which neural events result in the dilation of
inversely with household income (Figure 29-1).1,2 It occurs blood vessels, which, in turn, results in pain and further
in two principal forms: migraine without aura and nerve activation. In all probability, the basic biologic prob-
migraine with aura. Although most patients with migraine lem is dysfunction of an ion channel in the aminergic
have no symptoms related to an aura, slightly more than brainstem or diencephalic nuclei that normally modulates
30% experience aura on some occasions.3 Migraine sensory input and exerts neural influences on cranial
headaches are a major cause of work absenteeism and vessels.4
decreased work productivity. But despite its pervasiveness The migraine aura reflects a neural dysfunction, spread-
and its associated disability, migraine is underrecognized ing depression, that is followed by vasoconstriction and
and undertreated. It is estimated that almost 4 million oligemia. Spreading depression is actually a wave of
individuals who meet the diagnostic criteria for migraine4,5 neuronal excitation that travels over the cerebral cortex at
(Table 29-1) are diagnosed with sinus or tension-type a rate of approximately 3 mm/min that is followed by a
headache but not with migraine.6 prolonged depression of cortical neuronal activity.7,8 In
Of significance to otolaryngologists, vertigo and abnor- patients with typical scintillating scotoma, this process
mal sensitivity to motion are frequently associated with begins at the center of the visual cortex, propagates to the
migraine, and they also can be severe enough to cause periphery within 10 to 15 minutes and returns to normal
absence from work and disability. These facts are grossly within another 10 to 15 minutes. This wave of cortical
underappreciated by general physicians evaluating and spreading depression is responsible for the neurologic
treating patients with migraine, and by otolaryngologists symptoms of the aura. It is followed by a period of hypo-
evaluating and treating patients with vestibular symptoms. volemia representing a 20% to 30% reduction in cortical
This chapter discusses migraine from the perspective of blood flow that persists for 2 to 6 hours. During this time
the otolaryngologist and reviews the etiology and patho- period the patient suffers from headache but has no focal
genesis of migraine, discusses the relationship of migraine neurologic deficits.
to other neurotologic disorders, reviews the neurotologic The mechanisms underlying the pathogenesis of pain in
symptoms associated with migraine and the types of migraine are not fully understood, but key factors include
migraine that evoke those symptoms, and discusses current the cranial blood vessels, the trigeminal innervation of
management. blood vessels, and reflex connections of the trigeminal
510
 Migraine 511

patients with familial hemiplegic migraine,10 linking that

cellular mechanism with at least one form of migraine.
It is common to have several members of the same
family affected with migraine, and it is possible that similar
gene abnormalities may be involved in other forms of
migraine.

MIGRAINE AND NEURO-OTOLOGIC

DISORDERS

Benign Paroxysmal Positional Vertigo

Baloh and colleagues reviewed the records of 247 consec-
utive patients who met strict criteria for the diagnosis of
benign paroxysmal positional vertigo (BPPV) over a 5-year
period.11 Each patient completed a detailed questionnaire
and then was interviewed and examined. Criteria of the
International Headache Society (IHS) were used for the
diagnosis of migraine.
In 31 of the patients it seems unlikely that migraine was
involved in the pathophysiology because in 21 patients
BPPV occurred secondary to head trauma and in 10 it
began in the immediate postoperative period following
a variety of different operations. In the remaining
Figure 29-1. Correlation of low income and high incidence of migraines.
216 patients no cause was identified.
(From Stewart WF, Lipton RB, Celentrano DD, et al: Prevalence of migraine The incidence of migraine was three times greater in the
headache in the United States: Relation to age, income, race, and other large group of patients with no identifiable trigger than in
sociodemographic factors. JAMA 267:64–69, 1992.) the 31 patients who had an obvious cause. The age of onset
of BPPV in those patients with BPPV but without
migraine was skewed toward the older ages with a peak
system with the cranial parasympathetic outflow.4 The in the eighth decade, but when BPPV and migraine coex-
brain itself is essentially insensate, but pain can be gener- isted, the age of onset of BPPV was distributed rather
ated by large cranial vessels, proximal intracranial vessels, evenly over multiple decades. Nearly half of the patients
or by the dura matter. The ophthalmic division of the with onset of BPPV before age 50 had migraine, whereas
trigeminal nerve innervates the vessels, and branches of only 15% of the patients with onset after age 50 had
the second cervical nerve roots innervate the structures of migraine.
the posterior fossa. Stimulation of the trigeminal system Baloh postulated that vasospasm of the labyrinthine
causes release of vasoactive neuropeptides including arteries could be responsible for BPPV in migraine patients,
calcitonin gene-related peptide. Levels of this peptide are because vasospasm is a well-documented phenomenon
consistently elevated during migraine headaches with or with migraine, and BPPV is a well-documented sequela
without aura and are reduced when sumatriptan success- to ischemic changes of the inner ear. The ischemia is
fully ameliorates migraine headaches. postulated to cause the otoconia responsible for the BPPV
Voltage-gated calcium channels mediate the entry of symptoms to be released from the macular membrane.
calcium into the cell. The opening and closing of these
channels are controlled by changes in voltage across the Benign Recurrent Vertigo
cell membrane. The gradient between intracellular and
extracellular calcium controls neurotransmitter release, Recurring spells of vertigo unassociated with any auditory
neuronal excitation, and many other neuronal functions.9 or neurologic symptoms are a very common reason
Mutations in one such gene have been identified in patients are referred to both otolaryngologists and neurol-
ogists. In 1979 Slater described a series of patients who
experienced recurrent vertigo lasting a few minutes to as
TABLE 29-1. Modified Diagnostic Criteria for Migraine long as 3 or 4 days and coined the term benign recurrent
vertigo.12 Most were women, and their episodes were more
Migraine is defined as episodic attacks of headache lasting 4 to 72 hours common before or at the beginning of their menstrual
With two of the following symptoms:
Unilateral pain
periods and often awakened them in the morning. They
Throbbing were asymptomatic between spells. Many had a personal
Aggravation on movement or strong family history of migraine.
Pain of moderate or severe intensity Basser had previously described recurrent vertigo in a
And one of the following symptoms: group of young children and called the condition benign
Nausea or vomiting
Photophobia or phonophobia paroxysmal vertigo of childhood.12 The children exhibited all
the features of severe vertigo unassociated with auditory or
512 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

neurologic symptoms. The spells were brief and the of a migraine vertigo syndrome with decreased penetrance
children acted perfectly normal again after their cessation. in humans.12
The condition would frequently begin before age 4, recur The important clinical point of the study is that patients
for a few years, and spontaneously remit, although some- who present with disabling recurrent vertigo without
times it persisted into adulthood. neurologic or auditory signs and symptoms also are likely
Patients with histories and symptoms similar to these to have migraine, and the disabling vestibular symptoms
often receive different diagnoses in different locations and can often be ameliorated or eliminated by prophylactic
clinics. Leliever and Barber13 described a group of patients migraine medications (see Management section).
with recurrent isolated vertigo without auditory or clinical
neurologic abnormalities lasting 5 minutes to 24 hours and Ménière’s Disease
named the condition recurrent vestibulopathy. The mean
age of onset of symptoms was 37 years, significantly Ménière’s disease is difficult to clinically distinguish from
younger than that for a comparable, larger group of migraine. Both conditions lack a definitive diagnostic test
patients with unilateral Ménière’s disease seen during the and rely instead on clinical diagnostic criteria, those of the
same period. Migraine was said to be present in 3% of the American Academy of Otolaryngology—Head and Neck
Ménière’s group and 7% of the recurrent vestibulopathy Surgery and the IHS. But patients with Ménière’s disease
group. Both figures are well below current prevalence also have auditory symptoms and signs, and there are no
numbers for migraine in the general population, and the neurologic symptoms and signs associated with the spells.
study predated the development of the IHS criteria. Over Because the pathophysiology of Ménière’s disease is
a mean follow-up period of 3.5 years, the diagnosis was restricted to the cochlea, it cannot be responsible for any
changed to unilateral Ménière’s disease in only 10% of this associated positive or negative visual phenomena or
group of patients. proprioceptive symptoms, so their presence during spells
Vestibular Ménière’s disease is another diagnosis given to of vertigo rules out the diagnosis of Ménière’s disease.
patients who experience recurrent vertigo that lasts for a Similarly, although it is possible for central nervous system
few minutes to a few hours, but who have no associated pathophysiology to result in fluctuating sensorineural
auditory or neurologic symptoms. Although the American hearing loss and other auditory symptoms, it is exceed-
Academy of Otolaryngology—Head and Neck Surgery ingly uncommon.
Committee on Hearing and Equilibrium discarded the
diagnostic terms cochlear Ménière’s disease and vestibular
Ménière’s disease in 1985, some continue to use them.14
Familial Episodic Ataxia
Baloh and his colleagues have studied patients diag- The familial episodic ataxias are rare dominantly inherited
nosed with benign recurrent vertigo (BRV) who had diseases characterized by dramatic episodes of ataxia.15
vertiginous episodes that lasted minutes to hours, or Both sexes are equally affected. Episodic ataxia type 1 (EA-1)
occasionally a few days and whose attacks were commonly patients are usually children who exhibit brief episodes of
triggered by emotional stress, sleep deprivation, and the ataxia triggered by exercise, startle, or emotional upset that
beginning of menstrual periods.12 There was a female have a duration of seconds to a few minutes. Aura-like
preponderance of more than 2 to 1, and most patients with symptoms are common, including a feeling of weakness or
BRV also had migraine headaches even though the falling, dizziness, and blurring of vision. The ataxia
headaches often occurred independent of the episodic involves the trunk and extremities and speech is slurred. In
vertigo. They studied 24 patients with BRV who also between episodes of ataxia, muscle rippling (myokymia) is
reported a history of similar vertiginous spells in some frequently clinically evident in the periorbital region and
family members. All patients underwent extensive evalua- the fingers or can be detected with electromyography. The
tion to rule out other causes of vertigo, and none had ataxia episodes associated with EA-1 frequently diminish
hearing loss or other auditory features of Ménière’s as the child becomes older and may completely disappear
disease. All were interviewed regarding a personal and later in life.
family history of vertigo and migraine, and completed the Patient with episodic ataxia type 2 (EA-2) have ataxia
standardized questionnaire, which was also sent to all episodes that last for hours, and one-third of the patients
relatives who agreed to participate. The IHS criteria for exhibit spontaneous vertical nystagmus, particularly down-
the diagnosis of migraine were used. Response rates were beat nystagmus, between spells. The episodes vary from
quite good; in addition to the 24 probands, 111 first- pure ataxia to a combinations of symptoms that usually
degree relatives (parents, siblings, children), 110 other includes vertigo, nausea, and vomiting. As with EA-1,
relatives (uncles, aunts, and cousins), and 43 unrelated episodes are triggered by exercise and emotional stress and
spouses participated in the study. often they are dramatically relieved by acetazolamide.
Twenty of the 24 probands were female, and 20 met the About half of the patients with EA-2 also have migraine
IHS diagnostic criteria for migraine. Nearly 40% of all of headaches, and there is a genetic association between the
the relatives who completed the questionnaire reported two disorders. Mutations at the same locus on chromo-
spontaneous recurrent attacks of vertigo. By contrast, only some 19p have been demonstrated for both diseases.16
1 of 43 unrelated spouses reported a history of benign
recurrent vertigo. Fifty percent of relatives met the
diagnostic criteria for migraine. Baloh postulated that the
Transient Ischemic Attacks
high prevalence of benign recurrent vertigo and migraine Differentiating migraine with aura from transient ischemic
in these groups suggests autosomal-dominant transmission attacks (TIAs) is clinically very important and sometimes
 Migraine 513

difficult especially if there have only been one or two it occurred sometime during the headache in 47% and in
sensory episodes. Repeated identical self-limited attacks the headache-free interval in 36%.20
occurring over weeks to months suggests migrainous aura, Spontaneous vertigo attacks in patients with migraine
but there may be other clues evident along the way. can last as little as 5 minutes or as long as 3 to 6 days but
Symptoms of the aura usually develop gradually and commonly last from 30 minutes to 2 hours. The spells of
consecutively over a 5- to 20-minute period and then each patient usually have a similar duration. Generally, the
subside, whereas TIA symptoms usually develop more spells are severe and evoke pallor, diaphoresis, nausea, and
rapidly and frequently simultaneously. Blumenthal17 stresses commonly vomiting. Cutrer and Baloh21 propose two
that the visual symptoms of TIA are usually negative phe- different mechanisms for the production of dizziness with
nomena presenting as a black or blank visual loss such as migraine. They believe that vertiginous episodes lasting
amaurosis fugax or hemianopic scotoma. In contrast, the minutes to 2 hours that are temporally associated with
visual sensations in migraine aura usually include positive headaches are due to the spreading wave of depression
phenomenon such as scintillations or fortification spectra or transient vasospasm (or both), as are the other aura
as well as negative phenomena such as scotomata. phenomena. When vertigo and motion sickness last for days,
with or without headache, Cutrer and Baloh postulate
that neuroactive peptides are released into peripheral and
Stroke central vestibular structures and cause an increased base-
Without question, individuals with migraine are at higher line firing rate of primary afferent neurons and increased
risk for ischemic stroke than those without migraine.18 sensitivity to motion.
The association is highest in those who have migraine with
aura, but the risk probably extends to those who have Motion Sickness
migraine without aura and to children with migraine. This
risk is increased in those under age 40 years, and by the use Several authors have noted a close relationship between
of oral contraceptive agents and smoking. Patients with migraine and motion sickness. In a classic study of 9000
migraine should not smoke. Women with migraine should Swedish schoolchildren, Bille22 matched children with
not use combined oral contraceptive pills, including those clearly established migraine to a similar group without
with low estrogen, even if no other risk factors for stroke migraine. Severe motion sickness was present in 49% of
exist.18 the children with migraine and only 10% of the control
Vertigo can also be a manifestation of cerebrovascular group. Barabas, Matthews, and Ferrari studied motion
disease, and since the circulation to the inner ear arises sickness in 60 children with migraine and three similarly
from the vertebrobasilar system, either central or periph- sized control groups.23 They defined motion sickness as
eral vascular insufficiency can be responsible. Infarctions three or more episodes in which an otherwise normal
of the vestibulocerebellar pathways in the most dorsolat- appearing child vomited during or immediately after an
eral portion of the rostral medulla and bilateral cerebellar automobile ride. Forty-five percent of the children with
infarctions in the distribution of the posterior inferior migraine had motion sickness compared with 5% to 7% of
cerebellar artery have been described in patients who the three control groups. In adults, Baloh19 reported two-
exhibited only gait ataxia and acute vertigo without other thirds of migraine patients to be motion-sensitive. Kayan
symptoms suggestive of Wallenberg’s syndrome.15 and Hood reported the association in more than 50% of
Otolaryngologists must be aware that isolated vertigo can their 200 unselected migraine adults,20 and Kuritzky noted
be a manifestation of posterior fossa infarction and should motion sickness to be more prevalent in patients who had
suspect it in elderly patients and those with cerebrovas- migraine with aura than in those without aura.24
cular risk factors. Within the large number of migraine patients who have
motion sickness exists a subset of patients who have
such severe motion sickness that it significantly restricts
NEUROTOLOGIC SYMPTOMS their life. They limit their head motion to an absolute
minimum, plan their day’s activities to minimize move-
Vertigo ment, and rest several times during the day, remaining
motionless for a half hour or so until symptoms abate.
At least 25% of all patients with migraine experience If they cannot avoid continuous motion, the queasiness
vertigo.19,20 The episodes can constitute all or part of a proceeds to nausea and imbalance, vertigo, emesis, and a
migraine aura, can occur spontaneously and seem to be migraine headache.
unrelated to any migraine headaches, or can develop in
response to motion of the individual or the individual’s
surrounding environment.
Auditory Symptoms
In some patients 10- to 15-minute episodes of vertigo Hearing loss and tinnitus are much less common than
precede a migraine headache as a prodrome and are vestibular symptoms in migraine. However, in the small
sometimes or always sequentially associated with other subset of patients with basilar migraine, a fluctuating
symptoms of the aura, most commonly scintillations or low-frequency sensorineural hearing loss identical to that
numbness and tingling. However, the vertiginous spells do seen in Ménière’s disease is found in more than half of
not always precede the headaches as a prodrome. In Kayan affected individuals.25 Phonophobia (and photophobia) is
and Hood’s 53 patients with both symptoms, vertigo extremely common and helps differentiate migraine from
immediately preceded the headache in only 15%, whereas nonmigraine headache.
514 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

MIGRAINE TYPES ASSOCIATED headache. The vestibular aura may precede only some and
WITH NEUROTOLOGIC SYMPTOMS not all of a patient’s headaches, and visual scintillations or
numbness and tingling may be part of the aura as well.
Migraine with Aura
Basilar Migraine
In the IHS classification, aura denotes the occurrence of
any or all of the neurologic manifestations experienced as Bickerstaff27 described a subset of migraine in which the
a result of migraine whenever they occur and does not aura symptoms reflected ischemia in the distribution of the
represent the time period in relation to the headache in basilar artery. The majority of Bickerstaff’s patients were
which these symptoms occur.5 The IHS describes migraine adolescent girls in whom the migraine attacks often
with aura as an: occurred premenstrually. The clinical picture also can
include stupor, loss of consciousness, neurotologic symp-
idiopathic recurring disorder manifesting with attacks of neuro- toms, and extreme postictal fatigue. To establish the
logical symptoms unequivocally localizable to cerebral cortex or diagnosis of basilar migraine, the episodes must contain
brain stem, usually gradually developed over 5-20 minutes and two or more of the following symptoms5:
usually lasting less than 60 minutes. Headache, nausea, or photo-
phobia usually follow neurological aura symptoms directly or • Visual symptoms in both temporal and nasal fields of
after a free interval of less than an hour. The headache usually both eyes
lasts 4-72 hours, but may be completely absent.5 • Dysarthria
• Vertigo
Visual symptoms are by far the most common compo- • Tinnitus
nent of the migraine aura, and the most common visual • Decreased hearing
phenomena are (1) scotomata, or blind spots, (2) teichop- • Diplopia
sia or fortification spectra (a zigzag pattern in the visual • Ataxia
field resembling a fort), and (3) flashing of lights (photopsia) • Bilateral paresthesia
or colored lights. Bartleson3 has provided a clear concise • Bilateral pareses
summary and states that the visual symptoms: • Decreased level of consciousness

… usually affect both eyes simultaneously but can affect one eye
These symptoms reflects dysfunction of the involved
alone. The patient may experience negative phenomena only and neural structures, including the brainstem, cerebellum,
describe hemianopia and quadrantanopia, complete blindness, cranial nerve nuclei, and occipital lobe cortex.
tunnel vision, asymmetric field deficits, monocular blindness,
altitudinal defects, or one or more scotoma. More frequently, Migraine Aura without Headache
positive phenomena occur and consist of stars, sparks, unformed
flashes of light (photopsia), simple and complex geometric This category of migraine is confusing to many physicians
patterns, or jagged zigzags of light (teichopsia or fortification and patients alike. Often, neither group even considers
spectra). These visual hallucinations are usually white but can be migraine as a possible cause for vertigo when the headache
any color. They are typically present with the eyes open or and the vertigo occur at different times or when the
closed. The slowly evolving images have a shimmering, flickering
vertigo is much more distressing to the patient than the
quality. The positive and negative visual phenomena are fre-
quently combined and the term scintillating scotoma is used. The headaches.
patient may report wavy lines like heat off pavement or as though Whitty28 reported a series of patients who experienced
looking through rain covered glass … symptoms typically seen during a migraine aura, but who
had no headaches with their symptoms. Some of the
The most common sequence is the slow onset of bilat- patients had the same aura symptoms earlier in life associ-
eral central scotomata or luminous phenomena that move ated with migraine headaches, and some developed typical
slowly in an arc to the periphery of one visual field. The migraine headaches later in life in association with their
leading edge is a zigzag of light followed by moving aura. Other patients experienced the aura symptoms alone
geometric patterns, which in turn leave behind expanding on some occasions and together with a typical migraine
homonymous scotomata. (Author’s note—compare this headache on other occasions. Others have described
description with the discussion of pathophysiology.) similar patients and used the terms migraine equivalent
Paresthesias present as a numbness, tingling, or both, or migraine accompaniments.26 The key to the diagnosis is
and affect the face, upper or lower extremities, or occa- the history of repeated episodes in which neurotologic
sionally the trunk. According to Fisher26 “a reliable sign of symptoms coexist with symptoms typical of a migraine
migrainous paresthesias is the ‘march’ of numbness as it aura. A past history of migraine, motion sickness, premen-
gradually spreads over the face or fingers and hand and strual clustering of attacks, headaches associated with
migrates from face to limb or vice versa or crosses to the some of the attacks, or a family history of migraine are
face and hand on the opposite side.” These paresthesias frequently present in these patients.
are not the result of hyperventilation but rather reflect
the effects of spreading depression (see Etiology and
Pathogenesis section). MANAGEMENT
Vertigo can also constitute part of the migraine aura, but
the frequency with which this occurs is unknown. Five to Management of the neurotologic symptoms of migraine
fifteen minutes of vertigo are followed by a typical migraine is made difficult by at least three problems. First, as
 Migraine 515

mentioned above, migraine is underdiagnosed and the treatment of acute migraine headaches, but these are
neurotologists may not suspect it as the cause of the beyond the scope of this chapter.4
patient’s symptoms. Second, much of the general migraine Migraine prophylaxis is recommended for patients who
literature ignores any reference to neurotologic symptoms experience three or more attacks per month, whose attacks
associated with migraine, and concentrates on the are incapacitating and impair normal activities, who can-
headaches or the other neurologic symptoms of the aura. not tolerate or are not helped by abortive therapy, who
Third, there is almost no clinical research evaluating treat- cannot psychologically cope with attacks, and who have
ment of the neurotologic symptoms associated with certain other special situations.30 Drugs commonly used
migraine. for migraine prophylaxis include beta-blocking agents,
calcium channel-blocking agents, antidepressants, anti-
convulsants, and others.
Management of Headaches The benefit of prophylactic treatment by beta blockers
It is necessary to first review management of the headache. was detected incidentally in migraine patients being
Strategies typically include (1) lifestyle changes and treated for hypertension or angina pectoris. Propranolol is
the identification and avoidance of specific triggers, the most effective of these. Meta-analysis of 53 studies
(2) treatment of the acute headache, and (3) prophylactic including 2403 patients treated with 160 mg of propra-
therapy. nolol versus a reference substance or placebo yielded a
In many patients with migraine, the brain does not seem 44% reduction in migraine activity when daily headache
to tolerate the peaks and troughs of life very well. Regular recordings were used to assess outcome, and 65% reduc-
sleep, regular meals, exercise, and avoidance of peaks of tion in migraine activity when clinical ratings of improve-
stress and troughs of relaxation can help reduce the occur- ment in global patient reports were used.29 The dropout
rence of episodes.4 In some patients, barometric pressure rate due to side effects was 5.3%. Although calcium chan-
changes or excessive exposure to motion (especially in nel blockers such as verapamil and nimodipine are touted
children) regularly initiate migraine headaches. Many by some, others regard them as only marginally effective
women recognize that their migraine attacks are more or ineffective.29
predictable and more severe around menstruation, under- The antidepressant amitriptyline is an effective
scoring the influences of hormonal changes. Although it migraine prophylactic agent, even in children. Side effects
sometimes requires a personal headache and diet diary, usually necessitate initiating treatment with a subthera-
many patients are able to report a spectrum of migraine peutic dose and gradually increasing the dosage over a
triggers that that can initiate their attacks. For some period of several weeks until an effective therapeutic level
patients, certain forms of alcohol, such as red wine, beer, is achieved.
or champagne are common inciters; in other individuals The carbonic anhydrase inhibitor acetazolamide was
headaches are stimulated by caffeine, cured meats, originally developed as an antiepilepsy drug. In addition
monosodium glutamate, aspartame, strong cheeses, to its diuretic effects, it slightly acidifies blood and tissue
yogurt, or pickled foods. Finally, external sensory stimuli including the brain. It produces dramatic benefit in
such as cigar smoke, certain bath oils, perfumes, or visual patients with familial EA-2 and familial hemiplegic
sensory stimuli from bright lights or repeated striped migraine who exhibit mutations in the same calcium
or geometric patterns can provoke attacks.17 In all these channel gene necessary for both central and peripheral
situations, careful attention to the investigation, identifica- neurotransmission. That gene is expressed throughout
tion, and subsequent elimination of the offending stimuli the brain but is particularly prominent in the cerebel-
can dramatically reduce the frequency of migraine lum and is also heavily expressed in the neuromuscular
headaches. junction where it tightly couples with neurotransmitter
Since the introduction of sumatriptan in 1992, the trip- release.16
tans have become the mainstay of symptomatic or abortive Several controlled clinical studies have documented the
treatment for moderate to severe migraine headaches. prophylactic effectiveness of valproic acid in preventing
Today at least five triptans are available for prescription migraine headaches, but adverse effects resulted in suspen-
and, although oral, nasal, intramuscular, and suppository sion of treatment in up to 20% of patients in different
forms of administration are available, 80% of the prescrip- studies. Rarely hepatitis, pancreatitis, and significant
tions are for oral use. The cost, efficacy, and side effects platelet effects occur, and the drug has significant risk of
differences are reviewed elsewhere,4,29 but all the triptans teratogenicity.30 There is no evidence that valproic acid
are very effective in ameliorating the pain of a migraine mitigates vestibular symptoms accompanying migraine.
headache. However, they are not able to terminate an Another interesting approach to migraine prophylaxis
attack, and the headache recurs in 25% to 40% of patients is the use of botulinum toxin (Botox) injections into the
with long-lasting migraine attacks. Nearly 25% of all neck or scalp. The mechanism by which botulinum toxin
patients do not respond to any of the triptans. Another works to prevent migraine headaches is unknown, but it
problem is that with frequent migraines, repeated use of is probably unrelated to Botox’s known effect on muscle
the triptans decreases the time interval between migraine relaxation. Although not yet approved for use in migraine,
attacks, and drug-induced headaches result. Furthermore, several case studies and trials have demonstrated safety and
all triptans exhibit vasoconstrictive action and are efficacy, and the effects after pericranial injections can last
contraindicated in patients with ischemic heart disease, 3 or more months.31,32 No data indicate whether Botox
uncontrolled hypertension, cerebrovascular disease, and in injections eliminate or improve vestibular symptoms
pregnancy. There are other management strategies for the associated with migraine.
516 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

Management of Vestibular most migraineurs with disabling symptoms suffer from

Symptoms abnormal sensitivity to motion, it seems counterintuitive
to recommend as therapy an exercise program based on
Vestibular symptoms associated with migraine can be repetitive motion. One is reminded of the early therapeu-
managed symptomatically, can be treated prophylactically, tic efforts at treating BPPV with exercises designed to
or can be managed with vestibular rehabilitation therapy. bring on the symptoms.
Patients in whom personal or environmental motion initi-
ates migraine episodes routinely curtail their own head
movement to avoid the evoked imbalance, nausea, and
progression to vertigo. These patients will avoid turning SUMMARY
their head when the physician or nurse enters the room
and will react unfavorably if the examining chair is turned Migraine is common and often is disabling, both because
quickly. In such individuals, mild vestibular suppression of headaches and because of associated vertigo and motion
(e.g., with diazepam 2 mg every 4 to 6 hours as needed) is sensitivity. It is related to benign paroxysmal positional
often quite helpful if prophylactic measures are ineffective vertigo, benign recurrent vertigo (sometimes diagnosed as
(see later discussion). recurrent vestibulopathy, vestibular Ménière’s disease, or
Management of the acute severe vestibular episode benign paroxysmal vertigo), and familial episodic ataxia.
associated with migraine is supportive. If oral agents can be Understanding of the etiology and pathophysiology is
used, that is, if there is no emesis, low dosages of benzodi- improving, but there is a disturbing lack of awareness of
azepine drugs such as diazepam are helpful. The adminis- the association of vestibular symptoms in patients with
tration of antiemetic agents such as metoclopramide migraine by most nonotolaryngologists treating migraine
(Reglan) that increase gastric motility can facilitate the patients, and no research studies have evaluated drug
absorption of the primary drug and thus help ameliorate effectiveness in treating vestibular symptoms associated
the attack. Promethazine (25 or 50 mg orally or by sup- with migraine. However, empiric evidence suggests that
pository) has both antivertiginous and antiemetic proper- effective treatment is available, and the great majority of
ties and is also recommended. patients with severe or disabling vestibular symptoms can
When the associated vestibular symptoms are incapaci- be very effectively treated without surgery.
tating, prophylaxis is appropriate. No controlled clinical
trials have documented beneficial effects of drugs, but
in the author’s experience propranolol often dramatically REFERENCES
eliminates spontaneous spells of vertigo in these patients
and greatly ameliorates the abnormal sensitivity to motion 1. Lipton RB, Diamond S, Reed M, et al: Migraine diagnosis and
they experience. The effective dose is usually 80 to 120 mg treatment: Results from the American Migraine Study II. Headache
a day in two divided doses. Monitoring resting pulse for 41:638–645, 2001.
bradycardia is essential, and fatigue and reduced energy 2. Stewart WF, Lipton RB, Celentrano DD, et al: Prevalence of
are sometimes observed. The drug is contraindicated in migraine headache in the United States: Relation to age, income,
race, and other sociodemographic factors. JAMA 267:64–69, 1992.
patients with asthma. Beneficial effects may not be appar-
3. Bartleson JD: Transient and persistent neurological manifestations
ent for the first 2 to 3 weeks of therapy. of migraine. Stroke 15:383, 1984.
Several patients taking acetazolamide 250 mg bid have 4. Goadsby PJ, Lipton RB, Ferrari MD: Migraine—Current under-
had similar, sometimes dramatic improvements in sponta- standing and treatment. N Engl J Med 346(4):257–270, 2002.
neous vertigo and motion sensitivity associated with 5. Headache Classification Committee of the International Headache
migraine. Baloh believes the drugs beneficial effect results Society: Classification and diagnostic criteria for headache disorders,
from its altering the pH within the cerebellum, thus cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):1–96, 1988.
stabilizing the mutated calcium channel.16 All patients 6. Diamond ML: The role of concomitant headache types and non-
taking acetazolamide notice that carbonated beverages headache co-morbidities in the underdiagnosis of migraine. Neurol
taste terrible, and up to 20% experience episodic acral or 58(Suppl 6):S3–S10, 2002.
7. Lauritzen M: Cortical spreading depression in migraine.
facial paresthesias lasting up to 30 minutes. The paresthe-
Cephalalgia 21:757–760, 2001.
sias become shorter in duration and less frequent over a 8. Spierings ELH: Mechanisms of migraine and action of antimigraine
few months. Long-term therapy increases the risk of renal medications. Headache 85(4):943–958, 2001.
calculi, but this risk can be reduced by drinking citrus 9. Edvinsson L: Aspects on the pathophysiology of migraine and
juices. Because of cross-reactivity, the drug should not be cluster headache. Pharmacol Toxicol 89:65–73, 2001.
given to patients allergic to sulfa preparations. 10. Ophoff RA, Terwindt MN, Vergouve R, et al: Familial hemiplegic
The antiepileptic drug lamotrigine has not been used to migraine and episodic ataxia type 2 are caused by mutation in the
treat vestibular symptoms in migraine, but perhaps it Ca2+ channel gene CACNL1A4. Cell 87:543–552, 1996.
should be studied. Although it has been shown to be inef- 11. Ishiyama A, Jacobsen KM, Baloh RW: Migraine and benign
fective in preventing migraine headaches, it is very effec- positional vertigo. Ann Otol Rhin Laryngol 109:377–380, 2000.
12. Oh AK, Lee H, Jen JC, et al: Familial benign recurrent vertigo. Am
tive in treating the aura associated with migraine.30 It
J Med Genetics 100:287–291, 2001.
blocks voltage-sensitive sodium channels, leading to inhi- 13. Leliever WC, Barber HO: Recurrent vestibulopathy. Laryngoscope
bition of the neuronal release of glutamate and aspartate, 91:1–6, 1981.
which are essential to spreading depression. 14. Pearson BW, Brackmann DE: Committee on Hearing and
Vestibular rehabilitation therapy has been recom- Equilibrium Guidelines for Reporting Treatment Results in
mended for use in migraine patients. However, since Ménière’s Disease. Otolaryngol Head Neck Surg 93:579–581, 1985.
 Migraine 517

15. Baloh RW: Episodic vertigo: Central nervous system causes. Curr 24. Kuritzky A, Zergler DK, Hassanein R: Vertigo, motion sickness and
Opin Neurol 155:17–21, 2002. migraine. Headache 21:227, 1981.
16. Baloh RW, Jen JC: Genetics of familial episodic vertigo and ataxia. 25. Olsson JE: Neurotologic findings in basilar migraine. Laryngoscope
Ann NY Acad Sci 956:338–345, 2002. 101:1–41, 1991.
17. Blumenthal HJ, Rapoport AM: The clinical spectrum of migraine. 26. Fisher CM: Late-life migraine accompaniments as a cause of unex-
Headache 85(4):897–909, 2001. plained transient ischemic attacks. J Can Sci Neurol 7(1):9–17, 1980.
18. Tietjen GE: The relationship of migraine and stroke. 27. Bickerstaff ER: Basilar artery migraine. Lancet 1:15–17, 1961.
Neuroepidemiology 19:13–19, 2000. 28. Whitty CWM: Migraine without headache. Lancet 2:283–285,
19. Baloh RW: Neurotology of migraine. Headache 37(10):615–621, 1967.
1997. 30. Diener HC, Limmroth V: Advances in pharmacological treatment
20. Kayan A, Hood JD: Neuro-otological manifestations of migraine. of migraine. Exp Opin 10(10):1831–1845, 2001.
Brain 107:1123–1142, 1984. 30. Krymchantowski AV, Bigal ME, Moreira PF: New and emerging
21. Cutrer FM, Baloh RW: Migraine-associated dizziness. Headache prophylactic agents for migraine. CNS Drugs 16 (9):611–634, 2002.
31:300–304, 1992. 31. Gobel H, Heinze A, Heinze-Kuhn K, et al: Evidence-based medi-
22. Bille BS: Migraine in school children. Acta Paediatr Scand 51(Suppl cine: Botulinum toxin A in migraine and tension-type headache.
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23. Barabas G, Matthews WS, Ferrari M: Childhood migraine and 32. Silberstein SD: Review of botulinum toxin type A and its clinical sig-
motion sickness. Pediatrics 72:188, 1983. nificance in migraine headache. Exp Opin 2(10):1649–1654, 2001.
 Chapter
Seizure Disorders
30 Outline

Nancy M. Young, MD Diagnosis and Evaluation Vestibular Seizures

Management of Seizures Vestibular Vertigo in Children
John Grant, MD
Management of Status Vestibulogenic Seizures
Epilepticus Audiogenic Seizures
Neurotogenic Manifestations Summary
of Seizure Disorders

T he neurotologist may encounter seizure for a number

of reasons. First, it is a very common disorder. It is
estimated that 10% of the general population will experi-
or irreversible toximetabolic processes, which include
hyponatremia, hypocalcemia, hepatic encephalopathy, and
hypoxia.
ence at least one seizure and that 4% of persons who live Epilepsy refers to a chronic condition in which there are
until age 80 will have a chronic seizure disorder.1 Second, recurrent seizures of cerebral origin. This term implies
seizure activity can produce symptoms of vestibular and that a chronic underlying neurologic problem is present.
auditory disease that need to be recognized as central and Classification of epilepsy (Table 30-2) depends on age of
not peripheral. Third, surgeons who diagnose and operate onset, whether the seizures are partial or generalized, and
on lesions in the cranial vault need to understand the whether the etiology is idiopathic or acquired. Some
significance and treatment of seizures. authors reserve the term epilepsy for patients who have
Pain is a symptom of peripheral nerve irritation. idiopathic recurrent seizures. Seizure disorder is a more
Analogously, a seizure is a symptom of irritation of the general term for chronic recurrent seizure, regardless of
brain. A seizure occurs secondary to excessive neuronal etiology.
discharge in the cerebral cortex. It results in transient impair-
ment of sensation, movement, consciousness, or memory.
Epileptic seizures are classified according to clinical and DIAGNOSIS AND EVALUATION
electroencephalographic (EEG) findings (Table 30-1).
Seizures are either partial or generalized depending on Seizures need to be considered in the diagnosis of any
whether clinical or EEG data demonstrate the area of patient with a history of a lapse or alteration of conscious-
onset as limited to a part of the brain in one hemisphere or ness, memory, sensation, or movement. A blackout is a
beginning simultaneously in both hemispheres. Therefore, common presentation of seizures and many other disorders.
the onset of partial seizures is by definition focal. They are The differential diagnosis of blackout includes a number
further subclassified depending on whether consciousness of disorders including syncopal episodes secondary to car-
is impaired. If partial seizures occur without impairment of diac function or poor cerebral circulation, head trauma or
consciousness, they are classified by whether symptoms concussion, transient ischemic attacks (TIAs), and verte-
are sensorimotor, autonomic, or psychic. In contrast, the brobasilar migraine. Patients being initially evaluated for
onset of generalized seizures involves both hemispheres loss of consciousness of unknown etiology often undergo
and lapses of consciousness always occur. Generalized testing to determine whether cardiac syncope versus an
seizures can be nonconvulsive or convulsive. Absences are epileptic seizure has occurred. Unusual and subtle presen-
nonconvulsive generalized seizures. Petit mal epilepsy tations of recurrent seizures can include a history of “day-
consists of typical brief absences. In contrast, convulsive dreaming” episodes, frequent automobile accidents, bed
generalized seizures are characterized by major motor wetting, or aphasic or dysphasic episodes. Of special impor-
events. For example, tonic-clonic generalized seizures (pre- tance to the neurologist is the fact that vertigo can occur
viously referred to as grand mal) begin with extension of the secondary to seizure activity.
extremities followed by synchronous jerking movements. A careful history is critical to the diagnosis of seizure
Single seizures can occur and recur as a normal response disorders. Descriptions of any prodrome, aura (initial signs
of brain tissue to physiologic stress. These seizures are and symptoms), and the ictus (the event itself ), and postictal
often referred to as reactive. They can be caused by sleep events are critical. An aura consists of abnormal sensation
deprivation, alcohol or sedative withdrawal, and reversible of motion, thought, or movement. It signifies a partial

518
 Seizure Disorders 519

TABLE 30-1. International Classification not been reported as a consequence of acoustic tumor
of Epileptic Seizures removal via the translabyrinthine, middle fossa, or posterior
fossa approaches, all of which involve less manipulation of
I. Partial (focal, local) seizures
the temporal lobe. So although the potential for a seizure
A. Simple partial seizures disorder to develop is always present during surgery adjacent
1. With motor signs to or within the brain, it is more likely to occur when
2. With somatosensory or special sensory symptoms manipulation is traumatic or protracted.
3. With autonomic symptoms or signs In any patient with new onset of a seizure disorder or
4. With psychic symptoms
B. Complex partial seizures recurrence of previously controlled seizures, a thorough
1. Simple partial onset followed by impairment of consciousness examination must be done to look for an underlying etiology
2. With impairment of consciousness at onset and potentially treatable cause. The most important aspect
C. Partial seizures evolving to secondarily generalized seizures of investigation is obtaining a detailed history in order to
1. Simple partial seizures evolving to generalized seizures
2. Complex partial seizures evolving to generalized seizures
determine whether the episode was, indeed, consistent
3. Simple partial seizures evolving to complex partial seizures with a seizure and whether there have been recurrent
II. Generalized seizures (convulsive or nonconvulsive) episodes. In children with a family history of seizures, it
A. Absence seizures may not be necessary to perform additional studies.8 The
1. Typical absences most common causes of seizures are age related. In child-
2. Atypical absences
B. Myoclonic seizures hood, typical causes include perinatal asphyxia or trauma,
C. Clonic seizures congenital malformations, and toximetabolic disorders. In
D. Tonic seizures adolescents, trauma and neoplasms predominate. In older
E. Tonic-clonic seizures adults, stroke, tumor, and degenerative diseases are most
F. Atonic seizures (astatic seizures)
III. Unclassified epileptic seizures
frequently the underlying problem.
Many drugs are known to precipitate seizures. They
From: Commission on Classification and Terminology of the International League include many common agents, some of which are often
Against Epilepsy: Proposal for Revised Clinical and Electroencephalographic prescribed by otolaryngologists. Examples include antihis-
Classification of Epileptic Seizures. Epilepsia 22:489–501, 1981.
tamines, sympathomimetics, and prednisone (in the setting
of hypocalcemia). General and local anesthetics, narcotic
analgesics, and iodinated contrast agents (such as metriza-
seizure even if a generalized seizure follows as a result of mide) are also agents reported to cause seizures.9
spread of discharge from the initial focus. A patient is able Laboratory tests to be considered include studies of
to describe the seizure and the events that follow only if hepatorenal function, glucose, calcium, magnesium, and
a purely sensorimotor partial seizure has occurred. It is electrolytes, complete blood count (CBC) with platelets,
much more common, however, that seizures involve alter- erythrocyte sedimentation rate (ESR), and serologic and
ations of consciousness or memory that necessitate the immunologic studies. The occurrence of seizures second-
account of a reliable witness. Generalized tonic-clonic ary to hyponatremia must be kept in mind in any patient
seizures should not be remembered by the patient unless undergoing a surgical procedure. Hyponatremia in head-
they are due to malingering or hysteria.2 injured patients is not uncommon, especially in children,
The physical examination may provide information and usually presents as a seizure.10 Some patients secrete
regarding possible seizure etiology. Patients with neuro- inappropriate levels of antidiuretic hormone (ADH) dur-
cutaneous syndromes such as tuberosclerosis or Sturge- ing the postoperative period, which can lead to intractable
Weber syndrome may have characteristic skin findings in seizures.11 Selected patients may need to undergo a lumbar
addition to cerebral lesions. Papilledema and other signs puncture so that cerebrospinal fluid (CSF) can be sent
of increased intracranial pressure are important as well for protein, glucose, culture, and serology for syphilis.
as evidence of meningeal signs. Any sensory or motor Neuroimaging studies are often essential to the workup
asymmetry may point to the site of the structural lesion. of seizure disorders. Magnetic resonance imaging (MRI)
Seizure occurs as an initial symptom in 15% of brain and, in some cases, functional MRI have replaced com-
tumor patients.3 However, their occurrence depends puted tomography as the neuroimaging modality of
greatly on tumor location. Tumors in or near the sensori- choice.
motor cortex are more likely to cause seizure. The presen- EEG is one of the few diagnostic tests that is sensitive to
tation of tumors of the cerebellopontine angle (CPA) is not abnormalities of brain function as opposed to structure.
associated with seizure. In House’s initial series of 500 The use of EEG is important to confirm the clinical
patients with acoustic tumors, seizure was not a reported diagnosis of seizure and to assist in classification. Most
symptom.4 In terms of surgical management of CPA EEG laboratories use procedures to provoke seizure activ-
tumors, chronic seizures can occur in patients who ity in order to increase diagnostic yield. These procedures
have undergone procedures that include a transtentorial can include hyperventilation, photic stimulation, sleep
approach in order to expose the temporal lobe widely.5,6 deprivation, and use of pharmacologic agents. It is impor-
Cabral, King, and Scott7 reported that 22% of 45 tant to realize that a normal interictal EEG does not
patients with large tumors who underwent a combined exclude a seizure disorder. Nor does an abnormal EEG
translabyrinthine and transtentorial approach developed necessarily confirm the diagnosis of seizure disorder.
chronic seizures and required treatment with antiepileptic When there is doubt about the diagnosis, 24-hour video
drugs. In contrast, the occurrence of chronic seizures has EEG monitoring is useful.
520 NEURORADIOLOGY

TABLE 30-2. International Classification of Epilepsies and Epileptic Syndromes

1. Localization-related (focal, local, partial) epilepsies and syndromes

1.1 Idiopathic with age-related onset
At present, two syndromes are established, but more may be identified in the future: benign childhood epilepsy with centrotemporal spikes and
childhood epilepsy with occipital paroxysms
1.2 Symptomatic
This category compromises syndromes of great individual variability, which will mainly be based on anatomic localization, clinical features, seizure
types, and etiologic factors (if known).
2. Generalized epilepsies and syndromes
2.1 Idiopathic, with age-related onset, listed in order of age
Benign neonatal familial convulsions
Benign neonatal convulsions
Benign myoclonic epilepsy in infancy
Childhood absence epilepsy (pyknolepsy)
Juvenile absence epilepsy
Juvenile myoclonic epilepsy (impulsive petit mal)
Epilepsy with grand mal seizures on awakening
Other generalized idiopathic epilepsies, if they do not belong to one of the above syndromes, can still be classified as generalized idiopathic epilepsies.
2.2 Idiopathic and/or symptomatic, in order of age of appearance
West syndrome (infantile spasms, Blitz-Nick, and Salaam Krampfe)
Lennox-Gastaut syndrome
Epilepsy with myoclonic-astatic seizures
Epilepsy with myoclonic absences
2.3 Symptomatic
2.3.1 Nonspecific etiology
Early myoclonic encephalopathy
2.3.2 Specific syndromes
Epileptic seizures may complicate many disease states
Included under this heading are diseases in which seizures are a presenting or predominant feature.
3. Epilepsies and syndromes undetermined as to whether they are focal or generalized
3.1 With both generalized and focal seizures
Neonatal seizures
Severe myoclonic epilepsy in infancy
Epilepsy with continuous spike-waves during slow wave sleep
Acquired epileptic aphasia (Landau-Kleffner syndrome)
3.2 Without unequivocal generalized or focal features
This heading covers all cases where clinical and EEG findings do not permit classification as clearly generalized or location-related, such as in many cases of
sleep grand mal.
4. Special syndromes
4.1 Situation-related seizures
Febrile convulsions
Seizures related to other identifiable situations such as stress, hormonal changes, drugs, alcohol, or sleep deprivation
4.2 Isolated, apparently unprovoked epileptic events
4.3 Epilepsies characterized by specific modes of seizure precipitation
4.4 Chronic progressive epilepsia partialis continua of childhood

From: Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for Revised Clinical and Electroencephalographic Classification of Epileptic
Seizures. Epilepsia 22:489–501, 1981.

MANAGEMENT OF SEIZURES of the seizure disorder and the number of possible side
effects. In general, the drug of choice for partial and gen-
It is of utmost importance that any patient who has a eralized convulsive seizures is carbamazepine (Tegretol)
seizure disorder be fully evaluated for the presence of a and the drug of choice for absence of seizures is ethosux-
treatable underlying cause. It must be remembered that imide (Zarontin). These two AEDs have good efficacy and
seizure is simply a symptom of brain dysfunction and not a low incidence of unacceptable side effects. If these agents
disease entity in itself. The diagnosis of “idiopathic are unsuccessful, then alternative single agents should be
epilepsy” is a diagnosis of exclusion analogous to the diag- used. Adding drugs (polytherapy) can be tried in refractory
nosis of Bell’s palsy in patients with facial nerve paralysis. patients but is not highly successful.1 Because many newer
If an underlying disease is found, then in some cases agents are available in only oral form, Dilantin and pheno-
treatment with an antiepileptic drug (AED) may not be barbital are still useful anticonvulsants in the surgical pop-
required. Patients with an idiopathic seizure disorder or ulation. Intravenous phosphenytoin is a safer formulation
one due to a known lesion that cannot be corrected need of Dilantin and is usually preferred. The most common
to have their seizures medically controlled. There are reason for failure of monotherapy is failure to achieve
many AEDs, all of which nonspecifically increase the appropriate drug levels.12
brain’s seizure threshold. Often this effect is accomplished Common side effects of AEDs include sedation, behav-
by influences on ionic mechanisms critical to membrane ioral changes, tremor, vertigo, diplopia, nystagmus, and
excitability. The choice of AED depends on the classification ataxia.13 Thus, it is important to realize that a patient with a
522 NEURORADIOLOGY

sensation, which can occur before and between episodes of Vestibular vertigo in children can be suspected by
generalized seizures.17 the presence of a positive family history of seizures. A
Vestibular seizures are defined as seizures that are simple or careful history will elicit that at least some episodes of
complex partial sensory seizures in which the overriding vertigo are associated with focal or generalized seizure
symptom is vertigo. Patients with vestibular seizures experi- phenomena such as an alteration or loss of consciousness,
ence vertigo or disequilibrium, which is often associated with facial or extremity twitching, inability to speak, or progres-
body or head and eye rotation with or without nystagmus. If sion of the attack to an obvious tonic-clonic generalized
nystagmus occurs, its direction and that of measurable body seizure.
motion can be the same. This finding is in contrast to The differential diagnosis of vertigo in children includes
peripheral vestibular syndromes in which the direction of cerebellar and brainstem tumors, benign postural vertigo
nystagmus and body fall are opposite, because the latter (BPV) of childhood, perilymph fistula, labyrinthitis, post-
occurs on the basis of vestibulospinal compensation.18 traumatic vertigo, otitis media, vestibular neuronitis, and
A history of associated symptoms helps to distinguish a endolymphatic hydrops. BPV is an important cause of
central versus peripheral site of origin of vertigo. Patients episodic vertigo in children that does not occur in adults.
with vestibular epilepsy would not be expected to have posi- Its onset occurs when the child is between 1 and 4 years
tional vertigo or associated hearing loss. They would be old. The child experiences sudden episodic vertigo with-
likely to have associated symptoms of temporal lobe dys- out headache or change in consciousness. The disease is
function. However, these symptoms may go undetected self-limited; it resolves in months or years. BPV is thought
unless specifically sought. Phenomena suspicious of tempo- to be a migraine equivalent and therefore occurs secondary
ral lobe origin include auditory hallucinations, which may to a cerebral vasomotor disorder. Approximately 50% of
range from simple tinnitus to hearing words or sentences. affected children develop migraines as adults.18,22
Alterations of consciousness may occur. For example, the Children with vertigo may require careful workup
patient may describe himself or herself as being in a dream- by both a neurologist and an otolaryngologist. Even if
like state during attacks. Because of the importance of the obvious peripheral disease is found by the otolaryngolo-
temporal lobe in a perceptual integration, the patient may gist, this could be coincidental to the occurrence of
complain of a disorder of time perception. Time may rush by vertigo. In children the presence of an underlying central
or stand still during the episode. A feeling of déjà vu or disorder such as vestibular epilepsy or brain tumor must be
depersonalization may also be described.19 considered.
Kogeorgos, Scott, and Swash20 reported 30 patients with
vestibular seizures. These patients had a mean age at onset Vestibulogenic Seizures
of 25 years and represented less than 1% of the author’s
population of seizure patients. They had intermittent brief Vestibular seizures need to be distinguished from a rare
episodes of disequilibrium. Almost half experienced rota- phenomenon known as vestibulogenic seizures. This term
tional vertigo. Almost a quarter of the patients in the study refers to seizures evoked by stimulation of the labyrinth.
had a history of the occurrence of more generalized The term vestibulogenic was initially applied to seizures by
seizures. Nearly half had a history of brief alterations in Berhman and Wyke.23 Based on experimental and clinical
consciousness (absences or other features suggestive of data, they theorized that the mechanism of initiation is
temporal lobe epilepsy). EEG evaluations demonstrated a abnormal activation of the reticular system of the brainstem
posterior temporal lobe focus in the vast majority of secondary to caloric or rotary stimulation of the labyrinth.
patients. Almost all responded well to AEDs. Vertigo occurs and is usually followed by generalized
Note that vestibular epilepsy and a peripheral vestibular tonic-clonic convulsions with loss of consciousness.
problem can both exist by chance or can be a result of a Most authors believe that vestibulogenic seizures are
common etiologic factor such as head trauma or vascular extremely rare.24 However, a small number of well-
disease. The suspicion of vestibular epilepsy requires eval- documented cases of vestibulogenic seizure exist.24,25
uation in an EEG laboratory. If the diagnosis is confirmed,
then the search for an underlying cause of the cerebral Audiogenic Seizures
dysfunction must be performed. If no treatable cause is
found, then an AED can be used. If medical therapy fails, Auditory stimuli can precipitate seizure activity in rare
then surgical therapy remains an option. patients. These patients have an unusual form of reflex
epilepsy. Reflex epilepsy refers to seizures precipitated by a
specific sensory stimulus. The most commonly reported
Vestibular Vertigo in Children audiogenic seizures are induced by sudden loud noises.
Vestibular seizure is an important diagnosis to consider in Musicogenic seizures occur less commonly. Certain notes
children who have vertigo. Vertigo is not as common a or themes precipitate events in these patients.1,26,27
complaint nor as well studied in children as in adults. In Patients with audiogenic seizures have not been
adults it is more commonly due to peripheral disease. In described as having a history of hearing impairment. In
children, central disease must be strongly considered. Eviatar contrast, many of the animal models that are known to be
and Eviatar21 evaluated 50 children who were referred to a susceptible to audiogenic seizures have been shown to
neurology clinic with a chief complaint of vertigo. A high have elevated auditory thresholds. Correlation between
incidence of central vertigo (42 of 50 patients) was found. degree of loss and susceptibility to and severity of audio-
Vestibular seizure was the diagnosis in the majority of chil- genic seizures has been reported in the epilepsy-
dren (25 of 42). Age of onset ranged between 3 and 18 years. prone rat.28
 Seizure Disorders 523

SUMMARY 12. Temkin NR, Dikmen SS, Wilensky AJ, et al: A randomized, double-
blind study of phenytoin for the prevention of post-traumatic
seizures. N Engl J Med 323(8):497–502, 1990.
The neurotologist can encounter seizures in a variety of
13. Pellock JM: Efficacy and adverse effects of antiepileptic drugs.
ways. They may be the underlying cause of symptoms that Pediatr Clin North Am 35:435–448, 1989.
bring the patient to a physician’s office or the result of 14. Barber HO, Stockwell CW: Manual of Electronystagmography.
medical and surgical management of other conditions. St. Louis, CV Mosby, 1980.
Seizures are of special interest to the neurotologist in that 15. Wiebe S, Blume WT, Girvin JP, Eliasziw M: Effectiveness and
they need to be considered in the differential diagnosis of efficiency of surgery for temporal lobe epilepsy study group: A ran-
complaints of vestibular and auditory dysfunction. domized, controlled trial of surgery for temporal-lobe epilepsy.
N Engl J Med 345(5):311–318, 2001.
16. Currie S, Heathfield KWG, Henson RA, Scott DF: Clinical course
and prognosis of temporal lobe epilepsy. A survey of 666 patients.
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17. Hughes JR, Drachman DA: Dizziness, epilepsy and the EEG. Dis
1. Engel J Jr (ed.): Seizures and Epilepsy. Philadelphia, FA Davis, Nerv System 38:431–435, 1977.
1989. 18. Brandt T (ed.): Vertigo. Its Multisensory Syndromes. London,
2. Earnest MP (ed.): Neurologic Emergencies. New York, Churchill Springer-Verlag, 1991.
Livingstone, 1983. 19. Williams DJ: Central vertigo. Proc R Soc Med 60:961–964, 1967.
3. Grossman RG (ed.): Principles of Neurosurgery. New York, Raven 20. Kogeorgos J, Scott DF, Swash M: Epileptic dizziness. Br Med J
Press, 1991. 282:687–689, 1981.
4. House WF, Luetje CM (eds.): Acoustic Tumors, vol 1. Baltimore, 21. Eviatar L, Eviatar A: Vertigo in children: Differential diagnosis and
University Park Press, 1979. treatment. Pediatrics 59:833–838, 1977.
5. King T, Morrison A: Translabyrinthine and transtentorial removal 22. Blayney AW, Colman BH: Dizziness in childhood. Clin
of acoustic nerve tumors. J Neurosurg 52:210–216, 1980. Otolaryngol 9:77–85, 1984.
6. Morrison A, King T: Experiences with translabyrinthine-transtentorial 23. Behrman S, Wyke BD: Vestibulogenic seizures. A consideration of
approach to the cerebellopontine angle. J Neurosurg 38:382–390, vertiginous seizures with particular reference to convulsions produced
1972. by stimulation of labyrinthine receptors. Brain 81:529–541, 1958.
7. Cabral R, King T, Scott D: Incidence of postoperative epilepsy after 24. Barac B: Vertiginous epileptic attacks and so-called “vestibulogenic
a transtentorial approach to acoustic nerve tumors. J Neurol seizures.” Epilepsia 9:137–144, 1968.
Neurosurg Psychiatr 39:663–665, 1976. 25. Tartara A, Manni R, Mira E, Mevio E: Polygraphic study of vestibular
8. Tuxhorn I, Holthausen H, Boenigk H (eds.): Paediatric epilepsy stimulation in epileptic patients. Rev EEG Neurophysiol 14:227–234,
syndromes and their surgical treatment. London, England, John 1984.
Libbey, 1997. 26. Danbe JR: Sensory precipitated seizures: A review. J Neurol Ment
9. Messing RO, Closson RG, Simon RP: Drug-induced seizures: A Dis 141:524, 1965.
10 year experience. Neurology 34:1582–1586, 1984. 27. Mello DH: Precipitating factors in epilepsy. J Neurol Ment Dis
10. Lüders HO (ed.): Epilepsy Surgery. New York, Raven Press, 1992. 12:800–802, 1970.
11. Ketterer T, Gacek R: Convulsions secondary to hyponatremia 28. Faingold CL, Walsh EJ, Maxwell JK, Randall ME: Audiogenic
associated with labyrinthectomy. Arch Otolaryngol Head Neck seizure severity and hearing deficits in the genetically epilepsy-prone
Surg 115:387–388, 1989. rat. Exper Neurol 108:55–60, 1990.
 Increased Intracranial Pressure
Outline

Douglas A. Chen, MD Cerebrospinal Fluid Normal-Pressure

Dynamics HydrocephalUS
J. Diaz Day, MD
Cerebrospinal Fluid and lis Pseudotumor Cerebri
Relationship to the Inner Ear Conclusion
Hydrocephalus with Elevated
Cerebrospinal Fluid Pressure

igns and symptoms of increased intracranial pressure usually takes place in the ventricular system from an
S may be the features that send a patient to the neurotol-
ogist. Furthermore, most neurotologic procedures subject
imbalance between production and reabsorption.
Numerous adjectives are used in conjunction with the
patients to the possible complication of increased intracra- term hydrocephalus. Communicating and noncommunicating
nial pressure. A working knowledge of this topic is essential refer to the presence or absence, respectively, of free flow
to the neurotologist. of fluid from the ventricular system to both the lumbar and
Intracranial pressure is determined by the contents cerebral hemisphere subarachnoid space. Obstructive
within the volume-constant cranial vault, largely brain hydrocephalus implies an obstruction of CSF flow any-
tissue, blood, and spinal fluid. 1 This concept is known as where along its path and is the most common type.
the Monro-Kellie doctrine. To maintain a constant pres- Acute and chronic hydrocephalus describe the time
sure, if one component changes, one or both of the other course over which excessive CSF accumulates, acute accu-
two must change to compensate. Changes in blood and mulation taking place over days and chronic over months
spinal fluid volume, therefore, lead to changes in intracra- to years. Patients with acute hydrocephalus tend to be dra-
nial pressure. Acute changes in intracranial pressure are matically symptomatic, whereas those with chronic hydro-
compensated for by changes in venous and cerebrospinal cephalus tend to exhibit more subtle signs and symptoms
fluid (CSF) volume up to a certain point beyond which of elevated pressure. In chronic cases, neurologic signs and
intracranial pressure is increased. The pressure-volume symptoms may exist that are not obvious, especially if they
relationships are nonlinear and are a function of CSF pres- have occurred over a long time. Arrested hydrocephalus
sure. In most instances, intracranial pressure is reflected refers to a cessation of whatever factors initially led to
accurately through CSF pressure measurements. hydrocephalus. Active hydrocephalus implies progressive
Manifestations of increased intracranial pressure in ventriculomegaly or increased intracranial pressure.
adults classically include headaches, nausea, vomiting, Benign intracranial hypertension, or pseudotumor cerebri, is
abducens nerve palsies, and papilledema. Papilledema may a syndrome of increased intracranial pressure without
initially occur without visual deficits, but blurred vision, apparent intracranial mass or ventriculomegaly. The term
central scotoma, and "graying out" episodes suggest the otitic hydrocephalus refers to the condition of benign
end stages that lead to permanent visual damage. intracranial hypertension secondary to an infectious
Abducens nerve weakness and diplopia may be present process of the ear. Otitic hydrocephalus is consequently a
as a result of generalized increased intracranial pressure misnomer, because by definition the ventricles are of normal
without a localized intracranial lesion. Headaches classi- size.' Horowitz suggested otogenic intracranial hypertension as
cally occur in the morning, but can occur any time. If severe a preferable name.' The hypertension is a phenomenon of
enough, nausea and vomiting may relieve the headaches, venous outflow obstruction, causing increased intracranial
presumably secondary to the hyperventilation that accom- pressure.
panies vomiting. This results in hypercapnea, which causes
vasoconstriction, reducing the blood volume component
according to the Monro-Kellie doctrine. CEREBROSPINAL FLUID DYNAMICS
Increased intracranial pressure may be a manifestation
of hydrocephalus. Hydrocephalus in the most literal sense CSF is produced at a rate of approximately 500 mL/day in
means "water head" and refers to an excessive accumula- adults and children. Production is an energy-dependent
tion of CSF intracranially. This excessive accumulation process. It takes place via a sodium pump on the apical
524
 Increased Intracranial Pressure 525

surface of the choroidal epithelium, which transports Controversy exists as to whether the brain itself can
sodium into the ventricles. Water then flows passively. absorb spinal fluid. The argument centers on the periven-
Multiple factors, including drugs, can influence the pro- tricular edema seen in acute hydrocephalus and whether
duction rate." A classic example is the carbonic anhydrase this results from pressure-dependent transependymal
inhibitor, acetazolamide, which can decrease production of migration of CSF or from active absorption. I I
CSF by as much as 50% to 60%. Acetazolamide taken orally The pressure gradient between the ventricular system
achieves a peak plasma level 1 hour after ingestion and is and the subarachnoid space is referred to as the transman-
effective for 8 to 12 hours.' Given intravenously its peak tie pressure. The precise mechanism by which fluid passes
effect occurs in 15 minutes and is effective 4 to 5 hours.? into the sagittal sinus through the arachnoid villi is unclear
Few hydrocephalic states result from overproduction of but depends on a positive transmantle pressure gradient.
CSF, with exceptions such as hypersecretion from a Obstruction of the superior sagittal sinus results in ele-
choroid plexus papilloma or villous hypertrophy.o'' CSF vated transmantle pressure and subsequent hydro-
production may also occur in the brain parenchyma, but cephalus.F
control is poorly understood."
The choroid plexus is located primarily in the floor of
the lateral ventricles and roofs of the third and fourth CEREBROSPINAL FLUID AND ITS
ventricles. Fluid leaves the lateral ventricles through the RELATIONSHIP TO THE INNER EAR
foramen of Munro, traverses the third ventricle, and
reaches the fourth ventricle by way of the cerebral The inner ear is connected to the intracranial space via two
aqueduct (aqueduct of Sylvius). Fluid passes from the aqueducts, the cochlear and vestibular. The cochlear aque-
fourth ventricle through the foramina of Magendie and duct originates on the medial wall of the scala tympani
Luschka into the subarachnoid space. Several pockets of near the round window membrane and terminates on the
CSF exist at the base of the brain in the subarachnoid upper border of the jugular fossa in the petrous portion
space known as cisterns. The largest is the cisterna magna of the temporal bone. It is often filled with fibrous tissue.!'
located between the inferior surface of the cerebellum and In lower animal species and frequently in human adult
the medulla (Fig. 31-1). temporal bones, anatomically patent cochlear aqueducts
Spinal fluid diffuses upward from the basal areas of the can be found.?,14,ls Physiologic patency of the cochlear
brain over the cerebral hemispheres. Absorption of spinal aqueduct is believed to be poor or nonexistent in most
fluid into the venous system takes place primarily via the cases.
arachnoid villi mostly in the walls of the superior sagittal The vestibular aqueduct originates in the scala vestibuli
sinus and transverse sinuses.l'' Alternative routes of CSF near the elliptical recess and passes into the posterior cra-
absorption may exist. Substantial drainage occurs via the nial fossa midway between the internal auditory canal and
lymphatics of the nasal mucosa via the peri olfactory and the sigmoid sinus.l ' The vestibular aqueduct transmits an
optic nerve sheath in animals." artery, vein, and the endolymphatic duct, which dilates to

Body of Lateral Ventricle Arachnoid Villi

Sagittal Sinus

Sub Arachnoid Space

Third Ventricle

Figure 31-1. Formation, flow, and

absorption of CSF.
Foramen of Munro
(Interventricular Foramen) ...o~l-rr Fourth Ventricle

Temporal Horn

Aqueduct of Sylvius
(Cerebral Aqueduct)
Foramen of Magendie
(Medial Foramen)
Foramen of Luschka
(Lateral Foramen) Cisterna Magna
t
526 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

form the endolymphatic sac on the dura mater of the Idiopathic causes of hydrocephalus also make up a sig-
posterior fossa. nificant portion. Cerebellopontine angle tumors obstruct-
Maintenance of labyrinthine fluid pressure equilibrium ing the fourth ventricle, such as an acoustic neuroma,
in relationship to CSF has been proposed by Allen and account for only 2 % of all cases of obstructive hydrocephalus
widely accepted by other authors.lf-" He theorized that (Figs. 31-2 and 31-3).
increased intracranial CSF pressure exerted on the endolym- Increased intracranial pressure following neurologic
phatic sac and then to the endolymph were balanced by surgery occurs occasionally and can be transient or pro-
increases in the perilymph transmitted from the CSF via longed. The cause can be cerebral edema or hydro-
the cochlear aqueduct. However, recent animal experi- cephalus. It is most common with large tumors and cases
ments indicate that the endolymphatic sac is incapable or that have been complicated by excessive brain retraction,
has limited capability of transmitting pressure changes meningitis, and significant contamination of the CSF
from the CSF. In contrast, the cochlear aqueduct, if phys- pathways with blood. Blood can block the absorptive
iologically patent, is capable of transmitting changes in capacities of the arachnoid villi. 25 It can also produce an
CSF pressure without dampening effects." Furthermore, obliterative meningeal inflammatory response, as can
pressure gradients as small as 2 to 5 mm H 20 between surgical exposure of the posterior fossa."
endolymph and perilymph have been postulated to cause Clinical manifestations ofhydrocephalus include headache,
inner ear membrane ruptures. I? Thus, if the cochlear nausea, vomiting, ataxia, urinary incontinence, and visual
aqueduct is large and physiologically patent, the inner disturbance. The headaches tend to occur in the morning and
ear may be susceptible to damage from sudden extreme are usually bifrontal. As symptoms progress, they may occur
variations of CSF pressure. 18 in the evening and progress into the neck. Nausea and vom-
Clinically, reports of both auditory and vestibular symp- iting usually relieve the headaches. Ataxia is usually truncal.
toms coexisting with hydrocephalus occur in adult and A wide-based, unsteady gait may also be present.
pediatric literature. Barlas and colleagues'? reported two Visual disturbances include decreased visual acuity, cen-
cases of fluctuating hearing loss and vertigo as the pre- tral scotoma, and diplopia. Momentary episodes of "gray-
senting symptoms in aqueductal stenosis and hydro- ing vision" in both eyes are important signs of serious optic
cephalus. Symptoms in both patients were relieved by nerve and retina ischemia secondary to increased intracra-
ventricular shunts. Loppenen and coworkers/? described nial pressure. Papilledema and abducens nerve palsy are
audiologic findings of shunt-treated hydrocephalus in nonlocalizing signs, but are indicative of increased
children. Eighteen of 47 shunt-treated hydrocephalic intracranial pressure.
children had a high-frequency sensorineural hearing
loss. The majority of these cases had only very mild losses,
with hearing thresholds between 20 and 30 dB at 4, 6,
and 8 kHz. Edwards and colleagues/! described auditory
brainstem response audiometry in 16 neonatal hydro-
cephalus patients but felt the findings were more a
reflection of a neurologic condition than peripheral
hearing loss.

HYDROCEPHALUS WITH ELEVATED

CEREBROSPINAL FLUID PRESSURE
Virtually all hydrocephalus associated with increased CSF
pressure is secondary to obstruction. Any pathology
obstructing the free flow of CSF from its origin in the ven-
tricles to its site of absorption can cause hydrocephalus.F
The most common cause in adults is subarachnoid hemor-
rhage either from aneurysm rupture or secondary to
trauma. Like other causes such as meningitis, in cases of
subarachnoid hemorrhage mechanical obstruction is pro-
duced by obliteration of the subarachnoid pathways over
the convexity: As red cell lysis occurs, scarring of arach-
noid villi leads to decreased absorption and hydrocephalus.
Repeated or chronic subarachnoid blood can also cause
neurotologic symptoms without hydrocephalus by chronic
hemosiderin deposition in the central nervous system
(CNS). Superficial siderosis of the CNS can result in cere-
bellar ataxia and progressive sensorineural hearing loss, as
well as motor deficits and dementia.P Magnetic resonance
imaging (MRI) findings are characteristic. T2-weighted
images show marked hypointensity of the pial and arachnoid Figure 31-2. Axial MRI with a large petroclival meningioma distorting the
membranes.i" brainstem and fourth ventricle.
 Increased Intracranial Pressure 527

Fremont-Smith'? found a range between 70 and 180 mm

H 20 in 971 patients. Massermarr'! found a mean CSF
pressure of 148 mm H 20 in 824 patients. In neonates and
children, it can be considerably less.'?
The Queckenstedt test examines the patency of the sub-
arachnoid space, but is seldom used today.32 In this test,
lumbar CSF pressure is measured when applying pressure
to the major venous outflow of the head. In normal CSF
circulation through the subarachnoid space, compression
of the jugular vein for 10 seconds increases CSF pressure
in the head. This increased pressure in return will be
reflected in the lumbar spinal fluid pressure by an increase
of 150 to 300 mm H 20 . 3D On release of venous compres-
sion, the spinal fluid pressure returns to normal levels in
10 seconds. When the subarachnoid space is obstructed or
when the venous outflow system is obstructed, spinal fluid
response to jugular vein compression and release is
delayed or absent.
As alluded to earlier, lumbar puncture can be dangerous
in the face of increased intracranial pressure. Under these
conditions, the procedure may lead to uncus herniation
through the tentorial incisura or the cerebellar tonsils
through the foramen magnum.P A less serious complica-
tion of lumbar puncture is spinal epidural, subdural, or
subarachnoid hemorrhage. Usually this passes, with local
pain as the only complication; however, the occurrence
of paralysis or sphincter disturbance demands prompt
drainage.l" The most common complication, but least
serious, is a postspinal tap headache, which last hours to
Figure 31-3. Coronal image of the same tumorwith moderate hydrocephalus several days. This complication is caused by continued
of the lateral and third ventricles aswell as the temporal horns. leakage of CSF into the paraspinal soft tissues leading to
failure to replenish the normal CSF volume. Typically this
is relieved by the patient lying down for a period of time.
The diagnosis of hydrocephalus is generally made with Rarely, a blood patch is necessary to seal the dural punc-
a computed tomographic (CT) scan. Contrast agents ture site and halt further leakage of CSF.
should be used so any underlying process can be If high-pressure hydrocephalus results from an
established. Making the diagnosis by CT scan can be prob- obstructing mass lesion, treatment is centered around
lematic. The first difficulty is deciding whether the removal of the mass or shunt placement, with the former
ventricles are truly enlarged. The second difficulty is becoming increasingly advocated. A shunt drains CSF to a
deciding, if they are enlarged, whether the enlargement body cavity, such as the peritoneal or pleural, or a vein.
is a result of brain atrophy or hydrocephalus. Temporal Preoperative shunting before definitive removal of an
horn dilatation, "rounding of the third ventricle," and intracranial mass has been advocated, and the results
periventricular edema are all fairly reliable signs of true appear to be similar to those from centers that do not
hydrocephalus. shunt preoperatively." If a shunt is not used preopera-
MRI is also useful in evaluating hydrocephalus and its tively, the patient must be followed closely after surgery
underlying cause. An advantage of MRI is its ability to and be prepared for a shunt later.
assess the flow of CSF in the cerebral aqueduct.i" In the There are several common types of shunts. Ventricular
hydrocephalic state, CSF flow signal void in the cerebral shunts are usually inserted into the frontal horn of the
aqueduct is more prominent due to pulsatile CSF motion, lateral ventricle. Alternatively, the catheter is inserted into
which is thought to be a reflection of increased ventricular the lateral ventricle via an occipital trajectory. A catheter
compliance." connecting the ventricle is buried subcutaneously and
Despite CT and MRI, spinal puncture has remained a terminates in the peritoneal or pleural cavity (Fig. 31-4).
valued diagnostic technique in CNS diseases. Its utility in Alternatively, the catheter may be directed into the
the setting of hydrocephalus is limited to patients with common facial vein and subsequently to the atrium, the
normal-pressure hydrocephalus as a provocative tool. so-called ventriculoatrial shunt (Fig. 31-5). The lumbo-
Drainage of CSF in this setting may result in temporary peritoneal shunt drains fluid from the lumbar subarach-
alteration of symptoms, thus predicting a favorable out- noid space to the peritoneum (Fig. 31-6). This shunt is
come from shunting the CSF. Otherwise, in patients with indicated in cases of communicating hydrocephalus. A
elevated pressure secondary to hydrocephalus, the proce- lumboperitoneal shunt is ill advised if hydrocephalus is
dure is ill-advised. noncommunicating because of the higher risk of tonsillar
The normal CSF pressure/? in adults in the lateral herniation. All shunts have a valve system that regulates
recumbent position is less than 180 mm H 20. Merrit and pressure and prevents retrograde flow.
528 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

Burr Hole approximately 6cm above

and 3cm to right of Occipital
Protuberance

Catheter tip in Ant. Horn

of R. Lateral Ventricle
11-12 em from Burr Hole

Figure 31-4. Ventriculoperitoneal shunt. ./---------

/

/ -0"
Catheter brought
through subcutaneous
tunnel over chest
and R, side of neek

I ~IF'"

"I
.;, I Catheter anchored
~,: - - to the Peritoneum
j~
18 to 20 em tI

Temporary ventricular drainage into an external closed obstruction, and shunt reVISIOn is indicated. Several
system, a ventriculostomy, can be done under local anes- radionuclide methods for determining shunt patency and
thesia in the intensive care unit. This technique is com- flow have been described but have met with variable
mon in cases of hydrocephalus, trauma, stroke, and success. Radionuclide shunt evaluation determines the
subarachnoid hemorrhage. Placement of the catheter clearance of radioisotope from the ventricular reservoir into
allows for drainage of CSF and monitoring the intracranial the catheter and has been found to vary greatly depending
pressure. on the various components of the system. 37,38
Complications of shunts include infection, shunt mal- Chronic subdural collections occur most commonly in
function, chronic subdural collections, and seizure.l? normal-pressure hydrocephalus. This complication is
Shunt infections are especially common in infants. uncommon in high-pressure hydrocephalus.'? The mech-
Peritoneal shunt malfunction may be the only manifesta- anism is thought to be secondary to negative intracranial
tion, and CSF cultures should be obtained from the pressure that results in tearing of bridging veins or leakage
catheter on removal or replacement. If a shunt becomes around the ventricular catheter into the subdural space.f
infected antibiotics are administered. However, removal of Most subdural collections will not enlarge; however,
the entire shunt, with temporary placement of a ventricu- when they do, replacement with a higher pressure valve is
lostomy, is necessary until the infection resolves. usually necessary."
Progressive ventricular enlargement despite shunt
placement is typically a sign of shunt malfunction.
Ventricles will usually begin to diminish in size within a NORMAL-PRESSURE HYDROCEPHALUS
week after shunt placement, which is the best indicator
of shunt patency. In normal-pressure hydrocephalus, ven- Ventricular enlargement in the face of normal CSF pres-
tricles may remain large despite good shunt function. A sure may present a confusing clinical picture. This situation
shunt tap will test the patency of the catheter; however, may occur in association with neurodegenerative diseases,
risk of infection exists. Inability to withdraw fluid from such a Alzheimer's disease and cortical atrophy causing
the ventricular reservoir indicates ventricular catheter an "ex vacio" hydrocephalus. This scenario must be
 Increased Intracranial Pressure 529

Catheter tip in Ant.

Horn of R, Lateral
Ventricle 5-6 cm
from Burr Hole

Figure 31·5. Ventriculoatrial shunt.

Catheter enters through
Common Facial Vein

(
0=~acava
J.\
distinguished from normal-pressure hydrocephalus, which hydrocephalus. The gait disorder is usually characterized
is a syndrome clinically defined by the classic triad of gait by a broad-based shuffling with short steps." The patient
disturbance, dementia, and urinary incontinence. often reports imbalance when standing or sitting associ-
It was described by Hakim and Adamsf in 1965 and then ated with a history of falling."?
by Adams and colleaguesf and has been referred to as the The severity of recent memory loss can vary greatly.
Hakim, or Hakim-Adams, syndrome. A general degradation of mental faculties, which the family
A number of conditions that precede the syndrome have may report as lethargy, apathy, or attention, and con-
been identified." Most can be related to some low-grade centration difficulties may occur. CT and MRI should show
obstructive flow phenomenon, such as subarachnoid hem- large ventricles, and a lumbar puncture may be performed
orrhage, tumor, meningitis, or previous intracranial surgery. to establish CSF pressures. Pressure should be less than
High-pressure and normal-pressure hydrocephalus probably 180 mm H 20 and protein, sugar levels, and cell count
represent a spectrum of the same disease process with should also be normal.
different outcomes. The clinical response of normal-pressure hydrocephalus
The mechanism by which hydrocephalus occurs in the to shunting is mild improvement in approximately two-
face of normal CSF pressures remains controversial. thirds of patients and significant improvement in one-third;
Symon and Dorsch suggested that these patients have however, the range varies from 33% to 85% showing sig-
episodically raised intracranial pressure, especially at nificant improvement.t-!' The wide variation in results
night, which may not manifest on one lumbar puncture.t" probably reflects differences in patient selection criteria
Similarly, Di Rocco and coworkerst' postulated that CSF and evaluation of the shunt response.
pulse pressure with normal mean pressure in the ventricu- Many investigators have tried to prognosticate about
lar system could be responsible for increasing ventricular who will benefit from shunting. Certain factors have been
size. Hakim and Adarnsf suggested that according to associated with favorable shunt results, with evidence of
Laplace's law, the increased ventricular size represents altered CSF dynamics being the underlying theme.
increased force on the ventricular wall despite normal CSF Overnight, a CSF pressure of more than 180 mm H 20 was
pressure. Several explanations, which involve primarily associated with better shunt results.V Improvement after
brain parenchyma, have been proposed. Extensive athero- lumbar puncture is akin to a therapeutic trial of temporary
sclerotic changes in brains of patients with normal- shunting and has also been associated with good shunt
pressure hydrocephalus at postmortem have been observed; results.t" Lumboventricular perfusion is the measurement
however, they were not compared with controls.t'v" of CSF absorption capacities and has had good predictive
The triad of gait disturbance, memory loss, and urinary value.P Factors that have been of little importance when
incontinence are the chief clinical features of normal-pressure considering shunting include atrophy on CT scan,
530 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

ANTERIOR VIEW

I
~
Spinious process O;;;:;;:~\l~~6~~;

Figure 31-6. Lumboperitoneal shunt.

Catheter Tunneled
Subcutaneously L4
to right upper
Quadrant ~~~4=-::,......~'--- 1-inch incision
over L3 and L4
down to
Lumbodorsal fascia

\ J
radionuclide cisternography, cerebral blood flow measure- The pathophysiology of hearing loss in patients with
ments, and certain electroencephalographic patterns.50 increased intracranial pressure has been attributed to
transmission of increased pressure via the cochlear aqueduct
to the perilymph or stretching of the central ascending
PSEUDOTUMOR CEREBRI auditory pathways.60,61 An alternative hypothesis was pro-
posed by Sismanis and colleagues.55 They postulated that
Pseudotumor cerebri, or benign intracranial hypertension, when a venous hum is present in pseudotumor cerebri, it
is a syndrome of increased intracranial pressure without produces a "pseudosensorineural" hearing loss from the
apparent intracranial mass. The presenting signs and symp- masking of the low frequencies.l' The electronystagmog-
toms include headache and blurred vision, and it has a raphy findings of patients with pseudotumor cerebri were
predilection for young obese females.54 Diplopia and nausea described by Kaaber and Zilstorff.f with decreased caloric
can occur but are less frequent symptoms. Pulsatile tinnitus, response being the most common finding.
hearing loss, and vertigo have been described as being Neurologic imaging is important to rule out underlying
associated with it and can be the presenting symptoms.55 intracranial mass. Ventricular size is usually normal,
The tinnitus can usually be auscultated, and light digital although reports of slightly large or small ventricles do
occlusion of the ipsilateral internal jugular vein usually exist. Lumbar puncture is essential to confirm the diagno-
will improve the tinnitus and low-frequency sensorineural sis of elevated CSF pressures. Angiography may be indi-
hearing loss.56 Papilledema is invariably present on physical cated in cases where AVM or sinus occlusion is suspected.
exam. Sixth nerve palsies may also occur. The treatment of pseudotumor cerebri is directed at the
Causal factors associated with pseudotumor cerebri have underlying cause, if any can be found, such as anemia or
been identified as pregnancy, vitamin A disturbances, obesity. Direct management of the intracranial pressure
drugs, anemia, arteriovenous malformations, and sinus with serial lumbar punctures, acetazolamide, diuretics, and
obstruction.57 The pathophysiology remains poorly under- steroids has been used.v' Lumboperitoneal shunting has
stood, but the underlying mechanism appears to be defec- been advocated in cases refractory to medical manage-
tive CSF absorption leading to interstitial brain edema. ment. 51,64 Continued care by an ophthalmologist until
This theory has been supported by human studies linking intracranial pressures are reduced is also necessary to
pseudotumor cerebri to increased resistance to absorption minimize the possibility of permanent visual loss from
of CSF, probably at the level of the arachnoid villi of papilledema.
the superior sagittal sinuses. 58,59 Why this should lead Otitic hydrocephalus, despite its name, is actually a form
to interstitial edema instead of hydrocephalus is unclear. of pseudotumor cerebri.v' It is the least common of the
The resistance to reabsorption is probably secondary to intracranial complications of otitis media, and only infre-
venous hypertension. quent case reports exist in modern literature. The largest
 Increased Intracranial Pressure 531

series consists of a literature review of 44 cases by Foley.'" 15. Wlodyka ]: Studies on cochlear aqueduct patency. Ann Otol Rhinol
Most cases were associated with lateral sinus thrombosis or Laryngol 87:22-28, 1978.
perisinus abscess, but not all. The increased intracranial 16. Allen CWo Endolymphatic sac and cochlear aqueduct. Arch
Otolaryngol 79:322-327, 1964.
pressure is most likely related to obstructed venous flow
17. Henriksson, N, Gleisner L, ]ohanssan G: Experimental pressure
from the head. variations in the membranous labyrinth of the frog. Acta
The presenting signs and symptoms are the same as for Otolaryngol 61:281-291, 1966.
pseudotumor cerebri in association with recent or ongoing 18. Allen CW: Fluid flow in cochlear aqueduct and cochlea hydrody-
ear disease. It is most commonly seen in children and ado- namic consideration in perilymph fistula, stapes gusher, and second-
Iescents." CT will detect the ear disease but will also rule ary endolymphatic hydrops. Am] Otol 8:319-321, 1987.
out intracranial lesions. Imaging of the venous system via 19. Barlas 0 et al: Adult aqueductal stenosis presenting with fluctuating
angiography or magnetic resonance venography is critical hearing loss and vertigo.] Neurosurg 59:703-705, 1983
to establish the status of the sinuses. Lumbar puncture 20. Lopponen H et al: Audiological findings of shunt treated hydro-
should reveal elevated pressure but is otherwise normal.v? cephalus in children. Int] Pediatr Otorhinolaryngol 18:21-30,
1989.
Treatment consists of managing increased intracranial
21. Edwards CC, Smith A, Pictor TW: Auditory brainstem response
pressure to prevent permanent visual deficits. If steroids audiometry in neonatal hydrocephalus. ] Otolaryngol Suppl
and diuretics are of little benefit, serial lumbar punctures 14:40-46, 1985.
as a temporizing measure or a shunt procedure are indi- 22. Katzman R: Low pressure hydrocephalus. In \VilIs EE (eds.):
cated. The mainstay of treatment of the ear disease con- Dementia. Philadelphia, FA Davis, 1977.
sists of mastoidectomy and antibiotics. 23. Revesz T, Earl C], Barnard TO: Superficial siderosis of the central
nervous system presenting with longstanding deafness.
]R Soc Med 81:479-481, 1988.
24. Kwartler ]A, De La Cruz A, Lo WWM: Superficial siderosis of the
CONCLUSION central nervous system. Ann Otol Rhinol Laryngol 100:249-250,
1991.
In summary, increased intracranial pressure is primarily 25. Ellington E, Margolis G: Block of arachnoid villus by subarachnoid
a neurologic problem; however, ear signs and symptoms hemorrhage.] Neurosurg 30:651-657,1967.
can be the presenting manifestations of hydrocephalus or 26. Stein BM, Tenner MS, Fraser RAR: Hydrocephalus following
benign intracranial hypertension. Neurotologic proce- removal of cerebellar astrocytoma in children. ] Neurosurg
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28. Bradley WG, Kortmann KE, Burgoyne R: Flowing cerebrospinal
fluid in normal hydrocephalic states: Appearance on MR imaging.
Radiology 159:611-616, 1986.
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4:273-282, 1983. hydrocephalus with normal cerebrospinal fluid pressure.
 Increased Intracranial Pressure 532

Observations on cerebrospinal fluid hydrodynamics. J Neurol Sci 54. Weisberg LR: Benign intracranial hypertension. Medicine
2:307-327, 1965. 54:197-207,1975.
43. Adams RD, et al: Symptomatic occult hydrocephalus with "normal" 55. Sismanis A et al: Otologic symptoms and findings of the pseudotu-
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47. Hakim S, Modi SM: Normal pressure hydrocephalus and hyperten- 60. Best RLL: Perilymph hypertension and the indirect measurement
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 Chapter
Vertigo, Dysequilibrium, and
Imbalance with Aging

Outline 32
Introduction Labyrinthine Disorders Anil K. Lalwani, MD
Structural Changes Other Otologic and
with Aging Neurotologic Disorders
Alterations in Vestibular Cervical Vertigo
Function with Aging Systemic Disorders
Presbystasis Treatment and Rehabilitation
Evaluation of Vestibular Dysfunction
Vertebrobasilar Insufficiency

INTRODUCTION STRUCTURAL CHANGES WITH AGING

Vestibular dysfunction is common in the elderly, with The vestibular system, like other organ systems, under-
reported prevalence of vertigo, dysequilibrium, or imbal- goes degenerative changes with aging, resulting in variable
ance to be as high as 47% in men and 61% in women older functional disability. The specialized neural cells of the
than age 70.1–3 Dizziness is the most common presenting mammalian vestibular system are nonmitotic and thus can-
symptom in those 75 years and older seen in an office prac- not undergo replication and renewal. During the course of
tice.4,5 The incidence of falls in individuals older than age a lifetime, DNA transcription errors and insoluble pig-
65 is between 20% and 40% in those living at home.2,6–10 ments accumulate, and protein synthesis becomes increas-
It is twice as frequent for the institutionalized elderly.11,12 ingly inefficient. Additionally, environmental and external
By age 80, one in three people will have suffered a fall factors such as noise trauma, physical trauma, ototoxic
associated with significant morbidity. Vestibular symptoms substances, and medications also contribute to senescence.
precede these falls in more than half of the patients. These Degenerative changes (Table 32-1) and atrophy have
falls are associated with significant morbidity and mortal- been noted throughout the vestibular apparatus, including
ity and constitute one of the leading causes of death in the the otoconia, vestibular epithelium, vestibular nerve,
elderly.13 Scarpa’s ganglion, and cerebellum.14–19 In the utricle and
Spatial orientation and balance is achieved through the saccule, statoconia progressively demineralize and frag-
complex integration of visual, proprioceptive, somatosen- ment, resulting in decreased responsiveness to gravity and
sory, and vestibular information in the central nervous to linear acceleration.20 The migration of degenerated oto-
system. The visual oculomotor reflexes interact with the conial debris into the dependent ampulla of the posterior
vestibulo-ocular reflex to produce a stable visual field semicircular canal may result in positional balance distur-
necessary to maintain orientation. Posture is maintained bances (cupulolithiasis or benign paroxysmal positional
through the interaction of the collicovestibular and spin- vertigo).21 In the sensory epithelia, inclusion bodies, lipo-
ovestibular reflexes, segmental stretch reflexes, and several fuscin, and vacuoles accumulate. In addition, cell shrink-
exteroceptive sensory systems such as touch and tempera- age and atrophy and replacement of hair cells with scar
ture. The processing and integration of these various formation occur.22,23 After age 70, the number of hair cells
sensory and motor input in the brain allows for orienta- in the maculae of otolith organs decreases by 20%, and the
tion, balance, maintenance of posture, and locomotion. cristae of the semicircular canals decreases by 40%.24 The
The aging brain is less efficient at processing the variety of cell loss begins at about age 40.25 The type I hair cells are
mechanosensory inputs and effecting an appropriate affected more than type II hair cells.
motor response to maintain perfect balance. This is likely The reduction in the number of cells in the Scarpa’s
due to structural and physiologic alterations associated ganglion as well as the number of vestibular nerve fibers
with aging. parallels the loss of sensory epithelia.26 By age 60, the
533
534 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 32-1. Structural Changes in the Vestibular Apparatus ALTERATIONS IN VESTIBULAR FUNCTION
with Aging WITH AGING
Otoconia Demineralization
Fragmentation Vestibular testing of the elderly has demonstrated quan-
Migration tifiable functional decline with age. A variety of testing
Vestibular epithelium Inclusion bodies modalities are available, including physical examination,
Vacuoles electronystagmography, rotational testing, and posturog-
Lipofuscin accumulation
Hair cell loss and atrophy (type 1 > type II) raphy. The physical exam may assess the eye movements,
Vestibular nerve Decrease in number of fibers note the presence or absence of nystagmus, perform pos-
Scarpa’s ganglion Decrease in number of ganglion cells tural testing, and evaluate gait. Potvin36 has demonstrated
Alterations in synaptic bars decline in all postural tests with age, the most sensitive of
Vestibular nuclei Lipofuscin accumulation
Axonal degeneration
which was the inability of the elderly male to stand on one
Membrane invaginations leg with the eyes closed. Electronystagmography is a grad-
Cerebellum Loss of Purkinje cell uated series of evaluations of the vestibular and vestibulo-
Decreased axodendritic synapses ocular system that includes caloric responses. It can be
Reduction in size of cerebellar vermis useful in establishing the degree of vestibular function in an
Lipofuscin accumulation
Rodlike inclusions ear, determining the side of pathology, and differentiating
Other inclusion bodies central from peripheral diseases. After age 70, the elderly
exhibit a decline in caloric response, which peaks between
the ages of 50 to 70.37 Studies of the vestibulo-ocular reflex
in the elderly have shown decreased sensitivity and shorter
number of ganglion cells in the Scarpa’s ganglion is time constants over a wide range of frequencies of rota-
reduced.27 Examination of the vestibular nerve synapses tional stimuli.38,39
has demonstrated alterations in the synaptic bars in people Posturography is a relatively new method for studying
40 years of age and older.25 Beginning at age 50, there is the ability of the subject to maintain balance with chang-
loss of nerve fibers between the vestibule and the Scarpa’s ing visual and somatosensory input. The relative energy
ganglion. Compared with those 35 years of age or younger, required to maintain balance on the posturography test
the number of nerve fibers in specimens 75 years and older increases linearly with age until age 70. The elderly also
is reduced by 37%.28 The greatest loss occurs among the have larger sway excursions on balance platforms in
thick myelinated fibers of the cristae, resulting in decrease posturography.40 Further, Teasdale and colleagues41 have
in the neuronal condition velocity with age. Hair cell degen- shown that visual deficits along with platform disruption
eration likely precedes vestibular neuronal degeneration.27 has a much greater effect on posture than platform alter-
The effect of aging on the vestibular nuclei are less well ation in isolation. This and other work have highlighted
understood. Studies of other brainstem nuclei have failed the increased reliance on visual cues on maintenance of
to demonstrate significant age-related decline in neuronal balance in the elderly.42,43 In addition, the posture is also
cell populations.23 Lipofuscin accumulation in the vestibular negatively affected by decreased sensation and muscle
nuclei, similar to that seen in the hair cells, has been weakness in the lower extremities and increased reaction
observed. In the lateral vestibular nucleus of rats, membrane time.43–45 Rotational testing is available to evaluate the
invagination and axonal degeneration has been noted.29 vestibulo-ocular reflex. In the elderly, there is significant
In the cerebellum, there is loss of Purkinje’s cells begin- decrease in gain in the vestibulo-ocular reflex to different
ning in the fifth decade. Ellis30 reported a 38% decline in rotatory stimuli.46,47 Overall, aging affects the vestibular,
the number of Purkinje cells in the cerebellar cortex of five visual, and proprioceptive information available for central
adults age 62 to 100 years compared with younger popula- processing, as well as the ability of the central nervous
tion. Hall and colleagues31 noted a 25% reduction in system to process the sensory information and effect
Purkinje cell population in the cerebellum with aging, with motor response.
most rapid neuronal loss occurring after 60 years of age.
The Purkinje cell loss is highly variable among individuals,
with some individual in their nineties retaining nearly PRESBYSTASIS
normal number of cells. Glick and Bondareff32 have docu-
mented a 24% decrease with age in axodendritic synapses Dysequilibrium of aging, or presbystasis, a term coined by
in the rat cerebellar vermis paralleling cerebellar neuronal Belal and Glorig, is a common diagnosis in elderly patients
cell loss. Raz and coworkers,33 using magnetic resonance evaluated for dizziness.48 Its cause is multifactorial and is
imaging, have demonstrated a significant reduction in the related to the structural and physiologic deterioration of
total area of the cerebellar vermis. As in the peripheral the vestibular apparatus associated with normal aging as
sensory epithelia and the vestibular nucleus, lipofuscin, discussed earlier.49,50 Presbystasis is the vestibular counter-
rodlike nuclear inclusions, and other inclusion bodies have part to presbycusis, the hearing loss associated with aging
been observed to accumulate with age in the cerebellum.34,35 of the auditory system. It is a diagnosis of exclusion and
Other ultrastructural changes associated with aging not a specific pathologic diagnosis. In their original study
include a decreased amount of Nissl substance in the of 740 patients older than age 65 presenting with dizziness,
perikaryon, loss of demarcation between the nucleus and 79% of the patients were diagnosed with presbystasis fol-
cytoplasm, and paler nucleoli.34,35 The clinical significance lowing clinical evaluation.48 A specific cause for dizziness
of these changes is unclear.23 was found only in 21% of the 740 patients. However, with
 Vertigo, Dysequilibrium, and Imbalance with Aging 535

better and more complete testing of the vestibular and bal- term employed by the patient and may include vertigo,
ance function, including electronystagmography, postur- dysequilibrium, or imbalance. The diagnostic evaluation
ography, and rotational testing, the ability to assign a and management differs markedly depending on the exact
specific pathologic diagnosis has improved.23,51 In their nature of dizziness. Therefore, it is imperative for the physi-
review of 116 patients, 70 years and older, evaluated for cian to determine the true nature of patient’s symptoms.
persistent dizziness, Sloane and coworkers23 were able to Vertigo is the cardinal symptom of vestibular disease
identify the specific cause in 85% of their cases. A variety and is usually described as a rotatory sensation. However,
of vestibular disorders have been identified in the elderly, it may take the form of any illusion of movement, such as
including benign positional vertigo, Ménière’s disease, rocking, ground rolling, tilting, or a sense of falling for-
unilateral or bilateral vestibular deficits of various causes, ward or backward. Dysequilibrium is a sense of discoordi-
defective central nervous system adaptation to vestibular nation with erect posture or during a purposeful
injuries, cervical vertigo, cereberovascular disease, and movement. Although vertigo is usually episodic, dysequi-
vertebrobasilar insufficiency, among others (Table 32-2).52 librium is typically continuous. The term imbalance
Therefore it is imperative that a careful and complete clin- implies an orthopedic (e.g., hip disease) or neurologic (e.g.,
ical evaluation be performed in the assessment of an older hemiparesis) problem. Dizziness may also be used to
adult with vestibular symptoms prior to assigning the non- denote a lightheaded feeling, as in postural hypotension
specific diagnosis of presbystasis. or hypoglycemia, or to indicate an inability to concentrate.
The exact nature of dizziness, the time course, and the
associated symptoms are of great differential value and
EVALUATION should be elicited.53–55 Short-lived episodes of vertigo associ-
ated with nausea and vomiting are classically associated with
Thorough vestibular evaluation begins with a complete peripheral labyrinthine pathology. Likewise, the illusion of
history, general physical, and specialized neurotologic movement of self or the environment is highly suggestive of
examination (Table 32-3). Dizziness is an all-encompassing labyrinthine dysfunction. Acute rotational vertigo lasting
several days with slow recovery is characteristic of acute viral,
vascular, or traumatic labyrinthitis. Rotational vertigo lasting
TABLE 32-2. Causes of Vertigo or Dizziness in the Elderly less than a minute is usually due to benign positional vertigo.
Unsteadiness of insidious onset, lightheadedness, and faint-
Otologic Benign paroxysmal positional vertigo ness are more likely due to medical or neurologic disease.
Cholesteatoma The sensation of dysequilibrium is usually chronic. Vertigo
Labyrinthitis associated with hearing loss is consistent with peripheral
Ménière’s disease end-organ pathology, whereas involvement of other cranial
Perilymph fistula
Osseous dysplasia of temporal bone
nuclei is more characteristic of central pathology.
Otosclerosis A full medical history and examination are essential in
Ototoxic/vestibulotoxic drugs evaluation of dizziness.56 Specifically, history of diabetes,
Syphilis hypertension, coronary artery disease, peripheral vascular
Vestibular neuronitis disease, and any neurologic disease should be elicited. List
Neurotologic Cerebellopontine angle tumors
Acoustic neuroma of current medications should be reviewed. Table 32-4 lists
Arachnoid cyst some of the common medications associated with balance
Lipoma symptoms. Supine and standing blood pressure are useful
Meningioma in excluding orthostatic hypotension. Sadly, the skills and
Metastatic tumors
Cardiovascular Aortic stenosis
knowledge of health care personnel in accurately detecting
Carotid sinus hypersensitivity orthostatic hypotension is lacking and large differences in
Dysrhythmia measurement techniques has lead to underdiagnosis.57
Postural hypotension Therefore, it is critical that standardized measurement
Neurologic Epilepsy techniques are implemented to better diagnose this
Multiple sclerosis
Parkinson’s disease common problem in the elderly associated with balance
Psychogenic disorders disturbance. Absence or presence of nystagmus should be
Syncope
Hematologic Anemia
Hyperviscosity syndrome TABLE 32-3. Evaluation of Vertigo
Vascular Autommune vasculitis
Carotid artery stenosis
Cerebellar ischemia Complete clinical and medical history
Subclavian steal syndrome General physical examination
Vertebrobasilar insufficiency Otologic and neurotologic examination
Wallenberg’s syndrome Complete audiometry
Metabolic Diabetes mellitus Internal medicine, neurology, or other consultation as necessary
Hyperventilation Additional examinations:
Hyperglycemia Electronystagmography
Hypoglycemia Posturography
Other Cervical vertigo Rotational testing
Head injury Computerized tomography
Side effect of medications Magnetic resonance imaging
536 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 32-4. Common Medication Associated (BPPV) or cupulolithiasis, labyrinthitis, vestibular neu-
with Balance Symptoms ronitis, Ménière’s syndrome, labyrinthine concussion due
to trauma, and perilymph fistula among others. In younger
Anticholinergics Scopolamine, promethazine, amitriptyline, patients BPPV is usually secondary to trauma, whereas in
meclizine the elderly it is usually a result of degenerative
Anticonvulsants Phenytoin, carbamazepine, phenothiazines, processes.21,59 The patient complains of intermittent,
chlorpromazine irregular episodes of vertigo precipitated by rapid head
Antihypertensives Furosemide, propranolol, terazosin
Antineoplastic drugs Cisplatin
motion, particularly when turning over in bed or with neck
Dopamine agonists L-Dopa/carbidopa extension. Vertigo is of short duration usually lasting less
H2 blockers Cimetidine than a minute. The Hallpike maneuver, the brisk position-
Ototoxic drugs Gentamicin ing of the patient’s head backward and sideways with the
Sedatives Barbiturates, benzodiazepines test ear positioned down, performed during electronystag-
Tricyclic antidepressants Nortriptyline
Vasodilators Isosorbide, nifedipine mography is diagnostic. In a patient with BPPV, the
maneuver elicits a geotropic verticorotatory nystagmus
with a latency of a few seconds and lasting less than a
minute. The intensity of the rotatory nystagmus is reduced
noted in the examination of extraocular movements. on subsequent testing. Vestibular suppressant medications
Otoscopic examination, to rule out middle ear disease and are of limited usefulness, except during periods of exacer-
cholesteatoma, should always be performed. Examination bation. The severity of symptoms may diminish with rep-
of gait, rapid alternating movement test, finger-to-nose etition due to habituation. Patients usually respond to
testing, and heel-to-knee test are useful in assessing cere- vestibular exercises and spontaneous resolution occurs
bellar function. within a year in most cases.60 In persistent cases, singular
Complete audiometry should be obtained to evaluate neurectomy may be curative.61
auditory function. Further examinations may include Ménière’s syndrome is characterized by episodic severe
electronystagmography, posturography, rotational testing, vertigo, fluctuating sensorineural hearing loss, tinnitus,
computerized tomography, and magnetic resonance imag- and ear fullness. Pathologically, there is distension of the
ing. When cardiac or another medical cause is suspected, a endolymphatic system throughout the inner ear, presum-
complete evaluation by an internist should be obtained. ably due to dysfunction of the endolymphatic sac. Other
specific causes of endolymphatic hydrops include bacterial,
viral, immunologic, and syphilitic labyrinthitis. The clini-
VERTEBROBASILAR INSUFFICIENCY cal course is highly variable, with clusters of severe
episodes interspersed with periods of remission of variable
Vertebrobasilar insufficiency is an important cause of duration. Vertigo may last from 30 minutes to several
vertigo and dysequilibrium in the elderly because it sup- hours and is usually associated with nausea and vomiting.
plies both the peripheral and central components of A feeling of being off-balance or of unsteadiness may
vestibular system.58 It usually results from arteriosclerosis persist for several days with subsequent recovery until
with insufficient collateral circulation, but may also be due the next episode. The patient may complain of worsening
to compression of vertebral arteries by cervical spondylo- hearing loss and tinnitus that may precede the acute attack
sis, postural hypotension, or the subclavian steal syndrome. of vertigo. Management may include a low-salt diet,
The classic clinical presentation of vertebrobasilar diuretics, vasodilators, vestibular suppressants, and occa-
ischemia includes vertigo with head motion (especially sionally surgery to decompress the endolymphatic system.
looking up), dysarthria, numbness of the face, hemiparesis, Acute labyrinthitis, which most probably results from a
headache, and diplopia. Less frequently, visual distur- viral infection of the inner ear, causes both severe vertigo
bances, including oscillopsia, field defects, transient and hearing loss. Typically, it runs its course over a period
blindness, cerebellar ataxia, dysphagia, and drop attacks of 1 to 2 weeks, although residual hearing loss and periodic
may occur, reflecting ischemia of the brainstem and cere- recurrence of vertigo are frequent sequelae. In the elderly,
bellum. Vertigo or dysequilibrium may occur without the recovery may be incomplete and prolonged over
other neurologic signs or symptoms. A definitive diagnosis several months. Vestibular neuronitis also presents with
may be established by four-vessel cerebral angiography, vertigo similar to labyrinthitis, but is unaccompanied by
but is seldom indicated. Magnetic resonance angiography, auditory symptoms. Electronystagmography demonstrates
a noninvasive imaging modality, will likely play an increas- unilateral reduced caloric response.
ingly important role in the diagnosis of vertebrobasilar
disease. Presently, there is no effective medical or surgical
treatment for vertebrobasilar insufficiency, although reha- OTHER OTOLOGIC AND NEUROTOLOGIC
bilitative measures may be beneficial in the amelioration of DISORDERS
the vestibular symptoms.
Middle ear disease such as acute otitis media can present
with vertigo in the young and the elderly. Cholesteatoma
LABYRINTHINE DISORDERS may cause dizziness due to serous or bacterial labyrinthitis
or direct erosion of the semicircular canals. Perilymphatic
A host of peripheral vestibular disorders may cause ver- fistula resulting from chronic otitis media, cholesteatoma,
tigo, including benign paroxysmal positional vertigo or trauma can present with episodic vertigo. Ototoxicity
 Vertigo, Dysequilibrium, and Imbalance with Aging 537

secondary to aminoglycoside therapy is more common in suppressants should be used to lessen the unpleasant sen-
the elderly and is frequently associated with simultaneous sation and to alleviate vegetative symptoms such as nausea
diuretic therapy or diminished renal function.62 Acoustic and vomiting. However, they should only be used for a
neuroma, also called vestibular schwannoma, the most short duration of 1 to 2 weeks, because they adversely
common tumor of the cerebellopontine angle, presents affect the process of central compensation following acute
with unilateral hearing loss, tinnitus, and vertigo or vestibular disease. In acute severe vertigo, diazepam, 2.5 to
dysequilibrium. Selesnick and Jackler63 found that nearly 5 mg intravenously, may abate an attack. Relief from nau-
half of the patients complained of dysequilibrium that sea and vomiting usually requires an antiemetic delivered
was directly correlated to the size of the tumor. Vertigo, intramuscularly or by rectal suppository (e.g., prochlor-
present in 19% of their patients, was more common in perazine, 10 mg intramuscularly, or 25 mg rectally every 6
smaller tumors. Other symptoms of acoustic neuroma hours). Antihistamines may be used for less severe vertigo.
include facial nerve dysfunction, and other cranial neu- Examples include meclizine or dimenhydrinate, 25 to 50
ropathies, facial hypesthesia, headache, and cerebellar dys- mg orally every 6 hours. Transdermal scopolamine, which
function. Audiogram usually reveals a unilateral, is in widespread use for the suppression of motion sick-
asymmetrical, sensorineural hearing loss with poor speech ness, is also useful in the management of vertigo. In the
discrimination. Gadolinium-enhanced magnetic reso- elderly, however, anticholinergic therapy is frequently
nance imaging is the study of choice and is capable of iden- complicated by mental confusion and urinary obstruction,
tifying tumors millimeters in size. Surgical removal is the latter especially in males. The use of transdermal
curative. Other tumors of the cerebellopontine angle scopolamine may also be limited due to side effects of dry
include meningioma, epidermoid, arachnoid cyst, lipoma, mouth and blurred vision and is contraindicated in glau-
and metastatic tumor, among others.64 Clinically, they coma patients. Therapeutic effect with fewer side effects
mimic an acoustic neuroma and may present with may be achieved by cutting the patch in half or even to
dizziness. one-quarter size. Careful handwashing after handling the
patches is necessary to prevent inadvertent eye contact
with resultant prolonged pupillary dilatation and possible
CERVICAL VERTIGO acute narrow-angle glaucoma. Therapy with a combina-
tion of pharmacologic agents may be efficacious when
Vertigo occurring with neck motion is defined as cervical single-drug therapy has been ineffective.
vertigo. The exact cause of this disorder is controversial. Once nausea and vomiting have resolved, exercise
Possible explanations include altered spinovestibular should be encouraged to enhance central compensation
input, vertebrobasilar ischemia due to compression by following peripheral labyrinthine dysfunction. Physical
osteophytes, and irritation of the vertebral sympathetic activity is the single most important element in functional
plexus due to cervical spondylosis.65–67 The aortic arch recovery after acute labyrinthine dysfunction.69,70 Patients
syndrome and subclavian steal syndrome may also cause should be instructed to repeatedly perform maneuvers that
cervical vertigo. Cervical spine films are not helpful due to provoke vertigo—up to the point of nausea or fatigue—in
the large prevalence of asymptomatic osteoarthritic disease an effort to habituate them. Many patients find vestibular
in the elderly. Neck exercises and proper posture may be exercise programs (e.g., Cawthorne’s exercises) helpful.71
of help in relieving the symptoms. A formal physical therapy program designed to identify
and correct maladaptive compensation strategies may also
prove beneficial to patients with a central or peripheral
SYSTEMIC DISORDERS vertigo. The benefit from vestibular rehabilitative therapy
is not significantly influenced by the age of the patient72
A plethora of systemic disorders may affect equilibrium but may be negatively affected by the presence of multiple
and balance in the elderly, including cardiovascular disease causal factors. Subjective and objective benefit with
(hypertension, arrhythmia, ischemic heart disease, hyper- vestibular rehabilitation is seen in patients with balance
active carotid sinus reflex, postural hypotension), cere- disturbance associated with migraine headache.73 Surgical
brovascular disease, peripheral vascular disease, neurologic intervention may be helpful in selected patients who con-
disorders (Parkinson’s disease, dementia, epilepsy, vitamin tinue to have disabling symptoms despite a prolonged and
B12 deficiency), visual impairment, metabolic disease varied course of medical therapy. Surgical therapy may
(diabetes, thyroid disorder), and musculoskeletal prob- include sectioning of the vestibular nerve in a hearing ear
lems.51 Therapeutic drugs are frequently responsible for or a labyrinthectomy in a deaf ear.74
dysequilibrium and postural instability, especially the anti-
hypertensive, antidepressant, psychotropic, and sedative-
hypnotic classes.68
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12. Tinetti ME: Factors associated with serious injury during falls by 39. Stefansson S, Imoto T: Age-related changes in optokinetic and rota-
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15. Babin RW, Harker LA: The vestibular system in the elderly. 42. Simoneau GG, Leibowitz HW, Ulbrecht JS, et al: The effects of
Otolaryngol Clin N Am 15(2):387–393, 1982. visual factors and head orientation on postural steadiness in women
16. Engstrom H, Ades HW, Engstrom B, et al: Structural changes in 55 to 70 years of age. J Gerontol 47:M151–M158, 1992.
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85:310–326, 1976. vestibulo-ocular reflexes of elderly patients with vertigo. Acta
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24. Rosenhall U: Degenerative patterns in the aging human vestibular 50. Linthicum FH Jr: Presbyastasis. In Goldstein JC, Kashima HK,
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of myelinated vestibular nerve fibers in man at various ages. Acta 54. Luxon LM: Disorders of the vestibular system. In Pathy MSJ (ed.):
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59. Bloom J, Katsarkas A: Paroxysmal positional vertigo in the elderly. 67. Wyke B: Cervical articular contributions to posture and gait: Their
J Otolaryngol 18:96–98, 1989. reaction to senile dysequilibrium. Age Ageing 8:251–258, 1979.
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64. Lalwani AK: Meningiomas, epidermoids, and other nonacoustic 72. Whitney SL, Wrisley DM, Marchetti GF, Furman JM: The effect
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65. Barre HJ: Sur un syndrome sympathique cervical posterieure et sa 73. Wrisley DM, Whitney SL, Furman JM: Vestibular rehabilitation
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1926. 23(4):483–487, 2002.
66. Sheehan S, Bauer RB, Meyer JS: Vertebral artery compression in 74. Gacek RR, Ham R: A clinical approach to the management of
cervical spondylosis. Neurology 10:968–986, 1960. geriatric dysequilibrium. Ear Nose Throat J 68:958–960, 1989.
 Chapter
Cervical Proprioceptive Dysfunction
33 Outline

Mark J. Syms, MD Introduction Differential Diagnosis

Definition Treatment
Cervical Proprioceptive Conclusion
Function
Clinical Evidence

INTRODUCTION spine receptors and the vestibular nuclei.9,10 Large popula-

tions of receptors have been found in the neck muscle in
A sense of balance is obtained through integration of three close proximity to the facet joints of the cervical spine.11
sensory systems—visual, vestibular, and somatosensory. Various reflexes have been demonstrated between the neck
The sensory information is redundant, which allows the and vestibular and ocular systems. The vestibulocollic
loss, or decreased input, of one sense to be compensated reflex (VCR) is mediated by vestibulospinal projections.12
for, in part, by input from the other two sensory systems. The function of the VCR is to stabilize the head in space
When the information from two sensory sources conflict, by means of neck muscle movements. The VCR operates
disorientation and vertigo results. The intensity of the in conjunction with the cervicocollic reflex (CCR), which
disorientation and vertigo is a function of the magnitude employs proprioceptive information from the neck to sta-
of the sensory mismatch. bilize the head on the body.13 In 1906 Bárány was the first
to observe, in rabbits, coordinated deviations of the eyes
toward the direction of trunk movements when the head
DEFINITION was held stationary in space.14 Later, the cervico-ocular
reflex (COR) was demonstrated in normal human subjects
Cervical vertigo, a controversial term that has been com- and found to contribute to visual stabilization.15 It is
monly used in the literature,1 was introduced by Ryan and thought that neck joint receptors rather than muscle spin-
Cope2 to describe a condition affecting four patients with dles are the primary source of neck afferents involved in
vertigo and common neck complaints. Neck afferents not the COR.16,17 The body employs these reflexes to maintain
only assist in coordination of the eye, head, and body, but position of the head in space. Any perturbations of the
also influence spatial orientation and posture. On this information or interruptions of the reflexes could poten-
basis, it is argued that stimulation or lesions of the neck tially lead to a proprioceptive disorder.
proprioceptive system could result in vertigo. The skeptics
question the existence of cervical vertigo for two reasons.3
First, there is no reliable clinical test for the syndrome and CLINICAL EVIDENCE
a typical time course for the condition has not been estab-
lished. Second, reliable and well-established signs and tests Despite the evidence demonstrating cervical contribution
can establish a convincing alternative diagnosis in about to proprioception, skeptics argue that no reliable tests
90% of patients presenting with vertigo. exist.3 The presence of nystagmus with neck movement
is not diagnostic of a cervical proprioceptive disorder.
Cervical nystagmus has been found in subjects without the
CERVICAL PROPRIOCEPTIVE FUNCTION complaint of vertigo.18
Since neck control is the product of input of multiple
The neck enables rotation of the head independently of systems, isolation of the cervical region as the source of the
the trunk. In order to maintain a stabile position, the “dizziness” is impossible with simple postural maneuvers.3
vestibular input has to be complemented with neck pro- Animal experiments have demonstrated that surgical
prioceptive input.4 There is considerable experimental deafferentation of C1–3 in squirrel monkeys19 and in the cat20
evidence from animal studies demonstrating neck and caused ataxia. Additionally, injection of local anesthesia in
vestibular signals converge and interact in the brain.5–8 the suboccipital region caused ataxia in rhesus monkeys.21
Anatomic studies have identified links between the cervical When suboccipital anesthesia is performed in humans,
540
 Cervical Proprioceptive Dysfunction 541

transient increased ipsilateral and decreased contralateral TABLE 33-2. Differential Diagnosis of Cervical Vertigo
extensor muscle tone results with a tendency to fall, and a Disorder Assumed Mechanism
deviation of gait and past-pointing toward the injected side
occurs.3 Based on this evidence, the characteristics of cer- Labyrinthine
vical proprioceptive dysfunction is likely to be a sensation
of numbness or floating with ataxia of stance and gait. The Benign paroxysmal positional vertigo Canalotolithiasis, cupulolithiasis
Post-traumatic otolith vertigo Dislodged otoconia, causing
relative contribution of the neck afferents to the vestibular unequal heavy load of macula
nuclei is small compared with the major, direct input from Perilymph fistula Floating labyrinth
the labyrinth and the indirect input from the visual sys-
tem.22 The work of De Jong and colleagues did demon- Vestibular Nerve
strate vertigo when C2–3 were anesthetized.21 However, it
Unilateral vestibular failure Cross coupling effects with acute
has been demonstrated that lesions involving the neck vestibular tone imbalance
afferents in primates compensate rapidly.23 This rapid Bilateral vestibular failure Defective vestibulo-ocular reflex
compensation would make chronic dysequilibrium or ver- Vestibular paroxysmia Neurovascular cross compression
tigo difficult to explain on the basis of disruption of cervi- Nerve compression by Conduction block or ectopic
cerebellopontine angle mass discharges
cal structures. Despite the inability to clearly define the
cause and time course of cervical proprioceptive disorders, Ocular Motor
certainly cervical dysfunction can contribute to dizziness.
After whiplash injuries, dizziness/vertigo is reported to be Extraocular eye muscle or gaze paresis Inappropriate vestibulo-ocular
one of the most frequent, distressing, and persistent symp- Central vestibular: reflex
Central positional nystagmus/vertigo Cerebellar disinhibition
toms (Table 33-1). Since dizziness is very common with Migraine without aura Motion sickness due to sensory
whiplash injuries, the controversy surrounding cervical hyperexcitiability
vertigo is understandable given the economic and legal Migraine with aura (basilar migraine, Spreading depression involving
ramifications of injuries resulting in whiplash. vestibular migraine) vestibular structures
Vestibulocerebellar ataxia Vestibulocerebellar dysfunction

Vascular
DIFFERENTIAL DIAGNOSIS
Rotational vertebral artery occlusion Ischemic depolarisation
Skeptics of the existence of cervical vertigo argue the Carotid sinus syndrome Global cerebral ischemia
Intoxication:
symptoms of cervical vertigo have an alternative explana- Positional alcohol nystagmus/vertigo Cerebellar and specific gravity
tion.24 Brandt argues that well-established signs and tests differential between cupula and
can provide a convincing alternative diagnosis in about 90% endolymph
of patients presenting with vertigo.3 Prior to making the Drugs (e.g., antiepileptics) Cerebellar and ocular motor
diagnosis of cervical vertigo, alternative causes need to be
From Brandt T, Bronstein AM: Cervical vertigo. J Neurol Neurosurg Psychiatry
excluded (Table 33-2). Others argue that cervical vertigo is 71(1):8–12, 2001.
very common. Karlberg and colleagues evaluated 65 pa-
tients and found 22 of the patients had dizziness of cervical
origin.25 Despite the controversy surrounding the definition Each patient underwent a neurologic and otolaryngologic
and existence of cervical vertigo, vertigo with a cervical examination to rule out other causes of the vertigo. The
component surely exists. In the context of a thorough neu- patients underwent a chiropractic evaluation, which demon-
rotologic examination, clinicians can recognize that cervi- strated dysfunction of the upper cervical spine in 31 (62%)
cal disorders are a component of the dizziness a patient is of the 50 patients. The remaining 19 (38%) patients did
experiencing and should attempt to address the cervical not show signs of upper cervical dysfunction. All of the
disorder with the hope of improving the symptoms. patients underwent extensive outpatient physical therapy
for 3 months and were followed up 2 weeks after the end
of the therapy. If the patient’s vertigo was not resolved, the
TREATMENT patients underwent another 3 months of physical therapy
and were reevaluated 2 weeks after the completion of the
Cervical physical therapy has been reported to be very physical therapy. In the group with cervical dysfunction,
successful in the resolution of vertigo attributed to cervical the vertigo was improved in 16 of 31 patients after the first
dysfunction. Galm and colleagues reported on a group of 3 months of therapy. None of the 19 patients without
50 patients who presented with symptoms of dizziness.26 cervical dysfunction had improvement of their vertigo.
After the second 3 months of physical therapy, 24 (77.4%)
of the 31 patients reported improved vertigo symptoms.
TABLE 33-1. Dizziness/Vertigo after Head Injury The remaining seven reported no improvement. Of the
Author Number of Patients Incidence (%) group without cervical dysfunction, only five patients
(26.3%) reported any improvement of the vertigo symp-
Linthicum and Rand27 30 90 toms. Similarly, Karlberg and associates reported that
Glaser 70 40 physiotherapy in patients with dizziness of a suspected
Procter et al28 32 50
cervical origin significantly reduced the neck pain and
Luxon L: Posttraumatic vertigo. In Baloh R, Halmagyi G (eds.): Disorders of the intensity and the frequency of the dizziness.25 Even skeptics
Vestibular System. New York, Oxford University Press, 1996, pp 381–395. of the existence of cervical vertigo acknowledge that vertigo
542 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

can be accompanied by cervical pain and associated with 11. Dutia MB: The muscles and joints of the neck: their specialisa-
head injury or whiplash injury and that in some cases it tion and role in head movement. Prog Neurobiol 37(2):165–178,
improves dramatically with physiotherapy.1 1991.
12. Peterson B, Baker J, Perlmutter S, Iwamoto Y: Neuronal substrates
of spatial transformations in vestibuloocular and vestibulocollic
reflexes. In Cohen B, Tomko D, Guerdy F (eds.): Sensing and
CONCLUSION Controlling Motion: Vestibular and Sensorimotor Function. New
York, New York Academy of Sciences, 1992, pp 485–499.
Cervical vertigo is a controversial entity. Despite the con- 13. Peterson B, Goldberg J, Bilotto G, Fuller F: Cervicocollic reflex:
troversy, vertigo with a cervical component surely exists. Its dynamic properties and interactions with vestibular reflexes.
Clinicians should perform a thorough neurotologic exam- J Neurophysiol 54:90–109, 1985.
ination and recognize if a cervical disorder is a component 14. Bárány R: Augenbewegegungen durch Thoraxbewegungen ausgelöst.
of the dizziness a patient is experiencing. If a cervical pro- Zbl Pysiol 20:298–302, 1906.
prioceptive disorder is thought to contribute to the dizzi- 15. Barnes GR, Forbat LN: Cervical and vestibular afferent control of
ness, the patient should be referred for physiotherapy to oculomotor response in man. Acta Otolaryngol 88(1–2):79–87,
address the cervical disorder. 1979.
16. Biemond A, De Jong JM: On cervical nystagmus and related
disorders. Brain 92(2):437–458, 1969.
17. McCouch G, Deering I, Ling T: Location of receptors for tonic
REFERENCES neck reflexes. J Neurophysiol 14:191–195, 1951.
18. Norre ME, Forrez G, Stevens A, Beckers A: Cervical vertigo diagnosed
1. Brandt T: Cervical vertigo—Reality or fiction? Audiol Neurootol by posturography? Preliminary report. Acta Otorhinolaryngol Belg
1(4):187–196, 1995. 41(4):574–581, 1987.
2. Ryan G, Cope S: Cervical vertigo. Lancet 2:1355–1358, 1955. 19. Igarashi M, Alford BR, Watanabe T, Maxian PM: Role of neck
3. Brandt T: Vertigo: Its Multisensory Syndromes. New York, proprioceptors for the maintenance of dynamic bodily equilibrium
Springer-Verlag, 1991, pp 277–288. in the squirrel monkey. Laryngoscope 79(10):1713–1727, 1969.
4. Roberts TD: Reflex balance. Nature 244(5412):156–158, 1973. 20. Manzoni D, Pompeiano O, Stampacchia G: Cervical control of
5. Fredrickson JM, Schwarz D, Kornhuber HH: Convergence and inter- posture and movements. Brain Res 169(3):615–619, 1979.
action of vestibular and deep somatic afferents upon neurons in the 21. De Jong PT, de Jong JM, Cohen B, Jongkees LB: Ataxia and
vestibular nuclei of the cat. Acta Otolaryngol 61(1):168–188, 1966. nystagmus induced by injection of local anesthetics in the Neck.
6. Boyle R, Pompeiano O: Convergence and interaction of neck and Ann Neurol 1(3):240–246, 1977.
macular vestibular inputs on vestibulospinal neurons. J Neurophysiol 22. Luxon L: Posttraumatic Vertigo. In Baloh R, Halmagyi G (eds.):
45(5):852–868, 1981. Disorders of the Vestibular System. New York, Oxford University
7. Rubin AM, Liedgren SR, Odkvist LM, et al: Labyrinthine and Press, 1996, pp 381–395.
somatosensory convergence upon vestibulospinal neurons. Acta 23. Baloh R, Honrubia V: Clinical Neurophysiology of the Vestibular
Otolaryngol 86(3–4):251–259, 1978. System. Philadelphia, FA Davis, 1990.
8. Kasper J, Schor RH, Wilson VJ: Response of vestibular neurons to 24. Brandt T, Bronstein AM: Cervical vertigo. J Neurol Neurosurg
head rotations in vertical planes. II. Response to neck stimulation and Psychiatry 71(1):8–12, 2001.
vestibular-neck interaction. J Neurophysiol 60(5):1765–1778, 1988. 25. Karlberg M, Magnusson M, Johansson R: Effects of restrained
9. Bankoul S, Neuhuber WL: A direct projection from the medial cervical mobility on voluntary eye movements and postural control.
vestibular nucleus to the cervical spinal dorsal horn of the rat, as Acta Otolaryngol 111(4):664–670, 1991.
demonstrated by anterograde and retrograde tracing. Anat Embryol 26. Galm R, Rittmeister M, Schmitt E: Vertigo in patients with cervical
(Berl) 185(1):77–85, 1992. spine dysfunction. Eur Spine J 7(1):55–58, 1998.
10. Neuhuber WL, Zenker W: Central distribution of cervical primary 27. Linthicum F, Rand C: Neuro-otological observations in concussion
afferents in the rat, with emphasis on proprioceptive projections of the brain. Arch Otolaryngol 13:785–821, 1931.
to vestibular, perihypoglossal, and upper thoracic spinal nuclei. 28. Procter B, Gurdjian E, Webertser J: The ear in head trauma.
J Comp Neurol 280(2):231–253, 1989. Laryngoscope 66:16–61, 1956.
 Chapter
Paraneoplastic Disorders

Outline 34
Paraneoplastic Syndromes Generated by Neurotologic Tumors A. Julianna Gulya, MD, FACS
Paraneoplastic Syndromes from Disorders Associated with
Neurotologic Tumors
Paraneoplastic Syndromes Associated with Carcinoma
Summary

T he concept that cancers could evoke remote effects

was first articulated by Guichard in 1956 when he
referred to the polyneuritis seen in patients with known
phenylethanolamine-N-methyltransferase; thus, in para-
gangliomas dopamine and norepinephrine are produced.9,11
Tryptophan metabolism results in the production of the
cancer as a paraneoplastic syndrome (PNS).1 Fundamen- indole amine serotonin (5-hydroxytryptamine) (Table 34-3),10
tally, a PNS describes an “association of symptoms and a capacity within the repertoire of human glomus cells, as
signs not directly related to the site or local manifestations evidenced by their serotonin immunoreactivity.12–15
of a malignant tumor or its metastases.”1 Although the term In addition, the chief cells of paragangliomas have been
is most appropriately used when referring to the remote documented to contain a wide variety of neuropeptides
effects of cancerous lesions, for the purpose of discussion (Table 34-4), enzymes, and other proteins typical of,
in this chapter it is expanded to encompass the remote although not entirely specific for, members of the DNES.13
effects of benign tumors as well. Neuron-specific enolase (NSE), chromogranin, and
PNSs are of significance to neurotologists for they may leuenkephalin in particular serve as markers for chief cells,
be generated by tumors managed by neurotologists, they and sustentacular cell markers include S-100 protein, glial
may be generated by neoplasms occurring in association fibrillary acidic protein (GFAP),13 and nerve growth factor
with disorders managed by neurotologists, or they may receptor.
give rise to auditory and vestibular dysfunction requiring The clinical consequences of amine production by para-
neurotologic evaluation and management. In addition, a gangliomas are manifested in the PNS of the “functional”
PNS provides a unique vantage point from which to tumor. Although, as pointed out by Batasakis,16 “nearly all”
observe the basic biology of the tumor cell involved. of these tumors “demonstrate intracellular catecholamines,”
only 1% to 3% actually give rise to the hypertension,
headaches, excessive perspiration, tremor, palpitations, pal-
lor, nausea, anxiety, flushing, epigastric or chest pain, and
PARANEOPLASTIC SYNDROMES weight loss related to elevation of serum norepinephrine
GENERATED BY NEUROTOLOGIC and possibly dopamine.9 The disparity between potential
TUMORS and actual catecholamine-related symptomatology is gen-
erally attributed to the requirement for a four- to fivefold
The chief cells of paraganglions and paragangliomas (glomus elevation of serum norepinephrine for the development of
tumors) are of neural crest origin and are constituents of the symptoms.9 Tumor burden in and of itself does not appear
diffuse neuroendocrine system (DNES) (Table 34-1).2,3 to predict whether or not a tumor will be “functional.”17
Cells of the DNES, although seemingly disparate in Ultrastructural and immunocytochemical analyses18 have
nature, are linked by shared cytochemical and ultrastruc- suggested that functional tumor cells, in contrast to those
tural features, particularly with regard to their capacity to of nonfunctional tumors, have larger secretory granules
synthesize, store (in osmiophilic granules), and secrete (220 to 280 nm vs. 100 to 180 nm), contain numerous dilated
physiologically active products, for example, amines and mitochondria) profiles (indicative of metabolic activity), and
neuropeptides,4 which variably function as neurotransmit- express at least two of the antigens enkephalin, neuropep-
ters, neurohormones, hormones, and parahormones.4 tide Y, or tyrosine hydroxylase.
The chief cells of paragangliomas have a demonstrated The carcinoid syndrome, consisting of “episodic cuta-
capacity for catecholamine synthesis and secretion.5–9 The neous flushing, cyanosis, abdominal cramps, diarrhea, and
metabolism of tyrosine, key in the generation of valvular heart disease (and less commonly asthma and
catecholamines, is illustrated in Table 34-2.10 Only the arthropathy),”19 has been related to elevated serum levels
adrenal medulla, heart, and brain possess the enzyme of serotonin. Farrior and associates20 presented one
543
544 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

TABLE 34-1. Cells of the DNES TABLE 34-3. Tryptophan Metabolism

Pituitary chief cells TRYPTOPHAN
Pancreatic islet cells
Thyroid C-cells Tryptophan hydroxylase
Paraganglion chief cells
Adrenal medulla cells
Parathyroid chief cells* 5-HYDROXYTRYPTOPHAN
Lung endocrine (Feyrter) cells
Gastrointestinal argyrophil and enterochromaffin cells Decarboxylation

*Debated. SEROTONIN (5-Hydroxytryptamine)

DNES, diffuse neuroendocrine system.
Adapted from Bolande RP: The neurocristopathies: A unifying concept of disease arising
in neural crest maldevelopment., Human Pathol 5:409–429, 1974. Data from Diem K, Lentner C: Scientific Tables, 7th ed. Ardsley, NY, Geigy
Pharmaceuticals, 1970.

paraganglioma (jugulare) in which carcinoid-like symptom- histories. In an attempt to determine whether neuropep-
atology resolved with resection of the tumor, providing tide secretion by the paragangliomas precipitated such
circumstantial evidence for the association of paragan- symptomatology, routine serum screening of paragan-
gliomas with yet another type of PNS. glioma and other skull base tumor patients for vasoactive
More convincingly, Galan and colleagues21 reported the intestinal polypeptide, cholecystokinin (CCK), somato-
development of hypotension, bradycardia, and bron- statin, pepsinogen I, human pancreatic polypeptide, and
chospasm with intraoperative manipulation of a glomus thyroid-releasing hormone was undertaken. The degree of
tympanicum tumor that had been associated preopera- postoperative ileus was then contrasted to the preoperative
tively with elevated urinary 5-hydroxyindoleacetic acid serum levels of these neuropeptides, as well as to sacrifice
(5-HIAA), the urinary metabolite of serotonin. Within of the vagus nerve. In a review of 25 cases (19 paragan-
5 minutes of the administration of intravenous octreotide, gliomas and 6 nonglomus tumors) it became evident that
the bronchospasm and the hemodynamic changes vagus nerve sacrifice was not a determinant factor in post-
resolved, and by the fifth postoperative day the patient’s operative ileus. Interestingly enough, serum CCK levels in
urinary 5-HIAA dropped to nearly normal. patients with paragangliomas were significantly higher
The neuropeptides found within paraganglioma cells, ( p < 0.05) than those of nonparaganglioma patients, and
both chief and sustentacular, remain of uncertain signifi- the patients with more than 3 days of postoperative ileus
cance. Investigations have focused on the possibility that had preoperative CCK levels approximately twice that
neuropeptides give rise to PNS(s),22 that they prognosti- of patients with postoperative ileus of briefer duration.22
cate tumor behavior,23 or that they can be used for tumor A major difficulty in drawing firm conclusions from these
localization.24 data is the wide variability in normal CCK serum levels;
In the course of caring for patients who had undergone nonetheless, further investigation appears warranted,
infratemporal fossa removal of paragangliomas, members especially of the tracking serum neuropeptide levels post-
of the Otology Group noted postoperative ileus, acalcu- operatively.
lous cholecystitis, and pancreatitis not seemingly related A few reports of anemia, usually normochromic/normo-
to the surgical procedure nor the patients’ past medical cytic, were associated with metastatic paragangliomas.25–28

TABLE 34-2. Tyrosine Metabolism TABLE 34-4. Immunohistochemical Markers

for Paragangliomas
TYROSINE
Chief Cells Pancreatic polypeptide
Tyrosine hydroxylase Somatostatin
Catecholamines Gastrin
Norepinephrine Calcitonin
DOPA Dopamine Neuropeptide Y
Dopa decarboxylase Serotonin Corticotropin
Neuron-specific enolase Vasoactive intestinal polypeptide
DOPAMINE Chromogranins Bombesin
Synaptophysin Neurotensin
Neurofilaments Insulin
Dopamine hydroxylase
Sustentacular Cells Glucagon
Substance P
NOREPINEPHRINE S-100 protein
Cholecystokinin
Glial fibrillary acidic protein
Alpha melanocyte stimulating
Nerve growth factor receptor
Phenylethanolamine-N-Methyltransferase hormone
Neuropeptides
Enkephalins
EPINEPHRINE
Data from Kliewer KE, Cochran AJ: A review of the histology, ultrastructure,
Data from Diem K and Lentner C: Scientific Tables, 7th ed. Ardsley, NY, Geigy immunohistology, and molecular biology of extra-adrenal paragangliomas. Arch Pathol
Pharmaceuticals, 1970. Lab Med 113:1209–1218, 1989.
 Paraneoplastic Disorders 545

Two patients with nonmetastatic, cervical paragangliomas with multiple endocrine neoplasia II (MEN II—Sipple’s syn-
experienced normalization of reduced hematocrits subse- drome), an autosomal-dominant, familial disease consisting
quent to tumor removal.27,29 Interference with production of pheochromocytomas, medullary carcinoma of the
of, or enhanced destruction of, erythropoietin are mecha- thyroid, and parathyroid hyperplasia.
nisms proposed by Schwartz and Israel26 based on their A familial tendency has been described for paragan-
finding of depressed erythropoietin levels in a patient with gliomas, typified by autosomal-dominant transmission and
metastatic paraganglioma. The precise mechanism of such an exaggeration in the tendency for multiple para-gan-
an “antierythropoietic effect,” if it truly exists, has yet to be gliomas,39,40 occurring in 25% to 50% of the cases39–42
determined. and also perhaps in the occurrence of associated lesions.39
Linnoila and colleagues23 conducted immunohistochem- Thus, regardless of the functional status of the
ical analyses of 99 human adrenal and extra-adrenal para- paraganglioma that brings the patient to the attention of the
gangliomas for neuron-specific enolase and a total of 10 neurotologist, it is possible for an associated lesion to give
neuropeptides. They found that malignant paragangliomas, rise to the symptomatology of a PNS. It is important to
that is, those with “proven regional or distant metastases,” recognize that elevated serum epinephrine levels in a
were positive for only an average of two neuropeptides per patient with a paraganglioma mandate a thorough investi-
tumor, in contrast to the benign tumors, which were posi- gation for a concurrent pheochromocytoma, because, as
tive for an average of five neuropeptides per tumor. They discussed earlier, paragangliomas cannot metabolize
suggested that there was a “definite relationship between norepinephrine to epinephrine.
expression of neuropeptides and the biologic behavior of Patients with neurofibromatosis (von Recklinghausen’s
these paragangliomas.”23 disease, NF1) also tend to manifest associated lesions.
Lamberts and associates24 reported on the utility of 123 I- For example, they have a 10-fold greater incidence
labeled Tyr3-octreotide (a somatostatin analogue) in visu- of pheochromocytoma than the general population.43
alizing some tumors, including paragangliomas, with The occurrence of parathyroid adenoma in NF1 has been
somatostatin receptors. Of the 20 paraganglioma patients speculated to represent a variant of MEN IIb, that
scanned, 10 jugulotympanic, 9 carotid, and 10 vagal para- is, the MEN II that occurs in patients with diffuse
gangliomas were detected. Scanning missed small tumors ganglioneuromatosis of the alimentary tract, mucosal
(less than 5 mm)—one carotid body and one tympanic neuromas, and often a marfanoid habitus.44 Griffiths
paraganglioma. and colleagues45,46 have even suggested that the triad of
Scintigraphy with 111In-diethylenetriaminepentaacetic NF1, pheochromocytomas, and duodenal carcinoid
acid octreotide (indium-111-pentretreotide) is able to reveal constitutes a specific multiple endocrine neoplasia
tumors of at least 1 cm and perhaps as small as even 0.5 cm30 syndrome, which they labeled MEN IIIa. Terminology can
and may aid in the differentiation of paraganglioma versus cause confusion, for MEN IIb also has been referred to as
neuroma, meningioma, radionecrosis, and postoperative MEN III.44
scar from recurrent paraganglioma. Thus in managing neurofibromatosis the neurotologist
Octreotide may have some utility in the treatment of must be cognizant of the possibility of an associated lesion
unresectable or recurrent paragangliomas. In one report,31 with functional potential and may consider endocrinology
octreotide therapy for up to 35 months was associated with consultation for appropriate diagnosis and treatment.
either no tumor growth or reduced tumor volume as Finally, neurofibromatosis has been associated with
visualized by magnetic resonance imaging; side effects of pheochromocytomas, a paraganglioma (jugulare), and
the therapy were mild, consisting largely of fatty stool. multiple pulmonary paraganglioma,43 as well as with
a vagal paraganglioma.3 Although such an association
may merely be a chance event, it may be more reasonable
to consider all of these lesions as reflecting an abnormality
PARANEOPLASTIC SYNDROMES of neural crest derivatives, or, as stated by Bolande,3 a
FROM DISORDERS ASSOCIATED neurocristopathy.
WITH NEUROTOLOGIC TUMORS As defined by Bolande,3 a neurocristopathy is a condition
with roots in aberrant neural crest development. Isolated
PNSs may arise from tumors occurring in conjunction paragangliomas, pheochromocytomas, and carcinoid tumors
with disorders managed by the neurotologist; such situa- are some examples of what Bolande categorized as simple
tions are exemplified by the occurrence of additional non- neurocristopathies, or single, localized pathologic processes.
paraganglioma tumors with paragangliomas, as well as Complex neurocristopathies or neurocristopathic syndromes
with neurofibromatosis. include such entities as von Recklinghausen’s disease and the
Paragangliomas have long been recognized for their multiple endocrine neoplasia disorders, which are typified by
propensity to manifest associated lesions; approximately a vast array of possible combinations of the simple neuro-
10% of nonfamilial jugulotympanic paragangliomas will cristopathies. In fact, von Recklinghausen’s disease, because
exhibit another tumor of the paraganglioma type.32–34 it can potentially involve a wide range of neurocutaneous
In addition, pheochromocytomas,35,36 papillary thyroid and neuroendocrine disorders, is considered the prototype
carcinoma,37 medullary carcinoma of the thyroid,38 and of the complex neurocristopathies.3
parathyroid adenoma9 have been reported in association Thus it is perhaps more useful in terms of extending our
with paragangliomas. knowledge of the basic biology of the paraganglioma not
Kennedy and Nager38 pointed out a potential relation- merely to dismiss associations with other neural crest
ship between the occurrence of paragangliomas (tympanic) disorders as random events, but to consider them as clues
546 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

to the existence of neurocristopathic syndromes, in which vertigo or ataxia may be the initial symptoms of PCD,57 and
paragangliomas represent only one manifestation. although concurrent hearing loss has been reported,59,60 no
histopathologic correlates have been reported.
The appropriate diagnosis of PEM and PCD is of sig-
nificance because the onset of either PNS may precede the
PARANEOPLASTIC SYNDROMES diagnosis of the underlying malignancy.61 Nonspecific clues
ASSOCIATED WITH CARCINOMA for PEM are sudden hearing loss occurring in a patient
older than 50 years in association with diffuse neurologic
Certain PNSs associated with malignancies rarely will symptoms. PCD is part of the differential diagnosis of
encompass auditory or vestibular symptomatology leading sudden-onset or progressive vertigo and ataxia, particu-
to neurotologic consultation. Despite their rarity, such larly in a middle-aged female. Both PEM and PCD can
PNSs are of significance because they provide a unique per- manifest the cerebrospinal fluid (CSF) findings of pleocy-
spective on the biology, not only of the underlying cancer,47 tosis with lymphocytic predominance, an elevated protein
but also of the auditory and vestibular systems. Substantial count, oligoclonal bands, and an elevated IgG level.50,51
progress, accelerated by advances in immunochemistry and More specific tests have been developed for the diagnosis
immunohistochemistry, has been made in elucidating the of PEM and PCD, as discussed later.
operative mechanisms of two PNSs of potential relevance to The preponderance of evidence favors an autoimmune
neurotologists, namely, paraneoplastic encephalomyelitis pathogenesis for both PEM and PCD. The foundation of
(PEM) and paraneoplastic cerebellar degeneration (PCD). the autoimmune hypothesis is that the cancer patient pro-
PEM describes a group of neurologic PNSs sharing duces antibodies that react with antigens displayed by the
inflammatory changes in neural tissue, especially perivas- tumor; the antibodies may or may not have an adverse
cular round cell infiltrates, microglial activation and effect on tumor growth,62,63 but they do react with anti-
neuronal loss,48,49 and an autoimmune pathogenesis.50 A gens of specific neural cells, causing their dysfunction or
small-cell lung carcinoma (SCLC) is the underlying malig- death.63 Certainly, in the case of PEM, such a hypothesis
nancy in the majority of cases.51 The various types of appears feasible because the cells of origin of SCLC,
PEM, namely, cerebral encephalitis, brainstem encephali- Kulchitsky cells of the lung, are members of the DNES
tis, cerebellar encephalitis, subacute myelitis, and dorsal and can express a variety of neuronal differentiation anti-
root ganglionitis, are distinguished according to predomi- gens.64–67 Further support for the autoimmune hypothesis
nant anatomic site of the lesion. Clinical application of this has come with the identification of the antibodies anti-Hu
nosology is confronted with the reality of considerable and anti-Yo being relatively restricted to patients with
overlap among the various types.51 PEM and PCD, respectively.50,68–70
The brainstem form of PEM manifests the hallmark Anti-Hu reacts with 35- to 36-kilodalton nucleoproteins
inflammatory neuronal destruction, especially in the expressed only by brain tissue, for example, the neurons of
medulla,51 that commonly involves the vestibular brain- the nuclei of the brain (including the vestibular and
stem nuclei and uncommonly affects the cochlear nuclei.51 cochlear nuclei), and dorsal root and gasserian ganglion
In addition, cranial nerve motor nuclei, such as XII and X neurons, as well as SCLC tissue. The nuclear staining
may be affected,51 and in the pons, the cranial nerve nuclei observed immunohistochemically with anti-Hu spares the
involved include VI and VII.51 nucleolus and is not observed with satellite, Schwann, or
Sudden unilateral sensorineural hearing loss has been doc- non-neural cells.62,71 Anti-Hu has been detected in the
umented well in only one case of brainstem encephalitis.52 blood and CSF72,73 and has also been eluted from tumor
McGill52 found diffuse cochlear neuronal loss in the spiral (SCLC) and brain tissue of patients with PEM.74 The anti-
ganglion as well as in the dorsal and ventral cochlear nuclei body may be taken up from the blood by central nervous
and peripheral vestibular structures ipsilateral to the side system (CNS) neurons in a process that involves endocy-
of a sudden sensorineural hearing loss in a 54-year-old tosis and retrograde axonal transport,75 or from the CSF,
female whose underlying SCLC was detected only on which is linked to intrathecal anti-Hu production.72 Copy
autopsy. Such diffuse neuronal loss is not characteristic of DNA (cDNA) clones have been isolated from both normal
viral sudden sensorineural hearing loss.53,54 brain tissue76 and SCLC tissue,77 which code for the Hu
Márquez and coworkers55 reported the development of antigen. A quantitative assay for anti-Hu sera has been
a bilateral, rapidly-progressive sensorineural hearing loss developed that uses the fusion protein encoded by these
associated with gait instability in a 50-year-old man who cDNA clones.76 The target of the anti-Hu antibody is a
was subsequently found to have lung carcinoma with anti- family of neuron-specific RNA-binding proteins (Hu).78
Hu antibodies (see following discussion). Unfortunately, It is thought that “antibody mediated disruption of the
an autopsy was not performed. Hu RNA-binding activity might lead to neuronal death,”78
PCD describes the subacute cerebellar degeneration seen in but the mechanism remains unclear.
patients with carcinoma (especially of the ovaries, breast, and Anti-Yo is the anti-Purkinje cell antibody found in the
lung [SCLC]) and lymphoma.56 Histopathologically, inflam- serum and79 CSF72,80 of women with gynecologic or breast
matory and noninflammatory variants occur,57 and although cancer and PCD.69 Immunofluorescent study of anti-Yo
the exact relationship of the two forms is uncertain,50 they reveals a coarsely granular fluorescence of the cytoplasm,69
both share the finding of a diffuse loss of Purkinje cells. which by immunoelectron microscopy81 is correlated to
Patients with PCD manifest progressive pancerebellar binding to the endoplasmic reticulum (Nissl substance) and
dysfunction, particularly truncal and appendicular ataxia, Golgi complexes of Purkinje cells. Two groups of proteins
nystagmus, dysarthria, and diplopia.2,57-59 Abrupt-onset (cerebellar degeneration–related [CDR] proteins)—one with
 Paraneoplastic Disorders 547

a relative molecular weight of 62 to 64 kilodaltons (CDR 10. Diem K, Lentner C: Scientific Tables, 7th ed. Ardsley, NY, Geigy
62) and one with a relative molecular weight of 34 to Pharmaceuticals, 1970.
38 kilodaltons (CDR 34)—are recognized by anti-Yo; 11. Matsuguchi H, et al: Noradrenalin-secreting glomus jugulate tumor
with cyclic change of blood pressure. Arch Intern Med 135:
CDR 62 accounts for the majority of the reactivity.82 Both
1110–1113, 1975.
CDR 34 and CDR 62 are also expressed in the tumor tis- 12. Heym C, Kummer W: Regulatory peptides in paraganglia. Prog
sues of women with PCD, and anti-Yo, similar to anti-Hu, Histochem Cytochem 18:1–95, 1988.
is produced in the CSF,72,73 from which it is extracted by 13. Kliewer KE, Cochran AJ: A review of the histology, ultrastructure,
the Purkinje cells.83,84 CDR 62 is thought to function in immunohistology, and molecular biology of extra-adrenal paragan-
the regulation of gene expression85—and if interfered with gliomas. Arch Pathol Lab Med 113:1209–1218, 1989.
by anti-Yo could prove lethal to the host Purkinje cell. A 14. Warren WH, et al: Neuroendocrine markers in paragangliomas
sensitive and specific assay for anti-Yo sera has been devel- of the head and neck. Ann Otol Rhinol Laryngol 94:555–559, 1985.
oped that utilizes the fusion protein produced by a cDNA 15. Warren WH, et al: Paragangliomas of the head and neck:
clone, which encodes the CDR 62 antigen.85,86 Ultrastructural and immunohistochemical analysis. Ultrastructural
Pathol 8:333–343, 1985.
Currently it is thought that the protein target of the
16. Batasakis JG (ed.): Paragangliomas of the head and neck. In Tumors
anti-Yo antibody is a neuronal signal transduction pro- of the Head and Neck: Clinical and Pathological Considerations,
tein.78 The mechanism whereby anti-Yo antibodies cause 2nd ed. Baltimore, Williams & Wilkins, 1979, pp 369–380.
Purkinje cell death is not yet determined, although Tanaka 17. Farrior JB, Packer JT: Glomus tumors of the temporal bone:
and colleagues87 theorize that cytotoxic T lymphocytes Electron microscopic and immunohistochemical evaluation.
may be involved. Otolaryngol Head Neck Surg 104:24–28, 1991.
Thus, for both PEM and PCD, the autoimmune, or 18. Hamid Q, et al: Extra-adrenal paragangliomas: An immunocyto-
antionconeural (since the tumor is not really “self”), mech- chemical and ultrastructural report. Cancer 60:1776–1781, 1987.
anism82 appears to be operational. Antibodies, anti-Hu 19. Reid JD: Carcinoid syndrome. In Berkow R (ed.): The Merck
and anti-Yo, have been demonstrated in the serum and Manual of Diagnosis and Therapy, 15th ed. Rahway, NJ, Merck
Sharp and Dohme Research Laboratories, 1987.
CSF of patients with PEM and PCD, respectively, which
20. Farrior JB III, et al: Carcinoid apudoma arising in a glomus jugulare
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with PNS. Laryngoscope 90:110–119, 1980.
21. Galan FG, et al: Octreotide and a serotonin-secreting glomus
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SUMMARY 22. Jackson CG, et al: A paraneoplastic syndrome associated with glo-
mus tumors of the skull base? Early observations. Otolaryngol Head
PNSs, or the remote effects of neoplasia, are of practical Neck Surg 100:583–587, 1989.
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of theoretic importance in leading to a better understand- Pathol 19:41–50, 1988.
ing of neurotologic tumors and cochleovestibular system 24. Lamberts SW, et al: Somatostatin-receptor imaging in the localiza-
tion of endocrine tumors. N Engl J Med 323:1246–1249, 1990.
biology.
25. Pinsker KL, et al: Cervical chemodectoma with extensive pul-
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26. Schwartz ML, Israel HL: Severe anemia as a manifestation of metasta-
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 Paraneoplastic Disorders 549

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from the cerebrospinal fluid by Purkinje neurons. Science 228: encoding the 62K-cerebellar antigen recognized by patients with
346–348, 1985. antibody-associated paraneoplastic cerebellar degeneration.
84. Borges LF, Busis NA: Intraneuronal accumulation of myeloma Neurology 41 (Suppl 1):363, 1991.
proteins. Arch Neurol 42:690–694, 1985. 87. Tanaka M, et al: Cytotoxic T cells against a peptide of Yo protein in
85. Fathallah-Shaykh H, et al: Cloning of a leucine-zipper protein patients with paraneoplastic cerebellar degeneration and anti-Yo
recognized by the sera of patients with antibody associated parane- antibody. J Neurolog Sci 168:28–31, 1999.
oplastic cerebellar degeneration. Proc Natl Acad Sci USA 88:
3451–3454, 1991.
 Chapter
Dizziness in Childhood

Outline 35
Development of the Perilymphatic Fistula Fred F. Telischi, MEE, MD
Vestibular System Vestibular Neuronitis
Grayson K. Rodgers, MD
Diagnostic Evaluation Labyrinthitis and Meningitis
History Specific Disease Entities: Thomas J. Balkany, MD
Physical Examination Central
Testing Migraine
Developmental Effects of Vertiginous Seizures
Vestibular Dysfunction Tumors
Congenital and Hereditary Neurosyphilis
Hearing Loss Congenital Nystagmus
Congenital Anomalies Ataxia
Specific Disease Entities: Familial Ataxia
Peripheral Multiple Sclerosis
Otitis Media and Complications Other Disease Entities
of Otitis Media Metabolic/Systemic Disease
Benign Paroxysmal Vertigo Toxic
of Childhood Functional
Ménière’s Disease Summary
Trauma

Vestibular symptoms as a chief complaint in the pedi-

D izziness is both frightening to the child and worri-
some for the parents. As in adults, the symptoms of
dizziness, giddiness, unsteadiness, and imbalance can arise
atric patient population are uncommon. Series reported
in the literature are small. Fried1 found 14 out of 2088
from a variety of body systems. True rotational vertigo patients in 12 months claiming dizziness as the chief com-
generally implies a disorder of the vestibular system and its plaint. Eviatar and Eviatar2 reported 24 patients with
relationship to the appropriate proprioceptive and visual vertigo from a pediatric neurology clinic of 5000. The
systems. A team approach, involving neurotologist, neurolo- University of Nebraska experience published by Beddoe3
gist, pediatrician, ophthalmologist, and audiologist/neuro- included 22 cases of dizziness or vertigo in children from
physiologist provides the best chance for an accurate diagnosis 1960 to 1974.
and effective treatment. Although the neurotologist is gen-
erally consulted about how the vestibular system contributes
to the child’s problem, he or she should be familiar with
the associated pathways and disorders relating the vestibu- DEVELOPMENT OF THE VESTIBULAR
lar system to other systems that may play a part in the SYSTEM
dizziness. The clinical presentation of vertigo and ataxia in
the pediatric age group may resemble that of the adult, but Although postural changes occur prenatally,4 the neural
the differential diagnoses in the two groups are different. interconnections among the visual, cerebellar,
Many relatively common disorders that produce dizzi- labyrinthine, proprioceptive, and peripheral neuromuscu-
ness in adults are rarely seen in children. The neurologic lar systems are incompletely developed at birth.2
and vestibular systems mature during childhood, which Myelination of the various pathways occurs after birth.5
results in different interpretations of physical findings in Vestibular pathways myelinate earlier (by 16 weeks) than
children and adults. The vestibular system is one of the pyramidal tracts (by 24 months). Peripheral labyrinthine
first central nervous system (CNS) projections to begin functions, however, appear to be even more advanced.
functioning in infancy. As in adults, the history and physi- When an embryo reaches the size of 8 mm, the otocyst
cal examination are the basis for the majority of diagnoses, differentiates into a wider dorsal (vestibular) portion and
with assorted diagnostic tests used for confirmation. a narrow ventral (cochlear) portion. The endolymphatic
553
554 PEDIATRIC NEUROTOLOGY

duct can be recognized on the medial aspect of the otocyst various developmental milestones. Significant delays of
at this stage. When the embryo reaches 14 mm (6 weeks), motor function occur in children with bilateral vestibular
pouches are formed on the vestibular portion of otocyst dysfunction.9 When physical activity is delayed or abnor-
that will eventually give rise to the semicircular canals. At mal, vestibular disorders should be included in the differ-
20 mm (7 weeks), the vestibule divides into the utricle and ential diagnosis. Parents should be specifically questioned
saccule. When the embryo has reached a 30-mm size about abnormal movements, especially of the head and
(8 weeks), the inner ear nearly resembles the adult form. neck. Nystagmus or unusual eye movements may be noted
Although the anatomic pathways may be developed in by the parents. Loss of consciousness or alteration of
utero6,7 vestibulo-ocular reflexes and the Moro response behavior suggests seizure activity.
cannot be elicited until birth.4 When the child can communicate either with the physi-
Woollacott and colleagues8 summarized the current cian or with the parents, the character of the dizziness
understanding of the development of balance and posture should be elucidated. True vertigo, the sensation of move-
in humans. Children appear to rely more on visual sensory ment of the surroundings or self, is distinguished from
information than vestibular and proprioceptive between feelings of lightheadedness, faintness, floating, or “just not
18 months and 3 years of age, during which time they being right.” Children may recognize the sensation pro-
acquire locomotor skills. Vision becomes especially impor- duced by calorics or rotation testing as equal to their own
tant at transition periods when the child progresses to the symptoms of dizziness. Vertigo arouses suspicion of a
next milestone of mobility (e.g., between crawling and peripheral vestibular disorder, whereas dizziness suggests
standing). At school age (4 to 6 years), integration of dysfunction in other systems such as cardiovascular, respi-
visual, vestibular, and somatosensory information appears ratory, hematologic, or psychoneurologic. Episode vertigo
to expand and become more sophisticated, perhaps reflect- with constitutional symptoms suggests peripheral vestibu-
ing functional changes in the nervous system connections. lar dysfunction. Hearing loss, tinnitus, and aural fullness/
With further maturation comes greater control reflected pressure further localize the problems to the inner ear.
by more efficient use of postural muscles. Vertigo that lasts more than 12 hours suggests a cause
central to the vestibular nerve.
Falling, difficulty ambulating with eyes closed, or diffi-
DIAGNOSTIC EVALUATION culty ambulating in the dark suggests bilaterally decreased
vestibular function. Difficulty walking under normal con-
Disorders of the peripheral vestibular system and labyrinth ditions does not usually accompany isolated stable periph-
are usually reflected by tangible symptoms and signs such eral vestibular disease.
as the sensation of spinning or movement, actual falling, Finally, a thorough but directed past medical history
constitutional symptoms (nausea, vomiting, sweating), and should be obtained, including but not limited to perinatal
abnormal eye movements. Other symptomatology related problems, medications, prior otologic disease and hearing
to the vestibular system also occurs, but may result from loss, use of alcohol and illicit drugs, and neuromuscular
disorders in the cerebellar, CNS, metabolic, and hemody- problems. Parents and the patient may be questioned
namic systems, as well as being caused by exogenous regarding the degree of disability caused by the vestibular
substances. symptoms. Contrast the child who continues to play and
Ataxia indicates poor coordination and encompasses a attend school with one fearful of leaving the house lest the
wide range of disorders. Gait ataxia refers to incoordination dizziness cause physical or emotional damage.
of ambulation. Walking is a highly complex skill dependent
on proper functioning of a number of neuromuscular Physical Examination
structures and pathways.
The neurovestibular evaluation of the pediatric patient The neurotologic exam of the dizzy child includes a com-
includes a history, neurotologic exam, general neurologic plete head and neck examination, general neurologic survey,
survey, and indicated testing and imaging. Emphasis should and specific neurovestibular testing. Many clues can be
be placed on the team approach even though referral to all obtained by observing the child before and during the
specialties may not be needed in every case. physician encounter.
Otoscopy identifies inflammatory processes of the ear
and mastoid. Use of the pneumatic otoscope may elicit a
History positive fistula test (see the section on Perilymphatic
Historical information provides the most important data Fistula). A complete cranial nerve assessment should be
on the diagnosis and treatment of many dizzy patients. performed. Tuning forks identify the presence and charac-
Benign paroxysmal vertigo, for example, represents a diag- ter of hearing loss and confirm audiometry. With a child
nosis made almost solely by history. Unfortunately, in the sufficiently mature, Romberg, tandem or augmented
pediatric population the history may be incomplete. Romberg, and tandem gait testing are performed.
Perseverance frequently is rewarded with important facts Eye movements should be observed. Normally, a few
obtained not only from parents but more frequently than beats of nystagmus can be seen on extreme lateral gaze.
expected from the child. Obviously the age of the patient Pathologic spontaneous nystagmus may be observed occa-
determines the quantity and quality of information. In sionally, but specific measures usually are necessary to elicit
younger children and infants, parental observation consti- the finding. Frenzel lenses eliminate the patient’s ability to
tutes the history. As myelinization proceeds during the first extinguish peripherally induced nystagmus by visual fixa-
months and years of life, the infant progresses through tion. The Dix-Hallpike maneuver can elicit positionally
 Dizziness in Childhood 555

provoked nystagmus. Generally, positionally provoked, based on age and disposition, including behavioral
fatigable nystagmus with a several-second latency accom- audiometry using pure tone and speech tests, play and
panies a peripheral vestibular lesion, and nonfatiguable startle localization, evoked auditory brainstem response
nystagmus without latency accompanies a CNS cause. (ABR), otoacoustic emissions, and others. Children with
Reflexes specific to neurovestibular function are present sensorineural hearing loss (SNHL) are at risk for vestibu-
and can be tested in infants as described by Eviatar.10 lar hypofunction. Phillips and Backous have published a
Appropriate tone and movement of the cervical muscula- comprehensive, detailed review of vestibular testing in chil-
ture indicate that input from the vestibular end-organ and dren.15 The remainder of this section outlines available tests.
cervical proprioceptive receptors exists. Abnormal postur- Electronystagmography (ENG), rotational chair testing,
ing of the neck in an infant may indicate a vestibular prob- and posturography may be used in evaluating dizziness in
lem. The vertical acceleration test qualitatively measures children. Electrical recording of nystagmus can be per-
response in the extremities to gravitational acceleration formed even in young children. Caloric-induced nystag-
sensed by the otolithic organs.2 While holding the infant mus in children may be slower and more erratic than that
in his or her arms with the head well supported, the exam- in adults due to their developing/myelinating nervous
iner abruptly lowers the patient toward the floor. A normal system. Ice water may be necessary to measure vestibular
response is abduction and extension of the upper extremi- dysfunction adequately.
ties and an embracing posture. Semicircular canal response Rotation testing stimulates both labyrinths and may be
can be identified by rotating the upright infant with neck an appropriate alternative for children who cannot coop-
flexed 30 degrees. A doll’s eye response is elicited in the erate for calorics or when calorics cannot be measured.
newborn. Nystagmus with the fast component in the Atretic or abnormal external auditory canals and perfora-
direction of rotation appears at 2 to 3 weeks. tions of the tympanic membrane are contraindications to
Vestibular dysfunction also may be identified by exam- open system ENG testing. Patients with bilateral vestibu-
ining the righting response. This reflex involves the child lar weakness may demonstrate some response by rotation
extending the arm to prevent falling in the direction of when calorics are negative. Rotary chair testing may be
applied force or tilt. The response presents at 6 months more sensitive than calorics for identifying very early
and becomes voluntarily inhibited after 2 to 4 years of age. bilateral weakness. Infants can be held in their parent’s lap
The test should be performed with the eyes closed to elim- for testing. Cyr and coworkers16 developed modifications
inate visual input, which isolates the vestibular component of ENG and harmonic rotation for screening pediatric
of the reflex. A patient with vestibular dysfunction will not patients for vestibular hypofunction and asymmetry.
exhibit the reflex and may fall in the direction of tilt. By 6 weeks, the majority of normal infants demonstrate
Similar righting tests can be performed in various posi- nystagmus to caloric or rotary stimulation.17 It must be
tions until the age when the child can cooperate with the remembered, however, that vestibulo-ocular response test-
Romberg and other tests. ing primarily examines only horizontal semicircular canal
A stepping test has been described in which the child function and that these tests may not reflect the fluctuat-
steps in place over a grid with eyes closed and arms out- ing nature of many pediatric vestibular disorders.
stretched.11 The angle and distance of displacement are Static and dynamic posturography examine the interac-
compared with that of normal subjects. Patients with tion of the vestibular system with the visual, propriocep-
unilateral lesions rotate greater than 45 degrees toward tive, and other systems involved in maintaining balance.
the affected side, whereas patients with bilateral lesions Posturography can be performed in children old enough
display forward or backward displacement of greater than to cooperate and, in fact, can be treated as a game.
20 inches. Information similar to that in adults is obtained, although
Detailed cerebellar and gait examination may be indi- results must be compared with size- and age-matched
cated when the history does not suggest vestibular disorder normals.18 Normal children younger than 4 to 6 years
or when the patient’s complaints focus on ambulation.12 often fall in the sensory conflict situations (posturography
Information from physical findings regarding the location conditions 3 to 6), which makes this test inaccurate at
of dysfunction causing ataxia may help differentiate present for that age group.19
vestibular, proprioceptive, and cerebellar causes. Problems Tests of vestibular sensory organization and postural
in the vestibular system usually become exacerbated with sway strategies have been standardized to normal children
the eyes closed, whereas cerebellar dysfunction may so that abnormal responses can be identified.18,20 These
appear or worsen during visual fixation. Proprioceptive examinations aid physical therapists in designing vestibular
losses may mimic the other two in some respects but are and balance exercise programs for patients. They cannot as
usually discovered during position testing of the lower yet, however, reliably localize pathology and they demon-
extremities. Neurologic consultation is indicated in these strate low sensitivity and specificity for the disorders of
circumstances. balance in children.
ABR can be used as a screen for retrocochlear pathology
and in infants when behavioral response audiometry can-
Testing not be performed. However, Brookhouser and colleagues21
Hearing evaluation in dizzy children becomes especially demonstrated a lack of correlation between abnormal ABR
important when considering the 49% to 95% estimates of and abnormal vestibular testing. Prolonged vestibular
vestibular abnormalities in children with congenital and symptoms or signs of central dysfunction are evaluated
acquired hearing impairments.13,14 An audiologist experi- with computerized tomographic (CT) scanning or mag-
enced in testing children will employ a variety of tests netic resonance imaging (MRI). CT is preferred when
556 PEDIATRIC NEUROTOLOGY

temporal bone structures are presumed to be involved found many children with symptoms of incoordination
such as in chronic ear disease, skull base pathology, and and imbalance, whereas in adults episodic vertigo was
congenital abnormalities. MRI provides excellent detail of more common. Endolymphatic sac surgery, done mainly
soft tissues of the brain and CNS. Neurology consultation to stabilize hearing, was complicated by a high rate of
may order electroencephalography (EEG) when seizure hearing loss in patients with an enlarged vestibular aque-
activity is suspected. duct, and no benefit could be shown in other congenital
malformations. Sac surgery is therefore not recommended
for these patients.30
DEVELOPMENTAL EFFECTS OF
VESTIBULAR DYSFUNCTION
SPECIFIC DISEASE ENTITIES: PERIPHERAL
A variety of developmental delays have been attributed to
disorders of vestibular function as reviewed by Horak and Otitis Media and Complications
coworkers.22 Reported disabilities usually result from bilat- of Otitis Media
eral vestibular dysfunction and include impairments of learn-
ing, postural coordination, motor skills, and developmental Middle ear disease is, of course, extremely common in
milestones. Children gradually compensate for many of the children. Acute and chronic otitis media are commonly
postural problems and by the time they become teenagers seen from infancy to adulthood. Although most of these
demonstrate no postural disturbances in everyday situations patients present with pain, drainage, or hearing loss, dizzi-
compared with normals.23–25 Vestibular testing, particu- ness may accompany the spectrum of this disease.
larly posturography, will identify balance problems. Serous otitis media (otitis media with effusion) can pro-
Compensation is encouraged by vigorous physical educa- duce ill-defined balance disturbances manifesting as a
tion and, when required, by formal vestibular therapy. delayed ability to walk, clumsiness, running into things,
and so on.31 Clearing the middle ear fluid, either medically
or surgically, rapidly resolves imbalance due to this cause.
Congenital and Hereditary Hearing Loss The mechanism by which the dizziness is produced is
Many congenital and hereditary hearing losses are unclear, but one hypothesis is that negative middle ear
accompanied by vestibular deficits.26,27 Usher’s type I and pressure causes displacement of the round window mem-
Waardenburg’s syndromes are notable for the relatively brane and subsequent movement of the perilymph in a
common occurrence of vestibular abnormalities. Newborn susceptible individual.32
hearing screening is identifying hearing loss at younger When active infection is evident in the middle ear,
ages, and some type of vestibular assessment should be serous labyrinthitis can occur, which produces vertigo and
performed in these children. This can vary from an office SNHL. Transmission of toxic substances across the round
neurotologic exam to more sophisticated testing. According window membrane presumably creates a serous labyrinthi-
to the clinical circumstances, children with audiovestibular tis. Treatment is aimed at resolution of the infection of the
dysfunction typically seek help because of hearing loss and middle ear with antibiotics and middle ear drainage. Steroid
rarely list imbalance as a chief complaint. The reader is therapy may play a role in decreasing inflammation.
referred to the chapter on pediatric auditory disorders Suppurative labyrinthitis as a complication of otitis
(Chapter 36) for more detail regarding hearing loss. media is a very rare, but extremely serious situation. Here,
bacteria gain access to the perilymphatic space and pro-
Congenital Anomalies duce a purulent inner ear infection. The route of bacterial
spread may be from the middle ear through a fistula in the
Temporal bone development anomalies often involve the otic capsule or, more commonly, from the meninges and
vestibular apparatus. These anomalies may affect the cerebrospinal fluid (CSF) through the cochlear aqueduct or
membranous labyrinth only or the bony and membranous internal auditory canal. Patients with bacterial labyrinthitis
labyrinths together. The former must be diagnosed by are seriously ill and have severe auditory and vestibular
histopathology, but the latter can be seen radiographically impairment compared with patients with serous labyrinthi-
due to the bony malformation. Jackler and colleagues28 tis. Management is directed at controlling the underlying
have shown that this distinction can provide a classification infection in either the middle ear/mastoid or the CSF.1,33
with clinical relevance and can be further broken down into Cholesteatoma, acquired or (less commonly) congenital,
more specific subtypes. These conditions are usually con- can erode into the otic capsule, producing a labyrinthine
sidered in terms of congenital SNHL, although children fistula. The horizontal semicircular canal is the most com-
may have associated vestibular deficits that can manifest mon site for this destruction to occur, but other areas can
clinically. be involved. Cholesteatoma at this stage is generally easily
Children born without vestibular function will not expe- seen on otoscopy. Pneumatic fistula testing will produce
rience vertigo because this is a static lesion. Although fine symptoms in most cases and increase suspicion of the
aspects of balance may be lacking, these children will com- diagnosis. Audiometry may demonstrate SNHL in addi-
pensate well with their somatosensory and visual systems. tion to the expected conductive component. CT scanning
Vestibular symptoms may occur in patients who have should suggest the erosive process and allows for appro-
vestibular function and a dynamic lesion. The enlarged priate preoperative planning. Surgical management of a
vestibular aqueduct as an isolated anomaly has received fistula is quite individualized and depends on a number of
some attention in the literature. Jackler and De La Cruz29 factors, such as hearing in the diseased ear, hearing in the
 Dizziness in Childhood 557

contralateral ear, size of the mastoid, and experience of the although some patients have been noted to improve on
surgeon.34 antimigraine regimens.37,40 The efficacy of pharmacologic
therapy remains unclear, given the natural spontaneous
Benign Paroxysmal Vertigo remission.
of Childhood
Ménière’s Disease
Basser35 described benign paroxysmal vertigo (BPV) of
children in 1964. Including their own cases, Finkelhor Episodic vertigo, fluctuating hearing, and low-pitched
and Harker36 in 1987 counted 113 cases reported in the tinnitus were described in 1861 by Prosper Ménière as a
literature. Age of onset has been reported37 between 2 and disorder localized to the labyrinth. Harrison and
12 years of age, the majority before age 6. This disorder Haftalin45 noted that 75% of cases occur between 30 and
should be distinguished from benign paroxysmal posi- 60 years of age. The first case reported of Ménière’s dis-
tional vertigo, which is rare in the pediatric population, ease in a child (6 years old) was by Crowe46 in 1938. Since
but common in adults. that time, only a small number of reports of this entity in
The typical pattern involves the sudden onset of vertigo children have appeared.47 Sade and Yaniv48 outlined three
lasting from seconds to a minute. Nausea and vomiting cases of Ménière’s occurring in infants having episodes of
may or may not be associated with the episode. The child vomiting. Specific review of pediatric Ménière’s disease
usually becomes frightened and clutches the nearest object has been published by Rodgers and Telischi.49
in an apparent attempt to prevent falling. Observant par- The diagnosis of Ménière’s disease is clinical and relies
ents will note unusual eye movements suggestive of nys- heavily on the history. In the pediatric population, it will
tagmus. The child remains completely lucid with no likely be difficult to elicit the classic history, especially in
alteration in consciousness. children younger than age 10 years. Therefore, a certain
Fenichel38 first suggested an association between BPV index of suspicion must be kept for this disorder. Once
and migraine headache in children in 1967. Parker39 hearing loss has been documented, the differential diagno-
reported an overall incidence of 43% for family history sis of vertigo and hearing loss includes physical and acoustic
positive for migraine among series of BPV patients trauma, spontaneous perilymphatic fistula, allergy, inner
reported in the English language literature. He also calcu- ear malformation (e.g., Mondini’s), cerebellopontine angle
lated a 13% incidence of subsequent development of tumor, hypothyroidism, syphilis, and adrenal pituitary
migraine along with other symptoms associated with insufficiency in addition to Ménière’s disease.
migraine, such as cyclic vomiting, recurrent abdominal The diagnostic evaluation in such patients should include
pain, scotomata, and photophobia. A history of motion basic and impedance audiometry that is age-appropriate,
intolerance is a common finding. Headache provocation ABRs, ENG, electrocochleography, and detailed CT scan-
tests that made use of nitroglycerin,40 histamine, and ning of the temporal bones. Serologic syphilis testing,
fenfluramine37 resulted in headache or vertigo (or both) in thyroid function studies, glucose tolerance testing, adreno-
12 out of 12 and 10 out of 15 patients with BPV, respec- corticotropic hormone-stimulated cortisol levels, and
tively. Paroxysmal torticollis of infancy (PTI) also has allergy testing in selected cases should be obtained. Filipo
been reported to precede BPV.41,42 PTI and BPV may and Barbara50 found glycerol testing particularly helpful in
represent early manifestations of the full migraine com- this age group for whom histories often lack important
plex, progressing from one to the other as the nervous details. They had a positive test in four of five children
system develops. The International Headache Society with suspected Ménière’s disease.
now places BPV, PTI, and cyclic vomiting in the migraine Once a diagnosis is made, treatment is the same as for
family.43 adults. Diuretic therapy is the mainstay of the therapeutic
Because these patients are rarely at the doctor’s office regimen along with dietary modification (e.g., low sodium
during attacks, audiometry and vestibular testing generally and decreased caffeine).
are normal. Eighty-nine percent of 90 cases reviewed in
the literature had normal caloric responses.39 Abnormali- Trauma
ties on ENG, when present, are subtle and transitory.
Earlier reports demonstrated abnormal ENG results This section is limited to closed-head trauma and
(primarily with respect to calorics), whereas more recent whiplash-type injuries as causes of dizziness and vertigo.
series have shown normal ENG findings.35,44 EEG has Eviatar and coworkers51 categorized post-traumatic vestibu-
demonstrated mild abnormalities in wave patterns in a lar symptoms without hearing loss into “labyrinthine con-
few patients with family history or other symptoms sug- cussion, whiplash syndrome, vertiginous seizures, migraine
gestive of seizure activity, but generally has been normal and post-traumatic neuroses.” Temporal bone fracture and
in BPV patients.36,37 Imaging studies have been uniformly perilymphatic fistula also can be caused by blunt injuries
normal. and result in dizziness or vertigo along with hearing loss.
The natural history of BPV is one of spontaneous remis- Loss of consciousness at the time of trauma may or may
sion of vertiginous episodes prior to the teenage years. As not be associated with all of these disorders.
already noted, some patients resolve their vertigo only to Labyrinthine concussion is the name given to the symp-
develop migraine. The important aspects of treatment tom complex similar to BPV that occurs after head trauma
include ruling out other treatable conditions and reassur- with no detectable fracture or injury to the labyrinth.
ance and counseling regarding possible later development Patients typically develop vertigo and imbalance immedi-
of migraine. Antiseizure medication has not been useful, ately after the injury that persists for several days. As these
558 PEDIATRIC NEUROTOLOGY

symptoms resolve during the first week, patients are left Antecedent trauma, physical exertion, or barotrauma
with residual positional vertigo, which can persist for are reported by some patients. Supance and Bluestone56
weeks to months. Episodes of positional vertigo last documented such a history in 6 of 22 (27%) patients with
seconds to a few minutes and may be associated with nau- surgically confirmed leaks. No symptoms are pathognomic
sea. Hearing loss and tinnitus are not typical complaints. for fistula, but some of the following historical findings
Dislodged particulate debris trapped in the semicircular should heighten the index of suspicion:
canals (posterior canal most commonly) causes these
1. No other obvious diagnosis to explain the symptoms
symptoms, and treatment with partial repositioning
2. Antecedent trauma blunt or penetrating to the
maneuvers is usually effective. Vestibular exercises can be
temporal bone, physical straining/Valsalva’s maneu-
helpful as well.
ver, barotrauma (atmospheric changes or internally
Audiometry may reveal mild SNHL, although more
induced such as violent sneezing/coughing and
commonly shows no change in thresholds. ENG demon-
playing wind instruments)
strates positional nystagmus and, less often, canal paresis.
3. Hearing loss associated with trauma, sudden,
Rotary chair and posturography are helpful for severe
fluctuating, and progressive
injuries resulting in bilateral vestibular paresis.
4. Vertigo or dizziness occurring with straining or
Whiplash injuries, in addition to head trauma, can result
position changes
in positional vestibular symptoms. Hearing generally is
5. History of recurrent, unexplained meningitis
normal although some patients complain of tinnitus.
6. Vestibular symptoms brought on or magnified during
Physical examination and ENG may elicit positional nys-
exposure to loud sounds (Tullio’s phenomenon)
tagmus. Audiometry is normal. A cervical collar may be
7. Congenital anomalies or syndromes involving the
prescribed to splint the neck and minimize discomfort.
head and neck
Vestibular habituation exercises may be designed to pro-
mote compensation to rapid head movements. Vestibular Physical examination may be completely normal.
suppressants and muscle relaxants are helpful initially but Occasionally, perilymph in the middle ear masquerades as
not on an ongoing basis. Even severe symptoms generally serous otitis media. Position changes may elicit peripheral-
resolve during a period of weeks to months. type nystagmus, or the patient may exhibit spontaneous
In some patients, no diagnosis matches the symptoms. nystagmus. Gross ataxia or abnormalities in Romberg/
The physical examination is normal. Some patients may tandem gait testing may be present. Congenital deformi-
exhibit nonspecific abnormalities on ENG or even ABR. ties should be noted.
Eviatar and coworkers51 termed this nonspecific post-traumatic The fistula test is not accurate but has been reported to
dizziness. They postulated brainstem injury, psychosomatic be more specific (50%) than sensitive (35%) in children.56
disorder, or secondary gain associated with litigation as This test is based on acute changes in middle ear pressure
causes. Patients whose symptoms resolve spontaneously transmitted via a fistula to the inner ear, causing vertigo
during a period of weeks to months, not in association with and nystagmus. Properly performed, a good seal is
lawsuit settlements, are more likely to have an organic obtained in the external auditory canal while positive and
basis for their symptoms than those whose complaints are negative pressures of 200 to 300 mm H2O are induced
protracted and less specific. acutely, maintained for 5 to 10 seconds, and repeated several
Closed-head trauma can produce other conditions times. Although the sensation of vertigo suggests the diag-
manifested by dizziness or vertigo, such as perilymphatic nosis, a positive result requires the eliciting of nystagmus or
fistula, temporal bone fracture, and trauma-induced a change in the magnitude of spontaneous nystagmus. Eye
migraine or seizures. These are described in detail in other movements may be visually documented with Frenzel
sections of this chapter or other chapters. glasses and a pneumatic otoscope in the office, or ENG
can be employed with independence/admittance instru-
mentation. ENG may be normal or abnormal. Positional
Perilymphatic Fistula testing and platform posturography have been reported to
Perilymphatic fistulae are fluid connections between inner be abnormal more frequently than have oculomotor
and middle ear spaces. Many aspects of the diagnosis screening, calorics, and rotation tests in children with
and management, indeed even the existence, of this disor- confirmed leaks.56 Pure tone and electrical audiometry
der are controversal.52,53 Perilymphatic leaks unrelated commonly reveal SNHL.
to prior otologic surgery were reported initially in 1968.54 CT remains the best modality for imaging temporal
Theories of their pathogenesis have been well described. bone structures and should be undertaken when
Individual predisposition, congenitally weak areas in the labyrinthine fistula is suspected. More than half of children
temporal bone, patent cochlear aqueduct, and other with surgically confirmed fistulas exhibit abnormal tempo-
anatomic explanations have been proposed to account ral bone tomography. Mondini’s and other inner ear defor-
for the failure to contain the perilymph subjected to mities are the most common abnormalities identified.
pressure differential with respect to the CSF or ambient Still, the only way to definitely identify a leak remains
pressure. operative exploration. Even at surgery, with Valsalva’s
Perilymph leaks can result in vertigo, ataxia, disequilib- maneuvers, there may be questionable fluid accumulation
rium, and nonspecific dizziness symptoms. The most com- and the timing of exploration may not correspond with
mon symptom is SNHL. Tinnitus occurs less commonly. perilymph flow from an intermittent leak. Analysis of any
Any combination of vestibular and auditory complaints identified fluid for β2-transferrin held promise, but has not
have been reported, either stable or fluctuating over time.55 been uniformly helpful.57
 Dizziness in Childhood 559

Treatment in cases of acute barotrauma in otherwise SPECIFIC DISEASE ENTITIES: CENTRAL

normal patients may begin with bedrest with head elevation
and avoidance of Valsalva’s maneuvers for several days. Migraine
Significant or progressive hearing loss or persistent vertigo
mandates surgical exploration. This involves an exploratory Migraine is generally believed to be a vascular disorder
tympanotomy with exposure similar to that for a stapedec- associated with vasospasm of vessels supplying the CNS,
tomy. Oval and round window areas should be fully visible. which produces neurologic symptoms, followed by vasodi-
The anterior aspect of the oval window is the most com- lation of extracranial vessels, hence producing headaches.
mon site of leak. Careful suctioning and diligent observa- A wide spectrum of symptomatology can occur from this
tion with Valsalva’s maneuver may identify small leaks. process.39 An array of symptoms may be produced by the
Abnormalities in the ossicles, oval window niche, or round vasospastic phase while headache, if any, symptoms occur
window are commonly identified. Many surgeons will during the vasodilation phase. Also, the time course
reinforce the oval and round window areas with fibrocon- between the phases can vary widely, and the phases can
nective tissue grafts even if a specific leak is not seen due occur independently. Migraine precursors, variants, or
to the vagaries of diagnosis. equivalents signify the vasospastic phase and can manifest
as vertigo.62 Consider migraine in the differential diagno-
sis for children experiencing episodic vertigo without audi-
Vestibular Neuronitis tory symptoms. As previously noted, BPV of childhood
Vestibular neuronitis usually occurs in children older than and PTI are thought to be manifestations of migraine.
10 years and follows a clinical course similar to but milder The diagnosis of migraine is one of elimination. Other
than that seen in adults.33,44,58,59 Vertigo occurs suddenly and otologic or neurologic diseases should be excluded prior
may last 1 or 2 days with nausea and vomiting. A period to a diagnosis of migraine. A history of repeated episodes
of imbalance and ataxia may follow for several weeks. It com- with recovery between spells is suggestive. A detailed fam-
monly accompanies or follows a viral illness and may be diag- ily history must be obtained because a history for migraine
nosed as gastroenteritis or a similar disorder. Intermittent is often present. This history should include questioning
episodes of vertigo may occur, decreasing in severity during of family members that may have had BPV of childhood or
the ensuing week. Vestibular neuronitis is not associated with PTI. Migraine associated vertigo may be treated similarly
changes in hearing. As in adults, ENG frequently demon- to adult disease in conjunction in consultation with pedi-
strates unilateral decreased caloric response. Vestibular atric colleagues. Johnson has contributed a very thorough
suppressants can be employed temporarily for symptomatic review of migraine-related dizziness.63
treatment, but ultimately this is a self-limited disorder.
Vertiginous Seizures
Labyrinthitis and Meningitis Changes in cognitive function and alteration or loss of
The presence of hearing loss accompanying the acute consciousness accompanying vertigo suggest seizure activ-
onset of severe vertigo, nausea, vomiting, and fever heralds ity. Vertigo may be a manifestation of the ictal phenome-
labyrinthitis. The cause may be viral or bacterial. non (vertiginous seizures), or the abnormal vestibular
Labyrinthitis may be classified as serous, suppurative, or activity may stimulate convulsion (vestibulogenic seizures).
chronic.60 Acute or chronic ear infections can result in Vertigo or dizziness not uncommonly occur as an aura pre-
toxins and noxious enzymes entering the inner ear.61 Viral ceding a generalized seizure.
infection presumably invades the membranous labyrinth Vertigo is the sole or primary symptom in vertiginous
via a hematogenous route. Suppurative labyrinthitis seizures. The differentiation between this entity and other
involves bacterial entry into and infection of the perilym- varieties of paroxysmal vertigo is made by identifying
phatic space. This may occur via a bony fistula of the otic altered mental status and abnormal sleep-deprived EEG.
capsule or infected CSF through the internal auditory Imaging and vestibular testing will be normal but are usu-
canal or cochlear aqueduct. ally indicated to rule out other disorders.
The diagnosis is suggested by noting the acute onset of Vestibulogenic seizures are a rare form of sensory
severe vertigo with either sudden or progressive hearing epilepsy. Altered afferent vestibular stimuli or abnormal
loss. Signs and symptoms of otologic disease or meningitis central processing of robust peripheral input lead to gen-
support the diagnosis. A careful fistula test should be per- eralized epileptic activity via the reticular activating system
formed. Audiometry and vestibular tests will demonstrate in the brainstem and thalamocortical pathways. Simultane-
hypofunction of one or both labyrinths. Bilateral involve- ous ENG and EEG recording during caloric stimulation
ment suggests meningogenic spread; unilateral suggests will reveal abnormalities.
otologic. Management is directed at controlling the Anticonvulsants are the primary treatment for both of
underlying infection. Viral and serous labyrinthitis leave these types of seizures.
mild inner ear dysfunction, and suppurative disease results
in severe auditory and vestibular hypofunction. Tumors
Vertigo following meningitis in children may be the
effect of scar traction on the meninges surrounding the Tumors involving the CNS at the brainstem and above
vestibular nerve or a direct postinflammatory effect on may cause vertigo. Posterior fossa tumors constitute
the labyrinth or vestibular nerve.31 Vestibular exercises and almost two-thirds of brain tumors in children.64 Intrinsic
time generally result in resolution of symptoms. cerebellar and brainstem lesions make up the majority of
560 PEDIATRIC NEUROTOLOGY

those in the cerebellopontine angle. Medulloblastomas, attacks, but interim examination is normal. In contrast to
astrocytomas, gliomas, hematomas, and inflammatory many of the recessive ataxias, this dominantly inherited
masses can cause mass effect on nearby vestibular structures. disorder does not appear to involve significant progressive
A high index of suspicion is sometimes necessary to neurologic or systemic impairment. A defect in pyruvate
diagnose these lesions. The combination of vertigo with metabolism has been postulated as the cause, leading to
hearing loss, other cranial nerve palsies, ataxia, or seizures cerebellar atrophy observable by MRI.73,74 Griggs and
warrants a vigorous diagnostic work-up that includes colleagues74 and later others reported clinical response to
imaging. Signs of increased intracranial pressure, such as acetazolamide.71,75
headache, vomiting, and papilledema, also require a search Among a number of forms of recessive ataxia,
for a mass lesion. MRI with gadolinium contrast provides Friedreich’s ataxia ranks as the most common.72 This dis-
detailed images of the soft tissue structures in the CNS. order affects many organ systems, beginning with spin-
CT scans are best for identifying changes in bony struc- ocerebellar degeneration of the CNS. The cause remains
tures such as those caused by tumors in the skull base. unknown. Gait ataxia or scoliosis develops during child-
hood or early adolescence. Other neurologic findings
Neurosyphilis include dysarthria, loss of position and vibratory sense in
the lower extremities, muscle atrophy, and areflexia.
Neurosyphilis is known to be a cause of true vertigo as well Eighth nerve and cochlear nucleus degeneration with
as other forms of dizziness in childhood. The spirochete preservation of the end organ lead to hearing loss and
Treponema pallidum may infect any portion of the vestibu- vestibular hypofunction.76 Visual loss from optic atrophy
lar system as well as the cochlea, eighth nerve, and central and diabetes occur in less than half of patients. Most
auditory and vestibular pathways. patients die from the complications of hypertrophic car-
The onset of dizziness in childhood due to neurosyphilis diomyopathy. No effective treatment exists.
is often accompanied and overshadowed by bilateral sym- A number of other inherited ataxias exist that are
metrical profound hearing loss. The audiogram may show beyond the scope of this chapter. Treatable varieties
a flat configuration with disproportionately poor speech include Refsum’s disease, Wilson’s disease, Hartnup
discrimination. disease, Bassen-Kornzweig syndrome, urea cycle, and
Vestibular symptoms occur more commonly in congen- multiple carboxylase enzyme deficiencies.
ital and late syphilis than in early acquired syphilis. These
symptoms may vary from mild imbalance to severe attacks
of vertigo lasting days.65 Symptoms on occasion may be Multiple Sclerosis
indistinguishable from Ménière’s disease and consist of Multiple sclerosis (MS) is uncommon in childhood, but up
episodic vertigo, fluctuating SNHL, and tinnitus.66,67 to 10% of cases may present in the pediatric population.
As in adults, dizziness can occur if a focus of demyelination
Congenital Nystagmus (plaque) involves the vestibular system.77 Molteni78
reported 14 cases of MS in the children. Four (20%) had
Congenital nystagmus is characterized by horizontal, vertigo as the presenting symptom. The possibility of
conjugate jerky oscillations of the eyes.68 The abnormal MS increases if other neurologic symptoms such as visual
eye movements occur at birth or during infancy.69 disturbance or gait disturbance are present. The diagnosis
Dizziness, vertigo, and oscillopsia are notably absent. may only become clear as time passes and other symptoms
These children generally have good vision although they develop.
may adopt compensatory head posturing to compensate MRI of the brain may show the sclerotic plaques. Visual
for visual changes during periods of nystagmus. This form evoked potentials and analysis of spinal fluid may be help-
of nystagmus increases during fixation and decreases ful in the diagnosis. Treatment of acute exacerbations with
during eye closure or convergence. Treatment involves steroids is often effective.
reassurance and monitoring of vision.

Ataxia OTHER DISEASE ENTITIES

Ataxia implies impaired coordination. The causes of ataxia
are protean and affect any aspect of muscular activity.70 We Metabolic/Systemic Disease
discuss those entities that manifest vertigo/dizziness as Imbalance and lightheadedness may be the result of cer-
part of the symptomatology and primarily involve gait or tain systemic conditions. Anemia and vasovagal reactions
balance disturbances in children. are common causes of dizziness. Congenital heart disease
and arrhythmias also may present with vestibular com-
plaints. Hypoglycemia is another consideration and symp-
Familial Ataxia
toms should have a relationship to food intake. Adrenal
Familial ataxias may be inherited in a dominant, recessive, insufficiency, dysautonomia, and thyroid disease all are
or sex-linked fashion. Up to one-third of patients with other uncommon systemic causes of dizziness. A careful
recessive disease do not fit current diagnostic classifications history and physical examination will often lead to clues
of familial ataxia. Dominant recurrent (periodic) ataxia is that point to a need for further work-up. Where indicated,
characterized by childhood onset with episodic imbalance a battery of blood tests can be pursued to rule out these
and vertigo.71,72 Nystagmus and ataxia are observed during disorders.
 Dizziness in Childhood 561

Toxic 3. Beddoe GM: Vertigo in childhood. Otolaryngol Clin North Am

10:139–144, 1977.
Many medications can produce dizziness as a side effect. 4. Prechtl HFR: Prenatal motor development. In Wade M, Whiting H
Therefore, a review of medications is always required, and, (eds.): Motor Development in Children: Aspects of Coordination
where appropriate, elimination or substitution may deter- and Control. Boston, Martinus Nijhoff, 1986, pp 53–64.
mine if a drug is causing the symptoms. Anticonvulsants 5. Anson BJ: Developmental anatomy of the ear. In Paparella MM,
such as phenytoin and carbamazepine as well as various Shumrick DA (eds.): Otolaryngology. Philadelphia, WB Saunders,
1973.
vasoactive medicines are common offenders. Patients who
6. Gessel A, Amatruda CS: The embryology of behavior: The begin-
experience dizziness taking these medications should have ning of the human mind. New York, Harper & Row, 1945.
blood drug levels checked. Another consideration is of 7. Hamilton WJ, Mossman HW: Human embryology: Prenatal devel-
illicit drugs. This may be more likely in the teenage popu- opment of form and function, 4th ed. Cambridge, England, Hoffer,
lation. Urine screening can help in this matter. 1972.
Other considerations include vestibulotoxic medications. 8. Woollacott MH, Shumway-Cook A, Williams HG: The develop-
Aminoglycosides are by far the most common in ment of posture and balance control in children. In Woollacott MH,
this category. A history of severe infection treated with Shumway-Cook A (eds.): Development of Posture and Gait Across
intravenous antibiotics should prompt an investigation into the Life Span. Columbia, SC, University of South Carolina Press,
which medications were used. Topical application of 1989, pp 77–96.
9. Cyr D: The vestibular system: Pediatric considerations. Semen
aminoglycoside-containing drops to the middle ear can
Hear 4(1):33–45, 1983.
result in vestibulotoxicity via round window absorption. An 10. Eviatar L: Vertigo. In Swaiman KF (ed.): Pediatric Neurology:
audiogram, otoacoustic emissions measurement, and ENG Principles and Practice. St. Louis, Mosby, 1989.
will reveal deficits in these cases. Other medications that 11. Fukuda T: The labyrinth and ataxia. Japan J Clin Med
can be toxic to the vestibular system include loop diuretics, 29(8):1848–1851, 1971.
quinine, and some cancer chemotherapeutic drugs. 12. Swaiman KF: Gait impairment. In Swaiman KF (ed.): Pediatric
Neurology: Principles and Practice. St. Louis, Mosby, 1989.
13. Rosenblut B, Goldstein R, Landon WM: Vestibular responses of
Functional some deaf and spastic children. Ann Otol Rhinol Laryngol
Although not usually seen in very young children, the 60:747–755, 1960.
school-age child may manifest a number of functional 14. Sanberg L, Terkildsen K: Caloric tests in deaf children. Arch
symptoms that not uncommonly include dizziness.2,31 Otolaryngol 81:350–354, 1965.
15. Phillips JO, Backous DD: Evaluation of vestibular function in
Underlying the symptom can be anxiety, behavior distur-
young children. Otolaryngol Clin North Am 35:765–790, 2002.
bance, depression, difficulty with social adaptation, and 16. Cyr D, Brookhouser P, Valente M, Grossman A: Vestibular evalua-
hyperventilation. Dizziness rarely occurs as an isolated tion of infants and preschool children. Otolaryngol Head and Neck
symptom in these cases, which adds to the confusion. Surg 93:463–468, 1985.
Particular attention must be given to the history, which 17. Mitchell T, Cambon K: Vestibular response in the neonate and
should include the social and family dynamics. These cases infant. Arch Otolaryngol 90(5):556–557, 1969.
often become clearer if the physician is able to sort out this 18. Horak FB, Nashner LM: Central programming of postural move-
portion of the history. All laboratory testing is normal as is ments: Adaptation to altered support-surface configurations.
the physical examination. Treatment is directed at resolving J Neurophysiol 55(6):1369–1381, 1986.
the underlying problem through appropriate counseling. 19. Forssberg H, Nashner LM: Ontogenetic development of postural
control in man: Adaptation to support and visual conditions during
stance. J Neurosci 2(5):545–552, 1982.
SUMMARY 20. Shumway-Cook A, Woollacott MH: Dynamics of postural control
in the child with Down syndrome. Phys Therapy 65(9):1315–1322,
As in adult patients, dizziness in children is a complex 1985.
problem that may be difficult to diagnose. Making matters 21. Brookhouser PE, Cyr DG, Peters JE, Schulte LE: Correlates of
vestibular evaluation results during the first year of life.
more difficult is the limited history possible from the
Laryngoscope 101:687–694, 1991.
patient. Parents are helpful, but they are not the ones with 22. Horak FB, Shumway-Cook A, Crowe TK, Black FO: Vestibular
the symptoms and as such can only provide limited and function and motor proficiency of children with impaired hearing,
indirect information. The examination and laboratory or with learning disability and motor impairments. Devel Med
evaluation of the vestibular system, as well as imaging in Child Neurol 30(1):64–79, 1987.
selected cases, can help to solidify a diagnosis. This chap- 23. Brunt D, Broadhead GD: Motor proficiency traits of deaf children.
ter has provided an outline and discussion of disorders that Res Q Exercises Sport 53:236–238, 1982.
can produce dizziness in children. An understanding of 24. Butterfield SA: Gross motor profiles of deaf children. Percept Mot
these diseases helps to provide a framework of knowledge Skills 62:68–72, 1986.
with which each individual case can be compared. With a 25. Enbom H, Magnusson M, Phykko I: Postural compensation in
children with congenital or early acquired bilateral vestibular loss.
systematic approach, these challenging cases can be solved.
Ann Otol Rhinol Laryngol 100:472–478, 1991.
26. Konigsmark BW: Genetic hearing loss with no associated abnor-
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 Chapter
Central Auditory System Development
and Disorders

Outline 36
Development of the Central Infancy (28 days to 2 years) Debara L. Tucci, MD
Auditory System and Early Childhood
Introduction Edwin W Rubel, PhD
Central Auditory Testing
Anatomic Development Influence of Environmental
Spiral Ganglion Cells Factors on the Developing
General Aspects of Central Central Auditory System
Auditory System Abnormal Central Auditory
Development System Development
Cochlear Nucleus Conductive Hearing Loss:
Superior Olivary Complex Effects of Deprivation
Lateral Lemniscal Nuclei of Sound Input
Inferior Colliculus Human Studies
Medial Geniculate Body Animal Studies
Auditory Cortex Sensorineural Hearing Loss:
Myelination Effects of Deafferentation
Functional Development of Animal Studies
the Central Auditory System Human Studies
Behavioral Responses Reintroduction of Activity by
to Sound Electrical Stimulation in the
Hearing by the Human Fetus Deaf Subject: Cochlear
Postnatal Development Implant
of Auditory Competence Pathology of the Central
Methodology Auditory System
Neonatal Period (Birth
to 28 days)

DEVELOPMENT OF THE CENTRAL An appreciation of the process of auditory development

is important not only for an understanding of the normal
AUDITORY SYSTEM auditory system, but also for the impact of hearing loss on
this system. In this chapter on the development of the
Introduction central auditory system, we are concerned with the well-
The human, unlike most nonprimate mammalian species, referenced but little understood mechanisms of neural
is born with highly developed auditory sensitivity. Complete plasticity, which presumably allow the child to adapt to
maturation of auditory processing capabilities takes place changes in auditory input. These mechanisms for adapta-
over the first year of life, and, to a lesser extent, perhaps for tion have become particularly important when considering
the first several years. The recent refinement of techniques clinical issues such as the timing and aggressiveness of
to assess behaviorally the auditory processing skills in the medical and surgical treatment of conditions that produce
infant have added to our understanding of auditory devel- hearing loss in children.
opment. Such measures can be correlated with anatomic, We will first discuss our understanding of central audi-
physiologic, and behavioral data from animal studies to tory system (CAS) development as revealed in human and
gain a more complete understanding of the developmental animal studies of auditory system anatomy, physiology, and
process. Animals such as the cat and various rodents have behavior. We then review the literature pertaining to
been extensively used for these investigations. As altricial changes in the system that occur in response to decreased
animals, the period of most rapid maturational change is auditory input and attempt to draw general conclusions
after birth and, hence, unlike the human, readily accessible that may be applied to clinical situations. Central auditory
for study. system pathology is reviewed at the end of the chapter.
563
564 PEDIATRIC NEUROTOLOGY

ANATOMIC DEVELOPMENT maturation gradient is preserved in cochlear nerve projec-

tions to the dorsal cochlear nucleus (DCN).14 However,
The following section provides a brief review of develop- no such gradient was identified for second-order neurons
mental auditory system anatomy. For further information in any division of the CN.15 A tonotopic order has been
the reader is referred to discussions of the subject by identified in most mature nuclei of the CAS including the
Rubel1 and Brugge.2 CN (see Altman and Bayer16 for a review). In nuclei with
demonstrated cytogenetic gradients (exceptions include
the CN, the medial superior olivary nucleus, and the ven-
Spiral Ganglion Cells tral nucleus of the lateral lemniscus), a relationship can be
Embryologic development of the vertebrate inner ear has identified between time of origin and tonotopic gradient.
been described by Yntema,3,4 Rubel,1 and Van De Water.5 In these nuclei, cells produced first are located in the high-
Yntema3 described two overlapping waves of inductive frequency response area of the nucleus. Exceptions to this
activity during inner ear development—a mesodermal rule are the dorsal nucleus of the lateral lemniscus and the
followed by a neural influence. Briefly, the chordameso- medial trapezoid nucleus, where the gradient is reversed.
derm is thought to induce determination of the cephalic Several spatiotemporal gradients have been demonstrated
ectoderm to form the otic field. This ectoderm thickens to in the developing chick auditory system, including cell loss
become the otic placode, which invaginates to become the and nuclear volume increases17 and dendritic absorption18
otic cup. Later, under the inducing influence of the adja- in CN, and dendritic growth in third-order neurons.19
cent neural tube, this tissue further differentiates into the We now consider whether lower order neurons are
otocyst. capable of imposing a topographic organization on succes-
First-order neurons are derived solely from the otic sively higher structures of the CAS. Specifically, we can
placode, without contribution from the adjacent neural determine if successively higher nuclei are generated in
crest.6,7 Studies in chick embryos have demonstrated the a sequence that allows for developmental influence by
presence of auditory and vestibular ganglion cells as a
common ganglionic mass during the otocyst stage.8,9 Cells
in the medial portion of this mass are later identifiable as
cochlear ganglion cells. These cells are bipolar early in
development, and central axons penetrate the marginal
layer of the medulla before peripheral processes enter the
cochlear epithelium. The possible role of neural induction
in hair cell differentiation was investigated by Corwin and
Cotanche.10 The authors found that transplanted dener-
vated embryonic chicken ears developed phenotypically
normal cochlear hair cells, a finding that allowed them to
reject the hypothesis that neural connections are necessary
for normal hair cell development. Cochlear nucleus (CN)
neurons and cochlear hair cells may play a trophic role in
the survival of ganglion cells11 or the direction of axonal
growth.

General Aspects of Central Auditory

System Development
Temporal ordering of neuron generation in the CAS is
of interest for two reasons. First, it has been suggested
(see later discussion) that the order of appearance of neu-
rons may correlate with the tonotopic organization evi-
dent in adult auditory nuclei. Second, it is conceivable
that brainstem nuclei influence the differentiation of neu-
rons in sequentially higher auditory processing centers.
Most investigators, however, agree with the assertion of
Ramon y Cajal12 that primary central pathways are formed
and develop function well in advance of cochlear function.1
For the most part, CAS structures develop concurrently,
and there is little evidence that they influence each other
substantially during early maturation.
A series of studies by Altman and Bayer indicate a
correlation between the time of origin of neurons in most Figure 36-1. Position of labeled SGCs within the mature cochlea. Gestation
nuclei of the CAS and the tonotopic organization found in day is the day of injection of the tritiated thymidine. Note that earliest labeled
cells are in the basal segment of the cochlea. (Reprinted with permission
the mature system. Ruben13 identified a frequency-specific from Ruben RJ: Development of the inner ear of the mouse: A
developmental gradient for spiral ganglion cells (SGCs), radioautographic study of terminal mitoses. Acta Otolaryngol 220(Suppl):
with basal cells produced first (Fig. 36-1). A similar 1–44, 1967, p 30.)
 Central Auditory System Development and Disorders 565

lower centers. Comprehensive studies of time of origin of

CAS nuclei have been performed using autoradiographic
techniques with radioactive thymidine labeling of mitotic
cells in the mouse, chick, and rat. Based on dating of
time of origin, neurons of the lower brainstem and infe-
rior colliculus are generated in a caudorostral sequence.
However, the majority of medial geniculate neurons are
generated several days before those of the inferior collicu-
lus. In addition, thalamocortical fibers may be present
by the time that medial geniculate structure is evident.16
It appears, therefore, that the topographic organization of
the SGCs is not imposed sequentially on higher centers to
the level of the cortex, although segmental influences may
exist. However, certain aspects of neuronal maturation
may occur sequentially, as Morest20 has suggested that
dendritic differentiation in several mammalian species pro-
ceeds centripetally.
For the following discussion, the reader is referred to
Figures 36-2 through 36-4 for schematic diagrams of the
mature central auditory system.

Cochlear Nucleus
The CN complex, which includes the anteroventral and
posteroventral as well as the dorsal cochlear nucleus
Figure 36-3. Connections of the intermediate brainstem pathway (solid lines)
and monaural brainstem pathway (dotted line). As in Figure 36-2, only
projections from one side are shown. Forebrain auditory pathways are
dashed. Abbreviations as in Figure 36-2. (Reprinted with permission from
Rubel EW, Dobie RA: The auditory system: Central auditory pathways. In
Patton H, Fuchs A, Hille B, Scher A, Steiner R [eds]: Textbook of Physiology.
Philadelphia, WB Saunders, 1989, p 390.)

(AVCN, PVCN, and DCN), is derived primarily from the

rhombic lip at the midrostrocaudal level of the brainstem;
it has been suggested that at least the granule cells of the
DCN may derive, along with the cerebellum, from the
germinal trigone of the recess of the fourth ventricle.21
In the human embryo, the CN root is present in the
medulla by the eighth week.22 Human brainstem nuclei are
apparent at about 6 to 7 weeks.1
Cellular development was emphasized in a comprehen-
sive study of the postnatal maturation of the cat CN.15
Large cells were found to originate first, followed by
medium and then small-size cells, confirming a general
rule of cellular development also observed by Pierce23 and
Altman and Bayer.21 However, certain large cells mature
very slowly, particularly the large spherical (“bushy”) cells
of AVCN, which reach only 70% to 75% of their adult size
by 12 weeks. The octopus cell of PVCN is the first large
cell to reach adult morphology (3 to 4 weeks) and size
(6 to 8 weeks).24 All cells of the CN were found to demon-
strate rapid growth during the first month and slower
Figure 36-2. Binaural auditory pathways in the brainstem illustrated for the growth thereafter. Webster and Webster25 note that in
left CN. The connections from the other cochlear nucleus would form a mirror
image. AVCN, anteroventral cochlear nucleus; DCN, dorsal cochlear nucleus; the mouse, the most rapid period of neuron growth takes
DLL, dorsal nucleus of the lateral lemniscus; IC, inferior colliculus; LSO, place between postnatal days 3 and 12, before the onset of
lateral superior olive; MG, medial geniculate nucleus; MNTB, medial nucleus auditory function.
of the trapezoid body; MSO, medial superior olive; PVCN, posteroventral J. Moore26 has investigated neuron soma development in
cochlear nucleus; VLL, ventral nucleus of the lateral lemniscus. (Reprinted
with permission from Rubel EW, Dobie RA: The auditory system: Central
prenatal human tissue as well as in the early postnatal rat.
auditory pathways. In Patton H, Fuchs A, Hille B, Scher A, Steiner R [eds]: Cellular development in human CN tissue at 20 weeks’
Textbook of Physiology. Philadelphia, WB Saunders, 1989, p 388.) gestational age is similar to that of the rat at birth. In both
566 PEDIATRIC NEUROTOLOGY

interactions. On the other hand, Parks and colleagues18,33–35

have shown that many of the normal developmental events
in CN proceed unaltered in the absence of AN input (see
later discussion of afferent influences).
Development of DCN is prolonged compared with that
of VCN. Fusiform cells of DCN are not fully mature by
electron microscope criteria until the fourth postnatal
month in the cat. Unlike AVCN, DCN neurons receive
a large variety of inputs from several descending sources
and have a complex network of intranuclear connections.
These facts may explain the lengthy maturation period.
For example, eight types of synaptic endings were found to
mature in a systematic manner, with the earliest synapses
formed by fibers originating close to the nucleus.36

Superior Olivary Complex

The superior olivary complex (SOC) comprises several
nuclei that occupy the ventral region of the pons. The
primary regions contributing axons to the more cephalad
auditory regions are the lateral superior olivary nucleus
(LSO), the medial superior olivary nucleus (MSO), and
the medial nucleus of the trapezoid body (MNTB). In
addition, a series of so-called periolivary nuclei are
equally important and issue descending inputs to the oli-
vary nuclei, CN complex, and cochlea. Neurons of the SOC
Figure 36-4. The major descending auditory pathways for one side of the probably arise from the dorsal aspect of the medullary
brain. Abbreviations as in Figure 36-2. (Reprinted with permission from epithelium in the region of the rhombic lip and migrate
Rubel EW, Dobie RA: The auditory system: Central auditory pathways. In a considerable distance to their final location in the ventral
Patton H, Fuchs A, Hille B, Scher A, Steiner R [eds]: Textbook of Physiology. brainstem.37 Developmental changes in the primary
Philadelphia, WB Saunders, 1989, p 391.)
olivary regions largely mirror those observed in the CN.

species, cells are numerous and demonstrate a high nuclear-

to-cytoplasmic ratio. Morphology similar to adults is
Lateral Lemniscal Nuclei
achieved by 30 weeks’ gestation in the human and by Information on the developmental anatomy of the lateral
21 days postnatal in the rat, when neuropil as well as cel- lemniscal nuclei is lacking. The only information available
lular cytoplasm is significantly increased. Studies of human is that reported by Altman and Bayer,16 discussed earlier,
tissue have relied primarily on classical cell body (Nissl) on the time of origin of this nuclear group.
and myelin stains, and little information on the intricate
complexities of dendritic, axonal, and astrocyte processes Inferior Colliculus
is available.
Auditory nerve (AN) axons connect in a highly specific Virtually all ascending (lemniscal) and descending auditory
fashion with large spherical (“bushy”) cells of AVCN in a pathways synapse in the inferior colliculus (IC). The
specialized synapse, the end-bulb of Held. Only one to convergence of input from numerous sources makes this
three AN axons contact each spherical cell in the AVCN. structure critical for processing auditory information.
End-bulbs are evident in the 2-day-old kitten; at this time Several schema have been devised to subdivide the IC. All
the endings appear as irregular spoon-shaped swellings. include the central nucleus (CNIC), which is the most
By 45 days of age, nearly all cells exhibit characteristic highly organized and frequently studied nucleus within
adult-like endings with highly branched terminal arboriza- this structure. Other divisions include the cortex and
tions, which appear to envelop the postsynaptic cell body.27 paracentral nuclei, according to one classification.38 The
The early development of this highly elaborated cellular human IC is identifiable in the 3.7-cm (approximately
contact may serve to decrease the probability of multi- 3 months’ gestation) fetus.39 The three main subdivisions
cellular input to the large spherical cell. Some evidence of the IC are readily identified in the kitten at birth, and
suggests that these developing second-order neurons may evidence suggests that the CNIC develops first.40
be transiently innervated by four or more auditory nerve In CNIC laminae formed by neurons and afferent axons
fibers.28 However, the slight overproliferation of fibers correspond to isofrequency contours. This highly organ-
requires a small amount of “pruning” to arrive at the mature ized pattern is evident early in development. In fact,
configuration, synaptic connections formed early in devel- neurons destined to form the IC demonstrate distinct
opment are typically maintained.29,30 Jhaveri and Morest31,32 proliferative gradients (rostrocaudal, lateromedial, and
demonstrated that morphologic changes in the end-bulbs ventrodorsal), so that neurons generated at a certain time
are accompanied by parallel changes in their spherical will have a characteristic distribution throughout the adult
cell targets in the chick, possibly reflecting developmental nucleus. This is in contrast to the superior colliculus,
 Central Auditory System Development and Disorders 567

which develops concurrently and demonstrates no obvious and after age 5 years axons that connect the cerebral hemi-
spatiotemporal gradients.41 spheres are evident. By age 11 to 12 years the density of
All neuronal cell types are present at birth in the cat cortical axons approximates that of adults. Moore
CNIC.42 Several changes have been documented over the correlates cortical maturation with advancing auditory
first month of life, including an increase in soma size25; processing abilities, beginning in infancy when most
decrease in extracellular space43; increase in lipid con- abilities reflect brainstem function to late childhood
tent44; and changes in dendritic length, morphology, and and adolescence when more complex auditory skills are
orientation.42,45,46 perfected, such as speech perception in noise and complex
Adult patterns of connectivity to other CAS structures binaural processing.
are present by postnatal day 7 in the rat.47 Some fibers
originating in CN and SOC are present in the CNIC
at birth, whereas the first projections from auditory cortex Myelination
(AC) are identified on postnatal day 3.48 Dendritic matu- In contrast to the late development of myelination in the
rational changes, not confined to the CAS, include an auditory cortex, brainstem auditory axons develop an
increase in length, loss of hairy or filiform processes, and adult-like content of neurofilaments between the 16th
a decrease in number (or complete loss) of dendritic and 28th weeks of gestation,55 and myelination of the
spines.42 axons first occurs between the 26th and 28th weeks.56
There is no evidence for centripetal axonal maturation in
Medial Geniculate Body the human brainstem; the brainstem auditory pathway
matures as a unit, rather than sequentially from lower
The medial geniculate body (MGB) comprises three main centers to higher.
subdivisions—ventral, dorsal, and medial—each with Latency of auditory brainstem response (ABR) wave-
component nuclei. The relatively early development of this forms decreases significantly with increasing age.57–60 This
diencephalic structure is recognized in the human embryo. change has been attributed by numerous investigators to
The MGB can be defined in the 29- to 30-mm embryo progressive myelination of CAS pathways.44,59,60 Walsh
(≈8.5 weeks), before the IC is identifiable.39,49 Nuclear and colleagues61 have quantitatively investigated myelina-
organization is evident in the 6-month-old (16 to 21 cm) tion of the CAS of the cat. They compared rate and timing
fetus.49 Most investigators believe that the MGB forms of maturation of axons and ABR latency and amplitude.62
from dorsal thalamus (also see Stroer50), which is depend- Interestingly, they found that the rate of myelination does
ent on the presence of the telencephalon for normal not correlate highly with either ABR latency decline or
differentiation.51 amplitude growth during the postnatal period in the
kitten. Fibers of the AN, trapezoid, and inferior brachium
Auditory Cortex have acquired only roughly half of the adult myelin sheath
by the time the ABR latency and amplitude have achieved
The AC is, like other CAS structures, comprises several adult values (Figs. 36-5 and 36-6). The authors suggest
divisions defined by morphologic and functional criteria. that changes in ABR waveforms occur as a result of a
The organization of the auditory cortex of the cat has been combination of developmental processes, including myeli-
described by Wong.52 AI, or primary auditory cortex, is a nation and synaptic maturation. Moore and coworkers63
laminated, tonotopically organized structure. It is sur- further discuss factors that interact to produce develop-
rounded by subregions that either are tonotopically organ- mental maturation reflected in the ABR. Based on their
ized (A, anterior auditory cortex; P, posterior auditory structural knowledge of brainstem development, they
cortex; VP, ventral posterior auditory cortex) or demon- constructed a model that allows separate analysis of the
strate no apparent tonotopicity (AII, secondary auditory ABR components of axonal conduction time and synaptic
cortex; DP, dorsoposterior area; V, ventral auditory area; delay. These two components have different maturational
T, temporal area). The columnar organization characteris- time courses—although synaptic maturation proceeds
tic of cerebral cortex is most highly developed in AI. until age 3 years, axonal conduction time is mature at
Functional properties organized according to binaural birth. Because the brainstem auditory pathways continue
interaction columns and tonotopicity exist concurrently to lengthen postnatally, they surmise that conduction
over the spatial map of this subregion. velocity must also continue to increase. This may be due
Moore and Guan53 and Moore54 recently described the both to increasing thickness of the myelin sheath and
maturation of the human auditory cortex through docu- increasing axon diameter.
mentation of neurofilament proliferation in specimens
ranging in age from 16 weeks of gestation to 27 years of
age. Neurofilament proliferation reflects axon maturation FUNCTIONAL DEVELOPMENT OF THE
in terms of increase in diameter, myelin sheath develop- CENTRAL AUDITORY SYSTEM
ment, and increase in conduction velocity, and can be used
to document patterns of connectivity and general brain Functional capabilities of the CAS may be defined either
maturation. During the perinatal period, between the in physiologic or behavioral terms. Although physiologic
third trimester and fourth postnatal month, mature axons methods can sometimes be more objective, precise, and
are present only in the most superficial layer of the cortex, less dependent on the motor system development and “state”
with no connections to areas outside the cortex. In early of the organism, behavioral measures have the advantage
childhood, the first thalamocortical afferents are identified, of reflecting the animal’s ability to respond to the acoustic
568 PEDIATRIC NEUROTOLOGY

A B
Figure 36-5. A, Distributions of the number of myelin lamellae investing auditory nerve axons, trapezoidal fibers, and fibers within the brachium of the inferior
colliculus are shown for several postnatal ages for the cat. B, Average number of myelin lamellae investing myelinated axons for the three axonal populations in
(A) are plotted as a function of postnatal age. (From Walsh EJ, McGee J: Development of auditory coding in the central nervous system: Implications for in utero
hearing. Semin Perinatol 14:281–293, 1990, p 291. Modified from unpublished abstract data.)

environment in a meaningful way. Recent advances in or even be required for normal functional auditory system
techniques of behavioral assessment have greatly increased development.
the objectivity of these measures and added to our under- Until the advent within the past decade of sophisticated
standing of human infant auditory processing. means of measuring sound transmission through the
A wealth of data are available to detail the physiologic abdominal and uterine wall, it was believed that what little
development of animal species. Many of these studies use sound reached the fetus was largely masked by internal
precocial species, or those with immature hearing ability at noise.66 More recent studies have used the hydrophone,
birth, so that the early events of hearing development can rather than the standard microphones, to measure attenu-
be studied. In this chapter, we focus on developmental ation of external sound in humans67,68 and sheep.69–72 For
hearing milestones that can be measured in the human. low-frequency signals, at or below 250 Hz, reduction in
Physiologic developmental studies are summarized by sound pressure levels is less than 5 dB. Above 250 Hz,
Rubel,1 Brugge,2 Sanes and Rubel,64 and Walsh and attenuation increased at a rate of about 6 dB per octave up
McGee,65 and the reader is referred to these sources for to approximately 4000 Hz, where the average attenuation
discussions of the physiologic development of the CAS. was 20 to 25 dB. Results obtained in sheep were similar to
those obtained in humans, supporting the use of the sheep
as a model for in utero sound transmission studies. In addi-
BEHAVIORAL RESPONSES TO SOUND tion, a hydrophone can be implanted surgically in the
Hearing by the Human Fetus sheep prior to delivery, whereas in the human the location
of implantation is less accurate and requires taking mea-
The human auditory system is well developed structurally surements with the amnion ruptured.
by the third trimester. Furthermore, as discussed later, Intrauterine basal noise is dominated by low frequen-
behavioral studies of auditory skills of the neonate reveal cies. Highest intensities are measured at frequencies below
the presence of discrimination capabilities that require 32 Hz, to which the human auditory system is not respon-
perception of complex auditory cues. The existence of sive. Measurements obtained by Querleu and colleagues73
these skills so early in life has led some investigators to sug- suggest that basal noise is of sufficiently low level that
gest that the auditory experience of the fetus may facilitate, external sounds are not masked. Their A-weighted sound
 Central Auditory System Development and Disorders 569

responses used most often for neonatal testing, including

the registration of limb and body movements, heart rate
changes, and eye blink responses, provide less precise
information than obtained by use of the conditioning
procedures applied in children 3 months and older. Newer
methods for detecting auditory responses in infants use
“observer-based” strategies (observer-based psychoa-
coustic procedure, or OPP). In these procedures, an
observer judges not whether the infants responded but
whether a signal occurred, using the infant’s behavior as
the only basis for the judgment.79 This test strategy is
more objective and more sensitive in assessing auditory
abilities in this age group than other methods of assess-
ment. After age 5 to 6 years, children can be evaluated
using routine audiometric testing techniques. Interpretation
of developmental studies must take into account the accu-
racy of the method of evaluation. Clearly, development of
Figure 36-6. Comparison between myelination of the auditory nerve nonsensory processes such as memory and attention may
(expressed as percent of the adult average number of lamellae per axon) and
normalized ABR latency and amplitudes for wave I as illustrated. Latencies
confound interpretation of experimental results, particu-
are expressed as percent of adult values, and amplitude as percent of larly for infants and young children. Thus, it is useful to
maximum. (From Walsh EJ, McGee J: The development of function in the use varied experimental strategies to address each question
auditory periphery. In Altschuler RA, Hoffman DW, Bobbin RP [eds]: of human auditory system development.
Neurobiology of Hearing: The Cochlea. New York, Raven Press, 1986, p 254.) Postnatal hearing development is well summarized by
Werner.79
pressure level measurements of internal noise were 28 dB.
(The A-weighted scale excludes the lowest frequencies, see Neonatal Period (Birth to 28 days)
Green74). Voices emerged above the basal noise level by
8 to 12 dB for exterior voices and 24 dB for the mother’s The newborn is able to discriminate a number of the
voice. Independent observers asked to repeat what they elements of speech, including voiced versus unvoiced
could hear from an interuterine recording of male and consonants, consonants by place of articulation, and several
female speakers (including the mother) were able to cor- vowel pairs, by about 2 months of age (see Querleu et al.73
rectly reproduce 30% of the phonemes, regardless of the for review). DeCasper and Fifer80 determined that 3-day-old
source. Although the mother’s voice was louder, it was not neonates consistently respond preferentially to their
better perceived, presumably because of greater distortion mothers’ voices. Responses rely at least partially on into-
of the internally transmitted sound. nation patterns, as there is no preference for the mother’s
Transmission of sound into the interuterine environ- voice when text is read backwards.81
ment is meaningful only if the fetus is capable of perceiv- The neonate is also able to localize the origin of a
ing the stimulus. Investigators attempting to measure fetal sound.82,83 Interestingly, this behavior is more difficult to
hearing have used a variety of unconditioned responses, elicit in 1- to 2-month-olds, but reappears around 3 to 4
such as body movements, heart rate changes, and eye blink months of age.84 This developmental pattern is thought to
responses. Such measures are primarily startle responses to reflect a difficulty in organization of auditory space and
sound and are subject to rapid habituation with repetitive coordination with appropriate motor behavior. When the
stimulation.75 The earliest eye blink responses to noise head-orienting response reappears, it is accompanied by
bursts can be elicited in the 25th gestational week, and visual search; this may represent the beginning of true
consistent eye blink, heart rate, and motor responses are spatial hearing.84
measured from the seventh month of pregnancy.76,77 A number of studies have shown a substantial improve-
Studies by Lecanuet and coworkers78 have demonstrated ment in pure tone thresholds in quiet in the first 6 months
response (cardiac deceleration) to stimuli of 90 to 100 dB of life. Thresholds of 2- to 5-week-old infants have been
sound pressure level ex utero. measured as 40 to 50 dB greater than those of adults across
frequency (500, 1000, 4000 Hz85). By 3 months of age the
gap has narrowed to about 20 dB.86 Thresholds appear to
Postnatal Development of Auditory be poorest initially at high frequencies, relative to adult
Competence thresholds, and demonstrate the most improvement during
the first 6 months of life.
Methodology
Psychoacoustic tests must be designed to optimize the
acoustic stimulus control of the subject and the adaptive- Infancy (28 days to 2 years) and Early Childhood
ness of the task to the behavioral repertoire of the
Absolute Sensitivity and Intensity Discrimination
subject.75 Different response strategies will be most effec-
tive at different points along the developmental timeline; As reported by Werner,79 the available evidence suggests
herein lies the challenge to investigators interested in that, in quiet, detection thresholds at 6 months are 10 to
development of auditory competence. Unconditioned 15 dB higher than those of adults and that thresholds are not
570 PEDIATRIC NEUROTOLOGY

adult-like through the entire frequency range of hearing measure of temporal processing is gap detection. Studies
until at least 10 years of age. of gap detection report that this ability doesn’t reach
Although responses are initially most adult-like in the maturity until about age 5,96 but it is possible that stimulus
low frequencies, high-frequency responsiveness improves duration and adaptation effects influence this measure.
more rapidly, so that the adult values are first achieved in Using one technique designed to separate the effects of
the high frequencies. The trend toward earliest develop- intensity and temporal processing, Levi and Werner97
ment of low-frequency hearing parallels that seen in the suggest that infants may have mature temporal resolution,
physiologic studies87 and behavioral studies of hearing in but immaturity of intensity processing contributes to the
animals.88 Low-frequency threshold elevation is reported experimental findings that reflect apparent deficits in
as late as 10 to 18 years of age (Fig. 36-7).89–91 temporal processing.
It is possible that threshold, frequency resolution, and
Frequency Resolution temporal resolution are all nearly mature within the first
Frequency resolution capabilities are among the earliest couple of years of life and that development of intensity
to mature. Werner and Bargones92 report that frequency coding lags behind, mature by some measures by about
resolution is adult-like at all but the highest frequencies by 5 years of age.
6 months of age. Psychophysical data obtained from chil-
Spatial Hearing
dren have indicated that frequency resolution continues to
improve until at least age 4 years93,94 and may continue to Clifton84 summarized the ability of infants to respond
improve as late as age 12.90,95 to auditory spatial cues. Sensitivity to binaural time cues
is well developed in 4-month-olds; development of binau-
Temporal Resolution
ral intensity cues has not been studied. Investigations
Animal studies of physiologic response development have of minimal audible angle (MAA) have reported that
revealed that temporal response properties are the last of 6-month-olds can discriminate a change in sound location
the “simple” auditory system coding mechanisms to reach of 12 to 19 degrees off-midline. Gradual improvement is
maturity. Accordingly, one might expect that behavioral noted to 18 months (6 degrees). Performance of 5-years-olds
measures of temporal processing would reflect this pro- is similar to that of adults, who can detect an MAA of
longed developmental time course. Although absolute 1 degree.
sensitivity and frequency resolution is nearly mature by The “precedence effect” aids in localizing a sound by
6 months, temporal resolution continues to mature after suppression of echoes, or reflections from surrounding
6 months of age. The developmental time course of surfaces. Clifton84 presents evidence that development of
temporal processing is difficult to assess independently this ability is delayed in infants compared with their abil-
because of dependence on intensity coding. One common ity to localize single-source sounds. Infants younger than
4 months do not demonstrate a precedence effect (cannot
inhibit the echo), and thus are unable to accurately local-
ize the source of the sound.
The ability to discriminate auditory distance reflects the
infant’s ability to integrate a representation of space and
object location in space. Clifton and colleagues84 have
shown that a 6-month-old will reach correctly for an
unseen, sounding object when presented within reach.
When the object was beyond reach, infants typically did
not attempt to grasp it. Clifton and colleagues84 demon-
strated that 6-month-old infants can use sound to identify
an object. Infants were able to correctly reach for an object
(response differentiated by bimanual grasp vs. one-handed
reach) identified by a learned associated sound. Thus,
6-month-old infants are capable of evaluating and
responding to environmental events through an integra-
tion of cognitive functioning, motor activity, and auditory
information.

CENTRAL AUDITORY TESTING

Keith (see Chapter 17, Central Auditory Testing) has
defined an auditory processing disorder as the inability or
impaired ability, in the setting of normal intelligence and
hearing sensitivity, to attend to, discriminate, recognize,
Figure 36-7. Absolute thresholds as a function of age for five octave-band remember, or comprehend information presented to the
noises. Individual exponential decay functions have been fit to the data
at each frequency. (From Trehub SE, Schneider BA, Morrongiello BA,
auditory system. Although efforts have been made to
Thorpe LA: Auditory sensitivity in school-age children. J Exp Child Psychol tailor tests of central auditory function to young children,
46:273–285, 1988, p 278.) behavioral assessments are difficult in children younger
 Central Auditory System Development and Disorders 571

than 6 years of age, and normative data are often lacking. click stimuli. Other late responses occur in response to
A thorough discussion of behavioral assessment of central speech stimuli, with total durations out to 700 msec.
auditory function is provided by Keith in Chapter 17 of Kurtzberg and colleagues108,109 described a series of corti-
this text. The reader is also referred to the discussion by cal auditory evoked potentials (CAEPs) in response to
Musiek and Baran.98 speech stimuli that show an orderly sequence of matura-
Many of the shortcomings of behavioral testing in this tion until adult-like responses are achieved at about age 2.
age group can theoretically be circumvented by the use of Patients with various brain lesions have been shown to
carefully administered and interpreted electrophysiologic have abnormal late potentials, and attention of some inves-
tests for evaluation of central auditory processing skills. tigators has focused on the use of these responses for iden-
Interpretation of many of these responses is poorly under- tification of neurologic disease (see Kraus and colleagues110).
stood. However, recent advances in the understanding of Another set of late responses is elicited only in reaction
middle latency and late responses may lead to improved to a deviant or unexpected stimulus inserted into a repeti-
clinical utility. tive identical stimulus train, presented in an “oddball” par-
A comprehensive review of the electrophysiologic tests adigm. Some of these responses include the mismatch
of central auditory system function is provided by Kraus negativity response (MMN), P300, and the cortical dis-
and McGee.99 Responses to sound are classified by latency criminative response (CDR).110
into early, middle, and late waveforms. The ABR, the The MMN is a robust response that, unlike other corti-
development of which was discussed earlier, consists of cal potentials, appears to be mature in school-age chil-
seven peaks, all occurring within 15 msec of signal onset. dren.111 It is passively elicited from nonattending subjects,
Studies of Moller and Jannetta100,101 suggest that wave- in response to stimulus pairs (such as /da/ and /ga/) that
forms are generated at sites from the peripheral AN to the are at or above behavioral discrimination threshold.
IC. The ABR provides a highly reliable indication of audi- Stimulus pairs may be within or across phonemic bound-
tory function in subjects of all ages and shows predictable aries. The MMN is thought to originate from the auditory
changes in neurologically impaired systems.102–104 cortex, with contributions from auditory thalamus and
The middle latency response (MLR) comprises a series hippocampus.112–115 Thus, it may be useful for evaluation
of waveforms (Na, Pa, Pl, and TP41) that occur between of central auditory processing skills such as auditory short-
10 and 60 msec after stimulus onset. Generator sites term memory, stimulus detection in background “noise,”
include auditory pathway structures central to the IC temporal processing, or speech discrimination. It also may
(“primary pathway”) as well as structures outside this be useful for evaluation of children with attention deficit
pathway, such as the so-called reticular activating system, disorders.111 Another potentially exciting use of the MMN
and nonprimary divisions of the auditory thalamocortical is in evaluation of speech discrimination in cochlear
pathways, which process multisensory stimuli (“nonpri- implant recipients, particularly children with limited audi-
mary pathway”). The MLR derives from multiple sources tory processing skills.116
that mature at different developmental rates and are The P300, originally described by Sutton and cowork-
variously affected by anesthetics and sleep state. Whereas ers,117 is also elicited by an oddball paradigm. P3a can be
the ABR is developmentally mature by 18 months of age, elicited in nonattending subjects, but the P3b component
the MLR exhibits a much longer developmental time requires active discrimination of the stimulus by the sub-
course; the primary cortical generator is likely mature by ject. Multiple subcortical as well as cortical sites are
age 10 to 12 years, but the nonprimary areas may not be thought to contribute to the response (see Kraus and
fully mature until early adulthood. McGee and Kraus105 McGee99 for a review). Definitive norms have not been
suggest that this extended developmental process may established for the P300 because of great intersubject vari-
account for the relatively late development of selective ability in latency and amplitude. For this reason, the P300
auditory attention. may be more useful as a measure of changes over time in
The MLR has been used in pediatric populations pri- one individual subject (i.e., recovery from injury, response
marily to assess low-frequency hearing thresholds that are to treatment, etc.). It has been suggested that the P300
not easily measured with the traditional ABR.106 One correlates more with global cognitive function than with
problem with this application has been the lability of the any specific disorder.118
response in the pediatric population, particularly in sleep- Speech evoked CAEPs and CDRs have been investi-
ing children. Problems of recording this response in gated by Kurtzberg and colleagues108,109 in clinical popula-
children may be circumvented by targeting response mea- tions. They studied infants identified to be at risk for
surements made during favorable sleep stages as described language disorders based on low birth weight or perinatal
by McGee and colleagues.107 asphyxia and discovered a high incidence of abnormal
Late auditory evoked potentials occur after 70 msec and speech-elicited responses. On follow-up, children with
reflect primarily responses of structures central to the abnormal responses in the neonatal period were later found
brainstem. In general, these responses are less stimulus- to have deficiencies of language-processing skills. The
dependent and more state-dependent and, thus, variable. authors concluded that the abnormal CAEPs and CDRs
Although certain of the late response waveforms are well were meaningful predictors of later language performance.
defined and useful as clinical entities, others are much Finally, the N400 (latency 400 msec) is elicited only in
more variable and controversial. Some of the more well- response to a stimulus that presents a semantic incongruity
documented responses include the N1–P2 complex (P1, N1, (e.g., “I am going to walk the house”). It is elicited, as is
P2, N2), present at a latency range of 50–300 msec. All are the P300, by auditory, visual, and sign language stimuli.119
elicited by a stimulus train of repetitive identical tonal or Generators of the N400 have not been identified, but it is
572 PEDIATRIC NEUROTOLOGY

assumed that since many modalities can be involved in the

response that it is generated from many areas of the brain.
Some abnormalities of the N400 have been identified in
language-impaired children.99

INFLUENCE OF ENVIRONMENTAL
FACTORS ON THE DEVELOPING
CENTRAL AUDITORY SYSTEM

Abnormal Central Auditory

System Development
Abnormalities of CAS development may occur as a result
of direct insult by disease processes affecting the brain
(see later section on Pathology of CAS) or secondary to
pathology of the peripheral auditory system. Numerous Figure 36-8. Sites of manipulations of the peripheral auditory system
studies describe the often profound effects of afferent represented on a section through the human ear (schematic from Pickles
manipulation on the developing CAS. Conversely, effects 1988). 1, pinna removal; 2, ear plug; 3, tympanic membrane puncture;
4, ossicular disarticulation or removal; 5, application of pharmacologic
on the mature auditory system are usually modest or substances to the cochlea; 6, round or oval window puncture; 7, cochlea
nonexistant. Investigators have described a sensitive, or removal or destruction. (Reprinted with permission from Moore
developmental, period during which abnormal experience DR: Developmental plasticity of the brainstem and midbrain auditory
can adversely influence development, and a more pro- nuclei. In Romand R (ed): Development of the Auditory and Vestibular
Systems 2. Amsterdam, Elsevier, 1992, p 299. Modified from Rubel and
tracted critical period during which normal afferent input Parks, 1988.)
appears to be necessary to affect normal CAS develop-
ment. However, rather than being confined to discrete
periods, the dependence of neuronal integrity on afferent
activity seems to decline gradually with age. Despite an deprivation with an intact end-organ. It should be empha-
ability to define for various species and experimental sized, however, that a meaningful interpretation of depri-
conditions the time of maximal sensitivity to afferent vation and deafferentation experiments requires rigorous
manipulations, the cellular mechanisms that affect the quantification of the effect of the manipulation on the
response to environmental manipulation in the developing pattern and amount of activity in the CAS.30,120
animal have yet to be delineated.
Disruption of afferent input to the CAS may be
separated, at least theoretically, into one of two types of Conductive Hearing Loss: Effects
insults (Fig. 36-8). These are usually termed deprivation and of Deprivation of Sound Input
deafferentation, based on the nature of the manipulation
Human Studies
intended by the experimenter. Deprivation describes a
manipulation that decreases sound transmission through Physicians initially assumed that because the conductive
the outer or middle ear system, producing a conductive hearing loss (CHL) typically associated with otitis media
hearing loss. Blockage of sound transmission results in a may be mild, unilateral, and fluctuating, the functional
decrease in sound-evoked activity in the CAS, but may have consequences were likely to be minimal. As early as the
little short-term effect on spontaneous activity of these 1960s, however, it was noted that children with a history of
neurons.120,121 Effects of purely conductive pathology on repeated episodes of otitis media with hearing loss lagged
CAS anatomy and function are often subtle, but appear to behind their normal-hearing peers in measures of language
involve the entire CAS, in particular the CN.122–125 Depri- development and educational achievement. These early
vation of sound input may be unilateral or bilateral; if studies lacked many of the necessary features of a well-
unilateral, development of binaural processing strategies may designed investigation of clinical outcomes, and critical
be affected. Another type of experimentally induced depriva- commentary took issue with the conclusions of these
tion is interference with patterned activity. For example, investigators.128–131 Nevertheless, these early investigations
introduction of a repetitive environmental sound can deprive nearly universally reported a negative effect of hearing loss
the CAS of the pattern of neuronal discharges evoked by a on development.
normal acoustic environment and can disrupt the acquisition By the late 1980s several research groups initiated
of central auditory-processing capabilities.126,127 experimentally sound prospective studies of sufficiently
The second type of insult, deafferentation, occurs with large numbers of subjects to draw statistically valid
the partial or total destruction of the peripheral end-organ. conclusions about the consequences of CHL on hearing,
The lesion produces a sensorineural hearing loss and as well as on more global measures of speech, language,
invariably results in diminution or elimination of all cognition, behavior, and educational achievement. Some
input—spontaneous as well as sound-evoked—to the CAS. of the most compelling evidence of long-standing deficits
Deafferentation results in degenerative changes that pro- in individuals with chronic CHL comes from studies
ceed sequentially to more central structures. CAS pathol- that assess performance on specific auditory processing
ogy is usually much more marked than is the case of sound tasks. Hall, Pillsbury, and colleagues,132–134 and others135,136
 Central Auditory System Development and Disorders 573

have used the masking level difference (MLD) to assess the consequences of CHL and the potential for reversal of any
ability of subjects with a history of CHL to process binau- CAS changes.
ral information in the presence of noise. The MLD meas-
ures the subjects’ ability to use binaural difference cues of
time and amplitude introduced during the test by chang- Animal Studies
ing the phase of the signal presented to the two ears.
MLDs are significantly smaller in children with a history Anatomic Effects of Conductive Hearing Loss
of CHL than in age-matched control children. In a study Animal models of CHL have been developed and give us
population that was selected for placement of middle ear some insight into the CAS consequences of conductive
ventilation tubes, the abnormality in MLDs noted prior to impairment. These studies must be interpreted with con-
tube placement, in the presence of hearing loss, persisted sideration of the species studied, the developmental stage
in approximately half of the children after hearing thresh- at which the experiment is conducted, species-specific
olds were normal.133 Interestingly, Pillsbury and col- characteristics such as the frequency range of hearing, and
leagues132 commented that postsurgical MLDs were most the effect of the manipulation used on activity in the
likely to be abnormal in subjects who had experienced auditory nerve and CAS. A valid model of CHL requires
asymmetrical hearing losses, although this was not con- that the manipulation used to create the hearing loss
firmed in their later studies. damage only the sound-conducting mechanism of the
ABRs have been studied in subjects who have normal middle ear and not the inner ear. Results of studies in
hearing and a history of CHL.137–139 All three studies which concomitant sensorineural hearing loss has been
reported an increase in latency to waves III and V of the inflicted are confounded by the associated degenerative
ABR and an increase in interwave latencies. Binaural inter- changes typically observed following cochlear damage (see
action was assessed by subtracting binaural from summed later discussion).
monaural waveforms and was significantly diminished in A number of investigations, mostly in rats and mice,
normal subjects and subjects with a history of otitis media have documented that CHL or other forms of auditory
with effusion. deprivation (e.g., sound isolation) introduced during a
Prospective investigations have examined the effect of “critical period” of auditory development result in smaller
otitis media with effusion and CHL on development of than normal brainstem nuclei and neurons,143–152 and other
speech and language skills and on behavior and cognition. structural changes.149,153,154 Webster145 documented that
Vernon-Feagans140 noted risk factors that may affect lan- sound amplification introduced during the critical period
guage and attention outcomes. Her model predicts that, of auditory development in the mouse decreases the
in the presence of an environment that facilitates commu- atrophy of the CN in mice with external canal atresia
nication, children develop normal speech, language, and and CHL. Subcutaneous administration of a neurotrophic
behavior. In less optimal situations, language skills develop agent, monosialoganglioside, significantly ameliorates
poorly, and a lack of attentive behavior complicates CHL-induced atrophy of spiral ganglion cells and neurons
language processing. Children in the latter group with a of the VCN.155 Tucci and coworkers124,125 identified
history of hearing loss from otitis media may tend to marked changes in CAS neuronal activity using the
“tune-out” language and attend to less auditory parts of 2-deoxyglucose method, as well as changes in capacity for
the environment. Such children have a more difficult time oxidative metabolism in gerbils with unilateral conductive
with complex listening tasks such as comprehending hearing impairment.
extended discourse in conversation, storytelling, or Investigations in chick,123 monkey,156 and ferret122 failed
extended topic elaboration, such as they might encounter to demonstrate changes in cross-sectional area of brain-
in a school setting. Therefore, prompt and aggressive stem neurons following conductive impairment. Thus,
management of childhood medical conditions associated species differences do appear to be important in assessing
with hearing loss seems well advised. Such interventions the effect of CHL. However, it is likely that other struc-
are not always implemented, secondary to lack of knowl- tural or functional modifications occur, particularly if the
edge of the implications of such impairment and to con- loss is asymmetrical or unilateral. For example, in the fer-
troversy regarding the most cost-effective method of ret, Moore and colleagues122 found, despite the lack of
medical management of disease.141,142 change in neuron area in the CN, a significant change in
The above-mentioned studies provide compelling the projection from the CN opposite the affected ear to
evidence that changes in central auditory processing the ipsilateral IC following unilateral conductive impair-
abilities persist long after hearing loss resolves in children ment. This change may occur secondary to the newly
with a history of conductive impairment. The existence of introduced asymmetry of peripheral input with the unilat-
long-term alterations in processing of auditory signals eral hearing impairment (see following section).
could imply that hearing loss in early life is associated with
Evidence that Unilateral Conductive Impairment
structural or functional modifications in the CAS. Very
May Affect the Symmetry of Central Auditory System
little is known about the specific structural and functional
Projections
changes that occur in response to this impairment, and
the mechanisms of these neuronal changes are even less As discussed earlier, unilateral conductive impairment has
well understood. The need to effectively manage hearing been found in one experimental paradigm to change the
loss in children is one ultimate goal that drives our need symmetry of projections from the CN to IC. It has also
to understand the factors, such as duration of impairment been argued that compensatory changes occur in brain-
and effect of developmental stage, which influence the stem neurons of the CN opposite an ear with CHL.
574 PEDIATRIC NEUROTOLOGY

Coleman and O’Connor151 reported that the mean neuron From the foregoing data, it appears that experience with
area in the spherical cell region of the rostral AVCN a normal acoustic environment may influence cellular
decreased in the CN ipsilateral to a conductive hearing response properties of the CAS. The full range of effect of
impairment but increased in the contralateral CN. Tucci altered experience is probably not appreciated at this time.
and coworkers124 reported a similar effect on their measure Certainly, binaural integration is influenced by asymmetri-
of oxidative metabolism in the gerbil with a unilateral cal acoustic input. Refinements in our ability to study these
CHL. Some evidence suggests that the symmetry of input properties in the nervous system are necessary to deter-
between the two ears may be important in establishing and mine if other complex integrative capacities are influenced
maintaining neuronal projections. Killackey and Ryugo154 as well. Whether a sensitive period exists during which
reported that the laminated structure of the central these abilities must develop or be lost forever is unclear.
nucleus of the IC in the rat is altered following unilateral Several of the previously cited studies seem to suggest that
but not bilateral ear canal closure. Studies by Knudsen and certain capabilities are never achieved if hearing loss is
colleagues in the barn owl157 reveal evidence of reorgani- allowed to persist during the developmental period.
zation of a binaurally innervated nucleus of the CAS and The obvious question raised to the otologic surgeon is
altered localization cues following unilateral conductive that of the urgency of correcting a CHL in the young
impairment secondary to an earplug placed during a criti- child. Agreement is widespread that aggressive interven-
cal period in development. tion is warranted for treatment of recalcitrant middle ear
effusion with tympanostomy tubes for prevention of
Physiologic Responses to Conductive Hearing Loss repeated infections and correction of CHL. However, less
Studies of physiologic responses from the auditory cor- of a consensus is achieved on the issue of correction of
tex158 (cat) or inferior colliculus159,160 (rat) in animals with other types of CHL in children, particularly when the loss
unilateral ear canal atresias imposed at an early stage in is unilateral. Bone conduction hearing aids provide rea-
development show abnormal responses to binaural stimu- sonable levels of amplification, but compliance is a prob-
lation. This apparent inability to appropriately integrate lem, and identical signals are presented to both ears, thus
auditory input from the two ears following unilateral ear eliminating cues for binaural hearing.161 A treatment deci-
canal occlusion may reflect physiologic changes that could sion must be based in part on the needs of the child, the
be associated with structural abnormalities noted in the wishes of the parents, and the likelihood of achieving nor-
animal studies discussed earlier. Auditory processing mal hearing with surgical intervention (i.e., in the case of
abnormalities noted in children with a history of CHL, congenital atresia).
such as problems with localization136 and use of binaural
cues for signal detection in noise,133 may reflect similar
changes in the human central auditory system. Sensorineural Hearing Loss: Effects
Although monaural CHL decreases the level of acoustic of Deafferentation
stimulation that reaches the inner ear, it does not entirely Animal Studies
deprive the ear of patterned input. Several investigators
have examined the effect of restriction of auditory experi- In contrast to the little-understood effects of conductive
ence on CAS development. It has been hypothe- impairment on the CAS, the repercussions of sensorineural
sized29,126,127 that response properties of the CAS may hearing loss (SNHL) is well documented, and investigators
be fine-tuned through selective elimination of synapses are developing an increasingly sophisticated understanding
during development. Evidence from studies such as of the mechanisms of CAS changes following sensorineural
Jackson and Parks28 shows that immature CAS neurons impairment. Transneuronal degenerative effects of end-
may receive a slight overabundance of excitatory inputs. organ damage include changes in neuronal and synaptic
Although which factors influence the final synaptic morphology,162–164 dendritic morphology,165,166 protein
configuration is unknown, it is possible that activity, both synthesis,167 and metabolic activity.168–173 Changes are most
spontaneous and evoked, influences the establishment of marked in young developing animals, and maximum sus-
mature synaptic anatomy. If this is the case and a diversity ceptibility is confined to a “critical period” in develop-
of auditory experience is necessary for normal maturation, ment.174–178 Neuronal changes are generally greatest in the
it is possible that restriction of auditory experience could VCN, which receives its primary afferent input from the
result in postsynaptic cells manifesting a larger than ipsilateral ear. However, changes are also seen in more cen-
normal receptive field and poorer frequency resolution tral structures, including the ipsilateral LSO and contralat-
secondary to failure to eliminate inappropriate inputs eral MNTB in young gerbils179,180 and ferrets.181,182
during development. Sanes and Constantine-Paton126,127 Morphologic changes similar to those seen following
tested this hypothesis by raising mice in the presence of a deafferentation (destruction of the auditory end-organ)
repetitive click stimulus. Clicks were demonstrated to can be produced by pharmacologic blockade of auditory
entrain a large portion of primary afferents in both the AN nerve activity. Tetrodotoxin (TTX), when applied at the
and IC during the developmental period. The investigators round window, immediately and reversibly eliminates
demonstrated that single-unit tuning curves to tone pip auditory nerve action potential.177,183–186 Presynaptic
stimuli obtained from recording in the central nucleus of action potentials regulate protein synthesis in second-
the IC were less sharp (poorer frequency resolution) for order auditory neurons of the chick brainstem.183 Born and
click-reared than for normal control animals. The authors Rubel183 examined the effect of a perilymph injection of
concluded that normal temporal patterns of neural activity TTX on numbers and size of neurons in nucleus magno-
help to structure synapses in the developing auditory system. cellularis (the avian equivalent of the AVCN in mammals)
 Central Auditory System Development and Disorders 575

and on incorporation of 3H leucine using autoradiography. Thresholds for these neurons are initially grossly elevated
Short-term effects (1.5 hours) of TTX were very similar to compared with thresholds for normal neurons in this
changes seen after deafferentation,167,187 but by 24 hours region, but over time neurons in this region develop near
after injection—as the reversible effects of TTX dissi- normal thresholds at the new CFs. This progression sug-
pated—these changes reverted to normal. Similarly, TTX gests that the representation of frequencies above and
application produces reversible cell size changes in the CN below the lesion is expanded. Similar results have been
of the gerbil.186 Synaptic activation is essential for mainte- reported by Harrison and coworkers194 for the newborn
nance of normal cell metabolism, as antidromic activation kitten and by Schwaber and colleagues195 for the adult
of neurons via electrical stimulation of axons in a brain macaque monkey. Furthermore, studies by Recanzone and
slice preparation did not enhance protein synthesis.184 coworkers196 in the adult owl monkey and Bakin and
These studies of afferent manipulation suggest that the Weinberger197 in the guinea pig have demonstrated that
activity of auditory afferents regulates the metabolism and cortical responses can be changed in response to behav-
morphology of neurons in the CAS. The early changes ioral conditioning in the absence of a peripheral lesion,
observed following deafferentation (either anatomic or thus demonstrating exceptional functional plasticity. The
pharmacologic) appear to be due to a reduction in activity- functional significance of this reorganization has yet to be
dependent interactions between presynaptic and post- understood. As pointed out by Schwaber and coworkers,195
synaptic cells.186 Studies in chicks have shown that such findings raise questions about the utility of reintro-
second-order auditory system neurons rely on eighth duction of auditory stimuli after the onset of hearing loss,
nerve activity-dependent activation of a metabotropic glu- either with a hearing aid or a cochlear implant. However,
tamate receptor to maintain physiologic intracellular cal- it appears likely, although not proven, that the extreme
cium. Loss of intracellular calcium is thought to contribute plasticity of cortical organization would allow further
to the early stages of neural degeneration and cell death.188 reorganization to accommodate the reintroduction of
The balance of input from afferent projections to bin- activity.
aurally innervated nuclei may influence structure and Mutant strains of animals with congenitally determined
function in the CAS. Kitzes and colleagues studied the lesions of the organ of Corti provide another means of
effects of unilateral cochlea removal in the neonatal gerbil assessing degenerative changes and may offer useful mod-
on patterns of connectivity and physiologic responses (see els for studying genetic CHL in human subjects. In this
Kitzes189 for review). Projections from the VCN, which in case, deafferentation is generally gradual and bilateral.
the normal gerbil innervate the ipsilateral LSO, the con- However, unlike the case of cochlear ablation, findings
tralateral MNTB (via the ventral acoustic stria), and both may be confounded by genetic defects in central struc-
the ipsilateral and contralateral MSO, are altered after tures, so that all observed degenerative changes may not be
neonatal cochlear ablation. Labeling experiments showed secondary to peripheral destruction. In the deaf white cat,
aberrant projections from the unoperated side to the con- for example, degenerative changes have been observed in
tralateral LSO, the ipsilateral MNTB, and both MSO. It auditory brainstem nuclei prior to the time when changes
has been suggested that these abnormal patterns of con- are noted in SGCs.198
nectivity may occur because of lack of inhibition or com- One of the most widely cited studies is that of West and
petition from the projections of the lesioned side, implying Harrison199 in the deaf white cat. Pathologic alterations
that such interactions are important for normal develop- observed for this species occur postnatally, from the 5th to
ment of innervation patterns.189 Further studies in the 21st day after birth. The authors demonstrated severe
neonatal gerbil190 demonstrated changes in the patterns of atrophy of the organ of Corti, although SGCs of the two
connectivity between the CN and IC, with an increase in animals studied were largely normal in appearance.
the ipsilateral CN–IC projection on the side opposite Despite the normal ganglion cell population, the volume
cochlear ablation, and a decrease in the CN–IC projection of medullary nuclei and soma areas in these nuclei were
on the side of the ablation. These results again suggest that decreased compared with normal animals, much like the
an interaction of binaural inputs may influence the final results of Powell and Erulkar162 discussed earlier. Thus,
configuration of innervation patterns for this CAS struc- central degenerative changes may be primary rather than
ture. Investigation of physiologic responses obtained by secondary to SGC degeneration and loss of activity. The
stimulation of the unoperated ear in neonatally ablated authors provide an excellent summary of work on congen-
gerbils revealed larger responses from the ipsilateral IC itally deaf animal models published before the date of
than was observed in normal animals or those ablated as their study.
adults, indicating functionality of this enhanced projection More recent work in the deafness mutant (dn/dn) mouse
from the ipsilateral ear.191 Similar effects were noted on highlights physiologic changes in central structures.200,201
recorded responses from auditory cortex ipsilateral to the Horner and Bock201 studied IC unit responses to electrical
nonoperated ear of neonatally cochlear ablated cats.192 stimulation of the periphery and discovered that, at least
Another study of auditory cortex plasticity investigated by certain measures, responses measured from congeni-
the tonotopic organization of auditory cortex contralateral tally deaf animals were more robust than those of the nor-
to a partial unilateral cochlear lesion in the guinea pig.193 mal-hearing control animals. They found a preponderance
Immediately after restricted peripheral lesion, neurons in of multispike single-unit responses in contrast to the sin-
the region of cortex in which the damaged portion of the gle-spike responses more often observed in the control
cochlea is normally represented undergoes a change in animals. Similar observations have been made in animals
tonotopicity such that neuron characteristic frequencies genetically susceptible to audiogenic seizures202 and noise-
(CFs) are shifted outside the frequency range of the lesion. induced hearing loss.203 The maximum number of evoked
576 PEDIATRIC NEUROTOLOGY

spikes in response to stimulation was greater in mutant these central structures or, if instituted immediately after
animals, and the group mean threshold of response was the onset of deafness, prevent degenerative changes from
lower in mutant than control animals. Peak-to-peak ampli- occurring. However, the limited histologic material avail-
tudes of responses recorded in the IC were also greater in able from human subjects who received a cochlear implant
mutant mice.200 The absence of spontaneous activity in prior to their death demonstrates no consistent effect of
this mutant was confirmed (in 6- to 7-month-old animals) chronic electrical stimulation on CAS anatomy. This state-
using the 2-deoxyglucose method.204 ment is based on the temporal bone histopathologic
studies by Linthicum and coworkers209 and the studies of
brainstem tissue conducted by Moore and colleagues205
Human Studies
cited earlier.
Investigations of the effects of deafferentation in the Linthicum and colleagues209 quantitatively evaluated the
human CAS are quite limited. Moore and colleagues205 number of SGCs in 22 temporal bones from 13 cochlear
reported their analysis of brainstem specimens from seven implant patients. Contrary to what might be expected, SGC
deaf and six normal-hearing control subjects. Neuron population did not appear to correlate with patient per-
areas in a restricted location in the PVCN were correlated formance with the implant; in fact, satisfactory performance
inversely with length of period of deafness, so that the was achieved with as few as 3212 ganglion cells, or slightly
patients with the longest period of deafness prior to death greater than a tenth of the usual population of approximately
tended to have the smallest cell size. Furthermore, consis- 30,000. Interestingly, the duration of electrical stimula-
tent with the foregoing discussion, the two congenitally tion, which ranged from 9 months to 14 years (mean
deaf patients in this sample were found to have the most 5 years) had no effect on the number of ganglion cells.
severe degenerative changes. They also reported a positive Of the seven specimens from bilaterally deaf subjects
correlation between cell size and spiral ganglion cell num- analyzed by Moore and colleagues,205 four subjects had
ber. Therefore, even though these populations of SGCs been implanted unilaterally with either a single- or multi-
were receiving no or little afferent stimulation, their pres- channel cochlear implant. In no subject was there a signif-
ence appeared to affect the population of second-order icant increase in ganglion cell number or PVCN cell area
neurons. This raises the possibility that, although short- on the side of the brain ipsilateral to the implanted cochlea
term studies of spontaneous activity following cochlear (J. Moore26). Duration of stimulation for the four subjects
lesion demonstrate dramatic loss of activity in the CN, prior to their death was 7 months, 9 months, 2 years,
long-term evaluation may reveal some level of activity in and 23 years, respectively. The last subject, however, never
the auditory nerve that may partially sustain more central responded to stimulation with the implant, and on tempo-
structures. Liberman and Kiang206 studied spontaneous ral bone histology was found to have no surviving ganglion
discharge rates of auditory nerve fibers in cats 4 to 8 weeks cells. Thus, stimulation of this population was very limited.
after noise trauma. Although the majority of fibers Another way to examine plasticity is through functional
determined to be unresponsive to sound demonstrated no measures of implant performance. Although more global
spontaneous activity, low spontaneous discharge rates were measures are evaluated, and many potential confounding
recorded in many fibers. Those unresponsive units that variables are present, performance as a function of factors
were found to have spontaneous activity had abnormal such as length of deafness or duration of stimulation may
patterns of activity, typically bursts separated by long provide some insight into the ability of the CAS to use
periods of silence. newly available auditory information. Early studies210,211
Wu and Moore207 developed three-dimensional recon- reported that, for children and adults, age of onset of deaf-
structions of the CN complex in normal-hearing and deaf ness, length of total auditory deprivation, and age at
subjects, including two patients with acoustic neuromas. implantation are all important factors in predicting
Their findings in normal-hearing subjects were consistent postimplant performance. Longitudinal studies of implanted
with the report of Konigsmark and Murphy208 that showed deaf children show significant gains in speech production
a continuous decline in nuclear volume with increasing and language acquisition in the implanted children relative
age. Interestingly, in the deaf subjects, all over age 60 at to their matched nonimplanted peers.212–214 Best results
the time of death, there was a less marked decline in are obtained with early implantation, particularly before
nuclear volume, secondary to gliosis and replacement of age 3.215 Such results would seem to imply that electrical
much of the neuropil by glial processes. Thus, the authors stimulation instituted soon after the onset of profound
conclude that nuclear volume is not a good correlate of deafness is more effective in stimulating auditory pathways
sensory loss in humans. than stimulation begun after progressive degenerative
changes have taken place.
Animal Studies
Reintroduction of Activity by Electrical Stimulation
in the Deaf Subject: Cochlear Implant Several animal studies have addressed the questions raised
in the foregoing discussion about auditory system plastic-
Human Studies ity in response to the reintroduction of electrical activity
Given the apparent relationship between auditory nerve by means of a cochlear implant. Most investigators have
activity and integrity of the CAS system structures, it has concluded that electrical stimulation instituted soon after
been suggested that the reintroduction of electrical stimu- deafening results in an increase in SGC density ipsilateral
lation of the auditory nerve, as via a cochlear implant, to the stimulated ear. More central effects of stimulation
might provide sufficient stimulation to either maintain are less clearly demonstrated.
 Central Auditory System Development and Disorders 577

Measures of metabolic function have shown increased between the stimulated and nonstimulated side were
activity following deafening and subsequent chronic elec- observed in two kittens that received only 4 weeks of stim-
trical stimulation. Wong-Riley and colleagues216 used the ulation, or in implanted nonstimulated control animals.
cytochrome oxidase technique to determine if brainstem Analysis of SGC area revealed no effect of stimulation.
auditory pathways in the cat would demonstrate evidence In a follow-up study using the same animals, Lustig and
of return of function after 5 to 6 months of deafness. coworkers222 reported that, although ototoxic deafening
Levels of cytochrome oxidase increased to nearly control resulted in a 20% to 26% reduction in AVCN spherical
levels after 1 month of electrical stimulation. Although cell size compared with the normal cat, intracochlear stimu-
sample size was small (n = 2), they demonstrated return of lation was associated with a 7% increase in ipsilateral AVCN
function in a previously deficient system. El-Kashlan and spherical cell area. No changes were seen in nuclear
coworkers217 also reported evidence of metabolic activity volume or AVCN cell density following stimulation.
in the CAS following prolonged deafferentation using the Matsushima and colleagues223 deafened four cats at age
2-deoxyglucose technique. They demonstrated response 37 to 40 days with a one-time dose of ototoxic drugs,
to electrical stimulation of the CN through at least 16 weeks implanted an intracochlear electrode array at age 70 to
after deafening. 80 days, and delivered electrical stimulation unilaterally
Chouard and colleagues218 presented early evidence that beginning 10 days after surgery. Animals were stimulated
implantation and stimulation may prevent degenerative 16 hours per day for a total of 3 to 4 months. An auto-
changes following cochlear damage in the guinea pig CN. mated image analysis system was used to measure all
Lousteau,219 noting Chouard’s results, first demonstrated cells in the CN, so the chance of sampling error was
that the early introduction of electrical intracochlear stim- greatly reduced. Cell area in AVCN was significantly
ulation in young guinea pigs deafened with systemic greater ipsilateral to the stimulated ear. However, mean
kanamycin and ethacrynic acid affected a significant cell areas for the stimulated AVCN were still less than
increase in spiral ganglion cell density compared with the reported for normal-hearing cats.15,224 Thus, more robust
nonstimulated ear. Modest amounts of stimulation were effects were obtained in studies with a longer duration of
used in this study—animals were stimulated at 100 μA for stimulation and a more complete sampling of AVCN
1 hour daily, 6 days a week for a 45-day period. Hartshorn neurons.
and coworkers220 also assessed SGC survival in ototoxically An alternative explanation for the failure of electrical
deafened guinea pigs stimulated at various current levels stimulation to completely reverse the CAS effects of deaf-
for a 9-week period, 2 hours per day, 5 days per week. SGC ness may involve the nature of the stimulus used in these
survival was significantly enhanced for cells in the basal studies. Although the repetitive stimuli delivered chroni-
turn of the cochlea only. Leake and colleagues221 reported cally in the cited studies may replicate the effects of spon-
a similar pattern of enhanced survival of SGCs only in the taneous activity in these structures, they allow for no
basal cochlear region following chronic intracochlear stim- simulation of evoked activity or for any alteration in the
ulation in four cats (Fig. 36-9). In this investigation, new- pattern of activity. Snyder and coworkers225 evaluated
born kittens were ototoxically deafened, unilaterally frequency resolution of responses in the IC of cats that
implanted (age 9 to 17 weeks) and chronically stimulated at underwent chronic electrical stimulation as described for
6 dB above electrically evoked ABR thresholds for 1 hour the experiments of Leake and colleagues.221 The CNIC is
per day for 1 to 3 months. No differences in SGC density characterized by a well-organized spatial tonotopic gradi-
ent that is not altered by deafness or chronic electrical
stimulation.226 Spatial “tuning curves” were generated
from single and multiunit data by determining the thresh-
old for an electrical stimulus generated by a particular
intracochlear electrode pair at all levels in an CNIC elec-
trode penetration. Results in chronically stimulated deaf
cats were compared with results in deaf implanted, non-
stimulated cats. Although tuning curves obtained from
deaf nonstimulated cats were similar to those obtained
from normal animals, spatial tuning curves obtained from
chronically stimulated animals were significantly broader,
indicating that the volume of CNIC stimulated by activa-
tion of an electrode pair appears to be significantly
expanded, or less finely tuned. As discussed earlier, Sanes
and Constantine-Paton126,127 also demonstrated broader
CNIC tuning curves in click-reared mice.
Snyder and colleagues226 also reported on temporal
Figure 36-9. Pooled data for eight neonatally deafened cats that were
implanted and chronically stimulated at 2 dB above threshold for periods of properties of neurons in the IC of deafened nonstimulated,
about 3 months. For each cochlear sector the mean spiral ganglion cell deafened stimulated, and normal cats. Chronic stimulation
density and standard errors are shown for the stimulated and control was found to increase the response threshold back toward
specimens. The mean ganglion cell density averaged over all segments was normal (compared with deaf nonstimulated animals);
significantly higher in the stimulated cochleas than in the control specimens.
(From Leake PA, Snyder RL, Hradek FT, Rebscher SJ: Chronic intracochlear
decrease the average response latency of neurons in the
electrical stimulation in neonatally deafened cats: Effects of intensity and IC; and substantially increase the frequency of occurrence,
stimulating electrode location. Hear Res 64:99–117, p 107.) amplitude, and latency of long latency responses. The
578 PEDIATRIC NEUROTOLOGY

finding, similar to that reported by Horner and Bock201 of Although CNS abnormalities and mental retardation
lower response thresholds in deaf nonstimulated animals is have been reported for a few syndromes associated with
paradoxical, as it occurs coincident with a decrease in the early-onset deafness, including Cockayne’s syndrome
SGC population. One possible explanation is that the (retinitis pigmentosa, dwarfism, microcephaly, premature
disappearance of myelinated fibers from the habenula and senility, photosensitive dermatitis), Sylvester’s disease (optic
bony spiral lamina provides a preferential path for excita- atrophy, ataxia), and Norrie’s disease (oculoacousticocere-
tion of remaining neural elements, allowing stimulation of bral degeneration), evidence of auditory pathway degener-
SGCs at lower current levels. Secondly, lower thresholds ative changes has been demonstrated only for Cockayne’s
may be secondary to denervation supersensitivity to audi- syndrome.229 Studies have documented loss of peripheral
tory nerve excitation. Interestingly, thresholds increase sensory cells, loss of over half of the spiral ganglion cell
toward normal following chronic electrical stimulation. population, and degenerative changes in auditory nuclei,
Based on these findings, the authors suggest that low presumed secondary to transneuronal degeneration.235,236
thresholds to electrical stimulation may not accurately Auditory dysfunction has been well documented for
predict numbers of surviving neural elements in cochlear patients with Friedrich’s ataxia, a disorder of spinocerebellar
implant patients.226 degeneration. Abnormalities have been noted in the VCN,
In summary, although steady progress is observed in medullary striae, and superior olive.237–239 Van Bogaert and
patients following cochlear implantation, particularly when Martin238 provide a comprehensive summary of previously
performed early after the onset of deafness, investigators published literature on auditory system involvement in
have not been able to document irrefutably that the rein- this disorder. Reports of CAS pathology are difficult to
troduction of chronic electrical activity substantially alters interpret because of the paucity of data on the integrity of
central auditory pathways in deaf animals. It is likely that a the peripheral auditory system. Spoendlin240 reported that,
multitude of factors must be accounted for to document in two patients with Friedrich’s ataxia, the organ of Corti
alterations in CAS anatomy. Changes in the pattern, type, was essentially intact, but severe degenerative changes
level, duration, and intracochlear location of stimulation were noted in more central structures. Satya-Murti and
are likely to be important, as is the method of data analysis. colleagues241 performed audiometric tests and brainstem
auditory evoked potentials on four patients with
Friedrich’s ataxia who had no subjective hearing impair-
PATHOLOGY OF THE CENTRAL ment. Behavioral audiometry revealed a mild to severe
AUDITORY SYSTEM bilateral SNHL in all subjects, with no consistent config-
uration. Three of the four patients demonstrated “roll-
Pathologic conditions associated with CAS abnormalities over,” or a decrease in speech recognition scores with
during the developmental period include the following: increasing word intensity. ABRs for all four subjects were
chromosomal aberrations, skeletal CNS deformities, cer- markedly abnormal, with no identifiable waveforms. The
tain forms of hereditary deafness, congenital and neonatal authors argue based on their findings that the primary
infections, metabolic disorders, and storage diseases such lesion producing auditory dysfunction in these patients is
as leukodystrophies.227–229 In many cases, central findings spiral ganglion cell degeneration.
are incompletely documented, and their significance often Intrauterine and early-onset infections are rarely associ-
disputed. Primary CAS pathology is most clearly docu- ated with CAS abnormalities. Congenital deafness result-
mented for two metabolic disorders: anoxia and hyper- ing from maternal rubella results primarily from cochlear
bilirubinemia. destruction. However, Rorke and Spiro242 documented
Morphologic studies of the CNS have documented cerebral lesions in these patients, although not specifically
structural abnormalities in patients with Down syndrome in CAS pathways. Extensive degenerative changes were
(trisomy 21), Edwards’ syndrome (trisomy 18), and Patau’s noted in association with vascular lesions, confined
syndrome (trisomy 13). Gandolfi and coworkers230 primarily to the deep white matter and nuclei. Ames and
reported several abnormalities in the VCN in Down syn- coworkers243 identified central auditory processing deficits
drome, including reduced cell number, cell density, and in children demonstrated to have congenital rubella. In a
nuclear volume. Abnormalities of the VCN were also sample of 118 affected children, 50% were found to have
noted in Edwards’ syndrome, and abnormalities of audi- central auditory impairment. Of these, none were diagnosed
tory cortical neurons noted in Edwards’ and Patau’s syn- as mentally retarded, and 30 patients had no concomitant
dromes. In all cases, overall brain development is peripheral auditory system abnormalities.
retarded.229 Skeletal and structural abnormalities associ- Cytomegalovirus infections cause CNS abnormalities
ated with Arnold-Chiari malformation and Klippel-Feil in approximately half of affected cases. Abnormalities
syndrome can result in compression and kinking of the include microcephaly, seizures, mental retardation, and
eighth cranial nerve. In Arnold-Chiari malformation the deafness.143,244 Again, inner ear involvement and CNS
CN can be compressed,227 and compression of blood ves- degenerative changes have been documented, but abnor-
sels can lead to brainstem ischemic changes.231 Hearing malities of CAS pathways have not been investigated.229
loss is reported in patients with this disorder, in percent- Several postnatal infections have been documented to
ages ranging from 12% to 44%.232 Rydell and Pulec232 have CAS involvement.228 Bacterial meningitis usually
report that 20% of 29 patients studied had both vestibular produces hearing impairment by labyrinthine destruction.245
and auditory symptoms. The hearing loss can be asym- However, the infection may spread to involve the eighth
metrical and progressive,233 and surgical decompression nerve and spiral ganglion cells. Cerebral arteritis may
has been reported to halt the progression of hearing loss.234 produce focal brain lesions, particularly in the infant.245
 Central Auditory System Development and Disorders 579

Meningoencephalitis due to Listeria monocytogenes or recorded ABRs in nine full-term infants before and after
tuberculosis may involve the CAS,229 although this pathol- exchange transfusion for hyperbilirubinemia (mean
ogy has not been demonstrated in children. Syphilis concentration 22.3 mg/dL), and noted significant improve-
involves both the peripheral and central auditory system. ment in waveform morphology, latency, and amplitudes
Severe demyelination and degeneration of the CN following transfusion.
may occur.228 The homozygote jaundiced ( jj) Gunn rat, which lacks
Hearing impairment has been demonstrated in patients the hepatic enzyme glucuronyl transferase necessary to
with storage diseases, particularly those that involve white conjugate bilirubin, has been used as a model for human
matter degeneration, or leukodystrophies.229 Ochs and col- bilirubin encephalopathy. Shapiro and colleagues250,262–265
leagues246 identified abnormalities in the ABRs of 10 patients have documented abnormalities of ABR waveforms and
with various leukodystrophies, including poor waveform auditory brainstem morphology in this species. In order to
morphology and increased interwave latencies. Abnormal- accentuate neuropathologic abnormalities, brain bilirubin
ities were presumed to be secondary to the severe demyeli- concentration was artificially raised in heterozygotic (Nj)
nation associated with these diseases. The ABR was also and homozygotic Gunn rats by the administration of
studied in an infant with Gaucher’s disease. Progressive sulfadimethoxine, an albumin-binding drug that increases
deterioration of waveforms was noted. Postmortem patho- free bilirubin levels. Increased latencies were demon-
logy revealed no abnormalities of the central auditory strated for waves II and III of the ABR, as well as the I–II
pathways, however.247 and I–III interwave latencies, following administration of
Anoxic encephalopathy is one of the major causes of sulfadimethoxine to jj rats only.262 As with transfusion-
hearing loss of central origin; this insult is typically associ- treated neonates,260 abnormalities were reversed after
ated with a bilateral high-frequency sensorineural deficit.248 treatment, which in this case consisted of administration of
Although the inner ear and spiral ganglion cells are albumin (to bind bilirubin). ABR abnormalities were found
relatively immune to the effects of anoxia, the CAS, partic- to correlate in severity with degenerative changes in the
ularly the CN, is severely affected.228 Hall249 studied CN.264 Anatomic analysis of brainstems of sulfa-treated jj
brain and temporal bone specimens from 39 patients with rats revealed a significant decrease in CN volume, AVCN
neonatal anoxia. Although temporal bone specimens were spherical cell area, and area of principal cells in the nucleus
essentially normal, severe degenerative changes were noted of the trapezoid body, as compared with treated heterozy-
in the CN complex. Cell loss ranged from 20% to 45% in gotes. The authors suggest that these two cell groups are
the VCN, and up to 66% in the DCN. Less marked changes uniquely targeted in bilirubin toxicity, possibly through a
were observed in the IC. Degree of cell loss appeared to neurotoxic mechanism related to presumed glutaminergic
correlate with length of the hypoxic period. The vulnerabil- inputs.250
ity of the CN to anoxic-related injury is attributed to the Auditory neuropathy, a disorder first described by Starr
relatively high metabolic rate of this region. and colleagues,266,267 is characterized by hearing loss for
Some investigators have attributed the CAS injury pure tones, impaired word discrimination out of proportion
produced by hyperbilirubinemia to the effects of hypoxia, to pure tone hearing loss, absent or abnormal ABRs, and
produced by hemolysis and intracapillary sludging of normal outer hair cell function as measured by otoacoustic
erythrocytes.228 It is likely, however, that several factors emissions and cochlear microphonic.268 Causes of this
influence the development of bilirubin encephalopathy. condition have not been determined; some patients have
For example, anoxia during the perinatal period may result an apparently isolated auditory abnormality, and others
in acidosis, which may increase cellular uptake of bilirubin are diagnosed with a variety of disease processes, includ-
(discussed by Conlee and Shapiro250). Ahdab-Barmada and ing Charcot-Marie-Tooth disease, hyperbilirubinemia,
Moossy251 described different patterns of CNS abnormal- Friedreich’s ataxia, multiple sclerosis,268,269 and severe
ities observed with kernicterus and anoxic/hypoxic injury. neonatal illness.270 Sites of involvement may include the
Evidence presented by MacDonald and coworkers252,253 cochlea (central to the outer hair cells), the auditory nerve,
suggests that bilirubin neurotoxicity may act through and the auditory pathways of the brainstem, or all of these
glutaminergic excitotoxicity in the hippocampus, and Conlee structures. In cases of delayed auditory maturation function
and Shapiro250 argue that a similar mechanism may con- may improve over time; however, if the auditory neuropa-
tribute to CAS toxicity, particularly in AVCN and MNTB. thy is a manifestation of a generalized neurologic condi-
Crabtree and Gerrard254 presented the first evidence of tion, function may deteriorate.269,271
an association between kernicterus and SNHL. A typically
high-frequency loss was identified in 80% of 20 cases
tested. Early audiometric studies reported results consis-
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in the premature neonate: Diagnostic problems. J Neuropath Exp Electroencephalogr Clin Neurophysiol 104(1):17–22, 1997.
Neurol 43:45–56, 1984. 271. Stein LK, Tremblay K, Pasternak J, et al: Auditory brainstem
252. McDonald JW, Shapiro SM, Silverstein FS, Johnston MV: neuropathy and elevated bilirubin levels. Semin Hear 17:197–213,
Excitatory amino acid neurotransmitter systems contribute to the 1996.
 Chapter
Cochlear Hearing Loss

Outline 37
Cochlear Physiology and Adult-Onset Acquired Syphilis John S. Oghalai, MD
Sensorineural Hearing Loss Human Immunodeficiency
Noise-Induced Hearing Loss Virus
Presbycusis Sequelae of Acute and Chronic
Ototoxicity Otitis Media
Aminoglycosides Poststapedectomy
Cisplatin and Carboplatin Sensorineural Hearing Loss
Loop Diuretics Congenital Hearing Loss
Salicylate and Quinine Congenital Anomalies of the
Topical Otic Preparations Inner Ear
Chemical Teratogens Membranous Labyrinth
Monitoring during Ototoxic Malformations with a
Drug Administration Normal Otic Capsule
Idiopathic Sudden Membranous Labyrinth
Sensorineural Hearing Loss Malformations with Otic
Temporal Bone Trauma Capsule Malformations
Temporal Bone Fracture Genetic
Perilymphatic Fistula Metabolic Cochlear
Diving Barotrauma Hearing Loss
Infectious Causes of Otic Capsule Bony Diseases
Cochlear Hearing Loss Autoimmune Hearing Loss
Meningitis
Congenital Infections

COCHLEAR PHYSIOLOGY AND Active filtering properties are found only in the mam-
SENSORINEURAL HEARING LOSS malian cochlea. A positive feedback loop locally amplifies
sound vibrations at each characteristic frequency along the
Hearing allows us to be conscious of what is going on basilar membrane. This cochlear amplifier dramatically
around us. It is always working to warn us of danger. Most increases cochlear sensitivity (the ability to hear quiet
important, hearing permits communication. Hearing loss sounds) and improves frequency selectivity (the ability to
affects 28 million Americans (1 out of every 10 people). distinguish between adjacent frequencies). Outer hair cell
The isolation from society that occurs with hearing loss electromotility (discussed below) is the source of the active
can lead people to depression and behavioral problems. filtering of the mammalian cochlea.
Understanding the pathophysiology of hearing loss neces- The organ of Corti is a highly organized structure
sitates an understanding of the mechanism of sound trans- (Fig. 37-1). There are a single row of inner hair cells and
duction in the cochlea. The cochlea acts as both a passive three rows of outer hair cells. These cells run the length of
filter and an active filter. The passive filtering properties cre- the cochlea and are positioned on top of the basilar mem-
ate a tonotopic distribution of the frequency spectrum along brane by supporting cells. There are tight junctions between
the length of the cochlea, based on the inverse relationship the apex of the hair cells and the surrounding supporting
between the mass and the stiffness of the basilar membrane. cells, which form the barrier between the endolymph and
The basilar membrane is narrow and stiff at the base of the the perilymph (the reticular lamina). Movement of the
cochlea, which corresponds to high-frequency tuning. At the stapes footplate at a certain frequency produces a traveling
apex of the cochlea, the basilar membrane is wider and wave that maximally vibrates the section of the organ of
less stiff, which corresponds to low-frequency tuning. Thus, Corti tuned to that frequency. This leads to sharing forces
each point along the basilar membrane has a characteristic between the hair cells and the tectorial membrane, which
frequency to which it is tuned. deflects stereocilia and depolarizes hair cells.
589
592 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Additionally, inner hair cell and supporting cell damage lost hearing at an average rate of 3 dB per decade, and
begins.10 When hair cells die, a permanent hearing loss patients 55 years and older lost hearing at a rate of 9 dB
results because mammalian cochlear hair cells do not per decade. Thus, hearing declines gradually in the
regenerate. With extremely loud noise trauma, such as majority of the population and the rate of decline accelerates
from a blast injury, there is widespread fracture of the tight over time.
junctions between cells in the organ of Corti, as well as The pathophysiology of presbycusis appears to be
damage to Reissner’s membrane, the basilar membrane, predominantly a peripheral phenomenon (i.e., cochlear
and the pillar cells. This can lead to mixing of endolymph and spiral ganglion degeneration). Although there is
and perilymph, resulting in a severe sensorineural hearing clearly a generalized degeneration of the central nervous
loss. Other evidence of cochlear trauma secondary to noise system during aging, there is significant evidence against a
exposure is changes in the terminals of cranial nerve VIII. central lesion being the main contributor to presbycusis.
There can be swelling of dendritic terminals at the inner Although few, some elderly people have normal pure tone
hair cell junction, as well as high densities of synaptic vesi- average and word recognition scores, which suggests that
cles in efferent nerve terminals on the outer hair cells. CNS atrophy does not cause hearing loss.17 Physiologic
Following a noise exposure that leads to loss of outer and studies concur in that otoacoustic emissions diminish with
inner hair cells, there is retrograde degeneration of VIIIth age, lending evidence toward the hypothesis of presbycusis
nerve fibers. being associated with peripheral degeneration.18 The best
The interaction between ototoxic drugs and noise is designed studies have been performed by Schuknecht.19–21
important. Administration of a low dose of cisplatin to By correlating pure tone audiometry and temporal bone
laboratory animals may cause no hearing loss and only histologic findings in patients with presbycusis, four types
minimal hair cell damage. When the same dose of drug of presbycusis can be defined: sensory (hair cell loss), neural
is delivered in concert with a mild noise exposure, (spiral ganglion cell loss), metabolic or strial (loss of the stria
however, the animal may show dramatic hair cell loss and vascularis), and mechanical (change in the mechanical stiff-
hearing threshold shifts.11 The pathophysiology of this ness of the cochlear duct with aging). Sensory presbycusis
potentiation is unclear. In contrast, loop diuretics, which has histologic findings of lipofuscin deposition in hair cells
cause reversible threshold shifts due to loss of the and loss of hair cell stereocilia. Neural presbycusis has a
endolymphatic potential, and salicylate, which inhibits reduction in the number of spiral ganglion neurons. About
outer hair cell electromotility, do not potentiate noise- 2100 out of 35,000 spiral ganglion neurons are lost every
induced hearing loss.12 decade.20,21 Clinically significant sensorineural hearing loss
An interesting conundrum in the investigation of patients develops only after about 50% of the neurons are lost.20,21
with acoustic trauma is a large intersubject variability to Metabolic presbycusis has histologic findings that demon-
noise-induced hearing loss. Patients can be characterized as strate a thinning of the stria vascularis.19–21 This presumably
having “tough” ears or “tender” ears based on their suscep- diminishes the endolymphatic potential. Mechanical pres-
tibility.13 Although one protective mechanism against noise bycusis (cochlear conductive) is thought to be due to a
damage is the middle-ear muscular reflex, efferent olivo- change in the mass and stiffness of the cochlear duct and
cochlear projections from the brainstem to the outer hair basilar membrane. However, no clear histologic abnormality
cells also may affect a person’s susceptibility to noise- has been identified.
induced hearing loss. Animal studies have demonstrated Animal models for presbycusis have been developed by
that cutting the efferent fibers to the ear reduces the inter- maintaining animals in quiet environments as they age.
subject variability to noise trauma.14 Efferent fibers Serial histologic and electrophysiologic studies can then be
probably work to reduce cochlear trauma during noise performed on the cohort. Studies in the chinchilla demon-
exposure by becoming activated in the presence of loud strate that inner hair cells degenerate at a rate of about
noise. In this way, loud noise acts to hyperpolarize the outer 0.29% per year and outer hair cells degenerate at a rate of
hair cells, reduce their electromotile response, and turn 1% per year.22 There is also mild strial and spiral ganglion
down the gain of the cochlear amplifier. atrophy. Studies involving the Mongolian gerbil have been
mixed. Some investigators have found that a majority of
age-related changes occur at the hair cell level, with the
PRESBYCUSIS stria vascularis and spiral ganglion being spared.23 Others
have found the opposite.24,25 Laboratory data about the
Presbycusis is defined as progressive sensorineural hearing interaction of noise and age are sparse. Because of the large
loss associated with aging. Several major studies have variability in age-related hearing loss, it is often difficult to
shown the epidemiology of presbycusis. The U.K. distinguish the influences of noise and age. However, aged
National Study of Hearing Disorders in 1995 involved animals and young animals appear to be equally susceptible
more than 48,000 patients.15 Twenty percent of patients to noise.24
had hearing impairments greater than 25 dB, 75% of these The etiology of presbycusis is unclear. Studies with the
being older than 60 years. This large cross-sectional study Framingham cohort show no association between hyper-
demonstrates that the majority of sensorineural hearing tension or cardiovascular disease and presbycusis.26,27
loss occurs in the elderly. Longitudinal studies of hearing Additionally, atherosclerosis, hypercholesterolemia, and
loss accounting for age, sex, and noise exposure history hyperlipidemia do not appear to be associated with pres-
demonstrate that 97% of subjects experienced a decrease bycusis.18 Another potential etiology of presbycusis is
in hearing over time.16 Patients younger than 55 years related to repeated exposure to low-intensity noise, not
 Cochlear Hearing Loss 593

loud enough to produce temporary threshold shifts. (A155G and D961Cn) account for roughly 17% to 33% of
Constant sound exposure causes an increase in calcium familial aminoglycoside ototoxicity.34 Further mutations
in the hair cells and spiral ganglion cells. A high rate of have yet to be identified.
calcium influx could lead to cell toxicity and possibly cell According to one major study,35 predictors of the devel-
death. The association of noise and presbycusis has been opment of aminoglycoside ototoxicity include the type of
carefully studied by comparing cross-sectional studies of aminoglycoside used, duration of therapy, presence of bac-
noise-exposed and nonnoise-exposed populations. Non- teremia, presence of fever, liver dysfunction, and the serum
noise-exposed populations include the Mabaan tribe from urea nitrogen/creatinine ratio. Factors that do not predict
the Sudan, the Todas tribe in South India, and islanders in the development of ototoxicity include the plasma drug
North Scotland. The nonnoise-exposed populations had level, aminoglycoside type, use of furosemide, diabetes,
significantly greater preservation of hearing into old age age, renal function, initial hearing acuity, hematocrit value,
than did subjects from noisy industrial centers.28–30 and the presence of shock. It should be noted that not all
Finally, a genetic explanation for presbycusis has been studies agree with all of these findings. Neonates appear to
sought. Although multiple genes have been identified with have an increased risk of aminoglycoside ototoxicity.36
congenital hearing loss, no specific genes have been Additionally, some data suggest that noise exposure can
associated with human presbycusis. It is possible that mito- potentiate aminoglycoside ototoxicity.37
chondrial gene mutations that result in progressively lower The monitoring of aminoglycoside plasma concentra-
production of adenosine triphosphate (ATP) lead to tion is an important part of most therapeutic uses of this
hearing loss. Spiral ganglion, stria vascularis, and hair cells agent. Aminoglycosides have a low therapeutic index and
have large energy requirements and may be most affected their bactericidal efficacy is related directly to their peak
by this type of mutation. In summary, although an exact concentration level (concentration-dependent killing). In
etiology for presbycusis has not been identified, many contrast, aminoglycoside toxicity is related to the total
possibilities exist. In all likelihood, a combination of these amount of drug given.38 The pharmacokinetics f aminogly-
factors render people susceptible to progressive cochlear cosides are relatively simple. These drugs are hydrophilic,
degeneration and sensorineural hearing loss associated have low-protein binding, and are excreted renally. Their
with aging. Certainly, the genetics and history of noise volume of distribution in the body is roughly that of the
exposure for any individual play a large role. extracellular fluid and the clearance is that of the glomeru-
lar filtration rate. The half-life of this drug in people with
normal renal function is roughly 2.5 hours. However, sys-
OTOTOXICITY temic infections are associated with variable levels of hydra-
tion and increased permeability of normal biologic barriers.
Therefore, the extracellular fluid volume and the clearance
Aminoglycosides rate may change during therapy.39
It is estimated that 6% to 16% of patients who receive Aminoglycoside nephrotoxicity is usually reversible, but
aminoglycosides suffer sensorineural hearing loss and an ototoxicity is usually irreversible. Although the best dosing
equal percentage suffer some form of vestibular dysfunc- regimen for most antibiotics would be to have the
tion. Aminoglycosides have varying degrees of vestibular concentration of the drug at a constant level above the
and cochlear toxicity. The more vestibulotoxic aminoglyco- minimum inhibitor concentration of the bacteria that it is
sides are streptomycin, tobramycin, and gentamycin, killing, the desired concentration versus time profile
whereas the more cochleotoxic aminoglycosides are for aminoglycosides is that of a high-peak concentration
kanamycin, neomycin, and amikacin. A multistep hypothe- (for increased efficacy) followed by low trough concentra-
sis of aminoglycoside ototoxicity has been proposed.31 The tion (to prevent accumulation and toxicity). Therefore, a
first step is an electrostatic attraction of the positively large dose is used. However, the dosing interval is sub-
charged aminoglycoside molecule to the negatively charged stantially longer than the drug’s half-life. During tradi-
hair cell plasma membrane.32 The aminoglycoside is then tional aminoglycoside therapy (multiple daily doses), it is
transported into the cell and binds to phosphatidyl-inositol routine to monitor both a peak and a trough concentra-
biphosphate. Toxicity is thought to occur through free rad- tion, with the peak concentration reaching roughly 6 to
ical formation. In the vestibular system, type I hair cells are 10 milligrams per liter, and the trough concentration
more prone to aminoglycoside toxicity than type II hair being less than 2 milligrams per liter. Recently, there has
cells.33 In the cochlea, outer hair cells are much more sensi- been a change to once daily dosing of aminoglycosides
tive to aminoglycosides than inner hair cells. Outer hair cell with the same total daily dose. Measuring the peak plasma
damage first occurs at the base of the cochlea, leading to concentration with this regimen can help to identify the
high-frequency hearing loss. With continued intake of actual level of drug being delivered. However, a trough
aminoglycosides, the damage progresses down the length of level is not needed in patients with normal renal function
the cochlea, causing low-frequency hearing losses as well.33 because all of the drug should have been excreted after
Genetic mutations can predispose certain individuals to 24 hours. Currently there are no clearly established thera-
aminoglycoside ototoxicity. Deafness has even been peutic ranges for once-daily dosing39; however, the risk
reported after a single dose. There is a maternal form of of ototoxicity or vestibular toxicity with this regimen is no
inheritance for this susceptibility and genetic mutations in higher than that with conventional dosing protocols.40,41
the 12S ribosomal RNA gene in the mitochondrial RNA Providing a correct dose of drug to patients with renal
have been identified. Currently, the two known mutations impairment and to elderly patients with impaired
594 PERIPHERAL AUDIOVESTIBULAR DISORDERS

glomerular filtration is crucial because there can be buildup hearing loss of roughly 40 dB to 50 dB. The dose of aspirin
of drug over time. needed to produce a measurable hearing loss is on the
Aminoglycoside ototoxicity is different from aminogly- order of 10 to 12 325 mg tablets per day.57 The exact
coside nephrotoxicity in that ototoxicity is not associated mechanism of quinine ototoxicity is unclear, but is thought
with high plasma concentration of drug.42 This may to pertain to the disruption of normal outer hair cell func-
be because the penetration of aminoglycoside into and tioning. Its effects are also reversible.
elimination from the labyrinth is much slower than its
corresponding plasma or cerebrospinal fluid concentra- Topical Otic Preparations
tions.43,44 However, one similarity between ototoxicity and
nephrotoxicity is that similar therapies may protect both Common topical otic preparations include ototoxic agents
the cochlea and the kidney from aminoglycoside toxicity.45 such as aminoglycosides, antifungals, and antiseptics
Coadministration of iron chelators and free radical scav- (including ethanol and povidone-iodine). Although topical
engers with aminoglycosides has been shown to reduce ototoxicity has been demonstrated in abundant experi-
hearing loss and nephrotoxicity in animals.46,47 To date, mental studies with animals, information regarding human
there is no firm evidence to suggest that free radical scav- topical ototoxicity is minimal.58 It appears that ototoxicity
engers reduce aminoglycoside ototoxicity in humans. occurs during absorption of the drug through the round
window membrane, through fissures around the oval win-
dow, or through vascular channels. The round window
Cisplatin and Carboplatin membrane in humans is much thicker than that in the
Cisplatin and carboplatin are antineoplastic agents that chinchillas and guinea pigs, common animals in studies
have permanent high-frequency hearing loss as a frequent (40 to 70 microns compared to 10 to 14 microns).59
side effect. Cisplatin is similar to aminoglycosides in that it Additionally, in humans the round window niche is deep
is both nephrotoxic and ototoxic, presumably because of and there are often mucosal folds partially covering it,
the formation of iron-induced free radicals48 and apopto- whereas this is not the case in the chinchilla and guinea
sis.49 Histologically, cisplatin causes outer hair cell degen- pig. Finally, humans who are receiving topical otic drops
eration.50,51 The damage starts in the basal turn of the most commonly have chronic otitis media with inflamed
cochlea, producing a high-frequency hearing loss. As the middle-ear mucosa, which is thought to have a higher
duration of treatment and total dose increase, further absorbability than uninflamed mucosa and likely reduces
hearing loss develops as outer hair cells in the lower- the quantity of drug reaching the inner ear. Interestingly,
frequency region of the cochlea become involved.52 a survey of 2235 otolaryngologists found that 3.4% admit-
Interestingly, carboplatin has similar effects in most mam- ted to having witnessed irreversible cochlear damage as a
mals; however, in the chinchilla, it appears to cause only result of ototoxic antibiotic drops.60 However, there is no
extensive inner hair cell damage and little, if any, outer hair demonstrated proof of ototoxicity in human subjects with
cell damage.51 The reason for this is unknown. Younger topical otic preparations used to treat chronic otitis media.
children seem to be more affected than older patients.53,54 Of course, intratympanic gentamicin certainly can cause
The ototoxicity is enhanced with the concomitant hearing loss when used to treat vertigo, so clearly the
administration of loop diuretics.36 potential for ototoxicity exists. The use of topical fluoro-
quinolones does not demonstrate any ototoxic effect in
laboratory animals61 and is rapidly becoming the drug of
Loop Diuretics first choice for the treatment of chronic otitis media in
The loop diuretics, including furosemide and ethacrynic patients with a perforated tympanic membrane.
acid, are direct inhibitors of the Na+-Cl−-K+ cotransport
proteins found in both the tubular cells in the loop of Chemical Teratogens
Henle and in the cells of the stria vascularis.55 Because the
stria vascularis is responsible for maintaining the endolym- Although never available in the United States, even a
phatic potential as well as the high potassium level in the single dose of thalidomide taken by the mother during
endolymph, loss of ionic transport causes reversible a susceptible period of fetal development can produce
hearing loss. With higher and higher doses of loop diuret- dramatic fetal defects. Defects in the temporal bone
ics, eventual permanent damage can occur; however, this is include atresia of the ear canal, sensorineural hearing loss,
uncommon. The exact mechanism of the permanent and paralysis of the facial nerve.62 Findings can include
ototoxicity associated with loop diuretics is unclear. malformation of the cochlea and absent acoustic and
vestibular nerves.
Ethanol is a highly abused drug throughout the world.
Salicylate and Quinine Sensorineural hearing loss is associated with fetal alcohol
Salicylate and quinine cause reversible sensorineural hear- syndrome. Most studies suggest that more than two alco-
ing loss. This is best characterized with salicylate holic drinks per day by the mother is the threshold for
(a metabolite of aspirin, which is acetylsalicylic acid). teratogenicity.62 Fetal alcohol syndrome is characterized
Salicylate is known to reversibly block outer hair cell elec- by a series of neurologic and behavioral aberrations, in addi-
tromotility56 and disrupt membranous structures in tion to craniofacial dysmorphic features. These children
the outer hair cell. These effects inhibit the active process have a high incidence of external- and middle-ear abnor-
in the cochlea responsible for the “cochlear amplifier.” malities and a 29% incidence of bilateral sensorineural
Clinically, this is seen as a reversible moderate sensorineural hearing loss.63
 Cochlear Hearing Loss 595

Isotretinoin is a retinoid used for the treatment of patients with idiopathic sudden sensorineural hearing
refractory and cystic acne. Taken by pregnant mothers, it loss.70 The second theory of idiopathic sudden sen-
can cause severe fetal deformities. These include shorten- sorineural hearing loss is viral inflammation of the cochlea
ing of the cochlea, a nearly total absence of spiral ganglion and/or auditory nerve. Many patients report having had an
cells, and enlargement of the sacculus and utricle.64 upper respiratory syndrome 1 to 2 weeks before onset of
their hearing loss. Some patients have seroconverted to a
Monitoring during Ototoxic variety of viruses, including influenza B, mumps, measles,
rubella, cytomegalovirus, and varicella-zoster. All of these
Drug Administration viruses can cause a viral cochleitis.71 Histologic study of
There are no universally recognized protocols to monitor temporal bones with idiopathic sudden sensorineural hear-
patients for early evidence of ototoxicity. Many experts ing loss demonstrates features consistent with viral infec-
recommend weekly audiograms during the administration tion, including hair cell loss, ganglion cell loss, strial
of ototoxic medications; however, the major morbidity is atrophy, and inflammatory cochleitis.72
actually not hearing loss, but vestibular toxicity. Therefore, The prognosis of idiopathic sudden sensorineural hear-
even though conventional audiometry is the simplest mon- ing loss is highly variable. Overall, untreated patients have
itoring technique, it has the disadvantage of not being very a spontaneous recovery rate of about 65% to “functional
sensitive.65 Because most ototoxic agents cause a predomi- hearing.”73,74 Recovery, however, appears to depend on the
nantly high-frequency hearing loss, a more sensitive test severity and the pattern of the hearing loss. Patients with a
might be high-frequency audiometry (above 8 kHz). predominantly low-frequency loss have the best prognosis
Additionally, otoacoustic emissions could be measured, but for recovery, while those with a high-frequency hearing loss
detailed studies as to the sensitivity of otoacoustic emis- have a worse prognosis. Patients with a flat profound hear-
sions when used to screen for ototoxicity have not been ing loss across all frequencies have the worst prognosis.73
performed. Monitoring for vestibular toxicity is limited to Although the spontaneous recovery rate is high, the likeli-
serial electronystagmography and rotary chair testing. hood of recovery declines with time. If a patient is to
These tests are almost never performed during the admin- recover from an idiopathic sudden sensorineural hearing
istration of ototoxic medications because of their variabil- loss, it usually occurs within the first few weeks, and typi-
ity and low sensitivity. In addition, it is very difficult to cally no improvement is noted after 1 to 2 months. Luckily,
perform these tests in debilitated patients. long-term follow-up studies have shown that if improve-
Overall, drug-induced ototoxicity can best be prevented ment does occur, the risk of further hearing loss is low.75
by using strategies similar to those used to prevent The treatment of sudden sensorineural hearing loss
nephrotoxicity. This involves keeping the patient well remains confusing and controversial. Countless studies
hydrated and monitoring the patient’s renal function. If have been performed purporting to have identified the
the plasma drug concentration reaches toxic levels, it is ideal treatment regimen for this disease, only to have a
important to consider using hemodialysis or peritoneal later study report the opposite. The difficulties in analyz-
dialysis to remove the drug rapidly in order to limit toxic- ing this disease include its rarity, highly variable prognosis,
ity. Although a decrease in creatinine clearance definitely variable time of presentation, and variable severity of hear-
increases the risk of ototoxicity, the literature is unclear as ing loss. Additionally, the spontaneous recovery rate is
to the importance of avoiding loop diuretics and loud quite high. Because of this confusion, many physicians
noise exposure during ototoxic medication therapy. manage this disease with many simultaneous treatments,
hoping one will work—in other words, a “shotgun”
approach. As we move toward evidence-based medicine, it
IDIOPATHIC SUDDEN SENSORINEURAL is important to study and characterize this disease further
HEARING LOSS with rigid statistical criteria rather than base our current
treatment protocols on anecdotal evidence and hypotheses.
Sudden sensorineural hearing loss is defined as a threshold The following summaries describe many of the current
increase of more than 20 dB over at least three contiguous treatments for idiopathic sudden sensorineural hearing. It
audiometric frequencies occurring within 3 or fewer days. is important to note that although statistically significant
Idiopathic sudden sensorineural hearing loss is a diagnosis differences between treated and untreated groups may
of exclusion; other causes of sudden hearing loss must be have been reported, further studies have not backed this up
ruled out. These include cerebellopontine angle tumors,66 in the majority of cases.
autoimmune disease, multiple sclerosis, infectious etiolo- Corticosteroid therapy is among the few therapies to
gies,67 intralabyrinthine hemorrhage, and perilymph treat patients with idiopathic sudden sensorineural hearing
fistula. Additionally, ototoxicity and noise-induced hearing loss to have demonstrated effectiveness by randomized,
loss must be considered in the differential diagnosis. prospective study.76–82 Not all studies agree with this
Two theories behind the etiology of idiopathic sudden conclusion, however.83,84 The specific action of steroids
sensorineural hearing loss exist.68 The first is vascular is based on its anti-inflammatory properties and there-
compromise to the inner ear through thrombosis, fore should be beneficial in infectious, inflammatory, and
hemorrhage, or vascular spasm. In support of this hypoth- immune-mediated conditions. A common therapeutic reg-
esis, the concentration of oxygen in the perilymph from imen is 80 mg of prednisone per day for 4 days, 60 mg per
patients with idiopathic sudden sensorineural hearing loss day for 4 days, 40 mg per day for 4 days, 20 mg per day for
is 30% lower than in controls.69 Also, disturbances in 4 days, and then discontinue the prednisone. Some authors
microcirculatory blood flow have been identified in have advocated transtympanic administration of the steroid
596 PERIPHERAL AUDIOVESTIBULAR DISORDERS

in patients who do not improve on oral steroids.85 Antiviral results in a transverse fracture of the temporal bone.
therapy has not been shown to be beneficial in the man- Transverse fractures course directly across the petrous pyra-
agement of idiopathic sudden sensorineural hearing loss. mid, fracturing the otic capsule, and then extend anteriorly
A recent randomized double-blinded, placebo-controlled, along the eustachian tube and geniculate ganglion as well.
prospective, multicenter clinical trial comparing patients Longitudinal temporal bone fractures represent 80% and
who received prednisone and a placebo to patients who transverse temporal bone fractures represent 20% of tem-
received prednisone with valcyclovir demonstrated that poral bone fractures.
the antiviral medication did not provide any more benefit Sensorineural hearing loss and vertigo are found in
than steroid therapy alone.86 patients who sustain a transverse temporal bone fracture
Treatments to optimize cochlear blood flow include with otic capsule involvement. Audiogram usually demon-
vasodilatory agents (histamine, papaverine, verapamil, etc.) strates a complete sensorineural hearing loss in that ear.
or drugs that decrease blood viscosity (dextran, pentoxi- Clinical examination also reveals the patient to have nys-
fylline, procaine, and heparin). None of these agents tagmus, consistent with a unilateral vestibular deficit.
appear to offer a significant improvement in hearing Interestingly, sensorineural hearing loss can be sustained
recovery over controls.68,87–91 The theory behind using without otic capsule fracture if a labyrinthine concussion
vasodilatory agents can be questioned because these drugs occurs. This is thought to involve shearing of the mem-
predominantly cause a peripheral vasodilation. Since cere- branes or hair cell stereocilia caused by the rapid acceleration
bral blood flow has strong autoregulatory mechanisms, and deceleration forces in the inner ear. Labyrinthine con-
vasodilators may cause a systemic hypotension and actually cussion typically manifests as a high-frequency hearing loss.
reduce blood flow from the inner ear. Carbogen inhalation
therapy (95% oxygen and 5% carbon dioxide) is one of the Perilymphatic Fistula
few vasodilators that override intracranial autoregulation.
Although some studies have demonstrated an Patients with perilymphatic fistula usually present with
improvement in the outcomes of patients with idiopathic disequilibrium and vertigo, although some also have
sudden sensorineural hearing loss with carbogen,69,92,93 hearing loss, tinnitus, headache, and aural fullness.
others have demonstrated no improvement.84,94 The effi- Patients may state that their symptoms are least intense in
cacy of carbogen remains controversial. A stellate ganglion the morning but that they worsen progressively during the
block is another therapy thought to elicit vasodilation day. Most important, symptoms become much worse with
within the inner ear since sympathetic fibers to the inner any type of coughing, sneezing, or straining. Occasionally,
ear vasculature originate from the stellate ganglion. No altitude change such as going up and down in an airplane
study convincingly demonstrates that a stellate ganglion or in an elevator can precipitate symptoms. Patients often
block improves recovery over the natural rate of sponta- complain of Tullio’s phenomenon, whereby loud noises
neous recovery.95,96 precipitate a vertiginous attack.
Other therapies, including hyperbaric oxygen (to increase Perilymphatic fistula is difficult to diagnose. The fistula
cochlear oxygen levels), vitamins (free radical scavengers), test can be performed by insufflating air into the external
gingko biloba, and magnesium have been studied. 97 None of auditory canal and observing the patient for evidence of
these therapies have shown significant efficacy in the man- nystagmus. This test is very insensitive, and is positive in
agement of idiopathic sudden sensorineural hearing loss.68 only about 50% of patients with a fistula. Additionally, it
is not specific because many patients without a fistula
experience dysequilibrium during the test. Serial audiom-
etry should demonstrate a fluctuating sensorineural hear-
TEMPORAL BONE TRAUMA ing loss. Vestibular testing may demonstrate a unilateral
deficit. Nystagmus brought on by straining can be docu-
Temporal Bone Fracture mented with electronystagmographic (ENG) monitoring
Temporal bone fractures represent roughly 20% of skull and evaluation. Computed tomography (CT) is not partic-
fractures. Risk factors include being male and younger ularly useful in the identification of a perilymphatic fistula.
than 21; more often than others, this population is Its sensitivity is estimated at 20%; however, if a fistula is
involved in risky activities that predispose them to blunt identified on CT scan, this is obviously highly specific.
head trauma. The most common causes are motor vehicle The only definitive way to make the diagnosis of peri-
accidents, falls, bicycle accidents, seizures, and aggravated lymphatic fistula is surgical exploration with visualization
assaults. Penetrating trauma, predominantly gunshot of the leak. Even this is not necessarily definitive because
wounds, are much more damaging to the temporal bone it is quite difficult to verify that small amounts of clear
than is blunt trauma. Labyrinthine fractures are common fluid in the middle-ear cavity represent a perilymphatic
after a gunshot wound to the temporal bone. leak and not serous transudate from the middle-ear mucosa.
Blunt trauma to the squamous portion of the temporal Fluid suspicious for perilymph can be sampled on a
bone often results in a longitudinal fracture. Longitudinal Gelfoam pledget and tested for β2-transferrin testing, a pro-
fractures follow along the axis of the external auditory canal tein found only in cerebrospinal fluid (CSF) and perilymph.
to the middle-ear space, and then the course anteriorly The most common etiology of perilymphatic fistula is
along the geniculate ganglion and eustachian tube, ending head trauma. This may be either following a temporal
near the foramen lacerum. The otic capsule is spared in a bone fracture involving the otic capsule or with stapes
longitudinal temporal bone fracture. In contrast, a blow to subluxation into the oval window. Barotrauma during
the occipital skull often goes through foramen magnum and scuba diving, a rapid descent in an airplane, an explosion,
 Cochlear Hearing Loss 597

or a difficult childbirth can also cause perilymphatic during ascent after a prolonged dive. Most divers breathe
fistula. Postsurgical perilymphatic fistula is also a well- compressed air, which includes both oxygen and nitrogen,
recognized entity. This can occur after stapedectomy if the and the partial pressure of these gases increases in the
oval window fails to seal appropriately. Poor surgical tissues as the dive deepens. Although the oxygen is
technique while performing a mastoidectomy can lead to metabolized during diving, the nitrogen is not and
iatrogentic lateral canal fistula. Additionally, an expanding becomes dissolved in the body’s tissues. During rapid
cholesteatoma can erode into the lateral semicircular canal ascent, the partial pressure of nitrogen decreases and the
or cochlea, causing a fistula. Finally, patients may present dissolved nitrogen is released as bubbles in the blood-
with congenital perilymphatic fistula. These patients typi- stream and other tissues.100 Decompression sickness is
cally have stapes footplate anomalies or other temporal classified into types 1 and 2. In type 1 decompression sick-
bone anomalies identified on CT scan. The superior semi- ness, symptoms are mild and include fatigue or pain in the
circular canal dehiscence syndrome, with a fistula from joints or muscles. Type 2 decompression sickness is more
the superior canal into the intracranial space, may be severe, with injury to the lungs, inner ear, and central
identified by CT scan. nervous system. Within the inner ear, nitrogen bubbles
Fluctuating, but progressive, sensorineural or mixed can injure the delicate structures either by mechanical dis-
hearing loss occurs in patients with a perilymph fistula. ruption of the membranes of the inner ear or through
Also, these patients have progressive dysequilibrium. Since labyrinthine artery occlusion.101 Studies in guinea pigs
there is a fistula from the middle-ear space to the inner ear, have shown that the primary damage during hyperbaric
an episode of acute otitis media is worrisome because bac- exposures includes inner-ear hemorrhage and damage to
teria in the middle ear can easily enter the inner ear and the cochlear hair cells.102
CSF. This can lead to permanent sensorineural hearing When a patient is suspected of having inner-ear decom-
loss or meningitis. pression sickness, the dive profile should be evaluated,
Treatment is based on conservative therapy. The patient including the depth of the dive, the time at the bottom,
should be on bedrest with the head elevated for 3 to 6 and the number of earlier dives. All patients with
weeks and take stool softeners, and serial audiograms cochleovestibular symptoms after diving should be consid-
should be obtained to follow up for evidence of disease ered to have type 2 decompression sickness and treated
progression. If symptoms persist or the sensorineural accordingly. This includes the use of 100% oxygen as
hearing loss worsens, surgical treatment is indicated. One immediate first aid during transport of the patient to a
option is to simply draw blood from the patient’s arm and recompression facility.99 If air transport is required, the
inject it through the eardrum into the middle-ear space. patient should be flown at an altitude lower than 1000 feet
This blood seal often allows a fistula to heal. Alternatively, to reduce symptom exacerbation. The recompression pro-
a middle-ear exploration can be performed. This is done tocol includes initial recompression to 60 feet of salt water
by a transcanal approach with elevation of the tympa- with 100% oxygen for 60 minutes, followed by decom-
nomeatal flap and careful examination of the oval and pression to 30 feet of salt water for two additional periods
round windows. If a defect is noted, a graft of fascia or while breathing a mixture of pure oxygen and air.100 This
muscle should be laid over the defect. Many surgeons recompression therapy reduces the size of the bubbles,
place fascia around both the oval window and the round allowing their resorption and dissipation. Other support-
window even if a fistula is not definitively seen because ive therapies reported to be useful in the treatment of
defects are quite difficult to detect. inner-ear decompression sickness include steroids, diuret-
ics, low-molecular-weight dextran, heparin, and diazepam.
Diving Barotrauma Long-term follow-up studies of scuba divers who
sustained inner-ear barotrauma and continue to dive
Barotrauma during diving most commonly affects the against medical advice suggest that no further deteriora-
middle ear. It can involve hemorrhage and rupture of the tion of cochleovestibular function occurs after these
tympanic membrane, along with ossicular chain disloca- patients were counseled as to how to equalize middle-ear
tion. It is associated with a conductive hearing loss and, in pressure.103
most cases, resolves spontaneously with minimal sequelae.
In contrast, inner-ear barotrauma can lead to permanent
sequelae. There are two types of inner-ear barotrauma: INFECTIOUS CAUSES OF COCHLEAR
(1) perilymphatic fistula and (2) inner-ear decompression HEARING LOSS
sickness.98,99 Perilymphatic fistula can occur through
either the round or oval window because of the pressure Meningitis
gradient between the perilymph of the inner ear and the
middle-ear cavity. Symptoms include the acute onset of By the age of 3 years, the percentage of children with an
vertigo, sensorineural hearing loss, tinnitus, nausea, and acquired hearing impairment out of all those children with
vomiting. Treatment includes reducing intracranial and bilateral profound deafness is 20%. Of those with acquired
perilymphatic pressures by bedrest, elevation of the head impairments, the hearing loss of 90% is due to postmenin-
of the bed, and the use of stool softeners. If conservative gitic sequelae.104,105 Persistent sensorineural hearing loss
treatment is ineffective, after 1 week surgical exploration has been documented in 10.3% of 185 infants and children
of the middle ear can be performed. with acute bacterial meningitis.106 The risk of deafness
Inner-ear decompression sickness is caused by the release after bacterial meningitis is most frequent following
of nitrogen gas bubbles into the bloodstream and tissues infection with Streptococcus pneumoniae (31.8%) compared
598 PERIPHERAL AUDIOVESTIBULAR DISORDERS

to Haemophilus influenzae and Neisseria meningitidis 25% of the children with localized infections present with
(7.5%).104,107 The incidence of bacterial meningitis is drop- hearing loss.107
ping because of immunization against Haemophilus influen- The classic triad of congenital rubella includes congeni-
zae type b.107 There have also been a few documented cases tal heart disease, ocular diseases (cataracts and retinopathy),
of hearing impairment after viral meningitis, although this and sensorineural hearing loss. If the rubella infection
appears to be quite rare. Hearing impairment after menin- occurs in the second or third month of pregnancy, there is
gitis can have several causes. Most commonly, a suppura- a 50% incidence of deafness, although deafness can occur
tive labyrinthitis occurs during the episode of acute even if the infection occurs late in pregnancy.112 Sixty per-
meningitis due to direct spread of the infection from cent of newborns with congenital rubella have subclinical
the subarachnoid space to the inner ear via the cochlear infections in the neonatal period. However, 71% of these
aqueduct. This results in destruction of the sensory struc- children develop disease manifestations during the next
tures of the inner ear, and no hearing recovery. If only a 5 years. Sensorineural hearing loss is the most common
serous labyrinthitis occurs, partial recovery of hearing is manifestation, and it affects 68% to 93% of children with
possible. Meningitis can also lead to ischemia of the audi- congenital rubella.112 Characteristically, the sensorineural
tory nerve or brainstem neuron, and result in hearing hearing loss is profound and bilateral, affecting all frequen-
loss. Finally, sensorineural hearing loss after meningitis can cies equally. Since the introduction of the rubella vaccine,
be caused by ototoxicity from the antibiotics used to treat congenital rubella infection has become quite rare.
the meningitis, often an aminoglycoside. The administra- The seroconversion rate of pregnant women for toxo-
tion of steroids to patients with pneumococcal meningitis plasmosis is roughly 1 in 10,000 and the overall of risk of
does not affect the rate of postmeningitic sensorineural toxoplasma infection involving the fetus is 33%. At birth,
hearing loss.108 90% of these babies are asymptomatic; however, late-onset
It is important to get an audiologic assessment on every sensorineural hearing loss has been reported in 10% to
patient with meningitis. This should start during their first 15% of these children.113
admission to the hospital if possible and should be followed Because of the increasing prevalence of syphilis in the
postoperatively. A common sequela of postmeningitic adult population, the prevalence of congenital syphilis has
sensorineural hearing loss is labyrinthine ossificans. been increasing in recent years. About 50% of newborns
Presumably, the inflammation in the cochlea leads to a with congenital syphilis are asymptomatic; however, hear-
fibrotic reaction, which in time ossifies. This typically hap- ing loss is a late manifestation that can occur even after
pens in the first few months after the meningitis has 2 years of age.107 The hearing loss results from active
resolved. Studies have shown that the intense inflamma- inflammation and scarring within the inner ear. Sen-
tory response begins around the area of the cochlear aque- sorineural hearing loss can even begin to develop in early
duct.109 Earlier, rather than later, cochlear implantation is adulthood even though the infection initiated in utero. The
suggested in patients with postmeningitic deafness because onset of deafness is usually sudden, bilaterally symmetric,
of the difficulty in inserting the cochlear implant in an and profound without associated vestibular symptoms.
ossified cochlea. The other common manifestation associated with congen-
ital syphilis is interstitial keratitis, which is noted in about
90% of patients with congenital syphilis. Teens or young
Congenital Infections adults with late-onset congenital syphilis identified present
Cytomegalovirus (CMV) infection has been found in 0.2% with Hutchinson triad: sensorineural hearing loss, intersti-
to 2.2% of all newborn children in the United States and tial keratitis, and notched incisors.
is the most common intrauterine infection.107 One-third of
pregnant women are serial negative for CMV during Adult-Onset Acquired Syphilis
pregnancy and about 5% of these women become infected
during pregnancy. Of those 5%, one-fourth will transmit Primary syphilis occurs initially 1 week to 3 months after
the infection to their fetuses. Up to 10% of children with inoculation as a chancre on the area of contact.
congenital CMV infection demonstrate systemic symp- Occasionally, there is large regional lymphadenopathy.
toms at birth and 61% of this group of patients develop The chancre usually heals spontaneously after 2 to 6 weeks
sensorineural hearing loss.110 The hearing loss can begin and 6 months after this, the patient develops secondary
soon after birth but usually progresses over the next syphilis. Symptoms include widespread mucocutaneous
5 years. It may be unilateral or bilateral, and occasionally lesions, as well as constitutional symptoms. Thereafter, the
it fluctuates. It is recommended that children with asymp- untreated patient enters a period of latent subclinical
tomatic CMV infections receive regular hearing tests infection. Fifty percent of untreated patients with latent
through childhood because of the potential for late-onset syphilis never develop clinically evident tertiary syphilis.
sensorineural hearing loss. Of those who do develop tertiary syphilis, sensorineural
Herpes simplex infection occurs in roughly 1 in 2500 hearing loss is most common in patients with evidence of
pregnancies.111 Infections are caused by exposure to the neurosyphilis (80%).114
herpes simplex type II virus during delivery. Children with Among those with sensorineural hearing loss, there is
herpes simplex infection, either disseminated or localized, seldom a history of primary or secondary syphilitic symp-
usually present with symptoms within the first 3 weeks of toms. Patients can present with either progressive or
life. All patients with a disseminated presentation of herpes sudden sensorineural hearing loss, as well as vestibular
simplex virus (HSV) II infection have sensorineural hear- symptoms. The diagnosis can be made by serologic tests of
ing loss, while 40% of the children with encephalitis and the plasma, as well as by the visualization of spirochetes in
 Cochlear Hearing Loss 599

the CSF after lumbar puncture. Histopathologic lesions of inflammatory mediators from the middle ear diffused
otosyphilis are identical for congenital and acquired through the round window into the inner ear. Alternatively,
syphilis. This includes an obliterative endarteritis and the presence of an occult perilymphatic fistula could
mononuclear infiltrates with varying degrees of tissue produce subtle sensorineural hearing loss. Acoustic trauma
necrosis. In tertiary syphilis, there can also be perivascular from repeated loud office suctioning of the ear could
round-cell osteitis of the temporal bone, productive produce noise-induced hearing loss. The use of potentially
periostitis, and gummatous periostitis/osteomyelitis. A ototoxic topical ear drops in the affected ear could also be
gumma is defined histologically as an area of central necro- responsible. Ear surgery can also cause sensorineural
sis with surrounding lymphocytic infiltration and vascular hearing loss because of the exposure to loud drilling noise
occlusions. Gummatous changes can be found in all of the and ossicular manipulation. Finally, the difference in the
middle-ear bones but are most frequently identified ipsilateral bone-conduction threshold may not represent
around the labyrinthine capsule. These findings can result an actual sensorineural hearing loss. Middle-ear mass and
in labyrinthine ossificans. Treatment of this disease is with stiffness can affect bone-conduction thresholds (similar to
long-term penicillin therapy. the phenomenon of Carhart’s notch in otosclerosis), and
patients with unilateral chronic otitis media certainly can
Human Immunodeficiency Virus have asymmetric middle-ear mechanics.

Human immunodeficiency virus (HIV) can produce Poststapedectomy Sensorineural

sensorineural hearing loss.115,116 The prevalence of sen-
sorineural hearing loss in this population ranges from less Hearing Loss
than 1% to 33%.117 Patients with more severe disease have After stapes surgery, sensorineural hearing loss can
an increased degree of hearing loss. Additionally, antiviral develop. This could be due to suppurative labyrinthitis as
drug therapy may be associated with an increased risk of just discussed. However, if the sensorineural hearing loss or
sensorineural hearing loss.118 vertigo persist beyond 5 days postoperatively or occur after
an initial improvement in hearing, a poststapedectomy
Sequelae of Acute and Chronic granuloma (reparative granuloma) should be suspected.
Otitis Media In contrast, mild symptoms occurring within a few days
of surgery are consistent with serous labyrinthitis and are
Sensorineural hearing loss secondary to otitis media can relatively common. The incidence of reparative granu-
occur under several conditions. It is quite uncommon for loma after a stapedectomy is estimated at 0.1%.125
recurrent acute otitis media to lead to sensorineural hear- The incidence of sensorineural hearing loss in reparative
ing loss. However, acute labyrinthitis can occur during an granuloma varies from 70% to 100% of patients.126
episode of acute otitis media. Presumably, the causative Histologically, a reparative granuloma is not actually a
organism traverses into the spaces of the inner ear via fis- granuloma. It is a clump of granulation tissue with evi-
sures around the oval or round windows. Initially, patients dence of chronic inflammation.127 When a reparative
may present with vague symptoms of vertigo and slight granuloma is suspected, a CT scan should be obtained.
symptoms of sensorineural hearing loss. This is thought to Evidence of soft tissue in the oval window within the cor-
be due to the diffusion of toxic inflammatory mediators rect time frame after surgery is highly suspicious of
through the round window membrane into the inner ear. reparative granuloma.128 Management of this entity
This can progress into serious labyrinthitis if organisms remains controversial and can range from either conserva-
enter the inner ear. A full-blown, suppurative labyrinthitis tive management with oral steroids to early surgical inter-
can result if frank inflammatory exudate forms in the inner vention with delicate removal of the granulation tissue. An
ear. As the degree of suppuration worsens, the patient’s MRI is also occasionally useful in that it will demonstrate
chances of permanent sensorineural hearing loss increases labyrinthine hemorrhage (bright signal on T1 and T2
dramatically. Labyrinthitis can also occur after a stapedec- without contrast in the labyrinth), a perilymphatic fistula
tomy or stapedotomy, presumably by the introduction of (air bubble in labyrinth), a reparative granuloma, and
bacteria through the fenestra in the oval window. suppurative labyrinthitis (intense enhancement inner ear
Suppurative labyrinthitis after stapes surgery usually with gadolinium contrast).129
occurs within days of surgery. However, it can occur even
after a long delay if a perilymph fistula exists.
Sensorineural hearing loss has been demonstrated to CONGENITAL HEARING LOSS
occur in patients with chronic otitis media. Several studies
have demonstrated a significant difference in hearing Congenital Anomalies of the Inner Ear
between the two ears in patients with unilateral chronic
otitis media, both in terms of poor speech discrimination Overall, about 1 in 1000 children is born with a significant
scores and higher bone-conduction thresholds in the ipsi- degree of sensorineural hearing loss.130 It is estimated
lateral ear.119–122 Although the differences are statically sig- that about 25% of these cases of hearing loss are attributed
nificant (changes in speech discrimination scores of 4% to identifiable prenatal or postnatal disease or trauma,
and changes in boned-conduction thresholds of 3 to 5 dB), 18% to undiagnosed genetic factors, 15% to autosomal-
they are minimal and probably have no clinical rele- dominant genetic mutations, 40% to autosomal-recessive
vance.123,124 It is unclear why sensorineural hearing loss can genetic mutations, and 2% to sex-linked genetic
develop after chronic otitis media, although presumably mutations.131 The hearing loss may not be present at birth,
600 PERIPHERAL AUDIOVESTIBULAR DISORDERS

but progress during childhood (and so be missed by semicircular canals and utriculus are normal. It is often
newborn hearing screening).132,133 Indigent patients are at inherited as an autosomal-recessive gene and can be found
a higher risk of neonatal hearing loss than the average U.S. in diseases such as Usher’s syndrome. There is partial or
population and have a different risk factor profile.134 complete aplasia of the organ of Corti with collapse of the
Malformations of the inner ear occur because of an scala media. The wall of the sacculus is collapsed onto
arrest in normal development during embryogenesis, dur- an atrophic sensory epithelium. Additionally, the stria vas-
ing the first trimester of pregnancy. This may occur cularis is degenerated.
because of a genetic mutation or teratogenesis. At about Cochlear basal turn dysplasia (Alexander’s deformity) is
the fourth week of gestation, the otocyst develops from an a limited malformation of the high-frequency region of
invagination of the otic placode. It then differentiates and the cochlea. This condition is related to familial high-
forms the membranous labyrinth. By the 12th week, the frequency sensorineural hearing loss and there is usually
cochlea has fully developed. Chondrification followed by sufficient low-frequency hearing to allow good benefit
ossification occurs in the second trimester to form the otic from the use of hearing aids.
capsule. Maturation of the sensory epithelium within the
inner ear develops throughout the second trimester of
Membranous Labyrinth Malformations
pregnancy and is essentially complete by the 26th week of
with Otic Capsule Malformations
gestation.
The management of a congenital hearing loss is frus- Malformations of the otic capsule can be diagnosed by
trating in that there is little that can be done to alter the radiographic imaging. Although thin-cut CT scans are
progression of the disease. Patients who sustain decre- traditionally used, newer fast-spin echo T2-weighted MRI
ments in hearing may be treated with steroids in an effort images are also quite good at demonstrating inner-ear
to reduce further hearing loss; however, there is little evi- anatomy. There is a wide spectrum of hearing disability
dence to support the efficacy of this therapy. Patients among this patient population. Although some are com-
should be adequately rehabilitated with the use of hearing pletely deaf, most retain some hearing into adult life and
aids initially and if this does not prove useful, then they have a slowly progressive sensorineural hearing loss.
should be considered for cochlear implantation. The only Interestingly, there is a higher risk of sudden hearing loss
absolute contraindications of cochlear implantation in a associated with even minimal head trauma. This is pre-
congenitally dysplastic ear are complete cochlear aplasia or sumably because of latent weaknesses in the membranes of
absence of the auditory nerve. Both of these conditions can the inner ear or the osseous spiral lamina that are easily
be diagnosed with the use of high-resolution CT scan of damaged, permitting mixture of the endolymph and
the temporal bone. Additionally, patients with congenital perilymph.
malformations of the inner ear are at a higher risk for CSF Complete labyrinthine aplasia (Michel’s deafness) is an
leak and meningitis. Families need to be counseled as to extremely rare defect in which there is a complete absence
the early signs and symptoms of meningitis. Immunization of inner-ear structures and, therefore, total deafness. This
against the common organisms implicated in meningitis is likely due to a developmental arrest early in gestation,
should also be considered. before the formation of an otocyst. This defect has
Abnormalities of the inner ear can be divided in those been seen in association with thalidomide exposure and
in which the membranous labyrinth is abnormal, but the anencephaly.138
otic capsule is normal, and those in which both are Cochlear aplasia is absence of the cochlea with only
abnormal.135,136 semicircular canals present. These are usually deformed as
well, however.
Cochlear hypoplasia results from an arrest in develop-
Membranous Labyrinth Malformations
ment at about the sixth week of gestation. The cochlea
with a Normal Otic Capsule
consists of only a small bud (1 to 3 mm in diameter) pro-
Malformations limited to the membranous labyrinth truding from the vestibule. Auditory function is quite vari-
account for about 90% of congenital sensorineural hearing able and may be surprisingly good, considering the small
loss. These patients have normal otic capsules and hence size of the cochlea.139
cannot be identified by current radiographic techniques. Incomplete partition (Mondini’s malformation) occurs
However, it can be safely assumed that all children with with an arrest in development at the seventh week of ges-
congenital sensorineural hearing loss would be found to tation. This is a very common cochlear malformation and
have abnormalities of their membranous labyrinth if they it accounts for more than 50% of cochlear deformities.
could be examined histopathologically, unless there is a The cochlea is smaller than normal (5 to 6 mm in vertical
purely central cause for their hearing loss. height instead of the normal 8 to 10 mm). It may possess
Complete membranous labyrinthine dysplasia (Bing- fewer turns than normal, although this is difficult to quan-
Siebenmann deformity) is extremely rare and may be asso- tify by CT scanning. The interscalar septum is partially
ciated with cardiac abnormalities. It can be found in the or completely absent. The severity of hearing loss is quite
Jervell and Lange-Nielsen syndrome and in Usher’s variable among patients and can range from normal
syndrome.137 hearing to profound deafness.
Cochleosaccular dysplasia (Scheibe’s deformity) repre- In the common cavity deformity the cochlea and
sents the most common inner-ear abnormality that results vestibule are confluent and form an oval space within the
in hearing loss. This occurs in the phylogenetically otic capsule. Although there may be recognizable seg-
newer portion of the inner ear, while the more ancient ments of the organ of Corti on histologic evaluation of the
 Cochlear Hearing Loss 601

specimen, overall the hair cell population is quite sparse. no nonsyndromic deafness genes had been cloned. To
Hearing is typically poor. date, 70 loci have been identified as being involved in non-
Dysplasia of the lateral semicircular canal is a common syndromic deafness and more than 400 distinct syndromes
malformation and is often associated with cochlear malfor- are associated with hearing impairment. However, clearly
mations as well. The lateral semicircular canal is the most many more genes remain unidentified. Although single-
common canal to be affected by dysplasia. During its for- gene deficits probably account for more than 50% of the
mation, the lateral semicircular canal is first a confluent cases of congenital hearing loss, the pathophysiology of
broad cystic space contiguous with the vestibule. Then, a the genetic contribution to presbycusis has not been
bony septum forms in the center (like a donut hole). defined. Several animal models of genetic deafness have
Deformities range from no septum to a rudimentary sep- been created, but relatively few of these have been shown
tum to a nearly normal septum. There may be reduced to be involved in human deafness. The limited overlap
caloric responses noted by electronystagmography. Hearing between genes that cause sensorineural hearing loss in
may be normal if the malformation is limited to the mice and humans makes these research endeavors quite
vestibular system. This deformity may be associated with challenging.
Goldenhar’s syndrome.140–142 The genetic contribution to sensorineural hearing loss
Semicircular canal aplasia is much less common than can be associated with several areas in the cochlea. Being
semicircular canal dysplasia and is usually associated with unique to the inner ear, the hair cells are the most obvious
cochlear abnormalities. It is presumed to arise as a conse- potential site of involvement. There are several essential
quence of failure in the development of the vestibular bud molecules for hair cell transduction, which if mutated, will
before the sixth week of gestation. cause hearing loss. These include unconventional myosins
Large vestibular aqueduct syndrome is the most com- found specifically in the hair cell transduction region,
mon radiographically detectable abnormality of the inner including myosins VI, VIIa, and XV. Myosin VIIa muta-
ear.143 The normal diameter of vestibular aqueduct is tion is associated with Usher’s syndrome type 1c. These
between 0.4 mm and 1.0 mm (measured between the patients are born with congenital hearing loss and develop
common crus and the posterior face of the temporal bone). progressive blindness. Mutations in these myosins lead to
The vestibular aqueduct is said to be enlarged when its abnormal stereocilia anatomy, as well as disorganization of
diameter exceeds 2.0 mm. Vestibular aqueduct abnormali- the stereociliary bundle.145–148 Other hair cell genes in
ties often accompany cochlear and vestibular organ abnor- which mutations cause deafness include cadherin-related
malities and are quite commonly seen in conjunction with genes (involved in cell-to-cell interactions), aspin (an
Mondini’s deformity. Patients with large vestibular aque- actin-bundling protein), and Atp2b2 (a calcium pump in
duct syndrome usually have a mild sensorineural hearing the stereocilia).145
loss that progressively deteriorates during childhood and Additionally, hair cell synaptic transmission is unique in
early adult life. Forty percent develop profound sen- that very accurate timing information needs to be relayed
sorineural hearing loss. to the central nervous system. Mutations that disrupt this
Enlargement of the cochlear aqueduct has been can cause a sensorineural hearing loss. These include the
reported; however, most cases demonstrate a wide, funnel- otoferlin gene (a protein located at the base of inner hair
shaped opening from the cerebellopontine angle with no cells involved in synaptic vesicle recycling),149 and muta-
evidence of widening of the remainder of the aqueduct. tions in L-type calcium channels (required for calcium-
Since the tube narrows to a normal diameter laterally, it is dependent exocytosis during synaptic transmission).150
quite possible that the wide medial end is of no conse- The final site in a hair cell that might be a target for a
quence. Hence, this entity has not been convincingly genetic mutation that produces a hearing loss would be
demonstrated to be clinically important.129 outer hair cell electromotility. The gene for the molecular
A wide internal auditory canal is usually of no signifi- motor responsible for electromotility has been identified
cance clinically. However, patients with stapes fixation and (prestin),1 and there is evidence of patients who are deaf
a wide internal auditory canal may be noted to have a because of amutation in this gene.151 Electromotility is not
stapes “gusher” during stapes surgery (a CSF leak), partic- found in any other cells in the body, so a mutation in this
ularly if the lateral end of the internal auditory canal (IAC) gene causes a limited clinical phenotype (i.e., hearing loss).
is widened. In patients with congenital stapes fixation, a Other targets in the outer hair cell that could inhibit elec-
CT scan of the temporal bone should be obtained before tromotility include mutations in the exquisitely organized
consideration of surgery to evaluate for this entity. cytoskeleton or in the plasma membrane.2–4
A narrow internal auditory canal may indicate the Surprisingly, mutations in other areas of the cochlea are
absence of the VIIIth cranial nerve. This can be crucial much more clinically relevant than hair cell mutations.
during the consideration of cochlear implantation in Mutations that affect the endolymphatic potential are the
patients with congenital hearing loss because a diameter of most common cause of genetic hearing loss. These include
the IAC smaller than 3 mm is a strong predictor of genes important for proper functioning of the stria vascu-
decreased neural population. This finding is a contraindi- laris or for gap junctions in supporting cells that recycle
cation to cochlear implantation.144 ions from the hair cells back to the stria vascularis. KCNQ4
encodes a potassium channel found predominantly in
Genetic outer hair cells that serves as the first step in recycling
potassium after transduction. Mutations in this gene cause
The identification of genes involved in deafness has made a dominant progressive hearing loss.152 Mutations in the
dramatic progress over the last several years. Prior to 1996, Kcc4 gene for a potassium-chloride cotransporter protein
602 PERIPHERAL AUDIOVESTIBULAR DISORDERS

found in supporting cells also causes deafness.73 Connexin loss secondary to severe hypoxia is about 1% to 5%. This
genes form gap junction proteins, and mutated gap junction is a difficult number to estimate because of the multiple
proteins do not permit ion recycling mutations. Mutations comorbid conditions in this complex patient population.
in connexin genes are quite frequently involved in human The auditory system is very sensitive to hyperbilirubine-
genetic deafness.153–157 The pendrin gene is expressed in mia. Damage occurs predominantly to the auditory nerve
the endolymphatic duct and sac, and is mutated in and brainstem nuclei, producing a sensorineural hearing
Pendred’s syndrome.158–160 The pendrin protein acts as an loss.168 This is usually caused by Rh incompatibility
iodide-chloride transporter and may be involved in between the mother and infant, although ABO incompat-
endolymph homeostasis. Finally, defects may occur in the ibility can also be the cause. Aggressive treatment of
tectorial membrane matrix from mutations in genes hyperbilirubinemia to lower the plasma levels reduces the
encoding alpha tectorin (Tecta), collagen 11A2 (COL risk of sensorineural hearing loss.
11A2), and otogelin (otog),145 producing ultrastructural
deformities of the tectorial membrane and hearing loss.
OTIC CAPSULE BONY DISEASES
METABOLIC COCHLEAR HEARING LOSS Otosclerosis is a disease of the endochondral otic capsule
bone. Although usually this disease presents as a conduc-
Renal disease is associated with sensorineural hearing loss. tive hearing loss secondary to stapes fixation, sensorineural
Many enzymatic functions of the kidneys and the stria vas- hearing loss can develop in the late stages of this disease.
cularis are similar. The most important is ion transport. Pathologically, there is replacement of normal compact
Patients with renal disease can have hearing loss because of otic capsule bone by irregular loose or cancellous bone
disorders of fluid and electrolyte balance. It is possible that with an increase in the size of the haversion canals, inter-
altered plasma electrolyte concentrations compromise the cellular spaces, and marrow spaces. There is an increase in
ability of the stria vascularis to produce the endolymphatic the vascularity of the involved bone. If this disease involves
potential. However, the exact pathophysiology is not the otic capsule bone adjacent to the cochlea, sensorineural
known. Additionally, it has been shown that distal renal hearing loss can develop. Although the exact reason for a
tubular acidosis, an autosomal-recessive inherited syn- sensorineural hearing loss is not known, the increased vas-
drome in which there is an inability of the distal renal cularity of the surrounding otic capsule bone may reduce
tubule to excrete hydrogen ions into the urine, is associ- the blood supply to the stria vascularis. Cochlear otosclero-
ated with sensorineural hearing loss at a young age.161,162 sis is described as a pure sensorineural hearing loss in the
Diabetes mellitus is also probably associated with sen- presence of otosclerosis without conductive hearing loss.
sorineural hearing loss, although evidence in the literature This could occur if there is no fixation of the stapes, yet
is conflicting.163,164 The pathologic process is thought to the otic capsule bone around the cochlea is involved with
be a microvascular angiopathy with progressive decrease in disease. By computed tomography, severe otosclerosis can
the functioning of the stria vascularis. Histologically, there be seen as lucency around the cochlea (also known as a
has been shown to be thickening in the stria vascluaris sim- “double ring” sign). This represents the extensive endo-
ilar to vascular changes seen elsewhere in these patients.165 chondral demineralization of the otic capsule.
It is also possible that there is an associated primary neu- Osteogenesis imperfecta encompasses a group of connec-
ropathy of the auditory nerve. Some evidence suggests that tive tissue disorders with defects in bone formation. There
insulin-dependent diabetes and hypertension have syner- is a high rate of bone turnover and deposition
gistic effects that exacerbate the hearing loss.166 of immature, osteopenic bone that is quite weak and
Hyperlipidemia and hypercholesterolemia have been shown fragile. The most common otologic condition associated
to be associated with sensorineural hearing loss, but again with osteogenesis imperfecta is hearing loss. The hearing
the literature is conflicting. Presumably, this occurs due to loss is mixed in 54% of cases, purely conductive in 24%,
atherosclerotic changes in the vascular supply to the inner and sensorineural in 22%. Usually, the hearing loss is
ear similar to that seen in other places in the body (i.e., the noted between the second and third decades of life.
coronary arteries). Temporal bone CT scan findings in osteogenesis imper-
Hypothyroidism can lead to sensorineural hearing loss in fecta are similar to those found in severe cochlear otoscle-
utero (cretinism). The histologic effects appear to be pre- rosis, with lucency of the otic capsule bone surrounding
dominantly cochlear, with atrophy of the stria and degen- the cochlea.
eration of the spiral ganglion neurons and hair cells of the Paget’s disease is another disease of bone that can cause
organ of Corti. Pendred’s syndrome is an inherited auto- sensorineural hearing loss. Involvement of the otic capsule
somal-recessive trait with a deficiency of peroxidase that causes hearing loss in about 50% of sufferers. The initial
prevents the organification of iodine (this has also been finding is usually conductive hearing loss due to stapedial
associated with large vestibular aqueduct syndrome). ankylosis similar to otosclerosis, although most patients do
There is no fixed definition of hypoxia in the newborn; end up developing sensorineural hearing loss as the otic
however, this term is typically used when the neonate fails capsule bone surrounding the cochlea becomes involved.
to establish spontaneous regular breathing after birth. Fibrous dysplasia of the temporal bone may cause a con-
Persistent hypoxia can lead to cerebral damage and sen- ductive hearing loss by impinging on the ossicular chain or
sorineural hearing loss. Apoptosis of cells in the organ of via external auditory canal stenosis. It does not involve the
Corti and spiral ganglion neurons occurs.167 Retrospective otic capsule. However, compression of the internal audi-
studies suggest that the frequency of sensorineural hearing tory canal could occur, with the potential for sensorineural
 Cochlear Hearing Loss 603

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150. Platzer J, Engel J, Schrott-Fischer A, et al: Congenital deafness 160. Wilcox ER, Everett LA, Li XC, et al: The PDS gene, Pendred syn-
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 Chapter
Electronystagmography
and Rotation Tests

Outline 38
Introduction Abnormal Dennis I. Bojrab, MD
Electronystagmography Electronystagmography Does
Vincent B. Ostrowski, MD
Eye Movement Recording Not Always Rule in
Equipment Vestibular Disease as the
Routine Components of Cause of Dizziness
Electronystagmography It Is Important to Test the
Dix-Hallpike Maneuver Patient When Symptomatic
Gaze Test if Possible
Positional Test Rotation Chair Test
Bithermal Caloric Test History
Saccade Test Rotary Chair Test
Pursuit Tests Clinical Indications for
Summary Rotational Chair Testing
Normal
Electronystagmography Does
Not Rule out Vestibulopathy

INTRODUCTION ELECTRONYSTAGMOGRAPHY
Vestibular testing should be considered an important tool in ENG is a method of monitoring eye movements. For nearly
the evaluation and management of dizziness. A careful and 40 years, it has been widely used in the diagnostic evaluation
thorough bedside history and neurotologic examination is of dizziness or unsteadiness. The examination consists of a
key for making an accurate clinical diagnosis in the patient battery of tests collectively referred to as the ENG. This
with dizziness. The physician must couple the results of the battery was designed to reveal vestibular and nonvestibular
bedside evaluation with the results of vestibular tests to functional tests of eye movement abnormalities. The
manage the disorder. In other words, the vestibular tests of vestibular and ocular systems are connected through the
electronystagmography (ENG) or rotary chair test (RCT) VOR. Patients with peripheral or central balance disorders
should not be considered stand-alone diagnostic tests for often exhibit abnormal eye movements that can be mea-
the patient with dizziness, but instead should be coupled sured and recorded. The most common method involves
with clinical impressions. It is important to remember that monitoring eye movements using electro-oculography.
not every patient needs quantitative vestibular testing. Also,
other important information provided by the ENG does not Eye Movement Recording Equipment
involve the vestibular system and may be of value when
treating the patient with dizziness. A variety of eye movement recording equipment is cur-
Assessing the integrity of the vestibulo-ocular reflex rently available. In performing the ENG, the patient’s eye
( VOR) is an integral part of vestibular testing. The VOR is movements are measured relative to head position, which
a reflex that acts at short latency to generate eye movements can be achieved in a number of ways:
that compensate for head rotations encountered in daily
1. Electro-oculography (depends on the corneoretinal
activity. The VOR preserves clear vision during locomotion
potential)
to prevent slip of a visual image that is focused on the retina.
2. Video-oculography (depends on video camera goggles)
Measuring the VOR requires stimulation of vestibular sys-
3. Magnetic search coil technique
tem and measurement of the resulting eye movements.
4. Infrared oculography
There are advantages but also limitations to the current
methods of this analysis, which will be discussed in the body Electro-oculography ( EOG ) is the most common technique
of this chapter (Table 38-1). of monitoring eye movements during the ENG and is
607
608 PERIPHERAL AUDIOVESTIBULAR DISORDERS

TABLE 38-1. Benefit of Electronystagmography Eye movement effects a change in the magnetic field, and
and Rotational Chair Testing this is recorded. The advantage of this method is that it
gives very high-resolution data for all types of eye move-
1. Localize a central verses a peripheral lesion. ments, including torsional nystagmus. Disadvantages of the
2. Lateralize the deficit.
3. Offer documentation of clinical examination.
technique include slight patient discomfort (due to the
4. Assist in establishing a diagnosis and developing a treatment plan and lens) and the very high cost of the procedure. This proce-
long-term management. dure has yet to gain widespread acceptance and is rarely
used clinically.
Infrared oculography is based on the differing reflectance
properties of the iris relative to the sclera and the fact that
based on the fact that steady DC potentials—corneoretinal the photocells of the eye remain stationary while the edge
potentials—exist between the corneas and retinas of the of the iris moves with the eye. As a result, the light sensed
eyeballs. These potentials create an electric field in the by the photocells differs according to eye position. The
front of the head that rotates as the eyes rotate in their advantage of this technique is that a direct estimate of the
orbits. The cornea is relatively positively charged in com- eye position as a function of time can be calculated. Disad-
parison with the retina; thus, an electrical potential exists vantages of this technique include the bulkiness of the
between the two. This potential is generated by the meta- equipment, which limits visual stimulation somewhat, and
bolic activity of the retinal pigment epithelium. The retina the interference with eyelid motion (e.g., blink), which
is negatively charged relative to the cornea and therefore makes vertical recording difficult at times.
electrical potential can be measured between the two by
means of skin surface electrodes. In neutral position the Routine Components of
average potential measured is about 1 mV. Movement of
the eyes causes potential changes relative to the skin elec-
Electronystagmography
trodes. Movement of this electric field produces a roughly The ENG test battery generally consists of seven tests.
linear change in the voltage between electrodes attached to The first four tests are primarily tests of vestibular func-
the skin on either side of the eyes. Electrodes placed on the tion, although they sometimes also reveal nonvestibular
patient’s temples monitor horizontal eye position. Vertical eye movement abnormalities as well: (1) the Dix-Hallpike
eye position is monitored by electrodes placed above and maneuver, designed to provoke a nystagmus response in
below one of the patient’s eyes. Some benefits of the EOG patients with benign positional vertigo, (2) the gaze test,
surface electrodes are that they are simple and relatively designed to detect nystagmus induced by eccentric gaze,
inexpensive. Disadvantages include the inability to moni- (3) the positional test, designed to determine if different
tor ocular torsion, being subject to bioelectric noise from head positions induce or modify nystagmus, and (4) the
facial muscles and a resolution of about 1 degree/sec while bithermal caloric test, designed primarily to detect unilat-
monitoring eye movements (Fig. 38-1). eral lesions of the labyrinth or vestibular nerve. The final
Video-oculography, a technique that has recently become three tests are tests of nonvestibular eye movements:
commercially available, involves digital video-recorded eye (5) the saccade test, designed to detect disorders of the sac-
movements. Videonystagmography (VNG) is a computer- cade eye movement control system, and (6) the tracking
based system that records eye movement under test situa- test and (7) the optokinetic test, both designed to detect
tions. The eye position is located by detecting the pupil and disorders of the pursuit eye movement control system.
tracking its center. The internal computer program plots, Although saccade and pursuit eye movements are of sec-
measures, and analyzes the eye movements under a battery ondary interest to those who evaluate dizziness, they are
of tests. nevertheless routinely tested because abnormalities are
VNG permits visualization and recording of eye move- occasionally detected in such patients.
ments that are conveniently stored on a database for For many years, eye movements were recorded on strip
retrieval or transfer of data. This is helpful for later study charts. Recently, ENG has been computerized, permitting
and for teaching of personnel and patients. This technique efficient storage and easy retrieval of eye movement data
is easier and quicker than using electrodes with minimal and eliminating the cutting and pasting of strip chart
patient preparation, and only one calibration is necessary, recordings. In addition, computerized ENG allows rapid
speeding the over all test time. Depending on the system, and sophisticated analysis of saccade, tracking, and caloric
ocular torsion can be measured and video-captured, unlike tests—analyses that could not be done on strip chart
EOG. Without the bioelectric interference from facial recordings.
muscles, tracings are clean with no drift as seen with tradi-
tional EOG tracings. Dix-Hallpike Maneuver
Monitoring resolution can detect 0.1 degree/sec move-
ments. Blink artifact can be an issue because the eyes must The most frequently employed test for positioning nystag-
be kept open during testing, and some patients experience mus is the Dix-Hallpike maneuver. The patient is subjected
claustrophobia and may not tolerate the sensation of to two brisk movements, both beginning with the patient
confinement. In addition, the test equipment is expensive in the sitting position. The patient’s head is first turned
(Fig. 38-2). 45 degrees toward one side. Then the examiner, standing to
The magnetic search coil technique places the patient in a the side or behind the patient, pulls him briskly backward
three-dimensional electromagnetic field. The patient so that he is lying supine with his head still turned to
wears a soft contact lens in which a wire coil is embedded. that side and hanging over the end of the examining table.
 Electronystagmography and Rotation Tests 609

Figure 38-1. Corneoretinal potential.

Horizontal Channel
right

Vertical Channel
up

hallmark of the disorder. Paroxysmal positional nystagmus

The examiner holds the patient’s head in that position for
has four distinctive characteristics1,2:
at least 20 seconds and monitors his eye movements. Then
the examiner returns the patient to the sitting position. If a 1. It has a delayed onset. Usually an interval of at least a
response was elicited, the examiner repeats the same few (2 to 20) seconds elapses after the patient reaches
maneuver to determine if it fatigues. Then she performs the head-hanging position before the nystagmus begins.
the maneuver with the patient’s head turned 45 degrees to 2. It is always transient; that is, it rapidly builds in inten-
the other side, and if a response is elicited, repeats the sity (crescendos), slowly abates (decrescendos), and
maneuver to determine if it fatigues (Fig. 38-3). finally disappears (within 45 seconds) as the head
During the backward movement, the Dix-Hallpike remains in position.
maneuver normally induces a few beats of nystagmus. 3. It is always accompanied by vertigo, usually intense,
After the head has reached the hanging position, normal that follows the same time course of the nystagmus.
individuals do not have nystagmus, but some patients with 4. It is usually fatigable; that is, it progressively dimin-
benign positional vertigo display a burst of intense ishes in intensity with repetition of the Dix-Hallpike
nystagmus—paroxysmal positional nystagmus—that is the maneuver.
610 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Figure 38-2. Video-oculography.

A B
Figure 38-3. Dix-Hallpike maneuver and illustration
of canalithiasis.

Head tilted back 135

and turned to left 45

Canalithiasis Cupulolithiasis
C
 Electronystagmography and Rotation Tests 611

The pathophysiology of the response is believed to be TABLE 38-2.

due to two types of pathology: canalithiasis and cupu- Fast Phases Semicircular Canal Involvement
lolithiasis, with the former being much more prevalent. In
canalithiasis, otoconia or other debris are presumed to be Upward right torsional Right posterior canal BPPV
floating freely in the endolymph of one of the canals. If Upward left torsional Left posterior canal BPPV
the head is positioned so that the involved canal is vertical Downward right torsional Right anterior canal BPPV
and then rotated quickly in the plane of that canal, the oto- Downward left torsional Left anterior canal BPPV
conia fall to the lowest position in the canal, moving BPPV, benign paroxysmal positioning vertigo.
endolymph along with them. This movement of endolymph
deflects the cupula of that canal, causing the hair cell stim-
ulation and therefore inducing nystagmus and vertigo. The Dix-Hallpike maneuver sometimes provokes types
The characteristics of the eye movement response may be of nystagmus response other than the posterior semicircu-
explained. The latency of the response is due to inertial drag lar canal on the downward ear. The examiner may identify
of the endolymph as the debris falls to the dependent posi- the specific canal involved by noting the direction of the
tion. The nystagmus response is due to cupula deflection fast phases of the abnormal nystagmus with the patient’s
and stimulation. Once the debris settles, the endolymph eyes looking straight ahead (Table 38-2).
flow ceases, the cupula goes to the neutral position, and the Horizontal semicircular canal benign paroxysmal positioning
nystagmus stops (see Fig. 38-3C). vertigo (BPPV) can be detected with the Dix-Hallpike
Nearly always only one labyrinth is involved, and the maneuver. A more effective maneuver involves placing the
response is provoked when the Dix-Hallpike maneuver patient in the supine position, turning the head quickly to
places the involved labyrinth undermost. Paroxysmal posi- the right-ear-down position, and holding it there for at least
tional nystagmus can be readily appreciated by visual 30 seconds (or, if nystagmus is provoked, for up to several
observation with the patient’s eyes open or, better yet, with minutes). The patient’s head is then returned slowly to the
the patient wearing Frenzel’s lenses in a darkened room. supine position; lastly, the head is turned quickly into the
The examiner sees primarily the torsional component of left-ear-down position and held there for at least 30 seconds
the nystagmus, with counterclockwise fast phases when the (or, if nystagmus is provoked, for up to several minutes). In
right ear is involved and clockwise fast phases when the left patients with horizontal canal BPPV, this maneuver
ear is involved. In other words the nystagmus seen by the provokes horizontal nystagmus, as described by Baloh and
examiner appears to be torsional toward the floor of the colleagues.3 The nystagmus of horizontal canal BPPV is
downward ear. ENG is useful in documenting the response
(Fig. 38-4). ENG is insensitive to the torsional component 1. Geotropic (right beating in the right-ear-down posi-
of the nystagmus, but does record the horizontal and ver- tion and left-beating in the left-ear-down position) and
tical components. The horizontal component generally often followed by an ageotropic secondary nystagmus
has fast phases away from the undermost ear, and the ver- 2. Stronger when the ear presumed to be pathologic is
tical component invariably has upward fast phases. Parox- undermost
ysmal positional nystagmus changes somewhat with the 3. Transient (although more persistent than the
direction of the patient’s gaze. The torsional component is response of posterior canal BPPV )
more prominent during gaze toward the undermost ear; 4. Accompanied by vertigo, usually intense, that follows
the vertical component is more prominent during gaze the same time course as the response
toward the uppermost ear. 5. Not delayed in onset
6. Not fatigable
Another abnormal response is downbeat nystagmus,
which is exacerbated when the patient is moved to the
head-hanging position.4 If downbeat nystagmus is mild, it
may be absent when looked for during the gaze or posi-
tional tests and appear for the first time in response to the
Dix-Hallpike maneuver. Generally it is not accompanied by
vertigo. The maneuver may also provoke horizontal posi-
tional nystagmus, which, if intense, is accompanied by
vertigo. This type of positional nystagmus would also be
observed during the positional test. Other types of nystag-
mus response, generally of central nervous system origin,
are rarely provoked by the Dix-Hallpike maneuver. Usually
this nystagmus is strictly downbeating without any tor-
sional component. If so, it may be due to an Arnold-Chiari
malformation, cerebellar degeneration, or a selective lesion
of the cerebellar flocculus.
Figure 38-4. Paroxysmal positional nystagmus in response to the One limitation of the Dix-Hallpike maneuver is that it
Dix-Hallpike maneuver with right ear undermost. Horizontal channel shows cannot be performed on patients with cervical spine dis-
left-beating nystagmus, and the vertical channel shows upbeating
nystagmus. Upward pen deflection denotes rightward eye movement on ease that limits neck extension or back disorders that
horizontal eye position tracing and upward eye movement on vertical eye prohibit rapid positioning of the patient into the head-
position tracing. hanging position. In those patients, a sideling Bojrab
612 PERIPHERAL AUDIOVESTIBULAR DISORDERS

maneuver may be employed. The senior author has been The gaze test detects nystagmus from vestibular origin as
using this technique for over 15 years as his primary well as central nervous system origin. An example of one
technique in elderly patients or patients with significant type—upbeat nystagmus—is shown in Figure 38-6. Upbeat
cervical neck disease. This maneuver allows the same posi- nystagmus occurs most commonly as a result of medullary
tioning of the posterior semicircular canal as with the lesions involving vertical vestibular pathways.5 Leigh and
Dix-Hallpike maneuver, without the head hanging. Zee describe additional types of central nystagmus seen in
With the Bojrab maneuver, the patient is positioned sit- the gaze test.6 Barber and Stockwell illustrate ENG
ting up, facing the examiner. The head is turned to the right tracings of many of these.7 The gaze test may also detect
45 degrees, so that the external auricle is perpendicular to spontaneous nystagmus caused by a unilateral vestibular
the plane of the table. The examiner then holds the head in lesion, although spontaneous nystagmus is better appreci-
that position as he briskly lowers the patient onto her shoul- ated during the positional test with visual fixation denied.
der, with the head resting on the table. The position is held
for at least 20 seconds while the eye movements are Positional Test
monitored. The patient is then returned to the sitting posi-
tion. If nystagmus was elicited, the examiner repeats the The purpose of the positional test is to determine if differ-
same maneuver to determine whether the nystagmus is fati- ent head positions induce or modify vestibular nystagmus.
gable. The maneuver is then performed on the contralateral The patient’s eye movements are monitored while his head
side. As with the Dix-Hallpike maneuver, the ear, which is is in at least four positions: sitting, supine, right ear down,
dependent at the time the nystagmus is elicited, is usually and left ear down. If nystagmus appears or is modified in
the one containing the diseased labyrinth (Fig. 38-5). either of the latter two positions, the patient is tested again
while lying on that side to determine if the effect was due to
Gaze Test neck rotation. Some examiners also test the patient in the
head-hanging position. Eye movements are monitored in
The patient’s eye movements are monitored as she fixates each position both with visual fixation permitted (eyes open
while gazing 30 degrees to the right, 30 degrees to the left, and fixating on a visual target at center gaze) and with visual
30 degrees up, and 30 degrees down. Some examiners also fixation denied. Most examiners deny fixation simply by ask-
attempt to monitor eye movements in these gaze positions ing the patient to close his eyes, but eye closure may inhibit
with visual fixation denied, but the tracing is often difficult nystagmus. A better method is to monitor eye movements
to interpret. with eyes open in total darkness. The examiner usually asks
Young normal individuals rarely have any nystagmus at the patient to perform a mental task, such as mental arith-
all while fixating at any of these gaze positions, but many metic, when testing with visual fixation denied to maintain
elderly individuals have endpoint nystagmus. This nystag- mental alertness and thus avoid nystagmus suppression.
mus is always faint with centripetal slow phases that gen- The most common abnormality seen in the positional
erally are of equal intensity on right and left gaze. test is so-called spontaneous nystagmus (Fig. 38-7). This

Figure 38-5. Bojrab maneuver.

 Electronystagmography and Rotation Tests 613

Figure 38-7. Left-beating spontaneous nystagmus with eyes closed.

Upward pen deflection denotes rightward eye movement.

often modulated by changes from the right-ear-down to the

supine to the left-ear-down position, as illustrated by the
example shown in Figure 38-7. In some cases, the modula-
Figure 38-6. Upbeat nystagmus. Upward pen deflection denotes rightward tion is sometimes so deep that nystagmus even changes in
eye movement on horizontal eye position tracings and upward eye movement direction, for example, from strongly right-beating in the
on vertical eye position tracings.
right-ear-down position, to more weakly right-beating in the
supine position, to left-beating in the left-ear-down position.
nystagmus is horizontal-torsional, although ENG is insen- The positional test also detects another variant of posi-
sitive to the torsional component and only records the tional nystagmus (Fig. 38-8). There is no nystagmus in the
horizontal component. It is suppressed by visual fixation, sitting or supine positions. Nystagmus beats in one direc-
and often suppression is so strong that spontaneous nys- tion in the right-ear-down position and in the opposite
tagmus is abolished by fixation. Poor fixation suppression direction in the left-ear-down position. Generally strong
indicates a central nervous system lesion involving the nystagmus appears when the patient first assumes the posi-
pathways responsible for VOR cancellation. tion, followed by persistent nystagmus of lower intensity. If
Spontaneous nystagmus is a reflection of tonic left-right the nystagmus is strong enough, the patient experiences
vestibular asymmetry. It is typically seen after a recent vertigo. Like spontaneous nystagmus, this type of positional
unilateral peripheral vestibular lesion and has fast phases nystagmus provides evidence of vestibular dysfunction, but
away from the side of the lesion. Sometimes spontaneous is nonlocalizing.
nystagmus is seen in the absence of a recent unilateral Like the Dix-Hallpike maneuver, the positional test occa-
peripheral lesion, in which case it provides evidence of a sionally provokes nystagmus of central origin. It also may
vestibular lesion but does not localize it. provoke paroxysmal positional nystagmus if the response
Spontaneous nystagmus has been defined as nystagmus has not previously been provoked and fatigued by the
that is unmodulated by changes in head position and has Dix-Hallpike maneuver.
been distinguished from positional nystagmus, which is
modulated by head position changes, but this distinction
does not appear to be clinically useful. In fact, tonic horizon-
Bithermal Caloric Test
tal-torsional vestibular nystagmus is occasionally modulated The bithermal caloric test has proven highly sensitive to
by a change from the sitting to the supine position, and it is unilateral lesions of the peripheral vestibular system, that
614 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Figure 38-9. Caloric responses of a patient with a 65% unilateral weakness

of the right ear.

caloric stimuli. If both ears are normal, they should produce

responses of approximately equal intensity. Therefore the
strength of the caloric responses from the two ears is com-
pared. Most examiners use the following formula:
(RW + RC) − (LW + LC) × 100 = UW
RW + RC + LW + LC
RW, RC, LW, and LC are peak slow-phase velocities of the
responses to right warm, right cool, left warm, and left
cool responses, respectively, and UW is unilateral weak-
ness. The normal limit of +20% to 25% for UW is widely
accepted. Figure 38-9 shows the caloric responses of a
Figure 38-8. Direction-changing positional nystagmus with eyes closed;
right-beating with right ear down and left-beating with left ear down.
patient who has a left UW of 65%, which signifies a lesion
Upward pen deflection denotes rightward eye movement. of the right labyrinth or vestibular nerve.
Patients may have both a unilateral weakness and sponta-
is, to unilateral lesions of the labyrinth or vestibular nerve, neous nystagmus. This pattern is typical of patients with
because it permits the examiner to stimulate each ear sep- acute sudden unilateral peripheral vestibular lesions. Such a
arately. Other vestibular test procedures, such as rotation lesion causes a reduction in the resting input coming from
testing and posturography, necessarily involve stimulation the damaged ear, producing an asymmetry that induces
of both labyrinths together and therefore permit masking nystagmus with slow phases toward the damaged ear.
of abnormal responses from one labyrinth by normal Figure 38-10 shows the result of a test performed on a
responses from the opposite ear. patient 3 days after the onset of a right peripheral vestibular
The bithermal caloric test is specifically a test of the lesion. Caloric irrigations provoked no response from the
integrity of the horizontal semicircular canals and their right ear. The patient also had spontaneous nystagmus with
afferent pathways. The patient is placed in the supine rightward slow phases at velocities of about 6 degrees/sec.
position with her head elevated by 30 degrees to place the
horizontal canal in the vertical plane. The standard caloric
stimulus consists of 250 mL of water irrigated into the
external ear canal within 30 seconds. The temperature of
the water is 30°C for the cool irrigation and 44°C for the
warm irrigation. Some examiners use air (8 L at 24°C and
50°C within 60 seconds) instead of water as the caloric
stimuli. Others use a “closed-loop” system, in which water
continuously circulates within a watertight system, which
includes a small balloon that inflates in the external ear
canal during the irrigation. All three irrigating methods—
water, air, and “closed-loop”—yield approximately equiva-
lent stimuli.
Caloric stimuli are uncalibrated, that is, stimulus strength
varies from person to person depending on the size and
shape of the external ear canal and other uncontrollable
variables. However the basic assumption of the caloric test Figure 38-10. Caloric responses of a patient with absent caloric responses
is that, for a given individual, the two ears receive equal from the right ear and spontaneous nystagmus with rightward slow phases.
 Electronystagmography and Rotation Tests 615

TABLE 38-3. Advantages of Caloric Testing

1. Tests for unilateral disease and comparison of sides
2. Results are quantified and are well-defined normal limits
3. Follow patients with known vestibular disease
4. Medical legal documentation

responses to the initial bithermal stimuli. In this case, the

test is repeated with ice water (approximately 0°C) irriga-
tions. However, one should keep in mind that the absence
of a caloric response does not always imply absent periph-
eral function, because the stimulus levels are below the
level within which the vestibulo-ocular reflex generally
functions (Tables 38-3 and 38-4).
Figure 38-11. Caloric responses of a patient who has no unilateral weakness,
but who does have spontaneous nystagmus with rightward slow phases.
Saccade Test
This nystagmus created a bias; caloric responses were sym- The purpose of the saccade test is to detect abnormalities
metrical about a new baseline corresponding to the slow- of saccadic eye movement. The test is performed differ-
phase velocity of this nystagmus. It would be difficult to ently in various laboratories. In one version of the test, the
distinguish between the effects of this bias and a unilateral patient’s horizontal eye movements are monitored as she
caloric weakness on the basis of peak slow-phase velocities if fixates on a computer-controlled visual target that jumps
only one temperature of irrigant were used in the caloric test. back and forth in the horizontal plane in an unpredictable
When both warm and cool irrigants—eliciting responses in sequence. The complete sequence consists of 80 target
both directions—are used and then the sum of the two peak jumps (40 to the right and 40 to the left) with amplitudes
responses is used as the measure of response strength of a ranging from 5 to 25 degrees. After testing, the computer
particular ear, the effects of the bias are canceled and a valid deletes invalid eye movement data, then calculates three
comparison between the two ears is possible. values—peak velocity, accuracy, and latency—for each sac-
Figure 38-11 shows the caloric responses of a patient cade and plots these data in graphic form.
who does not have a unilateral caloric weakness, but does Patients may show abnormalities on any of these three
have spontaneous nystagmus with rightward slow phases at measures. Figure 38-12 shows saccade test data of a patient
velocities of about 10 degrees/sec, which creates a new with abnormally slow saccades bilaterally, which are char-
baseline on which the caloric responses are superimposed. acteristic of many degenerative and metabolic diseases of
The spontaneous nystagmus in this case cannot be attrib- the central nervous system. Patients may also show abnor-
uted to a recent unilateral peripheral vestibular lesion, since malities of saccade accuracy, making saccades that are too
the caloric responses of the two ears are equal. A lesion small or too large, indicating a lesion of the cerebellar
within the central vestibular pathways could have caused nodulus. They may also show abnormally long saccade
it, but other explanations, such as recovery of a previously latencies, which have been associated with lesion of the
compensated for peripheral lesion, are also possible. frontoparietal cortex.10
Therefore spontaneous nystagmus that cannot be attrib- Some examiners also monitor vertical eye movements as
uted to a recent unilateral peripheral vestibular lesion must the patient performs vertical saccades, although the verti-
be regarded as nonlocalizing. cal eye movement tracing is often difficult to interpret and
Although the bithermal caloric test is highly sensitive to well-established normal limits are lacking. Also if the
unilateral peripheral vestibular lesions, it is relatively examiner detects internuclear ophthalmoplegia during the
insensitive to bilateral lesions. The reason is that the pretest eye movement examination, he will monitor eye
caloric stimulus is uncalibrated. Even though the stimulus movements separately for each eye in order to document
at the entrance to the external ear canal is the same for this abnormality.
everyone, the amount of stimulus reaching the inner ear
varies widely across individuals due to differences in the
size and shape of the ear canal and middle ear structures. Pursuit Tests
Therefore, normal limits for absolute response intensity
are extremely wide, and bilateral caloric weaknesses must TABLE 38-4. Limitations of Caloric Testing
be extreme to fall below them. The usual rule of thumb is
that a bilateral weakness exists if caloric responses (warm 1. Caloric stimulus is:
poorly controlled
response plus cool response) of both ears fall below poorly tolerated
12 degrees/sec. A bilateral weakness usually indicates bilat- an unnatural way of vestibular stimulation
eral peripheral vestibular lesions.8,9 Central nervous system considered to be a very low frequency test of vestibular function
(CNS) disorders also produce bilateral weaknesses, but 2. Measures relative function, one ear with respect to the opposite ear
3. Measures only lateral semicircular canal function
other signs of CNS dysfunction usually accompany bilat- 4. Does not test the dynamic range of the vestibular system (much like
eral weaknesses of CNS origin. Patients with labyrinthine testing the auditory system with a single frequency)
hypofunction may demonstrate reduced or absent caloric
616 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Figure 38-14. Optokinetic test results of the patient whose tracking test
results are shown in Figure 38-13.

This patient’s abnormality indicates an asymmetrical CNS

lesion involving the pursuit eye-movement control system.
The optokinetic test is also performed differently in dif-
ferent laboratories. In one version, the patient’s horizontal
Figure 38-12. Saccade test results of a patient with slow saccades bilaterally.
Saccade accuracies and latencies are normal.
eye movements are monitored as she follows a series of
visual targets moving first to the right and then to the left.
This stimulus provokes nystagmus with slow phases in the
direction of target motion, periodically interrupted by fast
Two tests of pursuit—the tracking test and the optokinetic phases in the opposite direction.
test—are commonly performed in the ENG examination. The optokinetic test, like the tracking test, is a test of
The tracking test is performed in different ways in vari- pursuit eye-movement pathways, and the results of the
ous laboratories. In one version, the patient’s horizontal tracking and optokinetic tests agree if task difficulty is the
eye movements are monitored as he follows a computer- same. In normal individuals, the velocities of nystagmus
controlled visual target moving in the horizontal plane. slow phases approximately match target velocity for both
The target moves back and forth following a sinusoidal rightward- and leftward-moving targets. Figure 38-14
waveform at frequencies from 0.2 to 0.7 Hz. After testing, shows the results of the optokinetic test for the patient
the computer deletes invalid eye movement data. Then it whose tracking test results were shown in Figure 38-13.
deletes interpolated saccades, differentiates the eye position Her optokinetic nystagmus was virtually absent for left-
signal, calculates the gain of eye velocity with respect to ward-moving targets and mildly reduced for rightward-
target velocity separately for rightward and leftward track- moving targets.
ing at each target frequency, and plots these data. Normal
individuals are able to follow the target smoothly in both
directions at all target frequencies. SUMMARY
Figure 38-13 shows the results of the tracking test in a
patient with a unilateral pursuit defect. The patient was Although ENG essentially replicates portions of the physi-
unable to follow the leftward-moving target smoothly and cal examination, it is an important part of the evaluation of
instead approximated its motion using successive saccades, many complaints of dizziness or balance disturbance. ENG
producing a stairstep pattern on the eye movement trac- testing has a number of advantages: (1) the results of the test
ing. Tracking of rightward-moving targets was normal. are quantified, and the normal limits are well-defined; (2)
the bithermal caloric cannot be done as accurately without
the precise stimulus control and response quantification
provided by ENG; (3) because ENG provides accurate doc-
umentation of results, it can be used to follow the patient
with known vestibular disease; (4) standardized documenta-
tion is helpful in medicolegal and workers’ compensation
cases; and (5) it is the only test that tests each ear separately
and can give side-of-lesion localizing information.

Normal Electronystagmography Does

Not Rule out Vestibulopathy
Results of ENG testing may fluctuate in concordance with
the patient’s disease process. Two of the more common ill-
nesses seen in our patients are BPPV and Ménière’s disease
(MD). Both illnesses can be associated with a normal ENG
despite “classic” symptoms. For example, on the day of
testing a patient with complaints consistent with BPPV,
Figure 38-13. Tracking test results of a patient with an asymmetrical pursuit the response may have been fatigued or the disease may
defect. Upward pen deflection on horizontal eye position tracing denotes have gone into remission. For that patient, the test results
rightward eye movement. may be normal or indicate a unilateral vestibular weakness
 Electronystagmography and Rotation Tests 617

on the suspect side. Nevertheless, we maintain clinical sus- 20 seconds. The status of the VOR was then evaluated by
picion of BPPV, and we ask the patient to return for retest- comparing the duration of the evoked nystagmus. In 1948
ing on a particularly “dizzy day.” Similarly, the patient Von Egmond and coworkers proposed an elaboration of
suspected of having MD may have a normal ENG early in this test called cupulometry, and the duration of nystagmus
the course of the illness, and only later, on a particularly in response to a series of velocity steps was measured and
“dizzy day,” will the caloric evaluation demonstrate a uni- plotted as a function of stimulus velocity. The use of the
lateral peripheral weakness, gaze-evoked nystagmus, or sinusoidal stimuli was introduced with the advent of the
even spontaneous nystagmus. It is important to have torsion swing test. In this test, the subject was seated on a
patients abstain from taking vestibular suppressant med- spring-loaded chair that oscillated back and forth when the
ications (e.g., diazepam) for at least 48 to 72 hours prior to chair was pressed against the springs and then released.
ENG, as this can also be a cause of a “false-negative” test. The springs were calibrated so that the chair underwent
sinusoidal oscillation at 0.05 Hz. These methods of testing
Abnormal Electronystagmography Does proved to be of limited clinical value due to their insensi-
tivity to common vestibular abnormalities.
Not Always Rule in Vestibular Disease Rotation testing entered the modern era in the 1960s
as the Cause of Dizziness when methods became available for generating precise,
Some patients may present with dizziness not related to repeatable rotational stimuli and for making quantitative
vestibular system dysfunction, for example, syncope or measurements of eye movements. Today, computers
presyncope, vertebral basilar insufficiency, migraine- control all aspects of rotation testing including stimulus
associated dizziness, multiple sclerosis, ocular dizziness, generation, response measurement, and data analysis.
motion sickness syndrome, or cardiovascular disease. In
these patients, a unilateral weakness found on ENG does Rotary Chair Test
not necessarily implicate vestibular dysfunction as the
cause of their symptoms. The ENG finding may be inci- The most widely used rotation test is the so-called slow
dental and must be considered in light of the clinical harmonic acceleration test.11 The patient is seated in a chair
history and physical examination. mounted on a servo-controlled torque motor enclosed
within a light-proof, sound-attenuating booth. The hori-
zontal semicircular canals are in the plane of rotation, and
It Is Important to Test the Patient horizontal eye movements are monitored by EOG, the
When Symptomatic if Possible same method used in ENG testing. The patient is tested in
total darkness with eyes open while performing mental
The ENG results may change with the course of disease;
arithmetic. She undergoes sinusoidal oscillation about a
some patients may be in remission, and others may have
vertical axis at several different frequencies. The exact test
their disease escalate later. We therefore try to test patients
protocol varies somewhat among laboratories, but a com-
without medication on the day of their complaint of dizzi-
monly used procedure employs oscillation frequencies of
ness if at all possible.
0.01, 0.02, 0.04, 0.08, 0.16, 0.32, and 0.64 Hz, with peak
ENG testing is an important tool in the management of
angular velocities of 50 degrees/sec at each frequency.12
dizziness. It is by no means a substitute for a thorough
The patient undergoes multiple cycles of oscillation at each
neurotologic history and physical examination, and results
frequency.
should be interpreted in light of the clinical evaluation.
The relationship between head and eye movement dur-
Those who use ENG testing should have a thorough
ing several cycles of sinusoidal oscillation for a normal
understanding of how the test is performed, what its
individual is shown in Figure 38-15. The oscillation fre-
components are and the significance of the results. The
quency in this example is 0.16 Hz, which is near the mid-
clinician with a critical eye should always evaluate ENG
dle of the test frequency range. Figure 38-15, top, shows
reports. When used properly, ENG is the single most
head angular velocity. Figure 38-15, middle, shows hori-
valuable test currently available in the vestibular laboratory.
zontal eye position recorded by EOG. The patient has
nystagmus with leftward slow phases when her head moves
rightward and nystagmus with rightward slow phases when
ROTATION CHAIR TEST her head moves leftward. As shown in bottom graph of
Figure 38-15, the computer then differentiates the eye
History position signal, removes nystagmus fast phases, and dis-
Rotational tests have been used to evaluate vestibular func- plays slow-phase eye velocity. The computer then com-
tion for nearly a century. Over the years, various testing pares the head velocity and slow-phase eye velocity and
methods have been tried, but the one that has proven most calculates three measurements—phase, gain, and symme-
useful involves positioning the patient so that the rotational try—for each of the test frequencies.
axis is vertical and passes through the center of her head, The purpose of the vestibulo-ocular reflex is to produce
thus stimulating only her horizontal semicircular canals. eye movements that compensate for head movements. If
Horizontal eye movements are monitored. the reflex performs perfectly, the slow-phase eye velocity
Rotation tests have been used to evaluate vestibular func- plot in Figure 38-15, bottom, would have the mirror
tion for a century. Bárány, in 1907, described an impulsive image of the head velocity plot in Figure 38-15, middle.
rotation test in which the subject was brought to a sudden However compensation is less than perfect. The gain of
stop after manual rotation of approximately 10 turns within slow-phase eye velocity signal with respect to head veloc-
618 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Figure 38-16. Phase, gain, and asymmetry values in relation to oscillation

frequency for a normal person. Note that the eye velocity signal is inverted
during analysis, so that a phase angle of 180 degrees is expressed as a
phase angle of 0 degrees.

in a patient who underwent the slow harmonic accelera-

tion test shortly after the sudden onset of severe vertigo.
ENG, performed at the same time as rotation testing,
showed left-beating spontaneous nystagmus as well as
weak caloric responses from the right ear. At the lower
oscillation frequencies, this patient displayed progressively
Figure 38-15. Head and eye movement of a normal person during oscillation greater than normal phase leads, which is thought to be
at 0.16 Hz. Upward pen deflection denotes rightward movement.
caused by a loss of velocity storage that is normally pro-
vided by the central vestibular system to enhance the low-
frequency response of the vestibulo-ocular system.14–16
ity is only about 0.6. In other words, the eyes do not move Loss of velocity storage seems to represent habituation to
quite fast enough during the nystagmus slow phases to the strong tonic asymmetry produced by the unilateral
compensate entirely for head movements. peripheral vestibular lesion.17 Loss of velocity storage is
The relationship between slow-phase eye velocity and not an exclusive feature of unilateral peripheral vestibular
head velocity is described by two parameters in addition lesions. It is seen in a variety of vestibular disorders, both
to gain. The first parameter, phase angle, is a measure peripheral and central, and has also been observed in nor-
of the timing relationship between eye and head velocity. mal individuals who have undergone prolonged rotation.18
In Figure 38-15, the direction of slow-phase eye velocity is This patient also has a rightward asymmetry. That is,
exactly opposite the direction of head velocity at all times; nystagmus with rightward slow phases is stronger than nys-
that is, the phase angle is 180 degrees. The second param- tagmus with leftward slow phases. At low oscillation fre-
eter, symmetry, is the ratio of rightward and leftward quencies, the asymmetry is about equal to the slow-phase
slow-phase eye velocities. In Figure 38-15, slow-phase eye velocities of the patient’s spontaneous nystagmus with eyes
velocities are roughly equal in the two directions. closed; but at higher frequencies, the asymmetry is greater
Figure 38-16 shows graphic plots of phase, gain, and sym- than could be accounted for by the spontaneous nystagmus.
metry data (from left to right in the figure) for a normal This additional asymmetry is thought to be due either to
individual over the entire range of test frequencies. Phase saturation of inhibitory responses of the intact labyrinth
and gain values show the progressive phase lead and gain during rotation toward the side of the lesion or to an asym-
reduction as oscillation frequency decreases. Symmetry
values are approximately zero at all frequencies. At the
higher frequency of 0.64 Hz, these relationships are about
the same as they are at 0.16 Hz, but when the person is
oscillated at progressively lower frequencies of 0.04, and
finally 0.01 Hz, these relationships show progressive
change. Slow-phase eye velocities exhibit progressively lower
gains, and they are no longer exactly opposite in phase, but
rather displayed progressively larger phase leads.13 In other
words, changes in slow-phase eye velocity occur more and
more in advance of head velocity.
The slow harmonic acceleration test shows abnormali-
ties primarily at the lowest and at the highest oscillation
frequencies. Low frequencies reveal abnormal phase leads
and gain reductions. High frequencies reveal asymmetries.
Patients with acute unilateral peripheral lesions show the Figure 38-17. Phase, gain, and asymmetry values in relation to oscillation
most severe abnormalities. Figure 38-17 shows test results frequency for a patient with an acute right peripheral vestibular lesion.
 Electronystagmography and Rotation Tests 619

Figure 38-18. Phase, gain, and asymmetry values in relation to oscillation Figure 38-19. Phase, gain, and asymmetry values in relation to oscillation
frequency for a patient with a chronic left peripheral vestibular lesion. frequency for a patient with bilateral absence of caloric responses, showing
absent responses at all oscillation frequencies. Phase values were not plotted
due to low response gains.
metrical loss of velocity storage.19 This response pattern—
abnormal low-frequency phase leads and high-frequency
asymmetry—is routinely observed in patients with acute
unilateral peripheral vestibular loss, and the asymmetry is The remaining 27 patients showed various abnormalities
always toward the side of the loss.20 on ENG, mostly either evidence of CNS system dysfunc-
A second type of abnormality consists solely of abnor- tion or a combination of abnormalities.
mally large phase leads at the lower oscillation frequencies. The slow harmonic acceleration test also shows abnor-
An example is seen in Figure 38-18 from a patient with a malities in patients with bilateral loss of vestibular function.
left acoustic neuroma. ENG showed a severe left caloric An example is shown in Figure 38-19. This is a patient with
weakness in this patient. The rotation test abnormality seen total bilateral absence of caloric response of unknown
here is presumed to reflect the same loss of velocity storage origin. Rotation confirmed the bilateral caloric loss. The
that is seen in patients with acute vestibular disorders. The patient failed to show a clear nystagmus response at any
velocity storage loss is persistent, remaining for years oscillation frequency.
following vestibular malfunction although partial recovery The result shown in Figure 38-19 is actually quite
nearly always occurs.21,22 uncommon. Most patients with bilateral absence of caloric
The absence of tonic asymmetry in this patient illustrates response show absent responses or reduced response gains
the effect of vestibular compensation. If a peripheral at the lower oscillation frequencies, but normal gains at the
vestibular lesion develops slowly, as it generally does in a highest frequencies. An example is shown in Figure 38-20
patient with acoustic neuroma, the compensation process is from a patient who developed unsteadiness following a
able to rebalance the tonic asymmetry continuously and course of gentamicin therapy and showed a bilateral
therefore to prevent the vertigo and spontaneous nystagmus absence of caloric response. Baloh and colleagues reported
that would otherwise occur. Even when the lesion develops that rotation testing often demonstrates normal vestibular
suddenly, as it did in the previous patient with vestibular function at high frequencies even when ice water irriga-
neuritis, compensation would quickly rebalance the tonic tions have failed to provoke a response from either ear.25 In
asymmetry over a period of days.23 Thus the response pat- these cases, the results of caloric and rotation tests are not
tern in a patient with an acute lesion like that shown in contradictory, since the caloric response is a response to a
Figure 38-17 would evolve into a pattern like that shown low-frequency stimulus and therefore should be similar to
in Figure 38-18 if the patient were tested after a few weeks. responses to low-frequency rotational stimuli. However, in
This response pattern—abnormal low-frequency phase
leads—is by far the most common abnormality seen in the
slow sinusoidal rotation test. Stockwell reported abnormal
low-frequency phase leads as the sole abnormality on the
slow harmonic acceleration test in 109 of 305 dizzy
patients.24 Twenty-seven of these patients showed no
abnormalities on ENG—eight with a diagnosis of unilat-
eral Ménière’s disease and the rest scattered across diagnos-
tic categories. Fifty-five of these patients showed evidence
of a chronic unilateral peripheral vestibular lesion, that is, a
significant unilateral caloric weakness without significant
spontaneous nystagmus, and most were diagnosed as having
either Ménière’s disease or acoustic neuroma. The caloric
weaknesses in these patients were nearly always greater
than 50%. Patients with unilateral caloric weaknesses of Figure 38-20. Phase, gain, and asymmetry values in relation to oscillation
less than 50% generally did not show abnormal phase leads. frequency for a patient with bilateral absence of caloric responses, showing
normal response gains at the higher frequencies.
620 PERIPHERAL AUDIOVESTIBULAR DISORDERS

other cases, rotation testing shows normal response gains at 6. Leigh RJ, Zee DS: The Neurology of Eye Movements.
all frequencies, despite absent caloric responses, indicating Philadelphia, FA Davis, 1991.
a false-positive caloric test result. Clearly the slow har- 7. Barber HO, Stockwell CW: Manual of Electronystagmography,
2nd ed. St. Louis, CV Mosby, 1980.
monic acceleration test is the procedure of choice in evalu-
8. Baloh RW, Jacobson K, Honrubia V: Idiopathic bilateral vestibu-
ating suspected bilateral loss of vestibular function. The lopathy. Neurology 39:272–275, 1989.
caloric test, even with ice water, does not define the extent 9. Chambers BR, Mai M, Barber HO: Bilateral vestibular loss, oscil-
of the loss and sometimes yields false-positive results. lopsia, and the cervico-ocular reflex. Otolaryngol Head Neck Surg
93:403–407, 1985.
10. Leigh RJ, Zee DS: The Neurology of Eye Movements.
Clinical Indications for Rotational Philadelphia, FA Davis, 1991.
Chair Testing 11. Stockwell CW, Bojrab DI: Background and Technique of Rotational
Testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
RCT stimulates both peripheral vestibular systems simul- Handbook of Balance Function Testing. St. Louis, Mosby Year Book,
taneously; however, it may be helpful in determining the 1993, pp 237–248.
site of lesion in certain disorders. Clinicians have made 12. Shepard NT: Rotational chair testing. In Goebel JA (ed.): Practical
some suggestions as to when chair testing may be helpful Management of the Dizzy Patient. Philadelphia, Lippincott
in patient evaluation. Williams & Wilkins, 2001, pp 129–141.
First, when the ENG is normal and oculomotor results 13. Stockwell CW, Bojrab DI: Interpretation and usefulness of rota-
are either normal or observed abnormalities would not tional testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
invalidate rotational chair results. RCT is used to expand Handbook of Balance Function Testing. St. Louis, Mosby Year Book,
1993, pp 237–248.
the assessment of peripheral system dysfunction and status
14. Raphan T, Matsuo V, Cohen B: Velocity storage in the vestibulo-
of compensation. Second, when the ENG suggests a well- ocular reflex arc (VOR). Exp Brain Res 35:229–248, 1979.
compensated state, despite the presence of a clinically sig- 15. Honrubia V, et al: Vestibulo-ocular reflexes in peripheral
nificant unilateral weakness and active symptomatology. labyrinthine lesions: I. Unilateral dysfunction. Am J Otolaryngol 5:
RCT is used to expand the investigation of compensation 15–26, 1984.
in a patient with a known lesion site and complaints sug- 16. Raphan T, Matsuo V, Cohen B: Velocity storage in the vestibulo-
gesting poor compensation. Third, when the caloric irriga- ocular reflex arc. Exp Brain Res 35:229–248, 1979.
tions are below 10 degrees/sec bilaterally, when caloric 17. Honrubia V, et al: Vestibulo-ocular reflexes in peripheral,
irrigations cannot be performed, or when results in the two labyrinthine lesions: I. Unilateral dysfunction. Am J Otolaryngol 5:
ears may not be compared reliably because of anatomic 15–26, 1984.
18. Baloh RW, Henn V, Jager J: Habituation of the human vestibulo-
variability. RCT is used to verify the presence of and define
ocular reflex by low frequency harmonic acceleration. Am J
the extent of a bilateral weakness or to investigate further Otolaryngol 3:235–41, 1982.
the relative responsiveness of the peripheral vestibular 19. Honrubia V, et al: Evaluation of rotatory vestibular tests in periph-
apparatus in each ear when caloric studies are unreliable or eral labyrinthine lesions. In Honrubia V, Brazier MAB (eds.):
unavailable. Lastly, when a baseline measure is needed to Nystagmus and Vertigo. Clinical Approaches to the Patient with
follow the natural history of the patient’s disorder (e.g., Dizziness. New York, Academic Press, 1982, pp 57–78.
possible early Ménière’s disease) or to assess the effective- 20. Stockwell CW, Bojrab DI: Interpretation and usefulness of rota-
ness of a particular treatment (such as chemical ablation). tional testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
Handbook of Balance Function Testing. St. Louis, Mosby-Year Book,
1993, pp 237–248.
21. Stockwell CW, Bojrab DI: Interpretation and usefulness of rota-
REFERENCES tional testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
Handbook of Balance Function Testing. St. Louis, Mosby-Year Book,
1. Baloh RW, Honrubia V, Jacobson K: Benign positional vertigo: 1993, pp 237–248.
Clinical and oculographic features in 240 cases. Neurology 37: 22. Honrubia V, Jenkins HA, Baloh RW, et al: Vestibulo-ocular reflexes
371–378, 1987. in peripheral labyrinthine lesions: I. Unilateral dysfunction. Am J
2. Baloh RW, Sakata SM, Honrubia V: Benign paroxysmal positional Otolaryngol 5:15–26, 1984.
nystagmus. Am J Otolaryngol 1:1–6, 1979. 23. Halmagyi GM, Curthoys IS: Clinical changes in vestibular function
3. Baloh RW, Jacobson K, Honrubia V: Horizontal semicircular canal with time after unilateral vestibular loss. In Herdman SJ (ed.):
variant of benign positional vertigo. Neurology 43(12):2542–2549, Vestibular Rehabilitation. Philadelphia, FA Davis, 2000, pp 172–194.
1993. 24. Stockwell CW: Vestibular function testing: 4-year update. In
4. Baloh RB, Spooner JW: Downbeat nystagmus: A type of central Cummings CW, et al (eds.): Otolaryngology-Head and Neck
vestibular nystagmus. Neurology 31:304–310, 1981. Surgery: Update II. St. Louis, Mosby-Year Book, 1989, pp 39–53.
5. Fisher A, Gresty M, Chambers BR, Rudge P: Primary position up 25. Baloh RW, et al: Changes in the human vestibulo-ocular reflex after
beating nystagmus: A variety of central positional nystagmus. Brain loss of peripheral sensitivity. Ann Neurol 16:222–228, 1984.
106:949–964, 1983.
 Chapter
Ménière’s Disease

Outline 39
Introduction Endolymphatic Sac Surgery Stephanie Moody Antonio, MD
Definitions Endolymphatic Sac Surgery
Rick Friedman, MD, PhD
Reporting Criteria Technique
Incidence Vestibular Nerve Section
Clinical Presentations and Gentamicin
Natural History Cochleosacculotomy
Etiology and Pathophysiology Cochleosacculotomy
Theories of Pathogenesis Technique
Anatomic Factors Transcanal Labyrinthectomy
Viral/Immune Theory Transcanal Labyrinthectomy
Allergy Technique
Genetics Transmastoid
Post-traumatic Hydrops Labyrinthectomy
Delayed Hydrops Transmastoid
Labyrinthectomy Technique
Clinical Evaluation
Translabyrinthine Vestibular
Differential Diagnosis
Nerve Section
Medical Management Translabyrinthine Vestibular
Acute Treatment Nerve Section Technique
Prophylaxis
Surgery and Hearing
Diuretics Outcomes
Vasodilators
Surgery and Quality of Life
Steroids
Other Approaches
Allergy Management
Gentamicin and Surgical
Management

INTRODUCTION object to randomization to a nontreatment or sham treat-

ment control group.1
Ménière’s disease (MD) is the idiopathic disorder defined by
a symptom complex of episodic vertigo, fluctuating hearing
loss, tinnitis, and aural fullness. Its etiology and pathophysi- DEFINITIONS
ology are incompletely understood. The underlying pathol-
ogy is thought to be endolymphatic hydrops, and many The diagnosis of classical MD is suspected based on the
processes are suspected to share this end point, including clinical history. People with MD experience incapacitating
viral infection, allergy, and autoimmunity. The treatment of vertigo, often with nausea and vomiting, typically lasting
MD remains controversial partly because of the unpre- hours. Dysequilibrium of a more constant nature may per-
dictable nature of the disease with periods of remission and a sist for 24 to 72 hours after the attack, but it usually
substantial rate of spontaneous resolution. Empirical medical resolves completely. Otologic complaints include tinnitis
therapy consists of low-salt diet and diuretic medication, but and pressure in the head or ear during vertigo spells.
this approach is unproved. Surgical intervention continues to Audiologic evidence of fluctuating low-frequency or pro-
prompt heated debate. Randomized placebo-controlled tri- gressive sensorineural hearing loss is required to confirm
als are very difficult to perform for several reasons: (1) MD the diagnosis. Tinnitis, hearing loss and aural pressure
lends itself poorly to definition and staging, (2) defining allow identification of the affected ear.
treatment outcomes in a disease largely characterized by sub- The term cochlear hydrops describes fluctuating
jective symptoms is imprecise, and (3) placebo-controlled low-frequency hearing loss without associated vertigo.
trails are unfeasible as long as investigators and patients Fluctuating low-frequency hearing loss with tinnitis and
621
622 PERIPHERAL AUDIOVESTIBULAR DISORDERS

aural fullness may precede MD. Eventual development of TABLE 39-1. Reporting Recommendations
the full syndrome occurs in 37% to 42% of patients with for Ménière’s Disease
cochlear symptoms.2 Of patients with definite MD, 40% Vertigo Class Numeric Score* Description
have purely hearing symptoms prior to the first vertigo
attack.3 Class A 0 Complete control
Patients with severe and long-term MD are at risk Class B 1–40 Substantial control
of developing Tumarkin otolithic crisis, or drop attacks. Class C 41–80 Limited control
These are abrupt attacks of falling after loss of lower- Class D 81–120 Insignificant control
Class E >120 Worse
extremity muscle tone without loss of consciousness.4
The incidence is reported as 6% to 7% of patients with *Numeric score = 100 × Spells per month in 24 months after treatment.
MD, although in one report, the incidence was as high Spells per month in 6 months before treatment.
as 72%.5 The cause is thought to be a sudden stimulation
of the vestibular end organ by a shift of the utricular
macula or rupture of inner ear membranes,6 but the exact hearing thresholds at 500, 1000, 2000, and 3000 Hz; or a
cause is unknown. This symptom may be secondary to a change in a word recognition score of 15% or more. The
cardiac, cerebrovascular, or seizure process and these must worst pretreatment audiogram up to 6 months before treat-
be ruled out.7 ment is compared with the worst post-treatment audiogram
Lermoyez’s syndrome is a variant of MD wherein hear- at 18 to 24 months follow-up. Longer follow-up is pre-
ing loss and tinnitis precede an attack of vertigo by days to ferred.10 These guidelines for defining the disease and
months, subsiding with the onset of vertigo.8 The patho- reporting treatment outcome provide a common reference
physiology is unknown. In one patient with the syndrome point for critical assessment of treatment efficacy as
whose temporal bones were studied, hydropic changes reported in the literature. Improved methods to classify
were limited to the upper basal turn and saccule in contrast and quantify this disease are needed.
to more wide involvement of the cochlea with classic MD.9 New clinimetric methods for the study of MD have
been developed, including clinical scales of dizziness,
hearing loss, and tinnitus. These types of scales may
REPORTING CRITERIA provide valuable insight into the natural history and
management of MD since they allow quantification of sub-
The Committee on Hearing and Equilibrium of the jective symptoms. In addition, the disability resulting from
American Academy of Otolaryngology–Head and Neck these symptoms is influenced by psychological, physical,
Surgery publishes guidelines for defining, reporting, and and social-support structures. Common scales include the
interpreting results of the treatment of MD.10 (We suggest Dizziness Handicap Inventory (DHI),11 the Tinnitus
familiarity and attention to these criteria to anyone Handicap Inventory (THI),12 and the Hearing Handicap
reviewing the literature.) Diagnostic criteria for MD are Inventory for Adults (HHI).13
categorized as certain, definite, probable, or possible MD.
Certain MD includes definite MD plus histopathologic
confirmation. Definite MD is specifically defined as the INCIDENCE
presence of recurrent, spontaneous episodes of vertigo,
documented hearing loss, aural fullness, and tinnitus. The incidence of MD is difficult to determine because of
Either tinnitus or aural fullness must be present. the character of the disease, with the sometimes subtle
The vertigo episodes last at least 20 minutes but more onset (cochlear symptoms only), fluctuating symptoms,
commonly for hours, are disabling, and are accompanied long periods of remission, and inconsistency in establish-
by nausea and vomiting. The diagnosis of MD requires at ing the diagnosis.14 Studies from Sweden and Great
least two definitive spells of 20 minutes or longer. Britain estimate the occurrence of MD in those popula-
Probable MD is defined by only one episode of vertigo tions as 46 in 100,000 people and 100 in 100,000 people,
with hearing loss and tinnitus or aural fullness. Possible respectively.15,16 In the population of Rochester,
MD may be used to describe typical episodic vertigo with- Minnesota, the annual incidence between 1951 and 1980
out hearing loss or sensorineural hearing loss with dizzi- was 15.3 per 100,000 and the prevalence on January 1,
ness, but without definitive episodes. Underlying causes 1980, was 218 per 100,000 population.17 In Finland, the
for the syndrome (otosclerosis, syphilis, trauma, etc.) are incidence was 4.3 per 100,000 per year in 1992 to 1996
excluded prior to the assumptive designation of idiopathic and the prevalence in 1996 was 43 per 100,000.18
MD. Specific criteria were outlined by the Committee for The onset of symptoms peaks at 40 to 60 years of age.
Requisite Hearing Loss. The disease is uncommon in children.3,19,20 Bilaterality is oft
When reporting treatment outcomes, the frequency of
attacks during the 6 months before treatment should be
compared with that of 18 to 24 months after treatment. TABLE 39-2. Stages of Ménière’s Disease
A numeric scale and a disability scale were suggested Stage Four-Tone Average (dB)
(Table 39-1). These scales can be used to evaluate changes as
improved, unchanged, or worse. Hearing stage (Table 39-2) 1 ≤ 25
can be applied to certain or definite MD. The criteria for 2 26–40
3 41–70
the determination that a hearing change is significant are a 4 >70
change of 10 dB or more in pure tone average (PTA) of
 Ménière’s Disease 623

debated with reported incidence ranging from 10% to for 20 years or longer, most have hearing loss of 50 dB or
70%.3 The frequency of bilateral disease increases with more and all have at least 30 dB of loss.21 Tinnitus and
time, and at 20 years reached 47% in 161 patients followed aural fullness are present in the majority of patients in the
in Sweden.21 In Haye and Quist-Hanssen’s longitudinal long term.20
study of 111 patients and in Green, Blum, and Harner’s Quality of life measures suggest MD adversely affects
study of 108 patients, 37% and 34%, respectively, developed daily life.24,25 Symptoms of MD correlate with other
bilateral disease.3,20 Subclinical disease in the asymptomatic medical and psychological complaints such as dysphoria,
ear was observed by Paparella who found that 78.6% of anxiety, insomnia, and lack of concentration.24 Using the
patients with clinically unilateral MD had abnormal audio- Medical Outcomes Survey-Short Form, Kinney found that
metric findings in the asymptomatic ear and that 32% had patients with MD functioned like patients with minor
the complete criteria necessary to diagnosis MD in that medical conditions on physical functioning subtests, but
ear.22 Friedrichs and Thornton used the traveling wave more like patients with major medical conditions for vitality,
velocity test (based on the stiffness of the basilar membrane) social function, and role limitations, and poorer than
and diagnosed subclinical hydrops in 27% of the contralat- patients with major medical conditions for mental health.26
eral ears in 100 patients with clinically unilateral MD.23
ETIOLOGY AND PATHOPHYSIOLOGY
CLINICAL PRESENTATION AND
NATURAL HISTORY The etiology and pathophysiology of MD are not known.
Some proposed etiologies of “idiopathic” MD are
The typical presentation of MD includes sudden attacks of anatomic abnormality, viral infection, autoimmune
vertigo with unilateral hearing loss, tinnitus, and aural full- disease, and allergy. The underlying cause-and-effect
ness. The vertigo is incapacitating, often with nausea and relationship of these possible etiologies on the function of
vomiting, lasting several hours. It is not uncommon for the inner ear and endolymphatic system is unknown.
vertigo to last only minutes or for as long as 24 hours. One of the most well accepted theories of the patho-
Dysequilibrium accompanies the vertigo and may persist genesis of MD is based on the belief that endolymphatic
for 24 to 72 hours after the acute vertigo subsides. hydrops is the pathological correlate of MD. In this
Between attacks patients are usually completely asympto- theory, hydrops is caused by mechanical obstruction to
matic, but may describe persistent disequilibrium. endolymphatic flow or by intrinsic malfunction of the
Some patients describe a chronic state of dizziness with endolymphatic system resulting in an overabundance
intermittent superimposed vertigo spells. Patients may also of endolymphatic volume and/or pressure.27 There are
describe positioning vertigo. The attacks may be preceded many proposed mechanisms that may contribute to aber-
by an aura consisting of a vague sense of dizziness, aural rations in endolymphatic pressure and volume and
fullness, tinnitus, or a change in hearing. The attacks may endolymphatic sac and duct malfunction. While reading
also be sudden and without warning. Associated otologic the following discussion on the etiology and pathophysiol-
complaints include hearing loss, tinnitus, and pressure in ogy of MD, the reader should note that hydrops is not
the head or ear before or during the vertigo attack. All four specific to MD and several scientists have raised significant
classical symptoms are often not recognized and may not problems with the proposed theories. No alternative
be present during early disease. Some patients are so theory has been advanced.
distressed by the vertigo that they have not noticed these
problems until instructed to record them. Diplacusis can Theories of Pathogenesis
be an early signal and can sometimes be elicited by
a thorough history. Theories for the underlying mechanism that results in
The frequency of vertigo attacks varies widely with a hydrops include excessive endolymph production,
mean of 6 to 11 episodes per year.21 At worst, episodes can decreased endolymph resorption, fibrosis of the endolym-
occur 30 times per year.3 Attacks may occur in clusters or phatic sac or duct, and altered glycoprotein metabolism.28
on a regular schedule. Periods of remission may last years, As a pathologic sign only, hydrops may or maynot be asso-
only to be followed by recurrence. Spells tend to change in ciated with MD symptoms.27 A trigger or other mecha-
severity over time, becoming more mild; but once again, nism must therefore provoke an acute change in
this is unpredictable, and a long period of time with mild physiology that results in the symptom complex of MD.
spells may be suddenly ended with a severe spell. Typically, The cause of the sudden attacks of vertigo and aural symp-
the disease eventually “burns out” with decline and cessa- toms associated with MD remains unknown. Figure 39-1
tion of vertigo and progressive deterioration of hearing. is a flowchart of these various factors. Schuknecht devel-
With minimum follow-up of 9 years in 108 patients, oped a theory to explain the acute attacks as well as the
Green reported vertigo was completely absent in 54% and progressing hearing loss and dysequilibrium.6
decreased in 30%.20 Hearing fluctuates in the early course
The disease probably begins with a prodromal stage of gradual
of disease, but eventually becomes progressively worse,
distention of the endolymphatic system, which may be associ-
stabilizing at about 50 dB PTA and 50% word discrimi- ated with very few or no symptoms. As the distension progresses,
nation score. Low frequency hearing loss extends to there is thinning and atrophy of the more yielding parts of the
involve high frequencies and the audiogram develops a flat membranous labyrinth (Reissner’s membrane and saccular wall),
pattern.2 The majority of hearing loss occurs in the first which leads to ruptures and the sudden release into the reduced
few years of disease.2,21 In patients who have been observed perilymphatic space of large volumes of endolymph (Fig. 39-2).
624 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Figure 39-1. Multiple etiological factors might contribute to endolymphatic dysfunction. The exact nature of the mechanisms promoting inner-ear dysfunction
is unknown. The pathologic correlate is endolymphatic hydrops. Hydrops can remain asymptomatic or become Ménière’s disease under the influence of
a trigger that brings about a sudden devastation in endolymphatic flow, either by rupture of membranes or by sudden release of obstructed longitudinal
endolymphatic flow.

Consequently, the sensory and neural structures that are exposed Anatomic Factors
to this potassium-rich (neurotoxic) endolymph are paralyzed,
resulting in sudden hearing loss or vertigo. As the biochemical Anatomic variations in the endolymphatic system may play
components of the perilymphatic compartment are restored to a role in the development of endolymphatic hydrops.
normal, the symptoms subside. Aided by the collapse of the Several studies have documented that the vestibular aque-
distended membrane, the rupture heals and the stage is set for duct and the external aperture of the vestibular aqueduct
a repetition of the process. Progressive hearing loss can be attrib- are shorter and smaller and the endolymphatic sac and
uted to progressive disturbances in motion mechanics caused by duct are less frequently visualized radiographically, surgi-
the distorted, dilated, and collapsed membranes (Fig. 39-3) as well
cally, and pathologically in patients with MD.30–33
as a loss of specialized cell types and alterations in inner ear
biochemistry and bioelectric potentials.6 Whether this anatomic difference contributes to the
pathophysiology of MD is unclear.
Another theory emphasizes a vital role of the endolym- Viral/Immune Theory
phatic sac. In this theory, described by Gibson and
Arenberg,29 a disturbance in longitudinal flow of One of the most accepted theories of etiology for idio-
endolymph (possibly linked to a narrow vestibular aque- pathic MD is the viral/immune theory.34,35 In this theory, a
duct) from the cochlear duct to the endolymphatic sac virus gains access to the inner ear via the middle ear or
results in hydrops. The sac is postulated to actively regu- hematogenously. The initial event might be a direct effect
late the flow by maintaining an osmotic gradient and secret- of the viral infection and its inflammatory, immune, and
ing glycoproteins that attract movement of endolymph microvascular-mediated injury. Subsequent attacks might
toward the sac. In addition, the sac may produce saccin, a not be caused by active virus but by immune-mediated cel-
hormone thought to increase the volume of endolymph, lular damage to various structures of the inner ear includ-
which may promote faster flow. In an ear affected by MD, ing the stria vascularis, dark cells, and the endolymphatic
metabolic debris obstructs longitudinal flow. The sac system. The basis of this theory is that the endolymphatic
responds by secreting saccin and glycoproteins and the sub- sac is primarily responsible for the immunodefense of the
sequent increase in flow overcomes the obstruction and inner ear.34 An alternative explanation for the recurrent
clears the duct. The sudden restoration of movement of nature of attacks is reactivation of viruses commonly found
endolymph results in the sensation of vertigo. In later-stage latent in the vestibular and spiral ganglion cells, resulting
MD, the sac is no longer able to affect flow of endolymph in production of new viruses, which can migrate back
through an obstructed duct. Vertigo episodes subside but along axons to the peripheral branches and into the peri-
saccin secretion may continue, resulting in worsened lymph, where they can cause direct injury or can provoke
hydrops and persistent hearing loss. a local inflammatory reaction.35–37
 Ménière’s Disease 625

Semicircular canals
Reissners membrane
Endolymphatic duct

Saccule

Figure 39-2. A, Mechanism of Ménière’s

disease, endolymphatic hydrops.
Obstruction of the normal pathways of Ductus
longitudinal flow among the cochlear
reuniens
duct, ductus reuniens, saccule, saccular
duct, and endolymphatic duct results in
distention of the cochlear duct, saccule,
and endolymphatic sac. An enlarged Cochlear aqueduct Endolymphatic sac
saccule may compress and obstruct the
A
ductus reuniens, saccular duct, and
utricular duct. A herniated cochlear duct
may obstruct the saccule and ductus
reuniens. B, Mechanism of Ménière’s
disease, membrane rupture. Release of
obstruction by rupture of dilated
membranes may lead to reversal of flow Semicircular canals
with release of excess fluid through the
cochlear aqueduct. (Courtesy of Fred
Reissners membrane
Linthicum, Jr., House Ear Institute, Endolymphatic duct
Los Angeles.)

Saccule

Ductus
reuniens

Cochlear aqueduct Endolymphatic sac

B

Evidence for the viral theory includes the demonstration cytokines by cells of the spiral ligament.49 A positive clinical
of herpes simplex virus (HSV) DNA in the vestibular gan- response to corticosteroids further supports the role of an
glion and intraosseous endolymphatic sac,38–40 antiviral IgE immune phenomenon.35,36
in the sera of MD patients,41 and elevated anti-HSV IgG in Despite this evidence, a direct causal link of HSV or
the perilymph of MD patients,36 all with levels greater than immunological reactivity to MD cannot be definitive.28,50
controls. The pathologic features of axonal degeneration Studies are needed that further demonstrate a clinical
are thought to be consistent with a viral etiology.35 association between MD and HSV or autoimmunity, doc-
The importance of the immunologic activity in the ument virus or immune mediators in inner ear tissues of
pathophysiology of MD is supported by evidence of ele- affected patients, and establish an animal model with sim-
vated circulating immune complexes,42 the presence of ilar clinical and pathologic characteristics.51
serum autoantibodies to inner ear antigens greater than in
controls and greater than in patients with other otologic
conditions,43,44 and evidence that the endolymphatic sac is
Allergy
the source of the inner ear immune response.37,45 Gluco- Allergy may be another trigger for immune reac-
corticoid receptors have been identified in the stria vascu- tions resulting in MD. A significant number of patients
laris and may play a role in inner ear fluid homeostasis.46–48 with MD report airborne and food allergy.52 Patients
In addition, Adams documented the production of treated with desensitization and diet showed a significant
626 PERIPHERAL AUDIOVESTIBULAR DISORDERS

autosomal-dominant mode of inheritance, although an

X-linked dominant form has been described.58
Features of familial MD have emerged in the literature.
There is a reported association between familial cases
of MD and migraine headaches.54,55 Most clinical reports
demonstrate similarities in symptom severity and bilateral-
ity in familial and sporadic MD.59,60 Morrison and
colleagues, however, have detailed several distinctive
features of the familial variant.59 In their series, more
females were affected than males, a higher proportion
of children and adolescents were affected, and many fami-
lies displayed vestibular symptoms only. Based on the
variability of inheritance and phenotypic expression noted
in the literature, familial MD is likely a genetically
heterogeneous disorder.
A Several observations have been made that not only sug-
gest a genetic basis in some cases, but also present a possi-
ble mechanism for their molecular characterization. An
association between MD and immune response genes has
been identified.61,62 These findings are consistent with the
clinical observation of a coincidence of MD and immune
and allergic disease. The pathogenesis in these cases might
be explained by a genetic predisposition to the identifica-
tion and processing of certain immunogens, which affect
endolymphatic homeostasis either directly or indirectly.

Post-traumatic Hydrops
Post-traumatic MD has been described secondary to head
trauma, barotrauma, and surgical trauma. As opposed
to symptoms of perilymphatic fistula or vestibular concus-
B sion that occur immediately after injury, post-traumatic
MD occurs months to years later. The mechanism is
Figure 39-3. A, Membrane ruptures. Cochlea with diffuse hydrops unknown, but fistulization of the bony labyrinth, direct
(A). Rupture of Reissner’s membrane healed, but the thin membrane is now
distended and collapsed against the spiral ligament (B). The saccular membrane injury to the membranous labyrinth, or disruption of the
is dilated and fused to the footplate of stapes (C). B, Rupture outpouching. endolymphatic flow have been suggested.63
Rupture of ampullary wall (*) with collapse of healed membrane filling ampulla
(arrows). (Courtesy of Fred Linthicum, Jr., House Ear Institute, Los Angeles.)
Delayed Hydrops
Delayed hydrops is the new onset of MD symptoms in the
improvement from pretreatment to post-treatment in both setting of a previous severe hearing insult, usually unilat-
allergy and Ménière’s symptoms, including significant eral. The onset of vertigo of Ménière’s type occurs 20 years
reduction in the number and the severity of vertigo.53 later and can be either ipsilateral or contralateral. It might
include fluctuating hearing loss, tinnitis, and fullness,
especially notable in the contralateral cases. The etiology
Genetics of the preexisting hearing loss can be sudden deafness,
Genetic defects in structural proteins, growth factors or head injury, mumps, measles, mastoidectomy, meningitis,
their receptors, ion channels and pumps, or proteins and influenza, often occurring during childhood.64,65
responsible for regulating the developmental cascade of Acoustic trauma has also been associated with delayed
the many genes involved in auditory development can lead hydrops.66,67 Pathologic findings of delayed endolymphatic
to auditory and vestibular dysfunction. The complex hydrops have been documented by Schuknecht.68
processes underlying endolymphatic homeostasis are made
possible by the coordinated temporal and spatial expression
of many genes during embryonic and adult life. If a defect CLINICAL EVALUATION
in one of these “homeostatic” genes were in the germ line,
endolymphatic hydrops could be an inherited process. The diagnosis of MD is based on the history and confirmed
There have been several reports of familial Ménière’s by the documentation of low-frequency sensorineural hear-
disease in the literature dating back to the first reports ing loss. Diagnostic testing is desirable to confirm the diag-
by Brown in 1941 and 1949 and followed two decades later nosis before undertaking destructive treatment procedures
by Bernstein in 1965.54,55 Since that time, several reports and to rule out contralateral asymptomatic disease.69
have citied an incidence between 2.5% and 12%.56,57 Despite the introduction of several diagnostic methods,
The vast majority of these descriptions have suggested an none has yet proved to be the gold standard.69
 Ménière’s Disease 627

Audiometric findings include low-frequency sensorineural includes other manifestations of late syphilis, such as inter-
hearing loss (occasionally with a mild conductive compo- stitial keratitis, cardiovascular disease, and neurologic
nent), reduced discrimination, and loudness recruitment. abnormalities. In otosyphilis, pathologic findings include
In early stages of the disease, hearing loss fluctuates. In microgummata, inflammatory osteitis, endarteritis, and
later stages, the audiometric pattern becomes flattened degeneration of the neurosensory structures.82,83 Irre-
with extension of hearing loss to higher frequencies. In versible obstruction of the endolymphatic duct and sac is
some cases, the pattern is “tent-like,” with both low and associated with endolymphatic hydrops and is probably
high frequency hearing loss and a peak at about 2000 Hz. responsible for treatment failures (Fig. 39-4).82
Loudness recruitment, the abnormal growth of perceived Cogan’s syndrome includes episodic vertigo, hearing loss,
loudness with stimulus intensity, was found in all 200 and interstitial keratitis or other ocular findings but nega-
patients with MD in Hallpike’s series.69,70 Otoacoustic tive tests for syphilis. Atypical Cogan’s syndrome may
emissions have not been helpful in differentiating hydropic include iritis, scleritits, papilledema, or systemic autoim-
from normal ears.71,72 mune disease such as sarcoidosis, rheumatoid arthritis, or
Vestibular testing is difficult to interpret in the presence of Wegener’s granulomatosis. Temporal bone findings include
a highly variable and fluctuating disease. Although 30% endolymphatic hydrops, degeneration of the cochlear duct
to 50% of patients may show a unilateral weakness, another and labyrinth, and deposition of new bone.84
25% may have completely normal exams.15,69 Some patients Acute vertigo lasting longer than 24 hours with a slow
have hyperactive caloric testing.73 One group of authors has recovery over weeks with hearing loss and tinnitis is con-
suggested that vestibular testing may vary with stage,73 sistent with acute labyrinthitis. Vestibular neuritis is charac-
suggesting a progressive dysfunction from hyperactive to terized by acute vertigo of the same nature without
normal and finally to reduced responses.74 auditory symptoms.85 It can occur as a single episode or be
Electrocochleography has been studied as a technique for recurrent. Both the single and recurrent types are associated
identifying hydropic ears, but its clinical role remains
unclear. The summating potential tends to be increased in
diseased ears, possibly because the basilar membrane is
displaced toward the scala tympani.69 A summating poten-
tial to action potential ratio more than 0.3 to 0.5 is more
common in ears with active MD than in normal ears.69
The sensitivity of the test is low; however, various modifi-
cations have been suggested to improve the identification
of ears affected by hydrops.69,75,76
The role of computed tomography (CT) and magnetic
resonance imaging (MRI) in the diagnosis of MD is limited to
ruling out vestibular schwannoma or other solid lesion.
Nonvisualization of the endolymphatic sac by CT and by
MRI has been suggested to correlate with the presence of
MD.31,32,77,78 Positive MRI findings have been confirmed
during surgery78 and by histology.33 However, MRI does not
differentiate an active hydropic ear from the inactive
contralateral side.79 In a guinea pig model, standard 1.5-Tesla
MRI showed enlargement of the scala media by preferen-
A
tially enhancing the perilymph over the endolymph, allowing
a clear demarcation between the two chambers.80 Gadolinium
enhancement of the endolymphatic sac has been documented
in a series of patients with auditory and vestibular symp-
toms.81 Corroborative studies and clinical correlation are
needed to further investigate these findings. The continued
advancement in imaging technology will no doubt enhance
our understanding of MD.

DIFFERENTIAL DIAGNOSIS
As defined, MD is idiopathic. However, some cases of
endolymphatic hydrops associated with the specific symp-
tom complex (Ménière’s syndrome) are not idiopathic and
are associated with syphilis, Paget’s disease, otosclerosis, or
autoimmune inner ear disease.82 B
Congenital or acquired syphilis may produce Ménière’s
Figure 39-4. Congenital syphilis. A, Vestibular aqueduct obliterated with
syndrome. Clinically, the disease is more likely bilateral. inflammatory fibrosis with multinucleated giant cell reaction (A) and inflam-
Congenital syphilis is associated with Hutchinson’s teeth matory infiltrate (B). B, Diffuse cochlear hydrops. (Courtesy of Fred
and interstitial keratitis.82 Late-stage otosyphilis usually Linthicum, Jr., House Ear Institute, Los Angeles.)
628 PERIPHERAL AUDIOVESTIBULAR DISORDERS

with acute loss of caloric response. In sharp contrast to drugs useful for vertigo include benzodiazepines (diazepam),
Ménière’s disease, the vertigo is prolonged and is followed antihistamines (meclizine, promethazine, diphenhydramine,
by dysequilibrium that persists for months with slow dimenhydronate), anticholinergics (meclizine, glycopyrro-
recovery.85 The histopathology includes atrophy of late), and antidopaminergic (prochlorperazine, droperi-
peripheral vestibular nerve fibers and end organ.85 A viral dol).95 Severe episodes may be treated with courses of oral
etiology is suspected.40,85–87 steroid tapering over 5 to 10 days. In the authors’ experi-
Vascular compression syndrome can be characterized by ence, steroid burst treatment may lessen the severity of
recurrent disabling vertigo with or without hearing loss. acute vertigo and promote earlier recovery of hearing.
These patients typically complain of disabling motion
intolerance including dysequilibrium or vertigo when Prophylaxis
walking, after quick head movements, and while riding in
a car.88–91 McCabe and Gantz reported an erroneous diag- Several good review articles address long-term medical
nosis of MD in 52% of patients who eventually underwent therapy for MD.2,95–100 Sodium restriction is the foundation
vascular loop decompression.88 The diagnosis can be made of the treatment regimen. It is commonly thought that
with constructive interference in steady state (CISS) MRI.92 a low-salt diet will reduce sodium-related volume overload
Cerebellopontine angle tumors such as vestibular schwan- with subsequent redistribution to the endolymphatic
noma and meningioma can cause symptoms similar to space.95,100 The effects are likely more complicated than
those of MD. Endolymphatic sac tumors in the posterior a simple change of plasma or endolymph sodium level,
fossa have been reported to present with Ménière’s-like since a low-salt diet is known to have extremely little influ-
symptoms.93 Dizziness or hearing loss atypical for MD or ence on the plasma sodium level and sodium levels in den-
otherwise suspicious should be evaluated with gadolinium- dolymph are near normal in animal models with hydrops.101
enhanced MRI. Anecdotally, patients have reported acute symptoms after
Migrainous vertigo is a diagnosis based on the presence of excessive salt intake and a positive response to salt restric-
episodic vertigo with migraine and/or photophobia, tion. There are no randomized controlled trials (RCT)
phonophobia, and visual auras. In patients presenting to a to support this impression. Patients should be counseled to
neurologic dizziness clinic, 7% were diagnosed with defi- limit dietary salt to 2 grams per day.
nite migrainous vertigo.94 Vertigo may last longer than
that of typical MD, and patients often report a personal or Diuretics
family history of migraine, motion intolerance, and onset
of symptoms with visual cues. Hearing loss is uncommon The use of diuretics is based on circumstantial evidence
in this group and can help differentiate these patients from of a positive effect on hearing and vertigo with osmotic
those with MD. agents (glycerol, isosorbide), animal studies, a few nonran-
domized studies, and one RCT.95,97 Acetazolamide
s recommended because it is thought to inhibit carbonic
MEDICAL MANAGEMENT anhydrase in dark cells and in the stria vascularis, thereby
reducing endolymph production. Hydrochlorothiazide
There is no cure for MD; that is, at this time intervention and combination hydrochlorothiazide and triamterene
does not eliminate the underlying cause of disease. The goals are commonly employed, but the mechanism of action
of medical management of MD are control and reversal of is unclear. In a nonrandomized placebo-controlled study,
vestibular and cochlear injury. In light of the etiologic vari- Klockhoff and Lindblom showed a significantly better
ability and the lack of understanding of the pathophysiology response of vertigo, hearing loss, and general condition
of endolymphatic hydrops, the design and evaluation to treatment with hydrochlorothiazide than with
of specific therapeutic interventions are challenging. The placebo.102 Van Deelen and Huizing published the only
prolonged but the fluctuating nature of the disease and RCT and used a crossover placebo-controlled design.
subjective nature of most of its important symptoms make During 17 weeks of triamterene (Dyazide) treatment,
randomized controlled clinical trials extremely difficult to subjects had significantly fewer vestibular complaints,
perform. Current treatment strategies are based on anec- but no reduction in hearing loss or tinnitis.103
dotal evidence and personal opinion. Nonetheless, clinicians Retrospective studies have also supported diet and diuretic
have noted that medical strategies can control disease in 80% therapy.104,105 Inasmuch as the disease fluctuates over time,
of patients (based on reduced frequency of acute vertigo), patients can be weaned from treatment after 6 to
although no treatment has been decidedly shown to halt the 12 symptom-free months; treatment can be reinitiated
progression of hearing loss. It is difficult to prove that any when needed.
intervention is better than natural history alone. Specific
goals in the treatment of MD include reduction in the fre-
quency and severity of acute attacks of vertigo and hearing
Vasodilators
loss, reduction of tinnitis and aural fullness, reduction of Vasodilators were historically recommended based on the
progressive hearing loss, and improvement of quality of life. belief that ischemia of the stria vascularis caused MD.
Histamine (subcutaneous or sublingual) and betahistine
Acute Treatment (peroral) acting on H1 and H2 receptors cause capillary
dilation.106 The authors found no RCT of histamine
Vestibular suppressant and antiemetic medications are therapy. Betahistine (the oral analogue of histamine) has
generally effective in controlling acute vertigo. Classes of been studied in a few RCTs.107–109 Fraysse and colleagues
 Ménière’s Disease 629

noted a significant reduction in vertigo (in frequency, Allergy Management

duration, and severity of attacks) at 60 days of betahistine
treatment compared to flunarizine. Cochlear symptoms Allergy management may be indicated in selected patients.
were also reduced in the group treated with betahistine.108 Indications for allergy evaluation include bilateral symp-
Schmidt and Huizing found no difference in imbalance toms, symptoms linked to food, seasons, or weather,
between the two groups.107 In a double-blind crossover steroid-responsiveness, or failure to respond to traditional
study reported by Oosterveld, patients had significant treatment.53 In Derebery’s review53 of 113 patients treated
reduction of the incidence and severity of dizziness during with immunotherapy and/or food elimination/rotation diet,
6 weeks of beta-histine treatment compared with 6 weeks there was a significant reduction in vertigo, tinnitus, and
of placebo treatment. This study included patients with hearing loss compared to pretreatment. Although a statis-
other types of peripheral vertigo, and interestingly, the tical comparison was not made because the allergy-treated
author’s opinion was that patients with MD responded less group had significantly worse symptoms before treatment,
than did patients with other vestibular disorders.110 Other the control group (patients who refused allergy treatment)
vasodilators such as nicotinic acid (50 to 200 mg), vitamin rated their symptoms worse than did the treated patients at
C, bioflavonoid complex, probanthine (15 mg), and the end of the study. This suggests that not only did the
diphenhydramine (50 mg) can be added, but there is little treated group show significant improvement, but also they
objective evidence to support their use.95 improved to levels that appeared better than the control
group. Allergy therapy may include antihistamines, nasal
steroid sprays, systemic corticosteroids, immunotherapy,
Steroids and elimination and/or rotation food diets.117 Immunosup-
Mounting evidence of immune and inflammatory etiology pressive management is closely linked to allergy therapy for
of MD has motivated the investigation of steroids in the immune-mediated MD. Preliminary studies of methotrex-
long-term management of MD. Although systemic steroid ate and etanerocept show promise, but must be evaluated
may distribute to the endolymphatic sac, vestibular nuclei, further.118–120
and central nervous system, it does not readily pass
the blood-labyrinth barrier, whereas steroid applied to the
round window accumulates in the perilymph and GENTAMICIN AND SURGICAL
endolymph in animal models.111–113 Intratympanic steroid MANAGEMENT
treatment for MD has been suggested as an alternative to
surgical or ablative procedures when medical treatment For the 10% to 20% of MD patients for whom medical
has failed to control vertigo. Shea reported 2-year results management fails, further intervention may include
after 48 patients with MD were treated with 16 mg of dex- vestibuloablative or nonablative and hearing preservation
amethasone intravenously and 8 mg of dexamethasone or nonpreservation approaches. When considering surgi-
intratympanically for 3 consecutive days followed by 3 to cal intervention, it is important to understand that the goal
90 days of oral dexamethasone. Of 30 patients, 19 (63.4%) is primarily to eliminate disabling vertigo and improve qual-
had class A results (see Table 39-1) and 4 (13.3%) had class ity of life, since no surgical treatment has been proved to
B results. Hearing was improved or unchanged in 45 or 48 cure the underlying disease. Ultimate control of progressive
(93.7%) ears based on the 1995 AAOHNS guidelines.113 hearing loss is ideal, but current strategies have not been
The study is difficult to interpret because its design was proved to significantly alter long-term hearing outcome.
not randomized and not controlled and treatment
consisted of three routes of steroid administration.
Silverstein and colleagues reported the only randomized
Endolymphatic Sac Surgery
controlled trial of intratympanic steroid. Seventeen Endolymphatic sac surgery (ESS), a nonablative hearing pre-
patients underwent placement of tympanostomy tube and serving approach, includes decompression and various
adhesiolysis of the middle ear and were then treated with shunting techniques and was first described by Georges
either intratympanic steroid or placebo for 3 consecutive Portmann in 1926.121 It has since been the focus of fervent
days. After 3 weeks, a crossover treatment was initiated. debate. The authors would direct the reader to examine
No significant difference in hearing or tinnitis was noted, the extensive literature but note that the only RCTs sug-
but follow-up was limited and the disease stage was late, gest limited efficacy.122,123 Quaranta and colleagues com-
suggesting the patients would be unlikely to gain signifi- pared ESS to natural history at 2, 4, and 6 years and found
cant hearing benefit from any medication.114 Vertigo was a significant benefit at 2 and 4 years. The benefit did not
not specifically evaluated in this study. In a nonrandomized differ at 6 years, at which time 85% of patients who
prospective study, the rate of substantial or complete received ESS and 74% of patients who did not had vertigo
vertigo control after intratympanic dexamethasone control.124 Various nonrandomized studies have reported
(applied by the patient through a tympanostomy tube 0.25 50% to 75% vertigo control in.124–128 Many series report
mg every other day for 3 months) was 72% at 18 months. ESS results in even higher rates of vertigo control but are
However, it was not significantly different than after uncontrolled.129–135 On the other hand, Jackson and
intratympanic gentamicin or endolymphatic sac decom- colleagues reported that only 7% of their patients had com-
pression.115 Intratympanic steroid may not produce plete control of vertigo at 2 years.136 Silverstein and
improvement in hearing outcome.115,116 Randomized colleagues reported no difference in a group of patients
controlled trials are needed to further investigate the role who were offered yet declined surgery and those who
of intratympanic steroid. underwent ESS, both achieving a control rate of 71%
630 PERIPHERAL AUDIOVESTIBULAR DISORDERS

at 2 years.137 Studies using standardized questionnaires Gentamicin

found no difference in patient-scored dizziness after ESS
compared to medically treated patients.26,138 The efficacy Chemical labyrinthectomy exploits vestibulotoxic properties
of the procedure is brought further into question when of gentamicin. The drug is administered intratympanically
considering that insertion of a ventilation tube or cortical via a myringotomy, tympanostomy tube, microwick,
mastoidectomy alone may reduce vertigo.139,140 Considering or microcatheter. Authors have outlined numerous proto-
the variability of vertigo control in reports of both surgical cols for drug delivery, each reporting excellent control
and nonsurgical management, the substantial spontaneous of vertigo (approximately 90%), but with variability in
resolution of vertigo over time, and the lack of RCTs, it is rates of hearing loss (0% to 50%). Profound hearing loss
extremely difficult to interpret the literature. Nonetheless, is less common.141–145 There is no consensus on the ideal
ESS is associated with a low rate of complications. It is dose or protocol for delivery. When comparing protocols
commonly used as the first-line surgical treatment for for chemical ablation, the method, frequency, and duration
patients with disabling vertigo despite maximal medical of installation and the treatment end point (total nonre-
treatment because it offers an alternative to surgical sponse on ENG, nystagmus, dizziness, or hearing loss)
procedures with higher risks. must be considered as important factors in treatment effect
and rates of complications such as perforated tympanic
membrane and hearing loss. Complete ablation of vestibu-
Endolymphatic Sac Surgery Technique lar function may not be necessary to abolish vertigo
The procedure is performed under general anesthesia. attacks, and it may be associated with a higher risk of hear-
Intraoperative facial nerve monitoring and perioperative ing loss.145 The mechanism of action and the kinetics of
antibiotics are not routinely used. After a routine cortical transtympanic gentamicin are incompletely understood.
mastoidectomy, the lateral semicircular canal and the short There are various theories as to how intratympanic treat-
process of the incus are identified through the mastoid ment results in ototoxic effects. Gentamicin can enter the
antrum. These two structures are critical landmarks for inner ear through the round window membrane, the annu-
the identification of the intratemporal facial nerve. lar ligament, or vascular channels.146 The mechanism of
The middle fossa plate is identified superiorly and the injury is through damage to the dark cells of the crista
sigmoid sinus and presigmoid posterior fossa plate poste- ampullaris of the semicircular canals, the posterior wall
riorly. The sigmoid sinus is skeletonized, with attention to of the utricle, the lateral wall of the crus communes, and
its anterior aspect. Following the sigmoid medially, bone the stria vascularis, resulting in a reduced production of
over the posterior fossa dura is removed. Exposure of the endolymph.146,147 Cochlear and vestibular hair cell death
posterior fossa dura is extended toward the jugular bulb has been consistently documented.148
and into the retrofacial air cells, allowing a wide decom- Generally, patients report dizziness and dysequilibrium
pression over the sac. Air cells over the posterior semicir- as vestibular injury takes place. This may persist for a few
cular canal can be removed to improve visualization, but weeks and can be improved with vestibular rehabilitation
the canal should not be excessively thinned to avoid a fis- exercises. The elderly seem to have greater difficulty with
tula. Staying behind and medial to the posterior semicir- compensation.146 Although titration of dose to effect may
cular canal and using diamond burrs will protect the reduce the incidence of hearing loss, sudden and profound
vertical facial nerve. The sac is identified by a whitish hearing loss can occur. The cause of this unexpected event
thickening of the dura extending toward the distal aspect is unclear and unpredictable.146
of the sigmoid sinus. An elevator can be used to lift the sac Minor has described a protocol with low risk of hearing
away from the overlying bone to define the operculum and loss.145 Gentamicin (40 mg/mL) is buffered with sodium
the endolymphatic duct. In contrast to the sac, the dura bicarbonate to a pH of 6.4 and a final concentration
appears thin and bluish. If a shunt is planned, the sac is of 26.7 mg/mL. Phenol is used to anesthetize a small area
carefully entered with a sharp hook or a sharp microblade of the tympanic membrane. The solution is injection using
and the lumen identified by its glistening character. It is a 27-gauge needle to fill the middle ear (0.3 mL to 0.6
important to visualize the shiny, smooth surface of the mL). The patient (in a supine position) is instructed to
lumen to avoid creating a false lumen. The lumen is maintain the head turned away from the affected ear and
opened wide with a long blunt right-angle hook with spe- remain in that position for 30 minutes. (Generally, the
cific attention toward the duct. AT-shaped Silastic may be patient is instructed to avoid swallowing during that time,
placed to stent the lumen. Potential complications include to reduce loss of medication through the eustachian tube).
cerebrospinal fluid (CSF) leak, fenestration of the posterior The patient returns weekly for audiogram and vestibular
semicircular canal, labyrinthitis, and facial nerve injury. testing. Treatment is stopped if pure tone thresholds
The rate of complications is less than 1%. increased by more than 15 dB or if the SDS fell by more
than 20%. Observation of spontaneous nystagmus or
post–head shake nystagmus with Frenzel glasses indicates
Vestibular Nerve Section termination of therapy. If these criteria are absent, the
Vestibular nerve section (VNS) can be performed via the mid- patient is treated with a second dose of intratympanic gen-
dle fossa, retrosigmoid, or is a vestibuloablative but hearing tamicin and reevaluated weekly for further doses until the
preservation approach and retrolabyrinthine approaches. end point criteria are identified. Using this protocol,
VNS can also be performed after labyrinthectomy as a non- Minor reported 91% complete or substantial vertigo con-
hearing preservation procedure. These surgeries are trol in 34 patients; 21% developed recurrent vertigo 10 to
discussed in Chapter 56. 24 months later, but all responded to additional doses of
 Ménière’s Disease 631

gentamicin. Only one patient (3%) developed profound window while the pick is held against the lateral wall of the
hearing loss. Long-term hearing outcome based on inner ear. Slight resistance will be felt as the pick violates the
AAOHNS criteria was better in 36%, unchanged in 32%, osseous lamina. The point of the pick will reach the saccule
and worse in 32%.145 Other authors have found similar and the footplate of the stapes. Occasionally, a bony over-
results with this protocol.143 hang at the round window niche interferes with introduction
Nedzelski and colleagues149 proposed a protocol using of the pick and can be reduced with a 2-mm diamond burr.
the same buffered solution of 26.7 mg/mL gentamicin Momentary vertigo may result, but usually not, presumably
(0.7 to 0.8 mL) administered through a ventilation tube because the vestibular sense organs are not mechanically dis-
and attached catheter three times daily for 4 consecutive turbed, and the endolymph from the fistula drains into the
days. The patient was evaluated for spontaneous and gaze- scala tympani rather than into the perilymphatic space of the
evoked nystagmus, abnormal tandem gait, and hearing vestibule. The perforation in the round window is sealed
loss prior to doses 4, 7, and 10. Treatment was discon- with muscle or perichondrium. The tympanomeatal flap is
tinued for abnormal findings. Of 114 patients treated replaced and secured with Gelfoam, antibiotic ointment, or
with this protocol and followed at least 24 months, 93.3% a small strip of silk cloth. Complications include hearing loss,
had complete or substantial control of vertigo. Hearing perforation of the tympanic membrane, facial nerve injury,
was worse in 32.5% at 1 month after treatment and at and perilymphatic fistula.
2 years improved in 25.9%, unchanged in 50.6%, and
worsened in 25.8%; 16.4% of patients suffered profound Transcanal Labyrinthectomy
hearing loss.150
Other authors report good results with a single planned Transcanal labyrinthectomy offers a few advantages over
injection followed by repeated injections for recurrent transmastoid labyrinthectomy including shorter operating
symptoms.142,151 time and perhaps less risk of CSF leak and facial nerve
There is no consistent relation between the total dose or injury. However, identification and removal of all vestibu-
the number of injections and the likelihood of profound lar end organs may be more difficult and the incidence of
hearing loss. In animal studies, a wide variation in peri- incomplete labyrinthectomy may be greater.
lymphatic concentration of drug has been documented and
is likely to occur in humans, which may explain the unpre-
dictable, dose-independent incidence of profound hearing Transcanal Labyrinthectomy Technique
loss after intratympanic gentamicin therapy.152 In an
attempt to standardize dosage and better define and A transcanal approach is performed through a tympa-
manipulate the pharmacokinetics of transtympanic nomeatal flap after routine preparation including canal
gentamicin, microwicks and microcatheters have been anesthesia. After raising the flap, a curette is used to
studied and may hold promise.153,154 Controlled clinical remove the bony tympanic annulus. The horizontal seg-
trials are needed. ment of the facial nerve, the entire stapes footplate, and
the round window niche should all be visualized within the
field. The stapedial tendon is sectioned and the stapes and
Cochleosacculotomy incus are removed. The vestibular end organs are
Cochleosacculotomy is a reasonable option for relief of approached by exposing the entire vestibule, either by
vertigo when general anesthesia is contraindicated. The extending the oval window anteriorly and inferiorly or by
operation creates an internal shunt by fracturing the removing bone between the oval and round windows.
osseous spiral lamina and disrupting the cochlear duct. Before aspiration of the vestibule, the utricle should be
The theoretic permanent fistula between the perilym- removed with a 4-mm hook. The utricle may be displaced
phatic and endolymphatic spaces may end episodic vertigo superiorly if the vestibule is inadvertently aspirated too
by disallowing periodic hydropic episodes. The procedure early. The saccule is destroyed by aspiration of the anterior
was developed by Schuknecht based on histologic observa- aspect of the vestibule. The ampulla of the lateral and
tions that the membranous labyrinth of patients with MD superior semicircular canals may be approached with blunt
can spontaneously fistulize, possibly accounting for remis- dissection with a 4-mm hook that will drop into the
sions and arrest of symptoms. In animal studies, fracture- ampullary ends of the canals. The posterior canal can be
disruption of the osseous spiral lamina and cochlear duct denervated by exposing the posterior ampullary nerve near
can result in a permanent fistula with minimal impairment the posterior aspect of the round window niche. After
of hearing.155 Although some patients may have mild dyse- destruction of the end organs, the vestibule is packed with
quilibrium, cochleosacculotomy does not appear to require Gelfoam or a small fat or muscle plug. Some surgeons use
prolonged vestibular compensation. Hearing loss is gentamicin or streptomycin as irrigation or to soak the
common and may be profound. Gelfoam in order to ensure complete destruction of the
neuroepithelium. The tympanomeatal flap is returned and
Cochleosacculotomy Technique secured with packing. Postoperatively, patients have acute
vestibular dysfunction comparable to the level of preoper-
The patient is prepared for a transcanal procedure includ- ative function. Hospitalization for treatment with vestibu-
ing anesthesia of the external auditory canal. A tympa- lar suppressants and rehabilitation is necessary. Profound
nomeatal flap is elevated. The round window is exposed. A hearing loss results. Complications include CSF leak,
3-mm right-angle hook is inserted through the round win- incomplete labyrinthectomy (usually because of failure to
dow membrane and guided in the direction of the oval remove the utricle), and facial nerve injury.
632 PERIPHERAL AUDIOVESTIBULAR DISORDERS

Transmastoid Labyrinthectomy nerve activity is suspected. This additional step results in

preganglionic denervation.
Transmastoid labyrinthectomy allows a standard access to all
neuroepithelium. Generally, it is 95% to 99% successful in
obliterating vestibular function. Translabyrinthine Vestibular Nerve
Section Technique
Transmastoid Labyrinthectomy Technique The procedure is performed under general anesthesia with
perioperative antibiotics. The labyrinthectomy is com-
The procedure is performed under general anesthesia with pleted as described. Further bone removal over the
facial nerve monitoring. Perioperative antibiotics are not sigmoid sinus and decompression of the sinus may be
routinely required. A routine mastoidectomy is performed required for adequate access to the medial aspect of the
with identification of the mastoid antrum, lateral semicircu- dissection. Compression of the sigmoid sinus is necessary
lar canal, and incus. The descending segment of the facial to obtain the angulated view of the contents of the lateral
nerve is identified using the short process of the incus and internal auditory canal. It is helpful to leave an island
the lateral semicircular canal as landmarks. The facial recess of bone (Bill’s island) over the sigmoid sinus during this
indicates the lateral position of the facial nerve and the hor- dissection to protect it from injury by the rotating burr and
izontal canal indicates its posterior extent. There is no need retraction of the suction-irrigator. The bone overlying the
to remove bone from the facial nerve. The bony labyrinth is posterior cranial fossa dura is progressively removed ante-
skeletonized by removal of perilabyrinthine air cells and rior to the sigmoid sinus. This bone removal extends from
retrofacial air cells. It is helpful to clearly visualize each semi- the jugular bulb inferiorly to the superior petrosal sinus
circular canal and the course of the facial nerve before superiorly. The natural starting point for this dissection
proceeding. A systematic approach to this dissection aids in is at the vestibule, where the thin bone that separates the
ensuring all the neuroepithelium is removed while protect- fundus of the IAC from the vestibule creates a natural
ing the facial nerve. It is perhaps best to “blue-line” all the blue-line. It may be sufficient to skeletonize only the lat-
canals before entering in order to preserve all the landmarks eral half of the IAC, but complete dissection to the porus
until the vestibule is entered. Using a medium cutting burr may be performed. Useful landmarks include a line drawn
(4 mm or 5 mm), the superior-posterior surface of the lateral between the superior semicircular canal ampulla and the
canal is blue-lined, then opened. Following the horizontal sinodural angle and a line drawn posteriorly parallel to the
semicircular canal posteriorly, the posterior canal will be superior line starting at the level of the posterior canal
identified. It is best at this point not to open that canal com- ampulla. Once the IAC is skeletonized, thin bone can
pletely, but again skeletonize it so that the common crus and be lifted with a right-angle pick. The transverse crest
superior semicircular canal are identified first. The superior is exposed in the fundus using small diamond burrs.
canal is followed using a circular motion and the ampullated Bill’s bar serves as a bony landmark for the facial nerve,
ends of the superior and lateral canal are then opened. which lies anterior to it. A diamond burr and copious
Next, the posterior canal is followed inferiorly, medial to the irrigation allow identification of Bill’s bar and the fallopian
facial nerve, and finally opened along the posterior aspect of canal. The dura is opened with a sharp right-angled hook
the ampullated end. All three canals are carefully dissected or sickle knife. A 1-mm hook is inserted and Bill’s bar
with preservation of the medial walls of the superior and lat- is palpated. Then after sliding posterior to Bill’s bar, the
eral semicircular canal ampulla and the inferior wall of the hook is used to avulse the superior vestibular nerve inferi-
posterior canal ampulla. Just deep to the medial walls of the orly. After identification of the plane between the superior
superior and lateral canal ampulla lies the labyrinthine seg- vestibular nerve and the facial nerve, small fibers are lysed
ment of the facial nerve. Just inferior to the inferior wall of with sharp or blunt dissection. The inferior vestibular
the posterior canal ampulla lies the region of the jugular nerve is also avulsed with specific attention to identifica-
bulb. The common crus is finally followed medially into the tion and division of the singular nerve (posterior ampullary
vestibule. The labyrinthine bone (Trautmann’s triangle) is be nerve). Scarpa’s ganglion lies centrally within the IAC.
saucerized, permitting complete opening of the vestibule Resection of a 5-mm length of vestibular nerve, medial
with a view of the utricle in the elliptical recess and the sac- to the fused portion will include Scarpa’s ganglion and
cule in the spherical recess. The medial wall of the vestibule complete the denervation. The surgical site is closed
is the landmark for the fundus of the internal auditory canal by reapproximating the dura, sealing defects with fat
(IAC). At this point all five portions of the neuroepithelium strips, and packing the mastoid with fat. The incision
are clearly visualized (the ampulla of three canals, the utricle, is closed in two layers and a bulky pressure dressing
and the saccule). Each is removed under high-power is applied. Complications include CSF leak, facial
microscopy with a fine round knife and suction. The area is paralysis, and meningitis.
inspected for CSF leak and if none is found, the surgical
defect can be closed routinely. If a leak is detected, the
antrum should be obliterated and the cavity packed with fat. SURGERY AND HEARING OUTCOMES

Translabyrinthine Vestibular The current literature on the ESS procedure and other
Nerve Section surgical procedures for MD provides conflicting evidence
as to the benefits of surgery on attenuating progressive
Translabyrinthine VNS is a helpful adjunct when hearing loss. The variability in results is, in no small mea-
labyrinthectomy or VNS fail to relieve vertigo and residual sure, due to the lack of randomized controlled studies with
 Ménière’s Disease 633

Figure 39-5. Management protocol for suspected Ménière’s disease.

objective outcome data comparing the hearing outcome of compared ESS to an active placebo group (simple
surgical procedures to that of MD natural history. mastoidectomy).122 The authors reported subjective hear-
The VNS procedure, although highly successful in ing loss to be “slightly” significantly better in the ESS
eliminating vertigo in MD patients, does not appear to group than in the placebo group. Objective testing showed
have an effect on hearing or other MD symptoms. Hearing no significant difference between the two groups but sup-
loss after VNS follows the expected course of progressive ported a “tendency” toward better hearing postopera-
loss associated with MD: About 50% of patients have sta- tively in the ESS group, mainly manifested at 250 Hz.
bilized or improved hearing and about 50% have worse When the data were reexamined by Welling and Nagaraja,
hearing.156–159 no significant difference in hearing outcome was found,
Hearing improvement or stabilization after ESS is sup- but the authors suggest “the data seem to favor the active
ported by several published studies but disputed by others. treatment even though statistical significance was not
A frequently quoted paper by Thomsen and colleagues attained.”160 Quaranta compared a control group (patients
634 PERIPHERAL AUDIOVESTIBULAR DISORDERS

who were offered but declined surgery) to patients after review of the last decade of publications. Clin Otolaryngol
ESS. At 7 to 19 years of follow-up, 65% of patients who 25(6):456, 2000.
declined surgery and 45% of patients who had ESS had 2. Grant IL, Welling DB: The treatment of hearing loss in Ménière’s
disease. Otolaryngol Clin North Am 30(6):1123, 1997.
stable or improved hearing.124 Goin and colleagues also
3. Haye R, Quist-Hanssen S: The natural course of Ménière’s
found no difference in hearing after ESS compared to disease. Acta Otolaryngol 82(3–4):289, 1976.
patients who were offered but declined surgery.161 In vari- 4. Odkvist LM, Bergenius J: Drop attacks in Ménière’s disease. Acta
ous uncontrolled series, objective hearing outcome has Otolaryngol Suppl 455:82, 1988.
been reported to be better or unchanged in 43% to 78% 5. Kentala E, Havia M, Pyykko I: Short-lasting drop attacks in
after undergoing ESS.124,125,127,132,161–163 Ménière’s disease. Otolaryngol Head Neck Surg 124(5):526, 2001.
6. Schuknecht HF: Endolymphatic hydrops. In: Pathology of the Ear,
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A review of studies using direct subjective evaluation of 8. Schmidt PH, Schoonhoven R: Lermoyez’s syndrome. A follow-up
study in 12 patients. Acta Otolaryngol 107(5–6):467, 1989.
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9. Xenellis JE, Linthicum FH Jr, Galey FR: Lermoyez’s syndrome:
these symptoms. Improvement in tinnitus has been Histopathologic report of a case. Ann Otol Rhinol Laryngol
reported in up to 75% of patients after ESS.127,134 99(4 Pt 1):307, 1990.
However, the range of improvement has been broad (21% 10. Committee on Hearing and Equilibrium guidelines for the diag-
to 75%).123,125,127,133,134,136,162 Quaranta and colleagues nosis and evaluation of therapy in Ménière’s disease. American
reported substantial improvement in tinnitus and aural Academy of Otolaryngology-Head and Neck Foundation, Inc.
fullness after ESS compared to patients who declined Otolaryngol Head Neck Surg 113(3):181, 1995.
surgery.124 In studies of tinnitus outcome, between ESS 11. Jacobson GP, Newman CW: The development of the Dizziness
and VNS125,162 and ESS and placebo,123 results were not Handicap Inventory. Arch Otolaryngol Head Neck Surg 116(4):
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12. Newman CW, Jacobson GP, Spitzer JB: Development of the
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pre- and postoperative SF-36 scores for patients who 18. Kotimaki J, Sorri M, Aantaa E, et al: Prevalence of Ménière’s
underwent ESS and found that although patients preoper- disease in Finland. Laryngoscope 109(5):748, 1999.
atively scored significantly lower than norms, postopera- 19. Akagi H, Yuen K, Maeda Y, et al: Ménière’s disease in childhood.
tively the scores improved to the level of the standardized Int J Pediatr Otorhinolaryngol 61(3):259, 2001.
normative scores.167 Eisenman and colleagues reviewed 20. Green JD Jr, Blum DJ, Harner SG: Longitudinal followup of
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and reported that both groups had scores suggesting mod-
21. Stahle J, Friberg U, Svedberg A: Long-term progression of
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treatment groups.168 22. Paparella MM, Griebie MS: Bilaterality of Ménière’s disease. Acta
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23. Friedrichs I, Thornton AR: Endolymphatic hydrops in asympto-
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Low-pulse pressure,169–171 ultrasound,172 cryosurgery173,174 24. Hagnebo C, Melin L, Larsen HC, et al: The influence of vertigo,
and alternobaric and hyperbaric oxygen therapy175 have hearing impairment and tinnitus on the daily life of Ménière’s
been introduced, but evidence to support their use is patients. Scand Audiol 26(2):69, 1997.
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26. Kinney SE, Sandridge SA, Newman CW: Long-term effects of
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 Chapter
Autoimmune Inner Ear Disease

Outline 40
Introduction Diagnosis Steven D. Rauch, MD
Autoimmune Inner Ear Immunosuppressive Therapy
Disease Conclusions and Future
Clinical Presentation Directions

INTRODUCTION hearing loss (IPBSNHL) with circulating antibodies

against a 68-kD protein antigen present in bovine inner
There has long been a notion that the immune system ear and renal extracts.3 They demonstrated that the
might be capable of damaging the inner ear or eighth presence of these antibodies correlated both with activity
cranial nerve, leading to symptoms of hearing loss or dizzi- of disease and steroid responsiveness. Using different
ness (or both). Some well-documented examples in which experimental approaches, Billings and colleagues and
systemic autoimmune disease does this include lupus Bloch and coworkers both identified the 68-kD protein
erythematosus, ulcerative colitis, Cogan’s syndrome, and antigen as heat shock protein 70 (Hsp70) in 1995.4,5 Hsp70
multiple sclerosis. In some inner ear diseases, for example, is a ubiquitous protein found in all living cells. It primarily
Ménière’s syndrome and idiopathic sudden sensorineural functions as a molecular chaperone, binding to nascent
hearing loss (SNHL), an immune-mediated mechanism peptide chains during protein synthesis and aiding in
has been hypothesized but not demonstrated. One intracellular and transmembrane transport of proteins. It
condition, characterized by the clinical presentation of has a peptide binding site that makes it very “sticky”; that
idiopathic, rapidly progressive, bilateral SNHL, has come is, it tends to bind to other proteins or protein fragments.
to be known as autoimmune inner ear disease (AIED). Since it is unclear why anti-Hsp70 antibodies would
Whether all patients with this presentation have the same specifically damage the ear and since the propensity for
underlying pathophysiology and whether that pathophysi- Hsp70 to bind other peptides is well documented, it may
ology is autoimmune are unknown. However, the disorder be that it colocalizes with some other inner ear antigen
is extremely important because it represents one of the that is the actual target in IPBSNHL.
medically reversible causes of SNHL. Another approach to understanding the cause of this
disorder was taken by Carey and coworkers. They immu-
nized mice with chick and guinea pig inner ear extracts and
AUTOIMMUNE INNER EAR DISEASE created monoclonal antibodies against inner ear cells. One
particular antibody, dubbed “KHRI-3,” binds to support-
In 1979, McCabe described 18 patients with idiopathic, ing cells of the organ of Corti, creating a characteristic
rapidly progressive, bilateral SNHL who regained hearing “wine glass” staining pattern using immunofluorescence.6–12
after administration of corticosteroids.1 He theorized an Infusion of KHRI-3 into live guinea pigs produces hearing
autoimmune cause based on the response to immunosup- loss.7–9 The KHRI-3 antibody also binds to a 68- to 72-kD
pressive drugs. The next decade saw proliferation of a host antigen on Western blot of inner ear extract.6 Sera from
of clinical reports, diagnostic tests, and treatment proto- some humans with IPBSNHL strongly stained a 68- to
cols for this entity, few of which have subsequently been 72-kD inner ear antigen immunopreciptated from guinea
validated. The next significant step toward understanding pig inner ear extract with KHRI-3, and these same patient
this disorder came in 1990 when Harris and Sharp sera stained organ of Corti supporting cells in a wine glass
reported circulating antibodies against inner ear antigens pattern.13 This is strong evidence that KHRI-3 and human
detected by use of a Western blot technique.2 Four years antibodies recognize the same inner ear supporting cell
later Moscicki and coworkers presented the clinical corre- antigen. The target antigen of KHRI-3 has not yet been
lation of idiopathic, progressive, bilateral sensorineural identified, but it is not Hsp70.
639
640 PERIPHERAL AUDIOVESTIBULAR DISORDERS

The Western blot assay for circulating antibodies reac- TABLE 40-1. Clinical Features of 61 Consecutive Patients
tive with 68- to 72-kD antigen, whether it is Hsp70 or Evaluated for Possible Autoimmune Inner Ear Disease
the inner ear supporting cell antigen target of KHRI-3, is Clinical Features n
of unproven clinical value. The assay is not standardized,
and it has not been widely applied to other inner ear Male-to-Female 32:29
disorders nor to other autoimmune disorders in order Vestibular Symptoms 30 (49.2%)
to characterize its sensitivity and specificity. Therefore, Ménière’s disease 13 (21.3%)
IPBSNHL remains a clinical diagnosis based on historic Unilateral:Bilateral 5:8
Other Autoimmune Diagnosis 9 (14.8%)
and audiometric criteria. Likewise, IPBSNHL is not
actually confirmed as an autoimmune disorder. Such con- Mean age was 47 years (range: 4–72).
firmation must meet three criteria: (1) identification of
antibodies or activated T cells reactive with a “self” pro-
tein, (2) identification of a characteristic immune-induced in this group of patients are essentially the same as
“lesion,” and (3) reproduction of this lesion by introduc- Moscicki’s original cohort. However, the proportion of
tion of the specific antibodies or activated T cells into patients with positive Western blot assay and the proportion
a naive host. Until these criteria are met, it is more accu- of Western blot-positive patients who responded to steroids
rate to refer to this entity by its clinical description (i.e., are both lower than in Moscicki’s retrospective study.
IPBSNHL) or acknowledge the undefined role of the AIED and idiopathic sudden SNHL are two distinct
immune system and call it immune-mediated inner ear dis- disorders. AIED is far rarer than sudden loss. AIED is by
ease. However, the popular notion that this is an autoim- definition bilateral, and sudden hearing loss is virtually
mune disorder has taken hold, and the condition is now always unilateral. Sudden hearing loss develops in ≤72 hours.
widely referred to as AIED. In contrast, AIED progresses over days to months such
that monthly serial audiograms will show continued
decline. Sudden hearing loss is an otologic emergency with
CLINICAL PRESENTATION a treatment of “window” of perhaps 2 to 4 weeks during
which a short “burst and taper” of corticosteroids must be
The hallmark of the condition originally described by administered in order to achieve optimum recovery. AIED
McCabe was the presence of rapidly progressive SNHL; is not urgent. Patients with progression over 6 to 12 months
too fast to be age-related degeneration and too slow to be can still achieve significant recovery with administration
sudden SNHL. This remains the most salient distinguish- of a long course of high-dose corticosteroids or other
ing feature of the disorder. Moscicki and colleagues artic- immunosuppressive drugs. Throughout the otolaryngol-
ulated a precise clinical description of AIED (which they ogy community some cases of SNHL are widely accepted
called IPBSNHL), which enabled them to minimize as potentially reversible with corticosteroids. Unfortu-
heterogeneity in their study population and, ultimately, to nately, however, few are aware that these two entities are
correlate this clinical presentation with results of Western quite different in cause, presentation, work-up, and man-
blot assays.3 Specifically, they defined the condition as a agement. Hasty administration of a short tapering course
bilateral SNHL of ≥30 dB at any frequency and evidence of steroids can delay diagnosis of AIED and can confuse
of progression in at least one ear on two serial audiograms interpretation of serologic testing.
performed ≤3 months apart; progression being defined as Approximately half of AIED patients also experience
a threshold shift of ≥15 dB at one frequency, 10 dB at two vestibular symptoms (see Table 40-1), including dysequi-
or more consecutive frequencies, or a significant change in librium, motion intolerance, positional vertigo, and
discrimination score. A single episode of threshold shift episodic whirling vertigo of the Ménière’s type. Approxi-
occurring in less than 72 hours and then stabilizing was mately 20% of AIED patients have a combination of
classified as sudden SNHL and was excluded. Fluctuating fluctuating and progressing SNHL and episodic vertigo that
hearing loss, however, qualified if progression also meets strict American Academy of Otolaryngology—Head
occurred according to the previous criteria. This is still and Neck Surgery diagnostic criteria for Ménière’s disease.
the most explicit description of AIED in the literature. Rauch and coworkers14 and Gottschlich and colleagues15
Analogous to Ménière’s disease, in the absence of a “gold have reported that approximately one-third of classic
standard” diagnostic test, adherence to these diagnostic Ménière’s disease patients have a positive Western blot
criteria permits comparison of observations and results assay for anti-Hsp70 antibodies. This overlap between
between different studies.
In the paper by Moscicki and colleagues, demographic
features, test results, and treatment outcome were TABLE 40-2. Relationship of Western Blot Assay for
reported for 72 patients with IPBSNHL.3 Subsequently, Anti-Hsp70 Antibodies and Response to Corticosteroid
66 additional cases of possible immune-mediated inner ear Therapy in 61 Patients with Autoimmune Inner Ear Disease
disease were studied using Moscicki’s same diagnostic Steroid Response
criteria. Five patients were excluded from analysis because
they had Cogan’s syndrome, an autoimmune vasculitis Western Blot + − No Rx
characterized by SNHL, vertigo, and interstitial keratitis
+ 14 11 7
of the eyes, leaving 61 cases. Results are tabulated in − 5 12 8
Tables 40-1 and 40-2. Demographic features and trends in ? 2 2 −
the correlation of Western blot assay with steroid response
 Autoimmune Inner Ear Disease 641

AIED and Ménière’s disease suggests that a subset of that they have reached a plateau of recovery. The medica-
patients falling into both diagnostic categories may share a tion is then slowly tapered over 8 weeks to a maintenance
common pathophysiologic mechanism. dose of 10 to 20 mg every other day. This maintenance
AIED can occur in combination with other systemic dose is continued for a variable length of time. Clinical
autoimmune diseases. Nearly 15% of AIED cases have observation suggests that patients with a total treatment
another autoimmune diagnosis (see Table 40-1), such as duration of less than 6 months are at increased risk of
multiple sclerosis, inflammatory bowel disease (ulcerative relapse compared with those treated for 6 months or
colitis and Crohn’s disease), systemic lupus erythematosus, longer.
rheumatoid arthritis, and ankylosing spondylitis. Though Patterns of response to corticosteroid therapy vary.
not definitely autoimmune, several other AIED patients Some patients have improvement in threshold, some in
listed in Table 40-1 had diabetes or thyroid dysfunction. discrimination only, and some show benefit to both. Some
Some reports of certain human leukocyte antigen (HLA) patients with fluctuation and progression before therapy
subtypes showed a correlation with immune-mediated show stabilization of their hearing without actual improve-
inner ear disease.16 This suggests the possibility of a ment. Historically, these cases have been considered non-
genetic predisposition to autoimmune disease that may responders, but this issue is currently under reassessment.
include AIED as well as other systemic disorders. The majority of responders are carried through their slow
taper, weaned from steroids, and do well. A subset of AIED
patients relapse while tapering or after discontinuing their
DIAGNOSIS medication. In some instances retreatment is effective.
However, occasionally the hearing loss becomes refractory
As noted earlier, the salient feature of AIED is audiomet- to corticosteroids. In such cases alternative immunosup-
ric evidence of progression over days to months. Serial pressive drugs are considered. An occasional patient,
audiometry performed at an interval of ≤3 months is especially in the pediatric age group, may show steroid-
necessary to confirm the diagnosis. When in doubt, monthly dependent hearing loss. In other words, they cannot be
audiograms for several months can be helpful. The pattern weaned below a certain level of steroid dosage without
of hearing loss is highly variable. As yet, no one has decline in hearing. Such patients often develop unaccept-
described a characteristic pattern of hearing loss. The loss able side effects of chronic steroid administration.
may be high tone, low tone, up- or downsloping, or Recently, benefit has been observed from combining
predominantly affecting discrimination rather than prednisone with low-dose (15-20 mg/week) methotrexate
threshold. Exclusion of retrocochlear disease such as mul- in these steroid-dependent cases. After several weeks of
tiple sclerosis or acoustic neuroma is mandatory and can combined therapy, the prednisone can be tapered and
be accomplished by evoked response audiometry or discontinued and the patient maintained on methotrexate
gadolinium-enhanced magnetic resonance imaging (MRI). alone for an additional 2 to 3 months, at which time the
Routine serologic tests in possible AIED patients last drug is also successfully discontinued.
include complete blood count with differential white Corticosteroid therapy has obvious limitations. Long-
count, erythrocyte sedimentation rate (ESR), rheumatoid term administration has risks, including gastritis and ulcers,
factor, antinuclear antibody (ANA), C3 and C4 complement fluid retention and weight gain, blood pressure lability,
levels, and Raji cell assay for circulating immune complexes. altered blood sugar metabolism and diabetes, mood changes
Serologic work-up is aimed at detecting evidence of or psychiatric problems, sleep disturbance, accelerated
systemic immunologic dysfunction; none of these tests has cataract formation, and cushingoid habitus. Ischemic necro-
been shown to correlate with the diagnosis of AIED. sis of bone is a rare complication more likely to be seen
in cases of prolonged high-dose steroid administration.17
Overall steroid response rate is approximately 60% in
IMMUNOSUPPRESSIVE THERAPY AIED patients. Some initial responders become refractory
at the time of subsequent relapse. Despite these limita-
Corticosteroid therapy for AIED has evolved over the last tions, corticosteroid therapy remains the mainstay of
15 years based on clinical experience. No prospective, ran- AIED treatment based on the extensive clinical experience
domized clinical trials have yet been conducted to validate with its use.
this empirical approach. Initial therapy for adults consists Alternatives to systemic corticosteroids include
of a therapeutic trial of prednisone 60 mg daily for methotrexate, etanercept, and cyclophosphamide. Low-dose
4 weeks. Pediatric patients receive prednisone 1 methotrexate appears to be especially useful as an adjunct
mg/kg/day for 4 weeks. Although occasional patients may in management of steroid-dependent hearing loss. It is
show a response early in the 4-week period, many do not the first-line drug of choice for patients unable to take
begin to improve until late in the month, and shorter corticosteroids. A low-dose protocol as for rheumatoid
courses of treatment usually result in relapse. The patient’s arthritis or psoriasis is used. Methotrexate is administered
hearing is tested at the initiation of therapy and again at 4 by mouth in three doses given at 12-hour intervals once
weeks. If the threshold has improved by ≥15 dB at one fre- weekly. The initial dose is 7.5 mg/week (three doses of
quency or 10 dB at two or more consecutive frequencies, 2.5 mg). If this is tolerated without toxicity for 2 weeks, the
or if the discrimination is significantly improved, patients dose is doubled to 15 mg/week. This dose is continued for
are considered steroid responders. The medication is 6 to 8 weeks as a therapeutic trial. Medication is discon-
tapered off in 12 days for nonresponders. Responders con- tinued in nonresponders; responders are carried on the
tinue full-dose therapy until monthly audiograms confirm 15 mg/week dose for 6 months. Potential toxicity includes
642 PERIPHERAL AUDIOVESTIBULAR DISORDERS

myelosuppression, gastrointestinal upset, oral ulceration, mechanism could disable neural signal transduction or
acute pneumonitis, and hepatic fibrosis. This last compli- transmission in the auditory system yet be reversed
cation is insidious and generally seen only when metho- months later by anti-inflammatory or immunosuppressive
trexate is given for more than a year. It may be associated drugs. Solution to this puzzle will come from systematic
with normal liver function tests, and early diagnosis is research into the nature of the humoral and cell-mediated
achieved by liver biopsy. Weekly testing including a com- immune response of affected patients. Though the Carey
plete blood count with differential white count, liver func- model using KHRI-3 is promising, as yet there is no
tion tests, blood urea nitrogen, creatinine, and urinalysis is widely accepted animal model of the AIED phenomenon
recommended to monitor for signs of toxicity. in which to carry out such research, and human studies
Etanercept, an inhibitor of tumor necrosis factor alpha, progress slowly due to the rarity of the clinical material.
has recently been used to treat AIED. Anecdotally, it This rarity does not diminish the significance of the topic,
appears to work well in combination with methotrexate however. Understanding the mechanism of AIED will
because of its steroid-sparing effect. As seen in rheumatoid provide a new level of insight into the role of systemic and
arthritis, etanercept alone does not appear nearly as organ-specific immune reactions in disease of the inner
effective. However, neither treatment protocol has been ear. The fact that 20% of AIED patients have a clinical
studied systematically. presentation overlapping with Ménière’s disease and 33%
Cyclophosphamide is a potent cytotoxic agent generally of Ménière’s disease patients have evidence of antibodies
used for cancer chemotherapy. It is somewhat selective to the 68- to 72-kD antigen by Western blot assay is strong
for B-cell and monocyte-macrophage function.18 Although evidence of a shared pathophysiologic mechanism. Though
some advocate its use as a first-line drug,19 the high risk of AIED is rare, Ménière’s disease is not. In the United States
toxicity makes it a better choice as a salvage drug or treat- alone an estimated 125,000 cases are reported yearly. New
ment of last resort. We have used it in a small number of ways of understanding Ménière’s disease could have great
patients at an initial dose of 1 mg/kg/day orally for 4 to 6 public health benefit.
weeks. When no response is apparent, the dose is doubled to Diagnosis of AIED currently relies on clinical factors
2 mg/kg/day. Responders are treated for 6 to 12 months. alone. As stated earlier, the observation that many AIED
Toxicity includes severe myelosuppression, opportunistic patients carry serum antibodies reactive with Hsp70 does
infection, hair loss, cystitis, infertility, and increased risk not prove that Hsp70 is the actual inner ear target antigen.
of malignancies. Weekly monitoring of hematologic status Hsp70 may carry an epitope shared with the true target
is mandatory. Many patients when confronted with the antigen or may otherwise colocalize with it biochemically.
risk of this medication would rather consider cochlear Despite our poor understanding of AIED pathophysiol-
implantation. ogy, detection of this or other marker antibodies may
Intratympanic steroid therapy, systemic IgG injections, become clinically useful. The utility of an assay will be
and plasmapheresis are possible treatments with sound greatly enhanced by development of a quantitative measure
theoretical justification. Intratympanic steroid therapy is enabling clinicians to follow antibody titers by serial test-
particularly appealing because it is minimally invasive and ing. In addition, estimation of sensitivity and specificity of
enables direct application of drug to the affected site with the assay must be made by its broad application to a wide
low risk of systemic effects; however, these treatments have variety of ear diseases and immunologic disorders.
not yet been systematically applied in any published series. Current therapy of AIED is based on empirical experi-
Determination of the best role for any of these treatment ence over the last 15 years rather than on a clear under-
modalities remains to be determined. standing of the underlying pathophysiology. In the future,
therapeutic protocols must be informed by expanding
knowledge of the pathophysiology of the disorder. Large
CONCLUSIONS AND FUTURE DIRECTIONS multicenter studies are necessary to carefully evaluate the
best use of corticosteroids and other immunosuppressive
The story of AIED from initial description by McCabe to drugs. Consensus must be achieved on the clinical diag-
present therapy routines has been presented here as a nostic criteria and treatment regimens to enable compari-
simple and direct path. That has not been the actual case. son between studies. Even with strict adherence to
It has been a broad and meandering path with significant rigorous methodology, it may take many years to address
contributions by many investigators and numerous inter- these questions. For the foreseeable future, AIED will
esting and important digressions. It is a story that still remain one of the most interesting, important, and chal-
has far to go. The clinical description of this disorder is lenging problems confronting otologists and otologic
confined to its auditory manifestations. However, as noted researchers.
earlier, 50% of AIED patients have vestibular symptoms.
This aspect of the illness has not been well characterized
clinically. Just as many AIED patients have exclusively
REFERENCES
auditory symptoms, an equal number may well have with
exclusively vestibular symptoms. Such a presentation has
1. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol
not yet been reported. Rhinol Laryngol 88:585, 1979.
Little is understood about the underlying pathophysiol- 2. Harris JP, Sharp PA: Inner ear autoantibodies in patients with rapidly
ogy of AIED. The very fact of reversible SNHL flies in the progressive sensorineural hearing loss. Laryngoscope 100:516, 1990.
face of accepted dogma that SNHL is not medically recov- 3. Moscicki RA, San Martin JE, Quintero CH, et al: Specificity of
erable. It is interesting to consider what pathophysiologic serum antibodies to a 68 kD inner ear antigen in disease associated
 Autoimmune Inner Ear Disease 643

with hearing loss and responsivity to corticosteroid therapy. JAMA 11. Ptok M, Carey TE, Altschuler RA: Relationship of monoclonal
272:611, 1994. antibody (KHRI 3 epitope) to cochlear supporting cell microvilli in
4. Billings PB, Keithley EM, Harris JP: Evidence linking the 68 kilo- the guinea pig. Eur Arch Otorhinolaryngol 250:345, 1993.
dalton antigen identified in progressive sensorineural hearing loss 12. Ptok M, Klein R, Ptok A, et al: Drug therapy of acute inner ear
patient sera with heat shock protein 70. Ann Otol Rhinol Laryngol hearing loss in childhood and adolescence. HNO 42:636, 1994.
104:181, 1995. 13. Disher MJ, Ramakrishnan A, Nair TS et al: Human autoantibodies and
5. Bloch DB, San Martin JE, Rauch SD, et al: Serum antibodies to heat monoclonal antibody KHRI-3 bind to a phylogenetically conserved
shock protein 70 in sensorineural hearing loss. Arch Otolaryngol inner-ear-supporting cell antigen. Ann N Y Acad Sci 830:253, 1997.
121:1167, 1995. 14. Rauch SD, Zurakowski D, Bloch DB, et al: Anti-Hsp70 antibodies
6. Zajic G, Nair TS, Ptok M, et al: Monoclonal antibodies to inner ear in Ménière’s disease. Laryngoscope 110:1516, 2000.
antigens: I. Antigens expressed by supporting cells of the guinea pig 15. Gottschlich S, Billings PB, Keithley EM, et al: Assessment of serum
cochlea. Hear Res 52:59, 1991. antibodies in patients with rapidly progressive sensorineural hearing
7. Nair TS, Raphael Y, Dolan DF, et al: Monoclonal antibody induced loss and Ménière’s disease. Laryngoscope 105:1347, 1995.
hearing loss. Hear Res 83:101, 1995. 16. Cao M-Y, Thonnard J, Deggouj M, et al: HLA Class II-associated
8. Nair TS, Prieskorn DM, Miller JM, et al: In vivo binding and hear- genetic susceptibility in idiopathic progressive sensorineural hearing
ing loss after intracochlear infusion of KHRI-3 antibody. Hear Res loss. Ann Otol Rhinol Laryngol 105:628, 1996.
107:93, 1997. 17. Zizic TM, Marcoux C, Hungerford DS, et al: Corticosteroid ther-
9. Nair TS, Prieskorn DM, Miller JM, et al: KHRI-3 monoclonal apy associated with ischemic necrosis of bone in systemic lupus ery-
antibody-induced damage to the inner ear: Antibody staining of thematosus. Am J Otol 79:596, 1985.
nascent scars. Hear Res 129:50, 1999. 18. Hadden JW, Smith DL: Immunopharmacology: immunomodula-
10. Ptok M, Nair TS, Altschuler RA, et al: Monoclonal antibodies to tion and immunotherapy. JAMA 268:2964, 1992.
inner ear antigens: II. Antigens expressed in sensory cell stereocilia. 19. McCabe BF: Autoimmune inner ear disease: Therapy. Am J Otol
Hear Res 57:79, 1991. 10:196, 1989.
 Chapter
Benign Paroxysmal Positional Vertigo
41 Outline

Lorne S. Parnes, MD, FRCSC Introduction and Background Diagnostic Maneuvers Lateral Canal Benign
Pathophysiology Subjective vs. Objective Paroxysmal Positional
Sumit K. Agrawal, BSc, MD
Posterior Canal Benign Benign Paroxysmal Vertigo
Paroxysmal Positional Positional Vertigo Controversy
Vertigo Differential Diagnosis Factors Affecting
Lateral Canal Benign Management Repositioning Maneuvers
Paroxysmal Positional Nonsurgical Management Surgical Treatment
Vertigo Vestibular Habituation Singular Neurectomy
Epidemiology Therapy Posterior Semicircular
Etiology Liberatory Maneuver Canal Occlusion
Diagnosis Particle Repositioning Summary
History Maneuver

INTRODUCTION AND BACKGROUND who had manifested benign paroxysmal positional nystag-
mus. Interestingly, the deposits were found only on the
There is nothing more gratifying for a physician than man- posterior canal cupulae of the presumed affected ears while
aging a disorder that is for the most part easily diagnosed, the cupulae from the other sides were normal. Schuknecht
and more important, simply and effectively treated using and Ruby5 reported another case and then studied 391
noninvasive means. Benign paroxysmal positional vertigo temporal bones from 245 patients without BPPV. They
(BPPV), the most common affliction of the vestibular discovered cupular deposits in 149 bones (37%), with small
labyrinth, is one such disorder. deposits in 125 (32%), medium deposits in 20 (5%), and
BPPV was first described by Barany1 in 1921. He describes large deposits in 4 (1%). However, none of these deposits
several key manifestations in his clinical description: was as large as those found in the three patients with BPPV.
Schuknecht4 had initially proposed that loose otoconia
The attacks only appeared when she lay on her right side. When from degenerating utricular macula floated in the region of
she did this, there appeared a strong rotatory nystagmus to the
right. The attack lasted about thirty seconds and was accompanied
the posterior semicircular canal cupula and caused displace-
by violent vertigo and nausea. If, immediately after the cessation ment. He then modified his theory and coined the term
of these symptoms, the head was again turned to the right, no cupulolithiasis to represent the findings of attached otoconia
attack occurred, and in order to evoke a new attack in this way, the to the posterior semicircular canal cupula. He proposed
patient had to lie for some time on her back or on her left side. that deposits would render the cupula sensitive to gravity.
Ampullifugal deflection of the posterior canal cupula in the
Barany mistook the condition as an error in head position provocative head-hanging position was thought to account
encoding by the otoliths because the symptoms seemed to be for the nystagmus seen in posterior canal BPPV.
independent of the positioning maneuver. Dix and In 1979, Hall and colleagues6 combined these two theo-
Hallpike,2,3 finding histologic evidence of unilateral utricular ries on the basis of the fatigability of the nystagmus. They
macular degeneration in a case of BPPV, also mistakenly con- proposed that BPPV could be caused by deflection of the
cluded that the disorder was caused by a lesion in the otolith posterior canal cupula by fixed deposits on the cupula (non-
organ. In 1952, they coined the term benign paroxysmal posi- fatigable nystagmus) or by the motion of free-floating par-
tional vertigo in their report of 100 patients. The description ticles in the posterior semicircular canal (fatigable
of the diagnostic nystagmus included (1) brief latency (1 to nystagmus). Free-floating particles in the semicircular
5 seconds), (2) rotational nystagmus with the fast component canal has been coined canalithiasis and represents the most
of the superior pole beating toward the affected (undermost) common form of BPPV that is diagnosed with the Dix-
ear, (3) limited duration (5 to 30 seconds), (4) reversal of the Hallpike maneuver.
induced nystagmus upon returning to the seated position, Parnes and McClure7 were the first to demonstrate in vivo
and (5) fatigability of the response with repetition. free-floating endolymph particles in the posterior canal.
In 1969, Schuknecht4 described basophilic cupular This intraoperative finding, from two patients with intrac-
deposits in postmortem temporal bones of two patients table BPPV undergoing posterior semicircular canal
644
 Benign Paroxysmal Positional Vertigo 645

occlusion surgery, further supported the theory of canalithia- inertia of the particles explains the latency seen during the
sis. A further study by Welling and colleagues8 examined the Dix-Hallpike maneuver.
extracted particles from another patient undergoing canal In the head-hanging position, the canalith mass would
occlusion surgery under electron microscopy and revealed move away from the cupula to induce ampullifugal cupular
that the particles were degenerating otoconia. deflection. In the vertical canals, deflection produces an
excitatory response. This would cause an abrupt onset of
vertigo and the typical torsional nystagmus in the plane of
PATHOPHYSIOLOGY the posterior canal. In the left head-hanging position (left
posterior canal stimulation), the fast component of the
Posterior Canal Benign Paroxysmal nystagmus beats clockwise as viewed by the examiner.
Conversely, the right head-hanging position (right posterior
Positional Vertigo canal stimulation) results in a counterclockwise nystagmus.
The vast majority of BPPV cases are of the posterior canal These nystagmus profiles correlate with the known neuro-
variant. The pathophysiology that causes most posterior canal muscular pathways that arise from stimulation of the
BPPV cases is thought to be canalithiasis (see Fig. 41-1). This posterior canal ampullary nerves in an animal model.13
is probably because most free-floating endolymph debris This nystagmus is of limited duration because the
tends to gravitate to the posterior canal, being the most endolymph drag ceases when the canalith mass reaches the
gravity-dependent part of the vestibular labyrinth in both limit of descent and the cupula returns to its neutral position.
the upright and supine positions. It is important to note that Reversal nystagmus occurs when the patient returns to the
the cupula forms an impermeable barrier across the lumen upright position; the mass moves in the opposite direction,
of the ampulla9 and is located at the shorter, more depend- thus creating a nystagmus in the same plane but opposite
ent end of the canal. Therefore, the particles become direction. The response is fatigable as the particles become
“trapped” and can exit the posterior canal only through the dispersed along the canal and become less effective in
nonampullated end (the common crus). Agrawal and creating endolymph drag and cupular deflection.
Parnes10 found obvious free-floating endolymph particles in Canalithiasis in the posterior canal likely accounts for the
30% of ears undergoing surgery for posterior canal BPPV. majority of BPPV cases. Based on studies at the Portland
The mechanism by which canalithiasis causes nystagmus Otologic Clinic, Epley12 has described two additional mech-
in the posterior semicircular canal was described by anisms for which diagnosis and treatment are not yet well
Epley.11,12 Particles must accumulate to a “critical mass” in defined in the literature. Cupulolithiasis, or “heavy cupula,”
the dependent portion of the posterior semicircular canal. refers to particles adherent to or impinging on the cupula.
The canalith mass moves to a more dependent position Unlike in canalithiasis, the observed nystagmus in cupu-
when the orientation of the semicircular canal is modified lolithiasis is gradual in onset, seldom severe, and persists
in the gravitational plane. The resulting drag must overcome while the head is in the provocative position. A gradual
the resistance of the endolymph in the semicircular canal decline in the nystagmus may occur after 1 to 2 minutes. A
and the elasticity of the cupular barrier in order to deflect third proposed mechanism, known as canalith jam, is thought
the cupula. The time taken for this to occur plus the original to be caused by particles creating a blockage in the canal or
by particles becoming wedged between the cupula and the
adjacent ampulla wall. The resultant nystagmus and vertigo
are persistent and unaffected by the patient’s head position.
Although testing and possible repositioning treatments have
been proposed, these entities need to be studied further.

Lateral Canal Benign Paroxysmal

Positional Vertigo
BPPV most commonly affects the posterior semicircular
cupula
canal, however, one report suggests that up to 30% of
BPPV may be of the horizontal canal variant.14 In our
dizziness clinic, the horizontal canal variant accounts for
less than 5% of our BPPV cases. However, our findings
may be biased by the long wait for an assessment in our
clinic (more than 5 months); it has also been our experience
ampulla that lateral canal BPPV resolves much quicker than posterior
cupulolithiasis canal BPPV. This latter observation is understandable
when one considers the orientations of the canals. The
posterior canal hangs inferiorly and has its cupular barrier
at its shorter, more dependent end. Any debris entering
canalithiasis the canal essentially becomes trapped within it. In contrast,
the lateral canal slopes upward and has its cupular barrier
Figure 41-1. Left inner ear. Depiction of canalithiasis of the posterior
canal and cupulolithiasis of the lateral canal. (Reprinted with permission
at the upper end. Therefore, free-floating debris in the
from Parnes LS, Agrawal SK, Atlas J: Diagnosis and management of benign lateral canal tends to float back out into the utricle as a
paroxysmal positional vertigo [BPPV]. CMAJ 169:681–693, 2003.). result of natural head movements.
646 PERIPHERAL AUDIOVESTIBULAR DISORDERS

TABLE 41-1. Lateral Canal BPPV Side of Origin BPPV.22 BPPV most often involves a single semicircular
and Mechanism canal, usually posterior, but may involve both posterior
Direction of Nystagmus
and lateral canals in the same inner ear. Posterior canal
BPPV may convert to lateral canal BPPV following reposi-
Intensity of Nystagmus Ageotropic Geotropic tioning maneuvers.23 Head trauma is the most common
cause of bilateral posterior canal BPPV.17
Stronger on left side Right cupulolithiasis Left canalithiasis
Stronger on right side Left cupulolithiasis Right canalithiasis

ETIOLOGY
In most cases, BPPV is found in isolation and termed primary
In lateral canal canalithiasis, particles are most often in or idiopathic BPPV. Rates of primary BPPV have been
the long arm of the canal relatively far from the ampulla.15 reported as approximately 50% to 70% of BBPV cases.
If the patient performs a lateral head turn toward the affected The most common cause of secondary BPPV is head
ear, the particles will create an ampullipetal endolymph trauma, which represents 7% to 17% of all BPPV
flow, which is stimulatory in the lateral canal. A geotropic cases.17,19 The blow to the head may cause the release of
nystagmus (fast phase toward the ground) will be present. numerous otoconia into the endolymph, which likely
If the patient turns away from the affected side, the parti- explains why many of these patients suffer from bilateral
cles will create an inhibitory flow. Although the nystagmus BPPV.17 Viral neurolabyrinthitis has been implicated in up
will be in the opposite direction, it will still be geotropic to 15% of BPPV cases.19 The function of the posterior
since the patient is now facing the opposite direction. canal must be preserved to a certain degree in order to be
Stimulation of a canal creates a greater response than inhi- symptomatic from BPPV.24
bition of a canal; therefore, the direction of head turn that Ménière’s disease has also been strongly associated with
creates the strongest geotropic nystagmus (i.e., stimulatory BPPV. There is a large variation in the literature regarding
response) represents the affected side in lateral canal what proportion of patients with BPPV also have
canalithiasis (Table 41-1). Ménière’s disease. One study by Karlberg and colleagues25
Cupulolithiasis is thought to play a greater role in lateral reviewed 2847 patients with BPPV and found 16 patients
canal BPPV than in the posterior canal variant. Since (0.5%) with Ménière’s disease. Another retrospective
particles adhere directly to the cupula, the vertigo is often study examined only 151 patients with BPPV and found
intense and persists while the head is in the provocative that more than 45 patients (31%) had Ménière’s disease.26
position. When the patient’s head is turned toward the However, upon examination of 162 patients with “defi-
affected ear, the cupula undergoes an (inhibitory) deflection, nite” Ménière’s disease, Gross and colleagues27 found
which causes an apogeotropic nystagmus (fast phase away 9 patients (5.5%) to have “certain” posterior canal BPPV.
from the ground). A head turn in the opposite direction The causative mechanism is not well understood but may
creates an ampullipetal (stimulatory) deflection, resulting be due to hydropically induced damage to the macula of
in a stronger apogeotropic nystagmus. Therefore, turning the utricle or by partial obstruction of the membranous
away from the affected side will create the strongest labyrinth.27
apogeotropic nystagmus in lateral canal cupulolithiasis Recently, migraine headaches have been associated to
(see Table 41-1). Apogeotropic nystagmus is present in BPPV. Ishiyama and colleagues28 found that (1) the inci-
about 27% of patients who have lateral canal BPPV.14 dence of migraine was three times greater in patients with
primary BPPV than in the general population and
(2) patients with migraines had the highest recurrence
EPIDEMIOLOGY rate (77%) after successful repositioning. Lempert and
colleagues29 found a higher lifetime prevalence of migraine
BPPV is the most common disorder of the peripheral in patients with BPPV (35% vs. 16%). They also found
vestibular system16 and represented 17% of patients in one that 83% of patients with BPPV and migraine were
large dizziness clinic.17 The incidence is likely severely women. This may help explain the female preponderance
underestimated since most untreated cases of BPPV of BPPV in the general population. Since vasospasm is well
resolve spontaneously within a few months. Also, most documented in migraines and BPPV has been associated
studies do not use a population-based model but determine with ischemic damage to the inner ear,28 vasospasm of the
incidence in patients who either report vertigo as their labyrinthine arteries has been suggested as an etiologic
chief complaint or undergo vestibular testing. Mizukoshi mechanism. Recurrent vasospastic ischemia of the utricular
and colleagues18 estimated the incidence to be 10.7 to 17.3 otolith could explain the significant recurrence rate of
per 100,000 in Japan. Several studies have suggested a BPPV in patients with migraine.30
higher incidence in women,18–20 but in younger patients Secondary BPPV has also been described after inner ear
and those with post-traumatic BPPV, the incidence in men surgery.26,31,32 Atacan and colleagues31 reviewed 63 stapedec-
and women may be equal.17 The age of onset is usually tomy cases for BPPV and found 4 patients (6%) who
during the fifth through seventh decades of life.18,19,21 The developed BPPV postoperatively. All patients responded
elderly are at an increased risk, and a study of an elderly to the Epley maneuver. The etiology is thought to be
population undergoing geriatric assessment for non-balance- linked to utricular damage during the procedure, leading
related complaints found that 9% had unrecognized to the release of otoconia.
 Benign Paroxysmal Positional Vertigo 647

DIAGNOSIS
History
Patients describe sudden, severe attacks of either horizontal
or vertical vertigo precipitated by certain head positions
and movements. The most common movements are
rolling in bed, extending the neck, and bending forward.
Patients can often identify the affected ear by stating the
direction of movement that precipitates the majority of the
attacks (e.g., rolling in bed to the right, but not the left,
precipitates the dizziness that indicates right ear involve-
ment). A study by Kentala and Pyykko33 reported that 80%
of patients experience a rotatory vertigo and 47% experience
a floating sensation. The attacks of vertigo typically last
less than 30 seconds; however, some patients overestimate
the duration by several minutes. Reasons for this discrepancy
may include the fear associated with the intense vertigo
along with the nausea and dysequilibrium that may follow
the attack. Patients may go to great lengths to avoid
precipitating movements. For this reason, some may not
realize that the condition has resolved, as it often does
spontaneously over time. A
Most patients experience several attacks per day (53%)
or week (23%).33 Before the development of effective
treatments, Schuknecht and Ruby5 had classified the
attacks into self-limited, recurrent, or permanent forms. Self-
limited BPPV occurs suddenly, resolves in weeks to months,
and does not recur. In the recurrent form, patients have mul-
tiple recurrent episodes of vertigo interspersed with asymp-
tomatic periods. In the permanent form, vertigo is present
without remission longer than 1 year. Chronic balance
problems have also been described by BPPV patients, often
upon awakening in the morning or after daytime naps.34,35
Although 50% to 70% of BPPV is primary or idiopathic,
history should be taken with a view to possible secondary
causes of BPPV. These include head trauma, viral
labyrinthitis/vestibular neuronitis, Ménière’s disease,
migraine headaches, and otologic and nonotologic surgery.

Diagnostic Maneuvers B
The Dix-Hallpike maneuver to diagnose posterior canal Figure 41-2. Dix-Hallpike maneuver. A, The patient is seated and positioned
BPPV was first described in 19522 (Fig. 41-2). The patient such that her head will extend over the edge of the table when supine. The
is seated and positioned such that his or her head will head is turned 45 degrees toward the ear being tested. B, The patient is
extend over the edge of the table when supine. The head quickly lowered into the supine position with her head extending below the
level of the table. The patient’s head is held in this position and the examiner
is turned 45º toward the ear being tested and the patient is observes the eyes for nystagmus. (Reprinted with permission from Parnes
quickly lowered into the supine position with the head LS, Agrawal SK, Atlas J: Diagnosis and management of benign paroxysmal
extending below the level of the table. The patient’s head positional vertigo [BPPV]. CMAJ 169:681–693, 2003.)
is held in this position and the examiner observes the eyes
for nystagmus. The use of Frenzel lenses adds little to the
identification of the nystagmus; unlike horizontal nystag- the patient will describe feeling vertiginous, the intensity
mus, rotational nystagmus is not suppressed by visual of which parallels the nystagmus response. The two poste-
fixation. The typical nystagmus has a brief latency (1 to 5 rior canals are tested independently.
seconds) and limited duration (typically less than 30 sec- Superior semicircular canal BPPV is exceedingly rare and
onds). It consists of a slight vertical component that is up- is not well described in the literature. The frequency has
beating and a torsional component that has the superior been reported as only 1% to 3% of BPPV cases.36,37 Since
pole of the eye beating toward the affected dependent ear. the posterior semicircular canal and contralateral superior
The direction of the nystagmus reverses when the patient semicircular canal lie in the same plane, the Dix-Hallpike
is brought into the upright position and the nystagmus will maneuver can be used to test for both entities. Therefore,
fatigue with repeated testing. Along with the nystagmus, the left Dix-Hallpike will test for the left posterior
648 PERIPHERAL AUDIOVESTIBULAR DISORDERS

semicircular canal and right superior semicircular canal. As well, the Dix-Hallpike test should not induce the burst
The observed nystagmus, however, will be opposite in both of nystagmus seen in BPPV. Very rarely, posterior fossa
its vertical (downbeating nystagmus) and torsional compo- tumors mimic BPPV, but there are no reports in the literature
nents (superior pole beating toward the uppermost ear).15 in which a tumor has perfectly replicated all of the features
Testing for lateral canal BPPV is done by laying the of a positive Dix-Hallpike maneuver. As mentioned previ-
patient supine and then quickly turning the patient’s head ously, BPPV can be secondary, so as to occur concurrently
(and body if necessary) laterally toward the side being with, or subsequent to, other inner ear or CNS disorders.
tested. A purely horizontal nystagmus occurs that is Also, being so common, it can often be a coincidental
geotropic (fast component toward the lowermost ear) in finding with other disorders.
the majority of cases, but it may be ageotropic (toward
the uppermost ear) in 27% of cases.14 Compared with the
vertical-torsional nystagmus of posterior canal BPPV, this MANAGEMENT
horizontal nystagmus has a shorter latency and stronger
intensity while maintaining the test position, and it is less Nonsurgical Management
prone to fatigue.15 Both sides are tested, and the direction
The management of BPPV has changed dramatically in the
of nystagmus coupled with the direction of roll causing the
past 20 years as our understanding of the condition has pro-
greatest nystagmus intensity often identifies the affected
gressed. Traditionally, patients were instructed to avoid posi-
side and the mechanism (see Table 41-1).
tions that induced the vertigo. Medications were prescribed
Overall, history and eye-findings during positional testing
for symptomatic relief, but one double-blind study showed
are the gold standards for diagnosing BPPV. Additional
that they were largely ineffective.42 BPPV is self-limited,
testing is not normally necessary and since electronystag-
and most cases resolve within 6 months. As the theories of
mography (ENG) does not record torsional eye movements,
cupulithiasis and canalithiasis emerged, several noninvasive
it adds little in the diagnosis of BPPV. More recently,
techniques were developed to correct the condition directly.
infrared videography has allowed direct eye observation
during the testing maneuvers, but three-dimensional eye
movement analysis38 is not common in clinical practice. Vestibular Habituation Therapy
Rotational-chair testing and posturography have no role in
the diagnosis of BPPV. Imaging with CT or MRI scans is In 1980, Brandt and Daroff43 introduced a specific series of
unnecessary unless there are atypical or unusual features to positional movements that they believed caused the
the assessment. mechanical loosening and dispersion of otolithic debris
from the cupula. The set of exercises were to be done every
3 hours during the day until 2 days after the positional
Subjective vs. Objective Benign vertigo had resolved. Many believed that these exercises
Paroxysmal Positional Vertigo worked through habituated central compensation, but the
A certain subset of patients may not demonstrate the typical authors concluded that the time course to the relief of
nystagmus during the Dix-Hallpike maneuver but may still symptoms was too short for this to occur.
experience the classic vertigo during positioning. This has Brandt and Daroff found that one-third of their patients
been termed subjective BPPV and several groups have had an abrupt resolution in symptoms and 66 of their 67
found repositioning maneuvers to be highly effective in patients had resolution within 3 to 14 days. Although several
this group of patients. Haynes and colleagues,39 Tirelli and other studies found excellent initial responses (96% to 100%)
colleagues,40 and Weider and colleagues41 found that to vestibular habituation,44–46 there is a high rate of recur-
patients with subjective BPPV treated with various reposi- rence (76%).44 The exercises are time-consuming and poorly
tioning maneuvers had response rates of 76% to 93% tolerated by some patients, especially the obese and elderly.
overall. Proposed theories to explain the lack of nystagmus
in patients with BPPV during the Dix-Hallpike maneu- Liberatory Maneuver
ver include (1) subtle nystagmus missed by the observer,
(2) fatigued nystagmus from repeated testing before the In 1988, Semont and colleagues47 described the liberatory
maneuver, and (3) a less noxious form of BPPV that elicits maneuver based on the cupulithiasis theory (Fig. 41-3).
vertigo but has an inadequate neural signal to stimulate the It was theorized that this series of rapid changes of head
vestibulo-ocular pathway.39 position freed deposits that were attached to the cupula.
The maneuver begins with the patient in the sitting position
Differential Diagnosis and head turned away from the affected side. The patient
is then quickly put into the side-lying position, toward the
Very few conditions can even remotely resemble BPPV. affected side, with the patient’s head turned up. After
In Ménière’s disease, the vertigo spells are not provoked by approximately 5 minutes, the patient is quickly moved
position change, and they last much longer (30 minutes to back through the sitting position to the opposite side-lying
several hours). Furthermore, there is accompanying tinnitus position with the head now facing down. The patient
and hearing loss. The vertigo in labyrinthitis or vestibular remains in this second position for 5 to 10 minutes before
neuronitis usually persists for days. The vertigo may be slowly being brought back to the sitting position.
aggravated by head movements in any direction, and this In their large series of 711 patients, Semont and
needs to be carefully extracted from the history so as not colleagues47 found an 84% response rate after one proce-
to confuse it with specific position change–evoked vertigo. dure and a 93% response rate after a second procedure
 Benign Paroxysmal Positional Vertigo 649

1
particles utricle
2 in posterior
canal 3

cupula

Figure 41-3. Liberatory maneuver of Semont. The

1 top panel shows the effect of the maneuver on
the canaliths. (Reprinted with permission from
Parnes LS, Agrawal SK, Atlas J: Diagnosis and
management of benign paroxysmal positional
vertigo [BPPV]. CMAJ 169:681–693, 2003.)

2 3

1 week later. Several other studies have had response rates the need for sedation and mastoid vibration52,53 (Fig. 41-4).
of 52% to 90%39,45,48,49 with recurrence rates of up to To perform the PRM:
29%.39 There has been no difference in efficacy shown
between the liberatory maneuver and particle repositioning 1. Place the patient in a sitting position.
maneuver in studies by Herdman and colleagues48 and 2. Move the patient to the head-hanging Dix-Hallpike
Cohen and Jerabek.50 The liberatory maneuver is effective position of the affected ear.
but is cumbersome with elderly and obese patients, and it 3. Observe the eyes for “primary stage” nystagmus.
shows no increased efficacy compared with the simple 4. Maintain this position for 1 to 2 minutes (position B).
particle repositioning maneuver. 5. The patent’s head is turned 90 degrees to the opposite
Dix-Hallpike position while keeping the neck in full
Particle Repositioning Maneuver extension (position C).
6. Continue to roll the patient another 90 degrees until
Although he had been teaching his technique for many the head is diagonally opposite to the first Dix-Hallpike
years, it wasn’t until 1992 that Epley51 first published his position (position D). The change from position B,
report on the canalith repositioning procedure (CRP). It is through C, into D should take no longer than 3 to 5
based on the theory of canalithiasis, which currently is seconds
thought to be the mechanism underlying most cases of 7. The eyes should be immediately observed for
posterior canal BPPV. This highly successful procedure “secondary-stage” nystagmus. If the particles continue
is done while the patient is sedated and with mechanical moving in the same ampullifugal direction, that is,
vibration to the mastoid bone and it involves moving through the common crus into the utricle, this
the patient’s head sequentially through five distinct posi- secondary-stage nystagmus should beat in the same
tions. Epley postulated that the procedure caused otolithic direction as the primary-stage nystagmus.
debris to move under the influence of gravity from 8. This position is maintained for 30 to 60 seconds and
the posterior semicircular canal into the utricle. Most then the patient is asked to sit up. With a successful
clinicians today are believed to use a modified version of maneuver, there should be no nystagmus or vertigo
the CRP. when the patient returns to the sitting position
One modified CRP is the particle repositioning maneuver because the particles will have already been reposi-
(PRM), which is a three-position maneuver that obviates tioned into the utricle.52
650 PERIPHERAL AUDIOVESTIBULAR DISORDERS

45°

90°
superior
canal

D
D
utricle
cupula

particles in
posterior canal
A C
135°

45°
135°

B D
Figure 41-4. Particle repositioning maneuver. Schema of patient and concurrent movement of posterior and superior semicircular canals and utricle. The patient
is undergoing the particle repositioning maneuver in the right ear. A, Patient is seated on table as viewed from the right side. The remaining parts show the
sequential head and body positions of a patient lying down viewed from the top. B, Patient in normal Hallpike head-hanging position. Particles gravitate in
ampullifugal direction and induce ampullifugal cupular displacement and subsequent counterclockwise rotatory nystagmus (right ear). Position is maintained for
1 to 2 minutes. Head is then rotated toward the opposite side with the neck extended. Head is brought through position C and into position D in a steady motion
by rolling the patient onto the opposite lateral side. Particles continue gravitating in ampullifugal direction through common crus into utricle. Eyes are
immediately observed for nystagmus. Position is maintained for another 1 to 2 minutes, and then the patient sits up. D, direction of view of labyrinth; dark
circle, position of particle conglomerate; open circle, previous position. (Reprinted with permission from Parnes LS, Agrawal SK, Atlas J: Diagnosis and
management of benign paroxysmal positional vertigo [BPPV]. CMAJ 169:681–693, 2003.)

Studies that use the repositioning maneuvers are difficult The patient is rolled away from the affected ear in 90-degree
to compare because they vary considerably in the length increments until a full roll is completed. This is believed to
of follow-up, number of treatment sessions, number of move the particles out of the involved canal into the utricle.
maneuvers per session, use of sedation, and use of mastoid For less agile patients, Lempert and Tiel-Wilck57 proposed
vibration. Table 41-2, adapted from Haynes and colleagues,39 the log roll where the patient is kept supine and only the
summarizes the efficacy and treatment protocols of many head is positioned. Here, the patient begins with the head
trials. The overall response rates range from 30% to 100% turned completely toward the affected ear. The patient is
and recurrence rates range from 5% to 30%. Most of then rapidly turned away from the affected ear in 90-degree
the studies presented are case series, however, Lynn and increments for a total of 270 degrees, with the head being
colleagues54 and Steenerson and Cronin46 provide evidence held in each position for about 1 minute. Only two
from randomized studies. patients were in the study, but both were completely
relieved of their vertigo.
Lateral Canal BPPV
Controversy
Several positioning techniques to treat lateral canal BPPV
have been developed. Perhaps the most simple is the Despite the excellent results from repositioning maneuvers,
prolonged position maneuver developed by Vannucchi and there has been some controversy as to whether they have
colleagues.55 In cases involving geotropic nystagmus, the an effect other than for central habituation over time.
patient lies on his or her side with the affected ear up for In 1994, Blakley58 published a trial of 38 patients randomly
12 hours. They had resolution in greater than 90% of their assigned to the particle repositioning group and the no
35 patients. Six of their patients converted to posterior treatment group. No significant difference was found
canal BPPV, but they were successfully treated with repo- between the treated and nontreated groups at 1 month,
sitioning maneuvers. and together, 89% showed some improvement. He con-
The barrel roll was described by Epley12,56 and involves cluded that the maneuver was safe but did not provide
rolling the patient 360 degrees, supine to supine, keeping treatment benefit for BPPV. Buckingham59 examined
the lateral semicircular canal in the earth-vertical plane. human temporal bones and attempted to demonstrate the
 Benign Paroxysmal Positional Vertigo 651

TABLE 41-2. Particle Repositioning Maneuver for BPPV

Number of Success Recurrence Treatment Treatment Postmaneuver Mastoid
Reference Patients Rate (%) Rate (%) Sessions Protocol Instructions Vibration

Epley51* 30 80 30 Single Multiple Yes Yes

Epley51† 30 100 NR‡ Repeated Multiple Yes Yes
Epley51 14 93 NR NR NR Yes Yes
Li63 10 30 NR Single Single Yes No
Li63 10 100 NR Repeated with Single Yes Yes
vibration
Li63 27 92 NR Single Single Yes Yes
Blakley58 16 94 NR Single Single No No
Smouha97 27 93 NR Multiple Multiple No No
Wolf et al.98 102 93 5 Single Single Yes No
Herdman et al.48 30 90 10 Single Single Yes No
Parnes and Price-Jones52 34 88 17 Multiple Multiple Yes No
Weider et al.41 44 88 9 Multiple Multiple Yes Yes
Steenerson and Cronin46 20 85 NR Multiple Multiple No No
Welling and Barnes99 25 84 NR Multiple Single Yes No
Harvey et al.100 25 68 20 Multiple Single Yes No
Lynn et al.54 18 61 NR Single Single Yes No

*Parenthetical numbers refer to entries in this chapter’s list of references.

†
Multiple entries from one reference indicate data extracted from a single study that used different treatments for groups of patients.
‡
Not reported.
§
Excluding patients lost to follow-up.
Table adapted from Haynes DS, et al: Treatment of benign positional vertigo using the Semont maneuver: Efficacy in patients presenting without nystagmus. Laryngoscope
112:796–801, 2002.

possible paths taken by loose otoliths under the influence Factors Affecting Repositioning Maneuvers
of gravity in different positions of the head. He found
Number of Maneuvers per Session
that although loose macular otoliths tend to fall into the
lumen of the utricle, they are not returned to their original The literature contains variations regarding how many
position in the macula of the utricle, which lies superior in repositioning maneuvers are performed in each treatment
the vestibule. He concluded that a mechanism other than session (see Table 41-2). Some perform a set number of
the repositioning of otoliths is responsible for the relief repositioning maneuvers regardless of response.62 However,
of BPPV seen in repositioning maneuvers. Gacek and the majority of groups are divided between performing only
Gacek60 have even questioned the entire pathophysiology one maneuver per clinic visit and performing maneuvers
of BPPV and claim that it is simply a clinical expression until there is a resolution of nystagmus or excessive patient
of vestibular ganglionitis. This conclusion is, however, discomfort. Our objection to repeating the maneuver until
based on very weak evidence that involved reviewing 51 there is a negative Dix-Hallpike response is that one cannot
temporal bones that contained evidence of ganglion cell know whether the response is abolished because of a
degeneration and only 3 of these patients had a history successful maneuver or because of fatigued that occurs nat-
of BPPV. urally with repeated testing. From the literature review,
Although most cases of BPPV are self-limited and spon- there does not appear to be significant differences among
taneously resolve within 6 months, a number of randomized these approaches in terms of short-term effectiveness and
studies have shown that repositioning maneuvers are highly long-term recurrence. Therefore, in our clinic, repeated
effective. One group in Bangkok performed a 6-month maneuvers are reserved for patients who do not demonstrate
efficacy trial comparing the CRP with no treatment in an ipsidirectional secondary-stage nystagmus or those
patients with BPPV.61 At 1 month, vertigo resolution was who have a reverse direction nystagmus at position D30
significantly higher in the CRP group (94%) than in the (see Fig. 41-4).
no treatment group, although this difference was not
Mastoid Vibration
seen at 3 and 6 months. Lynn and colleagues54 randomized
36 patients to a PRM and placebo treatment group with In Epley’s original description of the CRP,51 he used
blind assessment by an audiologist at 1 month. Resolution mechanical vibration of the mastoid bone thinking that it
of vertigo was significantly higher in the PRM group would loosen otolithic debris adherent to the membrane
(89%) than in the placebo group (27%). Steenerson and of the semicircular canal. In 1995, Li63 randomly assigned
Cronin46 randomly assigned 20 patients into either a PRM 27 patients to receive the PRM with mastoid vibration and
or a vestibular habituation group and 20 patients into a no 10 patients to receive the PRM without mastoid vibration.
treatment group. At 3 months, all patients in the treatment He found that the vibration group had a significantly
group were resolved of their symptoms while only 25% of higher rate of improvement in symptoms (92%) than did
the no treatment group were symptom free. the nonvibration group (60%).
652 PERIPHERAL AUDIOVESTIBULAR DISORDERS

These results do not, however, compare well with other of symptoms before treatment and success of the PRM.
published studies (see Table 41-2), in which the majority of They also found that the presence of recurrent or perma-
authors who did not use mastoid vibration achieved much nent BPPV before repositioning was not related to recur-
higher success rates. In 2000, a larger study by Hain and rence risk after treatment. Macias and colleagues66
colleagues62 reviewed 44 patients who had the PRM with followed 259 patients with BPPV and found no significant
mastoid vibration and 50 patients who had the PRM without relationship between either short-term success or recur-
mastoid vibration. There was an overall success rate of 78% rence risk and age, sex, etiology (idiopathic or secondary),
with no difference in short-term or long-term outcomes or the number of repositioning maneuvers performed per
between the two groups. treatment visit. It was found, however, that patients with
bilateral disease or BPPV in a canal other than the poste-
Postmaneuver Instructions rior canal required a greater number of treatment sessions
Another area of divergence among experts involves the use until resolution of symptoms. The prospective study of
of activity limitations after repositioning maneuvers. 168 patients using the CRP by Nunez and colleagues67
Epley51 asked his patients to remain upright for 48 hours suggests a recurrence rate of 15% per year, with a 50%
after the CRP. Certain investigators also request that, in recurrence rate of BPPV at 40 months after treatment.
addition to remaining upright, their patients avoid lying There was no significant association between cure or
on their affected side for 7 days. A study by Nuti and recurrence rate and sex, age, duration of symptoms, pre-
colleagues49 examined two sets of patients following the sumed cause, or treating physician.
liberatory maneuver. One group of patients was asked to
remain upright for 48 hours, while a second group of SURGICAL TREATMENT
patients was not given any postmaneuver instructions.
These two groups were retrospectively compared and no It should be stressed that BPPV, although incapacitating,
difference was found in short-term vertigo control. This is a benign disease, and surgery should be reserved for the
finding is consistent with an earlier study by Massoud and most intractable or multiply recurrent cases. BPPV often
Ireland,64 who also demonstrated that postliberatory undergoes spontaneous remission within 6 months and is
maneuver instructions were not efficacious. highly amenable to physical therapy and repositioning
maneuvers. The practitioner should exclude BPPV of
Objective vs. Subjective Benign Paroxysmal the lateral and superior semicircular canals and accurately
Positional Vertigo assess for secondary causes for BPPV. Furthermore, before
Subjective BPPV refers to the condition of patients with the physician considers surgery, the posterior fossa
positional vertigo who do not display the classic nystagmus should be imaged to rule out central lesions that might
during the Dix-Hallpike maneuver, but who experience mimic BPPV.68
the classic vertigo on history and positioning. As previously
Singular Neurectomy
discussed, several theories have been proposed regarding
the pathophysiology of subjective BPPV. Although most The singular neurectomy for BPPV was popularized by
studies in the literature include only patients with objective Gacek69 in the 1970s. It involves a transection of the pos-
BPPV, it has become clear that repositioning maneuvers in terior ampullary nerve in the singular canal. After raising
the subjective group is nearly as effective as they are for the tympanomeatal flap, the singular canal is approached
patients with objective BPPV. by drilling inferior to the round window. This puts at risk
Tirelli and colleagues40 prospectively examined two both the ampulla and vestibule; if either is injured, it may
groups of patients: 43 patients with subjective BPPV and lead to severe vertigo or sensorineural hearing loss. Initial
90 patients with objective BPPV, all treated with the PRM. reports by Gacek70 demonstrated high efficacy with
Although the objective BPPV group had a higher complete vertigo resolution in 91.7% of patients.
complete resolution rate than the subjective BPPV group However, there was a 7.3% risk of sensorineural hearing
(90% vs. 60.5%), the subjective BPPV group had 32.5% of loss with the procedure. Gacek published an update of his
patients who partially improved. Therefore, the overall personal series in 199571 and decreased the rate of sen-
success rate in subjective BPPV patients was 93%, which sorineural hearing loss to 3%. Although safe and reliable
compares well with the literature on objective BPPV. in experienced hands, this procedure is technically
Haynes and colleagues39 reviewed 127 patients with objec- demanding and has largely been replaced by the simple
tive BPPV and 35 patients with subjective BPPV who were posterior semicircular canal occlusion.15
all treated with the liberatory maneuver. Similar results
were found with no significant difference between the two Posterior Semicircular Canal Occlusion
groups in overall success rate: objective BPPV (91%)
History
versus subjective BPPV (86%).
It had long been a maxim in otologic surgery that the
Predicting Success and Recurrence Risk violation of the labyrinth would result in a “dead ear.” This
Several studies have attempted to identify variables that principle arose in the early days of otologic surgery when
would help predict initial short-term success and recurrence surgeons were forced to operate under less than optimal
risk with repositioning maneuvers. Beynon and colleagues65 conditions. These included the presence of chronic infection
followed 51 patients and reported no associations of age, and the difficulty of discerning surgical landmarks because
sex, etiology (primary or secondary), or the duration of poor magnification.
 Benign Paroxysmal Positional Vertigo 653

In the early 1960s, Money and Scott72 successfully brainstem evoked responses, remained stable for as long as
ablated individual semicircular canals without affecting 6 months following canal occlusion.85 This study provided
the response of the other ipsilateral semicircular canals. the groundwork for posterior semicircular canal occlusion,
At least in the cat model, this proved that invasive inner ear the surgical technique now used to treat intractable BPPV
surgery did not necessarily result in a “dead ear” under in humans.
optimal operating conditions. However, although the
Technique
vestibular labyrinth was spared by individual canal occlusion,
the possibility of sensorineural deafness secondary to The procedure is performed under general anesthetic and
cochlear damage was not addressed. should take no longer than 2 to 3 hours (Fig. 41-5). Using
Several experiments performed in the 1950s had a 5- to 6-cm postauricular incision, the posterior canal is
attempted to address this issue. Kristensen73,74 claimed to accessed through a mastoidectomy. With the use of an
preserve hearing when performing partial labyrinthec- operating microscope and drill, a 1 × 3 mm fenestration is
tomies in guinea pigs. Unfortunately, hearing was crudely made in the bony posterior canal. Particles can occasionally
measured using Preyer’s reflexes and the study failed to be seen in the posterior semicircular canal after fenestration.
control for hearing in the nonoperated ear. Wever and col- A plug, fashioned from bone dust and fibrinogen glue, is
leagues75 used cochlear potentials to determine that partial used to occlude the canal. Most patients are hospitalized
hearing was preserved after destruction of the lateral semi- for 2 to 3 days. Since the occlusion also impairs the normal
circular canal in monkeys. The degree of hearing preserva- inner ear physiology, all patients are expected to have post-
tion, however, varied a great deal among the subjects. operative imbalance and dysequilibrium. For most people,
More recently, animal studies by Kobayashi and col- the brain adapts to this after a few days to a few weeks,
leagues76 and Smouha and colleagues77,78 have demonstrated with vestibular physiotherapy hastening this process.
the preservation of cochlear function following the ablation A few variations of this technique have been published
of a semicircular canal. In humans, individual cases of inci- since the original description. A carbon-dioxide laser has
dental hearing preservation following injury to the lateral been used to ablate the posterior semicircular canal with
semicircular canal have been reported following fenestra- promising results in six patients.86,87 The use of an argon
tion surgery for otosclerosis79,80 and chronic otitis media.81–83 laser has been described with a guinea pig model.88
It was Parnes and McClure,84 however, who first mea- Brantberg and Bergenius89 described successful occlusion
sured the effect on hearing of posterior semicircular canal of the anterior semicircular canal in a patient with
occlusion in guinea pigs. Hearing, measured by auditory intractable anterior canal BPPV.

a Cutting drill

Diamond drill
b

Posterior canal

A
Figure 41-5. Surgical technique of posterior semicircular canal occlusion, right ear. A, Exposing the posterior semicircular canal otic capsule through a standard
postauricular transmastoid approach (a). Creating the 1 x 3 mm to 1 x 4 mm endosteal island with small diamond burr (b). Note that the drill-bit size is not to scale.
Continued
654 PERIPHERAL AUDIOVESTIBULAR DISORDERS

90° Pick

Figure 41-5, cont’d. B, Lifting out the

endosteal island with a fine 90-degree pick
(a). Magnified lateral view (b). C, Creating
the canal plug with two-component B
fibrinogen glue and mastoid cortex
bone chips.
Continued

A B

Bone
chips

Spatula

Plug
C
 Benign Paroxysmal Positional Vertigo 655

a Perilymph
b

Endolymph Membranous
labyrinth

Tisseel glue

Temporalis fascia

E
Figure 41-5, cont’d. D, Tamping plug through the fenestra into the canal (a). Cross-section schematic of canal showing intact but occluded membranous canal (b).
E, Covering the fenestra and surrounding bone with fascia and glue. (Reprinted with permission from Parnes LS: Update on posterior canal occlusion for benign
paroxysmal positional vertigo. Otolaryngol Clin North Am 29:333–342, 1996.)

Results and permanent profound loss, and one other had a mild
In 2001, Agrawal and Parnes10 published the largest series in loss (20 db). Obvious free-floating endolymph particles
the literature of 44 occluded posterior canals in 42 patients. were found in 30% of operated ears (Fig. 41-6).
All 44 ears were relieved of BPPV, with only one having a Essentially, all cases were followed by an initial 1- to
late atypical recurrence. Of the 40 ears with normal pre- 4-week period of imbalance and motion sensitivity. The
operative hearing, one had a delayed (3-month) sudden average duration of postoperative hospitalization is 2 to
656 PERIPHERAL AUDIOVESTIBULAR DISORDERS

5 days in uncomplicated cases. Older patients have slower

recoveries and require longer hospital stays. The degree of
postoperative motion sensitivity usually determines the
length of stay. Postoperative vestibular suppressants are
discouraged because they tend to prolong the recovery.
Patients are given instructions, however, for postoperative
vestibular physiotherapy.
There have been no late sequelae such as sensorineural
hearing loss or tinnitus. Rizvi and Gauthier90 published a
case where the patient was not resolved of BPPV following
canal occlusion. This was secondary to incomplete occlusion
of the canal intraoperatively and the creation of an iatrogenic
fistula. This was surgically corrected and the patient’s
hearing and vertigo resolved.
In addition to the study by Agrawal and Parnes,10
Hawthorne and el-Naggar91 (15 patients), Anthony92
(14 patients), Walsh and colleagues93 (13 patients),
Zappia94 (8 patients), Pace-Balzan and Rutka95 (5 patients),
and Dingle and colleagues96 (4 patients) have further
supported the safety and efficacy of this procedure.

SUMMARY

A Benign paroxysmal positional vertigo presents with a history

of brief, episodic, position-provoked vertigo with charac-
teristic findings on Dix-Hallpike testing. Whereas a variety
of positional maneuvers have been described, the particle
repositioning maneuver is a simple effective treatment for
most patients with objective or subjective BPPV. Current
evidence does not support the routine use of mastoid
vibration with repositioning. Although most investigators
are still advising patients to remain upright for 24 to 48 hours
after repositioning, recent evidence suggests that this is
unnecessary. In addition, the literature is equivocal regarding
the ideal number of repositioning maneuvers to perform
per treatment session. To date, no factors have been iden-
tified to indicate an increased risk of BPPV recurrence
after successful repositioning; however, the association
between BPPV recurrence and migraine warrants further
investigation. For the small group of patients with classic
posterior canal BPPV who do not respond to repositioning,
posterior canal occlusion is a safe and highly efficacious
procedure.

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 Chapter
Pharmacotherapy for Vestibular
Dysfunction

Outline 42
Introduction Vestibular Migraine P. Ashley Wackym, MD, FACS
Autonomic Dysfunction, Vertebrobasilar Insufficiency
Tammy S. Schumacher-Monfre,
Anxiety, and Panic Attacks: Familial Ataxia Syndrome
MSN, APNP
Vestibular Circuitry Psychophysiologic Dizziness
Specific Pharmacotherapy Future Perspectives
Ménière’s Disease Symptomatic
Chemical Labyrinthectomy Pharmacotherapy
Preparation of Gentamicin Mechanism of Action
Solution Strategy in the Treatment
Intratympanic of Vertigo
Dexamethasone Prophylaxis of Motion
Otosyphilis Sickness

INTRODUCTION book, therefore, the focus of this chapter will be on medical

management and the scientific rationale for each strategy.
Over the past three decades, the evolution in the diagnosis The peripheral causes of vestibular dysfunction (see
and management of peripheral and central vestibular Table 42-2) are presumed to be restricted anatomically to
disorders has been dramatic. Consequently, it is rare that a structures associated with the membranous labyrinth,
patient requires surgical intervention1; however, a clear peripheral branches of the vestibular nerve, Scarpa’s
understanding of the pathophysiology and the scientific ganglion, and the vestibular nerve root. The central causes
basis of medical treatment will help ensure appropriate of vestibular dysfunction, though, compromise central
treatment of these patients. Three peripheral vestibular vestibular circuits that mediate vestibular influences on
disorders are commonly encountered by the neurotologist: posture (via vestibulospinal and vestibulocollic pathways),
benign paroxysmal positional vertigo, Ménière’s disease, control of gaze (via vestibulo-ocular and vestibulocollic
and vestibular neuronitis (neuritis), and one central disor- pathways), and autonomic functions. However, unlike the
der that is frequently encountered by the neurotologist peripheral vestibular system, which may be viewed strictly
(vestibular migraine), therefore the medical management as sensors of linear and angular acceleration of the head,
of these disorders will be emphasized. Additional disorders central vestibular pathways are multimodal neural circuits
are amenable to medical management, and many of these that integrate a variety of sensory and motor signals
will also be addressed. related to balance, posture, and eye movements. The
Pharmacotherapy of vertigo can be divided into two vestibular nuclei are the primary central target of the
general categories: specific and symptomatic. Examples of vestibular nerve. Other sites that receive primary afferents
specific therapies include antibiotics for bacterial or syphilitic from the vestibular nerve include several other brainstem
labyrinthitis, anticoagulants for vertebrobasilar insufficiency, nuclei (abducens nucleus, nucleus prepositus hypoglossi,
and diuretics for Ménière’s disease. Whenever possible, cochlear nuclei [probably from the sacculus], external
treatment should be directed at the underlying disorder. In cuneate nucleus, and reticular formation). Since the
the majority of cases, however, symptomatic treatment is vestibular nerve terminates only in the ipsilateral brain-
combined with the specific therapy or is the only therapy stem, integration of information from coplanar pairs of
available (e.g., viral vestibular neuronitis). peripheral vestibular end-organs (e.g., left and right lateral
Common causes and mechanisms of dizziness are out- canal cristae, left superior and right posterior canal cristae,
lined in Table 42-1. Tables 42-2 and 42-3 distinguish the and left posterior and right superior canal cristae) is medi-
common peripheral origins of vertigo from the common ated by commissural connections. In addition to these
central causes.2–4 The diagnosis, pathophysiology, and vestibular inputs, the vestibular nuclei receive propriocep-
treatment of most of these disorders are presented tive, visual (optic flow), and premotor/motor signals from
throughout several other chapters in this section of the different of levels of the neuraxis (including cerebral
659
660 PERIPHERAL AUDIOVESTIBULAR DISORDERS

TABLE 42-1. Common Causes and Mechanisms of Dizziness

Symptom Causes Mechanisms

Vertigo Benign positional vertigo, labyrinthitis, vestibular neuronitis, Ménière’s disease, Imbalance of tonic vestibular
vestibular migraine, otosyphilis, superior semicircular canal dehiscence syndrome, signals
vertebrobasilar insufficiency, multiple sclerosis, brainstem or cerebellar infarction
Presyncopal lightheadedness Hyperventilation associated with panic disorders or chronic anxiety, postural Diffuse ischemia of the brain
hypotension, congestive heart failure, diffuse cerebrovascular disease
Disequilibrium Ototoxic drugs, peripheral neuropathy, presbystasis, autoimmune inner ear disease, Symmetric vestibular loss,
genetic vestibular hair cell loss, cerebellar atrophy, cerebellar infarction, posterior proprioceptive loss,
fossa tumors, meningitides cerebellar damage
Visual distortion New refractive prescription, cataract surgery with lens implant, ototoxic drugs, Visual and vestibular input
extraocular muscle dysfunction, multiple sclerosis, cranial nerve III, IV, or VI mismatch
dysfunction, corneal disease
Multisensory dizziness Psychophysiologic dizziness, diabetes mellitus, systemic vasculitis, adverse drug Integrative dysfunction involving
reaction, aging visual, proprioceptive,
or vestibular systems

cortex) that are related to postural and ocular control. One of eye movements in the plane of the horizontal semicir-
consequence of the polymodal inputs to these circuits may cular canal by connections with the vestibular nuclei.
be the ability to use other sensory information to compen- The direct cerebellar connections to the vestibular
sate for peripheral vestibular injury. nuclei appear to be important for coordination and con-
Specific cell groups (or circuits) within the vestibular tinual recalibration of motor responses to vestibular stim-
nuclei then contribute directly to vestibulospinal, ulation. Climbing fiber input from the inferior olive
vestibulo-ocular, vestibulocollic, and vestibuloautonomic appears to play a critical role in these functions. The
pathways. The activity of each of these functional circuits climbing fibers are believed to provide a sensorimotor error
within the vestibular nuclei is modulated by specific cere- signal to cerebellar Purkinje cells, which may alter the
bellar circuits in the flocculonodular lobe, the vermis of responsiveness of the Purkinje cells to parallel fiber inputs
the posterior lobe, and the anterior lobe. Classical clinical via a mechanism termed long-term depression, to achieve a
and anatomic evidence indicate that each of these cerebel- rapid correction of function.
lar regions contribute to different vestibular motor func- One important feature of central vestibular circuitry is
tions. For example, flocculonodular lobe dysfunction has a its ability to compensate for peripheral injury. Although
primary effect on eye movements, whereas anterior lobe the phenomenon is well known, the mechanisms of
degeneration (e.g., alcoholic cerebellar degeneration) pre- compensation are poorly understood. The present evidence
dominantly influences postural control. Cerebellar regions suggests that behavioral compensation involves synaptic
related to autonomic control have also been identified (for plasticity in both the brainstem and the cerebellum. Two
review see Balaban5). Each of these larger cerebellar factors in compensation appear to be of particular relevance
regions, though, are subdivided into smaller circuitry units clinically. First, the stability of the vestibular dysfunction
(zones) that appear to directly influence specific vestibular has an obvious influence on the efficacy of compensation.
nucleus output pathways. For example, a small region Stable, predictable dysfunction (e.g., vestibular nerve
(zone) in the cerebellar flocculus contributes to the control

TABLE 42-3. Common Central Causes of Vertigo

TABLE 42-2. Common Peripheral Causes of Vertigo Brainstem lesions
Arteriovenous malformation (AVM)
Benign positional vertigo Tumor
Ménière’s disease Trauma
Vestibular neuronitis (neuritis) Demyelinating disease
Post-traumatic Multiple sclerosis
Endolymphatic hydrops Infarction or ischemia
Labyrinthine concussion Vestibular migraine
Drug-induced toxicity Brainstem
Minocycline Cerebellum
Phenytoin Vertebrobasilar insufficiency
Quinidine Hereditary disorders
Gentamicin Spinocerebellar disease
Streptomycin Posterior fossa lesion
Other Acoustic neuroma
Bacterial labyrinthitis Meningioma
Viral labyrinthitis Arachnoid cyst
Tumors Metastatic tumor
Otosclerosis Other cerebellopontine angle tumor
Vasculitides Arnold-Chiari malformation
 Pharmacotherapy for Vestibular Dysfunction 661

section) provides a baseline of dysfunction as a target for panic attacks, and agoraphobia.8 The linkage appears to be
compensation. Conversely, compensation for fluctuating mediated by (1) ascending vestibular pathways involving
hypoactivity or hyperactivity (e.g., Ménière’s disease) is the parabrachial nucleus, amygdala, and infralimbic cortex;
expected to be ineffective because baseline function is (2) noradrenergic pathways; and (3) serotonergic pathways.
unpredictable or unstable. Second, the functional status of The consequences of this intimate neurologic linkage
the central nervous system (CNS), due to either age- among vestibular function, autonomic regulation, and
related or organic changes, is an important consideration. affective status are of great practical importance to the cli-
For example, individuals with preexisting cerebellar nician. In particular, it is important to consider a multifac-
damage may show decreased compensatory capability.6 torial treatment plan to address the pathogenic mechanisms,
obtain symptomatic relief from vertigo and nausea, facilitate
Autonomic Dysfunction, Anxiety, and vestibular compensation, and address the emergent anxiety
Panic Attacks: Vestibular Circuitry and depression of individual patients. The symptomatic
pharmacotherapy of vestibular dysfunction is discussed
Every clinician treating patients with vestibular disorders, later in this chapter; however, low doses of diazepam (2 mg
as well as astronauts experiencing the rapid changes of orally tid PRN), or lorazepam (0.5 mg orally tid PRN) are
vestibular input encountered during the various stages useful in managing the associated symptoms of autonomic
of space flight, are well aware of the marked autonomic dysfunction, anxiety, panic attacks, and agoraphobia. For
dysfunction associated with these alterations of vestibular symptoms that occur more consistently, clonazepam
input.7 These signs and symptoms of nausea, vomiting, (0.25 mg bid to tid) should be considered.13,14 Adjunctive
pallor, as well as changes in respiration and circulation are techniques such as stress reduction methods, biofeedback,
clinically apparent; however, the basis for these responses hypnosis, and yoga can likewise prove helpful in reducing
has only recently been elucidated via anatomic studies these symptoms.
identifying a network of vestibuloautonomic projections in
the brainstem of rabbits, rats, and cats.8,9
The finding that vestibular nuclear and secondary SPECIFIC PHARMACOTHERAPY
visceral projections converge in the parabrachial nucleus
(and other brainstem regions) provides important insights Specific forms of pharmacotherapy are directed at revers-
into potential neural substrates for phenomena such as ing the proven or presumed pathophysiologic mechanisms
respiratory, cardiovascular, and gastrointestinal (emetic) responsible for disorders associated with vestibular dys-
responses to vestibular stimulation, motion sickness, and function. Examples of such interventional schemes are
autonomic responses in altered gravitational environments. outlined in Table 42-4.
In particular, these findings provide a potential neurologic
basis for the close relationship between vestibular dysfunc-
tion and anxiety disorders with agoraphobia.8
Ménière’s Disease
Anxiety, panic attacks, and agoraphobia are also com- Medical therapy for Ménière’s disease includes dietary
monly associated with vestibular dysfunction.8 In 1945 Sir modification, physiotherapy, psychological support, and
Terrence Cawthorne described the terror that patients with pharmacologic intervention. Diuretic therapy and salt
acute vestibular injury may experience. Other clinicians restriction have long been considered the mainstay of
have identified specific situations involving changes in medical intervention for endolymphatic hydrops, based
spatial orientation that elicit symptoms of anxiety and on the assumption that these drugs can affect fluid bal-
panic. Levy and O’Leary10 coined the term street neurosis to ance within the inner ear and lead to a depletion of
describe the anxiety that some patients develop after an endolymph.15–17 Thiazide diuretics have been a popular form
acute vestibular attack. McCabe11 observed the supermarket of such specific pharmacotherapy for Ménière’s disease.
syndrome in patients with Ménière’s disease and character- These agents enhance excretion of sodium, chloride, and
ized these patients as experiencing an intolerance to look- water by interfering with absorption of sodium ions across
ing back and forth along aisles and up and down shelves. the epithelium of the cortical diluting segment of the
Patients with vestibular deficits who are visually or propri- nephron. Other electrolyte effects include enhanced potas-
oceptively dependent may have symptoms of imbalance, sium, magnesium, phosphate, bromide, and iodide excretion.
discomfort, anxiety, or phobic avoidance when in situations Long-term therapy produces decreased calcium excretion
with inadequate visual or proprioceptive balance cues. Jacob and hypocalciuria.
and colleagues have termed this situational specificity space Prolonged thiazide diuretic therapy can be associated
and motion discomfort. These unpleasant manifestations of with metabolic alkalosis with hypokalemia and
discomfort may also be considered as referred signs and hypochloremia. A potassium-sparing diuretic such as tri-
symptoms from vestibular pathways to visceral sites and may amterene or spironolactone is often used in conjunction
serve as eliciting or reinforcing stimuli for conditioned with thiazides to offset potassium loss (e.g., triamterene
avoidance of potentially dangerous situations.12 The diag- and hydrochlorothiazide). Thiazides can induce hyper-
nostic category space and motion phobia develops when situ- glycemia and exacerbate diabetes mellitus. Other potential
ational distress significantly impairs a patient’s normal adverse reactions include hyperuricemia and orthostatic
activities, particularly by producing avoidance behaviors hypotension. These agents may exacerbate preexisting
that reduce vestibular discomfort.4 The neurologic linkage renal or hepatic insufficiency.
model has been proposed to explain the association of Carbonic anhydrase inhibitors (e.g., acetazolamide)
vestibular disorders and autonomic dysfunction, anxiety, decrease sodium-hydrogen exchange in the renal tubule.
662 PERIPHERAL AUDIOVESTIBULAR DISORDERS

TABLE 42-4. Specific Pharmacotherapy These agents are used to decrease intraocular pressure
of Vestibular Disorders in patients with glaucoma by reducing the formation of
aqueous humor, and the analogy drawn between this
Peripheral Vestibular Disorders disease state and Ménière’s disease has led to the trial of
Ménière’s disease
Low sodium diet (1–1.5 g Na+/day)
these agents for treatment of endolymphatic hydrops. In
Diuretic addition they are capable of decreasing CSF production
Triamterene and hydrochlorothiazide (Dyazide) by up to 50%. These diuretic agents increase excretion of
Acetazolamide (Diamox) bicarbonate, sodium, and potassium. Reduction of plasma
Hydrochlorothiazide bicarbonate can produce mild metabolic acidosis with
Vasodilator
Isosorbide dinitrate chronic therapy. Rarely, hyperglycemia is exacerbated in
Niacin patients with diabetes mellitus. Possible adverse effects
Papaverine include nephrocalcinosis, hyperhidrosis, distal paraesthe-
Nylidrin sia, and gastrointestinal disturbance. Lip and distal paraes-
Histamine
Betahistine
thesias may resolve with continued use or with decreasing
Aminoglycosides the dosage; however, these symptoms, if tolerated by the
Gentamicin (transtympanic) patient, do not represent a contraindication to continued
Streptomycin (IM or selective perfusion) use. Particular caution should be taken in prescribing
Steroids acetazolamide to patients with a previous history of
Dexamethasone (transtympanic)
Otosyphilis nephrolithiasis, especially if the kidney stones were shown
Penicillin (IV, IM), Amoxicillin (PO) to be calcium oxalate. If a trial of acetazolamide therapy in
Doxycycline, Tetracycline, Erythromicin (for penicillin allergy) such a patient is necessary, a 24-hour urine collection should
Steroids be followed by analysis of calcium, oxalate, and citrate. If the
Viral neurolabyrinthitis (including vestibular neuronitis)
Antiviral agents
patient demonstrates hypocitruria, which can be a conse-
Acyclovir (Zovirax) quence of metabolic acidosis induced by acetazolamide,
Famciclovir (Famvir) administration of acetazolamide should be terminated, as
Valaciclovir (Valtrex) hypocitruria can induce calcium oxalate nephrolithiasis.
Steroids Vasodilators have been used for the treatment of
Central Vestibular Disorders
Vertebrobasilar insufficiency Ménière’s disease, based on the hypothesis that the patho-
Antiplatelet therapy genesis of endolymphatic hydrops results from ischemia of
Aspirin the stria vascularis. Such agents include niacin, papaverine,
Ticlopidine nylidrin, isosorbide dinitrate, intravenous (IV) histamine,
Pentoxyifylline
Anticoagulation (reserve for impending stroke)
and the oral histamine agonist betahistine. These agents
Heparin directly affect vascular smooth muscle, producing vasodi-
Warfarin lation. Isosorbide dinitrate principally affects the venous
Postinfarction syndromes system, whereas histamine causes vasodilation of small
Dihydroergocristine, dihydroergocriptine blood vessels and capillaries. Betahistine has also been
Flunarizine
Gangliosides shown to exert a direct inhibitory effect on polysynaptic
Free radical scavengers neurons within the vestibular nuclei, independent of
21-Aminosteroids changes produced in cerebral blood flow. The most com-
Amphetamine mon adverse reactions to these agents include flushing,
Vestibular Migraine
Migraine abortive therapy (not used in basilar artery migraine)
headache, and hypotension.18,19
Ergotamine tartrate The literature contains many anecdotal reports and
Sumatriptin uncontrolled studies reporting apparent beneficial effects
Migraine prophylaxis of specific pharmacotherapy in patients suffering from
Nortriptyline or Imipramine Ménière’s disease. Ruckenstein and colleagues20 critically
Verelan PM
Propranolol (first line agent for children) reviewed this literature in 1991 and concluded that non-
Neurontin specific vestibular suppressants are the only medications
Flunarizine that have been shown to alleviate vertigo associated with
Methysergide Ménière’s disease. Three small double-blind studies
Psychophysiologic dizziness (associated with panic attacks)
Antidepressants
showed short-term beneficial effects of betahistine, but
Imipramine this may be secondary to a nonspecific CNS suppression
Desimpramine rather that a direct effect on cochlear blood flow, as previ-
Nortriptyline ously described. Thus, no studies demonstrated definitive
Tranquilizers beneficial effects of vasodilator therapy in reversing
Alprazolam
Diazepam endolymphatic hydrops.
Lorazepam
Monoamine oxidase inhibitors
Phenelzine Chemical Labyrinthectomy
Familial ataxia syndromes
Acetazolamide (Diamox)
Compliance with medical management (daily sodium
restriction to 1500 mg/day plus triamterene hydrochloro-
thiazide [Dyazide] qd to bid) results in acceptable control
of signs and symptoms in most patients15; however,
 Pharmacotherapy for Vestibular Dysfunction 663

approximately 10% of patients reach a point when the persists or occurs later following chemical labyrinthec-
symptoms are so severe that an operation or aminoglyco- tomy, vestibular exercises or formal vestibular rehabilita-
side treatment should be considered.1 Henceforward in tion are usually helpful in improving balance function and
this chapter we will consider the aminoglycoside vestibu- comfort of movement.
lotoxic treatments to be included under the term chemical Interest in intratympanic aminoglycoside (ITAG) has
labyrinthectomy. When considering vestibular surgery or increased in recent years as an alternative to endolym-
chemical labyrinthectomy, it is often useful to have the phatic sac surgery and vestibular neurectomy. A key advan-
patient with Ménière’s disease consult a dietitian in order tage is that ITAG can be a nonsurgical office procedure.
to optimize the medical management prior to undertaking Nevertheless, ITAG is, at present, an imprecise treatment,
this course. From the standpoint of the severity of symp- difficult to control, and in at least one current form of drug
toms the most appropriate group for surgical or chemical delivery, appears to be associated with a 10% rate of deafness
labyrinthectomy treatment include patients who cannot in the treated ear.22 Nonetheless, vertigo can be relieved in
work, drive, make secure travel plans, or take care of a fam- 90% of cases.22,23 Other protocols may be associated with
ily. Candidates may also include those who are managing a lower rate of deafness. ITAG has a place in the treatment
to carry out these activities only with great effort because of Ménière’s disease, but the optimal treatment protocol
they are highly motivated to do so (American Academy of and the boundaries of its exact role remain to be defined.
Otolaryngology–Head and Neck Surgery [AAO-HNS] Since 1994, when the first edition of this textbook was
functional levels 4, 5, and 6).21 An endolymphatic sac pro- published, most otologists have greatly decreased the
cedure may be considered in some cases at AAO-HNS func- frequency with which they perform ITAG because of the
tional level 3, whereby no disability or immediate threat of risk of hearing loss. However, a recent longitudinal study
disability is evident, but daily activities are disrupted due to of ITAG administration in 31 Ménière’s disease patients
the attacks of vertigo. reported a markedly reduced rate of profound hearing
The overall goal of any treatment of vestibular disorders loss.24 In this study, Wu and Minor reported profound
is to help patients be as functional and comfortable as pos- hearing loss in only one patient (3%). In addition, hearing
sible. The operational goals are to control episodic vertigo improvement was seen in 5 (16%), unchanged in 21 (65%),
and to avoid or minimize treatment-associated disequilib- and worse in 5 (16%). Vertigo was controlled in 90% of
rium and hearing loss. The primary technical goal of the patients. Their protocol involves a single ITAG
chemical labyrinthectomy is complete unilateral vestibular administration (26.7 mg/mL gentamicin, 0.4 mL typically
ablation.1 The most common difficult problem to manage injected), 30 minutes of solution contact with the round
after any vestibular destructive surgery (vestibular neurec- window, and subsequent removal of the residual genta-
tomy, labyrinthectomy, or aminoglycoside treatment) is micin via aspiration. Minor’s protocol now involves a sin-
persistent, troublesome disequilibrium and this com- gle ITAG injection, and additional treatments are only
plication occurs in 20% of cases.1 Nearly all patients will administered if episodes of vertigo have persisted at the
experience vertigo and disequilibrium immediately after time of follow-up examination 3 weeks after injection.
surgical labyrinthectomy or vestibular neurectomy. With Aminoglycosides do not seem to be concentrated in
aminoglycoside treatments, the disequilibrium begins cochlear fluids, but the elimination half-life increases with
when the chemical labyrinthectomy effect occurs. This chronic administration, suggesting sequestration of the
effect typically occurs at least 4 days after the commence- drug by hair cells.25 Amikacin, dihydrostreptomycin, and
ment of treatment. kanamycin are primarily cochleotoxic, whereas gentamicin
Patients report symptoms of acute unilateral peripheral and streptomycin are primarily vestibulotoxic.16 At high
vestibular loss, including an acute sensation of rotational doses, streptomycin is also cochleotoxic. For example,
vertigo, imbalance, a tendency to fall toward the affected streptomycin, 25 mg/kg/day, administered systematically
side, and intolerance to rapid head movement. They usu- to cats resulted in loss of vestibular hair cells only, but at
ally experience autonomic dysfunction (e.g., nausea and 100 mg/kg/day, both vestibular and cochlear hair cells
diaphoresis), as well as anxiety and general malaise. These were lost.26
symptoms improve spontaneously such that most patients The hair cells of the cristae, the maculae, and the
are able to return to full activities by 6 to 8 weeks after cochlea degenerate to different degrees following the
labrinthectomy.1 administration of aminoglycosides. The primary vestibular
Patients treated with intramuscular (IM) aminoglyco- neurons, the cochlear nuclei, and the vestibular nuclei are
sides or those with a pretreatment contralateral vestibular not directly affected, even at high doses.26 The basal turn
deficit may also experience oscillopsia. This symptom is a of the cochlea is the region most susceptible to permanent
bobbing of the visual field on ambulation. Patients will loss of hair cells, resulting in an initial loss of high-
report that they have trouble reading street signs while frequency hearing. Although the mechanisms of this dif-
driving or riding in a car or difficulty reading labels as they ferential toxicity are incompletely understood, several
move down the aisle of a store. Oscillopsia is a manifesta- contributing factors have been identified, including the
tion of reduction of vestibulo-ocular reflex due to a loss of route of administration, dose variables, and the specific
vestibular sensation. Oscillopsia usually improves in time, aminoglycoside used.
possibly due to CNS compensation or tolerance by the Damage to vestibular dark cells, which are thought to
patient. play a role in the production of endolymph, has been
In nearly all instances, early postoperative disequilibrium reported following administration of doses of aminoglyco-
will gradually resolve following ambulation of the patient, side below the threshold for damage to hair cells. An
and additional treatment is not needed. If disequilibrium attractive hypothesis is that the impaired function of dark
664 PERIPHERAL AUDIOVESTIBULAR DISORDERS

cells would be beneficial in Ménière’s disease since cases of unilateral Ménière’s disease.22 A tuberculin syringe
decreased production of endolymph would affect the fluid is used to introduce 2.5 to 25 μg of streptomycin in solu-
homeostasis of the inner ear.27,28 tion (25 μg/mL) through a fenestration in the horizontal
semicircular canal. Shea and Norris30 have reported com-
Preparation of Gentamicin Solution plete elimination of caloric response and complete relief
of vertigo in 166 Ménière’s disease patients undergoing
Gentamicin solution may either be used as a stock solution streptomycin perfusion of the inner ear, with preservation
of 40 mg/mL with a pH of about 5.4, or be buffered to or improvement of hearing in 75% of patients. However,
a pH of 6.4 to reduce the discomfort associated with a multi-institution trial of this technique reported hearing
intratympanic injection. One method of preparing the loss in 68% of 47 patients undergoing labyrinthotomy
buffered solution is as follows1: 1.5 mL of gentamicin with streptomycin infusion.31
solution (40 mg/mL) is injected into a sterile 5-mL vial. A Parenteral streptomycin has been used successfully to
0.6 M sodium bicarbonate solution is prepared by com- manage cases of refractory bilateral Ménière’s disease.
bining 2 mL of 8.4% sodium bicarbonate and 1.36 mL of Therapy is titrated to preserve some vestibular function.
sterile water in a 5-mL sterile vial. Add 0.5 mL of the 0.6 This method has helped to avoid post-treatment disequi-
M sodium bicarbonate solution to the sterile vial contain- librium and oscillopsia associated with complete bilateral
ing 1.5 mL of gentamicin to form 2 mL of a solution of vestibular ablation. Total streptomycin dose varies from 5
gentamicin (30 mg/mL, pH 6.4) ready for injection. to 70 g in patients undergoing titration therapy, with a
mean dose of approximately 25 g administered to achieve
Injection Technique
the desired endpoint. Langman and associates32 improved
The patient should be comfortably positioned in the or completely relieved episodic vertigo in 16 of 19 patients
standard otologic position for examination under the oper- (84%) undergoing titration therapy for bilateral Ménière’s
ating microscope, supine with the head turned away from disease. Persistent severe post-treatment disequilibrium
the ear to be treated. In this position, the eustachian tube occurred in three patients (16%), and changes in hearing
will be uppermost to avoid dependent drainage of the gen- were independent of the effect of streptomycin.
tamicin solution out of the middle ear. This position is
maintained for 30 minutes following the injection, and the
Intratympanic Dexamethasone
patient is instructed not to swallow or clear the middle ear
during this period; providing a cup for gentle expectora- An emerging management technique for recalcitrant
tion during this period helps accomplish this goal. Topical Ménière’s disease is the intratympanic injection of dexa-
application of phenol to a small injection site on the surface methasone. The technical aspects are identical to those
of the tympanic membrane provides anesthesia, and the described in the ITAG section. The senior author injects
gentamicin is injected in the middle ear using a tuberculin dexamethasone (24 mg/mL) and allows the patient to
syringe and a 27- or 25-gauge spinal needle. Typically, about remain supine with the affected ear uppermost for 20 to 30
0.5 mL of solution fills the middle ear. The residual gen- minutes. The procedure is performed three times, 1 week
tamicin is aspirated from the middle ear after 30 minutes apart. Other authors have used single-dose applications
of contact with the round window. via an exploratory tympanotomy followed by application,
in the round window niche, of dexamethasone 8 mg, in
Administration Protocols
hyaluronic on an absorbable gelatin sponge. A retrospec-
Numerous administration protocols have been described. tive study of the latter approach in 21 ears of 19 patients
Nedzelski and colleagues22 had patients administer gen- was reported by Arriaga and Goldman.33 They found that
tamicin intratympanically three times a day via a tympa- a single application of dexamethasone/hyaluronan solution
nostomy tube and a small flexible tubing for 4 days. The did not produce dramatic short-term hearing improve-
protocol introduced by Beck and Schmidt29 advocates a ment in patients with endolymphatic hydrops; however,
once daily regimen until the earliest sign of ototoxicity is improvements of as much as a 38-dB gain in pure tone
observed. With this schedule, 1 to 12 doses are given, with acuity (PTA) and 38% gain in the speech discrimination
a mean of 4 to 6 doses. A number of other investigators use score were reported. This single patient’s gain was tempered
a dosing regimen that titrates the administration of ITAG by three ears that experienced deterioration after treat-
using patient response measured by caloric response, ment. Conservative performance of intratympanic dexa-
audiometric function, and patient symptoms. The ration- methasone is appropriate; however, some patients failing
ale is to reduce the risk of hearing loss while maintaining medical therapy may benefit from this technique prior to a
control of vertigo by giving less medication per dose and more aggressive surgical option. Long-term controlled
extending the time of treatment with repeated applications clinical trials remain to be completed that will determine
as necessary. A second intratympanic injection of approxi- the efficacy of this treatment modality.
mately 0.5 mL of gentamicin, 30 mg/mL, pH 6.4, is given
3 weeks after the first if vertigo is not controlled or recurs. Otosyphilis
However, based on the far lower rate of profound hearing
loss seen with the protocol developed by Minor (3% com- A presumptive diagnosis of otosyphilis is made in the
pared with 10%), it is anticipated that scheduled repeated patient with unexplained cochleovestibular dysfunction
injections will become less common. and positive fluorescent treponemal antibody absorption
Selective chemical vestibulectomy had also been used as (FTA-ABS). Penicillin and steroids have been the primary
an alternative to vestibular nerve section for refractory treatment modalities. Although previous studies have
 Pharmacotherapy for Vestibular Dysfunction 665

shown benefit of IM penicillin therapy,34 other studies with treatment.36 Patients with disabling tinnitus or
have demonstrated that the IM route of parenteral therapy vertigo should undergo such therapy regardless of the
fails to achieve treponemicidal levels in cerebrospinal duration of symptoms because the likelihood of improve-
(CSF) fluid. For IM therapy, treatment with 2.4 million ment is reasonably high. However, patients with isolated,
units of benzathine penicillin weekly for 3 successive weeks long-standing hearing loss without fluctuation are less
constitutes minimal therapy. Other authors advocate likely to respond to therapy.37
extending therapy for as long as 1 year. New outpatient
treatment regimens that include probenicid promise to Vestibular Migraine
achieve antitreponemal drug levels in the CSF. Probenecid
increases the half-life and facilitates CSF penetration of Since the appearance of the first edition, much has been
penicillin derivative antibiotics. These regimens include learned about vestibular migraine. Likewise, the frequency
1.8 million units of IM procaine penicillin G daily or 1 g of occurrence of this disorder in both adults and children
oral amoxicillin six times daily, in combination with has been recognized to a much greater degree. It is a
probenecid 500 mg four times daily. remarkably common disorder and no doubt represents
For patients receiving IV therapy, 10 million units of peni- many of the atypical Ménière’s disease patients described in
cillin G per day is administered in divided doses for 10 days, the past. Migraine has long been considered a vascular dis-
followed by 2.4 million units of IM benzathine penicillin order, with vasodilation responsible for the headache and
per week for 2 additional weeks. Patients with neurosyphilis, vasoconstriction responsible for the neurologic symptoms.
documented by a positive CSF VDRL, 24 million units of Basilar artery migraine produces symptoms related to
penicillin G per day is administered IV for 14 days, fol- those areas of the CNS supplied by the posterior circula-
lowed by a 2-week course of benzathine penicillin and an tion.38 However, serotonergic and central vestibular path-
8-week course of high-dose oral amoxicillin. Patients with ways may also be involved in migraine-associated vertigo
documented penicillin allergy receive 500 mg of tetracy- and vertiginous auras.8 Approximately 30% to 40% of
cline or erythromycin qid for 30 days. Alternatively, doxy- patients with classic migraine experience true vertigo. Other
cycline (200 mg/day for 15 to 20 days) may improve patients can present with vertigo without concomitant
patient compliance as it is dosed twice a day and may be headache, referred to as a migraine equivalent.39,40 This dis-
taken with food. ease also occurs in children; unfortunately, the misnomer
Many studies demonstrate enhanced efficacy when benign positional vertigo of childhood has been assigned by the
penicillin is combined with steroid therapy. Although dose neurology community.41
recommendations vary, prednisone 40 to 60 mg/day for Prophylactic therapy is indicated for those patients
2 weeks is accepted as minimal therapy. Therapy is contin- whose lives are being negatively affected by the recurrent
ued for 4 weeks in patients who respond and is subse- vertigo associated with vestibular migraine, as all success-
quently tapered according to patient symptomatology. ful regimens have potentially troublesome side effects.
Patients receiving prolonged therapy should be placed on The most common indication for prophylaxis is frequent
an alternate-day regimen to minimize adrenal suppression. migraine, with symptoms occurring more frequently than
Absolute and relative contraindications to steroid therapy two episodes per month for 3 successive months.
include hypersensitivity to corticosteroids, severe osteo- Interestingly, adults with vestibular migraine more often
porosis, brittle diabetes mellitus, peptic ulcer disease, respond to tricyclic antidepressants or calcium channel
diverticulitis, hypothyroidism, cirrhosis, thromboembolic blockers than to beta blockers. Conversely, children with
disorders, and psychiatric illness. Since glucocorticoid vestibular migraine respond to beta blockers extremely
therapy can reactivate tuberculosis, chemoprophylaxis well. Empiric therapy with the most commonly used agent
should be used for patients with a history of active may need to be followed with a change in class of medica-
tuberculosis. tion until symptoms are controlled. Once symptoms are
Seventy-five percent of patients undergoing antibiotic controlled with prophylactic therapy for 6 months, patients
therapy for secondary syphilis will experience an acute, are weaned from their medication. If this is tolerated, then
febrile reaction known as the Jarisch-Herxheimer reaction. retreatment is necessary only if symptoms recur. Sometimes
The reaction typically begins within 4 hours after treat- it is necessary to resume treatment with the prophylactic
ment begins and is manifest by fever and flulike symptoms. agent for another 3 to 6 months before attempting to wean
This reaction is probably related to release of endotoxin the medication. Rarely, ongoing therapy is necessary, and
from killed spirochetes or an allergic reaction to trepone- this decision is guided by the patients’ clinical features.
mal breakdown products. Symptoms typically subside Very often, children with vestibular migraine stop having
within 24 hours after instituting therapy and seldom this disorder as they approach puberty. Dietary counseling
require interruption of therapy. However, patients should is important, as tyramine- and caffeine-containing foods
be informed of this syndrome, as some will experience a such as blue cheese, red wine, grape juice, chocolate, and
transient exacerbation of cochleovestibular symptoms. tomatoes may serve as triggers for the migraine attacks.
Administration of prednisone for 24 hours prior to the ini- Likewise, excessive caffeinated-beverage consumption,
tiation of antibiotic therapy reduces the febrile component fatigue, stress, and skipping meals may induce vestibular
of this reaction.35 migraine attacks in some patients.
Penicillin and steroid therapy has been reported to Tricyclic antidepressants may be useful adjunct for pro-
improve vertigo in 58% to 86% of patients with symptoms phylaxis of migraine associated with panic attacks. For years,
secondary to otosyphilis. This compares favorably with the tertiary amine antidepressants such as amitriptyline
patients with hearing loss, of which only 31% improve and imipramine have been used. Though effective, such
666 PERIPHERAL AUDIOVESTIBULAR DISORDERS

medications have adverse anticholinergic side effects such it may induce coronary vasospasm. Currently, sumatriptan
as constipation, tachycardia, blurred vision, cognitive is not recommended for patients with basilar migraine.
impairment, and orthostatic hypotension.19 These side
effects can be detrimental, especially in the elderly popula-
tion. As individuals age, physiologic changes influence
Vertebrobasilar Insufficiency
pharmacotherapeutics. The specific changes involve water Approximately one-third of transient ischemic attacks
volume, cardiac output, circulatory blood flow, bareorecep- (TIAs) involve the territories of the vertebrobasilar system.
tor activity, gastric pH, intestinal absorption, hepatic blood These patients often manifest short-lived symptoms such
flow and function, hepatic enzymatic functions, kidney effi- as vertigo, diplopia, dysarthria, bilateral limb weakness, gait
ciency, renal blood flow and general function, and visual ataxia, variable and often bilateral sensory disturbance, and
acuity.42 New forms of tricyclics called secondary amines memory loss.48 Antiplatelet therapy has been demonstrated
(e.g., desipramine or nortriptyline) have decreased side to effectively reduce the incidence of stroke after TIA. This
effects and are effective in the treatment of migraines. For effect has been most clearly established for aspirin, which
this reason, the secondary amines are the tricyclics of can reduce by half the risk for stroke after TIA. Although
choice. most previous studies have used doses of 1200 mg daily, it
Beta blockers, calcium antagonists, anticonvulsants, and is likely that 325 mg/day is equally effective.49,50
tricyclic antidepressants are currently the most widely used Ticlopidine (Ticlid) is another platelet aggregate
agents for prophylaxis of migraine.43 Propranolol is nor- inhibitor shown to lower the risk for stroke after TIA,
mally used in a high-dose range (80 to 240 mg/day) and particularly for cases of vertebrobasilar insufficiency. This
can produce significant side effects, including fatigue, agent may be more effective than aspirin, reducing the risk
bronchospasm, congestive heart failure, and male impo- for stroke by 48% compared with aspirin during the first
tence.44 Calcium antagonists such as flunarizine (10-mg year after TIA. However, this agent is associated with a
dose at night) or verapamil (240 to 320 mg/day) have been risk of neutropenia, which may be life-threatening, and
beneficial. However, side effects include sedation, weight therefore it should be reserved for patients who are intol-
gain, depression, and extrapyramidal disorders.45,46 When erant to aspirin therapy. All patients on ticlopidine therapy
choosing a calcium channel blocker to treat vestibular should have complete blood count (CBC) and white cell
migraine in adults, the authors usually begin treatment differential determination made at least once every 2 weeks
with verapamil (Verelan PM) 100 mg each night. This through the first 3 months of therapy. Neutropenia
medication is a sustained release formulation, and the dose reverses within 1 to 3 weeks after discontinuing treatment.
is increased after 3 to 4 weeks if the symptoms have not The efficacy of other compounds remains unproven.
been controlled. Recent studies also identify valproic acid Dipyridamole (Persantine) and sulfinpyrazone (Anturane)
(Depakene) and divalproex sodium (Depakote) as medica- confer no added benefit to aspirin therapy and are no
tions for the prophylactic treatment of migraines. The longer recommended.50 Pentoxyifylline (Trental) is a xan-
recommended starting dose is 250 mg bid, though some thine derivative that decreases blood viscosity and enhances
patients may need to titrate to 1000 mg/day. Please note— microcirculation. This agent has been shown to enhance
anticonvulsants are contraindicated in individuals with tissue oxygen levels in patients with peripheral vascular
liver function impairments. disease, and it may be useful for cases of vertebrobasilar
Although infrequently used in vestibular migraine, insufficiency.
ergotamine tartrate has been the drug of choice for abort- Full anticoagulation is typically reserved for patients
ing migraine symptoms for many years. It is a vasocon- with impending or evolving stroke. Occasionally, anticoag-
strictive agent that stimulates α-adrenoceptors and acts ulants are used for tight stenosis of intracranial arteries,
as a serotonin antagonist. It also inhibits free uptake of particularly if TIAs persist despite antiplatelet therapy.50
monoamines and sensitizes vascular smooth muscle to Therapy is commenced with continuous IV infusion of
sympathetic stimulation. This agent is contraindicated in heparin to maintain a partial thromboplastin time that is
patients with sepsis or local infection, liver disease, and 1.5 to 2.5 times normal. Subsequently, warfarin is added,
vascular disease. It should be used with caution in patients and heparin is discontinued when the prothrombin time is
with hypertension or peptic ulcer disease. Usual dosage is elevated to 1.5 to 2.5 times normal.
2 mg PO or as a rectal suppository, followed by additional Over 150 drugs have been reported to speed recovery
1-mg doses every half hour for two or three additional after a stroke, but none has been proven to be effective by
doses if necessary. Frequent use of ergotamine can lead to a careful clinical study. Glucocorticoids have been used
rebound headaches.47 extensively to limit cerebral edema, which may render
Although sumatriptan (Imitrex) should not be used to viable brain that is sensitive to further ischemic damage.
treat vestibular migraine, it is a common parenterally However, clinical studies indicate that steroids are ineffec-
administered vasoconstrictor that is an effective form of tive after ischemic infarction. Other commonly employed
abortive treatment for nonbasilar artery migraine. It is a interventions, including osmotic and loop diuretics and
selective agonist for 5-hydroxytryptamine, a receptor hyperventilation, have not been subject to adequate clini-
found on the basilar artery and in the vasculature of the cal trial to confirm efficacy.51
dura mater. It is administered as a 6-mg SQ injection Several compounds are currently being investigated and
and relieves the headache associated with migraine within may prove beneficial for recovery after acute stroke. Such
an hour in 70% of subjects. This agent should be used agents include gangliosides, free-radical scavengers, 21-
with caution in patients with hypertension, and it is aminosteroids, and amphetamine.51 Preliminary studies
contraindicated in patients with ischemic heart disease, as show that dihydroergocristine, an ergot alkaloid with
 Pharmacotherapy for Vestibular Dysfunction 667

potent dopaminergic activity, may reduce hypoxia-induced These agents include the benzodiazepines, tricyclic anti-
cerebral metabolic changes.52 The calcium channel antag- depressants, and monoamine oxidase inhibitors. Though
onist flunarizine has been shown to protect brain tissue clinically all are effective, the side effects must be taken
against neuronal damage in several models of cerebral into consideration.3,16
ischemia.53 The ultimate utility of these agents in stroke Benzodiazepines can have rebound symptoms following
patients awaits further clinical investigation. medication cessation. In addition, anxiety disorders are
highly comorbid with depressive disorders and in fact can
be exacerbated by benzodiazepines. Addictive tendencies
Familial Ataxia Syndrome also must be taken into consideration. Tricyclic antide-
Familial ataxia syndrome is a rare, autosomal-dominant pressants have high anticholinergic side effects. Safety
disorder that manifests by recurrent episodes of vertigo and becomes an issue in patient populations with coronary
ataxia in several members of a family. Other prominent artery disease or cardiac dysrhythmias. Monoamine oxi-
symptoms can include diplopia, dysarthria, tinnitus, and dase inhibitors have multiple food and drug interactions.
paraesthesia, but symptoms can vary considerably between In fact, they are contraindicated in populations with heart
families. Familial ataxia syndrome is one of the most treat- failure, pheochromocytoma, hypertension, liver disease,
able causes of chronic episodic vertigo. Acetazolamide, a cardiovascular disease, seizure disorders, diabetes, and
carbonic anhydrase inhibitor diuretic, effectively prevents suicidal tendencies.13,19 Nevertheless, when used appropri-
the episodic vertigo and ataxia. The mechanism of this ately, these drugs can be highly effective.
action remains unclear. Systemic acetazolamide produces Because of the numerous side effects of the previously
CNS acidosis by reducing serum lactate and pyruvate, but stated compounds, a fourth class of drugs is presently
serum levels of lactate and pyruvate are normal in patients under investigation. These include the selective serotonin
with this syndrome. The antihistamine dimenhydrinate, reuptake inhibitors (SSRIs) such as Prozac, Zoloft, Paxil,
the benzodiazepine alprazolam, and the calcium antagonist Luvox, and Celexa. Side effects such as agitation, headache,
flunarizine have been shown to be effective for treating gastrointestinal upset, insomnia, and sexual dysfunction
symptomatic vertigo associated with the familial ataxia may occur. Formal analysis is pending at this time although
syndrome.54,55 Recently, mutations in the calcium channel the preliminary data look promising.13
gene CACNA1A have been demonstrated in patients suffer-
ing from episodic ataxia type 2.39 This subtype of familial Future Perspectives
ataxia syndrome is characterized by episodic vertigo and
ataxia. In contrast, mutations in CACNA1A have not been The pharmacotherapy of vertigo caused by other common
observed in families with migraine headaches and episodic causes of vestibular dysfunction currently relies on non-
vertigo.56 specific suppression of symptoms. This is often the case
because the underlying pathophysiology of many vestibu-
lar syndromes remains poorly understood. Current tech-
Psychophysiologic Dizziness niques of molecular biology promise to expand our
Dizziness is associated with a wide range of psychiatric understanding of both the physiology and pathophysiol-
illnesses. Patients with anxiety disorders manifested by ogy of the human vestibular system. This knowledge may
panic attacks are particularly susceptible to experience dis- lead to the development of future forms of specific phar-
equilibrium, often described as a feeling of imbalance or macotherapy. For instance, cell and molecular biologic
even a sensation of spinning inside the head. At present, techniques such as immunohistochemistry, in situ hybridiza-
the term psychiatric dizziness should be restricted to dizzi- tion histochemistry, and immunoelectron microscopy have
ness (1) that is a component of a recognized psychiatric been used to identify neurotransmitters and receptors
syndrome and (2) that cannot be explained by clinical involved in modulation of primary afferent pathways in the
evidence of vestibular dysfunction.4 Psychiatric disorders vestibular neuroepithelium.7 These types of studies could
associated with frequent complaints of dizziness include lead to the development of pharmacotherapy aimed specif-
psychosis, abasia, depression, hysteria, panic disorder with ically at the vestibular end-organ.
agoraphobia, acrophobia, phobic postural vertigo, light- Vestibular neuronitis (neuritis) is an idiopathic form of
headedness secondary to hyperventilation during panic, acute unilateral vestibular paresis that is the third most
and the obsessive personality disorder. Patients with common cause of vertigo. Current management relies on
schizophrenia are more susceptible to motion sickness nonspecific treatment employing vestibular sedatives,
and show an increased incidence of abnormalities on physical therapy, and vestibular exercises.55 The epidemic
vestibular testing. Certain compounds, including lactate, occurrence of this condition, frequently following upper
caffeine, isoproterenol, yohimbine, and benzodiazepine respiratory tract infections, suggests that viral infection
antagonists, have been shown to elicit panic attacks in sus- of the vestibular nerve may explain the underlying patho-
ceptible individuals. This evidence suggest a possible physiology of vestibular neuronitis. Polymerase chain
organic basis for the disequilibrium associated with psy- reaction amplification of nucleic acids from archival human
chophysiologic dizziness that would be amenable to specific celloidin-embedded temporal bone sections57 would pro-
pharmacotherapy.55 vide an extremely sensitive tool to search for specific viral
Treatment of psychophysiologic dizziness relies on agents in patients with a history of vestibular neuronitis.
patient reassurance, psychotherapy, and pharmacotherapy. This technique has recently been employed successfully to
Three classes of compounds have been shown to be localize varicella-zoster genomic DNA in temporal bone
effective in reducing the frequency of panic attacks. sections from patients with Ramsay Hunt syndrome, a
668 PERIPHERAL AUDIOVESTIBULAR DISORDERS

polycranial viral neuropathy with clinical involvement of Furthermore, although flunarizine was characterized ini-
the vestibular nerve in some of the cases.58,59 Histopatho- tially as nonspecific Ca2+ channel and Na+ channel blocker,68
logically, degenerative changes in the vestibular nerve, more recent studies indicate that acute doses increase69,70
Scarpa’s ganglion, vestibular neuroepithelium, and decreased and chronic treatment decreases extracellular striatal
synaptic density within the ipsilateral vestibular nuclei are dopamine and metabolites70 and that flunarizine administra-
consistent findings.60,61 Epidemiologic and serologic data tion inhibits dopamine uptake.71 Although ample evidence
suggest a viral cause.62,63 The latent virus (e.g., herpes sim- supports the contention that monoaminergic, histaminer-
plex virus) is thought to remain dormant within the gic, muscarinic cholinergic, and GABAergic mechanisms
vestibular primary afferent neurons (Scarpa’s ganglion). are present within the vestibular nuclei (for review see
Identification of viral genomic DNA in the temporal bone Smith and Darlington72), there is inadequate evidence to
of patients with vestibular neuronitis may lead to the associate the efficacy of these medications with any specific
development of new forms of such specific antiviral ther- central or peripheral sites. Four general classes of drugs are
apy. A few small studies appear to demonstrate benefit of useful for treating vertigo and the associated autonomic
high-dose, IV acyclovir (Zovirax), which acts as a substrate symptoms of nausea and vomiting.16 The classes include
for virus-specific thymidine kinase during DNA synthesis, anticholinergic agents, monoaminergic agents, antihista-
in patients with Ramsay Hunt syndrome.64,65 In addition, minic agents, and antidopaminergic agents. Miscellaneous
the new so-called pro-drugs such as valacyclovir (Valtrex) agents that are also effective include the benzodiazepine
and famciclovir (Famvir) are available and have the advan- diazepam (Valium), the calcium antagonist flunarizine, and
tage of achieving adequate therapeutic tissue levels via an the histaminic agent betahistine. Recent evidence has also
oral route. Some of the herpes viruses (e.g., varicella-zoster favored the use of SSRIs and clonazepam,13 which are also
virus) require an IV route for acyclovir to reach tissue levels particularly useful in minimizing the associated symptoms
necessary to treat these infections. Likewise, the use of oral of anxiety and panic. Carvedilol, a beta blocker that has
steroids would be appropriate in combination with an found clinical applications for treatment of hypertension,
antiviral medication. is currently being investigated as an agent for the sympto-
Gene transfer therapy is presently being developed for matic relief of vertigo.73
the treatment of peripheral hearing and balance disorders.
One strategy, termed in vivo gene therapy, employs defective Mechanism of Action
viral vectors to introduce a functional gene to replace a
damaged gene within the inner ear. Several groups have Numerous animal studies have documented that drugs
successfully developed and introduced nonreplicating viral with anticholinergic and monoaminergic activity diminish
vectors and other vehicles into ganglion cells in vitro or the excitability of neurons in the vestibular nucleus.74,75
directly into the cochlea in vivo.66 These methods will add Anticholinergic drugs suppress both the spontaneous
an important weapon to our surgical armamentarium after firing rate and the response to vestibular nerve stimula-
more mechanisms of vestibular and auditory dysfunction tion.76–78 Iontophoretically applied acetylcholine, metha-
are characterized at the molecular level. choline, and carbamylcholine excite neurons in the medial
and lateral vestibular nuclei; this excitation is blocked with
atropine.79 These observations suggest a cholinergic
SYMPTOMATIC PHARMACOTHERAPY innervation on secondary vestibular neurons. In addition,
cholinergic neurons in the nearby reticular formation
The commonly used antivertiginous medications and their project to the vestibular nuclei. However, since muscarinic
doses are listed in Table 42-5. The effectiveness of each cholinergic mechanisms are distributed widely in the
drug has been determined empirically; however, it is diffi- brain, actions at other levels of central vestibular pathways
cult to predict which drug or combination of drugs will be are also likely.
most effective, since a patient may respond to one drug but Drugs with significant antihistaminergic activity have
not to others in the same class. Antivertigo drugs are typi- long been used in treating vertigo and preventing motion
cally classified by their chemical structure (e.g., diazepam sickness, yet little is known about their mechanism of
is a benzodiazepine), behavioral properties (e.g., diazepam action. More recent evidence (see Table 42-5) further
has sedative and anxiolytic properties), or mechanisms of indicates that standard antihistaminergic antivertigo
action (e.g., benzodiazepines enhance inhibition via medications have significant antimuscarinic cholinergic
GABAA receptor-gated chloride channels; see Table 42-5). activity in addition to antagonism of histamine H1 recep-
As a group, current antivertigo medications have multiple tors. Since histamine excites neurons in the vestibular
mechanisms of action, which include potentially effica- nuclei,80 it is expected that the combination of antihista-
cious actions that range from antagonism of muscarinic minergic and antimuscarinic actions of these drugs will
cholinergic, histiminergic, and monoaminergic transmis- depress activity in the vestibular nuclei. Since appreciable
sion to calmodulin inhibition and blockade of voltage-gated histaminergic innervation is also present in brainstem
calcium channels (see Table 42-5). It is also important to autonomic regions and the parabrachial nucleus, the anti-
note that the direct effects of these drugs may also affect motion sickness efficacy of these drugs may reflect actions
central neurotransmitter levels, which have the potential at multiple levels in vestibuloautonomic pathways.
to affect vestibular pathways. For example, promethazine Antagonism of dopamine D2 receptors, serotonin 5-HT2
reduces dopamine turnover and increases noradrenaline receptors, and α1-adrenoreceptors are common features of
turnover, dimenhydrinate reduces dopamine turnover, and antivertigo drugs with significant antiemetic actions. These
meclizine has little effect on monoamine metabolism.67 drugs include the phenothiazines prochloroperazine
 Pharmacotherapy for Vestibular Dysfunction 669

TABLE 42-5. Drugs Used for the Symptomatic Treatment of Patients with Vestibular Dysfunction
Dryness
Antiemetic of Mucus Extrapyramidal
Class Drug Dosage Sedation Actions Membranes Symptoms

Anticholinergic Scopolamine 0.6 mg orally q4–6h or 0.5 mg + + +++ –

transdermally q3days (commercial
production suspended)
Atropine 0.4 mg orally or intramuscularly q4–6h – + +++ –
Monoaminergic Amphetamine 5 or 10 mg orally q4–6h – + + +
Ephedrine 25 mg orally q4–6h – + + –
1% nasal spray – + ++ –
Antihistamine Meclizine 25 mg orally q4–6h + + + –
(Antivert)
Cyclizine 50 mg orally or intramuscularly q4–6h + + ++ –
(Marezine) or 100 mg suppository q8–12h
Dimenhydrinate 50 mg orally or intramuscularly q4–6h + + + –
(Dramamine) or 100 mg suppository q8h
Promethazine 25 or 50 mg orally, intramuscularly, ++ + ++ –
(Phenergan) or as a suppository q4–6h
Phenothiazine Prochlorperazine 5 or 10 mg orally or intramuscularly + +++ + ++
(Compazine) q6h or 25 mg suppository q12h
Chlorpromazine 25 mg orally or intramuscularly q6h +++ ++ + +++
(Thorazine)
Benzodiazepine Diazepam 2, 5, or 10 mg orally, intramuscularly, +, or +++ + – –
(Valium) or intravenously q4–6h at high
doses
Clorazepam 0.25 or 0.5 mg orally q8h + + – –
(Klonopin)
Lorazepam 0.5, 1 or 2 mg orally q8h PRN ++ + – –
(Ativan)
Butyrophenone Haloperidol 1 or 2 mg orally or intramuscularly +++ ++ + ++
(Haldol) q8–12h
Droperidol 2.5 or 5 mg intramuscularly q12h +++ ++ + ++
(Inapsine)
Ca2+ channel Flunarizine 10 mg/day orally – + – ++
antagonist (Sibelium)
Beta-blocking Carvedilol Titrated (investigational) – – – –
agent
Histaminic Betahistine 8 mg orally q 8h + + – –

(Compazine) and chlorpromazine (Thorazine) and the Several tranquilizers are effective in suppressing vertigo.
butyrophenones haloperidol (Haldol) and droperidol Diazepam (Valium) decreases the resting activity of
(Inapsine). The antiemetic actions are presumed to be due vestibular nuclei neurons, possibly by decreasing another
to effects at sites other than the vestibular nuclei. reticular facilitative system. It also affects crossed vestibu-
However, several potential direct actions are possible on lar and cerebellovestibular inhibitory transmission and it
vestibular pathways. Since these drugs have antihistamin- decreases the production of CSF centrally.77,78,82,83
ergic (H1) activity, they are expected to share actions with
the antihistaminergic antivertigo drugs. Chlorpromazine Strategy in the Treatment of Vertigo
also has antimuscarinic activity and has been shown to
depress the responsiveness of vestibular nucleus neurons. The choice of drug or drug combination is based on the
The possible actions of these drugs on noradrenergic and known effects of each drug (see Table 42-5) and on the
serotonergic transmission in the vestibular nuclei are more severity and time course of symptoms. Prolonged severe
complex. For example, norepinephrine has been reported vertigo is an extremely distressing symptom. The patient
to increase and decrease the background activity of prefers to lie still with eyes closed in a quiet, dark room. In
vestibular nucleus neurons, presumably via both α1- and this setting sedation is desirable, and the tranquilizing
α2-adrenoceptors.81 Since serotonin also has excitatory, medications listed in Table 42-4 are most effective. Each of
inhibitory, and biphasic effects on different vestibular these drugs has significant side effects, however, and there-
nucleus neurons, the precise mechanisms of action are fore must be used with caution. Parenteral diazepam, for
unknown. However, the emergence of symptoms of a bal- example, can cause respiratory depression and hypotension
ance disorder after abrupt discontinuation of an SSRI and should be used only in a hospital, where emergency
(SSRI discontinuation syndrome)8 indicates that serotonin- resuscitation equipment is available. If nausea and vomit-
ergic mechanisms are perhaps a critical component of cen- ing are severe, the antiemetic prochlorperazine can be
tral vestibular neurochemistry. Clinically, it is important to combined with the antivertiginous medication.
note that extrapyramidal side effects of these medications The patient with chronic recurrent vertigo usually
result from their affinity for dopamine receptors. attempts to carry on normal activity, and therefore sedation
670 PERIPHERAL AUDIOVESTIBULAR DISORDERS

is undesirable. Antihistaminic, monoaminergic, and anti- sickness. The principal symptoms of motion sickness are
cholinergic medications are useful. Of the antihistamines, malaise and nausea rather than vertigo, which may be con-
promethazine (Phenergan) has the most sedating effect sidered as visceral referred symptoms of somatic origin.2
and is therefore useful only when moderate sedation is Tolerance develops after 2 or 3 days of constant stimulation,
desired. A combination of promethazine and the sympath- and prophylactic use of drugs several hours before travel is
omimetic ephedrine (25 mg of each) produces less sedation more effective than treatment of symptoms.16,85
than promethazine alone and is more effective in relieving Oral or parenteral scopolamine was one of the first
associated autonomic symptoms.16,19 Meclizine (Antivert), drugs used to treat motion sickness and was the first drug
cyclizine (Marezine), dimenhydrinate (Dramamine), and proved effective in its prevention. In the 1940s controlled
scopolamine can be effective in treating mild episodes of drug trials were carried out on military recruits during
vertigo. amphibious training, aviation training, and swing tests. A
Central compensation for peripheral vestibular dysfunc- dose of 0.6 to 0.8 mg of scopolamine protected 50% of
tion appears to involve changes in contributions of the susceptible subjects for at least 8 hours. However, unto-
intact labyrinth, use of alternative gravitoinertial sensory ward effects (primarily drowsiness, dryness of the mouth,
cues (vision, proprioceptive, somatosensory, and cardio- and blurred vision) limited the use of oral or parenteral
vascular), and adoption of different strategies for perform- scopolamine for motion sickness.19,42
ing movements. Since this process is a form of motor With the introduction and subsequent general use of
learning, it is essential that the patient return to normal antihistamines, particularly dimenhydrinate, scopolamine
activity to recalibrate central vestibular pathways. Viewed was neglected for many years. Interest in scopolamine was
from this perspective, the combined sedative and antiver- rekindled, in the form of transdermal scopolamine
tigo properties of medications for symptomatic relief (Transderm-Scop). With this delivery system, scopolamine
require a therapeutic trade-off of acute relief at the is gradually released through a microporous polypropylene
expense of attenuating compensation. On the other hand, membrane contained in a patch that is placed on the skin
sympathomimetics and vestibular rehabilitation therapy behind the ear. A small dose (0.05 mg) is slowly released
can be added to facilitate the compensatory process. and absorbed over a 3-day period. Initial clinical trials
Symptomatic management of positional vertigo is diffi- indicate that transdermal scopolamine is effective in pre-
cult because, although the vertigo is severe, it is short-lived. venting motion sickness with minimal side effects, the
To completely suppress these brief episodes, heavy sedation main side effect being dryness of the mouth.86,87 The use
throughout the day would be required, which is usually of transdermal scopolamine for more than 3 consecutive
unacceptable to the patient. The most common variety, days can, on discontinuation of therapy, result in with-
benign paroxysmal positional vertigo, has a short duration drawal symptoms that mimic motion sickness, including
(usually 30 seconds or less); however, some patients will dizziness, nausea, vomiting, and headache.88,89 To be effec-
complain of vestibular dysfunction lasting for much longer tive the patch must be in place several hours before expo-
intervals. This initial patient response can be extremely mis- sure to motion; however, production of this product has
leading, unless the otolaryngologist aggressively attempts to been suspended. Future studies will determine whether
separate the episode of true vertigo from the autonomic dys- other antivertiginous drugs can be effectively administered
function that follows. The severity of the autonomic dys- in this manner.
function varies on any individual and may be severe with Clinical trials of antimotion sickness drugs under
disabling imbalance and unsteadiness combined with nausea controlled laboratory conditions have shown that combi-
and diaphoresis. Other patients will experience mild true nations of drugs are often more effective than any single
vertigo with movement in the plane of the involved semicir- drug.16,19,42 Particularly effective combinations have
cular canal. Very often the patient will identify the plane of included scopolamine (0.6 mg), promethazine (25 mg) and
rotation that elicits the vertigo and assiduously avoid this dextroamphetamine (10 mg), and promethazine (25 mg)
movement. Spontaneous remission occurs in more that and ephedrine (25 mg). As in the treatment of vertigo, it is
90% of patients within 6 months, although a small percent- difficult to predict which drug or drugs will be most effec-
age do have recurrence.84 A simple explanation of the nature tive in preventing motion sickness in an individual. In
of the disorder and its favorable prognosis helps to relieve controlled laboratory experiments the responses of normal
the patient’s anxiety. Medications with mild sedative effects volunteers to the same drug or combination of drugs often
(e.g., diazepam, meclizine, or cyclizine) are useful when the vary greatly, even when identical motion stimuli are used.
episodes recur frequently and to decrease the autonomic
dysfunction that commonly impairs the patient’s quality of
life. Particle repositioning maneuvers and vestibular reha-
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 Chapter
Surgical Neurotology: An Overview

Outline 43
The Contemporary Concept Transbasal Approaches The Ventral Surface Robert K. Jackler, MD
of Neurotologic Skull Base to Intracranial Tumors of the Brainstem
Surgery Internal Auditory Canal and Combined Craniotomy of
Fundamental Considerations Cerebellopontine Angle the Middle and Posterior
Special Operating Room Retrosigmoid Approach Cranial Fossae
Requirements Transpetrosal Approaches Transcochlear Approach
Patient Positioning Middle Fossa Craniotomies Meckel’s Cave
Instrumentation Middle Fossa Approach The Craniovertebral Junction
Hemostasis to the Internal Auditory Surgical Anatomy
Vascular Considerations Canal Indications
Approaches to Lesions Extended Middle Fossa Technical Considerations
Primarily in the Cranial Base Approach to the Advantages
Temporal Bone Cerebellopontine Angle Disadvantages
Petrous Apex, Petroclival Middle Fossa-Transpetrous Vertebrobasilar Lesions
Junction, and Foramen Apex Approach to the Reconstruction of the
Lacerum Ventral Pons and Anterior Cranial Base
Clivus Cerebellopontine Angle Closure of Defects
Jugular Foramen Intracranial Aspect of Prevention of Cerebrospinal
Infratemporal Fossa Jugular Foramen Fluid Leakage

THE CONTEMPORARY CONCEPT OF simple platelike calvaria in preference to navigating the

NEUROTOLOGIC SKULL BASE SURGERY dauntingly complex osteology of the cranial base. This sim-
pler solution was seen as expeditious despite the fact that it
The earliest surgical efforts to approach the skull base took frequently required injurious degrees of brain retraction. In
place not long after the introduction of anesthesia in the the early 1960s, House and others, armed with modern
latter portion of the nineteenth century. Pioneering efforts operating microscopes possessing potent sources of illumi-
include those of Krause, Frazier, and others to approach nation and controllable high-speed drill systems, resur-
the trigeminal ganglion in Meckel’s cave for the relief of tic rected and ultimately made practical a number of skull base
douloureux.1 It was obvious even to early surgeons that the approaches that had been tried much earlier and discarded
most direct approach to certain inaccessible intracranial as impractical. (See William F. House’s personal commen-
lesions was through the cranial base rather than the con- tary on this early microsurgical era in this text’s foreword.)
vexity. Transtemporal approaches to the cerebellopontine As a specialized endeavor, skull base surgery is a rela-
angle were first proposed by Panse in 1904 (although he tively new field. It defined itself during the 1980s as a direct
never performed the procedure) and were tentatively result of the introduction of three fundamental technolog-
explored by Borchardt in 1905, Quix in 1911, and a few ical innovations: (1) high-resolution multiplanar imaging
others during the early decades of the twentieth century.2–4 (computed tomography [CT], magnetic resonance imaging
The openings provided in these fledgling efforts proved too [MRI]) to provide detailed tumor maps, (2) improvements
deep and narrow for effective action against the giant in microsurgical optical systems and instrumentation, and
tumors typical of the era. In addition, the problem of closure (3) the invention of neurophysiologic monitoring. Two
against cerebrospinal fluid (CSF) leakage had not yet been nontechnological factors were also essential in the devel-
surmounted, nor had methods been invented to permit opment of contemporary skull base surgery. The first was
atraumatic removal of bone from the carotid artery, the the increasing willingness of patients to travel from their
facial nerve, or other important neurovascular structures home region to distant centers with specialized expertise
that traverse the base of the skull. Thus, for the first two- and technical resources. This fostered the accumulation of
thirds of the twentieth century, surgeons preferred to expose sufficient experience to both hone skills and undertake
tumors in and around the base of the brain by opening the meaningful outcomes analysis. The second nontechnical
675
676 SURGICAL NEUROTOLOGY

7,8
advance has been the willingness of surgeons to collaborate
in a multidisciplinary fashion to share expertise and to IAC
mitigate the limitations imposed by operator fatigue in CO
prolonged microsurgical procedures. GG
As with most new endeavors, initial enthusiasm for
newfound surgical capabilities was at times out of proportion
to their ultimate value. Accumulated experience has tem-
pered practice to some degree and fewer adventuresome
resections for advanced high-grade malignancies are now
undertaken. With benign tumors, the usual goal is radical ME 5
resection when morbidity can be kept low. The current EAC
trend, in selected situations, is toward less than total resec-
tion when the risk of debilitating neuropathy (e.g., diplopia, P
facial palsy) is high. In many cases such remnants will not M

grow or can be controlled with stereotactic radiosurgery.

Although their place in the surgical armamentarium contin- Cb
SCC
ues to evolve, it has become abundantly clear that skull base
surgical approaches have greatly improved the prognosis for CPA
patients afflicted by lesions in and around the skull base in SS
terms of both the likelihood of cure and the preservation
of brain and cranial nerve function. 4V
The term skull base surgery is somewhat of a misnomer in
that only a minority of these procedures in neurotology are Figure 43-1. An axial view of the skull through the level of the internal
actually carried out for disease intrinsic to the skull base. auditory canal and cerebellopontine angle. Cb, cerebellum; Co, cochlea;
CPA, cerebellopontine angle; EAC, external auditory canal; GG, geniculate
Rather, a majority are undertaken to provide exposure for ganglion of the facial nerve; IAC, the internal auditory canal; M, mastoid air cell
inaccessible intracranial disease located either beneath the system; ME, middle ear; P, pons; SCC, semicircular canals; SS, sigmoid sinus;
cerebral cortex or adjacent to the brainstem. A high percent- 4V, fourth ventricle; 5, trigeminal nerve; 7, facial nerve; 8, audiovestibular nerve.
age of neurotologic skull base procedures are craniotomies
designed to expose lesions situated against the anterior or
lateral aspects of the midbrain, pons, and/or medulla. In its use of specialized surgical tools such as the Cavitron ultra-
essence, the fundamental concept of transbasal craniotomy is sonic aspirator (e.g., CUSA) or laser. An electrically quiet
the removal of skull base bone to minimize (or even prevent) environment is essential during neurotologic surgery
the need for retraction of the brain (cerebrum, cerebellum). because 60-cycle noise readily obscures the faint potentials
In line with this concept, the organization of this chapter has detected by neural monitoring equipment. The need for a
two major sections: (1) approaches to lesions that are largely television monitor to display the microsurgical view is
intrinsic to the cranial base (e.g., glomus jugulare, petrous obvious in educational settings, but it is also important to
apex cholesterol granuloma) and (2) procedures undertaken provide context to the neurophysiologic monitoring team
to expose primarily intracranial disease (e.g., meningioma, and to involve the scrub nurse and circulator better in the
schwannoma, epidermoid). progress of the procedure.
It has been traditional to present the subject of skull base
surgery by rostering each operative approach and explaining Patient Positioning
its utility. However, rational treatment decisions are based
on an analysis of the advantages and disadvantages of the The great majority of neurotologic procedures are done
various technical options for a given anatomic location. It with the patient in the supine position with the head rotated
hope that the topical organization of this chapter according away from the surgeon (Figs. 43-2 and 43-3). Exposure of
to the anatomic site of interest will prove more useful the suboccipital region may be accentuated by use of a bol-
during treatment planning. For additional illustrations of the ster under the ipsilateral shoulder. A headholder (e.g.,
procedures introduced in this chapter, please refer to this Mayfield design) that permits removal of the rostral portion
volume’s accompanying surgical atlas5 (Fig. 43-1). of the surgical table may enhance posterior exposure. This
also helps to maintain a stable head position and provides a
convenient attachment point for brain retractors.
FUNDAMENTAL CONSIDERATIONS Overrotation of the head should be avoided because it might
impair venous return via the vertebral system, thereby cre-
Special Operating Room Requirements ating a tendency toward cerebellar swelling. The true lateral
To be suitable for neurotologic surgery an operating room or park bench (3/4 rotated) positions may also be used, but
must be fairly large to accommodate the variety of instru- with greater pressure on the contralateral arm and hip.
mentation required for these procedures. Arrangement of Insufficient padding during a prolonged procedure may lead
the room requires complex planning to efficiently position to pressure necrosis or neurologic injury, particularly to the
the operating microscope, surgical drill, mono- and bipo- brachial plexus or ulnar nerve. The prone position is impor-
lar cautery, neural monitoring equipment, as well as a large tant for midline cerebellar tumors, but it has little role in the
table of surgical instruments and the considerable comple- extra-axial tumors typically addressed by the neurotologist.
ment of devices needed to monitor the patient undergoing The sitting position, which is still employed for poste-
neuroanesthesia. In addition, many situations call for the rior fossa surgery by a few centers, is steadily decreasing
 Surgical Neurotology: An Overview 677

Figure 43-2. Operating room setup used in neurotology for a lateral

transtemporal procedure.

in popularity. The primary advantage of the upright posi- Figure 43-3. Operating room setup used in neurotology for a middle fossa
tion is that blood drains away from the operative field. procedure.
However, the dual risks of air embolization and injury to
the cervical spinal cord render this position less desirable.6
It also creates an uncomfortable position for the surgeon with a well-padded kidney brace or a similar apparatus
in which to perform a prolonged microsurgical procedure. attached to the bed frame.
Under certain circumstances, the surgeon must be prepared
to change the patient’s position during surgery. When recon-
struction with a trapezius or latissimus dorsi myocutaneous
Instrumentation
flap is planned, the patient’s back must be prepped and In neurotologic surgery, a diverse set of microsurgical instru-
draped. During mobilization of the flap, the patient is tem- ments are required. Heavy, blunt elevators are needed for
porarily rotated into the lateral position. elevation of the periosteum and mobilization of dura from
During neurotologic surgery the operating table should the cranial base. More delicate dissection tools are needed
be reversed so that the patient’s head is located at the foot for mobilization of brain and cranial nerves as well as dissec-
of the bed. This permits the surgeon to sit during micro- tion of arachnoid planes. To accommodate for the deep field
surgery without obstruction under the table that might of action typical of neurotologic procedures, instruments
interfere with a comfortable leg position. Since a reversed must have considerably longer shafts than those used in con-
table might tend to tip over with obese patients, use of an ventional otologic surgery. An excellent collection of instru-
extra heavy table is desirable. Alternatively, additional ments for neurotologic surgery is the Rhoton microsurgical
weight (e.g., sandbags) can be tied to the end of the bed to instrument set, which includes a selection of arachnoid
counterbalance this tendency. The operating table is fre- knives of various sizes, hooks, needles, fine curettes, as well
quently turned from side to side during neurotologic proce- as blunt dissectors in several sizes and angulations.
dures. An electrically controlled bed-positioning system, A variety of suction instruments between 5 and 12 French
which can be operated by either the anesthesiologist or are needed. Large-bore suction catheters are required
nurse, is a substantial convenience. A typical operating table when rapidly removing bone or during episodes of brisk
has a limited range of side-to-side tilt, usually approximately hemorrhage. Smaller, fenestrated suctions facilitate main-
15 degrees. Certain models permit rotation in the range of taining a dry field while minimizing the potential of acciden-
30 degrees, which can be of significant advantage during tally injuring a cranial nerve or small vessel. Tip fenestrations
neurotologic procedures. To help maintain position when reduce the unwanted tendency of the suction to ingest and
using extreme tilts, it is important to support the patient tear delicate tissues such as cranial nerve fibers and small
678 SURGICAL NEUROTOLOGY

blood vessels. Often to work in a deep field, an extra long

suction is desirable (standard is 10 cm, extra long is 12.5 cm).
Hemostasis
It is often helpful to have two suction lines available during Hemostasis is important in neurotologic surgery both for
neurotologic procedures, one of which can be attached to the obvious reason of reducing blood loss and to maintain
the posterior arm of a retractor to facilitate removal of a blood-free field to permit an orderly microsurgical
irrigant solution. dissection. Bipolar cautery is most important intracranially
Although it should be minimized whenever possible, a to limit current spread to the adjacent neural structures.
degree of brain retraction is required in many neurotologic Recently developed bipolar cautery units with automated
procedures. Brain retractors may be anchored to the surgical irrigation systems are most convenient and reduce the ten-
table (e.g., Greenberg), to a headholder (e.g., Mayfield), or dency of the forceps to adhere to the cauterized tissue. At
on a Weitlander style retractor (e.g., Apfelbaum, Wiet, times, use of cautery is unwise either because of the prox-
Silverstein). As a general rule, the cerebellum is more tol- imity of the bleeder to a cranial nerve or because the hem-
erant to brain retraction than the temporal lobe. Moderate orrhage is diffuse and not amenable to pinpoint control. In
cerebellar retraction seldom leads to dysmetria; elevation such cases, an application of thrombin-soaked Gelfoam
of the temporal lobe to a similar degree occasionally pledgets or a pad of lyophilized collagen (Avitene) may
results in a transient dysphasia and memory disturbance, control minor oozing.
particularly when the dominant side is involved. Control of bone bleeding can usually be accomplished
The removal of most tumors managed by neurotologists with diamond burrs, especially if irrigation is momentarily
can be considered as two stages: (1) debulking of the tumor’s halted. Diamond burrs create a fine bone paste, which
core and (2) microdissection of the brain, cranial nerves, and impacts and occludes small vascular channels in bone.
vessels from the tumor’s capsule. Several special tools have Reversing the direction of a cutting burr may accomplish the
been developed to facilitate the former task. The ideal tumor same task. More stubborn bone bleeders can be controlled
debulking implement works rapidly, incites minimal hemor- through the application of bone wax.
rhage, and respects the tumor capsule in order to avoid acci- Not infrequently, while the surgeon is working around
dental injury to a vessel or cranial nerve coursing on the dural sinuses, hemorrhage develops due to either a mural
tumor surface. The ultrasonic aspirator (e.g., Cavitron ultra- tear or avulsion of an emissary vein. This may be controlled
sonic surgical aspirator) rapidly debulks lesions while mini- by placing a wad of oxidized cellulose (Surgicel) over the
mizing the risk of inadvertently violating the capsular plane.7 defect and holding it in position with a retractor. When
The House-Urban rotatory dissector is also in widespread controlling bleeding from a major sinus or the jugular bulb,
use but is less respectful of the capsular surface and is there- it is important to prevent embolization of the packing mate-
fore more dangerous, especially in inexperienced hands. rial. This risk is minimized by extraluminal application of a
Finally, the surgical laser performs the debulking task piece of Surgicel substantially larger than the defect. If fur-
admirably, but high-power densities are needed to provide ther drilling is required near the Surgicel packing, it must be
reasonable speed.8 Unfortunately, none of these special tools covered by a smooth material such as Telfa because Surgicel
is particularly useful in liberating delicate structures from the fibers readily become entangled in the shaft of the drill.
capsular surface. The heat generated by laser burst toughens
arachnoid much as heat coagulates the white of an egg. This
has the effect of rendering surgical planes both more obscure
Vascular Considerations
and tenacious. Development of the capsular planes requires The three major arterial braches of the vertebrobasilar sys-
painstaking microdissection using fine scissors along with a tem traverse the cerebellopontine angle: posterior inferior
combination of both sharp and blunt dissectors. cerebellar artery (PICA), anterior inferior cerebellar artery
A surgical drill used in neurotologic surgery must be suf- (AICA), and the superior cerebellar artery (SCA) (Fig. 43-4).
ficiently powerful to rapidly excavate bone as well as delicate The skill required to preserve these arterial structures is
enough to permit removal of thin osseous edge adjacent to a essential for a surgeon performing intracranial tumor
naked cranial nerve. Suitable designs with variable torque are microdissection.
available powered by either electricity or compressed air. PICA is located inferiorly, passing close to the roots of
Although most work may be accomplished with a straight the lower cranial nerves. It may become enmeshed in the
handpiece, an angled handpiece affords improved visibility in intracranial aspect of jugular foramen tumors and is occa-
deep and narrow operative fields. Special handpieces with sionally involved in meningiomas of the lower clivus and
long, narrow shafts have been developed for particularly con- craniovertebral junction. Disruption of PICA gives a
stricted exposures. Burrs in a variety of sizes and both cutting lesion of the lateral medullary (Wallenberg’s) infarc-
and diamond varieties are needed. Large diamond burrs tion characterized by a variable combination of dysphagia,
(e.g., 6 mm, 8 mm, and 10 mm) are especially important dysarthria, vocal cord paralysis, vertigo, facial paralysis,
because they permit atraumatic removal of bone from dural and ataxia, as well as ipsilateral Horner’s syndrome and
surfaces. Copious irrigation while the surgeon is drilling contralateral hemisensory disturbance.10
should both increase burr life as well as avoid untoward heat AICA is often mentioned to possess a “loop” in the CPA,
buildup, which may injure underlying neural structures. The which gives off a distal branch into the IAC, which sup-
use of topical antibiotics (e.g., bacitracin) in irrigant solutions plies the inner ear (internal auditory artery).11 However,
during neurotologic procedures has been suggested as a AICA has in reality two loops, the first of which is applied
means of lessening the bacterial inoculum, thereby reducing to the brainstem surface and provides nutrient perforators
infectious complications.9 It should be noted that bacitracin to the brainstem (Fig. 43-5). The second, more distal loop
solution induces a froth that may occlude the values in the lies laterally in the CPA, where it gives rise to the IAC
surgical suction line. artery. Interruption of the first loop gives a devastating
 Surgical Neurotology: An Overview 679

IAA

SCA

PICA

AICA

Figure 43-4. The major arteries of the cerebellopontine angle. AICA, anterior Figure 43-6. Occlusion of the proximal trunk of the anteroinferior cerebellar
inferior cerebellar artery; IAA, internal auditory artery; PICA, posterior artery results in an extensive pontomedullary infarction (gray region).
inferior cerebellar artery; SCA, superior cerebellar artery. Blockage of the distal segment give a focal infarction of the middle cerebellar
peduncle (dark circle).

neurologic injury with hemiplegia and multiple central

cranial nerve dysfunctions, whereas loss of the distal loop vein (also know as Dandy’s vein) parallels the trigeminal
causes a more focal cerebellar peduncular infarction with nerve just beneath the tentorium. It can often be preserved,
persistent ataxia11,12 (Fig. 43-6). but in large tumors is frequently taken without conse-
The superior cerebellar artery is sometimes placed at quence. Rarely does its division lead to cerebellar venous
risk in exposing transtentorial tumors. Injury to the SCA congestion.14 Numerous veins travel roughly rostrocaudally
causes dysmetria, dysdiadochokinesia, dysarthria, ataxia, on the brainstem surface. At least some of these need to be
vertigo, and sometimes diplopia.13 taken during removal of a large CPA tumor and, fortunately,
Preservation of the veins of the posterior fossa is much their interruption seldom leads to adverse consequences.
less critical than preservation of the arteries. The petrosal An important exception to the usual rule that dividing
veins is of low risk is the vein of Labbé.15 This large vein
drains the temporoparietal region and bridges from the
cortical surface to enter the transverse sinus (Figs. 43-7
and 43-8). It is at risk during tentorial division in the com-
bined approach to the posterior and middle fossa (see below).
Division or occlusion of a dominant-side vein of Labbé
may result in speech disturbance and contralateral hemipare-
sis or even hemiplegia (Fig. 43-9). In a combined-approach

Figure 43-5. The anteroinferior cerebellar artery has two loops: a proximal
segment providing nutrient branches to the brainstem and a lateral loop lying
free in the cerebellopontine angle. The lateral loop gives rise to the internal Figure 43-7. The vein of Labbé, which bridges from the cortex to enter the
auditory artery. transverse sinus, drains the temporoparietal region.
680 SURGICAL NEUROTOLOGY

Figure 43-9. A temporoparietal venous infarct resulting from occlusion of the

vein of Labbé.

origin, may also require a temporal bone resection. Sac

tumors have a tendency to traverse the posterior fossa dura
and press against the cerebellar hemisphere. Adenocystic
carcinoma of the temporal bone usually arises from salivary
tissue adjacent to the external auditory canal. Extensive
perineural invasion is usually well established even in early
lesions. In children, aggressive temporal bone tumors,
except sarcomas, are uncommon. Rhabdomyosarcomas,
the most frequent variety, are usually anatomically extensive
B upon presentation.
Figure 43-8. A, Two common courses of the vein of Labbé in its route The degree of temporal bone resection is determined by the
toward the transverse sinus. The vein may lie on the upper surface of the anatomic extent of the tumor and its biologic tendencies.17
tentorium or even run between its leaves. B, To avoid the vein of Labbé The minimal temporal bone resection for squamous carci-
during tentorial division in the combined middle and posterior fossa nomas entails en bloc removal of the external auditory
approach, it is prudent to first identify the course of the view on the upper
surface of the tentorium. When necessary, the tentorial division should be canal (Figs. 43-10 and 43-11). The so-called sleeve excision
placed more medially to prevent injury to this important venous structure. of the soft tissue of the ear canal is inadequate for malignant
disease. According to the extent of tumor involvement,
some or all of the adjacent parotid gland and temporal
craniotomy, great care is taken to preserve this functional mandibular joint may be included in the specimen. Medial
end vein whenever possible. extension into the inner ear or vascular compartment
(carotid canal and jugular bulb) is exenterated piecemeal
with the drill rather than en bloc by most surgeons. In
APPROACHES TO LESIONS PRIMARILY endolymphatic sac tumors, the posterior fossa dura must be
included in the specimen, and the ear canal can sometimes
IN THE CRANIAL BASE be preserved. Resection in adenocystic carcinoma should
be thorough but not unnecessarily radical. These lesions
Temporal Bone are seldom cured even when the primary lesion is small and
Several tumor types may necessitate extensive resection of initial surgery extensive. Fortunately, they tend to progress
the temporal bone.16 The most common such tumor is slowly. Surgery in temporal bone sarcomas is only adjunc-
invasive squamous cell carcinoma arising from the external tive to chemotherapy. Since perimeningeal or intracranial
auditory canal. Relatively early, it extends beyond the con- spread are risk factors for recurrence, cytoreduction by
fines of the ear canal and grows along the skull base into removing the peridural component is often desirable.
the infratemporal fossa. The inner ear, dura, and vascular One general theme in temporal bone resection is that,
compartment of the temporal bone can be involved in unless it is grossly infiltrated by tumor, a functioning facial
advanced cases. Adenomatous tumors, especially the nerve should be preserved whenever possible. When post-
aggressive papillary adenocarcinoma of endolymphatic sac operative radiotherapy is anticipated, it is usually wisest to
 Surgical Neurotology: An Overview 681

Figure 43-10. Axial view of the three types of temporal bone resection for
malignancy: sleeve resection of the external auditory canal (solid line), lateral Figure 43-11. Lateral temporal bone involves resection of the external auditory
temporal bone resection (dotted line), total temporal bone resection (dashed canal and may include a resection of the parotid and condylar head in continuity
line). Most of these resections are performed for squamous cell carcinoma with the ear canal. Condylectomy brings into view the pterygoid muscles that
arising from the external auditory canal. It is generally acknowledged that may be resected to the level of the pterygoid plates if necessary.
sleeve resection is insufficient therapy for malignant disease. In the lateral
temporal bone resection, the ear canal is removed en bloc with the tympanic
membrane and lateral ossicles. A parotidectomy and/or neck dissection often
and are most accurately called petrous apicotomy rather than
supplements the temporal bone specimen. apicectomy (Figs. 43-12 and 43-13). Actual resection of the
apex, petrous apicectomy, may be undertaken for tumor
resection, for the rare cholesterol granuloma that is not
close the external meatus to reduce the risk of osteora- amenable to either transtemporal or transsphenoidal
dionecrosis. Leaving the ear open in an effort to preserve drainage, or as an adjunctive procedure in the exposure of
hearing is usually ineffective because radiotherapy typically tumor located ventral to the pons of basilar tip aneurysms
induces a severe cochleopathy over time. Extensive bony (the latter to be discussed later). The most common primary
defects are best filled with well-vascularized tissue. A tumor of the petrous apex is chondrosarcoma arising from
regional flap of temporalis muscle is usually effective. When
large cutaneous defects are present (e.g., following resection
of the pinna), then either a myocutaneous flap (e.g., trapez-
ius) or a free flap (e.g., rectus abdominis) is necessary to
close the defect. When dural resection is required, it is
repaired with fascia, and the eustachian tube is obliterated
to prevent CSF otorhinorrhea. The role of carotid resection
in temporal bone tumors is controversial. Some advocate
resection when the artery is encased by tumor if the patient
passes a preliminary test occlusion. However, test occlusion
is a fallible predictor and devastating postoperative stroke
can still occur. In the author’s opinion, planned carotid
resection of high-grade malignancies is seldom justified and
should be considered contraindicated in benign tumors.

Petrous Apex, Petroclival Junction,

and Foramen Lacerum
The petrous apex is the medial portion of the petrous
ridge. It is bounded laterally by the otic capsule and medially
by the clivus. Most surgery of the petrous apex involves
creation of a small drainage portal between the middle ear
or mastoid and the petrous apex skirting the structures of
the inner ear.18 Such procedures are conducted for inflam- Figure 43-12. Petrous apicotomy for drainage of a cholesterol granuloma
matory conditions (petrous apicitis, cholesterol granuloma) into the middle ear.
682 SURGICAL NEUROTOLOGY

Figure 43-13. Subtemporal approach for petrous apicectomy as performed

for chondrosarcoma of the petroclival junction. In this case, the intrapetrous Figure 43-15. Exposure of a petroclival junction chondrosarcoma
carotid artery has been skeletonized. surrounding the intrapetrous carotid artery. Downward displacement of the
zygoma and division of the third division of the trigeminal nerve is necessary
only with substantial inferior spread.

the cartilage that fills foramen lacerum19 (Fig. 43-14). These elevation of the temporal lobe brings into view the anterior
originate at the petroclival junction and may erode laterally surface of the petrous ridge. The tumor is approached by
into the inner ear and medially into the clivus.20 Posteriorly, resecting the petrous ridge between the internal auditory
they may prolapse into the cerebellopontine angle. canal and Meckel’s cave. This necessitates division of the
Secondary involvement of the petrous apex may occur due to greater superficial petrosal nerve with resultant dry eye.
lateral spread of clival chordoma or deep penetration of Dissection can be carried medially into Meckel’s cave but
intratemporal tumors such as squamous cell carcinoma. caution must be exercised to avoid injury to the sixth nerve
The surgical approach to petrous apex chondrosarcoma in Dorello’s canal. The floor of the apical resection is
is via a subtemporal craniotomy (Fig. 43-15). Extradural the horizontal course of the intrapetrous carotid artery.

Figure 43-14. Chondrosarcoma of the petroclival junction arising in the

cartilage of foramen lacerum. Figure 43-16. Clival chordoma.
 Surgical Neurotology: An Overview 683

This subtemporal transpetrous apex approach also affords

limited access to the posterior cranial fossa. Most apical
chondrosarcomas can be resected in a single stage, but those
with extensive posterior fossa components require a two-
stage approach: retrosigmoid for the intracranial component
and subtemporal for the segment in the cranial base.

Clivus
The clivus is not a bone in and of itself. Rather it is a long
sloping plane extending from the anterior lip of the foramen
magnum to the dorsum sellae and clinoids. It is composed
of two bones: the occipital bone anterior to the foramen
magnum and the dorsal component of the sphenoid bone.
The brainstem and vertebrobasilar system lie adjacent to its
dorsal surface. The great majority of clival tumors that are
managed surgically are chordomas arising from notochordal Figure 43-17. Overview of jugular foramen relationships.
remnants oriented along the midline of the cranial base
(Fig. 43-16). Chordomas that have remained extradural and otic capsule. Laterally is the mastoid and, very important,
are confined to the midline skull base are approached ante- the vertical segment of the facial nerve canal. Posteriorly
riorly, most commonly via either a transsphenoethmoidal or a are the lower reaches of the posterior fossa adjacent to the
transoral approach.21–23 The anterior strategy is to create a lateral aspect of the pontomedullary junction and medulla.
modest opening into the tumor cavity and then blindly exca- The most common tumors of the jugular foramen are
vate the gelatinous tumor by scraping the cavity walls with paraganglioma (glomus jugulare), schwannoma of the
curettes. The neurotologist becomes involved in chordoma lower cranial nerves, and meningioma. Glomus tumors and
surgery when the tumors spread intradurally or spread meningiomas often present with a visible component in the
laterally behind the intrapetrous carotid arteries. middle ear, whereas schwannomas do not. Each may occur
Chordomas that breech the posterior fossa dura compress in one of four anatomical varieties: (1) limited to the jugular
the midbrain, pons, and/or medulla and abut the basilar foramen in the cranial base, (2) pear-shaped with a compo-
artery. Anterior approaches are not advisable for intradural nent in the infratemporal fossa, (3) pear-shaped with a lobe
tumors because they in the posterior cranial fossa, and (4) dumbbell-shaped with
1. Provide a deep field of action ill suited for microdis- sizable components both intra- and extracranially.
section Common to all jugular foramen operations is a transmas-
2. Approach the brainstem-tumor interface from a dis- toid opening of the jugular foramen and exposure of the
advantageous direction great vessels in the upper neck. Safe surgery in the jugular
3. Traverse contaminated spaces foramen requires proximal (sigmoid sinus) and distal (jugu-
4. Present great difficulty in resealing the dura to avoid lar vein) vascular control. Since the descending facial nerve
CSF fistula
Lateral approaches to the intracranial component of clival
tumors typically require a combination of middle and poste-
rior fossa craniotomy.24 This is most often achieved with a CA
P
9
single opening consisting of a limited petrosectomy (retro- TM 12
labyrinthine approach) and a middle fossa opening joined
by division of the tentorium. As is discussed throughout this
10
chapter, this combined-approach craniotomy has become a
workhorse for approaching tumors located anterior and lat-
eral to the brainstem. Tumor resection is carried out through
two intervals: between the jugular foramen nerves (IX–XI) JV
SCC
and the complex of cranial nerves VII–VIII, and also 11
between cranial nerves VII–VIII and the root entry of the
fifth nerve. Although this presigmoid combined approach JB
affords excellent access to the posterior intradural compo-
nent, it is limited anteriorly in the cranial base. A second FN
stage anterior approach to address a ventrally situated tumor SS
(e.g., in the perisphenoid region) may be required. Figure 43-18. Jugular foramen approach. It is possible to expose the jugular
foramen without rerouting the facial nerve or destroying the conductive hearing
Jugular Foramen apparatus. Jugular foramen surgery requires that the sigmoid-jugular complex
be controlled both proximally (either by suture ligature or extraluminal packing,
The jugular foramen is traversed by the jugular vein along as depicted here) and distally in the neck. The hypotympanum can be exposed
by an inferiorly based tympanomeatal flap. CA, carotid artery; FN, facial nerve;
with the glossopharyngeal (IX), vagus (X), and accessory JB, jugular bulb; JV, jugular vein; P, parotid gland; SCC, semicircular canals;
nerves (XI)25 (Fig. 43-17). Anteromedially is the internal SS, sigmoid sinus; TM, tympanic membrane; 9, glossopharyngeal nerve;
carotid artery. Superiorly is the hypotympanum and 10, vagus nerve; 11, accessory nerve; 12, hypoglossal nerve.
684 SURGICAL NEUROTOLOGY

EAM FN SM IX
XII

AP

EC
IC

MC
X
JV
SCM

XI
C1
DM

Figure 43-21. When the tumor extensively erodes the carotid wall, adequate
Figure 43-19. The fallopian bridge approach in which the vertical segment of exposure requires anterior rerouting of the facial nerve and a canal wall down
the facial nerve is skeletonized to afford exposure of the jugular foramen. mastoidectomy. This maneuver provides unrestricted access to the vascular
otobase. Note that the ear canal, tympanic membrane, and lateral two ossicles
have been removed and that the external meatus has been sewn shut. It is help-
ful to be familiar with the course of the ascending pharyngeal artery, the primary
overlies the jugular bulb, many advocate an anterior rerout- blood supply to the jugular foramen. In the presence of a vascular tumor, it is
ing to provide unhindered access.26 Others, including the often much larger than it is depicted here. AP, ascending pharyngeal artery; C1,
transverse process of C1; DM, digastric muscle; EAM, external auditory meatus;
author, prefer a fallopian bridge technique, leaving the facial EC, external carotid artery; IC, internal carotid artery; JV, jugular vein; MC,
nerve in situ and working around it27 (Figs. 43-18) through mandibular condyle; SCM, sternocleidomastoid muscle; SM, styloid muscles;
43-22). Unless there is extensive destruction of the middle 7, facial nerve; 9, glossopharyngeal nerve; 10, vagus nerve; 11, accessory
ear and ear canal (assuming integrity of the inner ear and nerve; 12, hypoglossal nerve.
eighth nerve), auditory function can usually be preserved.
Extensive erosion of the ear canal or inner ear many neces-
sitate removal of the canal wall, closure of the meatus, and
Infratemporal Fossa
obliteration with adipose tissue. Of course, this creates a The term infratemporal fossa is generally used to describe the
maximum conductive hearing loss. When necessary, tumor complex of structures located beneath the temporal bone.28
can usually be microdissected from the genu of the carotid This region includes a number of different anatomic com-
artery with minimal risk of injury. When the tumor is partments (e.g., parapharyngeal space, pterygomaxillary
markedly adherent to the carotid wall, a thin remnant fossa) and contains within it the deep portion of the parotid
should be left and thoroughly coagulated with bipolar gland, pterygoid muscles and their associated vascular plexus,
cautery. Planned carotid resection is not indicated in cranial nerves IX–XII, the jugular vein, and the carotid
benign tumors of the jugular foramen. Intracranial exten- artery. The more common primary lesions in this area
sion of a jugular foramen tumor necessitates a transjugular include tumors of the deep lobe of the parotid gland, glomus
posterior fossa craniotomy, which is discussed separately.

Figure 43-20. A medium-sized glomus jugulare tumor, which fills the jugular
bulb and extends intraluminally into both the sigmoid sinus and jugular vein.
Note the small tongue of tumor that has penetrated into the hypotympanum. Figure 43-22. A large glomus tumor, which erodes the genu of the internal
This otoscopically visible “tip of the iceberg” is often the clinical feature that carotid artery. It has significant intraluminal components in both the sigmoid
leads to the detection of these lesions. sinus and jugular vein. Note the extraluminal packing of the sigmoid sinus.
 Surgical Neurotology: An Overview 685

TRANSBASAL APPROACHES
TO INTRACRANIAL TUMORS
Internal Auditory Canal
and Cerebellopontine Angle
Surgery of tumors of the internal auditory canal and cere-
bellopontine angle is a central issue to neurotology.
Perhaps the greatest advances in neurotologic surgery in
recent decades have taken place in the management of
benign, extra-axial tumors of the posterior fossa, particu-
larly those of the cerebellopontine angle (CPA). The classi-
cal suboccipital approach, formerly the workhorse used in
virtually all such tumors, has been largely supplanted by the
retrosigmoid and transtemporal approaches (Fig. 43-24).
The retrosigmoid approach is a modified suboccipital
opening, which reduces the need for cerebellar retraction
while providing wide exposure and maintaining the possibil-
ity of hearing preservation in selected cases. A family of

Figure 43-23. The infratemporal fossa approach, as described by Fisch, has

three primary varieties: type A for the jugular foramen region, mandibular
fossa, and posterior infratemporal fossa; type B for the apical petrous bone
and clivus including the intrapetrous course of the carotid artery; type C is an
anterior extension used for exposure of the infratemporal fossa,
pterygopalatine fossa, parasellar regions, and nasopharynx.

vagale, and lower cranial nerve schwannomas. Examples of

secondary involvement include downward excursion of a
glomus jugulare, lateral penetration of nasopharyngeal carci-
noma, and neoplastic spread along the third division of the
trigeminal nerve. Meningiomas can also spread extradurally
to this area via either the foramen ovale or the jugular
foramen.
Operative approaches to the infratemporal fossa may be
considered in two broad categories: preauricular or
postauricular (Fig. 43-23). Postauricular approaches to the
infratemporal fossa are usually indicated for (1) tumors of
the jugular foramen with a substantial component in the
upper neck, (2) deep lobe parotid tumors that erode the
temporal bone (e.g., penetrate the fallopian canal or erode
the ear canal), and (3) ear canal squamous cell carcinomas
that penetrate beneath the temporal bone. Preauricular
approaches are used for more anteriorly based tumors that
do not involve the petrous bone. Some examples include
(1) schwannoma of the third division of the trigeminal
nerve, (2) meningioma penetrating foramen ovale, and
(3) tumors in the paranasopharyngeal region.
Figure 43-24. An axial schematic view of the common posterior fossa
Several adjunctive techniques are often needed to craniotomies used to access the CPA. In the retrosigmoid approach, an
enhance exposure during the infratemporal fossa proce- opening is created in the suboccipital bone plate behind the sigmoid sinus.
dure. Resection of the mandibular condyle facilitates wide The three transtemporal approaches open the posterior fossa dura anterior to
exposure for malignant disease. A pseudoarthrosis usually the sigmoid sinus, through the posterior aspect of the petrous pyramid. Note
forms and the effect on mastication is not usually debilitat- that the transtemporal craniotomies require removal of 1 to 2 cm of
retrosigmoidal bone to allow for posterior displacement of the sinus. In the
ing. Temporary downward displacement of the zygomatic retrolabyrinthine approach, bone is removed up to the semicircular canals.
arch facilitates exposure of temporal and sphenoidal (greater This provides a limited view of the posterior aspect of the CPA. In the
wing) floor lesions while minimizing the need for retraction translabyrinthine approach, the balance canals are also removed, a maneuver
of the temporal lobe. In such lesions, resection of the glenoid that both provides access to the IAC and enhances CPA exposure. In the
transcochlear approach, the entire inner ear is removed and the facial nerve
fossa may be necessary. Finally, approach to the more medial is posteriorly rerouted from its intratemporal course. This technique provides
aspect of the infratemporal fossa usually requires section of access to the anterior aspect of the CPA and the space ventral to the
the third division of the trigeminal nerve. brainstem.
686 SURGICAL NEUROTOLOGY

presigmoid or transtemporal approaches have been devel-

oped to further reduce the degree of brain retraction
required as well as to reduce the depth of the operative
field. Although the transpetrosal approaches are techni-
cally more complex than retrosigmoid openings, they do
possess a somewhat lower morbidity while providing ample
exposure for the vast majority of extra-axial posterior fossa
tumors. The amount of the petrous bone removed in the
transpetrosal approach depends on the degree of exposure
required. In the retrolabyrinthine approach, the only
transpetrosal craniotomy that spares the inner ear, only
limited exposure of the midportion of the CPA is provided.
This opening is generally considered suitable only for prob-
lems confined to the root entry zone of the seventh and
eighth nerve complexes, such as selective vestibular neurec-
tomy and vascular loop decompression. With the capability
of providing access to the entire CPA, the translabyrinthine
approach is much more versatile than the retrolabyrinthine.
The transcochlear approach, a more radical transpetrosal
craniotomy that involves a complete exenteration of the
inner ear and requires rerouting of the intratemporal
course of the facial nerve, extends the translabyrinthine Figure 43-25. Retrosigmoid approach to a medium-sized acoustic neuroma
exposure to include the ventral surface of the pons and the seen in axial section. Note that the internal auditory canal has been drilled
prepontine cistern. open to expose the intracanalicular component of the tumor. The degree
Logically, it seems obvious that the angle of view to the of cerebellar retraction required in this approach varies, but it is often less
CPA and brainstem should differ substantially between than depicted here.
retro- and presigmoid approaches. In practice, however,
the perspective of these structures is quite similar in the
two techniques. The reason is that in the retrosigmoid
approach, bone is removed up to the edge of the sigmoid
sinus and the surgeon views along the front edge of the
craniotomy opening; in the presigmoid approaches, bone
is removed behind the sinus, permitting its retraction
posteriorly, and the surgeon views along the posterior edge
of the opening. Thus, the angle of view toward the vital
structures of the CPA is actually quite similar. Some earlier
publications, particularly in the neurosurgical literature, SS
SSCC
have disparaged the presigmoid approaches (especially CC Co T
translabyrinthine) as providing insufficient exposure of PSCC e
n
the brainstem.29 These objections undoubtedly arise from t
o
neurosurgical collaboration with an inexperienced temporal VA I S r
JB VV i
bone surgeon who provided inadequate presigmoid opening S
PA u
m
for intracranial microdissection. JV 9 E
8 5
10
11C
11S 7
Ch Fl BS
Retrosigmoid Approach
Surgical Exposure
Cerebellum
The retrosigmoid (RS) approach provides a panoramic
exposure of the posterior fossa from the tentorium to the
foramen magnum (Figs. 43-25 and 43-26).30–32 Access is
provided to the cerebellar hemisphere, the lateral aspect of
the pons and medulla, and the root entry zones and cisternal
courses of cranial nerves V through XI. By unroofing the Figure 43-26. Retrosigmoid craniotomy (left side) illustrating the surgical
anatomy of the posterior fossa exposure. The venous sinuses and inner ear
posterior bony covering of the internal auditory canal (IAC), structures have been made visible to help clarify their relationships to
the seventh and eighth nerves can be readily exposed to intracranial structures. BS, brainstem; CC, common crus; Ch, choroid
the fundus of the canal. The fifth nerve can also be traced plexus; Co, cochlear; ES, endolymphatic sac; Fl, flocculus; IV, inferior
for part of its course into Meckel’s cave and the middle vestibular nerve; JB, jugular bulb; JV, jugular vein; PA, porus acusticus;
fossa floor by exenteration of the apical portion of the PSCC, posterior semicircular canal; SS, sigmoid sinus; SSCC, superior semi-
circular canal; SV, superior vestibular nerve; VA, vestibular aqueduct. Cranial
petrous pyramid. nerves: 5, trigeminal; 7, facial; 8, audiovestibular; 9, glossopharyngeal;
Exposure with the RS approach is limited superiorly by 10, vagus; 11C, accessory (cranial portion); 11C, accessory (spinal
the tentorium, although it may (as with all other types of portion).
 Surgical Neurotology: An Overview 687

posterior fossa craniotomy) be combined with a middle

fossa or transtentorial exposure. Inferiorly, the limit is the
foramen magnum, which can be exposed when the need
arises through inferior extension of the craniotomy
accompanied with upper cervical laminectomy as required.
Anteriorly, exposure is limited by the long field of action,
the bridging of cranial nerves VII and VIII superiorly and
IX–XI inferiorly, and the inadvisability of applying retraction
to the brainstem.
Indications
Because of its wide exposure, the RS approach is versatile.
Were it not for the lower morbidity of transpetrosal
approaches and their greater versatility with regard to cranial
base extension, the RS craniotomy could be used for virtually
all extra-axial posterior fossa tumors that did not arise in the
anterior midline or deeply penetrate the cranial base. Indeed,
a number of centers follow this policy. Even in centers expe-
rienced with transpetrosal approaches, the RS approach is
often used for selective vestibular neurectomy; vascular
decompression of fifth (trigeminal neuralgia), seventh (hemi- Figure 43-28. Retrosigmoid approach to a large acoustic tumor that deeply
facial spasm), eighth (disabling positional vertigo, tinnitus), invaginates the internal auditory canal. To expose the lateral extent of the
or ninth (glossopharyngeal neuralgia) cranial nerves; hearing tumor, portions of the inner ear must be removed.
conservation approaches to acoustic neuromas with small
cisternal components; and in the removal of meningiomas,
epidermoids, and other nonacoustic CPA tumors when hear- retraction is required to access the CPA and the IAC. The
ing is intact (Figs. 43-27 through 43-29).33–37 classical SO approach has largely supplanted the RS
approach in recent years. The bony opening in the RS
Technical Considerations
approach is situated immediately posterior to the sigmoid
In the suboccipital (SO) approach a large paramedian sinus and immediately inferior to the transverse sinus. The
opening is created in the suboccipital convexity, usually size of the opening varies according to the size and loca-
bounded laterally at the first encounter with the mastoid tion of the lesion being addressed, but it can usually be
air cell system. This usually places the anterior edge of the limited to approximately 3 × 3 cm. In most cases, two tech-
craniotomy well behind the sigmoid sinus. Because of its nical problems are created by this close approach to the
more posterior orientation, a greater degree of cerebellar dural sinuses. Entry into the mastoid air cells was greatly

V
C

8 5

Ch Fl

Figure 43-27. Retrosigmoid approach to a small acoustic tumor that does Figure 43-29. Retrosigmoid approach to selective vestibular neurectomy.
not deeply invade the internal auditory canal. In such cases, it may be A small craniotomy is performed with minimal cerebellar retraction, just
possible to open the internal auditory canal without violating the inner ear. sufficient to expose the entry zone of the seventh and eighth nerve
The endolymphatic sac and aqueduct are often helpful landmarks in complexes. To denervate the vestibular system, the rostral portion of the eighth
preventing injury to the otic structures. C, cochlear division of the eighth nerve is divided. C, cochlear division of the eighth nerve; Ch, choroid plexus;
nerve; 7, facial nerve; 8, audiovestibular nerve. Fl, flocculus; V, vestibular division of the eighth nerve; 5, trigeminal nerve.
688 SURGICAL NEUROTOLOGY

feared in the past due to concern for contamination of the surprisingly little retraction is often needed. In exposing
wound. However, it is now understood that the normal the mid-CPA, our measurements indicate the need for only
mastoid air cell system is sterile and thus wound inocula- 1 to 2 cm of medial displacement in the average case. After
tion seldom occurs. The second consideration is CSF leak- draining the cisterna magna and administering intravenous
age, which remains problematic especially when extensive mannitol to shrink the cerebellum, the more lateral por-
pneumatization is present. Transected air cells are sealed tion of the CPA can often be visualized without retraction.
with either bone wax or hydrophobic bone cement. To be A substantially greater degree of retraction is required,
most effective, not only should sealant be impacted into however, when the tumor deeply invaginates the pons and
opened air cells, but a continuous thin sheet should be cerebellar peduncle. Resection of the lateral one-third of
created as well. the cerebellum to improve exposure, a maneuver formerly
Due to the thickness of the musculature overlying this in widespread use, is virtually never required today. To
region, the bone may be simply removed (craniectomy) prevent injury to its surface, it is best not to place a retrac-
without leaving a particularly vulnerable skull defect. tor directly on the cerebellum. We prefer to use a Telfa
Some argue that the persistence of a bone defect permits strip (approximately 2 × 6 cm) under the retractor.
adherence between the posterior fossa dura and the sub- Alternatively, a Silastic-coated malleable retractor blade
occipital musculature, a condition that may contribute to may be used. Narrow retractors tend to indent or even lac-
the development of headaches. In addition, meningoceles erate the cerebellar surface. Wider retractor blades tend to
may occur, particularly in patients with hydrocephalus. To distribute the retraction force over a wider surface and
avoid this, an osteoplastic bone flap may be created, but minimize potential for injury.
this is technically difficult to produce without injuring the When tumors penetrate the IAC, the canal’s osseous
sigmoid sinus. We favor replacing the morselized bone posterior lip must be removed. Intradural drilling produces
fragments harvested during opening into the defect at the copious amounts of bone dust, which is a meningeal
end of the procedure. In our experience, this is more readily irritant that may contribute to postoperative aseptic
achievable technically than a bone flap and heals satisfac- meningitis and persistent headache. An effort should be
torily as a firm bony plate. made to confine the debris created while drilling so that it
The relative position of the sigmoid sinus effects exposure can be evacuated with suction. This may be achieved, with
via the RS approach. An anterior lying sigmoid sinus is incomplete success, by placing Gelfoam into the CPA and
favorable, affording a more directly lateral point of view. covering it with a rubber dam. Despite these precautions,
Conversely, a posterior lying sigmoid sinus may be a hin- it is not uncommon to find bone dust adhering to relatively
drance, forcing the exposure to a disadvantageously posterior inaccessible arachnoid surfaces in the prepontine cistern
perspective. In such circumstances, some have recom- along the basilar artery as well as in the jugular foramen
mended that a mastoidectomy be performed with decom- region.
pression of the sinus, thus allowing its retraction anteriorly Adequate exposure of the IAC contents requires not
with dural stay sutures. An inferiorly located transverse only visibility, but sufficient room for the unrestricted use
sinus may similarly impose limitations as it forces the of microsurgical instruments. Generally, this necessitates
surgeon to work from a more inferior perspective. When creation of troughs that are several millimeter wide above
the patient’s neck is short and the shoulder is large, there and below the IAC, which are deepened beyond the plane
may be both limited access to the retrosigmoid region and of the anterior face of the canal. This deep excavation is nec-
the need to carry out dissection at a relatively awkward essary to permit insinuation of a hook or other angled
angle. This circumstance may also prevail in patients with instrument into the plane between the tumor and the ante-
limited neck mobility due to advanced age or disease of the riorly located facial nerve. On occasion, an unusually high
cervical spine. The surgeon should avoid the tendency to jugular bulb may lie against the inferior aspect of the IAC
compensate for unfavorable anatomy by overrotating the or even overlap it to some degree. Care must be taken to
head because this may crimp the vertebral veins and con- avoid injury to this structure because it is difficult to com-
tribute to a tendency for cerebellar swelling. In extreme cases press it sufficiently without obscuring the intracanalicular
of a short and fat neck or cervical immobility, the sitting portion of the tumor. A high jugular bulb inhibits forma-
position may be chosen. tion of a trough beneath the IAC, particularly in the
After dural opening, it is essential to liberate CSF from medial portion of the canal adjacent to the porus acusticus.
the cisterna magna before retracting the cerebellum. This This limitation can generally be overcome by elevating the
is accomplished by gently elevating the cerebellum and tentorium and addressing the IAC component primarily
fenestrating the cistern’s arachnoid covering. Failure to from above.
release CSF at an early stage risks untoward swelling of When hearing conservation is a goal, it is important to
the cerebellum during premature efforts at retraction. be aware that only approximately the medial two-thirds
Such cases of cerebellar swelling, which may rarely occur of the IAC may be opened via the RS approach without
despite meticulous technique, require abandonment of the violating the vestibule of the inner ear (see Figs. 43-27 and
procedure. In cases of massive swelling, the protuberant 43-28).38,39 Some have advocated using the endolymphatic
cerebellum may need to be resected followed by a loose clo- sac and aqueduct as a guide to avoid entry into the
sure, leaving the dura open. Under such dire circumstances, labyrinthine structures. In most cases, we prefer opening the
opening of the foramen magnum ring may discourage canal to the level of the tumor’s deepest penetration, regard-
postoperative tonsillar herniation. less of its relationship to the inner ear. This allows tumor
To expose the midportion of the CPA, the cerebellum dissection to commence with direct visualization of the
must be gently retracted medially. In the RS approach, tumor-nerve interface and greatly reduces the likelihood of
 Surgical Neurotology: An Overview 689

tumor recurrence due to incomplete resection from the completed before opening the dura. Presumably, the irri-
fundus. Unlike tumor remnants in the CPA, which are tation of bone dust may lead to a form of chronic aseptic
often devoid of vascular supply, tumor residual in the fundus meningitis. Arguing in favor of this etiology is the relative
of the IAC is likely to possess a vascular stalk capable of responsiveness of such headaches to corticosteroids and
supporting tumor regrowth.40 In a few patients with normal nonsteroidal anti-inflammatory drugs. An additional
or near normal hearing, undertaking the risk of an indirect observation that supports this mechanism is the frequent
dissection may be warranted. In such cases, an attempt occurrence, during a severe headache, of a bulging opera-
should be made to confirm complete excision from the lat- tive site suggestive of transient increased posterior fossa
eral recess of the canal by visualization with an endoscope pressure. Other possible etiologies of post RS craniotomy
or mirror. headache include occipital neuralgia and a coupling of the
Opening of the IAC may transect mucosally lined air posterior fossa dura with the suboccipital musculature. In
cells that are present in proximity to the canal in 30% to support of the latter hypothesis is the fact that post RS
40% of adults. To avoid CSF leakage, these must be closed headache is triggered by cough or straining in some
with bone wax or hydrophobic bone cement. In addition, patients. In this regard, such headaches are similar to those
many surgeons place a tissue graft into the petrosal defect associated with the Arnold-Chiari deformity and other
created by opening the IAC. A free graft of either muscle malformations of the craniovertebral junction. Recently, it
or fat may be employed, which may be maintained in posi- has been reported that reconstruction of the suboccipital
tion by a dural suture, autologous fibrin glue, or a combi- skull somewhat reduces the risk of persistent headache.45,46
nation of the two. Since muscle may simulate recurrent Some have maintained CSF leak has been more common
tumor on subsequent enhanced MRI, fat is preferred in following RS craniotomy than following transtemporal tech-
most centers because its signal can be suppressed. When niques, as well as more stubborn and difficult to manage.47,48
pneumatization is extensive, we use a prophylactic lumbar Via the RS approach, it is technically difficult to hermeti-
subarachnoid drain to discourage CSF leakage. cally seal all transected cells when the petrous apex is
extensively pneumatized. In addition, closure is attempted
Advantages at only one location—along the cut edge of petrous bone.
The primary advantage of the RS approach is its versatil- In the transtemporal approaches, a second line of defense
ity. Because it provides a relatively panoramic exposure of is created either at the entrance of the aditus-ad-antrum or
the posterior fossa from the tentorium to the jugular fora- through obliteration of the eustachian tube. As opposed to
men, the RS approach is suitable for use in a wide variety CSF otorhinorrhea, CSF wound leak may be less common
of tumors as well as vascular abnormalities affecting this following the RS approach due to the multilayer closure
region. In selected lesions, it affords the possibility of afforded by the thick occipital musculature. In a recent
hearing preservation.41–43 study at the University if California at San Francisco, the
incidence of CSF leakage was equal (approximately 10%)
Disadvantages following the translabyrinthine (TL), RS, and middle fossa
The RS approach, due to its relatively posterior angle of (MF) approaches.49
view, provides only limited visualization of the region
ventral to the brainstem. Exposure of the ventral surface of
Transpetrosal Approaches
the pons and medulla and the posterior aspect of the clivus is
obstructed both by cranial nerves V through XI, which The transpetrosal approaches (also known as transtemporal)
bridge the CPA, as well as by the interposed lateral surface of are a family of three craniotomy techniques (retro-
the brainstem. The presigmoid transtemporal approaches, labyrinthine, translabyrinthine, and transcochlear) (see
which offer a more anterior angle of view, are more suitable Fig. 43-24), which progress from a limited petrosectomy
for the majority of tumors in front of the brainstem. that provides only a small view of the CPA to radical
Some argue that the need for cerebellar retraction is a resection of the contents of the petrous pyramid with wide
disadvantage of the RS approach. However, when per- posterior fossa exposure.
formed gently, retraction seldom leads to postoperative
cerebellar dysfunction. A more important disadvantage is Retrolabyrinthine
the frequent occurrence of persistent postoperative Surgical Exposure: The retrolabyrinthine (RL) approach
headaches. In a study of CPA tumors at the University of consists of a small posterior fossa craniotomy, which is
California at San Francisco, headache persisted beyond the performed between the sigmoid sinus and the otic capsule
sixth postoperative month in 64% of patients following RS (Figs. 43-30 and 43-31).50,51 It provides limited exposure of
craniotomy but in only 34% after the TL approach.44 the posterior fossa, confined to the region of the entry
More important, 12% of RS patients reported long-lasting zone of the fifth, seventh, and eighth nerves. More lateral
severe and disabling headache, whereas no TL patients structures, such as the porus acusticus and IAC, cannot be
were so afflicted. Of interest, most severe headache suffer- visualized because they are blocked by the otic capsule.
ers had small tumors and had undergone a hearing conser- Indications: The RL approach was first described in the
vation attempt. The reason for the higher incidence of early 1970s as an approach to the root entry zone of the
headache following the RS approach is uncertain, but it trigeminal nerve in tic douloureux, but was not used
may well be related to the widespread soilage of posterior widely until the early 1980s when it gained popularity as a
fossa arachnoid with bone dust generated during means of exposing the brainstem entry of the eighth nerve
intradural drilling of the posterior lip of the IAC. During for vestibular neurectomy.34,52,53 In recent years, the ret-
a transtemporal craniotomy, by contrast, all drilling is rosigmoid approach has regained favor for this procedure
690 SURGICAL NEUROTOLOGY

become popular for transtentorial lesions, which are

related to both the pons and midbrain (see later section on
combined craniotomies).56,57
Technical Considerations: The RL approach is a poste-
rior fossa craniotomy with a limited exposure to the
midportion of the CPA. A curved skin incision is
performed approximately 4 cm behind the postauricular
sulcus. The mastoid periosteum is elevated to the level of
the posterior aspect of the external auditory canal. With a
cutting burr, the mastoid air cell system is thoroughly
exenterated to the level of the semicircular canals. The
anterior limit of the dissection is the osseous external audi-
tory canal. Posteriorly, the sigmoid sinus is skeletonized
with a cutting burr, as are approximately 2 cm of retrosig-
moid dura. A large diamond burr is used to completely
remove the bony covering of the sinus and adjacent dura.
A thin bone plate (Bill’s island) may be left over the anterior
aspect of the sigmoid sinus. This has been advocated by
some to protect the sinus from injury by the rotating shaft
of the drill when working more deeply within the temporal
bone. When the bony island forms a cupula that restricts
sigmoid retraction, it may be broken up into small plates
(“cornflaked”) to facilitate retrodisplacement. Other sur-
geons completely remove this bony covering and use a
Figure 43-30. Retrolabyrinthine craniotomy in axial view. Note that the bone retractor to guard the sinus from inadvertent injury. The sig-
overlying the sigmoid sinus is removed together with 1 to 2 cm of moid sinus must be exposed superiorly from the transverse-
retrosigmoid occipital plate. sigmoid junction to the jugular bulb region inferiorly in
order to obtain the maximum posterior fossa exposure
due to its wider exposure. Much less common, the RL has afforded by this technique. Although a 6- to 8-mm diamond
been used to perform vascular decompression of the burr is satisfactory for this task, we prefer a 10- to 12-mm
eighth nerve for tinnitus or chronic vertigo or even as an burr, which is quicker and less traumatic. Frequently,
approach to midbasilar artery aneurysms.54,55 Recently, a mastoid emissary veins are encountered, which must be
combined retrolabyrinthine and subtemporal exposure has controlled with bipolar cautery. Lacerations of the sigmoid
sinus or avulsions of emissary veins are readily controlled
by extraluminal tamponade with hemostatic gauze (e.g.,
Surgicel). It is best to avoid intraluminal packing of the
sigmoid sinus because this risks embolization of the packing
L material. The possibility of air embolism should also be
kept in mind by the surgeon, although this risk is very low
when the patient is in the supine position. After decompres-
ES P sion of the sigmoid sinus, it is retracted posteriorly and the
posterior aspect of the otic capsule is carefully skeletonized.
Care must be taken to avoid entry into the posterior
semicircular canal because this is likely to harm hearing.
The dura is incised near to the sigmoid sinus and carried
7 medially both along the superior petrosal sinus and toward
the jugular bulb. This creates a rectangular dural flap,
which contains but does not interrupt the endolymphatic sac.
Exposure of the midportion of the CPA requires gentle
retraction of the cerebellum posteriorly. The flocculus fre-
8 quently must be mobilized through release of its arachnoid
tethers. Selective vestibular neurectomy is accomplished
by dividing the rostral fibers of the eighth nerve near the
brainstem entry. Following completion of the procedure,
the surgical defect is obliterated with an abdominal fat
graft. This is necessary to avoid CSF leakage because
watertight dural closure cannot easily be obtained.
Figure 43-31. Retrolabyrinthine craniotomy (left side) illustrating the surgical Advantages: The purported advantage of this approach
anatomy of the posterior fossa exposure. The dura has been incised anterior compared with retrosigmoid craniotomy is a lower incidence
to the sigmoid sinus, allowing the endolymphatic sac (ES) to be retracted
forward. A limited posterior fossa exposure in the region of the brainstem
of persistent postoperative headaches. However, little data
entry of cranial nerves 7 and 8 is provided. L, lateral semicircular canal; is available that compares the two openings. Although
P, posterior semicircular canal; 7, facial nerve; 8, audiovestibular nerve. most would agree that persistent headaches are more
 Surgical Neurotology: An Overview 691

frequent with the RS approach when the IAC is drilled open,

when the nerve is cut proximally (as in the RL approach), GG
there may be little or no difference in the incidence of this
bothersome complication. Meningitis and wound infection JV 7
are infrequent following the RL approach, partly because of 7
the relatively short duration of this procedure. Ca
JB
Disadvantages: The primary disadvantages of the RL I S
approach is its narrow field of action, which provides only V V
limited exposure of the CPA. In general, when used as the
sole opening, the RL approach is not particularly well 11 10 9 SPS
suited for tumor surgery. A second disadvantage is the 7 8 6
5
Ch
incidence of CSF otorhinorrhea, which is probably greater
Fl
than that for a comparable RS approach performed without
Cb
opening the IAC. This is due to the inability in the RL
approach to close dura primarily. Finally, the need for a SS T
separate incision on the abdomen to harvest a fat graft may
be seen as a disadvantage by some patients. D
Translabyrinthine TS

Surgical Exposure: The TL approach is an anterosig-

moid posterior fossa craniotomy, which provides exposure
of the CPA including the lateral aspect of the pons, the
ventral surface of the lateral cerebellar hemisphere and its
Figure 43-33. Translabyrinthine craniotomy (left side) illustrating the surgical
associated peduncles, and the proximal portion of cranial anatomy of the posterior fossa exposure. Ca, cochlear aqueduct orifice;
nerves V, VI, VII, and VIII (Figs. 43-32 and 43-33).8,58–63 Cb, cerebellum; Ch, choroid plexus; D, dura; Fl, flocculus; GG, geniculate
The root entry zone and CPA course of nerves IX, X, and ganglion; IV, inferior vestibular nerve; JB, jugular bulb; JV, jugular vein;
XI is seen to a variable degree depending on the course of SPS, superior petrosal sinus; SS, sigmoid sinus; SV, superior vestibular
nerve; TS, transverse sinus. Cranial nerves: 5, trigeminal; 7, facial;
the sigmoid sinus. 8, audiovestibular; 9, glossopharyngeal; 10, vagus; 11, accessory
Indications: The primary indication for the TL approach (cranial portion).
is acoustic neuroma (Fig. 43-34).64–70 Ample exposure is
afforded for even very large eighth nerve tumors. The
approach may also be used for meningiomas, epidermoids, Cochleovestibular neurectomy can also be accomplished
and other tumors of the CPA when hearing is poor.71,72 through this route.73 The TL approach is not suitable
for tumors that extend into the inferior aspect of the
posterior fossa because this region is obscured by the jugu-
lar bulb and the horizontal course of the sigmoid sinus.

Figure 43-32. Translabyrinthine approach to a 2-cm acoustic neuroma in

axial view. Bone is removed from the external auditory canal to behind the Figure 43-34. Translabyrinthine approach to a medium-sized acoustic
sigmoid sinus. The internal auditory canal is exposed by removal of the neuroma. Sufficient exposure is afforded to remove even very large
semicircular canals. cerebellopontine angle tumors.
692 SURGICAL NEUROTOLOGY

This anatomic limitation precludes exposure of the neural removed to the level of the porus acusticus. Removal of the
compartment of the jugular foramen or foramen magnum. middle fossa plate from the subtemporal dura is optional.
The TL approach has also been advocated for aneurysms Softening of the temporal floor permits extradural elevation
of the midportion of the basilar artery. For transtentorial of the temporal lobe and is indicated during exposure of
lesions, the TL approach may be combined with a large tumors. It is also helpful in small tumors when the
subtemporal opening (see later section on combined tegmen lies at an unusually low level.
craniotomies).60,74 A combined TL and RS opening with Wide exposure of the IAC is an essential part of the
sacrifice has been advocated for certain large CPA tumors procedure. Deep bony troughs are drilled above and below
in the past, but it is seldom used today.75 the canal to bring it into high relief. Superiorly, a furrow is
created between the IAC and the middle fossa dura. Care
Technical Considerations
must be exercised while removing the last eggshell of bone
In the TL craniotomy the bony opening extends from the from the superior aspect of the canal because the facial nerve
posterior aspect of the external auditory canal to behind the lies immediately beneath the dura in this location. The infe-
sigmoid sinus.76 The amount of retrosigmoid bone removal rior furrow is created between the IAC and the jugular bulb.
depends on the size of the tumor being removed and the The cochlear aqueduct is often encountered while removing
position of the sigmoid sinus. Although the distance between this bone and is a useful landmark in the identification and
the sigmoid sinus and the ear canal is initially narrow, pro- preservation of the dural envelope of the neural compart-
gressive removal of the petrous bone enlarges it substantially. ment of the jugular foramen.78 When the jugular bulb is
Thorough removal of the bone overlying the sinus and the atypically high, it may impede the creation of the inferior
posterior fossa dura behind it is essential to permit its mobi- bony trough. In extreme cases, it may cover part or all of
lization. This is accomplished by use of cutting burrs until the IAC just proximal to the porus. Some have advocated
the blue tint of the sinus is evident through a thin sheet of decompression and inferior displacement of the high jugular
bone. The remaining plate is removed using large diamond bulb in such cases. This remains an option but adequate
burrs (see section on RL approach for further discussion). exposure can usually be obtained, in spite of this anomaly, by
Use of large burrs is important because they are rapid and elevating the temporal dura and extending the superior
also present a relatively large working surface and are there- trough to the level of the tentorium to provide enhanced
fore less likely to tear the sinus or dura. The sigmoid should exposure of the canal from its superior aspect. It is important
be decompressed from the transverse-sigmoid junction supe- to realize that a high jugular bulb, even though it may
riorly to the jugular bulb inferiorly. There is much variabil- obstruct visualization of the midportion of the canal and the
ity to the anatomic location of the sigmoid sinus. When the porus, does not obscure the lateral end of the IAC. Thus,
sigmoid sinus lies far forward, it may even contact the ear even when the bulb is very high, the proximal facial nerve
canal. Even with such an adverse configuration, ample CPA plane may be readily established. It should be stressed that
exposure can be obtained. the removal of bone around the IAC, particularly at the
Following sigmoid mobilization, the remainder of the porus acusticus, should be aggressive. Inadequate beveling of
mastoid is rapidly removed to the level of the semicircular the porus may leave an overhang that impedes visualization
canals. In the process, bone is removed from the sinodural of the facial nerve at its vulnerable abrupt turn immediately
angle to expose the superior petrosal sinus. Labyrinthectomy medial to the porus. When the tumor is large, it is important
is performed using a cutting burr, commencing in the to extend the bony opening well beyond the level of the IAC
sinodural angle. By creating troughs parallel to the middle into the petrous apex to provide enhanced exposure of the
and posterior cranial fossa dura, the remaining labyrinth can anterior aspect of the CPA.79
be removed with the side of the cutting burr. This is prefer- The dura of the IAC is incised slightly inferior to its
able because the tip of a rotating burr tends to skate and is meridian to avoid potential injury to the facial nerve (FN),
therefore more difficult to control. The facial nerve is which usually lies superior and deep to the superior
closely related to the inferior aspect of the lateral semicircu- vestibular nerve. Separate flaps are then peeled superiorly
lar canal and to the inferoanterior end of the posterior semi- and inferiorly to fully expose the canal contents. There are
circular canal. The final remnant of the semicircular canals several methods of opening the dura of the posterior cra-
is removed with a diamond burr to permit atraumatic expo- nial fossa in the TL approach. In most widespread use is
sure of the horizontal and second geniculate portions of the a flap that parallels the superior petrosal sinus above and
facial nerve. Deepening the opening beneath the facial inferiorly spans the gap between the sigmoid sinus and the
nerve exposes the vestibule of the inner ear with all three apex of the jugular bulb. These are connected across the
semicircular canal ampullae and the otolithic organs. mouth of the porus acoustic, thereby creating a rectangu-
Obtaining this exposure is important in gaining access to the lar dural flap, which is then dissected off of the cerebellar
terminal portions of the superior and inferior vestibular surface.
nerves. Partial labyrinthectomy with sealing of the tran- When opening the dural overlying the CPA does not
sected portion of the inner ear with bone wax has been pro- result in the free flow of CSF, the inferior aspect of the
posed as a means of possibly sparing hearing.77 However, cerebellum should be gently elevated to permit incision of
complete exposure of the fundus requires a wide opening of the arachnoid of the cisterna magna before commencing
the vestibule, a maneuver very likely to severely traumatize tumor dissection. With this decompression accomplished,
the membranous labyrinth. Following labyrinthectomy, the the cerebellar attachments to the tumor can be liberated,
bone deep to the labyrinth is then rapidly removed to the permitting its gentle retraction laterally. After mobilization
level of the IAC. As the exposure progressively deepens, of the cerebellum’s arachnoidal and vascular tethers, partic-
the plate of bone over the posterior fossa dura is gradually ularly to the petrosal veins superiorly, little retraction is
 Surgical Neurotology: An Overview 693

required in smaller tumors. Significant cerebellar retrodis- rerouting permits repair of short FN deficiencies with a
placement may still be needed in large tumors that deeply single anastomosis, which is preferable to the two anasto-
invaginate the cerebellar peduncle. moses required with interposition graft. In the RS
In a properly performed TL craniotomy, excellent approach, the only option for repair of an FN dehiscence
exposure of the CPA is provided from the tentorium to the when the ends are not approximated is nerve grafting.
jugular foramen. Much as a high jugular bulb may obscure The TL approach also has a relative advantage over the
the IAC, a high lying sigmoid course may inhibit visualization RS approach under certain circumstances in the angle of
of the inferior aspect of the CPA. While there is some asso- view toward the brainstem. The more anterior perspective
ciation between high sigmoid course and high jugular bulb, permits a more direct view of the brainstem surface, partic-
either may occur in the absence of the other. Restricted ularly when the tumor has posteriorly rotated and deeply
access to the inferior portion of the CPA is seldom prob- indented the pons and middle cerebellar peduncle. By
lematic in acoustic neuromas which, once debulked, readily comparison, the exposure of the tumor interface via the RS
mobilize into the operative field. In addition, acoustic approach is more tangential in such cases.
tumors rarely adhere to the lower cranial nerves. A widely touted advantage of the TL approach is the
Meningiomas, by contrast, adhere to dural surfaces and ability to identify the FN at the lateral end of the IAC prior
typically do not easily mobilize. They also are more likely to its involvement with tumor. Although it is certainly
to enmesh the lower cranial nerves. For this reason, we do reassuring to the surgeon to locate the FN at the earliest
not use the TL approach in nonacoustic tumors that extend possible time, we have never had particular difficulty in
inferiorly toward the jugular foramen and/or foramen identifying or preserving the FN during removal of the
magnum unless a concurrent transjugular craniotomy is intracanalicular portion of an acoustic tumor. This advantage
planned. may be more important when anatomic arrangements are
A partial dural repair is often possible following a TL less predictable than in acoustic neuroma, such as in
craniotomy, but a substantial dural defect typically persists. meningioma or in revision cases.
Obliteration of both the osseous and dural defects is Disadvantages: The primary disadvantage of the TL
customarily accomplished with fat harvested from the approach is the necessity of sacrificing hearing in the
abdomen or iliac crest region. Fat is laid in strips into operated ear. This is less of a concern in acoustic tumors,
the cavity until it tightly fills the defect from the dura to the where useful hearing can seldom be preserved, that it is for
skull surface. Frequently, some fat prolapses into the cavity other lesions of the CPA and IAC such as meningioma and
left behind by tumor dissection and comes to abut the epidermoids. In many cases, the decision algorithm used to
brainstem. Fortunately, adipose tissue is pliable and seldom choose among the various surgical approaches is quite
induces a mass effect. Following a TL approach, the primary complicated and depends on numerous factors including
route for CSF leaks is via the aditus-ad-antrum, a narrow tumor size, location, and type. While sacrificing hearing in
cleft located quite superficial within the craniotomy opening. an ear should never be taken lightly, in many cases it is
A strip of fascia (temporalis or rectus) may be lain over this warranted when the probability of preserving hearing is
area in an attempt to seal it. Some surgeons prefer to remote or when the anatomic features of the tumor indicate
obstruct the eustachian tube orifice through a facial recess the need for more anterior exposure.
approach. However, this opening increases the communi- A minor disadvantage of the TL approach is the require-
cation between the craniotomy cavity and the middle ear ment for a fat graft to obliterate the defect. To some indi-
and provides only limited access to the tube orifice, making viduals, this may create an undesirable abdominal scar. This
closure via this method somewhat insecure. can be easily avoided in women, who usually have a fat pad
Advantages: When compared with RS craniotomy, TL in the hip region, which is accessible through an incision
approaches have a somewhat lesser morbidity.47 This is placed just below the iliac crest. This hides the scar under
most notable in the reduced incidence of persistent post- the waistband of most bathing suits.
craniotomy headaches, which are quite frequent following As previously mentioned, the TL approach provides only
the RS approach.44 Several factors may contribute to this limited exposure of the lower portion of the CPA, particu-
including the minimization of brain retraction, the reduced larly when the lower sigmoid sinus course is relatively high.
level of trauma to the suboccipital musculature, and the As a general rule, we prefer not to use this opening for nona-
ability to complete all drilling before the dura is opened. In coustic tumors that extend inferiorly medial to the jugular
the RL approach to acoustic tumors, the IAC must be foramen or toward the foramen magnum unless a concurrent
drilled open intradurally, a maneuver that inevitably leads transjugular exposure is planned.
to some soilage of the posterior fossa arachnoid with bone When the facial nerve takes an acute anterior angulation
dust and may contribute to postoperative aseptic meningitis. at the porus acusticus, the course of the displaced nerve is
Although the literature is quite variable on its relative inci- less well seen with the TL approach than with the RS
dence, in our experience CSF leak is equally common approach due to its more posterior angle of view. It is
among the various approaches to the CPA.49,80–83 Persistent possible to overcome this obliquity by mobilizing the
CSF leak that follows an RS craniotomy is often repaired nerve into the operative field, but we feel that dissection
through a transtemporal approach.84 of the nerve-tumor interface is less traumatic when the
A second advantage of the TL approach becomes apparent nerve is left in situ throughout its cisternal course.
when the facial nerve has become disrupted. To avoid a Fortunately, the geometry involved is seldom troublesome
nerve graft, it is possible to mobilize the nerve out of its and, in our experience, FN functional outcome in acoustic
redundant course through the temporal bone, thereby gain- neuroma surgery is the same following either the TL or
ing between 10 to 15 mm of length. This “mastoid-meatal” RS approach.
694 SURGICAL NEUROTOLOGY

Middle Fossa Craniotomies

The MF or subtemporal approach is actually a versatile
family of procedures carried out beneath the temporal lobe
that may provide access to a number of anatomic regions.
Historically, the earliest subtemporal procedures were
performed to expose the trigeminal nerve in the treatment
of tic douloureux. Over the past 20 years, the MF proce-
dure has gained widespread application for exposure of the
IAC and CPA in the management of small vestibular
schwannomas, facial nerve lesions, and in the performance
of selective vestibular neurectomy. MF procedures are also
employed for other lesions in the temporal floor. Lateral
to the otic capsule, the middle ear and mastoid may be
opened from above to continue facial nerve exposure
beyond the IAC, to gain exposure to tumors of this area, or
to repair encephaloceles or CSF leaks through the tegmen.
Medial to the otic capsule, lesions in the petrous apex and
the lateral aspect of the clivus (e.g., tumors,
cholesteatomas, cysts) may be addressed. Removal of the
petrous apex permits exposure of the intrapetrous portion
of the internal carotid artery. Approaches to the far ante-
Figure 43-35. Schematic view of the internal auditory canal from above in
rior reaches of the middle fossa floor, particularly cav- the middle fossa approach.
ernous sinus procedures, are often accompanied by
downfracture of the zygomatic arch to minimize the need
for temporal lobe retraction. the overhang of the transverse crest.86 In addition, the
An MF opening may also serve as a route to the posterior entry of the facial nerve into the labyrinthine segment
fossa. The extended MF approach widens the IAC exposure direct visualization of the anterior portion of the fundus.
and affords a limited view of the CPA. Removal of the When used in facial nerve lesions, the bony opening in
portion of the petrous pyramid between the IAC and the the temporal floor is often extended to expose the facial
Meckel’s cave creates an opening into the anterior, superior nerve distal from the IAC into its labyrinthine segment
CPA and provides a small exposure of the ventral aspect of and, by opening the tegmen tympani, in its horizontal
the upper pons. Finally, for tumors involving both fossae, an course as well.
MF approach may be combined with any of the posterior Indications: A major indication for the MF approach to
fossa craniotomies (retrosigmoid, retrolabyrinthine, the IAC is tumors, particularly intracanalicular acoustic
translabyrinthine, transcochlear) as circumstances warrant. neuroma, but also facial nerve schwannomas, meningiomas,
For details of these procedures, see section “Combined
Craniotomy of the Middle and Posterior Cranial Fossae.”

Middle Fossa Approach to the Internal

Auditory Canal
Surgical Anatomy
The MF approach to the IAC involves a small temporal
craniotomy followed by extradural retraction of the tempo-
ral lobe to expose the temporal floor (Figs. 43-35 and
43-36).85 The superior aspect of the IAC is opened
with a rotating burr. The MF approach is capable of expos-
ing the entire IAC from its fundus laterally to the porus
acusticus medially without violating any portion of the
inner ear. Among approaches to the IAC, it is unique in
this capability. To expose any portion of the IAC via the
direct lateral (translabyrinthine) approach requires removal
of the semicircular canals with resultant deafness in the
operated ear. The posterior (retrosigmoid) approach to the
canal is capable of exposing only approximately the medial
two-thirds of the canal without exenteration of a portion of
the otic capsule. Thus, the MF approach is particularly Figure 43-36. Middle fossa approach to an intracanalicular acoustic neuroma
well suited for intracanalicular tumors where hearing con- seen in surgical view. Note that the bony troughs around the internal auditory
canal are wide medially at the porus but narrow laterally to prevent injury to
servation may be possible. However, limitations exist in the cochlea and semicircular canals. When the tumor has originated from the
exposing the fundus via the MF approach. The inferior inferior vestibular nerve, the facial nerve may lie draped on the tumor’s
compartment of the distal end of the IAC is obscured by superior surface, as depicted here.
 Surgical Neurotology: An Overview 695

and vascular tumors, among others.87,88 It has also been EAC

widely used for nonneoplastic facial nerve diseases includ- GG
ing repair of nerve injury associated with temporal bone ME
fracture and decompression of the fallopian canal in Bell’s
palsy and herpes zoster oticus.89,90 Vestibular neurectomy GSPN
may also be accomplished via the MF route, although pos-
terior fossa approaches have become more popular in SSCC
recent years.91 A proposed indication is bony decompres-
sion of the IAC, without tumor removal, in patients with MMA
bilateral acoustic neuroma in an effort to retard progres- SPS
sive hearing loss.92 IAC decompression may also be under-
taken in osseous dysplasias, such as Paget’s disease and CO
osteopetrosis, where bony stenosis results in hearing dete-
rioration or facial nerve dysfunction.
7
Technical Considerations: For exposure of the IAC, the
craniotomy should be centered over the canal. A relatively
SVN
small opening, approximately 3 × 3 cm, is sufficient. Due
to the anterior angulation of the petrous pyramid, the
opening should be placed roughly two-thirds in front of
the ear canal and one-third behind it. To minimize the
need for temporal lobe retraction, bone should be
removed flush with the temporal floor. The dura over the
anterior face of the petrous bone is elevated to the level of Figure 43-37. Middle fossa approach to the internal auditory canal seen in
the bony trough made by the superior petrosal sinus at the surgical view. The external auditory canal (EAC), middle ear (ME), cochlea
crest of the pyramid. There is usually no need to elevate (Co), and superior semicircular canal (SSCC) normally lie beneath bone but
the MF dura anteriorly toward foramen spinosum because are made visible as an aid to orientation. GG, geniculate ganglion;
this risks troublesome bleeding from the middle meningeal GSPN, greater superficial petrosal nerve; MMA, middle meningeal artery;
SPS, superior petrosal sinus; SV, superior vestibular nerve; 7, facial nerve.
artery. A specialized MF retractor is very helpful in main-
taining stable and atraumatic temporal lobe elevation.93
The temporal floor is often relatively flat and featureless.
There are two methods of identifying the plane of the Although this is unlikely to result in severe injury to the
IAC. The technique popularized by William House nerve, it does require a greater degree of manipulation dur-
involves tracing the greater superficial petrosal nerve to ing tumor removal beneath it. In the author’s experience,
the geniculate ganglion and thereby identifying the fundus this makes transient nerve dysfunction more common with
of the canal. Ugo Fisch advocates identification of the supe- the MF approach than with lateral (translabyrinthine) or
rior semicircular canal lying within the arcuate eminence and
locating the canal at a 60-degree angle to it. The author
tends to use whatever clues are most apparent to suggest
the probable location of the canal and then to drill at the
deepest point of the exposure directly toward the porus
acusticus where the probability of injury to the otic capsule
is least.94 Once the anterior and posterior extents of the
IAC dura have been defined medially, the lateral portion of
the canal is then unroofed (Figs. 43-37 and 43-38).
Following completion of the procedure (tumor removal,
neurectomy, nerve decompression, or repair), the cut air
cells are waxed and a muscle plug is placed in the IAC.
When the middle ear has been opened from above, a small SV
bone graft harvested from the thin lower edge of the IV
craniotomy flap is placed over the opening to prevent the
temporal dura from resting on the ossicular heads and 7
causing a conductive hearing loss.
Advantages: The primary advantage of the MF approach
to IAC lesions is the possibility of hearing conservation.95
The approach also provides access to the geniculate gan-
glion region—a site of predilection for facial nerve tumors,
injuries, and inflammations—that is unequaled by other
techniques.
Disadvantages: In AN, the facial nerve may lie in a
disadvantageous position, between the surgeon’s line of Figure 43-38. Middle fossa vestibular neurectomy. After opening the internal
sight and the tumor, particularly when the tumor has origi- auditory canal, a segment of both the superior (SV) and inferior (IV)
nated from the inferior vestibular nerve (see Fig. 43-36). vestibular nerves is removed including both Scarpa’s ganglia; 7, facial nerve.
696 SURGICAL NEUROTOLOGY

posterior (retrosigmoid) exposures of intracanalicular

acoustic tumors.
As a general rule, the temporal lobe is less forgiving
of retraction than the cerebellum. Following the limited
extradural retraction necessitated by an IAC approach,
transient memory disturbances or auditory hallucinations
may occur but are seldom of clinical significance.
Dominant side retraction may result in disturbance of
speech, although this is rare in IAC surgery and generally
recovers promptly. Electroencephalogram (EEG) changes
have been reported in the early postoperative period, but
epilepsy is rare.96 Postoperative epidural hematoma may
occur and have serious consequences if not promptly rec-
ognized. Risk of this complication may be minimized by
tacking up the dura to the craniotomy flap during closure.
Compared with other approaches to the IAC, a final dis-
advantage of the MF procedure is the significantly less
cosmetically appealing head shave required.

Extended Middle Fossa Approach

to the Cerebellopontine Angle
Surgical Anatomy
Figure 43-39. Extended middle fossa approach to an acoustic neuroma with
The extended MF approach is a modification of the MF a 2-cm component in the cerebellopontine angle. To achieve greater posterior
approach to the IAC designed to increase the degree of fossa exposure, the superior petrosal sinus and the tentorium are divided.
exposure of the CPA (see Fig. 43-39).97–99 By skeletonization
of the superior semicircular canal and cochlea, the bone sur-
rounding the porus acusticus can be widely flared. Exposure medium-sized acoustic neuromas with the preservation of
of a small extracanalicular tumor component can then be hearing.
achieved by elevation of the superior petrosal sinus and ten-
torium. Increased exposure of the CPA may be realized by Disadvantages
either of two maneuvers: exenteration of the otic capsule or The main disadvantage of the extended MF approach is
division of the superior petrosal sinus and tentorial edge. that the facial nerve may lie over the superior surface of
the tumor in a position that requires it to be manipulated
Indications to a greater extent during tumor removal than with lateral
The extended MF approach to the CPA has been used (TL) or posterior (RS) techniques. At least in theory, the
increasingly in recent years. Its proponents recommend requirement for more prolonged and relatively vigorous
its use in small and medium-sized acoustic neuromas that retraction of the temporal lobe may increase the risk of
possess both an IAC and CPA component.99–101 The prac- postoperative speech and/or memory disturbance and may
tical upper limit on the use of this technique is with a contribute to the delayed development of a seizure disorder.
tumor that has significant brainstem contact (approximately Fortunately, these complications are seldom encountered.
15 to 18 mm) in the CPA component. Substantial hearing Another concern is the limited exposure of the inferior
conservation has been achieved in these larger tumors but aspect of the CPA. This may render it difficult to control
at the cost of some increased facial nerve morbidity.102 vessels, such as the AICA and PICA, which may be situated
below the tumor.
Technical Considerations
Following a standard MF opening with unroofing of the Middle Fossa-Transpetrous Apex Approach
IAC, bone anterior and posterior to the porus is exenter- to the Ventral Pons and Anterior
ated to the level of the dura of the posterior petrous face Cerebellopontine Angle
(Fig. 43-39). The posterior limit of the opening is the
superior semicircular canal. The theoretical anterior limit Surgical Anatomy
is the lateral wall of Meckel’s cave, although it is not usually The middle fossa-transpetrous apex (Kawase) approach
necessary to remove bone that far forward. A particularly employs a middle fossa opening to create a small poste-
wide mobilization of the subtemporal dura is required to rior fossa craniotomy via removal of the medial portion of
permit elevation of a broad segment of the superior petrosal the petrous pyramid and the lateral aspect of the clivus
sinus and tentorium. If division of the sinus is elected, its (Fig. 43-40). 103,104 Conceptually, it is similar to the extended
cut ends are controlled with hemoclips. middle fossa approach but instead of exposing the mid-CPA,
the target is the anterior CPA and the ventral surface of the
Advantages
pons (Fig. 43-41). The bony window in the petrous pyra-
When the otic capsule is preserved, the extended MF mid is rhomboidal. It is bounded posteriorly by the otic
approach offers the possibility of removing small and capsule and IAC, anteriorly by Meckel’s cave, inferiorly by
 Surgical Neurotology: An Overview 697

carotid from its bony canal; however, this maneuver carries

a significant morbidity and is seldom justified.
Indications
The primary indication for the middle fossa-transpetrous
apex approach are dumbbell-shaped tumors which,
although predominantly located on the middle fossa floor,
possess a small posterior fossa component.105–107 Particularly
suitable are meningiomas and trigeminal schwannomas that
traverse Meckel’s cave to involve both the middle and
posterior cranial fossae. The ideal tumor is limited to the
anterosuperior CPA and ipsilateral prepontine cistern. The
middle fossa-transpetrous apex approach has also been used
to expose aneurysms of the mid and lower basilar artery.108,109
Technical Considerations
The middle fossa-transpetrous apex approach requires a
large, anteriorly placed bone flap. Fracture and downward
displacement of the zygomatic arch flattens the angle of
view and reduces the need for temporal lobe retraction. The
petrous apex may be drilled either intra- or extradurally.
When the tumor extends anteromedially toward Meckel’s
Figure 43-40. Middle fossa-transpetrous apex (Kawase) approach to the cave and the cavernous sinus, intradural exposure is typically
ventral pons and the anterior cerebellopontine angle as viewed from above. required. During removal of the dura of the anterior petrous
By down fracture of the zygomatic arch and removal of the medial portion of
the petrous pyramid, a view of the lateral and anterior portions of the upper
face, the greater superficial petrosal nerve must be sacri-
pons is provided. ficed. Care should be taken to identify and sharply section
this nerve lest traction be placed on it during drilling, which
might injure the facial nerve at the geniculate ganglion. To
the petrous carotid artery, and superiorly by the tentorium. maximize the bony opening, the dura of the medial IAC
Posterior fossa exposure includes the pons, basilar artery, and Meckel’s cave is exposed. Caution must be observed
and cranial nerves V through VII. The posterior fossa toward the lateral end of the IAC due to the proximity of
exposure is limited inferiorly by the carotid artery in the the cochlea. The depth of petrous apex removal is dictated
base of the petrous pyramid. Enhanced inferior exposure by the most inferior extent of the tumor in the posterior
can be obtained by displacement of the intrapetrous fossa. At its maximum, the horizontal carotid artery is
skeletonized, leaving intact this eggshell of bone. By open-
ing the dura of Meckel’s cave, the entire fifth nerve can be
exposed from its brainstem origin to the foramen ovale
inferiorly and the cavernous sinus superiorly. The poste-
rior fossa exposure can be augmented, particularly in the
posterior direction, by division of the tentorium.
Advantages
The middle fossa-transpetrous apex approach provides
exposure of the ventral surface of the upper pons without
sacrificing hearing, requiring facial nerve rerouting, or
necessitating brainstem retraction, which may be needed
in either the lateral or posterior approaches to this region.
In selected tumors that involve both the middle and poste-
rior cranial fossae, this approach permits tumor resection
without the need for two separate or combined craniotomies
(see the earlier section “Approaches to Lesions Primarily
in the Cranial Base”). In addition, the middle fossa-
transpetrous apex approach, as a result of downward dis-
placement of the zygoma and the removal of the apical
petrous bone, requires substantially less temporal lobe retrac-
Figure 43-41. Middle fossa-transpetrous apex approach to the ventral pons
and the anterior cerebellopontine angle in surgical view. Following downward
tion than the classically described middle fossa-transtentorial
retraction of the zygomatic arch and temporalis muscle, the temporal lobe is approach.
elevated and the medial aspect of the petrous pyramid is removed between
the cochlea and Meckel’s cave. This affords a view (inset) of the fifth (5), Disadvantages
sixth (6), and eighth (8) nerves along with the lateral and ventral surface of
the pons and upper portion of the basilar artery. Co, cochlea; V3, third The primary disadvantage of the middle fossa-transpetrous
division of the trigenical nerve at foramen ovale. apex approach is its limited exposure of the posterior
698 SURGICAL NEUROTOLOGY

fossa contents. The abducens nerve is particularly vulnera-

ble where it enters Dorello’s canal just deep to the poste-
rior margin of the craniotomy. As a general rule, this
approach is suitable for tumors that neither extend inferior
to the nerve VII–VIII complex nor spread significantly
across the midline. The only nerve inherently sacrificed in
the process of the craniotomy, the greater superficial pet-
rosal nerve, may result in a dry eye, although this is seldom
troublesome in the absence of facial palsy. In addition,
prolonged temporal lobe retraction may be required with
its attendant risk of parenchymal hemorrhage or edema.

Intracranial Aspect of Jugular Foramen

The intracranial aspect of the jugular foramen (JF) can be
viewed via the retrosigmoid approach (Figs. 43-42 and
43-43). This exposure is sufficient for tumors that are wholly
intracranial or possess only small portions in the neural com-
partment of the JF. Most tumors (e.g., glomus, meningioma,
lower cranial nerve schwannoma) that possess a substantial
intracranial component also extensively involve the skull
base. However, some meningiomas arising from the lower A
clivus, sigmoid sinus, or posterior petrous ridge spread along
the dural surface and prolapse to a limited degree into the
funnel-shaped dural envelope surrounding the lower cranial
nerve entry into the skull base. Analogous to opening of the
posterior aspect of the IAC, the neural compartment of
the JF may be exposed to a degree working from behind via
the RS approach.
Most JF tumors with an intracranial component require
a transjugular craniotomy.110,111 This technique differs
from the presigmoid (transpetrosal) and retrosigmoid
approaches in that, taking advantage of the fact that these
tumors typically occlude venous flow within the jugular
foramen, it involves resection of the sigmoid sinus (Figs.
43-44 through 43-46). This affords an augmented view of
the lower CPA in the region of the intracranial component
of the JF tumors. Transjugular craniotomy permits single-
stage resection of virtually all large JF tumors. On rare
occasions, a two-stage procedure may be selected when a
very large neck component exists. Extensive neck dissec-
tion, when combined with a sizable cranial base defect, B
Figure 43-43. Limited access to the neural compartment of the jugular
foramen can be obtained by drilling open the intracranial aspect of foramen
during retrosigmoid craniotomy (A). Tumor, most commonly meningioma, is
microdissected from the lower cranial nerves (B).
IAC

presents a high risk of pseudomeningocele formation.

To discourage CSF leakage into the extracranial resection
cavity, tissue planes should be opened to the least possible
degree (e.g., no skin flaps are elevated) and meticulous
hemostasis should be obtained to avoid the need for place-
ment of a drain, which would only encourage flow across
the dural defect. When staging of a glomus tumor is
elected, it is essential to resect the neck component
HC first because this serves to devascularize the intracranial
aspect.
Figure 43-42. A saggital section through the midline illustrating the jugular Technical features of a transjugular craniotomy include
foramen and its osseous relations from the medial perspective. Tumors of
the jugular foramen are often dumbbell shaped, possessing both an
wide pre- and postsigmoid dural exposure. The sigmoid
intra- and an extracranial component connected by a segment within the sinus is ligated just below the transverse-sigmoid junction,
cranial base. HC, hypoglossal canal; IAC, internal auditory canal. the jugular view is tied off in the upper neck, and the petrosal
 Surgical Neurotology: An Overview 699

VA
XI
X
V IX
Ch
Cb

VII, VIII

Figure 43-44. Transjugular craniotomy illustrating the degree of intracranial Figure 43-46. Exposure of a jugular foramen schwannoma after transection
exposure obtained following resection of the sigmoid-jugular system and and removal of the sigmoid sinus and jugular bulb. Note that the fan of fibers
wide opening of the posterior fossa dura. Note the multiple small rootlets of comprising the ninth, tenth, and eleventh nerves takes an oblique course
the lower cranial nerves emanating from the lateral surface of the medulla. between their horizontally oriented intracranial roots and their vertically
In contrast to extracranial procedures, the sigmoid sinus is ligated proximally aligned peripheral trunks. In this case, the residual nerve fibers are
rather than packed extraluminal. Cb, cerebellum; Ch, choroid; F, flocculus; positioned on the medial surface of the tumor.
VA, vertebral artery; 5, trigeminal nerve; 7, facial nerve; 8, audiovestibular
nerve; 9, glossopharyngeal nerve; 10, vagus nerve; 11, accessory nerve.

augmented anterior exposure of the apical petrous bone

sinuses are controlled with Surgicel in the medial aspect of and carotid artery is needed. In our experience, rerouting
the jugular bulb. In most cases the ear canal and inner ear of the facial nerve is seldom required even with extensive
can be left in situ. Hearing can often be conserved in JF intracranial disease.
tumors even with large intracranial components. The ear The relationship of the lower cranial nerves to the tumor
canal is removed and the meatus sewn shut in only two penetrating the jugular foramen is the key determinant in
circumstances: when extensive erosion of the middle ear whether the nerves can be preserved.110,112 When the
and canal wall precludes their preservation and when nerves lack function preoperatively, they are resected with
the tumor. When at least partial function remains, a diligent
effort at their microsurgical preservation should be under-
taken with neurophysiologic guidance. Meningiomas that
arise laterally and glomus tumors are most favorable for
neural preservation. Meningiomas that arise off the lower
clivus and penetrate the neural compartment from its
medial aspect present themselves medial to the fan of
lower nerve roots and neural preservation is technically
challenging. Some larger glomus tumors come to lie
medial to the lower nerve through deep penetration along
the petrosal sinuses.

The Ventral Surface of the Brainstem

Combined Craniotomy of the Middle
and Posterior Cranial Fossae
Tumors that possess sizable components both above and
below the tentorium represent a particularly arduous sur-
gical endeavor.113 The majority are intimately related not
only to the pons but to the midbrain as well. The most
obvious approach to such lesions is to perform separate
craniotomies of both the middle and posterior cranial fossae,
either at one sitting or in two stages. A combination of
Figure 43-45. Transjugular craniotomy without rerouting of the facial nerve.
retrosigmoid and middle fossa craniotomies has been
Leaving the facial nerve in situ is not an impediment to exposure to the employed by some surgeons, but this approach has several
intracranial region adjacent to the jugular foramen. distinct disadvantages (Fig. 43-47).114,115 Foremost among
700 SURGICAL NEUROTOLOGY

4
P
MB
5

Figure 43-48. Division of the tentorium in the combined-approach

craniotomy. Care must be exercised when dividing the free margin to avoid
Figure 43-47. The classical method of exposing both the posterior and injury to the fourth cranial nerve. MB, midbrain; P, pons; T, tentorium;
middle cranial fossae is by creating two separate opening: retrosigmoid and 4, trochlear nerve; 5, trigeminal nerve.
subtemporal. This disconnected approach, with the surgical exposures
separated by the transverse sinus superficially and the tentorium in the
depth, necessitates a much greater degree of brain retraction than
contemporary approaches to tumors that involve both fossae. the brainstem. The tentorium cerebelli, a collagenous
dural membrane, separates the posterior and middle cranial
fossae. Posteriorly, the tentorium attaches to the transverse
sinuses and the internal occipital protuberance.
these are the need for significant retraction of both cerebel- Anterolaterally, it attaches to the crest of the petrous ridge
lum and temporal lobe and the tendency to place traction on where it intermingles with the dura surrounding the superior
the vein of Labbé. In addition, exposure ventral to the petrosal sinus. Anteromedially, the tentorium terminates
pons is quite limited due to the posterior angulation in a free edge dorsal to the midbrain. The space between
afforded by the retrosigmoid infratentorial opening. the free edge of the tentorium and the brainstem is known
The degree of brain retraction required to gain access to
both the supra- and infratentorial regions simultaneously
may be substantially reduced by partial or total petrosec-
tomy. The cranial base defect created by removal of the
temporal bone provides a cavity through which the surgeon
can visualize both above and below the tentorium with
relatively little brain retraction. The amount of petrous
bone removed depends on a number of factors—the status VL
of hearing, the size and location of the tumor, and the
severity of brainstem compression, among others. The
most frequently employed of the transtemporal-middle
fossa procedures is the retrolabyrinthine-middle fossa
approach, which offers the potential of maintaining hearing
(Fig. 43-48 through 43-51).56,54,116–126 A minor enhancement
of exposure with the retrolabyrinthine approach may be
obtained through partial labyrinthectomy.127 Combinations
of translabyrinthine or transcochlear openings with the
middle fossa approach may also be used under certain
circumstances.128,129 VL

Surgical Anatomy
The anatomy of the various middle and posterior fossae
craniotomies will not be repeated here, but certain
anatomic features relevant to interconnecting the middle Figure 43-49. Combining a retrolabyrinthine posterior fossa craniotomy with
a middle fossa craniotomy and splitting the tentorium provides exposure of
and posterior fossae will be reviewed. Tumors that traverse transtentorial tumors that involve the lateral aspect of the pons and
the tentorial plane usually pass through the tentorial midbrain. Retraction of the posterior portion of the temporal lobe should be
notch, Meckel’s cave, or the space between the clivus and gentle to prevent injury to the vein of Labbé (VL).
 Surgical Neurotology: An Overview 701

Certain tumors, particularly meningiomas and trigemi-

nal schwannomas, involve both the middle and posterior
fossae by traversing Meckel’s cave. Meckel’s cave is a dural
reflection that houses the trigeminal nerve and its semilunar
ganglion. It overlies the medial aspect of the petrous apex
4 and is bounded superiorly by the petroclival ligament. Its
superomedial border is related to the abducens nerve in its
course through Dorello’s canal.
Combined transtemporal-middle fossa procedures usually
expose the pons, midbrain, and cranial nerves IV through
VIII. Cranial nerves II, III, and IX through XI may be read-
ily exposed when required. The amount of pontine exposure
depends on the extent of petrous bone resection. With the
retrolabyrinthine approach, only the lateral aspect of pons is
visible; with the transcochlear approach, the ventral aspect
of the brainstem can be visualized as well.
Indications
Tumors that involve both posterior and middle fossae may
Figure 43-50. Combined approach craniotomy to a meningioma involving be divided into two broad classes: those that require a wide
the posterior petrous pyramid, the clivus, Meckel’s cave, and the cavernous
sinus. 4, trochlear nerve. exposure of both fossae and those that require a large
exposure of one fossa and only a limited opening of the
other. Among tumors that require wide exposure of both
as the tentorial notch, or incisura. The trochlear nerve closely fossae, meningioma is by far most common. In the spectrum
parallels the free edge of the tentorium and is frequently at of technical difficulty, meningiomas that arise from the
risk in transtentorial procedures. Immediately beneath this tentorium are usually more readily approached due to
edge is the petrosal vein (Dandy’s vein) and the superior their lateral location. At the other end of the difficulty
cerebellar artery usually lies just above it. scale are extensive clival meningiomas, which are particularly
challenging because of their deep midline location as well as
their intimate relationship with the vertebrobasilar system.
Tumors that predominantly lie in either the middle or
posterior cranial fossa and possess only a small extension
into the other fossa may occasionally be managed by modifi-
cation of conventional middle or posterior fossa craniotomy
technique. For example, during transtemporal approaches to
the CPA, the tentorium may be elevated or even divided to
enhance superior exposure for some distance above the ten-
torium into the incisura. Similarly, tumors that traverse
TL Meckel’s cave are often asymmetrically bilobed with a
predominant component in one fossa. Tumors largely on
the temporal side with a small posterior fossa component
T
9 T can be approached via a middle fossa-transpetrous apex
approach. Conversely, when the posterior fossa component
7
predominates, a limited opening through Meckel’s cave
may be created during posterior fossa craniotomy. In
8 either the retrosigmoid or translabyrinthine approaches,
Cb 4 this may be accomplished by drilling away a rhomboidal
5 portion of the petrous apex between the IAC and Meckel’s
P
MB
cave. This maneuver is analogous to that used in the middle
fossa-transpetrous apex approach, but it is done in reverse,
from posterior to anterior.
Technical Considerations
Figure 43-51. The exposure obtained from a left retrolabyrinthine-middle
fossa approach to a clival tumor. This technique is indicated when the lesion The details of the various middle fossa and transtemporal
has an intimate relationship with the anterior surface of the brainstem and approaches (retrolabyrinthine, translabyrinthine, and
vertebrobasilar system. It is also capable of addressing a tumor component
that lies posterior to the internal carotid artery, an area not accessible via the transcochlear) will not be repeated here and the reader is
anterior approaches. The tentorium has been incised to provide exposure of directed to the relevant section of this chapter. A special
both posterior and middle cranial fossae through gentle retraction of the consideration of the combined approaches is the need to
cerebellum and temporal lobe. The tumor can be seen prolapsing posteriorly divide the tentorium. The superior petrosal sinus can usually
from the clivus with indentation of the brainstem and splaying of the cranial
nerves. Cb, Cerebellum; MB, midbrain; P, pons; T, tumor; TL, temporal lobe;
be easily controlled by application of hemoclips. Care must
9, glossopharyngeal nerve; 4, trochlear nerve; 5 trigeminal nerve; 7, facial be exercised when dividing the free edge of the tentorium
nerve; 8, audiovestibular nerve. to prevent injury to the trochlear nerve.
702 SURGICAL NEUROTOLOGY

The cortical veins on the inferior aspect of the temporal There are actually three varieties of “transcochlear”
lobe merit special mention because they are a potential approaches: (1) the original TC approach described by
cause of significant morbidity during extensive subtemporal House in 1976 to approach the anterior CPA, (2) the
procedures.130 The vein of Labbé constitutes the major extended TC approach to the prepontine region and clivus,
superficial venous drainage of the posterior temporal and and (3) the transotic approach described by Fisch to remove
inferior parietal lobes (Fig. 43-7). Interruption of Labbé’s small acoustic neuromas.132–135 The term transcochlear
vein on the dominant side frequently induces aphasia. The has been adopted to describe an extension of the
left side is dominant in approximately 95% of individuals— translabyrinthine approach that entails an exenteration of the
100% of right-handed and 80% of left-handed persons. entire inner ear, not just the semicircular canals. It should be
Less common, massive swelling may occur followed by noted that many TC operations involve a great deal more
uncal herniation and ultimately death due to brainstem than mere removal of the cochlea and may be more aptly
herniation. Labbé’s vein is at greatest risk posteriorly, near termed transpetrosal or even petroclival craniotomies.
its entry to the transverse sinus. Retraction of the posterior Intracranial structures that can be exposed by the classical
portion of the temporal lobe must be performed gently, TC approach include the entire lateral aspect of the pons
lest traction be placed on this vein, which tears quite easily. and upper medulla, cranial nerves V through XI, as well as
Since prolonged retraction of the temporal lobe may the midbasilar artery. Its posterior fossa exposure is exten-
induce thrombosis of Labbé’s vein, it is wise to release sive except inferiorly where it is limited in the area of the
retraction periodically for short periods during lengthy jugular foramen and foramen magnum. The degree to
procedures and to use the minimal degree of retraction which the neural compartment of the jugular foramen is
needed to provide adequate surgical exposure. To reduce visible depends on the height of the jugular bulb.
traction placed on the vein of Labbé during combined Modifications to the TC approach have been described
procedures, Spetzler and Daspit advocate division of the which, in addition to the exposure provided by the standard
sigmoid sinus (when the contralateral sinus is patent) distal TC approach, permit visualization of the anterior aspect of
to the takeoff of the superior petrosal sinus.121,131 This the pons, both sixth nerves, and improves visualization of
permits the lateral sinus, along with the entry of the vein the basilar artery and vertebrobasilar junction.133,136 The
of Labbé, to be retracted superiorly along with the transotic approach of Fisch is the most limited of the
tentorium. three, designed to expose only the IAC and mid-CPA.132
Advantages Indications
Combining a posterior and middle fossa exposure into a The primary indication for the TC approach are CPA
single craniotomy around and/or through the temporal tumors such as meningiomas, which penetrate the petrous
bone has a number of advantages. First and foremost, it apex medial to the IAC. Lesions that arise in the apex
reduces the amount of brain retraction needed to expose (e.g., chondrosarcoma, chordoma) can also be approached
complex lesions adjacent to the brainstem. Second, it in this manner particularly when they possess substantial
typically requires only a single-stage procedure where two intradural components. For tumors limited to the upper
stages might otherwise have been needed. Finally, combined aspect of the prepontine space that do not encase the basilar
transbasal craniotomy often permits a greater degree of artery, the subtemporal transpetrosal approach is occasion-
tumor resection than could be achieved by separate retrosig- ally a viable alternative. An additional indication for the
moid and subtemporal procedures. TC approach is a large recurrent or residual acoustic
neuroma when the facial nerve has been disrupted during
Disadvantages the earlier surgery. When the audiovestibular and facial
There are few disadvantages of combined posterior and nerves are intact, every effort should be made to employ an
middle fossa craniotomy when compared with separate alternative approach that does not sacrifice these functions.
procedures. Of course, aggressive removal of the temporal In our institution, the TC approach has been seldom used
bone sacrifices hearing, but a hearing-sparing retro- in recent years because of its morbidity (deafness, facial
labyrinthine-middle fossa technique often provides sufficient nerve dysfunction), having been supplanted in most cases
exposure. Although unilateral hearing loss may be required by the combined-approach craniotomy. The TC approach
for tumors extending ventral to the brainstem, this is not an is still used in cases of preexisting facial palsy and for certain
unreasonable sacrifice in the context of these serious lesions. vascular lesions such as midbasilar artery aneurysms.
Posterior facial nerve rerouting (transcochlear-middle fossa The extended TC approach is indicated for tumors that
approach), which induces at least a temporary facial palsy, lie ventral to the brainstem, typically between the clivus
should be reserved for particularly complex tumors located and pons. The most common reason for performing an
largely in front of the pons. extended transcochlear approach is meningioma of the
clivus of petroclival region. The conventional retrosig-
moid approach to lesions that lie directly anterior to
Transcochlear Approach the pons is limited by (1) the narrow opening between
the pons and petrous pyramid when viewed from behind,
Surgical Exposure (2) cranial nerves V, VII, and VIII, which bridge across the
The transcochlear (TC) approaches are a group of three exposure and constrain working space to narrow intervals
anterosigmoid posterior fossa craniotomies which, when between these nerves, and (3) the need for vigorous retrac-
compared with the translabyrinthine approach, provide tion of the cerebellum and pons (Figs. 43-52 and 43-53).
an enhanced view of the anterior aspect of the CPA. In contrast to purely prepontine tumors, many petroclival
 Surgical Neurotology: An Overview 703

CA
ET

Figure 43-52. Transcochlear approach to a prepontine tumor seen

Figure 43-53. Transcochlear approach to a prepontine tumor seen
schematically in axial view. The facial nerve has been fully rerouted from the
schematically in axial view (a) and in surgical perspective (b) (left side). By
brainstem to the stylomastoid foramen and the external auditory canal, as
rerouting the facial nerve and exenterating the entire otic capsule, petrous
well as both middle and inner ear have been removed. The eustachian tube
apex, and lateral aspect of the clivus, an unobstructed view is obtained of the
(ET) is occluded. The intrapetrous carotid (CA) is the anterior limit of the
ventral aspect of the pons. Cb, cerebellum; Ch, choroid; ET, eustachian tube;
exposure.
Fl, flocculus; JV, jugular vein; SPS, superior petrosal sinus; SS, sigmoid
sinus; TS, transverse sinus; 5, trigeminal nerve; 6, abducens nerves;
7, posteriorly rerouted facial nerve; 8, transected audiovestibular nerve.

lesions can be removed successfully via the retrosigmoid

approach. Such lesions displace the brainstem toward the
opposite side, thereby opening the choke point between approach both of these structures are removed and the
the pons and petrous bone. This geometric arrangement external auditory meatus is closed in a fashion that is
can be appreciated on preoperative MRI scans. The addi- watertight to resist CSF pressure. Extended TC proce-
tional morbidity of the extended TC approach (unilateral dures remove the entire apical petrous bone and often the
hearing loss, transient facial palsy) is justified by the direct lateral aspect of the clivus as well. The inferior limits
and unencumbered view provided of the anterior and lateral of exposure inferiorly are the jugular bulb and intrapetrous
pontine surface. In these life-threatening lesions, direct portion of the carotid artery. In both the classical and
visualization of the tumor-brainstem and tumor-basilar extended TC approaches the operative defect is obliter-
artery interface is critical to achieve adequate tumor ated with abdominal fat. In the extended TC approach
resection and limit the risk of pontine infarction. The the eustachian tube is obliterated to prevent CSF leakage,
extended TC approach also provides a more favorable typically with bone wax followed by a muscle plug.
angle for the identification and preservation of the The transotic approach differs substantially for the TL
abducens nerve. and other TC approaches in that the sigmoid sinus is not
decompressed and only a limited posterior fossa opening is
Technical Considerations
created. As in the extended TC approach, the ear canal and
The initial stages of the TC approaches are identical to middle ear are completely removed, the meatus sewn shut,
those of the TL approach. In addition, both of the TC and and the eustachian tube obliterated. The transotic technique
extended TC approaches involve complete exenteration of is the only version of the TC approach that leaves the
the inner ear (cochlear and semicircular canals) as well as a facial nerve in situ.
posterior rerouting of the facial nerve. The facial nerve is
elevated from its canal over its entire course from the sty- Advantages
lomastoid foramen to the porus acusticus. It is then rotated The TC approaches, especially the extended TC approach,
posteriorly and inferiorly on the cerebellar hemisphere and provides access to tumors anterior to the pons that would, in
posterior fossa dura. This removes the major impediment many cases, otherwise be considered inoperable. Often, the
to anterior exposure in a transtemporal craniotomy. These ventral surface of the pons can be visualized without the
maneuvers permit opening of the posterior fossa dura to need for brain retraction.
extend substantially more anteriorly and medially than The transotic approach has been recommended by its
with the TL approach. inventor as a means of approaching small acoustic neuromas
In the classical TC opening the external auditory canal without brain retraction while minimizing the risk of CSF
and middle ear are left intact, but in the extended TC leakage.
704 SURGICAL NEUROTOLOGY

Disadvantages
As the cochlea is removed during the craniotomy, deafness in
the operated ear is inevitable. In addition, posterior rerout-
ing of the facial nerve usually results in a transient total facial
palsy. Recovery generally occurs over 6 to 12 months but
may be incomplete with a degree of asymmetry and synkine-
sis. Posterior rerouting requires sacrifice of the chorda tym-
pani and greater superficial petrosal nerves, which results in
minor diminution in taste and an ipsilateral dry eye. In con-
trast to posterior rerouting for the TC approach, anterior
rerouting of the facial nerve to expose the jugular foramen
region often leaves facial function intact, and when tran-
siently impaired, it usually returns to normal.

Meckel’s Cave
Figure 43-55. Trigeminal schwannoma with a predominant posterior fossa
The operative approach to Meckel’s cave depends on component is approached via a retrosigmoid posterior fossa craniotomy in
whether the tumor is largely in the middle fossa, posterior which Meckel’s cave is opened from behind.
fossa, or bilobed with substantial components in both
fossae5,137 (Figs. 43-54 through 43-56). Analogous to problems, approaches to anteriorly placed intradural
opening of the IAC during the RS approach, Meckel’s cave lesions may benefit from the skills of a neurotologist who
may also be exposed to a degree working from behind and is familiar with the posterolateral skull base. Conventional
below. By removing the bone of the petrous apex between FM approaches involve removal of the posterior aspect of
the IAC and tentorium, the posterior and inferior aspect of the osseous ring combined with suboccipital craniotomy
Meckel’s cave and the trigeminal ganglion within it can be and laminectomy of one or more cervical vertebra.
exposed. This maneuver is particularly helpful in the However, this opening affords negligible exposure of the
removal of petroclival meningiomas that penetrate Meckel’s ventral aspect of the medulla and upper cervical spinal cord.
cave as well as in trigeminal schwannomas that possess only A transoral route has long been used successfully for anteri-
a small subtemporal component. The rhomboidal bony orly placed extradural lesions (e.g., odontoid fractures,
opening created in opening Meckel’s cave from behind is intraosseous tumors). The problem with such exposures
identical to that exenterated from above during the for intradural lesions is the need to create a large and dif-
subtemporal-transpetrosal (Kawase) approach. Meckel’s ficult-to-reconstruct opening between the pharynx and the
cave tumor with substantial components in both fossae are subarachnoid space with resultant high risk of CSF leakage
approached via a combined retrolabyrinthine-subtemporal and infection.42 An additional problem with the midline
craniotomy138–140 (Fig. 43-57). transoral approaches is its limited ability to deal with lat-
eral tumor extensions.141,142 Anterior transcervical
The Craniovertebral Junction approaches that traverse the clivus have also been
proposed.143 These limitations with anterior and posterior
Surgical Anatomy
Although most posteriorly placed tumors that involve the
foramen magnum (FM) region are purely neurosurgical

Figure 43-56. A bilobed trigeminal schwannoma with significant components

in both the posterior and middle fossae is approach via a combined-approach
Figure 43-54. Trigeminal schwannoma with a predominant middle fossa craniotomy (retrolabyrinthine-subtemporal) made confluent by division of
component is approached via a subtemporal transpetrous apex approach. the tentorium.
 Surgical Neurotology: An Overview 705

HC

Figure 43-57. Operative view of a combined-approach craniotomy to a

bilobed trigeminal schwannoma. Figure 43-58. Far lateral approach to the foramen magnum. Superior
perspective of the cranial base illustrating the extent of osseous removal.

approaches lead to the development of far lateral

approaches to the craniovertebral junction. remaining suboccipital convexity is removed to the level of
The lateral approach to the FM provides exposure of the the foramen magnum ring. The attachments of the suboc-
lateral aspect of the pons, medulla, and upper cervical spinal cipital musculature can be liberated rapidly with electro-
cord.144–150 The space ventral to the brainstem and spine is cautery. As the FM is approached, caution must be
also brought into view to a variable degree depending on exercised while dividing muscles and ligaments not to stray
both the aggressiveness of bony removal (particularly the from the plane of the cranial base to prevent injury to the
extent of condylectomy) and the degree to which the tumor vertebral artery coursing over the arch of the atlas.
has posteriorly displaced these structures. Cranial nerves IX Extradural elevation of the cerebellum opens the narrow
through XII and the upper cervical nerve roots are in the cleft at the lateral aspect of the craniovertebral junction
surgical field. The approach is readily combined with a wide and permits orderly removal of bone using a rotating burr.
posterior fossa craniotomy with exposure of cranial nerves V As the last portion off the FM ring is removed, a diamond
through VIII in the cerebellopontine angle. burr is used to prevent injury to the marginal sinus.

Indications
C
The primary indication for the far lateral approach to the
JF
FM is anteriorly situated meningiomas that straddle the
craniovertebral junction.151,152 It may also be useful in a FN
variety of other benign and low-grade malignant tumors
that affect this region. A potential role in the management EC
of aneurysms of the lower vertebral artery has also been
proposed.153

Technical Considerations
The lateral approach to the FM begins with removal of the
suboccipital convexity and laminectomy of the upper cer-
vical vertebra as required for cervical extension of the
tumor. In preparation for removal of the lateral aspect of
the FM, the ring bone is removed up to the sigmoid sinus,
the posterior margin of which is exposed throughout its
cranial base course all the way to the jugular foramen
(Figs. 43-58 through 43-60). To prevent injury to the
vertical segment of the facial nerve in the mastoid, which Figure 43-59. Far lateral approach to the foramen magnum. Inferior
perspective of the cranial base illustrating the extent of osseous removal.
lies just superficial to the jugular bulb, mastoidectomy is Note the direct lateral angle of view achieved through partial removal of the
performed with identification of the fallopian canal. After occipital condyle. C, occipital condyle; JF, jugular foramen; FN, facial nerve
removal of bone behind the entire sigmoid course, the at stylomastoid foramen; EC, ear canal.
706 SURGICAL NEUROTOLOGY

transoral approaches, the lateral exposure of FM eliminates

the need for traversing bacterially contaminated regions and
has a lower potential for CSF leak. Exposure of both the
intra- and extracranial portions of the vertebral artery
reduces the risk of vascular injury and affords an opportunity
to establish vascular control in the event the vessel is injured.

Disadvantages
The tumor must be removed through a veil of closely
spaced fibers of the ninth, tenth, eleventh, and twelfth
cranial nerves. Often, some of these must be sacrificed;
others may be temporally dysfunctional due to the effects
of microsurgical manipulation. Postoperative aspiration
may require a temporary tracheotomy. Our policy is to per-
form a tracheotomy at the time of craniotomy when fibers
of both the ninth and tenth nerves are taken. Otherwise,
the patient is observed in the intensive care unit for several
days and feedings begun if a cine barium swallow does not
indicate a tendency to aspirate. Even with pronounced
postoperative aspiration, the patient’s swallowing ability
gradually recovers over several weeks. Augmentation of
the paralyzed vocal cord (e.g., Teflon injection) is often
Figure 43-60. Far lateral approach to the foramen magnum. The osseous beneficial.
opening involves retrosigmoid craniotomy, upper cervical laminectomy, and Excessive removal of occipital condyle may theoretically
mastoidectomy to permit tracing of the inferior aspect of the sigmoid sinus lead to craniovertebral instability or torticollis, although
to the jugular bulb without risking injury to the descending facial nerve. this has not been our experience to date. Reconstruction of
Exposure of the ventral aspect of the pons, medulla, and cervical spine is
created through the intervals between the lower cranial nerves (IX–XII) and
the condyle with a bone graft may reduce this risk.
the upper cervical roots. The view of the brainstem is obscured, in this
illustration, by the presence of a lower clival meningioma. Vertebrobasilar Lesions
Cranial base approaches are sometimes used in vascular
As removal of the ring proceeds anteriorly, it broadens to
lesions of the vertebrobasilar system. The subtemporal-
form the occipital condyle. A variable portion of the occip-
transapical approach was first described by Kawase for the
ital condyle is removed depending on the location of the
exposure of basilar tip aneurysms.155,156 Rare aneurysms of
tumor. In the process of removing the condyle, the posterior
the horizontal segment of the intrapetrous carotid artery
condylar vein is encountered. This often impressively
may all be exposed subtemporally. Aneurysms of the mid-
large branch, which communicates with the jugular bulb,
basilar artery are among the most challenging of intracranial
is occluded with bone wax or Surgicel. After dural incision
vascular lesions (Figs. 43-61 and 43-62). In contrast to
the tumor can be seen ventral to the medulla and spinal
most prepontine tumors, the brainstem has neither been
cord through the overlying lower cranial nerves IX
posteriorly displaced nor rotated to facilitate exposure of
through XII and the upper cervical roots. Tumor removal
its ventral aspect. Exposure of midbasilar artery aneurysm
is impeded somewhat by the interposition of these nerves
is one of the few instances in which we still recommend
so the surgeon must either work through the narrow inter-
the classical transcochlear approach with complete rerout-
vals between nerve fibers or sacrifice some of them. The
ing of the facial nerve and sacrifice of hearing.157 A lateral,
spinal portion of the accessory nerve is at particular jeopardy.
transcondylar approach to foramen magnum is often helpful
We have found that electrophysiologic monitoring of the
in the exposure of aneurysms of the vertebrobasilar
lower cranial nerves provides the surgeon useful information
junction and intracranial segment of the vertebral artery.
while dissecting around these nerves.154
Intraparenchymal vascular malformations of the brain-
Anterior lesions at the FM are typically intimately
stem are sometimes best approached via the lateral
related to the vertebral artery and vertebrobasilar junction.
perspective afforded by the transtemporal approach.
Exposure of the vertebral artery from its emergence out of
Exophytic brainstem tumors that involve the CPA can also
foramen transversarium across the atlas to its dural pene-
be approached transpetrosally.158
tration and ultimately to its junction with the basilar artery
is an essential part of this procedure. Particular care must
be exercised in liberating the dural cuff that surrounds the
vessel during its intracranial penetration. RECONSTRUCTION
OF THE CRANIAL BASE
Advantages
Closure of Defects
The primary advantage of the far lateral approach is its abil-
ity to expose inaccessible lesions ventral to the brainstem The workhorse for closing skull base defects (see also
while minimizing brain retraction. When compared with Chapter 59) is free adipose tissue harvesting from the
 Surgical Neurotology: An Overview 707

Figure 43-63. Obliteration of a translabyrinthine defect with overlapping

strips of abdominal adipose tissue.
Figure 43-61. Schematic axial view of a transcochlear approach to a
midbasilar artery aneurysm.

abdomen of iliac crest region (Fig. 43-63). For more Prevention of Cerebrospinal
extensive defects, particularly to repair the temporal floor Fluid Leakage
in encephalocoele, a temporalis muscle rotational flap is Prevention of CSF leakage is a central theme in neuroto-
versatile (Fig. 43-64). Most often only the posterior half is logic surgery. Free adipose tissue grafts, which shrink by
needed, thus avoiding a cosmetically significant hollowing about 50% of their initial volume over time, obliterate
of the temple. This flap is also commonly used in temporal defects and foster formation of a neodura on their medial
bone resection for cancer to provide a vascularized closure aspects. Others advocate use of hydroxylapatite or other
in preparation for radiation therapy. synthetic obliterative material.159 In transtemporal cra-
In extensive defects of the cranial base, particularly niotomies, it is sometimes possible to reconstruct the dural
those associated with a cutaneous defect, a regional
myocutaneous flap is indicated (Fig. 43-65). Options often
selected include the trapezius and pectoralis flaps. When
these flaps have been compromised, a free flap, such as the
rectus abdominis, is selected.

Figure 43-64. Temporalis muscle rotation flap. Often only the posterior half
Figure 43-62. Aneurysm of the midbasilar artery viewed through a of the muscle provides sufficient coverage. Using only this portion of the
transcochlear approach. The facial nerve had been posteriorly rerouted. The muscle eliminates the need for fenestration of the zygomatic arch and
anterior limit is the carotid genu. prevents a cosmetic defect in the temporal region.
708 SURGICAL NEUROTOLOGY

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 Complications in Neurotologic Surgery
Outline

G. Robert Kletzker, MD, FACS Introduction Postoperative Stroke:

Perioperative Considerations Evaluation and Managemeilt
Robert J. Backer, MD
Vascular Management Cerebral Edema: Evaluation
John P. Leonetti, MD in Neurotologic Surgery and Management
Peter G. Smith, MD, PhD Control of Venous Bleeding Pneumocephalus
Control of Arterial Bleeding Seizures
Hemorrhage Cerebral Spinal Fluid Leak
Blood Transfusions Infections
Intracranial Complications Cranial Nerve Injuries

INTRODUCTION instruments are registered to anatomic and fiducial

reference points, after the patient is secured on the opera-
Surgeons involved in neurotologic surgery need to be tive table (Fig. 44-2). The systems provide confirmation of
acquainted with the potential complications. Hemorrhage, anatomic landmarks with visualization of the correlate
cerebral edema, arterial or venous infarction, pneumo- position on the scans, in three-plane views. Fixed boney
cephalus, cerebrospinal fluid (CSF) leak, infection, and structures of the skull base are ideally suited to stereotac-
acquired cranial nerve deficits may occur in any surgical tic navigational systems for confirmation of anatomy and
procedure in which transcranial approaches are used. the precise localization of instruments. This is advanta-
Specific compartments of the cranial cavity have varying geous for estimating distances to anticipated vital struc-
degrees of tolerance to operative alterations. For example, tures particularly in narrow dissection fields, such as
relatively small changes in the blood flow in the posterior approaches to the petrous apex and middle cranial fossa
fossa may severely alter the delicate functions of the brain- (Fig. 44-3). Because the images do not show resected
stem. 1 Removal of lesions of the skull base may leave large structures or shifts in brain, which occur with tumor
intracranial or extracranial communications, requiring removal, there is a lack of "real time" quality to the systems
complex reconstructive techniques for closure. which must be considered when utilizing stereotactic
Manipulation of cranial nerves may affect the patient's imaging. The technology is adjunctive but not a substitute
appearance and daily function. for anatomic knowledge. The time required to register the
Minimization of complications begins with a compre- patient's anatomic reference points to confirm the accu-
hensive preoperative neuroradiographic assessment, racy of positions on the computerized images and the
including high-resolution computed tomography (HRCT), expense of the systems, have been proven cost effective at
magnetic resonance imaging (MRI), and conventional or institutions which are proficient in the use of stereotactic
magnetic resonance angiography (MRA) (Fig. 44-1). navigational systems.v"
Anticipation of the limits of resection and the neurovascu- Intraoperative monitoring of the cranial nerve provides
lar structures that may be encountered during the dissec- information to the operative team on the nerves' physio-
tion are the foundation of the collaborative planning by a logic status and thus aids in neural protection. Electro-
cranial base team to achieve a safe, oncologically sound physiologic information of the functional integrity of
resection.v" Advances in technologies have made intraop- cranial nerves has become both sophisticated and stan-
erative imaging available with MRI scanners based in the dardized in neurotologic surgery. Advances in interven-
operating theater. Few institutions currently use this tional radiology have added to the safety and efficiency of
expensive equipment. More widespread use of stereotactic cranial base surgery. Balloon occlusion testing of the inter-
navigational systems is improving the safety of neuroto- nal carotid artery estimates the patient's tolerance to
logic surgery in a cost-effective manner. Commercially carotid artery ligation and competency of the circle of
available systems allow for 1 to 3 mm of accuracy in local- Willis. Selective arterial occlusion with embolization tech-
izing anatomic structures during surgery. Preoperative niques has proven beneficial in the management of
images (CT and MRI) are computer loaded, and surgical selected highly vascular lesions.
712
 Complications In Neurotologlc Surgery 713

large tumors to prevent generalized cerebral hypoperfusion

(Fig. 44-4). Communication between all members of the
surgical team enhances the well-being of the patient and
efficiency of the operation. 10,11

VASCULAR MANAGEMENT
IN NEUROTOLOGIC SURGERY
The axiom that "bleeding is the enemy of the surgeon" is
apropos in neurotologic and cranial base surgery. Control
of bleeding is paramount in preventing the obscuring of
a critical dissection and to avoiding a potential catastrophic
complication. The vascular structures encountered with
the various approaches must be anticipated and managed
in a systematic fashion. Alterations of vascular structures
by lesions can often be predicted or visualized by imaging
studies. A familiarity with anatomic variations of vascular
structures is a prerequisite for the neurotologic surgeon.I'

Control of Venous Bleeding

Approaches to the posterior fossa require management of
bleeding from one or more emissary veins that drain the
transverse and sigmoid sinuses.P'!" Bone removal of the
mastoid and occipital cortex is carried out with a rotary
drill in sweeping motions with continuous suction irriga-
tion and bone rongeurs. The blue coloration of the venous
Figure 44-1. Coronal MRI demonstrating a petroclival meningioma with sinuses can be visualized under a thin shell of intact bone,
extension into the middle and posterior cranial fossa. which can be removed with blunt dissection after bleeding
from emissary veins is controlled with bone wax. Bipolar
electrocautery can then be used to ensure coagulation of
PERIOPERATIVE CONSIDERATIONS the venous stump at its point of entry into the sigmoid
sinus. IS Troublesome bleeding may ensue if the vein is tom
A preoperative assessment of cranial nerve status is neces- at its juncture with the sinus. Small dural tears can be
sary for objective evaluation of outcomes and assists in the controlled with bipolar cautery or placement of oxidized
intraoperative monitoring of cranial nerve function during cellulose gauze (Surgicel) held in place for a short time
surgery. The anesthesiologist, surgeon, nurses, and electro- under a cotton patty. A simple or figure-of-eight 4-0 silk
physiologist coordinate patient positioning, placement of suture can also approximate the dural margins and hold
catheters, and cardiac and neural monitoring leads to maxi- the Surgicel in place over the rent vessel. Larger sinus
mize the patient's safety and operative efficiency. Priority is openings require extraluminal or intraluminal packing
given to the induction of general anesthesia so as to reduce with a large sheet of Surgicel, with care not to further rend
the risk of increasing intracranial pressure." Once adequate the vessel with excessive pressure (Fig. 44-5).
airway control is established, adjuvant arterial, intraventric-
ular, or lumbar catheters are methodically inserted. A naso-
gastric tube, urinary catheter, and pneumatic stockings
are secured prior to placement of the patient in three-point
fixation. Avoidance of excess neck flexion that may impair
venous return is particularly important if major venous struc-
tures are obliterated or resected. Troublesome intracranial
hypertension may occur if flow through the contralateral
internal jugular vein is compromised. Integrity of all elec-
trophysiologic and hemodynamic monitors is confirmed
prior to the isolation of the operative field.
Attainment of adequate exposure with minimal brain
retraction is of paramount importance in these lengthy
operations. Adjustment of intracranial pressure by removal
of cerebral spinal fluid, hyperventilation, or osmotic diure-
sis assists surgical exposure. Hypotensive anesthesia aids in
minimizing blood loss in the resection of vascular lesions,
such as meningiomas. Caution must be exercised in using Figure 44-2. Perioperative registration of stereotactic neuronavigational
hypotensive techniques during prolonged operations for system to a fixed panel on skull post and fiducial markers.
714 SURGICAL NEUROTOLOGY

Figure 44·3. Triplanar CT views of stereotactic

navigational system. Instrument trajectory seen in
bottom rightfor petrous apex cholesterol granuloma
drainage via an intralabyrintine approach.

There is additional risk of air entry into the venous system emboli. Intravascular crepitation, hypotension, tachycar-
if the head is elevated above the level of the heart; a problem dia, or a decline in end-expiratory Pco, are the signals of
more often encountered in the sitting than in the supine air emboli, which require immediate treatment. Rotation
position. In the event of the inadvertent opening of the sinus of the table to a left Trendelenburg position should isolate
heralded by the brisk outflow of deoxygenated blood, the any intravascular air into the right cardiac ventricle where
anesthesiologist should be alerted so as to monitor for air it may be aspirated through a central venous catheter.

Figure 44·5. Sigmoid sinus obliteration with intraluminal packing of

oxidized cellulose gauze. (From Leonetti JP. Smith PG. Grubb RL:
Control of bleeding in extended skull base surgery. Am J Otol11 :254-259.
Figure 44-4. Sagittal MRI of large recurrent trigeminal schwannoma. 1990.)
 Complications In Neurotologlc Surgery 715

Discontinuance of nitrous oxide, administration of 100% carried out early in the procedure. Contrary to the occlu-
oxygen, positive pressure ventilation, and vasopressors are sion of draining veins, the selected intentional ligation of
infused while digital pressure is applied over the venous arteries has a more beneficial effect when there is a time
opening. Aggressive attendance to the earliest warning lapse between arterial ligation and tumor removal. The
signs of intravascular air can prevent the major complica- longer the time between venous occlusion and tumor
tion of a stroke from air emboli.P-'? excision, however, the greater the potential for vascular
The planned resection of dural sinuses may be indicated congestion within the tumor and intraoperative bleeding.
for such lesions as glomus jugulare tumors. The sigmoid Tumors arising in the infratemporal fossa and upper
sinus may be ligated with vascular clips or 2-0 silk sutures aerodigestive tract often have contributing vascularity
passed circumferentially around the vessel through small from the external carotid system. Preoperative angiogram-
stab incisions in the dura, several millimeters from the directed embolization of arterial feeders, 1 to 2 days before
margin of the sinus. IS Maintaining the patency of the trans- resection, is often helpful in hernostasis.i" This technique
verse sinus is of paramount importance whenever the has been used most successfully with paragangliomas,
sigmoid or superior petrosal sinuses are ligated. Retrograde meningiomas, and angiofibromas (Fig. 44-6). Ligation of
thrombosis through the inferior cerebral vein of Labbe is a the arteries as close to the tumor as possible offers signifi-
potential complication of transverse sinus ligation, leading cant vascular control, particularly when embolization has
to catastrophic venous cerebral infarction.'? The petrosal not been feasible.
vein may lie in close proximity to the superior petrosal Specific vessels that require control to gain adequate
sinus; preserving this vein with transpetrosal approaches tissue mobilization for tumor exposure vary with the
minimizes the risk of brainstem venous infarction.i? approach. Care in electrocoagulation is warranted, keeping
Proximal control of the internal carotid artery and jugular in mind adjacent structures that may be injured, as hemo-
vein with placement of vessel loops in the high cervical stasis is obtained. The facial nerve, which is skeletonized
region preempts resection of tumors within the jugular or mobilized in posterior approaches, is vascularized by
bulb via infratemporal fossa approaches. This precaution- the stylomastoid artery in the vertical mastoid segment.
ary measure should be taken as well when any approach Medial to the digastric ridge, this artery causes bleeding
requires extensive dissection around the petrous portion of that requires coagulation. The facial nerve, because of its
the internal carotid artery.n,n close proximity, may suffer irreversible electrothermal
Venous bleeding from the cavernous sinus is often injury if it is included in the field of cautery. Bipolar coag-
encountered with resection of lesions, such as menin- ulation at a low setting, with concomitant irrigation will
giomas, chondrosarcomas, or chordomas, from the trigem- minimize this risk. Mobilizing the facial nerve with its
inal ganglion and petroclival regions. Venous tributaries fibrous covering and attendant artery at the stylomastoid
from the ophthalmic, cerebral, and retinal veins of the foramen allows transposition without compromising its
superior orbital fissure, as well as the sphenoparietal and vascular supply." Similarly, isolation and ligation of the
petrosal (inferior and superior) sinuses, carry highly superior occipital artery from the underlying 11th cranial
oxygenated, bright red blood that may appear arterial. nerve is preferred over unipolar coagulation to obtain
Venous bleeding in this area may also have a pulsatile hemostasis with neural preservation. Isolation of the cranial
quality, further replicating an arterial hemorrhage. nerves exciting the jugular foramen, prior to ligation of the
Controlling hemorrhage from the cavernous sinus,
requires gentle pressure on Surgicel gauze held in place
with a suction tip covered by a cotton sponge. Vital neu-
rovascular structures contained within the sinus cavity
preclude injudicious pressure to tamponade the bleeding.
Overpacking of the sinus with thrombotic gauze may
result in pressure injury to cranial nerves III through VI
or compression of the internal carotid." Once bleeding is
controlled the Surgicel is trimmed with a few millimeters
of excess gauze left over the outer surface of the torn dura,
and care is taken not to dislodge the gauze during regional
dissection. Patience and gentle technique are required of
the surgeon to control venous bleeding from the cav-
ernous sinus.

Control of Arterial Bleeding

In addition to accessing the cervical vessels for proximal
control, gaining exposure of tumor vessels via combined
approaches has become a standard practice in extended
cranial base surgery. Ligation of feeding vessels can
immensely reduce operative blood loss during tumor
removal and improve visibility during resection and thus
the safety of the procedure. Guided by the preoperative Figure 44-6. Angiogram of glomus jugulare tumor showing preoperative
angiogram, the ligation of selected arteries is planned and vascularity (left), much decreased after embolization (right).
716 SURGICAL NEUROTOLOGY

internal jugular vein, is a standard principal of neck dissec- gentle tissue handling and frequent irrigation of the carotid's
tions proven successful in protecting adjacent nerves while surface with isothermal saline. Despite these precautions,
obtaining vascular control. vasospasm may develop. The sequelae of carotid artery
Control of the internal carotid artery (lCA) is of para- vasospasm vary with the severity and duration of the
mount importance in resection of the temporal bone. The constriction. In our experience the most profound conse-
pterional and infratemporal fossa approaches are used quences occurred in the younger patients whose vascular
when the carotid must be mobilized from its petrous tonicity and reactivity were relatively hypersensitive.tv'"
encasement (Fig. 44-7). Ideally, adequate proximal and Hemodilution and hypertensive therapy, as for vasospasm
distal exposure is obtained prior to any carotid mobiliza- following subarachnoid hemorrhage, may be effective in
tion. 26 ,27 Intraluminal balloon occlusion affords distal preventing catastrophic infarction. At the earliest detec-
control in managing pathologic lesions of the petroclival tion of segmental reduction of the vessel caliber, topical
region, where complete exposure is impaired.i'v" application of 10% lidocaine, 1.5% or 3% papaverine,
Preoperative balloon occlusion testing provides invaluable and 25 mg/mL chlorpromazine have been shown to
information concerning the collateral cerebral circulation inhibit vascular smooth muscle contraction. These agents
and the patient's ability to tolerate carotid resection with- are effective spasmolytics, which may be applied to the
out suffering irreversible neurologic sequelae.'? Failure of constricting vessel to counteract the myogenic response.
the carotid occlusion trial warrants bypass grafting of the The efficacy of calcium channel blockers (e.g., nimodipine)
internal carotid artery with a vein graft if the malignant has not been proven in large-vessel spasm, although it is
histopathology dictates ICA resection.l'<" The petrous systemically administered in the management of medium-
portion of the carotid is more often not included in the caliber cerebral artery spasm.
resection, but may need to be mobilized for adequate The sequelae of prolonged vasospasm are endothelial,
exposure (Fig. 44-8).34 The caroticotympanic artery arises intimal, and vessel media injuries. Spasm unabated for as
from the posterior aspect of the ICA proximal to the genu little as 2 hours can lead to irreversible injury and throm-
at the bony-cartilaginous junction of the eustachian tube. bosis. The darkened coloration of the vessel surface in
This small-caliber vessel can bleed profusely if avulsed the region of constriction is an ominous sign of significant
during carotid mobilization. Exposure of the petrous vascular injury and impending thrombosis. Decreased vessel
carotid is performed by thinning the bone with a diamond
burr and then gently separating the "eggshell" fragments
with a freer elevator off of the adventitia. Minimal vessel
compression is accomplished with bone removal." ICA
exposure is often required during transtympanic, infra-
labyrinthine, and middle cranial fossa approaches to the
petrous apex. The cochlea, geniculate ganglion, and greater
superficial nerve are valuable landmarks in guiding the
dissection and must be identified prior to complete bone
excavation of the petrous canal. Greater exposure is required
for ICA mobilization, which also necessitates extremely
gentle handling of the artery to prevent kinking or the
potentially disastrous complication of vasospasm.I'<"
Spasm of the carotid can occur with excess mechanical
manipulation, temperature changes, drying of the adventi-
tial surface, or prolonged exposure to blood. The preventa-
tive measures taken whenever the vessel is exposed include

Figure 44-7. Intraoperative exposure of the internal carotid artery (large Figure 44-8. Three-dimensional CT of a meningioma that encased the ICA
arrow) and the facial nerve (small arrow) after removal of boney encasement. and necessitated mobilization of the artery for tumor extirpation.
 Complications In Neurotologlc Surgery 717

pulsations, distal to the site of constriction, noted on visu- Identifying the location and size of the hematoma usually
alization, palpation, or Doppler auscultation, may be the requires CT scanning. Rarely, rapid brainstem deteriora-
first warning signs of impaired perfusion. tion or extensive hemorrhage, such as with a carotid
Slowing of electroencephalographic waves have been rupture, mandate immediate exploration prior to imaging
seen during intraoperative monitoring when regional blood studies, to control bleeding and evacuate extravasated
flow falls below 18 mL/lOO g/min. Altered ventilation to blood. Emergent wound decompression without imaging
elevate oxygen and carbon dioxide levels and maximizing studies may be warranted in these grave situations
blood pressure are undertaken in an attempt to maintain when likely fatality or devastating neurologic sequelae
cerebral perfusion.t'r" Anticoagulants are contraindicated would result from any delay in treatment (Fig. 44-9).
at the time of surgery, but may be considered in the patient
who has developed delayed thrombosis. The risk of Blood Transfusions
delayed carotid spasm and decreased perfusion has been
reported in both carotid mobilization and trauma. In the majority of neurotologic operations with extended
Declining neurologic status or increasing intracranial dissections, such as for glomus tumor and temporal bone
pressure in the postoperative period warrant evaluation resections, blood loss frequently exceeds 1 L. Planned
by CT and angiography. Surgical dressings that may transfusions with autologous or related donor blood
compress the carotid should be removed, and the wound reduces the risk of transmission of blood-borne infections
should be explored to evacuate hematoma if carotid such as AIDS and hepatitis. When necessary, banked blood
spasm is confirmed angiographically. Measures to decrease products are administered for restoration of blood volume
intracerebral pressure are concurrently undertaken. and hemostatic fluid balance. Excessive hemorrhage, often
encountered in tumor extirpation from the lateral cranial
base, poses additional potential complications with blood
HEMORRHAGE replacement. The incidence of direct transfusion reac-
tions, acid-base derangements, coagulation defects, and
Meticulous hemostasis around the dura is accomplished cardiopulmonary complications increase proportionally
with bipolar coagulation, especially of the bridging veins with the number of required transfusions."
to the sinuses. Dural tacking sutures prevent blood from Hypotension, bradycardia, and other cardiac arrhyth-
enlarging the epidural space. Coagulants, such as oxidized mias may be induced by the binding of citrate within
cellulose (Surgicel) or microfibrillary collagen (Avitene) preserved blood to the circulating ionized calcium. The
are packed in the epidural space securely under the tacking administration of 1 g of calcium chloride for every two
sutures. These precautions should tamponade any units of transfused blood will compensate for this relative
bleeding from a venous source and prevent epidural hypocalcemia. Cardiac arrest can be induced as well by the
hemorrhages, which arise from bridging veins between the administration of multiple units of banked blood, which
brain, dura, and diploe." Assurance that the branches of may have high levels of potassium. Massive transfusions
the middle meningeal artery, which supply the dura mater,
have been adequately coagulated prior to wound closure,
prevents hematoma formation. Postoperative epidural
hematomas from an arterial source may produce mass
effect with rapid onset of focal neurologic deficits.
Postoperative hematomas can occur in the subdural or
epidural space or within the excavation site of tumor
removal. Cessation of bleeding from the brain surface after
tumor removal may be assisted by the application of warm
saline, peroxide-soaked cotton, or freshly cut muscle plugs,
which will promote vasoconstriction and clot formation.
Topical thrombin or liquefied cellulose (gelfoam) can be
applied to surfaces that ooze blood to add stability to the
clots. Meticulous hemostasis on the brain surface with bipo-
lar cautery is essential to prevent intraparenchymal bleeding.
Highly vascular structures such as the choroid plexus around
the cerebellar flocculus, in the cerebellopontine angle, pres-
ent a risk of intraventricular hemorrhage and obstruction of
the aqueduct with clot if hemostasis is not obtained.t"
The rate at which focal neurologic signs develop varies
with location and source of bleeding. The presence of
accumulating blood will generate focal neurologic signs,
such as hemiparesis or aphasia, by mass effect. Hemiparal-
ysis, obtundation, a fixed dilated pupil, and respiratory
distress are the hallmarks of rapidly increasing intracranial
pressure with peduncular herniation. In attempting
to reverse the neurologic decline, urgent identification Figure 44-9. Noncontrast axial CT showing acute hemorrhage (White) in the
and treatment of a focal hemorrhage is rnandatory.v-" posterior cranial fossa after acoustic neuroma resection.
718 SURGICAL NEUROTOLOGY

should be a mix of fresh and stored whole blood to

prevent iatrogenic hyperkalemia. Lowered cardiac output
or acid-base alterations may be induced by the rapid infu-
sion of blood that has been refrigerated. Transfusion of
three to five units given over a 2-hour period may lower
core body temperature 4°C. In light of this, all transfu-
sions must be warmed to body temperature prior to
administration.
Coagulopathies resulting from dilutional thrombocy-
topenia or the clotting factor deficiencies in banked blood
may increase the risk of hemorrhage and make the task of
obtaining hemostasis excessively difficult. Aberrancies
in the calcium-dependent clotting cascade compound
bleeding tendencies, with hypocalcemia arising from
multiple transfusions. Intraoperative monitoring of
prothrombin and partial thromboplastin times, serum
calcium and potassium levels, and platelet counts is war-
ranted during these lengthy procedures. One unit of fresh
frozen plasma and concentrated platelet packs should
accompany the administration of each four units of banked
blood to prevent coagulopathies.F Cardiopulmonary com-
plications resulting from rapid volume replacement may
lead to pulmonary edema and acute respiratory distress
syndrome in the early postoperative period. Disseminated
intravascular coagulation due to escape of fibrin and Figure 44-10. Temporal venous infarction resulting from occlusion of the
microaggregated cells from standard mesh filters may vein of Labbe.
obstruct the pulmonary microvasculature and further
impair oxygen diffusion. Pulmonary emboli may prove
lethal, particularly in this compromised state, underlining venous infarction is usually supportive. Anticonvulsants
the importance of careful attention to anti thrombosis are indicated if seizures are present. Major venous sinus
measures, use of micropore filters, and meticulous fluid occlusion is treated with anticoagulation when the neuro-
balance. logic deficits appear to be progressing or the level of
consciousness continues to decline. Lysis of the clot with
tissue plasminogen activator (TPA) by the interventional
INTRACRANIAL COMPLICATIONS neurosurgeon or radiologist is indicated when anticoagu-
lation fails to halt the neurologic decline.
Postoperative Stroke: Evaluation Venous sinus occlusion may also lead to increased
intracranial pressure. Ventriculostomy is indicated when
and Management the Glasgow coma score falls to 8 or below. Aggressive
The incidence of stroke is fortunately low in neurotologic treatment with osmotic diuretics, sedatives, and mechani-
surgery. More extensive operations that include several cal ventilation may be necessary for the comatose patient.
intracranial compartments and require manipulation of Lumbar puncture may be appropriate for the awake
the vasculature have an increased risk of vascular compli- patient with complaints of headaches or visual changes.
cations. Prolonged operative time and brain retraction, Psuedotumor cerebri is not uncommon after major venous
inherent in some approaches, are contributing factors that sinus occlusion. Medical therapy with a carbonic anhy-
increase the risk of stroke. Cerebral vascular accidents may drase inhibitor (Diamox) will frequently control the raised
be caused by embolic or thrombotic vascular occlusion, pressure in the patient with papilledema. Rarely, either
arterial spasm, venous infarction, or progressive intralumi- ventriculoperitoneal or lumboperitoneal shunting will be
nal vascular occlusion due to intimal dissection. Venous necessary to control symptoms when the visual loss does
infarctions may result postoperatively, despite gentle tech- not respond to medical therapy.
nique in the manipulation of cortical veins. 48,49 CT detection of an area of confined infarction or intra-
Arterial insufficiency is usually manifested by the cerebral hemorrhage may only warrant aggressive medical
sudden onset of a new neurologic deficit, whereas venous therapy if the hemorrhage is not expanding or creating
infarction may have an insidious presentation. New-onset undue mass effect. A focal intracranial accumulation of
seizures, altered mental status, or mild motor deficits may blood or air will most likely create focal neurologic defects
be the first signs of venous infarction. CT may show an requiring emergent exploration and evacuation to relieve
area of hypodensity in the location of impaired venous the pressure effect and prevent irreversible sequelae.P'!'
flow or areas of hemorrhage adjacent to an infarction, The rapidity with which a neurologic alteration occurs
which appear hyperdense (Fig. 44-10). MRI reveals may prove helpful in the initial clinical assessment.
changes on the flair and diffusion images and magnetic Generalized cerebral edema is most apt to occur in the first
resonance venography (MRV) assists in diagnosing pro- few days, whereas postoperative stroke may occur in the
gression of major venous sinus occlusion. Treatment of immediate recovery period or remote from the operative
 Complications In Neurotologlc Surgery 719

session. Intense clinical monitoring of the patient's status eliminated as a cause of the clinical decline prior to institu-
and expedient imaging studies are mandated to detect and tion of pressure-reduction maneuvers. Surgical exploration
manage any intracranial complications, and thus minimize to evacuate intracerebral blood clots or subdural hematomas
resultant deficits. is performed on first detection of these causes of compro-
mised cerebral function. Controlling bleeding and removal
Cerebral Edema: Evaluation of pressure-producing lesions often arrests progressive
and Management neurologic injury if therapy is instituted quickly. The prin-
ciples of treatment rely on the ability to alter the volume
Tumors such as meningiomas may incite edema in the of brain, CSF, or blood to control intracranial pressure.P-"
adjacent brain tissue (Fig. 44-11).52 Retraction or manipu- Reduction of elevated intracranial pressure begins with
lation of the brain during tumor extirpation leads to vary- pharmaceutical, mechanical, and ventilatory measures.
ing degrees of cerebral swelling, which most commonly Ischemia will result from diffuse cerebral edema and should
manifests in the first 3 postoperative days. Preoperative be addressed in an aggressive manner to prevent neuro-
CT and MRI provide the initial assessment of tumor logic injury. 58,59
volume, cerebral edema, mass effect, and midline shift. Regulation of the intracranial fluid volume during sur-
Ventricular size and shape allow the volume of CSF and gery affords greater exposure and reduces the need for brain
the likelihood of hydrocephalus to be estimated. Cerebral retraction. Closed-system lumbar or intraventricular
compromise evident prior to surgery increases the likeli- catheters placed in a sterile fashion preoperatively provide
hood of significantly worsened cerebral edema with tumor access for CSF drainage and the regulation of intracranial
removal. Clinically significant edema is most commonly pressure. Lumbar CSF drainage may be contraindicated in
heralded by evidence of increased intracranial pressure as large posterior fossa or transtentorallesions when there is a
measured by an intraventricular drainage catheter, a decline risk of brain herniation with decompression (Fig. 44-12).
in the patient's mentation or level of alertness, or progres- Epidural manometry to monitor intracranial pressure is an
sive focal neurologic deficits such as aphasia or limb weak- alternative when drainage of CSF is prohibited. An intra-
ness. Generalized edema that occurs as a result of brain ventricular catheter is the preferred device for both removal
manipulation or retraction, or venous outflow obstruction of CSF and direct measurement of intracranial pressure."
becomes most pronounced several days after surgery. 53-55 In selected cases, preoperative intravenous steroids
Depending on the degree of lethargy, rapidity of the (dexamethasone in 4- to lO-mg doses) are begun preoper-
neurologic decline, or severity of the process, the first step atively and continued every 6 hours for 3 days. The dose is
in management is to obtain a CT scan. Expansile lesions, tapered and discontinued over the ensuing 3 to 10 days, as
such as a subdural hematoma or hydrocephalus, must be the patient's recovery allows.P'' This regimen is routinely

Figure 44-12. Bilateral acoustic neurofibromas responsible for aqueduct

Figure 44-11. Cerebral edema adjacent to a large petroclival meningioma. obstruction.
720 SURGICAL NEUROTOLOGY

used to rrururruze edema associated with tumor removal

when significant dissection or retraction of brain is required.
Hyperventilation is a short-acting method of decreasing
the intravascular blood volume, secondary to the effect of
hypocarbia on the autoregulatory controls of the cerebral
vasculature. The arterial Pea, should be maintained
between 25 to 30 mm Hg with hyperventilation.f This
method of pressure control is most pronounced in the
immediate perioperative period and loses efficacy as a
pressure control modality after approximately 36 hours of
continuous use. Controlled hypotension, hypothermia (30
to 32°C), and barbiturate-induced coma are other periop-
erative modalities that may be employed adjunctively to
minimize cerebral edema.
Hyperosmolar agents and diuretics are useful medica-
tions for reducing interstitial fluid volume. Their rapidity
of action allows for intraoperative use or to arrest acute
postoperative edema. Mannitol is a hyperosmolar agent
that remains in the intravascular compartment and draws
interstitial fluid into blood vessels by its osmotic gradient.
Mannitol is given intravenously in doses of 0.25 to 1.0 g
infused over 20 minutes every 6 to 12 hours. Furosemide is
a frequently used diuretic that promotes the egress of
interstitial edematous fluid by the renal excretion of excess
water and electrolytes. This creates an osmotic gradient,
which, like mannitol, mobilizes excess fluid from the
extracellular compartment. Furosemide is administered
intravenously in doses of 20 to 60 mg every 4 to 6 hours.
Care must be taken to monitor serum potassium levels and
replenish diuresed electrolytes.
Figure 44-13. A persistent pneumocephalus following a frontotemporal
craniotomy and infratemporal resection of a large meningioma.
Pneumocephalus
Pneumocephalus is not uncommonly seen on postopera-
tive CT. Small pockets of air trapped after craniotomy
Seizures
normally resorb within 7 to 10 days. Air accumulating The occurrence of seizures in the postoperative period may
under pressure causes focal neurologic deficits. A tension signal the development of a hemorrhage, venous or arterial
pneumocephalus, if untreated, can be a fatal complica- infarction, hematoma, or other complications leading to a
tion.?' "Ball valving" of soft tissues in the basicranium after mass effect and cerebral irritation. Manipulation, dissec-
removal of bone, with forced inspired air entering the tion, or resection of brain parenchyma can lead to an irri-
epidural space, can lead to mass effect and subsequent table focus of the cerebrum that manifests as focal seizures.
neurologic deterioration. Risk factors for this complica- Prophylactic anticonvulsant therapy with phenytoin
tion increase with positive pressure ventilation, especially (Dilantin) is advocated when considerable manipulation
with a tracheostomy tube, after combined intracranial and or resection of the brain has been required for tumor
parapharyngeal resections. Continuous lumbar catheter removal. The initial loading dose is 18 mglkg intra-
drainage may create a relative intracranial "vacuum" of neg- venously followed by maintenance dosing of 300 mg/day.
ative pressure and draw air into the intracranial space. Clinical observation of persistent seizure activity along
Particular caution with lumbar drains is warranted in elderly with serial serum drug levels guide adjustment of the
patients, whose brain laxity may increase the risk of pneu- dosing regimen.tl-?
mocephalus.f Intracranial air is significant when tension
develops, as indicated by signs of increased intracranial
pressure or CT evidence of midline shift of the ventricles. CEREBRAL SPINAL FLUID LEAK
A tension pneumocephalus mandates expedient decom-
pression (Fig. 44-13). Any source of air access in the inci- The most common complication reported after neuroto-
sion line or neck wounds must be sealed off with logic procedures is the development of a CSF leak. An 8%
appropriate tissues of fascia or vascularized muscle. incidence of spinal fluid leakage with posterior fossa
Residual accumulations of air, noted on scans, may need to acoustic tumor removal has been reported through the
be evacuated if they fail to resorb or if any neurologic com- Acoustic Neuroma Association by collaborative investiga-
promise may be caused by the pneumocephalus. Because a tors nationwide. Resection of large segments of dura with
concurrent CSF leak frequently accompanies a persistent extensive tumor removal has led to leaks of spinal fluid
pneumocephalus, a diligent search for potential sites of in a significant number of patients undergoing cranial
fluid leaks is warranted. base surgery through combined surgical approaches.v'<"
 Complications In Neurotologlc Surgery 721

The method of reconstruction significantly influences the neurotologic operations. Anticipation of potential prob-
incidence of CSF leakage. When the continuity of the dura lems associated with the manipulation of delicate neurovas-
has been disrupted, reestablishing a water-tight seal is cular structures helps to prevent complications. Meticulous
more difficult. Fascia grafts may be used to reconstitute patient preparation and refined surgical techniques in
the dura. Autologous fat grafts to fill a limited posterior resection and reconstruction help to optimize treatment
fossa dural defect in the mastoid cavity will provide a results. Early recognition of complications and expedient
water-tight seal. This reconstruction has proven reliable in intervention can minimize the sequelae of complications
translabyrinthine approaches for decades. Skull base sur- associated with neurotologic and cranial base surgeries.
gery, which exposes large areas of the basicranium, requires CSF leaks contribute to wound infections, fistulae forma-
more sophisticated methods of reconstruction.w-? Free- tion, and meningitis. Prevention of these complications is
tissue transfer, with myogenous and myocutaneous grafts, best accomplished by wound closure with well-vascularized
has markedly decreased the incidence of postoperative CSF tissues. Pedicled myocutaneous or vascularized free flaps is
leaks and subsequent wound infections (Fig. 44_14).7 3,74 required to reconstruct large defects of the basicranium. In
Intraoperative lumbar drainage catheters are used to the event of a CSF leak despite taking these precautionary
assist in the control of intracranial pressure and in the measures, wound exploration and secondary reconstruc-
relaxation of the brain to minimize retraction. Postop- tion may be required. Detection of clear rhinorrhea or
eratively the catheter may be left in place to drain CSF at otorrhea, with a "halo sign" on a cotton sheet, alerts
a maximum rate of 300 mLl24 hours, to help prevent the the clinician to the likelihood of a leak. If a sample of fluid
development of a CSF leak. The spinal fluid drainage may can be collected, chemical analysis showing a glucose con-
be used for 5 days with the patient on strict bedrest, with centration greater than 30 mg/mL or identification of
the head of bed elevated 15 to 30 degrees. A sterile mas- transferrin (~-1 or -2) by immunoelectrophoresis is confir-
toid or Barton's dressing is maintained over the wound to matory for CSF.77,78 Fluid in the nasopharynx, which is
promote water-tight healing. Antibiotics are continued for suspected to be CSF, can be collected in cotton pledgets
the duration of the catheter's placement.Z'v" Excess pro- and scanned for radioactive isotopes 12 hours following
duction of spinal fluid may need to be reduced if a persist- intrathecal nucleotide instillation. This study is beneficial
ent CSF leak or hydrocephalus develops following when chemical and protein analysis of fluid is inconclusive.
discontinuation of the lumbar drain. Acetazolamide Contrast cisternography with CT imaging is often helpful
sodium (Diamox 500-mg) is administered orally or intra- in confirming and localizing the site of a spinal fluid leak.
venously twice a day.
Advances in imaging modalities, stereotactic navigational
systems, electrophysiologic monitoring, and standardiza- INFECTIONS
tion of skull base approaches have improved the safety of
Fortunately, the general incidence of wound infections fol-
lowing neurotologic operations is low. The risk of wound
infection rises, however, with the extent of resection,
length of surgery, potential dead space, and hematoma
formation.i? The development of a wound infection in the
early postoperative period is significant, as meningitis,
brain abscess, or other potentially life-threatening compli-
cations may ensue. The use of prophylactic antibiotics,
which attain high CSF levels, are warranted in neuroto-
logic operations. One gram of cefazolin (Ancef) is infused
prior to skin incision and continued intravenously every
8 hours for three doses, following noncontaminated cases.
Similar effective prophylactic coverage of gram-positive
organisms is provided by vancomycin hydrochloride, 1 g
every 12 hours for 24 hours. There is minimal risk of oto-
toxicity or nephrotoxicity with this prophylactic regimen,
provided the serum creatinine level is normal. Admin-
istration of vancomycin beyond the peri operative period
requires serial monitoring of creatinine and serum drug
levels. Lengthy surgeries or those with likely bacterial
contamination by exposure of the aerodigestive tract with
the intracranial cavity, require prophylaxis against mixed
flora and anaerobic organisms. Unasyn is a single-regimen
administration of ampicillin sodium with sulbactam, given
in doses of 3 g every 8 hours. Alternatively, ampicillin (1 g)
and metronidazole hydrochloride (Flagyl, 500 mg) can be
infused every 6 hours. Protection against gram-negative
organisms, particularly Pseudomonas aeruginosa, is afforded
Figure 44-14. Sagittal MRI demonstrating a rectus abdominis myogenous, by combining clindamycin phosphate (Cleocin 600 to 900
free-tissue graft filling the surgical defect of the infratemporal fossa. mg) with either ceftazidime (Fortazl to 2 g) or gentamicin
722 SURGICAL NEUROTOLOGY

sulfate (80 to 100 mg) every 8 hours. Precautions against

nephro-ototoxicity are needed with the aminoglycosides,
particularly when used with vancomycin.
The classic findings of deep-wound infections may be
absent in the early stages of development. Febrile episodes
are often the early warning sign of a postoperative infec-
tious process, prior to the development of skin erythema,
tissue swelling, or wound drainage. Any deviation from the
normal postoperative course prompts evaluation with
white blood cell counts with leukocyte differential, chest
radiograph, urinalysis, and serial blood cultures. These
tests will help confirm an infectious source of fever. The
most common cause of postoperative fever is pulmonary
atelectasis. Incentive spirometry, positive pressure ventila-
tion, and vigorous pulmonary toilet typically correct alve-
olar collapse and normalize the temperature. A visible
Figure 44-15. Pedicled trapezius myocutaneous flap reconstruction following
pulmonary infiltrate on chest radiograph is managed simi- total temporal bone resection.
larly, with the addition of broad-spectrum antibiotic ther-
apy pending identification of a specific pathogen by
sputum culture. Indwelling urinary or central venous cystic carcinomas have a great propensity for intraneural or
catheters, in place for greater than 5 postoperative days, perineural growth, thus necessitating aggressive excision of
should be discontinued, cultured, and replaced. When a nerves adjacent to tumor (Fig. 44-17). Benign lesions that
febrile source cannot be rapidly discovered, meningitis cause compressive neuropathies, such as schwannomas,
should be considered and lumbar puncture performed." meningiomas, and paragangliomas, may exhibit extensive
Infectious disease consultation should be sought when an involvement of the nerves exiting the cranial base.P'
infection is not readily isolated but is suspected on clinical Neural preservation may not be feasible. Microdissection
grounds. Rare causes of fever, such as medication reac- techniques and electrophysiologic monitoring have
tions, deep venous thrombosis, pulmonary embolus,
parotitis, or prostatitis, can be identified more quickly
when consultation is obtained.
Deep-tissue infections are often quickly visualized by
CT or MRI of the head and neck. Lucency adjacent to
sites of resection, exhibiting peripheral contrast enhance-
ment, are indicative of an abscess. Computer-directed
aspiration will allow collection of materials for sensitivity
assays. Adequate drainage and antibiotic therapy are insti-
tuted after a focal site of infection is confirmed. Subdural,
epidural, and parapharyngeal abscesses mandate emergent
open drainage and may require revision of the reconstruc-
tion with well-vascularized tissues. Pedicled myocutaneous
or freely transferred myogenous grafts are most useful and
versatile in this regard (Fig. 44-15).81 Reconstruction revi-
sions are staged until the infection is well controlled to
prevent abscess loculation. Specific antibiotic therapy, as
directed by culture and sensitivity results, is continued
with assistance by infectious disease consultants, until all
infection is eradicated. Vigilant monitoring to recognize
potential adverse effects of therapy and to ensure complete
control of infection is paramount to the patient's eventual
recovery.V

CRANIAL NERVE INJURIES

Cranial nerves III through XII are at risk for injury in the
spectrum of neurotologic surgery (Fig. 44-16). The deci-
sion to resect specific nerves involved with tumor is dic-
tated by the histologic process and the degree of function
present before surgery.83 Malignant lesions that involve
neural structures mandate their removal and a careful search
for microscopic neural involvement by frozen section exam- Figure 44-16. Paralysis of leftabducens and facial nerves secondary to a
ination at the time of surgery. Squamous cell and adenoid temporal bone infection involving the petrous apex.
 Complications In Neurotologlc Surgery 723

Figure 44-17. Perineural growth

around the oculomotor nerve of a
squamous cell carcinoma resected
from the cavernous sinus.

evolved to enhance the preservation of cranial nerves

during tumor resection (Fig. 44_18).11,85 Attempts to con-
trol bleeding, particularly at the jugular foramen and cav-
ernous sinus, may produce nerve paresis due to overzealous
packing with oxidized cellulose. This complication is best
avoided by gentle technique to obtain hemostasis. Locating
the several inferior petrosal sinus openings into the medial
jugular bulb is particularly helpful in controlling bleeding
in the jugular fossa and preventing undue pressure on the
nerves in the pars nervosa.
The facial nerve is the most frequently impaired cranial
nerve in neurotology, and its preservation requires constant
management. The common immediate problems associated
with facial paralysis involve incompetent eye closure and
exposure keratitis. Lacrilube ophthalmic ointment and a
moisture chamber or lid taping at night, along with the
application of artificial tears every 2 hours, will prevent
drying of the eye in the immediate postoperative period.

Figure 44-18. Electrode on the cochlear nerve for direct intraoperative

monitoring of cranial nerve VIII during a vestibular neurectomy. Figure 44-19. Gold weight implant in upper eyelid.
724 SURGICAL NEUROTOLOGY

Figure 44-20. Fiberoptic

laryngoscopy showing paralysis of
the right vocal cord following glomus
jugulare tumor resection.

Ophthalmologic evaluation with corneal staining is advis- nerve section. Swallowing training by a speech pathologist
able for a baseline examination to rule out any corneal abra- is often most beneficial to these patients.
sions. The placement of a gold weight in the upper eyelid
will restore competent lid closure either temporarily or
permanently (Fig. 44-19). Canthoplasty of the lower eyelid REFERENCES
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 Chapter
Acoustic Neuroma
(Vestibular Schwannoma)

Outline 45
Introduction Utility of the Vestibular Assessing Candidacy for Robert K. Jackler, MD
History Test Batteries a Hearing Conservation
Markus H. F. Pfister, MD
Epidemiology Radiology Attempt
Tumor Biology Diagnostic Protocols for Definition of a Successful
Pathogenesis Suspected Acoustic Neuroma Result
Molecular Genetics Delayed Diagnosis Results in Clinical Series
Molecular Mechanisms Management Long-Term Hearing Results
Endocrine Relationships Conservative Management Special Considerations in
Radiation Microsurgical Management Bilateral Acoustic Neuroma
The Role for Incomplete and Only Hearing Ears
Gross and Microscopic
Pathology Resection Hearing Loss in the Ear
Gross Pathology Outcome of Acoustic Contralateral to an
Histopathology Neuroma Surgery Acoustic Neuroma
Decentralized versus Rehabilitation of Unilateral
Growth Characteristics
Centralized Hospitals Hearing Loss
Growth Pattern
Mortality Tinnitus
Growth Rate
Complications Vestibular Rehabilitation
Measurement of Acoustic
Intracranial Vascular Headache
Neuromas
Complications Social and Occupational
Clinical Manifestations
Traumatic Parenchymal Rehabilitation
Typical Clinical Presentation
Injury Radiation Therapy
Signs and Symptoms
Cerebrospinal Fluid Leak Conventional Radiotherapy
Hearing Loss
Meningitis Stereotactic Irradiation
Tinnitus
Impact of Acoustic Neuroma Fate of the Tumor following
Vertigo, Dysequilibrium,
Removal on the Quality Stereotactic Radiation
and Dysmetria
of Life Audiovestibular Function after
Facial Anesthesia and Pain
Facial Mimetic Function Stereotactic Radiation
Facial Weakness and Spasm
Vulnerability of the Facial Cranial Nerve Function
Headache
Nerve following Stereotactic
Ophthalmologic
Role of Facial Nerve Radiation
Manifestations
Monitoring Complications following
Lower Cranial Nerves
Results in Contemporary Stereotactic Radiation
Late Symptoms
Series Secondary Oncogenesis
Sudden Neurologic
The Course of Postoperative following Stereotactic
Deterioration
Facial Palsy Radiation
Audiologic Diagnosis
Management Options When Indications for Stereotactic
Pure Tone and Speech
the Facial Nerve Is Radiation in Unilateral
Audiometry
Disrupted Acoustic Neuroma
Auditory Brainstem
Care of the Eye in Facial Radiation after Surgery
Responses
Palsy and Surgery after Radiation
Otoacoustic emissions
Hearing Conservation Bilateral Acoustic Neuroma
Vestibular Testing
Pathology and Auditory Brainstem Implant
Electronystagmography
Pathophysiology of Conclusion
Rotatory Testing
Cochlear Nerve
Dynamic Posturography
Involvement

727
728 SURGICAL NEUROTOLOGY

INTRODUCTION
In neurotologic practice, a substantial fraction of the clin-
ician’s time is spent either in performing diagnostic evalu-
ation for or engaged in the treatment of acoustic neuroma
(AN). Historically, these tumors figured prominently in the
development of both diagnostic and surgical neurotology.
Techniques developed for their identification and removal
catalyzed the development of diagnostic audiology, imaging
technologies, microsurgery, hemostatic methods, cranial
nerve monitoring, and many innovative operative
approaches that have subsequently been expanded and
applied to other diseases. These tumors are characterized
by a multiplicity of clinical presentations, a technologically
sophisticated diagnostic armamentarium, a diversity of
challenging surgical approaches, and patients who respond
remarkably well to therapy, especially when compared
with results obtained with other intracranial tumors.
Given these attributes, it should not be surprising that
ANs, which have been termed the queen of intracranial
tumors by some, have captured the interest of so many
clinicians and researchers. The high level of interest in
these lesions has led to numerous recent advances in under-
standing their biology as well as progressive refinement of
diagnostic and therapeutic methods. Figure 45-1. Early drawing of an acoustic neuroma. (From Cruveilhier J:
Anatomie pathologique du corps humain. Paris, ii, Part 26, pp 1–8,
1835–1842.)
HISTORY
Acoustic neuroma was first described in the latter part of was frequent until the computed tomography (CT) and
the 1700s and by the mid-1800s, neurologists understood magnetic resonance imaging (MRI) era. In the past 5 years
that patients who manifest unilateral deafness, facial at our institution hydrocephalus was present in only 4% of
numbness, and progressive blindness caused by “optic patients with ANs.11
neuritis” (papilledema) were afflicted by a tumor of the The next era in AN surgery was ushered in by Harvey
cerebellopontine angle (CPA)1–4 (Fig. 45-1). At this time Cushing of Johns Hopkins and later Harvard (Fig. 45-3). In
the only intracranial tumors that could be reliably local- 1905, he advocated decompression of the posterior fossa by
ized involved either the motor strip or cranial nerves at the extensive removal of suboccipital bone.12 He reasoned that
base of the brain. ANs figured prominently in the early few tumors could be safely removed and that bony decom-
development of neurologic surgery because they were pression alone might be beneficial. After this proved fruit-
readily diagnosable with signs and symptoms alone. The less, he developed a technique of subtotal tumor debulking
earliest attempt to remove an AN was performed in 1891 via a bilateral suboccipital craniectomy. Cushing’s greatest
by Charles McBurney of New York, who has been immor- contributions were that he was gentle with tissues, meticu-
talized by the appendectomy incision that bears his name.5 lous with hemostasis, and operated deliberately without
They reported that after opening the suboccipital plate undue emphasis on speed.13,14 For hemostasis he employed
with a mallet and gouge, the cerebellum swelled massively, Horsley’s bone wax (described in 1892) and two of his
so much so that it became necessary “to shave off the own innovations: silver clips (1911) and electrocautery
excess.” No tumor was removed and the patient expired (1928).15–17 By gutting only the core of the tumor, he
12 days later. The first successful results were achieved in avoided interrupting the vasculature of the brainstem and
1894 by Ballance in London and Annandale in Scotland.6–9 often preserved cranial nerve function. The mortality rate
In these early attempts a unilateral suboccipital cran- of his surgical patients, which was 20% in 1917, decreased
iotomy was employed, complete removal was performed following adaptation of further technical refinements, such
by finger dissection, hemostasis was obtained by packing as partial cerebellar resection, to only 4% by 1931.18
the CPA with gauze, and there was great emphasis on oper- Although Cushing’s operative mortality was low, many
ative speed (Fig. 45-2). The outcome was dismal. At the patients succumbed to their residual tumor in later years.
International Congress of Medicine in London in 1913 the The next era in AN surgery was pioneered by Walter
results of Victor Horsley (London), von Eiselsberg Dandy of Johns Hopkins, a pupil of Cushing. In 1916,
(Vienna), and Fedor Krause (Berlin) were presented.10 In while still a resident in training, Dandy reported a case in
63 patients, surgical mortality was 78% and most of the which he removed an AN completely.19 Cushing, who had
survivors were severely crippled. It should be realized that vehemently maintained that attempts at total removal were
all of these early cases were moribund at the time surgery “foolhardy in the extreme” was infuriated. Subsequent
was undertaken. Indeed, hydrocephalus was virtually uni- reports by Dandy in 1922, 1925, 1934, and 1941 described
versal in AN surgical candidates well into the 1930s and a unilateral suboccipital approach during which, following
 Acoustic Neuroma (Vestibular Schwannoma) 729

Figure 45-3. Four surgical approaches to acoustic neuroma as envisioned by

Harvey Cushing in 1917. A, Suboccipital. B, Translabyrinthine. C, Combined
retrosigmoid-translabyrinthine. D, Bilateral suboccipital. (Cushing H: Tumors
of the Nervus Acusticus and the Syndrome of the Cerebello-Pontine Angle.
Philadelphia, Saunders, 1917.)

Figure 45-2. Removal of a posterior fossa tumor by finger dissection. (From

Krause F: Surgery of the Brain and Spinal Cord. New York, Rebman, 1912.) away the inner ear, including the facial nerve, to the level
of the carotid artery. Although the patient survived the
operation, he succumbed 6 months later. Postmortem
gutting of the tumor, he gently drew the capsule away examination revealed that only a tiny amount of tumor had
from the brainstem.20–23 His eventual surgical mortality been removed. Several reports followed by H. Marx of
rate of about 10% was higher than Cushing’s, but this Heidelberg (1913),30 Von Schmiegelow of Copenhagen
reflected his more radical philosophy of total tumor (1915),31 and Zange of Berlin (1915),32 but the technique
removal. There remained much animosity between passed into obscurity because of problems with inadequate
Cushing and Dandy throughout their careers and the two exposure, hemorrhage from the surrounding venous
rarely spoke with each other.24 sinuses, cerebrospinal fluid leak, and meningitis. The
The translabyrinthine approach, which was eventually translabyrinthine approach was dismissed by Cushing in
perfected by William House in the early 1960s, has a rich his classic monograph Tumors of the Nervus Acusticus (1917)
early history. It was proposed by two authors in 1904, one in which he maintained that it was a deep wound with a
in America and one in Europe. Rudolph Panse, an narrow field of action, which would be suitable only for
otopathologist from Dresden, proposed a translabyrinthine tiny tumors.13 In 1921, writing in Laryngoscope, Cushing
approach but did not actually perform one.25 George stated: “If the otologist has ambitions to treat these lesions
Woolsey and Charles Elsberg of New York also suggested there is no possible route more dangerous or difficult than
it, citing the poor results with the suboccipital approach of this one which has been proposed by Panse, Quix, and
the day.26 They performed cadaver dissections in which Schmiegelow.”14 He went on to say that “A proposal of this
they determined that the shortest route to the CPA sort I am sure would never occur to an otologist who has
commenced 1 cm to 2 cm behind the ear. In 1905, general surgical training before he engaged in the particular
M. Borchardt performed the first combined suboccipital- surgery of his specialty.” These sentiments were echoed by
transtemporal approach during which he chiseled away the Dandy who in 1925 called the translabyrinthine approach
temporal bone to the level of the internal auditory canal to “a wholly impractical suggestion.”21 Such vehement opinions
improve exposure of the tumor.27,28 The first purely from the masters of their day relegated the translabyrinthine
translabyrinthine craniotomy was performed by F. H. Quix technique to utter obscurity until William House, armed
of Utrecht in 1911.29 The initial operation was aborted with a surgical drill and operating microscope, successfully
because of bleeding from the superior petrosal sinus. It was resurrected it in the early 1960s.33–35 The degree to which
completed at a second stage 4 days later. The operation these early failed attempts passed from the common
consisted of radical mastoidectomy followed by chiseling knowledge is well illustrated by the fact that William House
730 SURGICAL NEUROTOLOGY

was unaware of these pioneering efforts until some years consistent over many decades.13,42 They occur in all races,
after he had reintroduced the method. although it is not yet known whether in equal frequency.
Facial nerve preservation, a primary issue in AN man- A female sex predilection has been noted by some,
agement, was not achieved until 1931 by Sir Hugh Cairns although not to a substantial degree. Because few countries
of London.36 Remarkably, cranial nerve monitoring had have comprehensive tumor registries, establishing the
first been used by Fedor Krause of Berlin in 1898 when he incidence of AN in the population at large is somewhat
identified the facial nerve “by faradic stimulation” during inexact. In Denmark, a country with a rather comprehensive
an eighth nerve section for tinnitus.37 Herbert Olivecrona national database, the reported incidence of newly diag-
of Stockholm, during the late 1930s and 1940s, was the nosed AN is 9.4 per million per year with a slow increase
first to place great emphasis on facial nerve preservation. in recent years to 13 per million, almost certainly due to
He also employed electrical stimulation to identify the better diagnostic imaging.43,44 A review of experience in a
nerve and had a special nurse to observe the face during large Health Maintenance Organization in the United States
the procedure. In 1940, he reported a 65% success rate in (patient population of 2 million) found a yearly incidence
anatomic preservation of the nerve, but only 4% early of approximately 10 per million per year.45 Given that the
function.38 What makes these results especially remarkable current U.S. population is some 250 million, this translates
is that they were achieved more than two decades before to roughly 2500 newly diagnosed tumors per year.
William House first used the operating microscope in It has been aptly pointed out that the frequency of
AN surgery.33 diagnosis of AN reflects not necessarily the true incidence
The presence of tumor in the internal auditory canal of AN in the population at large but rather merely the
was first recognized in 1910 by Folke Henschen, a Swedish fraction of tumors that have been discovered. Occult AN
pathologist.39 The radiographic appearance of porus erosion has been the subject of controversy for many years.
was well described by H. Stenvers of Utrecht (1917) and In 1932, Hardy and Crowe performed an autopsy series and
E. Towne of San Francisco (1926).40,41 Nevertheless, sur- purportedly detected a 2.5% incidence of AN (6/250).46
geons did not address this component of the tumor In 1970, Leonard and Talbot reviewed the same pathologic
routinely until the 1950s. Neither Cushing nor Dandy material and reclassified four of the previous cases as nontu-
removed this portion of the tumor. Most surgeons, even at mors, yielding a corrected incidence of 0.8%.47 Were this
the mid-twentieth century, truncated the tumor at the porus correct, some 2 million Americans would have an occult
acusticus and coagulated the remnant. In their excellent AN! Arguing against this prediction is the observation that
monograph of 1957, J. Pool and A. Pava of New York state with gadolinium-enhanced MRI scans, which are capable
that “removal of tumor from the IAC is an essential part of of detecting ANs down to the millimeter, very few ANs
the procedure.”2 They employed a sharp chisel, curette, and are being discovered incidentally on scans obtained for
Kerrison rongeur rather than the less traumatic rotating reasons other than suspected CPA disease. In a series from
burr that is popular today. the MRI era, only 2 entirely asymptomatic tumors were
It is clear that the excellent results obtained today with encountered over a 4-year period out of a population of
AN surgery are derived from efforts of intrepid early 126 tumors in the study group.48 Given the large number
surgeons who, despite primitive equipment and dismal of gadolinium-enhanced MRI scans being obtained in the
results, persevered until the fundamental obstacles to suc- United States today, if the actual incidence of asympto-
cessful results were painstakingly analyzed and ultimately matic ANs approached 0.8% of the population, centers
overcome (Table 45-1). specializing in AN management would be inundated by
patients with incidentally discovered tumors. Undoubtedly,
a significant prevalence of undetected ANs exist in the pop-
EPIDEMIOLOGY ulation, but the actual incidence is most likely several
orders of magnitude lower than the figure suggested by his-
Acoustic neuromas constitute approximately 6% of torical autopsy studies. In a recent retrospective review
intracranial tumors, a relative incidence that has been there were a total of 9 out of 46,414 patients with inciden-
tally discovered ANs, a prevalence of approximately 2 in
TABLE 45-1. Evolution of Operative Mortality 10,000 adults.49
in Acoustic Neuroma Surgery Acoustic neuromas occurs in two forms: sporadic and
those associated with neurofibromatosis type 2 (NF2).
Author Year Cases Mortality Sporadic tumors are unilateral and comprise some 95% of
Krause37 1913 31 84%
cases while NF2-associated lesions are typically bilateral
Horsley17 1913 15 67% and account for some 5% of patients with ANs. Age at the
von Eiselsberg10 1913 17 77% time of diagnosis tends to differ between the two tumor
Cushing13,14,18 1917 33 20% types. Sporadic ANs tend to begin in midlife with a recent
1921 19 16% study showing a mean presentation in of 50 years.48 A new
1932 50 4%
Dandy20,21,23 1922 3 33% study suggests that familial occurrence of unilateral
1925 22 50% vestibular schwannoma (VS) may be genetically inherited
1941 46 11% since it occurs more often than would be estimated by
Olivecrona38 1940 130 21% chance alone.50 ANs in NF2 patients present at a younger
Glasscock190 1986 610 0.6%
Luxford348 1990 500 0.4%
age with a mean presentation of 31 years according to a
Barker216 2003 2643 0.5% recent study.51 Much variability in the age of onset has
been noted with a few tumors being detected during
 Acoustic Neuroma (Vestibular Schwannoma) 731

childhood and a rather substantial fraction during (Fig. 45-4). Technically, they are neither neuromas nor
advanced age.52–54 Tumors in childhood may attain large acoustic, at least in the sense that their origin is not from
size and, presumably due to a rapid growth rate, may pos- auditory fibers. Because the term acoustic neuroma is a mis-
sess an unusual degree of vascularity. nomer, a Consensus Development Conference of the
Neurofibromatosis type 2 is a rare disease, with a National Institute of Health on the subject recommended
prevalence in the population of about 1 in 30,000 to that this widely used term be replaced by the more accurate
50,000 people. This means that there are no more than vestibular schwannoma.59 The vestibular nerve, which has an
several thousand afflicted individuals in the United States. approximately 2-cm course between the brainstem and the
NF1, by contrast, is much more common than NF2 with a inner ear, possesses two divisions. Although formerly some
prevalence of some 30 to 40 per 100,000 people. There are have maintained that superior vestibular schwannomas pre-
approximately 80,000 individuals with NF1 in the United dominate, current opinion favors an equal origin in the
States. Virtually all patients with NF2 eventually manifest superior and inferior divisions of the nerve.60 A recent study
bilateral ANs, but they are rare in NF1. The literature on from Japan suggests that about 85% of VSs originate in the
NF1 and NF2 was often ambiguous and overlapping until inferior vestibular nerve.58
relatively recently.55 Although the exact incidence is The eighth nerve is unusual among cranial nerves in
unknown, probably fewer than 2% of NF1 patients develop that it possesses a long segment of central myelin. It has
a unilateral AN and virtually none develop bilateral been proposed that ANs may arise in the region of the
tumors.56 transition zone between the central and peripheral myelin,
also known as the Obersteiner-Redlich zone.61 The evidence
in the recent literature indicates that most vestibular nerve
TUMOR BIOLOGY schwannomas originate lateral to the glial-schwannian
junction of the nerve and not from the transition zone.62 In
Pathogenesis the proximal segment of the eighth nerve, myelin is laid
Acoustic neuromas are schwannomas that arise from down by oligodendroglial cells, while distally it is produced
the vestibular division of the eighth cranial nerve57,58 by Schwann cells. The neuroglial-neurilemmal junction

A B
Figure 45-4. Schwannoma (A) compared with that of neurofibroma (B). Acoustic neuromas, even those associated with neurofibromatosis, are schwannomas
originating from the vestibular division of the eighth cranial nerve. (From Armed Forces Institute of Pathology: Tumors of the peripheral nervous system,
ATLAS #672-231, 1967.)
732 SURGICAL NEUROTOLOGY

most often occurs in the vicinity of the vestibular (Scarpa’s) the sole remaining functional copy of the AN suppresser
ganglion, but its location varies considerably. This variability gene, a tumor results. Because spontaneous events happen
has been argued to account for the variable site of origin of fairly frequently, these individuals eventually develop
ANs along the vestibular nerve. Arguing against the transi- multiple schwannomas.
tion zone as the site of AN formation is the appearance of The nature of the genetic injury of chromosome 22 in AN
schwannomas apparently originating distal to it as well as has been studied in some detail.73 A major rearrangement of
multicentric origins of AN along the eighth nerve in the the chromosome was detected in 57% (23/39). The most
same patients, particularly those who have NF2s.61,63 A rea- common finding was a large interstitial deletion. Deletion
sonable alternative explanation based on available evidence of one entire copy of chromosome 22 (monosomy) was
is that ANs originate from the Schwann cell population also noted in some cases as was terminal deletion, mitotic
associated with the vestibular ganglion. It has been recombination, and deletion with reduplication. In the 43%
observed that the greatest density of Schwann cells along (16/39) of tumors in which no chromosomal rearrangement
the eighth nerve exists at this location.64 Also supportive of was detected, more subtle mutations through the AN
this hypothesis is the finding that the junction zone and suppresser gene were suspected that were beyond the
other segments of the nerve possess a consistently lower resolution of the methods employed in the study. Newer
density of Schwann cells than the ganglion region does. studies reveal that nearly all sporadic VSs show evidence of
In larger tumors, it is seldom possible to ascertain the NF2 gene inactivation.74
precise site of origin along the nerve. Observations from Chapter 5 (Molecular Genetics in Neurotology) offers a
smaller tumors indicate that most ANs arise in the internal more detailed discussion of the molecular genetics of this
auditory canal (IAC). A small minority of tumors originate condition.
from the nerve in its course through the CPA cistern. In
our experience, all of these medial ANs began just outside
the porus. We have never observed a small tumor that Molecular Mechanisms
arose in the medial half of the cisternal course or in the
brainstem root entry zone. A few schwannomas have even Although the biochemical aberrations that lead to AN
been reported to have arisen in the inner ear, presumably growth have yet to be elucidated, some investigations have
from myelinated dendrites of the vestibular nerve proximal been performed concerning the possible role of substances
to Scarpa’s ganglion.65,66 known to be involved in growth regulation of neural tissue.
An increased expression of the mRNA that codes for
fibroblast growth factor (FGF), a potent mitogen for many
Molecular Genetics connective tissue types, has been found in AN.75 Of interest,
Great strides have been made in recent years concerning FGF mRNA was not elevated in meningiomas, a type of
the genetic basis of AN formation. Through a variety of tumor that often coexists with AN in NF2 patients. One
molecular genetic techniques, the gene responsible for AN growth-promoting substance that may be implicated
associated with NF2 has been localized to the long arm of circumstantially in AN pathogenesis is platelet-derived
the chromosome 22.67–70 The disease gene was identified in growth factor (PDGF). The gene for this polypeptide is
1993, and codes for a 587 amino acid protein.71,72 The located on chromosome 22 near the NF2 gene. Evidence
product of this gene resembles certain proteins (moesin, of a role for any of the above-mentioned growth factors in
ezrin, and radixin), which are thought to link the cell AN formation is decidedly preliminary. In recent studies,
membrane with cytoskeletal components. The NF2 gene the NF2 gene product, Merlin/Schwannomin, has been
has been shown to be inactivated both in familial as well as found to interact with the two PDZ domains (postsynaptic
sporadic cases. Oncogenes are regions of the genome that, density domains) that contain protein EBP50/NHE-RF,
when damaged, lead to tumor formation. In many instances, which is itself known to interact with the PDGF receptor
the defective gene elaborates a product that induces a neo- (PDGFR) in several cell types. An up-regulation of both
plasm. In AN, by contrast, evidence points to the existence PDGFR and EBP50/NHE-RF and an interaction of both
of a “tumor suppressor” gene, which, if inactivated, results proteins were found in primary human schwannoma tissue.
in tumor growth.57 It has been speculated that the gene Upon PDGF stimulation in culture, Merlin/Schwannomin
product is a substance that regulates Schwann cell division appeared to inhibit the activation of the MAPK and PI3K
which, when deficient, results in excessive cellular prolif- signaling pathways, impinging on the phosphorylation of
eration. Because the absence of this gene product results in Erk 1/2 and Akt, respectively. The data suggest that
tumor formation, it is necessary for both copies of the PDGFR is more rapidly internalized by the schwannoma
involved chromosome to be dysfunctional. Thus, two muta- cells overexpressing NF2. Therefore, this process is sug-
tions are required to induce an AN—one that damages gested as a model for a mechanism of Merlin/Schwannomin
each chromosomal copy. This “double hit” hypothesis fits tumor suppressor function, which intermediates accelera-
well with theories on the genetic origin of sporadic ANs as tion of the cell surface growth factor degradation.76
well as those associated with NF2. In sporadic AN, two Another recent study suggests that a major cellular
silencing mechanisms must occur in one cell to incite consequence of NF2 deficiency in primary cells is an
tumor growth. For this to occur, it must be assumed that inability to undergo contact-dependent growth arrest and
the gene has a high spontaneous mutation rate; otherwise, to form stable cadherin-containing cell-to-cell junctions.
such a dual event would be extraordinarily rare. It has been These studies indicate that merlin functions as a tumor
demonstrated that patients with NF2 carry a defective and metastasis suppressor by controlling cadherin-
copy of the gene. When a spontaneous event inactivates mediated cell-to-cell contact.77
 Acoustic Neuroma (Vestibular Schwannoma) 733

Endocrine Relationships was 0.9 (P = 0.07) and did not vary significantly by the
frequency, duration, and lifetime hours of use. The short
A possible influence of sex hormones over AN growth has duration of widespread cellular telephone use, however,
been postulated based on several clinical and experimental precludes definite exclusion as a risk for AN development.
observations. In terms of genetic expression, a maternal
effect has been noted in both NF1 and NF2. This was
established through the observation that there is a higher GROSS AND MICROSCOPIC PATHOLOGY
morbidity among NF patients born to an affected mother
than among those born to an affected father.78 Clinical Gross Pathology
series have consistently observed a slightly higher incidence
of AN in women than in men, particularly postmenopausal The great majority of ANs are benign, relatively slowly
women.44 In addition, the onset of NF2 may be earlier in growing neoplasms. Upon gross inspection, they are usually
women than men. It has also been proposed that the AN yellowish-white or gray and frequently possess cystic com-
growth rate may accelerate during pregnancy.79 A number ponents. Many ANs appear internally heterogeneous and
of investigations have been carried out in an attempt to contain interspersed regions of soft and firm consistency.
clarify the possible influence of estrogen, progesterone, Their surface is typically smooth and regular. The most
and testosterone in AN growth.80–82 High-affinity estrogen pronounced vascularity appears on the tumor surface, taking
and progesterone receptors have been identified in a variable its origin from numerous small vessels of the IAC, CPA,
percentage of ANs. 82,83 In one investigation, cytosolic estro- and brainstem surface. Although ANs are frequently
gen receptors were identified in 30% of ANs, cytosolic prog- described as well encapsulated, little true capsule appears
esterone receptors were detected in 40%, and cytosolic evident. Nevertheless, as a general rule, the tumor surface
androgen receptors in 80%.82 In a recent series, 33% of does tend to be firmer and more vascular than its central
schwannomas showed expression for progesterone receptor; regions.
estrogen receptor mRNA levels were undetectable in all
tumors.80 While the possible molecular mechanism of Histopathology
estrogen and progesterone effect on AN has yet to be
elucidated, it is possible that they promote growth through Classically, histopathologic examination of AN reveals two
inducing proliferation of the vascular endothelium.84 morphologic patterns: Antoni A and B89–92 (Fig. 45-5).
In breast carcinoma, the presence of estrogen receptors is Antoni type A describes a densely packed cells with small,
an important factor in predicting responsiveness to anti- spindle-shaped, densely staining nuclei. Antoni type B
hormonal chemotherapy. An evaluation of antiestrogen refers to a looser cellular aggregation of vacuolated, pleo-
chemotherapy may be undertaken in the future in both morphic cells. The Antoni B morphology seems to occur
sporadic AN as well as in NF2. However, the relatively low predominantly in larger tumors. In a particular AN,
rate of receptor positivity predicts that only a small subset of one type may predominate or they may be thoroughly
tumors, if any, will be influenced by this form of treatment. admixed. The predominance of one variety does not
The level of gastrointestinal hormones has also been appear to be of clinical significance. A whirled appearance
evaluated in AN.85 In an evaluation of 19 ANs, some of Antoni A type cells is a Verocay body. Nuclear atypia is
tumors demonstrated elevation of the precursors of gastrin occasionally seen and does not necessarily imply greater
and cholecystokinin, but enhancement of the active peptides clinical aggressiveness. In Antoni B configurations, the
was not present. The significance of these observations presence of large, atypical, hyperchromatic nuclei has been
is unknown.

RADIATION
Radiation therapy is a valuable adjunct in treatment of
head and neck malignancy and selected benign lesions of
the head and neck. To date, little attention has been paid
to the long-term effects of radiation to the temporal bone.
Recent reports highlight the possibility of radiation-induced
malignancies in the temporal bone86 at a low incidence but
with very poor prognosis. Therapeutic irradiation has also
been shown to be capable of inducing benign intracranial
schwannomas.87
Recent studies have examined the risk of radiofrequency
radiation emitted from cellular telephones on the develop-
ment of AN. The hypothesis that intracranial energy
deposition from handheld cellular phones might cause
AN was tested in an epidemiologic study of 90 patients Figure 45-5. Photomicrograph of an acoustic neuroma with regions of both
Antoni type A (more dense) and B (looser) morphology. Verocay bodies,
and 86 control subjects.88 In patients who used cellular palisading nuclei around regular central regions, are also typical of
telephones, the tumor occurred more often on the con- schwannomas. (From Armed Forces Institute of Pathology: Tumors of the
tralateral than ipsilateral side of the head. The relative risk peripheral nervous system, ATLAS #672-231, 1967.)
734 SURGICAL NEUROTOLOGY

termed ancient schwannoma by pathologists. A positive S-100

immunoperoxidase stain is confirmatory of Schwann cell
origin.93 Although not usually needed, electron microscopy
may assist in confirming the diagnosis of AN through iden-
tification of the typical Schwann cell basement membrane.94
During their growth ANs are “pushers” that progressively
displace adjacent structures, often without macroscopic
signs of invasion. Upon close examination, however, a
substantial tendency toward microinvasiveness has been
detected.63,95–98
Degeneration of a benign AN into a malignant schwan-
noma has been reported, but is exceedingly rare.99,100
Malignant schwannoma has been reported to arise in
approximately 5% of patients with NF1, although a thor-
ough search of the literature failed to identify such a tumor
of eighth nerve origin.101 A number of peripheral malig-
nant schwannomas have arisen following irradiation ther-
apy to apparently benign lesions.102

GROWTH CHARACTERISTICS
Growth Pattern
Growth of ANs can be considered in four anatomic stages:
intracanalicular, cisternal, brainstem compressive, and
hydrocephalic (Table 45-2). ANs typically begin in the
IAC and can be discovered at a stage when they are wholly
intracanalicular (Figs. 45-6 and 45-7). As they begin to A
protrude into the CPA cistern, they initially displace CSF,
cranial nerves VII and VIII, and the anterior inferior cere-
bellar artery (AICA) (Figs. 45-8 and 45-9). Upon contacting
the lateral pontine surface, the brainstem compressive
stage commences (Fig. 45-10). At approximately this time
the fifth cranial nerve becomes involved. As brainstem
compression becomes severe, the fourth ventricle collapses
and the hydrocephalic stage begins (Figs. 45-11 and 45-12).
This growth pattern is highly stereotypic, but some
variations exist. As mentioned earlier, the degree of IAC
involvement varies widely and some tumors even spare the

TABLE 45-2. Symptomatic Progression of Acoustic Neuroma

with Tumor Growth
Stage Symptoms

Intracanalicular Hearing loss B

Tinnitus
Vertigo Figure 45-6. Illustration (A) and MRI scan (B) in the axial plane of an
Cisternal Hearing loss worsens intracanalicular acoustic neuroma.
Vertigo diminishes
Dysequilibrium increases
Brainstem Compressive Midfacial and corneal hypesthesia (V)
Occipital headache (occasionally) IAC entirely. The cisternal component, which is typically
Ataxia begins globular and centered over the IAC, can be ovoid or have
Hydrocephalic Worsening trigeminal symptoms its center of mass lie above the plane of the IAC. Tumors
Gait deteriorates
Headache becomes generalized that are ovoid in the medial-lateral plane may indent the
Visual loss due to increased intracranial pressure brainstem to a degree that seems out of proportion to its
Lower cranial nerve dysfunction diameter. Similarly, tumors ovoid in the anterior-posterior
(Hoarseness, dysphagia, aspiration, shoulder plane may become relatively large with minimal brainstem
and tongue weakness)
Long tract signs
compression. Cystic components or intratumoral hemor-
Death due to tonsillar herniation rhagic regions can also distort the tumor’s geometry and
result in an asymmetric bulge.
 Acoustic Neuroma (Vestibular Schwannoma) 735

Figure 45-7. Schematic illustration of an intracanalicular acoustic neuroma

in the coronal plane.

Growth Rate
The growth rate of ANs has been studied both in vitro and
in vivo. The fraction of dividing cells in an AN has been
assessed by immunohistochemical means with the fraction
of proliferating cells ranging between 0.36% and
3.15%.103 Similar findings were obtained for schwannomas
of various sites of origin evaluated via preoperative infusion B
of the thymidine analog 5-bromodeoxyuridine. In this Figure 45-8. Illustration (A) and MRI scan (B) in the axial plane of
study, the fraction of tumor cells in replication (S-phase) an acoustic neuroma in the cisternal stage.
was found to vary from 0.1% to 3.1% (mean 0.9%).104
A wider range was detected in a study of archival formalin- may explain the difficulties in estimating the growth of
fixed tissue subjected to flow cytometric analysis.105 The neuromas on the basis of clinical aspects only.
S-phase fraction varied from 1.1% to 20.7% (mean 6.3%). Although ANs grow at a variable rate, they are, by and
Of interest, evaluation of the clinical records of the large, slowly growing tumors (Table 45-3). Only in recent
49 patients in this study failed to reveal a correlation years, since the advent of CT and MRI scanning, has accu-
between proliferative rate and patient gender, symptom rate serial measurement of untreated tumors become pos-
manifestation, or tumor size. A possible correlation with sible. There are numerous studies of ANs serially studied
tumor growth rate could not be excluded from this study. by high-resolution imaging studies in the literature. When
It has also been observed that small tumors have a lower the available data are analyzed, ANs increase in diameter
mitotic index on average than larger tumors.106 No corre- an average of 0.1 cm to 0.2 cm per year. In one large study,
lation has been detected between the age of the patient and 50 patients were followed an average of 41.7 months with
the proportion of mitotically active cells in AN.106 a range of 7 to 152 months.109 The mean diameter growth
Several studies have been performed using Ki-nuclear was 0.11 cm per year with a range from −0.51 cm (reduc-
antigen as well as PCNA (proliferative nuclear antigen) as tion in size) to 0.98 cm growth per year. Although only a
an indicator of tumor growth.107,108 The results suggest few patients had a reduction in tumor diameter, 34%
that the growth rate of vestibular schwannomas varies and showed no discernible growth, and in only 22% did
736 SURGICAL NEUROTOLOGY

A
A

B
Figure 45-9. Schematic illustration (A) and MRI scan (B) of a cisternal stage
acoustic neuroma in the coronal plane.

growth exceed 0.2 cm per year. In a meta-analysis study,

526 patients were followed an average of 36 months.110
The mean growth rate was 0.18 cm with 54% of patients
showing radiologic growth. The growth group with
178 patients showed a mean growth rate of 0.4 cm per year
(range 0.14 cm to 0.56 cm per year). B
One must be cautious in interpreting these data to indicate Figure 45-10. Illustration (A) and MRI scan (B) in the axial plane of an
that a large fraction of ANs remain stable over the long acoustic neuroma in the early brainstem compressive stage.
term. First, patients in the above studies were deemed suit-
able for observation, undoubtedly based, in most cases, on
a relatively mundane clinical course. Patients with more apparently stable for 1 or 2 years will eventually demonstrate
dramatic or rapid-paced symptomatology would not have clinically relevant progression if observed for a decade or
been managed conservatively and thus the patient popula- longer. Third, the criteria to measure the tumor size are
tion is somewhat biased. Second, insufficient observations still variable and not even consistent in the same institution.
are available for 5-, 10-, or even 20-year intervals and For this reason, the clinician is wise to avoid overly rea-
patients often relate a gradual symptomatic progression ssuring younger patients. Fortunately, the fraction of rapidly
over such periods. It is probable that most tumors that are dividing tumors (exceeding 1 cm per year) is small, perhaps
 Acoustic Neuroma (Vestibular Schwannoma) 737

B
Figure 45-11. Illustration (A) and MRI scan (B) in the axial plane of an
acoustic neuroma in the late brainstem compressive stage.

only 10. It is also helpful for the clinician to be aware that

once a growth rate has been established for a particular B
tumor, this tends to remain consistent over time.111 This
Figure 45-12. A, Coronal representation of the brainstem deflection
observation may be helpful in counseling the older patient associated with a large acoustic neuroma. (From Cushing H: Tumors of the
regarding likely growth of the tumor over his or her Nervus Acusticus and the Syndrome of the Cerebello-Pontile Angle.
predicted lifespan. Nevertheless, the correlation between Philadelphia, Saunders, 1917). B, Coronal MRI scan illustrating dramatic
the rate of tumor growth and the pace of symptomatic pontine compression caused by a large acoustic neuroma. Note the
progression is imperfect. Some patients suffer symptomatic obstruction of the fourth ventricle and dilatation of the lateral ventricles.
738 SURGICAL NEUROTOLOGY

TABLE 45-3. Natural History of the Untreated Acoustic Neuroma

Report Year No. of Patients Follow-up (mean) Stable Smaller Larger

Selesnick110 Pre-1998 558 3 yr — — 54%

Charabi349 2000 126 3.8 yr 12% 6% 82%
Walsh182 2000 72 3.2 yr 50% 14% 37%

progression, particularly in hearing and balance function,

despite imaging studies that demonstrate no growth. As a
final caveat, many clinicians have maintained, based on
anecdotal observations, that ANs seem to progress more
slowly in the aged. However, this contention is supported
by neither clinical nor laboratory studies, both of which
show a range of growth rates in the elderly similar to that
in younger individuals.
Vestibular schwannoma growth rates in NF2 are generally
higher in younger people but are highly variable, even
among multiple NF2 patients of similar ages in the same
family112 (Fig. 45-13).
Occasional ANs expand at a rate far exceeding the norm
due to rapid enlargement of a nonneoplastic component of
the tumor (Fig. 45-14). Abrupt hemorrhage into an AN
has been reported and may result in the sudden worsening
of neurological status.113 Such intratumoral hemorrhage
can be triggered by head injury or vigorous physical exertion.
In addition, accumulation of fluid in cystic regions of the
tumor may lead to a relatively rapid increase in mass effect.
Both intratumoral hemorrhage and cystic expansion can
result in a rise in tumor volume at a rate well in excess of
that possible through growth of the cellular component of
the tumor. It has been estimated that one of these events
occurs in approximately 2% of ANs.114
A

B
Figure 45-13. Bilateral acoustic neuromas associated with neurofibromatosis Figure 45-14. Cystic acoustic neuroma before (A) and after (B) sudden
type 2. expansion as a result of intratumoral hemorrhage.
 Acoustic Neuroma (Vestibular Schwannoma) 739

Measurement of Acoustic Neuromas CLINICAL MANIFESTATIONS

There is still no universally accepted method of measuring Typical Clinical Presentation
ANs. However, a common language for expressing tumor
size is essential for valid comparisons among diagnostic Although it is possible to describe a typical clinical presen-
and therapeutic modalities. Two features of ANs complicate tation of AN, it is important for the clinician to be aware
measurement: their irregular geometry and the nonlinear of remarkable degree of variability in the manifestations of
relationship between tumor diameter and volume. Were these tumors (Table 45-4). With this caveat in mind, it is
ANs spherical, then a simple assessment of tumor diameter helpful for the diagnostician to develop a mental framework
in a single plane would be sufficient. However, inclusion of based on the most representative symptom complex for
the narrow tongue of tumor in the IAC in diameter mea- each stage of AN growth. The symptoms associated with
surements tends to substantially overestimate tumor size. intracanalicular ANs are typically limited to the eighth
Most authors advocate description of an AN’s size in terms nerve: hearing loss, tinnitus, and vestibular dysfunction.
of the diameter of the CPA component of the tumor as During the cisternal stage, hearing loss may worsen and
measured in three axes: (1) parallel to the petrous ridge, vertigo gradually becomes replaced by dysequilibrium.
(2) perpendicular to the petrous ridge, and (3) vertically.115 At about the time when brainstem compression begins,
The first two measurements are determined from axially trigeminal symptoms commence, initially in the midfacial
oriented scans, the third from coronal images (MRI or CT). region. As brainstem compression becomes severe, the
Thus, a tumor may be expressed as being 3.2 × 4.1 × 3.9 cm, fourth ventricle collapses and hydrocephalus results.
for example. For ease of comparison, many would simplify Chronic hydrocephalus frequently results in visual loss and
this to the single largest axial dimension (e.g., 4.1 cm). persistent headache. The terminal stages involve contralat-
As little data is published in the literature using other than eral long tract signs (e.g., hemiparesis) and eventual respira-
a single diameter measurement, this method is used in the tory death due to herniation of the cerebellar tonsils.
present chapter. Of course, wholly intracanalicular tumors
must be considered separately because they possess no CPA Signs and Symptoms
component. Definition of AN size ranges into small, medium, Hearing Loss
large, and giant sizes is useful in permitting comparison
among treatment groups. While there is no unanimity in Occurring in well over 95% of patients, hearing loss is the
defining these ranges, it is reasonable to divide ANs into most frequent symptom of AN. The mechanism, in most
the following categories: intracanalicular, smaller than cases, is from compression and/or infiltration of auditory
1.0 cm, 1.0 cm to 2.5 cm, 2.5 cm to 4 cm, and larger than nerve fibers. Impairment of the blood supply to the nerve
4 cm. Attempts are under way to establish an internationally or inner ear also plays a role in some cases. In the majority
accepted measurement standard.115,116 of patients, hearing loss progresses gradually over many
It has been pointed out that relatively small increases in years, eventually leading to total deafness in the tumor ear.
tumor diameter produce a much greater increase in tumor The loss is typically unilateral or asymmetric which, in its
volume.117 If it is assumed that the CPA component of early stages, preferentially involves the high frequencies.
most ANs are roughly spherical, then the interrelationship of Characteristically, speech discrimination is affected out of
tumor diameter and volume can be estimated as 4/3 πr3 proportion to pure tone hearing loss.
where diameter = 2r. As computed imaging programs Atypical forms of hearing loss are relatively frequent. In
become more sophisticated, comparison of tumor size based a study of a large group of patients with ANs, only 66% had
on volumetric calculations is likely to replace diameter-based a high-frequency biased hearing loss and approximately
measurement systems. 20% had an upsloping or trough-shaped loss, configurations

TABLE 45-4. Clinical Symptoms of Vestibular Schwannoma

Clinical Manifestations Cushing13 Mathew350 Selesnick11 Matthies119

Hearing Loss 100% 97% 85% 95%

Tinnitus 66% 56% 63%
Dysequilibrium 46% 48% 61%
Vertigo 5% 19% 61%
Trigeminal Nerve 63% 33% 20% 16.5%
Facial Nerve 77% 22% 10% 17%
Headache 100% 29% 19% 12%
Visual Symptoms 87% 15% 3% 1.8%
Lower Cranial Nerves 0% 2.7%–3.5%
Dysphagia 53% 0%
Papilledema
Asymptomatic 1.6%

Modified after Driscoll CLW: Acoustic Neuroma. In Jackler RK, Driscoll CLW: Tumors of the Ear and Temporal Bone. Philadelphia, Lippincott Williams & Wilkins, 2000.
740 SURGICAL NEUROTOLOGY

frequently ascribed to other causes.118 A sudden decrease perhaps by destruction of the vestibular nerve or through
in hearing, often equated by clinicians with viral infection interruption of the blood supply to the labyrinth.
or vascular occlusion, occurs in some 26% of ANs.48,119 Dysequilibrium is much more prevalent than vertigo,
Presumably, sudden hearing loss results from a spasm or occurring in nearly half of patients with ANs.48 In contrast
occlusion of the internal auditory artery as a result of to vertigo, which decreases in incidence with increasing
tumor compression. In some patients it may be triggered tumor size, dysequilibrium becomes more frequent with
by head trauma or vigorous physical exercise. The loss may larger tumors. Larger tumors (>3 cm) have a higher than
be partial or total, and spontaneous recovery is possible.120 70% incidence of this disturbing symptom. The most
Sudden loss may be the sentinel event that leads to a diag- likely mechanisms involved in causing dysequilibrium are
nosis or it may occur months or years before the tumor’s uncompensated unilateral vestibular deafferentation and
discovery. The diagnostician’s dilemma stems from the persistent perverse input from the diseased vestibular
fact that only some 1% to 2% of patients who have sudden nerve.
hearing loss will ultimately prove to have an AN. As a The characteristic symptoms of cerebellar dysfunction
general rule, we advocate a diligent search for ANs in are intention tremor and gait ataxia. Large ANs indent the
patients with sudden hearing loss. lateral cerebellar lobe and peduncles and may impair the
A small fraction of patients with ANs have either normal output of a sizable fraction of the ipsilateral cerebellar hemi-
hearing or symmetric hearing loss.48,121 Before the era of sphere. Somewhat surprisingly, overt cerebellar dysfunction
high-resolution imaging, most series showed 1% to 3% of is uncommon in ANs and is limited to large tumors.124
patients with AN had normal hearing. In a recent series Although little information is available on its exact incidence,
from the MRI era, 15% of patients with ANs had subjec- truncal ataxia appears to be more common than limb
tively normal hearing, of whom 4% were audiometrically ataxia. Patients tend to fall toward the side of the tumor,
normal (SRT < 25 dB, SDS >85%). In addition, 7% of although not invariably so.
patients had audiometrically symmetric hearing. It is clear
that the clinician must be alert to nonauditory symptoms if Facial Anesthesia and Pain
such tumors are to be detected early.
Facial sensory dysfunction occurs in approximately 50% of
tumors larger than 2 cm and is rarely present with smaller
Tinnitus
lesions.48,125 Hypesthesia of the midfacial region is the most
Tinnitus is very frequent in AN since it is many inner ear common symptom. This decreased sensation is often
diseases. In several studies, up to 70% of the patients suffered associated with tingling. Many patients and physicians alike
preoperative tinnitus.48,119,122 In most cases, the tinnitus is erroneously attribute these symptoms to sinus or dental
high pitched and localized to the tumor ear.123 However, disease. Gradually, the upper and lower divisions of the
the symptom may be nonlocalizing and may be of unusual trigeminal nerve become involved with the evolution of
pitches. The tinnitus is seldom very disturbing to the more widespread hypesthesia, which eventually progresses
patient. A few patients with AN have unilateral tinnitus in to anesthesia. In patients with symptomatic trigeminal nerve
the absence of subjective hearing loss. Thus, unilateral tin- dysfunction, the corneal reflex is almost always decreased or
nitus without explanation is an indication for an evaluation absent. Of note, the corneal reflex is also impaired in a con-
for AN. siderable number of patients with larger tumors who have
not been aware of any facial sensory disturbance.
Facial pain may also result from ANs. Trigeminal neu-
Vertigo, Dysequilibrium, and Dysmetria
ralgia is an uncommon but certainly not rare manifestation
Disturbance of the vestibular and cerebellar functions may in large tumors.126 Tumor-associated pain responds quite
generate a variety of symptoms in patients with ANs. well to therapy with carbamazepine in much the same
Vertigo, the cardinal symptom of peripheral vestibular manner as the idiopathic form of the disease (tic douloureux).
dysfunction, is an illusion of motion that is usually evoked A possible pathogenic mechanism is displacement of a vessel
or worsened by a change of head position. Subjectively, the (e.g., the superior cerebellar artery or the petrosal vein) by
typical complaint is of a whirling sensation, but other sen- the tumor into the root entry zone of the trigeminal nerve.
sations such as that of ground rolling or falling backward Contralateral trigeminal neuralgia has also been reported
may occur. Vertigo is episodic, and dysequilibrium is a but is very rare.127
continuous sense of instability. The patient with dysequi- Dysfunction of the motor division of the trigeminal
librium may complain of a minor incoordination or clum- nerve is a symptom limited to a few advanced ANs.
siness, particularly of gait, as well as a generally unsteady Unilateral temporal wasting and masseter atrophy may be
feeling. Although there is some overlap, the symptoms of noted on exam, and cross bite is a possible functional seque-
vertigo and dysequilibrium are usually quite distinct in lae. We have encountered one NF2 patient with bilateral
patients with ANs. masticatory paralysis, a situation that made gavage feeding
True vertigo is not commonly associated with ANs. In a of puréed foods necessary.
recent series, only 19% of individuals reported this symp-
tom, most of whom had small tumors.48 Vertigo is decidedly Facial Weakness and Spasm
infrequent with larger tumors at the time of diagnosis,
although some patients relate having been through an It is indeed surprising, given the location of the facial nerve
episode some years before the discovery of their tumor. (FN) in the epicenter of tumor growth, that disturbances of
Thus, it appears that vertigo is generated early in AN growth, facial mimetic function are uncommon during the natural
 Acoustic Neuroma (Vestibular Schwannoma) 741

history of AN growth. The FN appears to be robust in that peripheral vision, the development of tunnel vision, and
it can sustain substantial compression, stretch, and torsion eventual blindness. It should be noted that not all patients
from an AN and maintain its functional integrity. with increased intracranial pressure develop papilledema,
Although overt weakness is uncommon except in very and not all patients with papilledema develop visual loss. In
large tumors, a degree of facial twitching occurs in approxi- one study of eight patients with papilledema due to AN,
mately 10% of patents.48 Facial hyperfunction appears to none demonstrated impaired vision.131 Papilledema is
be independent of tumor size. The most common manifes- usually bilateral and symmetric, although visual loss is
tation is a minor quivering of the orbicularis oculi muscle. frequently asymmetric.
Hyperfunction can coexist with weakness. Full hemifacial Diplopia is an unusual finding in AN. Either the fourth
spasm is uncommon. In one such case encountered in our or sixth nerves can be paralyzed by a large AN, although
group, an artery displaced by the tumor appeared to this is extremely rare. The function of the sixth nerve can
impinge on the root entry zone of the FN. The great major- also be impaired secondarily, as a result of increased intracra-
ity of patients with ANs possess clinically normal facial func- nial pressure.
tion; however, subclinical motor impairment is occasionally
detected electromyographically. Abnormalities in evoked
Lower Cranial Nerves
electromyography and the blink reflex may be demon-
strated in a minority of patients with apparently normal Dysfunction of the lower cranial nerves (IX–XII) can result
facial function.128 in hoarseness, aspiration, dysphagia, and/or weakness of the
The FN is a mixed nerve that possesses a sensory ipsilateral shoulder. Even very large ANs seldom penetrate
component. It is distributed over the posterior aspect of the jugular foramen, although the intracranial course of
the ear canal and conchal bowl of the pinna. Diminished these nerve fibers may lie draped on the lower pole of the
sensation over this region has been described as a sign of tumor. Dysfunction of these nerves is sufficiently rare
AN, although it is of little practical significance. This obser- (up to 3.5 %119) that, when present, suspicion of a coexisting
vation is generally known as Hitzelberger’s sign.129 schwannoma of the jugular foramen region is warranted.

Headache Late Symptoms

The incidence of headache with ANs depends greatly on As a result of much improved diagnostic modalities, the
size. Very few patients with small tumors have headaches advanced symptoms of AN are seldom seen today. In many
that can reasonably be attributed to the tumor. In ways it is illuminating to read the classical descriptions of
medium-sized tumors (1 cm to 3 cm) the incidence is the agonal stages of the natural history of AN’s symptomatic
approximately 20%, and in large tumors it exceeds 40%.48 evolution.3,13 Long tract signs are seldom reported in
Headache associated with AN is variable.2,124,130 Most contemporary studies. Indeed, patients may have advanced
commonly it is either focused in the suboccipital region or brainstem compression and hydrocephalus with severe loss
generalized. It is attributable to hydrocephalus in only a of balance but still have motor and sensory function to the
minority of cases. Interestingly, not all patients with extremities. The progression from hyperreflexia to paresis
obstructive hydrocephalus due to AN suffer from to paralysis can be quite rapid as increased intracranial
headache. pressure becomes critical. The level of injury may be
pontine, from direct tumor pressure, or indirect at the
Ophthalmologic Manifestations lower medulla due to herniation of the cerebellar tonsils.
Ipsilateral findings characterize the first mechanism, and the
The most common ophthalmic manifestations of AN are latter may cause bilateral or even contralateral dysfunction.
nystagmus and decreased corneal reflex.131 A degree of In the final stages of the AN natural history, depressed
spontaneous nystagmus in the horizontal plane is frequent consciousness and stupor results. Intractable vomiting may
with even small tumors, presumably as a result of vestibular occur. In the terminal event, the patient lapses into coma
nerve involvement. There is a tendency for the nystagmus and expires with respiratory arrest.
to beat toward the intact side, although much variation
exists.132 With large tumors, however, pronounced vertical
Sudden Neurologic Deterioration
plane nystagmus may be seen as a consequence of brainstem
compression. Intratumoral hemorrhage is a rare occurrence in patients
Another important ophthalmic manifestation is with ANs but may result in sudden neurologic deterioration
papilledema from hydrocephalus. Historically, increased due to the onset of an acute CPA syndrome (see Fig.
intracranial pressure was ubiquitous at the time of AN 45-14).113,133 The patient may experience hearing loss,
diagnosis. Today, it has become a rare finding. In our acute facial spasm or weakness, facial sensory disturbance,
series, only 4% of patients with ANs had hydrocephalus.48 hoarseness, and even somnolence and long tract signs.
While hydrocephalus is usually obstructive, due to collapse Episodes of hemorrhage might be triggered by vigorous
of the fourth ventricle, it may also be communicating. physical exercise or head trauma. Emergent surgical inter-
Communicating hydrocephalus presumably results from vention may be required.
substances secreted by the tumor into cerebrospinal fluid Extratumoral hemorrhage also occurs in association
(CSF), which impairs the resorptive function of arachnoid with AN but is very rare. The patient suddenly develops
granulations. Chronic increased intracranial pressure may signs and symptoms of subarachnoid hemorrhage with
lead to optic atrophy manifested by progressive loss of severe headache, nuchal pain, nausea and vomiting, and
742 SURGICAL NEUROTOLOGY

mental status changes. One possible cause of subarachnoid widespread use: rollover and acoustic reflex decay. In
hemorrhage is rupture of a contact aneurysm arising from rollover, the speech discrimination worsens with increas-
a vessel laying against the tumor capsule. In one reported ingly loud presentation of the phonetically balanced word
case, the posterior inferior cerebellar artery was aneurys- list. In reflex decay, the acoustic reflex fades during a pro-
mal.134 Other possible mechanisms include bleeding from longed presentation of the signal presumably due to fatigue
a tumor surface vessel or rupture of a hemorrhagic cyst.135 of the auditory nerve. Neither test is very sensitive nor spe-
cific, but when one is abnormal, it might trigger the next
step in the diagnostic algorithm even when the pure tone
AUDIOLOGIC DIAGNOSIS and speech results show little cause for suspicion.

Pure Tone and Speech Audiometry Auditory Brainstem Responses

Because Chapter 7 (Hearing Loss in Neurotologic The ABR is the most sensitive and specific of all audiologic
Disease) comprehensively covers the audiologic diagnosis tests for AN. In documented ANs, a review of the litera-
of AN, only a brief summary is provided here. The primary ture reveals that approximately 20% to 30% have no
role of audiologic tests is to help identify the population at waves, 10% to 20% have only wave I and nothing there-
risk of an AN.48,121,125,136,137 Conventional pure tone and after, 40% to 60% have all waves but a wave V latency
speech audiometry remain the most useful and cost-effec- delay, and 10% to 15% have normal findings.138 Among
tive screening tools in helping to define who should abnormal ABRs, the ABR pattern most specific for AN is
undergo auditory brainstem responses or an imaging study. the presence of a wave I and nothing thereafter. As a gen-
Based on these two tests a classification has been proposed eral rule, the larger the tumor, the more severe the ABR
by the Committee on Hearing and Equilibrium of the abnormalities. However, notable exceptions exist and we
American Academy of Otolaryngology-Head and Neck have encountered large tumors with normal ABRs.
Surgery to establish guidelines for reporting results in The diagnostic efficiency of ABR has been extensively
hearing preservation surgery. Therefore, this classification is studied for both its sensitivity and specificity in AN diag-
used in this chapter (Fig. 45-15). nosis.139 Many reports give the sensitivity of ABR in the
The so-called special testing battery, a mainstay in the diagnosis of AN in the range of 96% to 99%.138 However,
detection of ANs during the 1960s and 1970s, has essentially these studies typically rely on CT scanning or even poly-
no role today. This includes short increment sensitivity tomography as the gold standard of diagnosis. Recent
index, alternating bilateral loudness balance, tone decay, experience, from the era of enhanced MRI scanning,
and other tests. This protocol has been largely abandoned demonstrates a substantially higher rate of false-negative
due to its lack of specificity and sensitivity in AN detection results. Numerous reports of false-negative ABRs have
when compared with auditory brainstem response appeared in the literature.138,140 In 1992, Wilson and
(ABR). Two components of this test regimen remain in coworkers reported an overall false-negative rate of 15%
(6/40).141 Importantly, ABR was normal in 33% (5/15) of
intracanalicular tumors. ABR appears to be more sensitive
for larger lesions, with only a 4% (1/25) false-negative
rate. In a study of four patients with ANs who had normal
conventional ABRs, measurement of the latency-intensity
relationships detected abnormalities in three, a substantial
improvement in the diagnostic yield.142 The latencies were
abnormally long at low intensities but converged toward
normal as intensity increased.
Neurotologists have generally thought that an abnormal
ABR had a fairly high specificity for AN.143 However,
recent studies reveal a surprisingly high incidence of false-
positive studies. In one study, only 15% (4/26) of patients
with ABRs indicative of a retrocochlear loss proved to have
an AN.144 In another study, only 12% (23/185) of patients
with abnormal ABRs actually had tumors.145 In a third study,
which used the relatively stringent criteria of IT5 > 0.6 msec,
only 18% of tested patients actually had CPA lesions.146
Undoubtedly, the incidence of false-positive results is
somewhat affected by the sophistication of both the equip-
ment and test giver, as well as by the definitions of abnor-
mality employed. Nevertheless, in real-world audiologic
settings, the false-positive rate for ABR in AN diagnosis
appears to exceed 80%, a percentage consistent with
our own experience. This observation is important in
Figure 45-15. The American Academy of Otolaryngology-Head and Neck
Surgery classification system for hearing following acoustic neuroma
assessing the economic efficiency of diagnostic protocols
surgery. The vertical axis represents the four tone average (500, 1000, 2000, used in the evaluation of patients with suspected ANs.
3000 dB) and the horizontal axis is word recognition score (%). Of note, it has been reported that the specificity of a
 Acoustic Neuroma (Vestibular Schwannoma) 743

positive ABR is considerably greater in younger individ- that improved sensitivity for small tumors of inferior
uals.145 In large tumors that cause much brainstem defor- vestibular nerve origin may be achieved using an infrared
mation, the contralateral ABR may be abnormal.147 video system that records rotatory nystagmus, which can
Currently a new ABR technique called stacked ABR be missed by conventional systems.161
seems to show a higher detection rate of VN with fewer Pathologic nystagmus takes a variety of forms in patients
false-positive results. Time and studies, however, must with ANs and may result from either eighth nerve or brain-
show whether this technique has additional value.148–150 stem dysfunction.132,157,160 Only a minority of patients with
small tumors demonstrate spontaneous nystagmus, but it is
quite prevalent in larger tumors (75% to 95%). The charac-
Otoacoustic emissions ter of the nystagmus also differs between small and larger
In theory, otoacoustic emissions (OAEs) should make an tumors. In small tumors, it tends to be characteristic of
excellent screening tool for ANs because they reflect outer peripheral labyrinthine dysfunction; in tumors with brain-
hair cell function. With OAEs, significant sensory hearing stem compression, central patterns predominate (vertical
loss suggests a retrocochlear cause. Unfortunately, ANs plane, ageotrophic, nonfatiguing). The nystagmus can be
cause both sensory and neural hearing loss. The sensory spontaneous, positional, gaze paretic, or dissociated and
hearing loss is presumably caused by either decreased may be unilateral or bilateral. As a general rule, nystagmus
blood supply to the inner ear or other unknown factors. tends to beat preferentially away from the tumor ear.132
In recent years, several studies have proposed the use of Several ENG abnormalities in patients with ANs are
otoacoustic emissions in ANs as risk stratification for attributable only to brainstem compression, and thus are not
hearing conservation.151–154 These studies focused on the encountered in smaller tumors. Fixation suppression of
identification of patients with impaired retrocochlear con- caloric induced nystagmus is impaired in roughly 20% to
duction but intact cochlear function. Particularly patients 50% of large tumors.157,160 Disturbances in vestibulo-ocular
with preoperative class C and D hearing and largely control may also occur. Asymmetries in optokinetic nystag-
immeasurable ABR could benefit from hearing conserva- mus and poor tracking on smooth pursuit are present in a
tion surgery in case of intact cochlear function. However, minority of large tumors. Deficient optokinetic responses
the number of patients with these criteria seems to be very tend to occur in the direction opposite from the tumor ear.132
low and will probably not lead to a significant increase
of hearing conservation approaches in patients with pre-
operative class C or D hearing.155 Rotatory Testing
Further studies will have to evaluate the role of OAEs in The integrity of the vestibulo-ocular reflex can be assessed
AN surgery. physiologically through use of a rotatory chair device. In
one study of 18 patients with ANs, abnormalities were
demonstrated in all patients including disturbances in
VESTIBULAR TESTING phase lag (72%), gain (62%), and symmetry (100%).162 In
another investigation involving 84 tumors, far fewer
Electronystagmography abnormalities were noted. Overall 74% of patients were
normal, including 100% of patients with small tumors.157
Vestibular evaluation with electronystagmography (ENG), In yet another series of 24 patients, 33% of patients with
rotatory testing, and dynamic posturography is frequently ANs demonstrated no abnormalities on rotatory testing.163
abnormal in patients with ANs. The ENG test battery
detects some abnormality in approximately 70% to 90% of
patients with ANs.132,136,156–159 The caloric response is the Dynamic Posturography
most readily quantifiable test in the battery and the one
most able to localize the side of pathology. In the setting of In a study of 40 patients with ANs, a wide variation of
AN, a depressed or absent caloric response indicates injury responses on sensory organization tests was noted from
to the superior vestibular nerve or impaired vascularity to normal to falling.156 Average performance was somewhat
the labyrinth from compression of the internal auditory below normal levels. No correlation between posturography
artery. When tumors of all sizes are considered, approxi- performance and caloric test results was found. The
mately 50% of tumor ears have absent caloric responses, authors recommend the test as a means of quantifying the
and most of the remaining patients have a partial reduced complaint of unsteadiness as well as to monitor the effects
response.157,160 While very few larger tumors have normal of surgery and to guide postoperative rehabilitative efforts.
caloric responses, as many as 50% of small tumors demon- In a retrospective study of six patients with small tumors,
strate caloric symmetry. Since the caloric response is gen- patients with inferior vestibular nerve tumors had greater
erated by the superior vestibular nerve (innervation to the instability at higher sway-referenced gains than did those
lateral semicircular canal), tumors originating from this with superior vestibular lesions.164 Because each patient
nerve demonstrate a higher frequency of abnormalities. with inferior vestibular nerve tumors had normal calorics
It has been reported that 98% of ANs originating from the and abnormal posturography, it was proposed that postur-
superior vestibular nerve show a reduced caloric response; ography might help to make the preoperative distinction
this is true for only 60% of those arising from the inferior between superior and inferior nerve origin. An awareness
division.159 Of course, once an inferior vestibular nerve of the probable nerve of origin may be relevant to the
tumor has attained considerable size, it can be expected to decision of whether to pursue a hearing conservation
destroy the adjacent superior division. It has been suggested approach (as discussed later).
744 SURGICAL NEUROTOLOGY

Utility of the Vestibular Test Batteries bordered filling defect suggestive of an intracanalicular AN,
particular when the IAC was narrow.
Unfortunately, no vestibular test taken alone or in conjunc- The introduction of MRI in the early 1980s was a major
tion with others has demonstrated sufficient sensitivity or improvement in AN diagnosis. Early MRIs demonstrated
specificity to be of much use in the diagnosis of AN. The an excellent ability to detect ANs but were somewhat
high false-negative rates (i.e., normal test results in patients unreliable when it came to intracanalicular lesions. This
who have a tumor) preclude using normal vestibular data to has been greatly improved since the introduction of
exclude a patient from consideration of AN. The high gadolinium-enhanced MRI (Gd-MRI).165,166 ANs enhance
false-positive rate (i.e., abnormal tests results due to causes with contrast more brightly on T1-weighted scans than
other than AN) means that vestibular test data, if taken any other intracranial tumor. The sensitivity of a thin-section
alone, would tend to excessively recommend referral for a Gd- MRI scan targeted to the IAC is excellent, with lesions
definitive imaging study. For these reasons, we do not as small as 1 millimeter within its resolution.
routinely perform vestibular investigations in patients MRI also provides information relevant to surgical
suspected of having an AN, preferring to rely instead on approach, which was not made available by earlier studies.
ABR and imaging studies to decide the issue. Of course, Of particular importance in selecting the optimal surgical
when features of history or physical examination suggest approach is the depth to which tumor penetrates the IAC.
chronic vestibulopathy and AN has been excluded by other By examination of the lateral extremity of the tumor in
investigations, then a vestibular test battery is obtained to relation to the surrounding inner ear structures, which are
guide therapy and rehabilitation. evident on T1- and especially T2-weighted scans, it is pos-
The vestibular test battery can be helpful in prognosticat- sible to predict whether the tumor can be removed without
ing the speed and completeness of vestibular compensation violating the inner ear.
following AN resection. With progressive growth of an False-negative Gd-MRI scans seem to be very rare,
AN, the involved vestibular nerve is gradually rendered although the exact incidence is hard to establish because
nonfunctional. Because this is a slow process, compensation no more sensitive study is currently in existence. One
is often imperceptible to the patient who remains function- potential pitfall occurs when a only a screening MRI study
ally intact. However, during tumor removal all residual of the entire brain is obtained. With such a study, which is
functioning vestibular fibers are interrupted. This helps to typically performed in thick sections (e.g., 10 mm), it is
explain the paradoxic finding that patients with small possible to overlook a small lesion that falls between
tumors (and thus a greater fraction of intact vestibular slices. False-positive Gd-MRI studies have also been
nerve fibers) suffer more immediate postoperative vertigo reported.167–169 The most common cause appears to be viral
than those with large lesions. On preoperative ENG, the mononeuritis of the seventh or eighth nerve.170 In such
more depressed the caloric response in the tumor ear, the cases, the neural complex enhances brightly, but it can usu-
less acute vestibular withdrawal is noted postoperatively. ally be differentiated from tumor by its normal diameter.
We do not routinely obtain ENG for prognostic purposes Another possible source of mistaken AN diagnosis stems
because knowledge of this status does not materially alter from a reliance solely on contrast-enhanced scans. Because
management of the patient. some structures in or around the IAC are inherently bright
on T1-weighted scans, they might be mistaken for an
enhancing tumor when precontrast scans are not obtained
RADIOLOGY for comparison. For example, a globular region of bone
marrow (which is rich in fat and therefore bright on
Chapter 21 (Imaging the Cerebellopontine Angle) T1-weighted images) adjacent to the IAC may erroneously
comprehensively covers the radiographic diagnosis of AN, suggest the presence of a tumor. Such mistaken impressions
so only a brief summary is provided here. There have been can be prevented by obtaining both pre- and postcontrast
four major eras in the evolution of imaging technology in T1-weighted scans. Noncontrast MRI sequences have
the diagnosis of AN: plain films of the IAC (1910s), poly- been recently suggested as an alternative for screening
tomography (1950s), CT (1970s), MRI (early 1980s). Both examinations to decrease the cost of imaging (Fig. 45-16).
plain films and polytomography do not image the tumor However, these new protocols have a decreased sensitivity
directly, but rather rely on detection of osseous changes particularly for small intracanalicular ANs. Therefore, the
involving the IAC. Because a high percentage of ANs do gold standard is still a gadolinium-enhanced sequence in
not expand the IAC or do so only minimally, these were order to optimize the detection of small AN.171,172
not sensitive methods. The addition of contrast (e.g., In addition, enhanced MRI has proved very useful in the
Pantopaque) into the CPA cistern improved diagnostic evaluation of the postoperative patient.173 It readily identi-
efficiency with polytomography, but it was invasive and fies residual and recurrent tumor and can usually differen-
often difficult to interpret. Contrast-enhanced CT scanning tiate it from any associated scar tissue. Scar tissue may
was a substantial advance over prior studies. Tumors larger enhance to a degree, but it typically appears less intense
than 2 cm could be reliably detected, but small lesions were than tumor, and its distribution usually suggests its true
often overlooked. Diagnostic yield could be improved nature. It is common for the meninges of the IAC and
through instillation of several mL of gas into the CPA cis- CPA to enhance to a degree following AN surgery, and
tern and IAC, however, this was frequently followed by this should not be confused with recurrence. A free muscle
spinal headache. In addition, gas-contrast CT had a rela- graft placed in the drilled IAC during a retrosigmoid or
tively high false-positive rate due to poor penetration of the middle fossa procedure may enhance postoperatively. This
gas into the IAC. This had the tendency to create a convex- enhancement is usually not as intense as tumor, but serial
 Acoustic Neuroma (Vestibular Schwannoma) 745

acknowledged that there exists no clear consensus among

experts in the field. The first controversial issue is who
should be considered at risk and thereby enter into a
pathway of the diagnostic algorithm. Most decisions are
initiated from results of routine diagnostic pure tone and
speech audiometry. The most obvious indication for further
investigation is progressive unilateral sensorineural hearing
loss (SNHL) not explainable by another pathologic mecha-
nism (e.g., noise trauma). However, exact guidelines for
just how much asymmetry and at what frequency are diffi-
cult to codify into a set of practical rules. Overly stringent
criteria tend to provoke too many diagnostic excursions
Figure 45-16. Fast spin-echo T2-weighted high-resolution MRI of a small and are therefore not economically efficient. While 10-dB
intracanalicular acoustic neuroma. The seventh and eighth nerves can be or 15-dB asymmetry isolated to 4000 Hz and 8000 Hz very
seen emanating from the medial aspect of the tumor, which shows up as a seldom indicates an AN, this same degree of asymmetry
filling defect in the IAC through the exclusion of CSF, as they course toward across the auditory spectrum is more suspicious. Of
their brainstem entry.
course, greater amounts of asymmetry usually should be
evaluated. Also of substantial importance are the results of
imaging studies may be required to confirm that it does speech discrimination testing. A decrease in speech dis-
not represent residual or recurrent disease. Following a crimination score out of proportion to the pure tone loss is
translabyrinthine procedure, during which an adipose well accepted as a cause for heightened suspicion. The
graft is placed in the craniotomy defect, it is important to timing and audiologic pattern of the asymmetric SNHL
employ fat-saturation techniques to permit recognition of also affect risk assessment. Fluctuant, low-frequency
any subtle enhancing components. SNHL accompanied by the sensation of aural pressure is
Although the radiographic differential diagnosis of AN only rarely a sign of AN. In this circumstance, the clinician
is large, as a practical matter only meningioma is likely to may reasonably choose to follow the patient only if no other
lead to any confusion.174 In a substantial majority of cases suspicious indicators are present. By contrast, many clini-
it is possible to distinguish between AN and meningioma cians have been falsely reassured by sudden hearing losses,
of the CPA based on their typical imaging characteristics under the mistaken assumption that they are seldom associ-
(Table 45-5).175 The reliable feature that differentiates the ated with AN. The coexistence of vestibular symptoms also
two is that meningiomas are sessile, typically possessing a increases suspicion of AN to some degree unless the clinical
broad base along the petrous pyramid, and ANs are glob- pattern is characteristic of a peripheral disorder such as
ular. It is important to be aware that one of the most char- endolymphatic hydrops. For example, very few patients
acteristic features of meningioma, an enhancing dural tail with AN exhibit severe episodes of vertigo typical of
extending for several millimeters from the periphery of the Ménière’s syndrome. The same cannot be said for individu-
lesion, can also occur with AN.176,177 als with intermittent positioning vertigo or chronic dysequi-
librium. The presence of trigeminal nerve dysfunction
(hypesthesia, anesthesia, dysesthesia, or pain) coexisting
DIAGNOSTIC PROTOCOLS FOR with an asymmetric SNHL is highly suspicious for a mass
SUSPECTED ACOUSTIC NEUROMA lesion of the CPA. Until more comprehensive data becomes
available on the relative risk of the various historical and
Much discussion has appeared in the literature concerning audiologic points suggestive of retrocochlear pathology, the
the optimal evaluation of the patient suspected of having decision as to when to proceed with a retrocochlear evalua-
an AN or other mass lesion of the CPA, and it should be tion will remain a matter of each clinician’s judgment.
Once the decision to embark on a retrocochlear evaluation
has been made, the next controversial issue is what consti-
tutes the optimal diagnostic protocol. It is generally agreed
TABLE 45-5. Characteristics of Common CPA Tumors
that a hierarchic combination of auditory, vestibular, and
on MRI and CT Scans
imaging studies are included in the algorithm, but the
Acoustic Neuroma number and sequence of tests varies considerably.146,178
Elaborate schema have been proposed based on complex
Globular
Centered on IAC numeric treatments of test results intended to guide efficient
Typically penetrate the IAC use of expensive imaging studies.179 In our opinion, such
Often erode the porus acusticus synthetic constructions have little validity and are cumber-
May be cystic some and impractical in their implementation. In recent
Meningioma years, the our diagnostic protocol has become quite simple.
Sessile Following a routine diagnostic audiologic evaluation,
Usually extrinsic to IAC patients considered at low risk of having an AN undergo
Eccentrically placed to long axis of IAC ABR, providing that sufficient hearing remains to generate
Hyperostosis
Calcification
an evaluable response. If the ABR is entirely normal,
Enhancement of adjacent dura (meningeal sign) the patient is requested to return in 1 year for follow-up
clinical and audiologic examination, sooner if new
746 SURGICAL NEUROTOLOGY

symptoms arise. Some examples of patients considered at the United Kingdom, and Canada) than it is in the United
low risk include those with minimal pure tone asymmetry, States. We can only hope that the incidence of late diagno-
a decades long history of stable asymmetric loss, and uni- sis will not rise as a consequence of these economic realities.
lateral tinnitus with a symmetric audiogram. If the patient
is evaluated as high risk or if the screening ABR has been
abnormal, then the patient undergoes a gadolinium- MANAGEMENT
enhanced MRI scan. A technically well-performed
enhanced MRI with a negative result effectively excludes Three treatment options are currently available: (1) obser-
AN for diagnostic consideration. For patients who cannot vation with serial imaging, (2) microsurgery, and
undergo MRI because they have metallic implants or (3) stereotactic radiation.
claustrophobia, contrast-enhanced CT scan is obtained. The choice of option is based on the preservation of life
Because CT often misses ANs smaller than 1.5 cm in diam- considering the natural course of these benign tumors,
eter, a gas-contrast cisternogram should be obtained in possible neurologic sequelae (e.g., cranial nerve dysfunc-
high-risk individuals if the enhanced CT is negative. CT is tion, ataxia), tumor removal, preservation of facial nerve
also a reasonable, and less costly, alternative in elderly function, and preservation of hearing. Individual morbidities
individuals in whom a small tumor would be considered associated with surgery and radiation have to be considered
clinically inconsequential. in this decision-making process.181–184

Conservative Management
DELAYED DIAGNOSIS Conservative management is recommended for patients with
small tumors who have a good possibility of not needing any
The development of highly sensitive diagnostic technology treatment in their predicted natural lifespan. In these
in recent years (e.g., ABR, gadolinium-enhanced MRI) has cases, it is a reasonable choice of management instead of
led to an increased fraction of small tumors among radiation or microsurgery.185
patients with ANs. Nevertheless, despite the availability of Factors in favor of conservative management are
these sophisticated tools, many tumors remain undiagnosed advanced age, infirm health, minimal symptoms, and long
until they have attained considerable size. Undoubtedly, clinical history suggestive of a slow growth rate. If with
some of these tumors escape early detection because the conservative management these patients remain clinically
patient chooses to ignore the relatively minor symptom of stable, they should undergo yearly scanning.
hearing loss until it becomes accompanied by more distress- Patients with stable tumors and failing balance may be
ing neurologic symptomatology such as dysequilibrium, treated with gentamicin locally in the middle ear to decrease
facial sensory or motor dysfunction, headache, or even the aberrant vestibular input.
visual loss due to papilledema. However, the patient’s inat- The obvious advantage of “wait and scan” is that it
tention accounts for only a portion of late diagnosis. In a avoids a potentially morbid intervention. According to
distressing number of cases, the patient has consulted a several recent studies, a marginal fraction of patients need
physician with symptoms attributable to the tumor some additional treatment (Table 45-6).
years before its discovery.48,121,180 In our (admittedly anec- One disadvantage is the need for periodic radiologic
dotal) experience, approximately one-half of patients with follow-up. In addition, the probability for functional
large tumors give a history of consultation that did not preservation of hearing might be reduced in cases where the
lead to diagnosis. The majority of these physicians were tumor grows significantly. Last but not least, the psychologic
both expert and conscientious. One pitfall in leading to the
erroneous conclusion that a tumor is not present stems
from reliance on less sensitive diagnostic tests such as CT TABLE 45-6. Reasons for Wait-and-Scan Strategy
scan and “special” audiometric diagnostic tests that give and Outcomes
false reassurance to the clinician. Even ABR misses a signif- Reasons for Deen351 Glasscock352 Tschudi181
icant fraction of small tumors. When the index of suspicion Observation (n = 68) (n = 34) (n = 71)
is high, it is important to obtain an enhanced MRI or, if
unavailable, an air-contrast CT. Understandably, diagnos- Tumor size 68%
ticians have a low index of suspicion when faced with a Advanced age 55% 53% 4.2%
Patient preference 21% 53.5%
clinical scenario not conventionally associated with AN. Minimal symptoms 9% 19.7%
However, a surprisingly high percentage of ANs present Poor general health 7% 24% 4.2%
with atypical findings such as sudden hearing loss and Asymptomatic tumor 4%
unilateral tinnitus. Missed diagnostic opportunities will Better or only hearing ear 4% 6% 1.4%
continue to be common in such patients until an improved Clinical Outcome
awareness of the diversity of AN presentation becomes No treatment 85% 76% 88%
more widespread. Further complicating this issue is the Microsurgery 13% 24% 12%
increasing need for frugality in obtaining expensive imag- Stereotactic radiation 2 0%
ing studies, particularly MRIs, in an era of contracting Mean age 67 yr (35–80) 75 yr (71–90) 52 yr (19–78)
Mean follow-up 45 mo 41 mo 35 mo
resources for health care. The mean size of an AN at diag-
nosis is already substantially greater in medically advanced Modified after Jackler RK, Driscoll CLW: Tumors of the Ear and Temporal Bone.
countries with limited access to MRI (e.g., Denmark, Philadelphia, Lippincott Williams & Wilkins, 2000.
 Acoustic Neuroma (Vestibular Schwannoma) 747

factor for the patient who knows about the lesion should at Stanford University uses (Fig. 45-18); however, no con-
not be underestimated. sensus exists among experts on the relative role of the various
approaches.
Selection from the various approaches depends on a
Microsurgical Management number of factors including the level of serviceable
The priorities in AN surgery are first the preservation of hearing, the depth of tumor extension into the IAC, the
life, second the maintenance of facial nerve function, and size of the tumor, and the experience and familiarity of the
third the preservation of socially useful hearing in the surgeon.192 The TL, RS, TO, and extended MF techniques
tumor ear. Among these goals, the first is nearly always all provide exposure of both the IAC and CPA, and the
achieved, the second is obtained with regularity, and the standard MF approach is suitable only for tumor confined
latter is realized only under favorable circumstances. to the IAC. Of all the factors taken into account, the amount
Contemporary AN surgery requires an operating micro- of residual hearing is most influential. Conservation of
scope, cranial nerve monitoring, and good neuroanesthesia useful hearing is a highly desirable goal which, as will be
(see Chapter 57, Intraoperative Monitoring of Cranial discussed later, is achieved relatively infrequently. Only
Nerves). A substantial institutional commitment is necessary two procedures afford the possibility of maintaining residual
to provide appropriate instruments, skilled operating hearing; the RS and MF approaches. Undoubtedly, surgeons
room personnel, cranial nerve monitoring equipment, would always attempt to save hearing were there not
postoperative intensive care, and the ready availability of potential adverse consequences from having undertaken
neurodiagnostic imaging. the effort. For tumors that involve the CPA, the choice
AN surgery can be performed by either a neurotologist usually boils down to the TL versus the RS approach. The
or neurosurgeon alone, but many centers have found that TL approach inherently sacrifices hearing as it traverses
collaboration between the specialties is desirable because it the inner ear in the process of creating the craniotomy.
takes best advantage of the special skills of each.186 However, compared with the RS approach, which provides
Another factor that favors the use of a surgical team is that some chance of hearing conservation, the TL method has
removal of an AN often requires prolonged delicate a somewhat lower morbidity. This is particularly notable
microsurgical dissection. The availability of two surgeons in the incidence of persistent headache. Tumor size, in and
minimizes fatigue, which can lead the operator to become of itself, has little effect on the choice between the TL and
impatient and less facile, neither of which is conducive to RS approaches. Either allows removal of even the largest
optimal functional outcome. AN. Criticism of the TL approach for insufficient expo-
Surgical procedures employed in the management of sure of larger tumors stems from inexperienced temporal
AN take place in two broad stages: (1) craniotomy and bone surgeons who achieved insufficient CPA exposure. In
exposure of the tumor and (2) microdissection of the experienced hands, the TL approach is capable of expos-
tumor away from brain, cranial nerves, and adjacent vascular ing even the largest AN.193,194 The primary anatomic
elements (Fig. 45-17). A variety of surgical approaches are limitation of transtemporal craniotomy for posterior fossa
used to expose an AN. The most used procedures are the tumor is exposure of the inferior aspect of the CPA, par-
retrosigmoid (RS), translabyrinthine (TL), and middle ticularly when both the jugular bulb and sigmoid sinus
fossa (MF) approaches. In a few centers, the transotic (TO) course are high (see Figs. 43-8 and 43-9 in Chapter 43,
and extended MF techniques are in use as well.187,188 Each Overview of Surgical Neurotology). Since ANs seldom
of these options has advantages and disadvantages, which extend into the lower reaches of the CPA, this limitation is
must be considered by the surgeon in selecting the optimal seldom relevant. Even when an AN has an atypically infe-
operative approach to a particular tumor. For a more rior extension, its capsule can usually be mobilized, follow-
detailed description of each procedure, see Chapter 43 ing tumor debulking, away from the nerves of the jugular
(Overview of Surgical Neurotology). Centers with a special foramen into the central portion of the operative exposure
interest in ANs tend to fall into three broad categories in where resection can take place under direct binocular
terms of surgical preference: retrosigmoid preferred, vision.
translabyrinthine preferred, and eclectic. Surgeons who The depth to which the tumor penetrates the IAC, as
adhere to the first two philosophies usually do so as a result visualized on gadolinium-enhanced MRI scans, is also a
of their greater familiarity and comfort with a particular major determinant in the selection of surgical approach.
method based on their training and experience. The eclectic Although the TL approach is capable of exposing the
philosophy, in which the choice of opening is made entire IAC from fundus to porus acusticus, the RS and MF
according to the attributes of the tumor being exposed, is approaches often require, particularly at the lateral end, a
being adopted by an increasing number of surgical teams, blind dissection to permit removal of the intracanalicular
especially those in which neurotologists and neurosurgeons component of the tumor without need for exenteration of
collaborate in the patient’s care.189–192 While it would be a portion of the inner ear.195 Our current practice is to
desirable from a technical and experiential standpoint to inform patients that the MF approach is clearly superior
always perform the same approach, in our opinion the for hearing but it carries a higher incidence of persistent
differential morbidity among the various options justifies facial paresis and synkinesis in tumors with 10- to 18-mm
the complexity of a selective protocol. In any event, the CPA components. The patient then judges the relative
choice of opening technique is not the most important importance of hearing and facial function for himself or
determinant of success in AN surgery; rather, the micro- herself.196
surgical skills the surgeons employ while removing the In the RS approach only approximately the medial two-
tumor are. The protocol discussed next is the one our team thirds of the canal can be exposed without sacrificing a
748 SURGICAL NEUROTOLOGY

Figure 45-17. Steps in the surgical

removal of acoustic neuroma. A, After
opening the internal auditory canal, the
intracanalicular portion is debulked and
the facial and cochlear nerves are A
identified laterally. B, After debulking the
intracranial portion of the tumor, the facial
and audiovestibular root entry zones into
the pons are identified.
Continued

portion of the otic capsule and thus reducing the chance of of the vestibular schwannoma, a transcochlear approach
maintaining residual hearing.197–199 In one study where has been reported as the most suitable approach.201–203
postoperative CT scan was used to assess labyrinthine Hearing status also has a major influence in the choice
integrity, entry into the inner ear was highly correlated of surgical approach. When the hearing is poor (<50 dB
with loss of hearing.200 However, minor labyrinthine SRT, <50% speech discrimination), we advocate the TL
entries do not inevitably result in deafness. Our preference approach regardless of tumor size and location. When the
is to expose the most lateral extension of the tumor in the hearing is serviceable, an RS approach is selected providing
IAC to permit direct visualization of the tumor interface that the CPA component of the tumor is smaller than
with its nerve of origin. Indirect dissection of the fundus is 2.5 cm in maximal diameter and the lateral third of the
sometimes selected, however, particularly in case of good IAC is free of tumor. The tumor size limitation in hearing
hearing, even though it carries a small possibility of recur- conservation approaches is based on the observation that
rence. Some individuals have tried using right-angled useful hearing is almost never preserved following removal
endoscopes to inspect the end of the canal to identify of tumors larger than 2.5 cm in diameter.204 This rule need
tumor remnants. In our experience, this has not proved not be adhered to rigidly. It is reasonable to attempt hear-
helpful because it has been difficult to distinguish, from ing conservation in tumors with even relatively large CPA
indirect inspection, between blood-stained neural tissue components when the hearing is particularly good and the
and residual tumor. In patients with an inner ear extension IAC is minimally involved. Although the probability of
 Acoustic Neuroma (Vestibular Schwannoma) 749

Figure 45-17, cont’d. C, The most difficult

(and time-consuming) part of the dissec-
tion is usually the removal of the last rind
of capsule from the most splayed and
adherent segment of the facial nerve, typi-
cally located just proximal to the anterior
lip of the porus acusticus.

success in such cases is very limited, the well-informed this is seldom the case with the posterior approaches
patient might accept the somewhat higher morbidity of an (RS and TL) (see Fig. 43-32 in Chapter 43, Overview of
RS craniotomy in hopes of the remote possibility of Surgical Neurotology).
maintaining some hearing. The importance of the patient’s The choice of approach to intracanalicular tumors that
participation in the treatment planning cannot be fill the IAC from fundus to porus involves a number of
overemphasized. factors. If the amount of residual hearing is marginal and
Either the RS or MF can be used during a hearing con- preoperative indicators (e.g., ABR) are not favorable, then
servation attempt to an intracanalicular tumor. The MF a TL approach is recommended under the assumption that
approach probably has the best chance of saving hearing, minimizing the risk of facial neuropraxia is more important
but this comes at the expense of a greater need to manipulate than undertaking an MF approach, which is unlikely to
the FN. From the perspective of the MF approach, the FN maintain even imperfect hearing. The liability of FN
may lie between the surgeon’s point of view and the tumor; injury with the MF approach is influenced by whether the
tumor took its origin from the superior or inferior vestibular
nerve. Typically, the FN lies in a less favorable position on
the tumor’s superior surface with inferior vestibular nerve
tumors. Our group uses coronal MRI images to determine
the location of the tumor in relation to the transverse
crest. This approach can give a hint on the probable nerve
of origin; in addition, ENG may provide some insight.
Because the caloric response is generated by the lateral
semicircular canal, which is supplied by the superior
vestibular nerve, a robust caloric response is suggestive of
inferior vestibular origin. When caloric responses are absent,
it is by no means certain that the tumor has a superior
vestibular origin. An inferior vestibular tumor can compress
its neighbor and render it nonfunctional.
Aside from the FN factor, it is also more difficult to save
hearing in inferior vestibular nerve tumors. They possess a
more intimate relationship with the cochlear nerve and the
internal auditory artery than tumors that originate in the
superior compartment. Another useful factor in assessing
the probability of success in hearing conservation attempts
Figure 45-18. Acoustic neuroma microsurgical management algorithm used is the extent to which the bony walls of the IAC are
at Stanford University. This scheme represents a general guideline only.
Individualized treatment selection depends on numerous factors. Size is
eroded.196 Our impression is that extensive erosion of the
expressed in diameter of the CPA component. MF, middle fossa; IAC, particularly of its anterior wall, is an adverse prognos-
RS, retrosigmoid; TL, translabyrinthine. tic sign. Similarly, if the tumor prolapses into the cochlear
750 SURGICAL NEUROTOLOGY

modiolus on gadolinium-enhanced MRI scan, the proba- the FN brainstem entry is identified visually and electrically.
bility of hearing preservation is diminished. The tumor capsule is then sequentially liberated and excised
Once the craniotomy has been completed, tumor until only a small portion of capsular peel persists on the
removal proceeds in two stages: (1) debulking the central most adherent segment of the tumor-nerve interface.
region followed by (2) microdissection of the tumor capsule
away from adjacent brain, cranial nerves, and blood vessels.
Debulking, which is not technically difficult, can be THE ROLE FOR INCOMPLETE RESECTION
facilitated by use of an ultrasonic aspirator, laser, or suction
dissector. The biggest challenge in AN surgery is preser- It is generally held that completely excised ANs do not recur.
vation of the cranial nerves, which lie draped on the Under certain circumstances, it is reasonable to consider less
tumor’s surface. Since it shares the IAC and CPA with the than complete removal despite the attendant increased risk
audiovestibular nerve, the FN is invariably affected by of regrowth.205–210 This may be planned preoperatively,
acoustic tumors. Within the IAC, the FN becomes elected during surgery as a concession to cranial nerve
compressed between the tumor and the osseous walls of preservation, or mandatory in the case of adverse patient
the canal (Fig. 45-19). Fortunately, the nerve is seldom response to efforts at tumor removal. A planned incomplete
very adherent to the tumor in this location. In the CPA, resection may be undertaken when a more prolonged
progressive tumor growth stretches the FN over the tumor operation is judged unwise because of the patient’s
surface, most commonly in the anterior direction. advanced age or medical condition. Incomplete removal
Anterosuperior and anteroinferior courses are also frequent, may be elected intraoperatively when dissection planes are
and posterior courses are decidedly rare (Fig. 45-20). poor and the surgeon judges that total tumor removal carries
Familiarity with the variations of the FN course is essen- a high risk of anatomically disrupting the FN. The hearing
tial if optimal functional results are to be obtained. Unlike status of the contralateral ear is also relevant. If it is impaired
in the IAC, the FN is often adherent to the tumor in the from a second AN or other otologic disease, incomplete
CPA, particularly in the segment just medial to the porus removal increases the odds of hearing conservation.211
acusticus. The process of removing the tumor from the FN Whether the surgeon proceeds with radical resection or
usually commences with the identification of the nerve in performs an incomplete removal depends on several factors.
the distal IAC. After removal of the intracanalicular com- Most advocate a more aggressive approach in younger
ponent of the tumor, the CPA component is debulked and patients. When deciding on the extent of dissection, it is

A B
Figure 45-19. The effect of progressive acoustic tumor growth on the facial nerve. A, In the early stages of tumor growth, the nerve becomes compressed
between the tumor and the bony walls the IAC. B, As the extracanalicular component expands, the nerve becomes progressively more stretched and splayed
over the tumor surface.
 Acoustic Neuroma (Vestibular Schwannoma) 751

A B

C D
Figure 45-20. Relationship of the facial nerve to a medium-sized acoustic neuroma. In the vast majority of cases, the nerve courses over the anterior surface of
the tumor. Most common is direct anterior (A); less common are anterosuperior (B) and anteroinferior (C). Posterior courses are rare in acoustic tumors, but
complex superior-posterior routes (D) are occasionally encountered.
Continued

important to consider the patient’s priorities with regard to also occur during tumor dissection from the trigeminal
neural preservation versus the risk of suffering recurrent nerve and can be controlled by either deepening the anes-
disease. On rare occasions, incomplete resection becomes thesia or applying local anesthetic topically to the nerve
mandatory when a patient deteriorates intraoperatively, without need for curtailing the procedure.
either medically or neurologically, necessitating premature In any discussion of incomplete resection, it is impor-
termination of the procedure. An example of this situa- tant to distinguish whether removal has been “subtotal”
tion is the development of bradycardia associated with or “near total” because it has substantial impact on the
hypertension (Cushing’s reflex) during dissection of the risk of recurrence (Fig. 45-21). In subtotal excision, a sub-
tumor from the brainstem. This same phenomenon can stantial portion of tumor remains (>25 mm2, >2 mm thick),
752 SURGICAL NEUROTOLOGY

Figure 45-20, cont’d. Direct posterior courses (E) are exceedingly rare in
acoustic neuromas, although they are frequent in meningiomas and other
tumors of the cerebellopontine angle.

whereas in near-total removal the residual consists of only In our group we routinely use fat-saturation MRI in all cases
a small, thin capsular peel (<25 mm2, <2 mm thick). to differentiate tumors from scars and dural enhancement.
Because ANs receive their blood supply from both the IAC Little has been published on the long-term follow-up of
and brainstem, residual tumor left in contact with these near-total excision cases. In our experience, the recurrence
sites carries a higher risk of generating recurrence. rate after a near-total resection (1/33 = 3%) is low, but it is
Fragments of tumor left in the fundus of the IAC are well 10 times higher after a subtotal resection (6/19).210 In one
known to be capable of generating a recurrence.209,212 By other series of patients followed an average of 5.3 years
contrast, the thin capsular remnant that hangs free in the postoperatively, 38% (3/8) subtotally resected tumors
CPA after near-total excision is likely to be devitalized and demonstrated signs of growth but none (0/15) of the
carries a substantially lower likelihood of regrowth. CT nearly totally removed did.206 In another study, 29% (4/14)
and unenhanced MRI are relatively insensitive to small of tumor residuals less than 5 mm in diameter enlarged
amounts of residual tumor. Gadolinium-enhanced MRI, over a mean follow-up of 5.8 years.208 This study also
however, is quite sensitive to tumor fragments.166 suggested that cauterization of the tumor remnant reduced
(Fig. 45-22). However, enhanced MRI is not always able to the incidence of regrowth. Recurrent tumors enlarged at a
differentiate postoperative scar or dural enhancement from rate similar to that of unoperated tumors, an average of
tumor. When the presumed residual or recurrent disease is approximately 2 mm per year.213 Very-long-term follow-
small, only progressive growth on serial enhanced MRI up is required in order to assess the impact of recurrent
scans provides convincing evidence of the neoplastic disease on the patient’s longevity. In one study, a group of
nature of the lesion. Enhanced MRI should be able to 139 patients with presumed incomplete removal (the IAC
detect the residual tumor in all cases of subtotal excision; was never drilled open during the operation) was evaluated
following near-total excision, MRI is able to visualize the between 20 and 30 years following surgery. Compared
known tumor remnant in only some 50% of cases.206,208 with the population at large, there was no excessive mortality

Figure 45-21. Illustration of a

medium-sized acoustic neuroma
(A) compared with subtotal (B) and
near-total (C) removal. In near-total
removal, a thin piece of tumor capsule is
left attached to the most adherent portion
of the facial nerve.

A B C
 Acoustic Neuroma (Vestibular Schwannoma) 753

tumors occasionally are not generally as successful as those

obtained by specialized teams. An analysis of 59 patients
treated at five centers in Denmark over 11 years (1979 to
1990) was reported.214 In this series, each treating center
averaged just 1 AN surgery per year. Mortality was 8.5%,
well above the <1% reported in most contemporary series.
Furthermore, cranial nerve preservation rates were low, as
exemplified by the one-third of patients who required FN
reconstruction and 58% with grade 6 palsies, despite
incomplete resection in 29% of patients. Despite routine
use of a suboccipital approach, in no case was residual
hearing conserved. Complications such as CSF leak, which
occurred in 36%, were also unusually high. Of note, in 16
tumors smaller than 2.5 cm diameter in the CPA, mortal-
ity was 12.5%, CSF leak occurred in 50%, and normal
Figure 45-22. Axial postgadolinium T1-weighted MRI scan illustrating a less
facial function was maintained in only 6%.215 A recent
than complete resection of an acoustic neuroma. The thin remnant of the study in the United States revealed significantly better
tumor surface can be visualized where it was left in situ along the adherent outcomes after surgery at high-volume hospitals or by
course of the facial nerve. The temporal bone defect is filled with adipose tissue. higher volume surgeons, including a trend to lower mor-
tality. In addition, postoperative complications were less
likely in these institutions or in cases from higher volume
beyond the first postoperative year. Two symptomatic surgeons, which lead to a significant difference in length-
recurrences were encountered 13 and 17 years following of-stay as well as costs.216 In the anecdotal experience of
treatment. This emphasizes the need for late scans to detect the author, as well as that of many others interested in the
slowly evolving recurrence. Following complete excision management of these tumors, the findings of the Danish as
of an AN, we recommend enhanced MRI scanning including well as the U.S. study are not aberrations, but rather
fat-saturation technique at 3 years to screen for unantici- represent an accurate picture of results by well-intentioned
pated recurrence. After incomplete removal, scans are but less experienced surgeons undertaking AN removal.
obtained yearly for 5 years and then biannually until a While such arguments put forward by one with a special
decade of stability has passed and more frequently if growth interest in AN management may seem self-serving, the
is noted as clinical circumstances warrant. differential outcome implies that patients with ANs bene-
Cystic tumors are particularly likely to recur when merely fit substantially when managed at a center with experi-
debulked. We have encountered two cases, both in elderly enced personnel and the institutional commitment to
individuals, where brainstem compression recurred within achieve optimal results.
2 years following intracapsular debulking and cyst fenestra-
tion.113 In these cases, the cause was reformation of the
capsule and progressive expansion of the cyst with little
Mortality
growth in the residual neoplastic component of the tumor. The mortality of AN surgery has fallen steadily over
As a general rule, we strive to achieve total removal of recent years to a level under 2% in most major centers.
AN whenever possible. Near-total excision is most often However, there is a significant difference in outcome of
elected when continued dissection threatens disruption of patients who had surgery at lowest-caseload-quartile hospi-
the FN. In a recent series from the University of Michigan, tals (1.1% died), compared with 0.6% at highest-volume-
near-total excision was elected in 17% of AN surgeries, quartile hospitals.216 Causes of mortality fall into two
typically as a concession to neurologic preservation.206 broad categories: tumor related and medical. Most common
This incidence is in line with our experience of less than among tumor-related causes are ischemic brain injury due
10% incomplete resection.210 Our policy is to avoid subtotal to arterial or venous interruption, acute postoperative
removal whenever possible, particularly when the tumor CPA hemorrhage, meningitis, and air embolism.217,218
possesses a cystic component. Tumor-related mortality occurs almost exclusively in those
with large tumors. By contrast, the occurrence of serious
medical complications is more related to the patient’s age
OUTCOME OF ACOUSTIC and underlying medical condition than it is to tumor sta-
NEUROMA SURGERY tus. The possible lethal medical complications of AN sur-
gery are the same as those associated with any major
Decentralized versus operative procedure: pneumonia (atelectasis or aspiration),
Centralized Hospitals pulmonary embolus, peptic ulceration, and myocardial
infarction, among others.
Results in AN surgery, perhaps to a greater degree than
with other intracranial tumors, depends on the experience Complications
and microsurgical skill of the surgical team. The vast major-
ity of the published results are derived from experienced Postoperative complications are relatively frequent follow-
groups who have a special interest in the management of ing AN surgery, occurring in approximately 20% of
these tumors. Results from surgeons who operate on these patients.219 See Chapter 44 (Complications in Neurotologic
754 SURGICAL NEUROTOLOGY

Surgery). However, in recent years a significant reduction occur to a variable degree. The prognosis for the partial
in large series has been reported.220 As with mortality, the AICA syndrome is generally favorable, with gait rehabilita-
incidence of morbidity is higher in elderly and infirm indi- tion gradually progressing over a matter of months. Limb
viduals, in those with large tumors, and in hospitals with ataxia also improves, but writing skills and the ability to
fewer skull base procedures. Fortunately, the vast majority perform precise manual tasks may remain impaired on the
of complications are successfully managed and the patient operated side. Postoperative ischemia may also occur as the
recovers without sequelae. Nevertheless, these contribute result of vasospasm involving the vertebrobasilar system.223
to patient discomfort, can prolong recovery, and add to the Venous infarction can also occur following AN surgery,
cost of care. A small minority of complications lead to lasting but is less common than arterial injury. The sigmoid sinus
functional deficits. can be injured during either a TL or RS approach. Although
hemorrhage from an emissary vein or minor mural bleeding
is common, the sinus seldom requires ligation. Nevertheless,
Intracranial Vascular Complications
the required surface tamponade with a hemostatic such as
One of the most devastating complications of AN surgery Surgicel may lead to formation of a thrombus, which even-
stems from interruption of the anterior inferior cerebellar tually clots off the entire vessel. Sudden loss of a one sig-
artery (AICA) or one of its branches. This artery is moid/transverse system seldom results in significant
intimately related to the capsular surface of ANs. Since the venous ischemia. In rare cases where the surgical side carries
vessel often loops into the vicinity of the porus acusticus, most of the cerebral venous outflow, congestion and even
it is at risk during removal of even relatively small tumors. hemorrhage can occur. Because it may be particularly
The full-blown AICA syndrome results in extensive infarc- intense in the temporoparietal region, speech disturbance
tion of the pons and is usually fatal. Fortunately, with mod- may result. Rarely, venous congestion due to sigmoid sinus
ern microsurgical techniques, complete AICA syndrome thrombosis is fatal due to progressive cerebral edema.
has become very rare. Partial AICA syndrome, caused by Another possible sequela of sinus occlusion is papilledema
disruption of the terminal branches of the AICA, results in with progressive visual loss. In one of our patients, this
ischemic injury to the middle cerebellar peduncle and required fenestration of the optic nerve sheath to relieve
a variable amount of the lateral aspect of the pons221,222 neural compression. We have also encountered one case
(Fig. 45-23). Although we have never encountered a com- of isolated cerebellar venous infarction associated with
plete AICA syndrome, several of our patients have developed hemorrhage, the cause of which was uncertain. It may be
the partial variety. The dominant symptoms in such cases speculated that it resulted from interruption of the
have been ataxia and dysmetria resulting from blockage of petrosal vein (Dandy’s vein), which is routinely divided in
cerebellar connections with the brainstem. Long tract signs, larger tumors to permit mobilization of the cerebellar
manifested as hemiparesis or hemisensory disturbance, hemisphere. Anomalous cerebellar drainage may render
the cerebellum vulnerable to loss of this drainage route. The
veins that course along the inferior aspect of the temporal
lobe can also be injured during surgery.224,225 They are
particularly at risk during middle fossa and extended middle
fossa approaches. Fortunately, temporal lobe retraction is
extradural, so the risk of injury to these vessels is small.
Interruption of the vein of Labbé on the dominant side
may result in substantial speech disturbance and memory
loss, both of which generally improve with time.
Postoperative hemorrhage into the CPA is a dreaded
complication of AN surgery. It is axiomatic in AN surgery
that the procedure is not terminated until all bleeding vessels
are well controlled. Even when excellent hemostasis
appears to have been achieved, postoperative hemorrhage
may still occur in rare cases. The most probable causes are
postoperative hypertension, which dislodges a clot from
the cut end of a vessel, release from vasospasm, and coag-
ulopathy. When bleeding in the CPA is suspected, the
patient should either be rushed back to surgery or undergo
a noncontrast CT scan to assess for hemorrhage, depending
on the severity of the clinical situation.
Air embolism is another potentially serious vascular
complication of AN surgery.226 The risk of this complication
can be greatly reduced by adaptation of a supine operating
position. When the sitting position is used, precordial
Doppler monitoring should be performed and a central
Figure 45-23. Axial T2-weighted MRI scan demonstrating hyperintensity in venous line placed. At the first sign of air embolization, the
the cerebellar peduncle and lateral pons due to an interruption of the distal
branches of the anterior inferior cerebellar artery (arrows). This patient
field should be flooded with irrigant solution and the
suffered from transient ataxia and dysmetria for several months patient’s head lowered. Air within the right side of the heart
postoperatively. may be aspirated through the central venous catheter.
 Acoustic Neuroma (Vestibular Schwannoma) 755

planes are sufficiently obscure that the dissection becomes

Traumatic Parenchymal Injury
subpial in places. The underlying brain tissue may be
The cerebellum, pons, and temporal lobe are vulnerable to markedly softened or even gelatinous when compression
injury during resection of ANs. This can result from either has been extreme and long standing. Although this phe-
retractor injury or a breach of the pial lining during tumor nomenon is of little concern on the cerebellar surface, it
microdissection. Cerebellar and temporal lobe injury are could be very dangerous on the pons. By employing sharp
more likely to result from excessive retraction, and pontine dissection and using the pontine surface veins as a guide, it
injury is more likely due to traumatic dissection. Among is usually possible to prevent direct injury to the brainstem.
these cerebellar injury is fairly common. Postoperative However, in the rare instances where the capsule is inex-
MRI scans frequently reveal a degree of malacia involving tricable without risking pontine injury, we favor leaving a
the lateral 1 to 2 cm of the cerebellar parenchyma thin capsular peel on the most adherent regions. It is
(Fig. 45-24). This is particularly common following the important to realize that most pontine injuries associated
RS approach where retraction is relatively more vigorous. with AN removal arise indirectly, through vascular com-
The functional significance of this radiographic finding is promise, rather than as a result of direct injury.
not well delineated, and most of these patients recover
uneventfully from their surgery. T2-weighted scans are par- Cerebrospinal Fluid Leak
ticularly sensitive to detecting subtle degrees of parenchy-
mal injury and often remain permanently abnormal. Rarely, CSF leakage is the most common complication of AN sur-
cerebellar injury extends more deeply toward the midline. gery, occurring in some 5% to 15% of patients in most
In such cases prolonged ataxia, which may take many series with a trend toward a higher rate in older
months to resolve, may result. In the past, resection of the patients.219,220,228,229 CSF can escape through either the
lateral third of the ipsilateral cerebellar hemisphere was a skin at the wound site or mucosa via the nose (Fig. 45-25).
fairly common maneuver intended to improve exposure and CSF otorhinorrhea is much more common than seepage
provide space to accommodate postoperative swelling. through the wound. In our experience, CSF otorhinorrhea
Although this was usually well tolerated, modern surgical complicates approximately 13% of translabyrinthine, 10%
and neuroanesthetic methods have made it unnecessary. of middle fossa, and 10% of retrosigmoid procedures.
In rare instances, the cerebellum massively swells during Neither surgical approach nor tumor size affects the rate
surgery. The most likely factors contributing to this are of postoperative cerebrospinal fluid leakage.230 Wound
insufficient use of brain-shrinking measures (e.g., mannitol, leaks are substantially less common and occur with
hyperventilation) and premature application of the cerebel- approximately equal incidence from the two procedures.
lar retractor before liberating CSF from the cisterna magna. Leakage via the wound most often results from too loose a
Very recently, electroencephalogram (EEG) changes (low- closure of the muscle layers and subcutaneous tissue.
frequency activity and IEA) have been reported as part of However, even the most stoutly closed wound can fail
the middle cranial fossa procedure; in translabyrinthine- under the onslaught of increased intracranial pressure or
operated patients EEG changes are fewer.227 when healing is retarded through high-dose corticosteroid
Injury of the brain surface during microdissection of the therapy.
tumor capsule from it can nearly always be prevented. In Precautionary measures to decrease the incidence of
the vast majority of ANs, an arachnoid plane can be main- postoperative complications related to CSF leak in patients
tained throughout tumor dissection. Occasionally, particu- with preoperative hereditary coproporphyria (HCP) are
larly with very large tumors, the cerebellar and/or pontine the obliteration of exposed air cells, including those
around the internal auditory canal, accurate restoration of
the dural barrier, and temporary lowering of intracranial

Figure 45-24. Encephalomalacia of the lateral lobe of the cerebellum

resulting from retraction during acoustic neuroma surgery. This finding
is most likely to occur following a retrosigmoid approach to a large tumor. Figure 45-25. Cerebrospinal fluid rhinorrhea.
756 SURGICAL NEUROTOLOGY

pressure with a ventricular or lumbar drain. Patients with The initial management of postoperative CSF leak
persistent symptomatic HCP after tumor excision should involves simple medical measures such as limited activity,
be treated with a ventriculoperitoneal shunt. Delaying this fluid restriction, and administration of the carbonic anhy-
decision until the postoperative period is safe and avoids drase inhibitor acetazolamide (Diamox) to reduce CSF
unnecessary shunting in the majority of patients, accord- production and stool softeners to obviate the need for
ing to a recent study.231 straining. Only wound leaks are handled surgically from
In mucosal leaks associated with the RS or MF the outset. These are oversewn at the bedside with one or
approaches, the most common route of egress is via the more vertical mattress sutures. If the leak continues
transected pneumatic cells of the apical petrous bone, despite these measures, then a lumbar subarachnoid drain
which surround the IAC. Extensive peri-IAC pneumatiza- is placed and left in for 3 days. The same algorithm is used
tion is present in approximately 30% of adults. A second for CSF otorhinorrhea except that reoperation is undertaken
possible pathway into the temporal bone exists more only if the leak persists despite lumbar drainage or recurs
superficially at the anterior edge of the RS craniotomy. once the drain is removed.234–236 In transnasal leaks that
The retrosigmoid air cells are extradural in this location, traverse a deaf ear, we favor subtotal petrosectomy with
but dural closure is often not watertight and CSF may thus closure of the external auditory meatus and blockade of the
gain access to transected cells at this location. Both peri-IAC eustachian tube under direct vision with bone wax followed
and retrosigmoid leaks may occur despite diligent efforts by a muscle plug.237 When useful residual hearing persists,
by the surgeon to seal opened pneumatic tracts with bone an intact canal wall mastoidectomy is performed and the
wax, autogenous tissue, fibrin glue, and/or bone cement. fossa incudis is obstructed with an autogenous tissue graft.
Most surgeons occlude transected air cells with bone wax Transnasal obliteration of the eustachian tube is another
overlain with an autologous tissue graft. Some advocate method that has been advocated in cases of CSF otorhin-
the use of fibrin glue to augment this closure, although we orrhea.228 Following surgery for CSF leak, a fresh lumbar
did not find it helpful in a several-year trial.232 Ionomeric drain is placed and left in place for 3 days. A few leaks persist
bone cement shows promise as a superior material for filling despite all medical and surgical efforts to stem the flow. In
bony defects and may replace bone wax in the future.233 such cases, hydrocephalus is often the underlying cause.
Transmucosal CSF leaks following a TL craniotomy occur These persistent leaks are often best managed by permanent
via the fossa incudis directly into the middle ear. These CSF shunting. In communicating hydrocephalus, which pre-
may be discouraged by sealing the communication to the dominates in this situation, a lumboperitoneal shunt is used.
middle ear with a fascial graft or by obliteration of the A rare complication of CSF fistula through the ear is ten-
eustachian tube. Once CSF has entered the temporal sion pneumocephalus.238,239 Some amount of intracranial air
bone’s air cell system, the fluid traverses the middle ear and is inevitable following posterior fossa craniotomy, but the
eustachian tube en route to the nasopharynx. Cutaneous accumulation of large amounts under pressure is unusual.
CSF leaks are obvious, but the more common transmucosal Contributing to the development of this complication are
leaks can be subtle and hard to diagnose. The characteristic large-diameter CSF fistulae, the presence of a unidirec-
finding of episodic gushing of clear fluid from the nose tional flap valve over the leakage tract, and frequent nose
triggered by positional change or exertion is not always blowing or performance of Valsalva maneuver. Another
present. Some patients report only a sensation of postnasal factor that can trigger tension pneumocephalus is excessive
dripping or a salty taste in the mouth, both symptoms that drainage of CSF via a shunt or lumbar drain.
are hard to confirm objectively.
While prevention of CSF leakage begins with meticulous Meningitis
closure of the wound and sealing of any transected air cells,
postoperative measures are also important. A tight bandage Meningitis is among the more common complications of
helps to redirect the CSF gradient medially and discourages AN surgery. In reported series, the incidence varies
wound leaks, as well as those through the exposed retrosig- between 2% and 10%.219,228,240 The majority of infectious
moid air cells. Compressive bandages probably have little cases occur in association with CSF leak, which permits
effect on peri-IAC leaks because surface compression is bacterial contamination from the nose or across the skin.
unlikely to transmit significantly to this depth. Additional Meningitis also arises as a complication of lumbar subarach-
measures to discourage CSF leakage include elevation of noid drainage or as a result of aseptic necrosis of free
the head of the bed by 30 degrees and fluid restriction for fat graft placed during neurotologic surgery (Lipoid menin-
several days following surgery. Prophylactic placement of gitis).241 The peak incidence of meningitis is the third
a lumbar subarachnoid lumbar drain to divert CSF flow is through the fifth postoperative day. Rarely does it present
undertaken when extensive entry into well-developed air earlier than this, especially following intraoperative contam-
cells around the IAC has occurred during a RS approach. ination with a particularly virulent microorganism. Delayed
We do not routinely employ postoperative corticosteroids, meningitis, occurring weeks or months following surgery,
except in very large tumors or when surrounding parenchy- is usually due to cryptic CSF otorhinorrhea. The use of peri-
mal edema is evident on preoperative T2-weighted MRI operative antibiotics to discourage the development of
scans. However, when a patient shows signs of postoperative meningitis is controversial. At Stanford University, we
aseptic meningitis (headache, fever, bulging wound), they administer 2 grams of ceftizoxime just prior to incision and
are instituted. The detrimental tendency for steroids to irrigate the wound with a bacitracin solution at the end of
inhibit wound healing must be weighed against their the procedure. Favorable outcome in postoperative meningi-
beneficial ability to reduce the acute hydrocephalus, which tis hinges on early recognition of this complication. A high
may accompany aseptic meningitis. or persistent fever, unusually severe headache, and/or any
 Acoustic Neuroma (Vestibular Schwannoma) 757

sign of altered mental status can indicate the need for NF2 than it is in sporadic AN.63 However, little comparative
cytologic and chemical evaluation of the CSF. Since post- data has been published to support this contention, and
operative fever is common and headache is ubiquitous the author has observed a number of NF2 tumors that
immediately following surgery, much clinical judgment is have dissected readily.
required. Nuchal rigidity, a hallmark of meningitis diagnosis There are a variety of potential mechanisms for FN
in most settings, can be difficult to evaluate following AN injury during AN surgery.246 Stretch or torsion on the
surgery as a result of surgical trauma to the cervical mus- nerve can cause significant damage. In this regard, it is
culature. As a general rule, the clinician is wise to have a important to avoid pushing the tumor anteriorly because it
low threshold for performing a lumbar puncture when a further deforms the nerve in its typical direction of greatest
suspicion of meningitis arises. stretch. Similarly, it is important to avoid traction along
Interpretation of CSF findings following AN surgery is the course of the nerve because it risks disrupting the
complicated by the pleocytosis that normally follows nerve’s most fragile segment. It is important in preserving
posterior fossa craniotomy. Aseptic meningitis is even more both anatomic and functional integrity to maintain the nerve
common than bacterial in the postoperative AN patient. in its deflected position, contained within its surrounding
While a high white blood cell (WBC) count (>1000) with a arachnoid, rather than pull it up into the cavity created by
left shift is suggestive of bacterial meningitis, these bench- tumor debulking. This helps both to preserve its blood
marks are often breached in aseptic cases as well.242 supply and to provide mechanical support for otherwise
Conversely, when the clinical index of suspicion is high, fragile fiber bundles. Thermal injury may also occur, partic-
intravenous antibiotics should be commenced despite rela- ularly during bipolar coagulation or through heat generated
tively benign CSF findings and continued until the culture while drilling. Dissipating heat buildup through copious
results become known. Adequate treatment of postsurgical irrigation is important in preventing this type of neural
bacterial meningitis requires a minimum of 7 days of intra- damage. Probably the most frequent cause of FN injury is
venous antibiotics. mechanical disruption of attenuated nerve fibers during
Aseptic meningitis usually commences somewhat later microdissection of the nerve from the tumor capsule.
than infectious cases. The cause appears to be meningeal When it appears that radical removal will result in
inflammation induced by blood products, aseptic necrosis anatomic discontinuity of the nerve, some surgeons elect
of free-fat graft and other irritants (e.g., bone dust) liberated to leave a thin veil of tumor capsule attached to the most
into the posterior fossa during surgery. 240–242 The clinical adherent portion of the nerve.205 The willingness to consider
picture consists of headache, malaise, and occasionally a near-total removal is predicated on the assumption that a
low-grade fever. Symptoms may be rapidly ameliorated by tiny devascularized capsular peel is unlikely to generate a
administration of a course corticosteroids. In some cases, recurrence. The decision whether to undertake a near-total
symptoms recur with withdrawal of corticosteroids. When removal is complex and depends on a number of factors.
this occurs, a prolonged taper or every other day dosing Prominent among them are the age and the patient’s own
may be given. May patients can be weaned from cortico- priority regarding maintenance of facial function versus
steroid by gradual substitution of a nonsteroidal anti- assurance of tumor control.
inflammatory drug such as ibuprofen.
Role of Facial Nerve Monitoring
IMPACT OF AN REMOVAL A substantial improvement in FN outcome has been realized
ON THE QUALITY OF LIFE in recent years. Intraoperative FN monitoring has
contributed, in no small measure, to this favorable trend.
Facial Mimetic Function (See Chapter 57, Intraoperative Monitoring of Cranial
Nerves.) Several studies have verified the impact of FN
Vulnerability of the Facial Nerve
monitoring on functional outcome following AN surgery.
Most well-informed patients with ANs expect that they In a study that compared 91 monitored patients with 91
will survive AN surgery and avoid major brain injury. Of unmonitored controls, only slightly improved outcomes
greatest concern to most individuals is preservation of were noted in small and medium-sized tumors. In large
facial function.243 The FN is dysfunctional preoperatively tumors, however, anatomic continuity improved from
in only a small minority of patients; however, paresis and 41% to 71% when monitoring was used.247 In another
paralysis are frequent consequences of surgery. Numerous study, 111 monitored patients were compared with 207
factors contribute to the probability of maintaining FN unmonitored historical controls.248 A reduction in the rate
integrity.244 Tumor size has a major influence because as of total paralysis from 15% to 4% was noted when FN
the tumor’s diameter increases, the nerve becomes pro- monitoring was used. Good predictors of initial facial
gressively more thin and splayed over its capsule.245 Of nerve function are due to a combination of electrophysio-
even greater importance is the nature of the interface logic intensities and tumor size.249 It is now widely
between the tumor and the nerve. The degree of adherence accepted among experts in the field that FN monitoring,
is typically greatest just outside the porus acusticus. when skillfully employed, improves FN outcome in AN
Dissection is generally more difficult in larger tumors, but surgery. Other factors contribute as well to this trend
there are exceptions. Occasional intracanalicular tumors toward better FN prognosis. Of considerable importance
are markedly adherent while some very large tumors dissect is the fact that, in many countries, AN surgery has become
with remarkable ease. It has also been suggested that the concentrated in regional centers. This permits the surgical
FN is more intimately applied to the tumor capsule in team to accumulate the experience necessary to obtain
758 SURGICAL NEUROTOLOGY

TABLE 45-7. Anatomic Preservation of the Facial Nerve To facilitate interstudy comparison of results, assessment
in Acoustic Neuroma Surgery of FN function following AN surgery should be performed
Anatomic
using standardized measures, preferably the widely accepted
Author Year No. of Patients Preservation grading scale proposed by House and Brackmann.252
Reported functional results vary widely, at least in part as
House353 1979 500 97% a result of differences in patient population and grading
Glasscock190 1986 616 82% criteria (see Table 45-8). It is clear that, in many centers,
Sterkers354 1988 800 94% the occurrence of permanent severe or total paralyses has
Tos355 1988 400 95%
been reduced to well under 10%. Furthermore, most of the
patients with unfavorable outcome had tumors from the
largest size categories. In our own series, facial nerve out-
optimal results. The existence of a distinct “learning comes is similar for the RS and TL approaches. One cost
curve” in AN surgery, where functional results gradually of the hearing preservation attempt in our 10- to 18-mm
improve over time, is widely acknowledged.250 Another MF group was a significantly worse long-term
important factor in improved FN outcome is the progres- (>1 year) facial nerve outcome when compared with a
sive refinement of microsurgical instrumentation and size-matched TL cohort (81% grade 1 or 2 compared
tumor debulking implements such as the ultrasonic aspira- with 100%).
tor and laser. Finally, increasingly sophisticated diagnostic
technology has permitted detection of an increasing frac-
The Course of Postoperative Facial Palsy
tion of small tumors, thus favoring FN preservation.
The great majority of postoperative facial palsies occur in
Results in Contemporary Series cases where the FN has been left anatomically intact after
completion of tumor resection. The time course of neural
In this chapter no attempt has been made to review recovery depends on the extent of neural injury, as well as
exhaustively all the published series on FN outcome fol- its location. The pace of recovery falls roughly into two
lowing AN surgery. Rather, results from selected series are time courses. In less severe injuries, recovery often occurs
presented as representative of the state of the art in FN within 2 months. More severe injuries, presumably those
preservation. For a more detailed analysis, consult a recent that require remyelination, typically take 8 to 15 months
comprehensive review article on the subject.251 The major- to recover. The more delayed the onset of recovery, the
ity of the published series dwell on anatomic preservation less likely that the patient will regain near normal levels of
of the nerve as the primary measure for success or failure. function and the more likely that some degree of synkinesis
Results from large series are impressive, with continuity will develop. The time course of recovery is typically gradual
maintained in between 82% and 97% of cases (Tables 45-7 and is initially evident as improvement in symmetry and
and 45-8). Of course, the patient cares less about anatomy tone at rest. Return of voluntary movements usually
than physiology and is little consoled when the surgeon proceeds from the lower face to the midface and finally the
says the nerve was intact if it never recovers functionally. forehead. The process of recovery is often accompanied by
In addition, operative estimations of neural integrity an element of hyperfunction, manifested as subtle twitching,
are affected by subjective factors and may not always less commonly as frank spasm. Following severe injuries
accurately represent the actual status of the nerve. For with long recovery times, misdirected reinnervation is
these reasons, the most apt measure of success in FN common. This is manifested as mass motion where the eye
preservation is the level of function after the recovery tends to close during smiling and the corner of the mouth
period. elevates upon eye closure.

TABLE 45-8. Facial Nerve Function 1 Year Postoperative Follow-up

Author Year No. of Patients Normal (Grade 1) Paresis (Grades 2–5) Paralysis (Grade 6)

Nadol356 1992 60* 90% 8% 2%

Kanzaki250 1991 106 17% 36% 47%
Ebersold357 1992 161 52% 44% (grades 2 & 3 = 27%) 4%
(grades 4 & 5 = 17%)
Lalwani114 1993 129 71% 27% (grades 2 & 3 = 25%) 3%
(grades 4 & 5 = 2%)
Arriaga358 1994 164 77% 22% (grades 2 & 3 = 20%) 1%
(grades 4 & 5 = 2%)
359
Samii 1997 929 51% 28% (grades 2 & 3 = 28%) 4%
(grades 4 & 5 = 17%)
Satar196 2002 153† 82% 17.6% (grades 2 & 3 = 17%) 0.4%
(grades 4 & 5 = 0.6%)

*Report limited to small and medium-sized tumors suitable for a hearing conservation approach.
†
Report limited to small and medium-sized tumors operated with MF approach. A comparable cohort with translabyrinthine approach showed 87.5% grade 1 and 12.5% grade 2 facial
nerve function.
 Acoustic Neuroma (Vestibular Schwannoma) 759

It is possible, to some extent, to predict the degree and data is available to support its efficacy and our anecdotal
time course of recovery of facial function from the appear- experience is that corticosteroids are ineffective in this
ance of the nerve at the end of the procedure and its regard. Because neural edema may be expected to be
electrical stimulability. When surgical planes have been especially problematic within the bony confines of the
favorable, the nerve does not appear unduly splayed, and a Fallopian canal, performing a bony decompression of the
low threshold for electrical stimulation persists at the labyrinthine segment at the time of tumor removal has
nerve exit from the brainstem, then complete recovery is been suggested as a means of preventing the evolution of
likely. Conversely, a wide and attenuated nerve that is delayed palsy.254
discolored where it adhered to the tumor and does not The nonmotor components of the FN may also be dis-
stimulate proximally is at substantial risk of poor recovery. turbed following AN surgery. Transient taste disturbance
Recently, we examined the reliability of FN stimulability is not uncommon following AN surgery due to dysfunction
proximal to the lesion at the end of surgery as a prognostic of the taste fibers that supply the anterior two-thirds of the
indicator of eventual FN functional recovery. None of the tongue. Typically, this resolves within several months. Dry
102 patients with a threshold less than 0.4 volts had a eye due to decreased lacrimation (parasympathetics travel
recovery at 1 year worse than a grade 3/6. When stimulation with the greater superficial petrosal nerve) is also a common
was present under 0.1 volts, all achieved grade 1 (89%) or sequelae of AN surgery, even when facial motor function
grade 2 (11%) results. A word of caution is in order has been preserved. In the absence of facial paralysis, this
regarding the prognostic value of electrical stimulability. problem is a mild nuisance to most, although it may make
When the nerve is very splayed, excellent stimulability wearing of contact lenses difficult. Aberrant reinnervation
may remain for a small subpopulation of the FN fibers of the lacrimal fibers may result in gustatory tearing. So-
even when the majority have been disrupted. Thus, when called crocodile tears usually constitute only a nuisance.
the nerve is very ribboned, it is important to establish When they are particularly severe, relief may be obtained
whether the lowest threshold is representative of the entire through partial excision of the lacrimal gland.
wide band or only one limited region.
Postoperative electrodiagnostic testing may also be of
Management Options when
value in assessing the patient with postoperative facial
the Facial Nerve is Disrupted
paralysis. Electrical stimulability of the nerve may be
assessed using either the maximal stimulation test or elec- Clinicians must be aware of the distress felt by some
troneuronography.253 If the nerve conducts any electrical patients experiencing facial palsy after AN surgery and
response to the facial muscles, a more favorable prognosis that the level of distress may not be related to the clinical
is established. When no stimulability is found, electromyo- grade of the facial nerve paralysis. According to a recent
graphy may provide some prognostic information. In the study, people with low self-esteem, young people, and
late postoperative period, polyphasic reinnervation poten- women suffer from more distress from the facial palsy.
tials are an early sign of pending recovery, whereas electrical Clinicians should thoroughly counsel patients before and
silence is ominous in that it suggests muscular atrophy. after surgery and should implement measures that increase
Fibrillation potentials identify surviving muscle elements patients’ self-esteem and decrease their distress, especially
but imply that reinnervation has yet to commence. in these high-risk groups.255
Transcutaneous electrical stimulation of the facial muscles
has been proposed as a means of maintaining facial muscular Primary Reconstruction of the Facial Nerve
tone while awaiting reinnervation. This modality has the- Conceptually, immediate repair of a disrupted FN following
oretical appeal; however, there is little scientific data to tumor removal is appealing. It avoids the need for a second
support its use. Indeed, it has been suggested that it may surgery and, unlike nerve crossover procedures, it creates
adversely affect recovery through encouraging the devel- no new neurologic deficits. There are three methods of
opment of synkinesis (K. Doyle, MD: personal communi- immediate FN repair: direct suture, mastoid-meatal
cation, 1993). rerouting and suture, and interposition grafting. The sim-
It is not uncommon for a patient to awake from surgery plest way to repair cranial nerves VII–VII is by mobilization
with facial function only to have it gradually deteriorate in of the transected ends followed by direct suture (Fig. 45-26).
the early postoperative period. Although this usually In our experience, this is seldom possible because the
occurs within 72 hours of surgery, we have observed it as length of the deficient segment prohibits tension-free
much as several weeks later. The probable etiology of anastomosis. In the TL approach, the redundant FN in the
delayed weakness is neural edema, perhaps vasogenic, mastoid can be mobilized, yielding 5 mm to 10 mm of addi-
which may be associated with the sterile arachnoiditis that tional length and permitting repair by direct anastomosis256
frequently follows AN surgery. As a general rule, the prog- (Fig. 45-27). Defects that cannot be bridged in this manner
nosis of delayed onset facial palsy is favorable. Many require an interposition graft. During most neurotologic
recover within a matter of weeks as edema subsides. Others procedures, the greater auricular nerve is used because it is
require many months to recover, a course suggestive of readily available and a good size match. Repair with an
demyelination. Occasionally patients with delayed facial interposition graft differs from that with a mastoid-meatal
palsy have incomplete functional return, but only rarely is rerouting in that it require two anastomoses. When
recovery completely absent. Perioperative administration performing an intracranial anastomosis, it is important to
of corticosteroids has been suggested as a means of reducing realize that the intracranial segment of CN VII possess no
the incidence of delayed facial palsy through reduction in epineurium. For a suture to hold, it must be placed
neural edema. This treatment has theoretical appeal, but no through the substance of the nerve. For this reason, typically
760 SURGICAL NEUROTOLOGY

published series are 84% (16/19), 57% (12/21), 100%

(8/8), and 44% (4/9).256–259
Hypoglossal-Facial and Spinal
Accessory-Facial Anastomoses
In many cases of FN disruption resulting from AN
surgery, the proximal end of the FN exiting from the
brainstem is not usable for reconstructive purposes.
Although there is seldom complete absence of a stump
proximally, the residual fibers may be so ribboned that
they technically cannot be joined to a nerve graft which is
round in cross-section. Under such circumstances, the
proximal portion of a motor cranial nerve may be trans-
posed onto the distal segment of the FN. This technique
might also be indicated when an anatomically intact or
primarily repaired nerve has not shown signs of recovery
by 1 year following surgery. At this point, an electromyo-
gram (EMG) is obtained to detect subclinical signs of
reinnervation. When polyphasic potentials are detected,
several more months are allowed to pass. If no functional
return is evident at this time, or if signs of reinnervation
were absent at the 1-year evaluation, then nerve crossover
is recommended.
Figure 45-26. Direct facial nerve repair during the translabyrinthine approach The nerve crossover procedure in most widespread use
through mastoid-meatal rerouting. Mobilization of the redundant is the hypoglossal to facial anastomosis (Fig. 45-28). One
intratemporal course provides an additional 10 mm to 15 mm of length to advantage of using the innervation of the tongue is that it,
bridge a gap. like the facial nerve, is tonically active and therefore pro-
vides tone at rest. Hypoglossal-facial anastomosis is per-
formed as a secondary procedure, usually 4 to 6 weeks
only one suture is used passing through the center of the following tumor removal. It is usually unwise to undertake
nerve. A reasonable alternative is the use of a nonsuture this procedure at the time of tumor resection because
anastomosis such as a collagen tube or fibrin glue.257,258 The the neck and parotid flaps may fill with CSF flowing from
theoretical benefits of sutureless grafting include technical the craniotomy defect. In most individuals, sacrifice
simplicity, reduced foreign body reaction, and prevention of of the hypoglossal nerve leads to little difficulty with
neural trauma caused by the suture needle. Results speech or swallowing, in part due to the partially bilateral
with direct nerve repair, with or without use of a graft, innervation of the tongue. However, when vagal and
are modest. The usual result achieves at best a grade 3 or
4 function. Success rates (grade 4 or better) in representative

Figure 45-28. Schematic of the relationship between the hypoglossal and

Figure 45-27. Facial nerve repair in the cerebellopontine angle with a greater facial nerves in preparation of XII–VII anastomosis for reanimation of the
auricular nerve interposition graft. paralyzed face.
 Acoustic Neuroma (Vestibular Schwannoma) 761

glossopharyngeal deficits exist, sacrifice of the hypoglossal suboptimal for most patients. In recent years, restoration
nerve is contraindicated because this may decompensate of eye closure through use of upper eyelid gold weights or
the deglutition mechanism. Satisfactory results, defined as springs has largely supplanted tarsorrhaphy in most major
rest tone with some motion, are obtained in more than centers.266,267
80% of cases.260–263 It has been noted that somewhat bet-
ter results are realized when the procedure is performed
within a few months of the nerve disruption.260 However, Hearing Conservation
the procedure may be delayed 1 year or even longer and Pathology and Pathophysiology
still have an excellent chance of success. The facial reani- of Cochlear Nerve Involvement
mation afforded by a hypoglossal to facial anastomosis is
imperfect. At best, patients have excellent symmetry at rest Preservation of hearing in the tumor ear is one of the more
and can train themselves to make a fairly natural smile. challenging goals in AN management. There are approxi-
Despite excellent reinnervation, many patients obtain an mately 30,000 fibers in the human cochlear nerve.
imperfect result due to excessive tone (occasionally with Quantitative histologic studies in experimental animals
spasm) and marked synkinesis. have shown that up to 75% of the nerve population to a
An anastomosis between the spinal accessory and facial given region of the cochlea can be destroyed without
nerves is another reconstructive option. Success rates are raising the hearing threshold.268 Because greater numbers
similar to the hypoglossal to facial anastomosis if done of functioning fibers are needed to convey complex
early after resection of the lesion. However, results are less information, speech discrimination may be affected out of
favorable when the reconstruction has been delayed. To proportion to pure tone loss. Cochlear nerve fiber dys-
avoid the donor deficit of a weak and possibly painful shoul- function can result either directly from tumor infiltration
der, using only a portion of the nerve has been suggested to or indirectly from pressure-induced demyelination or
minimize loss of function. ischemia.
Patient satisfaction with the various facial reanimation Several studies have assessed the frequency of cochlear
techniques has been assessed through a survey of the mem- nerve infiltration by ANs. Although these tumors originate
bership of the AN Association.264 This report included from the vestibular division of the eighth nerve, micro-
opinions from 61 patients who underwent CN XII–VII scopic involvement of the cochlear division is frequent even
anastomosis and 6 who had CN XI–VII crossover. Slightly when the surgeon sees no gross involvement.96–98,269,270
less than half of the XII–VII group reported a functional When the cochlear nerve adheres to the tumor surface, it
return of greater than 50% when compared to the opposite is probably infiltrated to some degree. The converse, that
normal face. In the majority of patients, poor eye closure infiltration is absent when the tumor separates from the
and unsatisfactory facial appearance while smiling persisted. nerve easily, is not always true. In a study by Neely, in 3 of
The few patients who had undergone XI–VII procedures 15 cases where the cochlear nerve appeared normal during
were even less satisfied than the XII–VII group. microdissection from the tumor capsule, residual tumor
A number of additional options for reanimation of the was noted infiltrating between fibers.97 More important,
paralyzed face following excision of AN are available the proximal eighth nerve trunk medial to the tumor was
including masseter and temporalis muscle transfers, cross infiltrated despite a normal appearance in all 6 of 6 cases
face anastomosis, and innervated microvascular muscle investigated. Of note, the cochlear nerve lateral to the
transplants.265 Little data is available on the results of these tumor in the fundus of the IAC was often free of tumor.
procedures in patients with ANS. Although the surgeon may initiate a clean dissection plane
in this location, sharp dissection in the medial direction is
likely to cleave off fronds of tumor cells that interdigitate
Care of the Eye in Facial Palsy
with nerve fibers. A clinical-pathologic correlative study of
Poor eye closure caused by facial weakness creates a risk of 22 tumors showed significant fiber destruction and tumor
corneal desiccation. A dry cornea may become ulcerated infiltration even when the hearing was relatively good and
which, if not meticulously managed by physician and the tumor small.98 In none of these cases was a well-defined
patient alike, may lead to the formation of permanent connective tissue plane between the tumor and cochlear
opacities. The facial paralysis that follows AN surgery is nerve identified. In another study, immunochemical investi-
usually accompanied by decreased lacrimation resulting gation of the tumor-cochlear nerve interface in 10 medium-
from disruption of the parasympathetic innervation to the sized tumors demonstrated neural invasion in 6.95 Results
lacrimal gland. In addition, dysfunction of the fifth nerve, somewhat at variance with the above-cited studies come
which is frequent with larger tumors, leads to impaired from a study of 10 tumors scrutinized by both light
corneal sensation. A dry, anesthetic eye that lacks a blink and electron microscopy, which detected a relatively low
reflex is virtually certain to develop corneal decompensa- incidence of cochlear nerve invasion.270 Actual cochlear
tion without aggressive intervention. Medical management nerve invasion was confirmed ultrastructurally in only
includes the liberal application of artificial tears and lubri- three patients, each of whom had NF2. This greater
cating ointments. At night, the eye may be taped shut or tendency for cochlear nerve invasion in NF2 has been
protected with an occlusive plastic shield. reported by others as well.271 An attempt to distinguish
The classical surgical treatment for the paralyzed eye is subtle cochlear nerve involvement through the use of
tarsorrhaphy, the suturing together of the eyelids to narrow staining for the neural tissue–specific protein S-100 was
the palpebral fissure and thus improve eye closure. unrevealing as both AN and cochlear nerve stained for this
However, tarsorrhaphy is both esthetically and functionally marker.93
762 SURGICAL NEUROTOLOGY

Another factor that influences the probability of brainstem entry may avulse these fragile fiber bundles
cochlear nerve invasion by AN is whether the tumor arose from the base of the cochlea.
from the superior or inferior vestibular nerve. Because the Interruption of vascular supply to the cochlea undoubtedly
cochlear nerve lies in the inferior compartment of the accounts for some hearing losses associated with AN removal.
IAC, inferior vestibular schwannomas are typically more Either physical interruption or thrombotic occlusion of
intimately related to it. Tumors that involve the fundus of the internal auditory artery results in cochlear infarction.
the IAC may also be more prone to invade the cochlear In contrast to cochlear nerve injury, cochlear dysfunction
nerve due in part to the confined space of this lateral affects all waves of the ABR. Vasospasm may play a role in
recess. Such tumors also have the potential of invading the intraoperative hearing loss. Topical application of a vasodilator
cochlea via the modiolus.65 The most important implica- (e.g., papaverine hydrochloride 30 mg/mL) occasionally
tion of microscopic invasion of the cochlear nerve by AN is reverses a sudden deterioration in electrophysiologic
not the fear of leaving residual disease, but rather the jeop- measures.273 Based on experiences in an animal model, intra-
ardy it places the nerve in during tumor microdissection. operative monitoring of cochlear blood flow using a laser-
Undoubtedly, this tendency for the tumor to interdigitate Doppler technique has been proposed as a means of providing
with cochlear nerve fibers contributes to the difficulty of the surgeon an early warning of cochlear ischemia.274
preserving hearing in these tumors. The risk of leaving Some insights into the pathophysiology of intraoperative
microscopic tumor residuals, in terms of generating recur- hearing loss may be gleaned from observations of postoper-
rent disease, is unknown, but it is probably small (see the ative patients. Delayed hearing loss occurring in the first
section on “Incomplete Tumor Removal”). postoperative week is fairly frequent following AN surgery.
There are three requirements for success in a hearing This has been associated with intraoperative deterioration
preservation effort: (1) The tumor capsule must be separated of wave V with preservation of wave I.275 Presumably, late
from the cochlear nerve without disrupting or unduly hearing loss results from progressive neural edema or
traumatizing it, (2) the blood supply of the cochlea and ischemia. Occasionally an ear with poor hearing in the
nerve must be maintained, and (3) the inner ear must not early postoperative period spontaneously improves
be destroyed in the process of exposing the tumor. In only weeks or months later. This type of delayed recovery is
a small minority of ANs is it possible to fulfill all of these consistent with resolution of a transient neural conduction
requirements and totally excise the tumor. The most fre- defect.276 Electrophysiological observations have been
quent reasons for failure of hearing conservation efforts made in patients with an anatomically preserved cochlear
are gross infiltration of the cochlear nerve, which requires nerve but no postoperative hearing.277 In two of three
its resection, and the necessity of drilling away a portion of patients studied, promontory stimulation revealed pre-
the inner ear to expose the lateral terminus of the tumor in served electrical stimulability of the cochlear nerve despite
the IAC (see the section “Microsurgical Management”). deafness. This implies that cochlear infarction with
However, it is disconcerting how often the cochlear nerve death of hair cells was causative of the hearing loss in these
can be anatomically preserved, at times seemingly having cases.
sustained little or no apparent trauma, but nevertheless A recent study278 showed that the presence of either
hearing is lost or seriously degraded postoperatively. the ABRs or near-field cochlear nerve action potentials
There are probably multiple causes for this phenomenon. (CNAPs) was not related to AAO-HNS class outcome.
Dissection along the compressed segment of the nerve Both techniques had a useful rate of prediction of hearing
may interrupt microvasculature and result in fiber damage preservation surgery outcome but in nearly one-quarter of
or intraneural hemorrhage. Animal studies point to retrac- the cases, there was no association between ABR or CNAP
tion of the cerebellum as a frequent precipitator of auditory responses and hearing preservation.
dysfunction.272 Clinical observations from intraoperative These results have to be considered when determining
electrophysiologic changes confirm the occurrence of this the clinical usefulness of these techniques.
phenomenon in humans. Not uncommonly we have
observed a sudden loss or substantial latency prolongation Assessing Candidacy for a Hearing
of wave V accompanied by preservation of wave I occurring Conservation Attempt
at the time of cerebellar retraction. It is possible that this
maneuver places the eighth nerve and its arachnoid tethers A cardinal issue in hearing conservation is who should be
under tension, thereby stretching the nerve and/or vasa considered a candidate. Because the probability of success
nervorum. Traction on the nerve can also lead to nerve greatly influences the decision process, preoperative prog-
fiber disruption at one of two particularly weak points. nostic factors are important.279–281 As a general rule, the
One site of mechanical weakness occurs at the junction of better the hearing, the more likely is success in a hearing
central and peripheral myelin (the Obersteiner-Redlich conservation effort. No rigid auditory criteria can be
zone).272 At this transition the central myelin is surrounded developed because the decision must always take into con-
by delicate astrocytic processes, and the peripheral fibers sideration the level of hearing in the opposite ear. When
are reinforced by a collagenous endoneurial tube. Neural the contralateral hearing is normal or nearly so, most sur-
separation at this point may occur preferentially in the geons would not recommend a hearing conservation
central portion of the nerve and thus not be visible externally. approach when the SRT is greater than 50 dB and/or the
A second potential point of weakness exists laterally where SDS is less than 50%. If the concept of useful hearing is
the cochlear nerve splays into many small fibers as it pene- taken into account, these exclusionary criteria could rea-
trates the modiolus. Medially directed traction originating sonably be placed at greater than 30 dB SRT and/or less
anywhere along the course of the nerve from IAC to than 70% SDS. A normal or near-normal ABR is also a
 Acoustic Neuroma (Vestibular Schwannoma) 763

favorable indicator. Conversely, an absent or severely dis- retrosigmoid approaches (Table 45-9A and B). Others advo-
torted ABR, even when the hearing level is quite good, is cate using either approach depending on the characteris-
an unfavorable prognostic factor. An intact stapedial reflex tics of the tumor undergoing treatment.190–192,285 Reports
may also be an auspicious sign. In terms of vestibular testing, on the rate of success in maintaining hearing following AN
a reduced caloric response has been said to be favorable excision vary widely. Much of the published data is impossi-
because it suggests superior vestibular origin to the tumor.280 ble to analyze because the amount of residual hearing is not
Tumor location and size also play a key role in determining specified. Still other studies reporting a degree of success
candidacy. The depth to which the tumor extends into the include no audiologic data at all.
IAC is often the determining feature in the ability to conserve It is important to realize that hearing results discussed
hearing.192 The degree of IAC erosion can also affect results. next refer only to that subset of patients with ANs who are
It seems probable that substantial canal erosion predicts a deemed to be candidates for hearing conservation surgery.
greater compression of the eighth nerve, although this fea- While this fraction of the entire AN population varies
ture has yet to be studied as an independent variable. Success according to the availability of sensitive diagnostic tools
is only rarely achieved in tumors exceeding 2 cm in cisternal such as ABR and MRI, to the surgical team’s referral pattern,
diameter. Nevertheless, this size limit should not be rigidly and other factors, it probably constitutes between 10%
enforced. A few patients with larger tumors have excellent and 30% of all patients with ANs. With the MF approach
hearing, nearly normal ABR responses, and a minimal IAC to intracanalicular tumors, “measurable” hearing is main-
component. While the success rate in such patients is not tained in approximately 50% of cases.196,281,286 However,
high, it is also not negligible. It should be emphasized that “useful” hearing is probably achieved in no more than 25%
these criteria apply to AN alone and are not necessarily of these most favorable cases. In our own series of 150 patients
applicable to other tumors of the CPA. In angle tumors with the MF approach and tumors smaller than 18 mm in
not originating from the eighth nerve (e.g., meningioma, the CPA, the following results were recorded. In the MF
epidermoid), hearing conservation is much more probable group, class A or B hearing was preserved in 62% of patients
than with an AN of similar size and location. with tumors smaller than 10 mm in CPA component and
34% of tumors with 10 mm to 18 mm in the CPA.196
According to a recent study, valuable prognostic indicators
Definition of a Successful Result
for hearing preservation in the MF approach seemed to be
When one considers hearing conservation in AN, the the preoperative hearing status, ABR, and intraoperative
criteria for success must be appropriately defined. Many tumor origin data.153 A major drawback of the MFA tech-
studies report favorable outcome as mere persistence of nique is the fact that complete resection of IAC tumors
any residual hearing in the operated ear. As has been aptly involving the fundus requires some degree of blind dissec-
pointed out, when the contralateral ear is normal, most tion. Therefore, specialized tools and techniques are
patients derive little benefit from a postoperative tumor required to minimize the risk of neural injury during this
ear that hears substantially below normal levels.282,283 The indirect dissection. In addition, inspection of the fundus
Stenger effect predicts that the patient will little appreciate with either mirror or endoscope is often necessary to
hearing in the worse ear when it has a threshold in the exclude the possibility of retained tumor fragments.195
speech frequencies more than 30 dB higher than the better In the RS approach to tumors with a cisternal compo-
side. Such rules of thumb have long been employed by nent larger than 2 cm, preservation of useful hearing is
otologic surgeons when considering surgery for patients diminished.286–289 In our own series, up to 25% of patients
with conductive hearing loss, but this type of analysis has retained good hearing.290 The results are, however,
seldom been applied in AN surgery. Speech discrimination dependent on the age of the patients.291
is another very important measure of “useful” hearing in a Overall estimates of hearing success rates are less impor-
postoperative ear. A speech discrimination score 30% tant in deciding the optimal course for a given patient than
below the better side is unlikely to enhance the patient’s the interpretation of that individual’s prognostic factors. In
overall communicative ability. Using this 30/30 parameter the very best group with a small tumor, little IAC involve-
in assessing potential benefit allows the clinician to counsel ment, excellent hearing, and a normal ABR, the chance of
the patient more realistically about treatment options. preserving useful hearing may well reach 50%, whether
Overly optimistic counseling about hearing conservation operated via the RS or MF approach. Indeed, a few fortunate
may lead to disappointment on the part of the patient patients will actually achieve an improvement in hearing
whose surgeon proudly points to a postoperative audiogram following tumor removal.292 By contrast, patients whose
demonstrating “successful” hearing preservation when he hearing and tumor characteristics place them at the fringes
or she can discern little actual benefit. Rather than use a of candidacy for hearing conservation may have very little
single criterion to assess hearing outcome, a classification chance of success. Taking into account the relatively small
system analogous to the House-Brackmann scale used in fraction of patients with ANs who are candidates and the
reporting postoperative facial function has been proposed limited probability for success, it can be estimated that only
for reporting hearing results.284 about 5% of patients with ANs maintain useful hearing in
the tumor ear following surgical excision.
Results in Clinical Series
Long-Term Hearing Results
In recent years, a number of major centers have reported
their results with attempts at hearing conservation. Only recently has long-term follow-up become available for
Most reports emphasize use of either the middle fossa or a limited number of patients who have undergone successful
764 SURGICAL NEUROTOLOGY

TABLE 45-9A. Hearing Preservation Rates from Several Contemporary Studies

AAO-HNS Class‡
Study Number (n) Approach* Tumor Size (cm)† (A+B) (C)

Glasscock360 136 38 MF, 98 RS < 1.5 37 (27%) 7 (5%)

Brookes361 13 RS < 1.0 6 (46%) 2 (15%)
Arriaga358 26 RS Mean = 1.66 14 (54%) 1 (4%)
34 MF Mean = 0.72 24 (71%) 1 (3%)
Slattery362 143 MF Mean = 1.2 74 (52%) 5 (3.5%)
Irving290 25 MF Intracanalicular 11 (44%) 3 (12%)
20 MF 0.1–1.0 12 (60%) 2 (10%)
5 MF 1.1-2.0 1 (20%) 0 (0)
17 RS Intracanalicular 2 (12%) 0 (0)
12 RS 0.1–1.0 3 (25%) 1 (8%)
21 RS 1.1–2.0 3 (14%) 0 (0)
Satar196 104 MF IC – 0.9 57 (62%) 15 (15%)
47 MF 1–1.8 15 (33%) 3 (7%)

Hannover Class§
H1 + H2 H3

Samii289 29 RS T1储 6 (21%) 7 (24%)

96 RS T2储 25 (26%) 23 (24%)
249 RS T3储 39 (16%) 44 (18%)

*Middle fossa (MF), retrosigmoid (RS), or suboccipital.

†
Tumor size includes the posterior fossa component except when indicated.
‡
AAO-HNS classification system.
§
New Hannover classification system.
储
T1, intrameatal; T2, intrameatal and extrameatal; T3, filling the cerebellopontine angle.
Modified after Jackler RK, Driscoll CLW: Tumors of the Ear and Temporal Bone. Philadelphia, Lippincott Williams & Wilkins, 2000.

hearing conservation approaches. Unfortunately, there is a suffered symptomatic recurrence some years following RS
notable tendency for gradual deterioration in both pure approach with incomplete exposure of the fundus. This
tone threshold and speech discrimination. In 14 of 25 has been noted by others, particularly following a failed hear-
patients operated via the MF route (mean follow-up = 8.1 ing conservation attempt.209,279 In these cases it is suspected
years), SRT diminished an average of 12 dB while SDS fell that a macroscopic portion of tumor was left in the lateral
by 25%.293 A similar hearing deterioration was noted in terminus of the IAC, where it retained a blood supply. It is
only one of the nonoperated ears. In a study of 11 patients unclear at this time whether microscopic amounts of
operated via the RS approach, 4 showed significant hearing tumor left in the cochlear nerve are capable of generating
deterioration over the 3- to 5-year follow-up period.279 a recurrence.
The authors suggested fibrosis and impaired vascularity as
causes of the progressive loss. In yet another study, 4 of 18
Special Considerations in Bilateral
patients demonstrated significant hearing deterioration in
AN and Only Hearing Ears
the tumor ear over a mean of 5.4 years follow-up.294
Over the long term, an unknown fraction of patients Management of bilateral AN (NF2) differs in a number of
who have had a hearing conservation approach will develop ways from sporadic, unilateral AN (see Chapter 46)51,295
recurrent tumor. We have managed several patients who Because these patients nearly always develop profound,

TABLE 45-9B. Results of Hearing Preservation Surgery

Study Number (n) Approach Tumor Size (cm) Serviceable Hearing

Cohen287 128 RS <0.5 32 (37%)*

0.6–1.0 32 (34%)
1.1–1.5 38 (24%)
>1.5 26 (11%)
Dornhoffer363 65 MF <0.5 39 (60%)*
11 MF 0.5–1.0 7 (64%)
17 MF 1.0–1.5 8 (47%)
Rowed288 26 RS Intracanalicular 13 (50%)†
68 RS 0.4–1.5 20 (29%)

*Pure-tone average < 50 dB and speech discrimination better than 50%.

†
Pure-tone average < 50 dB and speech discrimination better than 60%.
 Acoustic Neuroma (Vestibular Schwannoma) 765

bilateral deafness over time, they should be advised to Although permanent deafness can result, in most of our cases
learn lip reading soon after the initial diagnosis. Because the contralateral hearing loss was temporary and returned to
these patients are never “cured” of their disease in that the preoperative levels within 1 to 3 months. It could be hypoth-
tendency to form intracranial tumors is lifelong, the ther- esized that low cisternal CSF pressure, transmitted to the
apeutic priority should be to maintain function, even at the inner ear via the cochlear aqueduct, could result in com-
expense of incomplete tumor removal, should this be pensatory endolymphatic hydrops.303 Contralateral hear-
required.296 One general rule we follow is that once the ear ing loss has also been reported in cases of bilateral ANs.304
has become deaf, the tumor should be removed. When Noise-induced hearing loss caused by cranial drilling is
both ears hear well, we often recommend a hearing con- unlikely to explain severe losses.193 Delayed contralateral
servation attempt be performed on the side with the larger sensorineural loss over the long term may also occur,
tumor. Incomplete removal is elected if the eighth nerve although this phenomenon has not been well studied. It
appears invaded or if the IAC is penetrated deeply. When has been proposed that patients with ANs may suffer long-
removal is successful, the tumor in the second ear may be term contralateral hearing loss due to activation of autoim-
similarly approached. Unfortunately, even incomplete mune mechanisms at the time of surgery.305 In rare cases,
removal can impair or eliminate residual hearing. We pre- decompression of the brainstem may improve auditory
fer to avoid surgery on the better hearing ear, unless the function on the opposite side.306
tumor substantially compresses the brainstem or is enlarg-
ing rapidly. Even when both tumors have been successfully
Rehabilitation of Unilateral Hearing Loss
removed, this does not preclude the development of new
eighth nerve tumors. It is important to realize that in NF2, Profound hearing loss in one ear constitutes only a minor
ANs are not just bilateral, they are also frequently multiple inconvenience for most individuals, and most choose not
on each side. As long as residual eighth nerve fiber is left in, to use amplification devices. Because sound directed toward
it may continue to generate new tumors. Some have advo- the deaf ear readily passes around the head, ordinary con-
cated preserving those eighth nerve fibers that are not obvi- versations are usually unimpaired. However, difficulty may
ously involved by tumor, even in a deaf ear, to maintain the occur when the good ear is masked by competing sounds
possibility of later electrical stimulation via a cochlear in a noisy environment. Two rehabilitative strategies to
implant. In our opinion, once an eighth nerve has become partially overcome this limitation reroute sounds from the
nonfunctional in a patient with NF2, it should be com- deaf side toward the better hearing ear. When the con-
pletely excised. If both eighth nerves become nonfunc- tralateral ear hears normally, a transcranial strategy can be
tional, consideration should be given to hearing employed in which a powerful hearing aid is placed on the
rehabilitation through electrical stimulation of the brain- deaf side to transmit sounds through the cranial base to
stem (see Chapter 82, Auditory Brainstem Implant). stimulate the intact cochlea.307 Alternatively, two devices can
Osseous decompression of the IAC has been suggested be placed—one on the deaf ear with a receiving microphone
as a means of slowing the hearing loss associated with AN and a second on the good ear with a speaker (CROS).
in NF2.297 The theory is that reducing the pressure cone in These may be connected by a wire across the back of the
the IAC permits continued tumor growth for a time with neck or wirelessly through an RF transmitter. When the
less constriction of the cochlear nerve and IAC artery. contralateral ear hears imperfectly, the signal in the better
Unfortunately, results reported to date have not been hearing ear can also be amplified (BICROS). While the
impressive. Even chemotherapy has been tried in patients effects of the head shadow can be partially corrected
with NF2, although experience is too meager to draw any through the above strategies, deficiencies in stereo hearing
conclusions.298 and the inability to localize sounds associated with monaural
Rarely, a patient has deafness in an ear contralateral to hearing are not correctable. Bone-anchored hearing aids
an AN due to causes other than a second tumor (e.g., (BAHAs) in transcranial routing of signal by implanting
labyrinthitis, trauma, Ménière’s disease). A conservative the deaf ear are currently under investigation. According to
approach to such tumors is also warranted, unless the his- two current studies, patients seem to have a significant
tory of the disease is a rapid hearing loss of the remaining improvement in speech intelligibility in noise and greater
hearing, brainstem compression has become substantial, benefit from BAHA compared with CROS hearing aids as
rapid tumor growth is evident, or operative intervention well as a reduced aversion to loud sounds.308,309 In compar-
carries relatively low risk of hearing loss.299,300 ison to the above-mentioned options of rehabilitation, this
technique needs a surgical procedure and bears small risks
of intracranial as well as intracerebral complications.310
Hearing Loss in the Ear Contralateral
Although unilateral hearing loss is seldom a severe func-
to an Acoustic Neuroma
tional deficit, loss of hearing in the tumor ear may result in
It is not widely appreciated that AN surgery may have an substantial psychological distress to the patient. Once an
effect on the contralateral ear. Sporadic cases in which an AN has been discovered, both patient and physician want
apparently normal contralateral ear has become deaf to cure the tumor without creating new neurologic deficits
following surgery have been reported.301 The possible or worsening existing ones. Intellectually, the physician is
roles of meningitis or CSF pressure changes have not been aware that unilateral deafness is a relatively small price to
well established. We have observed several patients who pay for ridding oneself of a life-threatening intracranial
suffered a transient (days to weeks) contralateral sen- tumor, and most well-informed patients adjust to this reality
sorineural hearing loss in the postoperative period that quite well. Emotionally, however, it is discouraging to both
resembles endolymphatic hydrops in some cases.302 patient and surgeon that it is seldom possible to maintain
766 SURGICAL NEUROTOLOGY

or restore useful hearing. Despite thorough and realistic and vigorous nystagmus typically abates over 1 to 3 days.
preoperative counseling, an occasional patient becomes In the short term, administration of vestibular suppressants
clinically depressed postoperatively over the loss of hearing and antiemetics may comfort the patient. However, when
and may benefit from short-term psychiatric care. We used beyond the early postoperative period, such medica-
have seen this phenomenon even in patients who had large tions may retard vestibular compensation and are best
tumors who have made an otherwise excellent recovery. It avoided. The most important factor influencing the com-
can only be hoped that the high level of interest in hearing pensation process is physical activity. Patients are encour-
preservation on the part of clinical investigators in recent aged to ambulate as soon as possible and given vestibular
years will ultimately lead to improved techniques that yield adaptation exercises to practice. Over the long term, even
a greater degree of success in this endeavor. fully compensated patients are not always entirely normal.
Having only one functioning labyrinth makes an individ-
Tinnitus ual somewhat more dependent on visual and proprio-
ceptive cues for maintaining balance and coordinating
Tinnitus is a common complaint in patients with ANs. movements. Because of this subtle deficit, patients with
The effect of tumor removal on tinnitus has been assessed ANs, whether before or after tumor removal, often notice a
in several studies.122,311–313 One study of 134 patients found mild imbalance in dark or visually confusing environments.
that those with preoperative tinnitus showed a small but From an occupational standpoint, this mild disability is
statistically significant improvement postoperatively seldom important, unless the individual is required to per-
although it seldom resolved entirely.311 Of note, those form tasks that take place at heights or otherwise require
patients with no tinnitus preoperatively had a 50% chance fine balance skills.
of developing it following resection of their lesion. In An objective measure of the pace and completeness of
another large study (273 patients), 62% complained of vestibular compensation following AN removal has been
tinnitus before surgery, half of whom improved postoper- obtained through a comparison of preoperative and sequential
atively.313 Most studies report that very few patients with postoperative rotatory chair testing results in 26 patients.315
ANs find the tinnitus very bothersome or intolerable. It As expected, tumor removal was associated with a acute drop
remains unpredictable which patients will improve, which in vestibulo-ocular reflex (VOR) gain, which gradually
will show no change, and which will deteriorate; age and returned toward normal over time. Abnormalities were most
tumor size do not seem to be associated with the impact of marked at 1 week following surgery and were largely
surgery on tinnitus.122 The data also suggest that tinnitus resolved by 3 months. Changes were most notable at lower
may be of relatively minor importance in the overall quality frequencies (e.g., 0.0125 Hz) with few abnormalities noted
of life of patients following AN surgery. However, candidates above 0.05 Hz. The rate of compensation was not signifi-
for surgery should be thoroughly informed about the cantly affected by clinical variables such as tumor size,
possible effect of the operation on their tinnitus. patient age, and gender. The lack of effect of advanced age
There is reason to suspect that hearing conservation on the rate of compensation was an important observation,
approaches, which leave the cochlear nerve anatomically which contradicts conventional wisdom. Many clinicians
intact, might have a higher incidence of postoperative tin- assume, perhaps incorrectly, that older individuals adapt
nitus. However, almost all of the published data on post- poorly following an acute loss of vestibular input. Of course,
operative tinnitus comes from patients who underwent a the elderly are more apt to have coexistent sensory deficien-
TL procedure, so it is not possible to ascertain the relative cies such as poor vision or a loss of proprioception which can
incidence following the various surgical approaches. In a adversely affect recovery. While the size of the tumor had lit-
report of an exceptional patient with very distressing post- tle effect on the pace of the compensation process, it did
operative tinnitus following a hearing conservation influence the ultimate level of compensation achieved. It has
approach, reexploration and section of the cochlear nerve been hypothesized that larger tumors, through compression
was performed.312 The neurectomy did not alter the tinnitus, of the brainstem, may adversely affect the ability of the
which suggests an autonomous source in the central auditory vestibular nuclei to reach full compensation.
system may be causative, at least in some patients. Only a few clinical studies that address recovery of equi-
librium following AN removal appear in the literature. In a
Vestibular Rehabilitation survey of 57 patients queried between 1 month and 13 years
following surgery, balance was generally impaired tem-
Preoperatively, many patients with AN have a degree of porarily following surgery but returned to the preoperative
vertigo and/or dysequilibrium, often accompanied by a level over time.316 In the early postoperative period, 60%
unilaterally reduced or absent vestibular response on complained of difficulties with walking, running, and stair
caloric testing. After tumor removal, the unilateral deficit climbing and 82% had difficulty when rapidly turning the
becomes complete if it was not so already. The vast majority head. In another study of 156 patients, following surgery
of patients compensate well using the contralateral intact dysequilibrium was better in 47%, worse in 17%, and
labyrinth together with their proprioceptive and visual unchanged in 29%.313 In a study of postural control ability
systems. Compensation is a gradual process, however, and in 57 patients with ANs both before and 6 months following
typically takes several weeks or months to achieve the ulti- surgery, a significant improvement was demonstrated
mate level of recovery.314 The decompensated state that following removal of the lesion.317 Based on observations of
follows tumor removal is often quite severe, especially for body sway with eyes both closed and open, it was postulated
patients with smaller tumors and relatively intact vestibular that decompression of the pons improved the use of visual
nerves. Severe vertigo accompanied by nausea, vomiting, clues in the feedback control of posture.
 Acoustic Neuroma (Vestibular Schwannoma) 767

over weeks or months. As a general rule, it is best to avoid

Headache long-term use of oral narcotics, although occasional use
As with all craniotomies, some degree of headache is for particularly severe episodes may be warranted. Simple
inevitable during the early postoperative period following measures such as neck muscle massage, application of heat
AN surgery. Significant headache persisting beyond the or cold, and biofeedback therapy bring relief to some
first month, however, occurs only in a minority of individu- patients. Surgical measures to abort persistent postoperative
als. Persistent headache after AN removal is occasionally headaches have generally not proved successful. This
focused toward the operative site but is more commonly includes avulsion of the occipital nerve as well reoperation
generalized. The headaches are typically episodic and may for the purpose of disrupting possible adhesions between
be quite severe, even debilitating in rare cases. Many the nuchal muscle and the dura.
patients report that headache is triggered by coughing or It is important to analyze the mechanism of postopera-
straining. In a few cases, exacerbation may follow ingestion tive headache following AN removal because insight into
of alcoholic beverages. The time course is variable, but the underlying cause may suggest preventive strategies.
most often headaches wax and wane over several months Numerous pathogenic mechanisms have been proposed,
and eventually disappear. Headache seldom persists including extracranial factors such as nuchal muscle spasm
beyond 1 year; in rare cases the headache diathesis appears and entrapment of the occipital nerve in the surgical scar
to be long lasting.318 with resultant neuropathy. Although these mechanisms
The incidence of persistent headache following AN may be responsible in a fraction of cases, most clinicians
surgery varies according to the surgical approach and the believe that either low-grade aseptic meningitis or an
tumor size. In one study, 100 patients (50 TL, 50 RS) were abnormal coupling of the posterior fossa dura with the
evaluated for headache during the first postoperative year. nuchal musculature are causative in the majority of cases.
At some time during the interval between 1 and 6 months In the classically performed RS craniectomy, the suboccipital
following surgery, 32% of RS patients and 16% of TL bone is discarded. Dense adhesion between the neck muscles
patients reported severe headache. By 6 months following and the dura has been frequently observed clinically and
surgery, 12% of RS patients continued to suffer severe demonstrated histologically in at least one reported case.318
headache (based on both intensity and frequency) while This phenomenon may be avoided by creation of a bone
the incidence in TL patients was zero. Of interest, an flap, which is replaced at the end of the procedure.320
inverse relationship between tumor size and the incidence However, the suboccipital bone plate is relatively thick and
of headaches was noted. The patients at highest risk of suf- turning a flap may be technically difficult, particularly on
fering persistent postoperative headaches were those with the edge adjacent to the sigmoid sinus. In recent years, we
small tumors (<1 cm diameter) whose surgeries took an RS have removed the suboccipital plate piecemeal and
approach for hearing conservation purposes. In addition, replaced the bone chips at the end of the procedure. In our
craniectomies tend to do worse in respect to postoperative experience, this reliably heals into a rigid plate, which
pain.319,320 In a survey of 541 patients enrolled in the AN effectively partitions dura from nuchal musculature.
Association, 34% identified headache as a significant Arguing against dura to muscle adhesion as a common
residual problem following their operation.321 In a series of cause of persistent postoperative headache is the observation
273 patients from Denmark, headache was identified as a that headache less frequently follows RS craniotomies per-
persistent problem in 29%.313 formed for other purposes (e.g., hemifacial spasm, tic
According to a recent study from Finland, the major risk douloureux, cerebellar tumors) than it does for AN. An
factors for postoperative problems with headache are a alternative explanation for long-lasting postoperative
retrosigmoidal approach, postoperative gait problems, headaches is chronic, aseptic meningitis. RS craniotomy
preoperative headache, and small tumors.322 These series for AN differs from other posterior fossa procedures in
also suggests that if headache is present before surgery, it that bone is drilled intracranially in the process of exposing
tends to continue after surgery, and if headache continues the intracanalicular portion of the tumor. Despite efforts
for 1 year, it usually persists without being reduced. to contain it, this tends to disperse bone dust widely
Management of persistent post-AN headache is largely throughout the arachnoidal surfaces of the infratentorial
empirical. In the early postoperative period, narcotics can compartment. With the TL procedure, by contrast, all
usually be replaced by nonsteroidal anti-inflammatory drilling is completed before the dural is opened. Evidence
drugs such as indomethacin and ibuprofen. These are in favor of the aseptic meningitis theory includes the
generally best taken regularly as a preventive measure. greater incidence of headache following the RS as opposed
This strategy is usually more effective than medicating in to the TL approach, the frequency of corticosteroid
response to each episode. As the headaches become mild responsiveness, and the occasional wound swelling noted
or infrequent, the medication should be tapered rather in association with headache episodes. The anecdotal
than abruptly discontinued. Headaches refractory to this observation that headache is more frequent following RS
regimen require additional therapy. During the first few vestibular neurectomy when the IAC is drilled open than
postoperative months, a short course of oral corticosteroids when it is left intact also tends to confirm the culpability of
many bring dramatic relief. This improvement may be bone dust. Although one or more pathogenic mechanisms
long lasting, but most often is transient with headache may predominate in postoperative headache, undoubtedly
recurring following withdrawal of the drug. Occasionally, a multiplicity of causes exist. Vascular headaches, including
steroid-responsive headaches can be gradually resolved migraine variants, are seen occasionally following AN sur-
with low-dose corticosteroids. When possible, they should gery. In one of our RS patients, classical cluster headaches
be administered every other day and gradually tapered onset following tumor resection. The clinician must be
768 SURGICAL NEUROTOLOGY

alert to the possibility of infectious meningitis, particularly RADIATION THERAPY

in the early postoperative period. Clues to this complication
include the severity and duration of the headache as well as Conventional Radiotherapy
its association with fever, malaise, nuchal rigidity, and
other neurologic symptoms. Cryptic CSF leak can also There are two forms of radiation therapy in use in the
cause chronic headache due to low CSF pressure. treatment of AN: conventional and stereotactic.
Historical clues to this entity include positional and exer- Conventional radiotherapy is seldom used in the developed
tional triggers, watery rhinorrhea or postnasal drip, and a world today although it is still occasionally employed in
history of meningitis. the developing world where stereotactic equipment is not
available. In conventional radiotherapy, a photon beam is
delivered at 1.5 to 2 Gy for 5 days per week over the course
Social and Occupational Rehabilitation of 4 to 6 weeks to reach a total dose of approximately
In recent years, several aspects on the social and occupational 50 Gy.325,326 Since radiation injury preferentially affects
recovery of patients from AN surgery has been published. In dividing cells, one benefit of fractionation is the opportu-
a survey of 541 members of the AN Association (a patient nity for a greater number of cells to enter mitosis during
information and support organization), only 5% were the treatment course. However, because ANs have a very
unable to return to work following tumor removal.321 low index of mitoses, only a relatively small number of
Eight percent reported an inability to resume normal tumor cells would enter this vulnerable stage during the
social life, and 15% noted easy fatiguability. Even these treatment course.
relatively low percentages of global lifestyle changes are Few reports are available on the effectiveness of con-
probably overestimates because many members join this ventional irradiation. In one study of 20 patients followed
group for help coping with long-term disability. This self- 7 to 46 months (mean 30 months) after radiation, 2 died of
selection skews the patient population toward those with their tumors, 2 died of unknown causes, 2 patients developed
less favorable outcomes. hydrocephalus, and 2 required salvage surgery.326 Such
In a Danish study of 273 patients, adverse vocational results are clearly poorer than those of surgical excision
impact was noted in 14%, 9% of whom ceased to work and and modern stereotactic radiation. The effects of conven-
5% required a change of employment. In a study of tional radiotherapy on partially excised AN has also been
57 patients from Japan, only 63% returned to their same studied. In a study of 31 patients with ANs, it was concluded
occupation following surgery and 70% resumed driving a that fractionated radiotherapy was of no benefit to those
car.316 It is intriguing to note that 80% of patients continued who had undergone total or near-total tumor removal.325
to play golf after their surgery. Several factors may con- Following subtotal excision, however, 46% (6/13) of unra-
tribute to the wide discrepancies in success of occupational diated tumors recurred and only 6% (1/17) of irradiated
rehabilitation among the different countries, including the tumors showed signs of symptomatic progression. This
amount of social support provided to disabled workers. In seemingly convincing data is open to several criticisms.
addition, the availability of sophisticated diagnostic tools The two groups may not have been equivalent because
such as MRI varies around the world, a factor that may patients accrued over nearly 40 years and the term subtotal
affect the size mixture of tumors at the time of diagnosis may have had different meanings to various surgeons over
and thus create a variable incidence of less favorable long- the decades of the study. In addition, recurrence was defined
term outcome. as symptomatic progression, and many seemingly controlled
Depression at some time in the postoperative course was patients could well have had tumor growth if they had
noted in 38% of patients in a study from the United States, been evaluated radiographically. Finally, this study showed
and it was noted in 17% in the Danish study.313,321 These a poor prognosis for patients irradiated at the time a post-
data are derived from patient response questionnaires and surgical recurrence was detected. Based on the published
do not reflect actual psychiatric diagnoses. In addition, data, there is little to commend conventional radiotherapy
neither the severity nor the duration of depression was in the management of ANs.
indicated in either study.
In our experience, global recovery of a patient following Stereotactic Irradiation
AN surgery depends most on the tumor’s size323 and the
patient’s age. It would be highly unusual for an individual The fundamental concept of stereotactic radiation (SR) is to
younger than 60 years with a tumor smaller than 2 cm not deliver a precise, conformal dose of radiation with isodose
to make an excellent functional recovery. If fact, most lines tailored to the margins of the tumors. In contrast to
younger patients with even very large tumors resume conventional radiotherapy, in which a large number of
active and productive lives within several months of fractions are delivered over many weeks, stereotactic radi-
surgery. By contrast, some elderly individuals remain dis- ation is designed to induce necrosis in the irradiated tissue
abled despite having only small tumors whether they through a single large dose delivered during a single session
were operated, radiated, or simply observed. The most or a few fractions delivered within a short period of time.
common cause of disability in the aged is chronic imbal- The dose delivered to the center of the tumor is more
ance. In summary, the economic, social, and psychological intense than that at the margin. Stereotactic radiation with
impact of AN and its surgical management appears to be photons is most commonly delivered either by a multisource
relatively minor, with few individuals having life-altering Cobalt-60 gamma unit (the Gamma Knife) (Fig. 45-29).
consequences.324 Single-source linear accelerator-based radiotherapy has
 Acoustic Neuroma (Vestibular Schwannoma) 769

also been developed, most notably with the Cyberknife,

which uses a contoured face mask and adaptive technology
to accommodate patient movement without the need for
rigid immobilization329 (Fig. 45-30). The Cyberknife is
essentially a linear accelerator attached to the arm of a
computer-controlled high-precision industrial robot.
Most centers believe that there are physical limits on the
volume of tumor that can be safely radiated, making this
a technique primarily suitable for small and medium-
sized tumors. Prior to the mid-1990s, the usual dose was
approximately 35 Gy to the tumor center and 16 to 18 Gy
to the margin. In an effort to reduce cranial nerve mor-
bidity, customary doses have been reduced recently to
approximately 25 Gy to the center and 12 to 14 Gy to the
margin.330
The effects of a single large dose of radiation on AN
cells growing in tissue culture have been evaluated.331
While doses between 30 and 150 Gy clearly induced some
damage in the schwannoma cells, a fraction of viable
tumor cells persisted even after the largest dose tested,
which was six times more than the maximal amount used
clinically. Little histopathologic material is available from
patients with ANs treated with stereotactic radiation.
Histopathologic evaluation of tumors that recurred follow-
ing stereotactic radiation shows some regions of residual
tumor cells but also evidence of necrosis, fibrosis, and
vascular hyperplasia.332 The interface between the facial
nerve and the tumor has also been noted to be more
fibrous following SR.333

Figure 45-29. The Gamma Knife® is a multisource cobalt radiotherapy unit.

been used less than multisource strategies, but the effect is

analogous.327 With the linear accelerator, a single beam
travels around the patient delivering doses either in a series
of arcs or individual “shots” to achieve a highly conformal
dose pattern. As a general rule, current generations of linear
accelerators require longer treatment times but are more
flexible in that they are not limited to the skull cap inherent
in the gamma knife and thus can be used anywhere in the
body. Either linear accelerator or gamma knife technique
is capable of delivering a precise dose to the tumor volume
while minimizing the amount of radiation to adjacent
normal brain and nerve tissue.
Recently, stereotactically delivered proton beams have
also been evaluated.328 Protons have a theoretical advantage
over photons in that the Bragg peak phenomenon ensures
essentially no exit dose beyond the intended limit of
treatment. Common to all high-precision radiotherapy
techniques is the need to maintain very precise registration
of head position during surgery. This begins with obtain-
ing high-resolution CT or MR images to localize the
tumor precisely. In most systems, a stereotactic head frame
is placed for use during treatment. Implanting metal balls
(fiducials) located on the skull surface is an alternative Figure 45-30. The Cyberknife® is a linear acceleration mounted onto an
method to maintain orientation. Frameless methods have industrial robot for delivery of highly precise stereotactic radiotherapy.
770 SURGICAL NEUROTOLOGY

TABLE 45-10. Fate of the Tumor following Single Treatment Stereotactic Radiation in Major Series with Longer-Term
Follow-up
No. of Marginal Dose
Report Year Patients Follow-up Mean (range) Stable Smaller Larger

Prasad364 2000 95 5–10 yr 13 Gy

(9–20)* 17% 74% 6%
Unger365 1999 56 4–6.7 yr 12–14 Gy — 34% —
(—)
Petit366 2001 23 3.5–7 yr 12 Gy 44% 52% 4%
(10–15)
Kondziolka367 1998 97 5–10 yr 16.6 Gy 29% 72% 0%
(12–20)
Flickinger330 2001 147 > 1 yr 13 Gy — 35% —
(2.5 median)† (11–18)

*Marginal dose data for a larger group. Dose for long-term subset is not defined but is likely on the high end of the range for these earlier cases.
†
This more recent Pittsburgh series using current dose regimens is included for comparison even though follow-up is short term.

Fate of the Tumor following cystic tumors, which have a higher rate of recurrence due to
expansion of the cystic component following radiation.334
Stereotactic Radiation A recent trend has been toward experimentation with
Although stereotactic radiotherapy has been used in AN fractionated stereotactic radiation.335,336 Doses are divided,
for more than 40 years after being introduced by Lars often into a few fractions delivered over 1 to 2 weeks. The
Leskell and his team in Stockholm, only recently has a concept of fractionation is to reduce complications, espe-
substantial body of outcome data been accumulated. cially neuropathy, by allowing biologic recovery time from
Following stereotactic radiotherapy, the tumor remains in radiation injury. Unfortunately, fractionation without
situ; the goal is stabilization against future growth rather increasing total dose also reduces the biologic effort on the
than the lesion’s disappearance. A modest degree of tumor itself. No significant long-term data has been pub-
shrinkage has been reported in roughly one-third to two- lished to elucidate whether or not fractionation increases
thirds of patients (Tables 45-10, 45-11, and 45-12). Not risk of recurrence.
uncommonly, the tumor swells somewhat during the first
6 to 18 months after treatment. This phenomenon, which Audiovestibular Function
likely stems from radiation-induced edema, should not be after Stereotactic Radiation
mistaken for neoplastic growth. Often a diminution of
gadolinium enhancement in the center of the tumor is Little data exists concerning the fate of hearing over the
observed (Fig. 45-31). long term. In three recent studies that followed fewer than
Numerous earlier studies have examined short-term 100 patients for 4 years, good hearing (Gardner-Robinson
outcome within the first few years, an inadequate period to grade 1 or 2) was preserved in 47% to 62% (Table 45-13).
assess long-term therapeutic efficacy. Only a few studies, Higher dose has been correlated with poorer hearing out-
totaling no more than a few hundred patients, report come.337 It is not yet clear whether fractionation improves
follow-up longer than 5 years (see Tables 45-10, 45-11, hearing outcome, although preliminary data suggest that it
and 45-12). In these studies, regrowth was observed in does.338 Hearing preservation in bilateral ANs associated
approximately 5% of cases over time. This contrasts with with NF2 appears to be somewhat less favorable than with
an approximately 50% chance an AN will demonstrate sig- sporadic unilateral AN.338–340 Hearing results do not
nificant growth over a 3-year period based on the natural appear to be as favorable with proton beam therapy as with
history of the disease. Caution must be observed in combin- photon-based modalities 328,335
ing earlier studies in which an @ 16 Gy marginal dose was Little data exists concerning the outcome of vestibular
used rather than the @ 12 Gy of protocols popular at pres- function after stereotactic radiation. Because the diseased
ent. Nevertheless, a substantial body of data has been accu- vestibular nerve remains, persistent aberrant vestibular
mulated indicating that stereotactic radiation controls ANs input is likely to remain in a sizable fraction of patients.
in a substantial majority of cases. One special circumstance is Anecdotal observations of experienced practitioners is that

TABLE 45-11. Fate of Tumors after Fractionated Treatment Stereotactic Radiation

Report Year No. of Patients Follow-up Marginal Dose Stable Smaller Larger

Williams336 2002 125 1–5.7 yr Not given 88% 12% 0%

(1.8 mean)
Fuss368 2000 42 1.4–10.9 yr Not given 52% 46% 2%
(3.5 mean)
 Acoustic Neuroma (Vestibular Schwannoma) 771

TABLE 45-12. Fate of Tumors after Proton Beam Radiation

Report Year No. of Patients Follow-up Marginal Dose Stable Smaller Larger

Harsh328 2002 64 0.5–8 yr 12 Gy 55% 39% 6%

(2.8 mean) (11–18)

radiation does not help older individuals with small tumors and permanent deafness evolved 2 days following radiation
and deteriorating balance. of a small NF2 tumor.342 Vertigo, seizures, and persistent
new headaches have been reported in the immediate post-
Cranial Nerve Function following treatment period.343 The author has seen several cases of
devastating brainstem injury following stereotactic radiation
Stereotactic Radiation (Fig. 45-32).
Facial neuropathy has been observed following stereotactic Precipitous enlargement of the tumor necessitating
radiation, typically commencing 6 to 12 months following urgent microsurgical decompression has been reported in
therapy. In the great majority of cases, it is transient and a few cases.344 This appears to be a phenomenon primarily
the patient recovers facial function. The incidence of facial for tumors larger than those typically radiated at most
neuropathy has been reduced by lowering the marginal centers.
tumor dose. In the 1970s, rates of facial neuropathy were
nearly 40%.341 The rate at 16 Gy marginal dose, common Secondary Oncogenesis following
through the early 1990s was on the order of 10% to 20%. Stereotactic Radiation
At current dose regimens of 12 Gy, the incidence appears to
be on the order of 5% with some series reporting even less. When contemplating radiation therapy for a benign neo-
Trigeminal neuropathy, which was formerly quite preva- plasm, the risk of inducing a secondary malignant tumor
lent at higher doses, occurs infrequently with current dose must be carefully weighed. Five cases of malignancy that
regimens. Hypesthesia is the most common symptom. evolved following stereotactic radiation for AN have been
The occurrence of trigeminal neuropathy is correlated reported in the literature to date (Table 45-14).
with larger tumors. Preliminary data suggests that frac- Unfortunately, each case was lethal. Three were malignant
tionation does reduce the risk of trigeminal or facial schwannomas and one each glioblastoma and meningeal
neuropathy.338 Proton beam appears to have a higher risk sarcoma. In three of the five cases, biopsy confirmed an
of new neuropathy than photon therapy.328 initially benign AN. The other two, who were treated
without biopsy, had clinical scenarios highly suggestive of
Complications following benign AN from the outset. Interestingly, the latency
period was 5 to 7.5 years in reported cases, much shorter
Stereotactic Radiation than the more usual decades-long interval following con-
Hydrocephalus may occur following stereotactic radiation, ventional radiotherapy.
presumably caused by leakage of proteins from the tumor The key issue, yet to be determined, is the rate of occur-
surface leading to impaired CSF resorption. This complica- rence of radiation-induced neoplasia following stereotactic
tion appears to occur in a small percentage of patients. radiation for AN. In the best studied intracranial model of
Most neurologic injuries following radiation have onset conventional radiation, pituitary adenoma, the risk is about
latencies measured in months; however, a few reports of 1% at 10 years, 2% at 20 years, and 3% at 30 years.345
early deterioration have appeared. In one case, facial palsy Because the radiobiology of stereotactic radiation is different

Figure 45-31. MRI of a small acoustic

neuroma before (A) and after
(B) stereotactic radiotherapy. Note the
loss of central gadolinium enhancement
of the tumor on follow-up imaging.
772 SURGICAL NEUROTOLOGY

TABLE 45-13. Long-Term Preservation of Useful Hearing Following Stereotactic Radiation

Report Year No. of Patients Follow-up Marginal Dose Preserved Hearing

Kondziolka367 1998 32 5–10 yr 16 Gy 47%

Prasad364 2000 36 4.3 yr 13 Gy 58%
Unger365 1999 26 4 yr 12–14 Gy 62%

(Single treatment gamma knife) among patients with serviceable hearing (Gardiner-Robinson grade 1 or 2, better than 50 dB speech reception threshold, and 50% word recognition
score) prior to therapy.

from that of conventional fractionated radiotherapy, the microsurgery almost exclusively and others advocate a
analogy is approximate at best. similar policy for radiation. The majority of centers use the
different modalities in a variable mixture based on criteria
Indications for Stereotactic Radiation that are not always consistent among groups. In general,
centers are more likely to recommend radiation for smaller
in Unilateral Acoustic Neuroma tumors in older individuals and microsurgery for younger
Because roughly 50% of ANs show little growth over a patients with a tumor of any size. Most large tumors are still
3-year period, it is reasonable to withhold treatment for managed with microsurgery. The rationale is that younger
smaller tumors that are minimally symptomatic, especially patients are more vulnerable to the potential long-term
in older individuals, until the tumor has proved that it adverse consequences of radiation (e.g., secondary neopla-
needs intervention by demonstrating growth on serial sia, vaso-occlusive disease). Also, microsurgery is usually
imaging studies. Much controversy exists concerning definitive, whereas MRI monitoring is needed indefinitely
the relative roles of microsurgery and stereotactic following radiation. Because after radiation therapy a
radiation. At the extremes of the range, some centers favor tumor is still present on MRI and has potential for resump-
tion of growth, some patients encounter eligibility difficul-
ties when seeking to change health insurance plans.

Radiation after Surgery

and Surgery after Radiation
A surprising fraction of stereotactic radiation cases have
been AN recurrences following microsurgery. In the author’s
experience, the vast majority of these recurrences stemmed
from decentralized care at nonspecialized centers where
large amounts of tumor were injudiciously left, particularly
in the well-vascularized IAC portion of the tumor. Outcome
for stereotactic radiation of tumor recurrence is similar to
that of unoperated cases.
It is not surprising that salvage surgery after radiation
failure has a higher rate of complications than primary sur-
gery.333,346,347 Radical resection has a high rate of permanent
A facial nerve neuropathy. Thus, incomplete removal (near
total or subtotal) is a reasonable option in many cases.

BILATERAL ACOUSTIC NEUROMA

For discussion of this condition, please see Chapter 46.

AUDITORY BRAINSTEM IMPLANT

For a discussion of this innovative rehabilitation method
for NF2 patients, please see Chapter 82 (Auditory
Brainstem Implant).

CONCLUSION
B
Figure 45-32. Precontrast (A) and postcontrast (B) MRI scans of severe In recent years, dramatic progress has been made in both
brain edema following gamma knife therapy of a large acoustic neuroma. the clinical and basic science aspects of acoustic neuromas.
 Acoustic Neuroma (Vestibular Schwannoma) 773

TABLE 45-14. Malignancies Reported after Stereotactic Radiation for Acoustic Neuroma
Report Year Dose AN Size Age at AN Dx Tumor Type Latency Outcome

Thomsen369 2000 12 Gy peripheral 1.5 cm 19 Meningeal 6 yr Death

20 Gy maximal sarcoma
Shamisa370 2001 11 Gy peripheral “8.6 mL” 49 Glioblastoma 7.5 yr Death
27.2 Gy maximal
Hanabusa371 2001 15 Gy peripheral 2–3 cm 57 Malignant 6 mo Death
30 Gy maximal schwannoma
Shin372 2002 17 Gy peripheral 3 cm 26 Malignant 6 yr Death
schwannoma
Comey373 1998 14.4 Gy peripheral 2.7 cm 44 Malignant 5 yr Death
34 Gy maximal schwannoma
Biopsy Confirmation of Initial Benign Schwannoma
Shamisa Yes Surgery post XRT confirmed benign schwannoma
Hanabusa Yes Subtotal initial surgery confirmed benign schwannoma
Shin Yes Subtotal initial surgery confirmed benign schwannoma
Thomsen No NF2. No prior biopsy but contralateral benign schwannoma
Comey No

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removal of a vestibular schwannoma after stereotactic radiosurgery: Neurological Surgery of the Ear and Skull Base, 1988,
Surgical and pathologic findings. Am J Otol 20:364–367, 1999. pp 203–205.
334. Shirato H, Sakamoto T, Takeichi N, et al: Fractionated stereotac- 355. Tos M, Tomsen J: Sequelae after translabyrinthine removal
tic radiotherapy for vestibular schwannoma (VS): Comparison of 400 acoustic neuromas. In Fisch U, Valavanis A, Yasargil M
between cystic-type and solid-type VS. Int J Radiat Oncol Biol (eds.): Proceedings of the Sixth International Symposium
Phys 48:1395–1401, 2000. of Neurological Surgery of the Ear and Skull Base, 1988,
335. Bush DA, McAllister CJ, Loredo LN, et al: Fractionated proton pp 175–184.
beam radiotherapy for acoustic neuroma. Neurosurgery 356. Nadol JB Jr, Chiong CM, Ojemann RG, et al: Preservation of
50(2):270–273, 2002. hearing and facial nerve function in resection of acoustic neuroma.
336. Williams JA: Fractionated stereotactic radiotherapy for acoustic Laryngoscope 102:1153–1158, 1992.
neuromas. Int J Radiat Oncol Biol Phys 54:500–504, 2002. 357. Ebersold MJ, Harner SG, Beatty CW, et al: Current results of the
337. Niranjan A, Lunsford LD, Flickinger JC, et al: Dose reduction retrosigmoid approach to acoustic neurinoma. J Neurosurg
improves hearing preservation rates after intracanalicular acoustic 76:901–909, 1992.
tumor radiosurgery. Neurosurgery 45:753–762, 1999. 358. Arriaga MA, Luxford WM, Berliner KI: Facial nerve function
338. Andrews DW, Suarez O, Goldman HW, et al: Stereotactic following middle fossa and translabyrinthine acoustic tumor
radiosurgery and fractionated stereotactic radiotherapy for the surgery: A comparison. Am J Otol 15:620–624, 1994.
treatment of acoustic schwannomas: Comparative observations of 359. Samii M, Matthies C: Management of 1000 vestibular schwanno-
125 patients treated at one institution. Int J Radiat Oncol Biol Phys mas (acoustic neuromas): The facial nerve—preservation and resti-
50:1265–1278, 2001. tution of function. Neurosurgery 40:684–694, 1997.
339. Kida Y, Kobayashi T, Tanaka T, Mori Y: Radiosurgery for bilateral 360. Glasscock ME 3rd, Hays JW, Minor LB, et al: Preservation of
neurinomas associated with neurofibromatosis type 2. Surg Neurol hearing in surgery for acoustic neuromas. J Neurosurg
53:383–389, 2000. 78:864–870, 1993.
340. Ito K, Shin M, Matsuzaki M, et al: Risk factors for neurological 361. Brookes GB, Woo J: Hearing preservation in acoustic neuroma
complications after acoustic neurinoma radiosurgery: Refinement surgery. Clin Otolaryngol 19:204–214, 1994.
from further experiences. Int J Radiat Oncol Biol Phys 48:75–80, 362. Slattery WH 3rd, Brackmann DE, Hitselberger W: Middle fossa
2000. approach for hearing preservation with acoustic neuromas [pub-
341. Noren G: Long-term complications following gamma knife radio- lished erratum appears in Am J Otol 18:796, 1997]. Am J Otol
surgery of vestibular schwannomas. Stereotact Funct Neurosurg 18:596–601, 1997.
70(Suppl 1):65–73, 1998. 363. Dornhoffer JL, Helms J, Hoehmann DH: Hearing preservation in
342. Tago M, Terahara A, Nakagawa K, et al: Immediate neurological acoustic tumor surgery: Results and prognostic factors.
deterioration after gamma knife radiosurgery for acoustic neu- Laryngoscope 105:184–187, 1995.
roma. J Neurosurg 93(Suppl 3):78–81, 2000. 364. Prasad D, Steiner M, Steiner L: Gamma surgery for vestibular
343. Werner-Wasik M, Rudoler S, Preston PE, et al: Immediate side schwannoma. J Neurosurg 92:745–759, 2000.
effects of stereotactic radiotherapy and radiosurgery. Int J Radiat 365. Unger F, Walch C, Haselsberger K, et al: Radiosurgery of
Oncol Biol Phys 43:299–304, 1999. vestibular schwannomas: A minimally invasive alternative to
344. Couldwell WT, Mohan AL: Enlargement of a vestibular schwan- microsurgery. Acta Neurochir (Wien) 141(12):1281–1285,
noma after stereotactic radiotherapy. Acta Neurochir (Wien) 1999.
144:1319–1322, 2002. 366. Petit JH, Hudes RS, Chen TT, et al: Reduced-dose radio-
345. Erfurth EM, Bulow B, Mikoczy Z, et al: Is there an increase in surgery for vestibular schwannomas. Neurosurgery 49:1299–1306,
second brain tumors after surgery and irradiation for a pituitary 2001.
tumor? Clin Endocrinol (Oxf) 55:613–616. 2001. 367. Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC:
346. Pollock BE, Lunsford LD, Kondziolka D, et al: Vestibular Long-term outcomes after radiosurgery for acoustic neuromas.
schwannoma management. Part II. Failed radiosurgery and the N Engl J Med 339(20):1426–1433, 1998.
role of delayed microsurgery. J Neurosurg 89:949–955, 1998. 368. Fuss M, Debus J, Lohr F, et al: Conventionally fractionated stereo-
347. Battista RA, Wiet RJ: Stereotactic radiosurgery for acoustic neuro- tactic radiotherapy (FSRT) for acoustic neuromas. Int J Radiat
mas: A survey of the American Neurotology Society. Am J Otol Oncol Biol Phys 48:1381–1387, 2000.
21:371–381, 2000. 369. Thomsen J, Mirz F, Wetke R, et al: Intracranial sarcoma in a
348. Luxford WM, House WF: Acoustic tumor. In Pillsbury HC, patient with neurofibromatosis type 2 treated with gamma knife
Goldsmith MM (eds.): Operative Challenges in Otolaryngology- radiosurgery for vestibular schwannoma. Am J Otol 21:364–370,
Head and Neck Surgery. 1990, pp 77–83. 2000.
782 SURGICAL NEUROTOLOGY

370. Shamisa A, Bance M, Nag S, et al: Glioblastoma multiforme 373. Comey CH, McLaughlin MR, Jho HD, et al: Death from a malig-
occurring in a patient treated with gamma knife surgery. Case nant cerebellopontine angle triton tumor despite stereotactic
report and review of the literature. J Neurosurg 94:816–821, 2001. radiosurgery. Case report. J Neurosurg 89:653–658, 1998.
371. Hanabusa K, Morikawa A, Murata T, Taki W: Acoustic neuroma 374. Arriaga MA, Chen DA: Facial function in hearing preservation
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372. Shin M, Ueki K, Kurita H, Kirino T: Malignant transformation of 127:543–546, 2001.
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27;360(9329):309–310, 2002.
 Chapter
Neurofibromatosis 2

Outline 46
Introduction Hearing Preservation William H. Slattery III, MD
Neurofibromatosis 2 Observation without
Laurel M. Fisher, PhD
Differentiated from Surgical Intervention
Neurofibromatosis 1 Middle Fossa Craniotomy
Clinical Characteristics and Internal Auditory
of Neurofibromatosis 2 Canal Decompression
Definition of without Tumor Removal
Neurofibromatosis 2 Retrosigmoid Craniotomy
Prevalence and Incidence with Partial Removal
Molecular Genetics Nonhearing Preservation,
Family History Translabyrinthine/
Tumor Types Suboccipital Approach,
Auditory Changes in Patients Total Tumor Removal
with Vestibular Auditory Brainstem Implant
Schwannomas Stereotactic Irradiation
Other Tumor Types in Management of
Neurofibromatosis 2 Neurofibromatosis 2
Treatment Options for Genetic Testing
Vestibular Schwannomas Summary
in Neurofibromatosis 2

INTRODUCTION • Freckling
• Optic glioma
Neurofibromatosis 2 (NF2) presents unique challenges to
• Lisch nodules (iris hamartomas)
the neurotologist. The disease is quite invasive, requiring a
• Osseous lesion (sphenoid dysplasia, thinning of the long
multispecialist team approach. At the same time, the
bone cortex)
primary impairment is hearing loss due to bilateral vestibu-
• A first-degree relative with NF1
lar schwannomas. Usually, the presenting complaint will be
hearing loss or balance problems, and the neurotologist Some patients manifest learning disabilities or language
will be the first specialist to diagnose the disorder. Here we disorders as well. A careful examination and a detailed
review the differential diagnosis of NF2 from neurofibro- history of the patient’s symptoms will help to distinguish
matosis 1 (NF1), characteristics of the disease, current the two diseases.
treatment, and management options.
Clinical Characteristics
NEUROFIBROMATOSIS 2 DIFFERENTIATED of Neurofibromatosis 2
FROM NEUROFIBROMATOSIS 1 Definition of Neurofibromatosis 2
In 1987, the National Institutes of Health Consensus
NF1 has a distinctly different clinical presentation from
Development Conference on NF developed the guidelines
that of NF2. Positive differentiation of NF2 from NF1 has
for diagnosis of NF2 as distinct from NF1. NF2 is distin-
occurred with genetic analysis. NF1 has been localized to
guished by bilateral acoustic neuromas (or vestibular
chromosome 17, NF2 to chromosome 22. NF1 is defined
schwannomas [VS]) with multiple meningiomas, cranial
as having two or more of the following:
tumors, optic gliomas, and spinal tumors.1 A definitive diag-
• Six or more café au lait macules nosis is made on the basis of the presence of bilateral vestibu-
• Two or more neurofibromas lar schwannomas, or developing a unilateral vestibular
783
784 SURGICAL NEUROTOLOGY

schwannoma by the age of 30 and a first-degree blood TABLE 46-1. Neurofibromatosis 2 Diagnostic Criteria
relative with NF2, or developing at least two of the follow-
ing conditions known to be associated with NF2: menin- Individuals with the following clinical features have confirmed (definite) NF2:
Bilateral vestibular schwannomas (VS) or family history of NF2 (first-
gioma, glioma, schwannoma, or juvenile poster subcapsular degree family relative) plus
lenticular opacity/juvenile cortical cataract1 (Table 46-1). 1. Unilateral VS < 30 years or
As the definition implies, the presentation of the disease 2. Any two of the following: meningioma, glioma, schwannoma, juvenile
and the genetic mutation linked to the manifestations of posterior subcapsular lenticular opacities/juvenile cortical cataract.
the disease exhibit considerable heterogeneity. Yet, within Individuals with the following clinical features should be evaluated for NF2
(presumptive or probable NF2):
a family, the expression of NF2 tends to be very much the Unilateral VS < 30 years plus at least one of the following: meningioma,
same.2 These two facts, taken together, indicate a large glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/
genetic component to the disease, yet with much variabil- juvenile cortical cataract.
ity within those parameters in the observed phenotype. Multiple meningiomas (two or more) plus unilateral VS < 30 years or one
of the following: glioma, schwannoma, juvenile posterior subcapsular
Studies have indicated that a truncating mutation (non- lenticular opacities/juvenile cortical cataract.
sense and frameshift) may be linked with the more severe
form of NF2.3–5 The more severe form, termed the Wishart NF2, neurofibromatosis 2.
form, is particularly virulent, with unrelenting growth
of schwannomas and meningiomas from childhood, result-
ing in blindness, deafness, paralysis, and death by the age of prevalence differences by ethnicity. Epidemiologic studies
40. Despite the strong genotype-phenotype correlation, place the incidence of NF2 between 1 in 40,000 live
individual differences in tumor growth occur within births13 and 1 in 87,410 live births.14
subjects, making it difficult to predict how an individual
tumor will change over time even when the genotype is
Molecular Genetics
known.
The mild, or Gardner form, of NF2 is less debilitating. In 1987, the NF2 gene was mapped to chromosome 2215
The schwannomas may remain the same size for years, few and was localized to 22q12.2 in 1993.16,17 Various types of
meningiomas will develop, the patient may not develop mutations have been identified, among them single-base
symptoms until late in life, and will have fewer disabili- substitutions, insertions, and deletions.4,18–20 The mild, or
ties.2–4,6–12 However, the genetic basis of the mild form has Gardner, type NF2 may be associated with missense muta-
not been well described. tions, whereas associations between the other mutations
and phenotypes are not as clear.21 The occurrence of NF2
Prevalence and Incidence is not restricted to families known to carry the mutation.
Frequently, genetic mosaicism occurs,22 which may not
Patients tend to be diagnosed with NF2 around age 25 be picked up by common mutation analytic techniques.
after experiencing symptoms of the disease for an average It appears that unilateral vestibular schwannoma may
of 7 years (Fig. 46-1). There are no differences in the pro- exhibit the same type of genetic markers as NF2.23
portion of men versus women who develop NF2 and no However, the mutation is confined to the affected tissue.

1.0
Kaplan-Meier Cumulative Proportion

0.8

0.6

Figure 46-1. Time from first symptom to first

surgery.
0.4

Family History
0.2

Yes

No
0.0
0 10 20 30
Years
 Neurofibromatosis 2 785

In persons with NF2, the mutation is present in other types considered if the cranial MRI scan is positive. An audio-
of cells as well.22 gram (pure-tone thresholds) and the current clinical stan-
dard auditory brainstem response (ABR) testing are likely
to miss small vestibular schwannomas that a MRI scan can
Family History
diagnose presymptomatically.
Individuals at risk for developing NF2 must be screened to MRI scanning is recommended for an at-risk minor
provide an early diagnosis. Individuals at risk include chil- when this test can be performed without sedation. This
dren of NF2-affected patients and their siblings. Because usually occurs when the child is 7 through 9 years of age.
NF2 has a 50% penetrance, all children of NF2 patients A recommended first step for children younger than age 7
have a 50% risk of developing the disease. Siblings of a is an audiogram. Any child with an NF2-associated symp-
diagnosed NF2 patient are at risk, especially if the parent tom (e.g., hearing loss or facial weakness) should be
has also been identified with NF2. The clinical presenta- screened without regard to the need of sedation or age
tion of NF2 is usually similar within families. The likeli- and should be performed as soon as possible after the
hood of NF2 occurring in related individuals who do not symptoms are apparent.
exhibit similar clinical symptoms to an affected family
member is small. Consideration may still be given for
screening. TUMOR TYPES
The type of screening and the timing of screening
depends on each NF2 center’s preferences. However, we Bilateral vestibular schwannomas (also acoustic neuroma)
advocate early screening, so that tumors may be diagnosed are benign neoplasms of the acoustic or eighth cranial
presymptomatically. nerve24 (Fig. 46-2). The tumors typically are located on
We screen potentially affected individuals with a post- the superior vestibular nerve at the glial-Schwann cell
contrast T1-weighted MRI of the full head, with fine cuts junction within the internal acoustic meatus. The conse-
(at most 3 mm slices, no skip) through the internal audi- quences of a vestibular schwannoma are numerous, includ-
tory canals (IACs). This test will identify most affected ing dizziness, imbalance, tinnitus, hearing loss progressing
NF2 patients by showing any vestibular schwannomas. to deafness, facial nerve paralysis, brainstem compression,
Screening of the spine or ophthalmology exams should be and, if left untreated, death.

A B

Figure 46-2. Bilateral vestibular schwannomas are characteristic of NF2.

A, Small bilateral vestibular schwannomas. B, Medium-size vestibular
schwannoma that are compressing the brainstem. C, Giant bilateral
vestibular schwannomas that are compressing the brainstem and causing
hydrocephalus.

C
786 SURGICAL NEUROTOLOGY

Despite the strong genotypic effect in NF2, there is enor- TABLE 46-3. First Symptoms of Neurofibromatosis 2
mous variability in the number of tumor types (Table 46-2),
Symptoms Percentage of Patients
the rate of progression, and the disabilities experienced.
This enormous variability is also found in patient presen- Neurologic 17.5
tation; surprisingly, some patients may be asymptomatic. Skin tumor 11.7
Vision loss 10.7
Patients who have no symptoms when diagnosed have Asymptomatic 10.7
generally been identified on the basis of genetic analysis, Tinnitus 7.8
conducted because a blood relative has NF2. Although the Weakness 2.9
National Institutes of Health (NIH) criteria for NF2 Vertigo 1.0
Other/Unspecified 4.9
require the presence of bilateral vestibular schwannoma
for diagnosis, patients may first develop a unilateral
vestibular schwannoma as a young child with no other
tumors, or adult patients may present with multiple level of analysis) or to auditory functioning (phenotype level
meningiomas (cranial and spinal) and no vestibular of analysis). For this reason physicians recommend at least
schwannoma.9,25 Although the NIH criteria for NF2 imply yearly MRI scans to track changes in size.33–40 Others have
that all NF2 patients will develop bilateral vestibular suggested that, after a baseline scan, the next scan be at
schwannoma, some researchers are not convinced of this.26 6 months in order to determine if the tumor is fast- or
Evans26 based his conclusion on the observation of a pos- slow-growing.41
sible variant form of NF2 presenting with skin and spinal
tumors in the absence of vestibular schwannomas. Auditory Changes in Patients
Nevertheless, in general, the phenotype is reflective of the with Vestibular Schwannomas
underlying genotype.
Preliminary data from the Natural History of Vestibular Hearing loss is well documented as the most common
Schwannomas in NF2 study conducted at House Ear presenting symptom in patients who have vestibular
Institute shows that 10 of 80 (12.5%) enrolled subjects had schwannoma.42–51 Auditory changes over time in vestibular
no symptoms at diagnosis, and 23 (28.8%) had cranial schwannoma patients are less well known. Rosenberg52
meningiomas and spinal meningiomas in addition to bilat- studied the natural history of 80 patients with non-NF2
eral vestibular schwannoma. Nearly half (47.5%) had one unilateral vestibular schwannoma for an average of 4.4 years.
vestibular schwannoma removed prior to enrollment. Rosenberg found a positive correlation between tumor
Generally, the tumor resected prior to enrollment was growth and worsening pure tone average. However, there
removed 1.5 years after discovery and was an average of 2.1 was no statistically significant correlation between positive
cm at removal. Few Natural History patients had spinal tumor growth and speech discrimination, change in brain-
tumors or meningiomas removed prior to enrollment. The stem auditory evoked response, and bithermal caloric
preliminary data would indicate that, for this sample of NF2 electronystagmography test responses over time. Lalwani
subjects, the most salient medical issue is the growth of their and colleagues53 reported that pure tone patterns, speech
vestibular schwannoma. reception threshold, and word recognition scores were
NF2 subjects tend also to develop cortical and posterior significantly worse in NF2 patients who had a mild form
subcapsular cataracts, which can lead to blindness27 of NF2 and large tumors compared with patients with
(Table 46-3). Retinal hamartomas have been observed in a mild NF2 with small tumors. Loss of acoustic reflexes and
few cases,2,28–30 but are not as frequent. Some subjects (2% prolonged wave III and V were also associated with larger
to 3% of subjects)31,32 present with numbness or tingling in tumors. In contrast, patients with severe NF2 showed
their arms or legs. Upwards of 30% of NF2 subjects may no relationship among tumor size and pure tone levels,
have surgery to remove spinal tumors, but the progression speech reception threshold, or word recognition scores.
of spinal tumors associated with NF2 is not well described. The lack of association may have been due to the complete
At this time, the presence of vestibular schwannoma in loss of hearing in the severe NF2 patients at the time of
NF2 and the consequences of not treating them are rela- the assessment. The larger tumors were associated with
tively well known, and these tumors may be the most prolonged ABR wave III and V latencies. No data across
debilitating. time were reported. In general, hearing is progressively
Rarely does a vestibular schwannoma turn malignant, impaired with increasing growth of vestibular schwanno-
and sometimes the unilateral vestibular schwannoma may mas, necessitating the need for surgical intervention or
regress in size altogether. Growth of the tumors does not medical treatment in NF2 patients.
seem to be related either to loss of heterozygosity (genetic
Other Tumor Types
in Neurofibromatosis 2
TABLE 46-2. Tumor Type NF2 has been associated with multiple central nervous
Tumor Type Percentage of Patients system tumors, the most common of which are intracranial
meningiomas (Fig. 46-3), spinal tumors, and optic gliomas
Bilateral vestibular schwannoma 99 (in addition to cataracts).54 Nearly all NF2 patients
Skin 50
Meningioma 46
will develop these tumors in time: 50% of NF2 patients
Spinal 60 present with schwannomas and meningiomas, 90% present
with spinal tumors in addition to schwannomas.25
 Neurofibromatosis 2 787

on their positioning relative to the spinal cord.

Extramedullary tumors are commonly schwannomas or
meningiomas, whereas intramedullary tumors are often
ependymomas, but can also be astrocytomas or schwanno-
mas.57 Although studies have been conducted to determine
the number of spinal tumors, they are often too numerous
to count, therefore making most observed numbers an
underestimation of the exact tumor burden.2,25 Spinal
tumors may cause cord compression and bone erosion and
can have solid and cystic components.58
As each NF2-related tumor grows and exerts pressure
on surrounding structures, treatment encompasses surgi-
cal resection or radiotherapy (or both). Another treatment
choice, early on in the disease course, is surgical decom-
pression, in which space is created for the growing tumor,
Figure 46-3. Multiple meningiomas can be seen in severe forms of NF2. relieving the pressure inside the skull or at the spinal cord.
Meningiomas may occur throughout the cranium and skull base area. Growing meningiomas result in increased intracranial
pressure, intractable headache, hydrocephalus, and seizure
disorders.59–61 Continued growth of spinal tumors causes
The presence of more than one type of tumor within an loss of motion, numbness, tingling, and, eventually, para-
individual usually indicates a more aggressive disease lysis. Treatment of optic gliomas frequently results in
course. The co-occurrence of vestibular schwannomas and removal of the eye (thus, blindness).27
meningiomas have been linked to a synergistic effect on
growth rate, increasing the growth rate of both the
schwannoma and meningioma beyond that expected of a Treatment Options for Vestibular
sporadic schwannoma or meningioma.55,56 Despite the Schwannomas in Neurofibromatosis 2
high numbers of patients with multiple tumors, initially, The treatment options for a patient with bilateral vestibular
most meningiomas and spinal tumors are asymptomatic schwannomas vary considerably as a result of the wide
and are first seen on an MRI. In addition, multiple skin variety of tumor sizes and clinical presentations. Associated
tumors are found in persons with NF2. symptoms (brainstem compression or hydrocephalus), loss of
A variety of spinal tumors (Fig. 46-4) occur in NF2 useful hearing, and the status of other intracranial tumors all
patients and can be found in the cervical, thoracic, and must be considered when discussing treatment intervention.
lumbar regions. These tumors are further categorized as
either extramedullary or intramedullary tumors, depending
Hearing Preservation
Individuals that present with bilateral small tumors (less
than 2 cm in greatest diameter) and good hearing may be
candidates for hearing preservation procedures. In these
patients, total tumor removal is attempted on the side of the
larger tumor or on the side with worse hearing. If hearing is
successfully preserved on the first side, then contralateral
tumor removal may be attempted 6 months later.
Hearing preservation rates for small unilateral tumors
have approached 70%.51 However, the results in NF2
patients appear to be worse than those reported in patients
with unilateral vestibular schwannomas.62 Doyle and
Shelton63 found that 67% of NF2 patients underwent
hearing presentation surgery using the middle fossa
approach, and 38% of those had serviceable hearing
postoperatively.

Observation without Surgical Intervention

Observation without surgical intervention is the most
common treatment option used in patients with NF2 and
is used when a small tumor is present in a patient with only
one hearing ear or when bilateral tumors are too large for
hearing preservation procedures. The individual is assessed
routinely to ensure that brainstem compression or hydro-
Figure 46-4. Spinal tumors may be seen in up to 20% to 50% of NF2
patients. Many of these are symptomatic; however, some can become quite
cephalus does not result. Initially, an MRI is performed
large, causing compression of the spinal cord and nerve roots. Excision is 6 months following diagnosis, and then annual MRI scans
necessary when neural function is compromised. are performed to document tumor size and determine if
788 SURGICAL NEUROTOLOGY

intervention is required. Surgical intervention is consid-

ered if life-threatening complications occur, the tumors
become excessively large (increasing the perioperative
morbidity), or the hearing becomes unserviceable.

Middle Fossa Craniotomy and Internal Auditory

Canal Decompression without Tumor Removal
This alternative allows the tumor to grow without causing
compression of the seventh and eighth cranial nerves. This
procedure is recommended when progression of hearing loss
occurs in a patient who is being observed. The bone sur-
rounding the IAC is removed extensively, allowing the entire
tumor and seventh and eighth nerve complex to be decom-
pressed. The tumor itself is not removed because this may
increase the risk of hearing loss. Stabilization and even A
improvement of hearing may occur following this procedure.

Retrosigmoid Craniotomy with Partial Removal

This procedure in NF2 patients carries a significant risk
because the cochlear fibers are dispersed throughout the
tumor, in contrast to unilateral vestibular schwannomas
(Fig. 46-5). The risk of hearing loss with partial removal is
much higher, and this procedure is typically not
recommended.

Nonhearing Preservation, Translabyrinthine/

Suboccipital Approach, Total Tumor Removal
This is the most common surgical procedure performed in
patients with NF2. Most patients present when the tumor B
is either too large for hearing preservation or the hearing
Figure 46-5. Histology of a vestibular schwannoma. A, Unilateral non-NF2
loss is already at a significant level and hearing preserva- vestibular schwannoma. Typical schwannoma stain with Bodian silver stain.
tion is not considered. This approach is used for individu- It stains only the nerve fiber, so the schwannoma cells are not evident.
als with large tumors who have brainstem compression However, the fibers on the surface of the tumor are visible. Nerve fibers of
even if serviceable hearing exists. The translabyrinthine or non-NF2 vestibular schwannomas are displaced by the schwannomas cells.
B, This slide shows another Bodian silver stain with black strands embedded
suboccipital craniotomy approaches may be used for this within the tumor, representing the nerve fibers invaded by the tumor. This
procedure. However, the risk of a recurrent tumor is invasion is different than seen with non-NF2 solitary vestibular schwanno-
slightly higher with the suboccipital approach and with mas. Non-NF2 solitary tumors invade the aggregates of cells and push the
inexperienced surgeons because residual tumor is often left fibers aside rather than invading between the fibers. Thus, NF2 vestibular
in the lateral aspect of the IAC. schwannomas are histologically different from non-NF2 sporadic, unilateral
tumors.

Auditory Brainstem Implant

previously received radiation therapy developed a malig-
The auditory brainstem implant was developed at the nancy in the irradiated ear.64
House Ear Institute to allow electrical stimulation of the Many algorithms have been proposed as treatment
cochlear nucleus following bilateral vestibular schwan- plans, but none are widely accepted among NF2 special-
noma removal. The device is placed on the brainstem ists. The range of treatment options is large, larger than
(Fig. 46-6) during translabyrinthine vestibular schwan- for any other nervous system tumor. The potential bene-
noma removal. This device is indicated in individuals who fits of treatment are great (hearing preservation), but the
have no serviceable hearing and are undergoing vestibular potential risks are also significant, and the riskiest proce-
schwannoma removal. The majority of patients obtain dures have the greatest potential benefit. Often patients
enhanced communication skills with the device. have a window of opportunity when they can choose a
risky but potentially beneficial procedure; once the win-
dow closes, they cannot go back. Therefore, patients, fam-
Stereotactic Irradiation
ilies, and care providers need to know the natural history of
Stereotactic irradiation has been recommended for some these tumors to better make rational recommendations
NF2 patients, but its use must be carefully considered and decisions regarding these treatment options. In addi-
since radiation exposure may induce or accelerate tumors tion, noninvasive and tumor-related markers of behavior
in a patient with an inactivated tumor suppressor gene. It need to be identified that can further tailor our anticipatory
was recently reported that two of four patients who had guidance for any one patient.
 Neurofibromatosis 2 789

still under investigation for all NF2 patients. Patients with a

significant tumor burden, a family history of spine tumors,
or spinal tumor symptoms should definitely have a spine
series. A spine series is required in all symptomatic patients.
A neuro-ophthalmology exam is required for all patients
with NF2. The potential for deafness in these individuals
requires that everything be done to preserve vision. A slit
lamp exam is required. It is preferable that a patient be
evaluated by an ophthalmologist familiar with NF2.
The initial comprehensive evaluation consists, at a
minimum, of MRI of the IAC with gadolinium, auditory
assessment, and physical examination. A comprehensive
examination will include the previously mentioned MRI
with the addition of a full spine series, an ABR test, and an
ophthalmology examination.
The timing of follow-up studies is currently inconsistent
Figure 46-6. CT scan demonstrating placement of auditory brainstem among NF2 specialty centers. We recommend repeat test-
implant within the lateral recess of the fourth ventricle.
ing at 6 months and then yearly testing consisting of an
MRI of the head and spine, neurology examination, and
Management of Neurofibromatosis 2 audiometric testing. Once the growth rate from the
tumors has been determined, some of these tests may be
Initial evaluation of an NF2 patient can be very complex spread out over time. Spinal tumors tend to be very slow-
because this is a multisystem disease. However, an inade- growing and, once diagnosed, may be imaged every 1 to 5
quate diagnosis may render a patient impaired because years. The potential for new tumor formation exists espe-
early diagnosis and treatment may have prevented further cially in patients with severe disease, and it is important
impairments. NF2 patients may typically see many differ- that this information be conveyed to the NF2 patient so
ent physicians, each with experience in a different field of that comprehensive follow-up may occur.
expertise. NF2 patients require one physician to lead the
treatment team, a case manager as it were, to ensure com-
prehensive care. Neurologist, geneticist, neurosurgeon, or Genetic Testing
neurotologist may all function as the lead physician, Identification of the NF2 gene on chromosome 22 has made
depending on the NF2 center. genetic testing possible. It is recommended that patients with
A comprehensive battery of tests is necessary for tumor NF2 see a genetic counselor to discuss the hereditary conse-
detection and adequate staging. The initial MRI scan quences of this disease. Genetic blood screening is able to
demonstrating the presence of bilateral vestibular schwan- identify the defect on the NF2 gene in approximately 70%
nomas may be inadequate for tumor follow-up. As an to 75% of patients with a known diagnosis of NF2. If the
example, a cranial scan may not have included the IACs, or defect is identified, then potential family members may be
a spine series may have focused on only one segment of the screened. If the gene is not identified, then blood screening
spine. An MRI with gadolinium and thin cuts through the of family members can be performed. The use of blood
IAC is necessary for the head. Particular attention is screening for patients without a diagnosis or with a suspected
focused in the IACs, caverness sinus, and jugular foramen diagnosis of NF2 is not recommended. New mutations in
areas. Any cranial nerve may have tumor formation and patients with mild presentation are most likely missense
thus should have complete imaging. mutations, which are difficult to identify by genetic testing.
Auditory assessment is necessary to determine the
extent of hearing impairment. At a minimum, this consists
of a standard audiogram, with air and bone pure tone SUMMARY
thresholds, and speech testing. Some centers prefer addi-
tional testing with ABR to assess cochlear nerve function. Care of the NF2 patient requires knowledge of all tumors
This is particularly helpful when considering a hearing and symptoms involved with the disorder. The role of the
preservation procedure. Electronystagometry testing has neurotologist in this care is determined by the specialty
benefit in determining tumor location; however, its utility center. It is recommended that patients receive care in a
for clinical assessment is still under investigation. center with expertise in NF2.
A complete neurologic exam is required for individuals
with suspected NF2. The standard neurologic assessment
of dermatomes and muscle strength is required for assess-
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2 neurofibromatosis: Molecular discrimination of NF2 and sporadic WF, Luetje CM, Doyle KJ (eds.): Acoustic Tumors: Diagnosis and
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approach for hearing preservation with acoustic neuromas. Am J 60. King A, Gutmann DH: The question of familial meningiomas and
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110:497–508, 2000. 61. Wiebe S, Munoz DG, Smith S, Lee DH: Meningioangiomatosis.
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2. Am J Otol 19:352–357, 1998. 62. Slattery WH, Brackmann DE: Hearing Preservation and restora-
54. Bouzas EA, Parry DM, Eldridge R, Kaiser-Kupfer MI: Visual tion in CPA tumor surgery. Neuosurg Q 7:169–182, 1997.
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 Chapter
Meningiomas of the Posterior Fossa
and Skull Base
47 Outline

Ameet Singh, MD History Posterior Fossa Meningiomas Origin and Classification

Epidemiology Cerebellopontine Angle Clinical Presentation
Samuel H. Selesnick, MD
Etiology Meningiomas Imaging
Radiation Introduction Surgical Approach
Trauma History Surgical Management
Gender Epidemiology Jugular Foramen
Viruses Origin Meningiomas
Molecular Pathogenesis Classification Introduction
Pathology Clinical Presentation Classification
Gross Pathology Diagnosis Clinical Presentation
Microscopic Pathology Surgical Management Diagnosis
Grade I Meningioma Complications Surgical Approach
Histopathology Internal Auditory Canal Surgical Management
Grade II Meningioma Meningiomas Foramen Magnum
Histopathology Clival and Petroclival Meningiomas
Grade III Meningioma Meningiomas Introduction
Histopathology Introduction Epidemiology
Immunohistochemistry Origin and Classification History and Classification
Extension Clinical Presentation
Diagnosis
Clinical Presentation Diagnosis
Audiovestibular Testing
Diagnosis Surgical Approach
Radiology
Preoperative Considerations Surgical Results
Plain Radiography
Approach Selection Hearing Preservation
Angiography
Surgical History Facial Nerve Preservation
Computed Tomography
Resection Recurrence
and Magnetic Resonance
Mortality and Quality of Life Radiation Therapy
Imaging
Meckel’s Cave Meningiomas
General Surgical Principles
Epidemiology
Preoperative Considerations

HISTORY Meningiomas are thought to have been present as far

back as the prehistoric era, as demonstrated by hyperosto-
The term meningioma was proposed by Harvey Cushing sis found in the skulls of the pre-Colombian Incas from the
in 1922 to describe a benign intracranial tumor of the Peruvian Andes.4 The first description of a meningioma,
meninges.1 Prior to this historic naming, the nomenclature however, was noted by a Swiss physician, Felix Plater, in
surrounding this tumor had been shrouded in controversy. 1614. He described a tumor as “a round fleshy tumor, like
The uncertainty involving the meningioma’s cell of an acorn … hard and full of holes and … as large as a medium
origin had produced a plethora of descriptive names— sized apple … covered with its own membrane … free of all
meningoexothelioma, endothelioma, mesothelioma, and connections with the matter of the brain.”5 Although the
arachnoidal fibroblastoma to name just a few.2 To elimi- first illustrations of a meningioma were published in 1730,
nate confusion, avoid a commitment to a histologic origin, the earliest work that dealt exclusively with these tumors
and coalesce several pathologic tumor types arising from was written in 1774 by Antoine Louis in Mémoires de l’
different locations, Cushing coined the term meningioma. Academie Royale de Chirugie. In his manuscript, Louis named
This was followed by a defining manuscript on meningiomas them tumeurs fongueuses de la dure-mere, or fungoid tumors
by Cushing and Eisenhardt in 1938, setting the tone for of the dura mater.6 Virchow, who noted the presence of
future investigations of this tumor.3 granules in meningiomas named them psammomas (sandlike
Acknowledgment: The authors wish to thank Marc Edgar, MD, for tumors) in 1859, and considered them akin to sarcomas.7
supplying the histopathologic material and for his comments on that Golgi, on the other hand, named them endotheliomas in
section. 1869, indicating a more benign histology.8 Several names
792
 Meningiomas of the Posterior Fossa and Skull Base 793

were used to describe these tumors even after Cushing’s on subjects 55 years and older found meningiomas in
Cavendish lecture in 1922. slightly more than 1%.14
The first known radiologic account of a meningioma was Meningiomas are most commonly found in middle-aged
written by Mills and Pfahler in 1902.9 This was followed by and elderly individuals, with a peak incidence in the sixth
several similar reports, including one by Heuer and Dandy in and seventh decades of life. These tumors rarely occur in
1916. They described the radiographic findings in 100 brain children and show a marked female predominance, with a
tumors, 9 of which were meningiomas.10 Ventriculography, female to male ratio of 3:2 or 2:1 in a majority of studies.12
a technique described by Dandy in 1918, although slowly This gender bias is reflected in the overall incidence for
adopted, marked a significant improvement in intracranial meningiomas, which ranges from 2 to 7 per 100,000 in
tumor localization and diagnosis. Skull radiographs and cere- women and from 1 to 5 per 100,000 in men.15 In males, the
bral angiography also aided in the diagnosis of brain tumors overall age-adjusted incidence rate of cases diagnosed before
in the first half of the century. In addition, the development death was 8.3 per 100,000 population per year, which
of sensitive film improved radiographic imaging by replac- included a rate of 1.2 for meningiomas. Among females,
ing glass plates and decreasing the time of exposure. The the overall rate was 10.1, which included a rate of 2.6 for
advent of computed tomographic (CT) scanning in the meningiomas.14 The female preponderance seen only in
mid-1970s followed by magnetic resonance imaging (MRI) middle-aged patients has been attributed to the effects of
with contrast agents, diffusion weighted imaging, and fluid estrogen on meningioma growth and development.12
attenuated inversion recovery sequences have greatly The incidence of meningiomas increases with age. In
improved the preoperative diagnosis, therapeutic planning, one series of patients treated from 1950 to 1977 in
and surgical outcomes of meningiomas. Rochester, Minnesota, where the postmortem examination
The surgical removal of a meningioma was first attempted rate approaches 70%, approximately 69% of meningiomas
in 1743 by Heister, a German surgeon from Helmstead, were diagnosed at autopsy. Long-term reports also suggest
Germany. He applied a caustic of lime juice to a menin- that the incidence of meningiomas is increasing over
gioma in a 34-year-old Prussian soldier who subsequently time.15 In addition, both an improved life expectancy and
developed an infection and died. One of the first successful better neuroimaging to detect asymptomatic meningiomas
meningioma operations was performed by Zanobi Pecchioli, may result in an increasing prevalence of meningiomas in
an Italian surgeon who extracted a right sinciput menin- future epidemiologic studies.
gioma in 1835. The patient was well at 30 months follow- Although the incidence of meningiomas is similar in most
ing the operation. In 1887, William Keen, a pioneer of countries, several series from Africa found that menin-
American neurosurgery, was the first to successfully giomas accounted for anywhere from 24% to 38% of all
remove a meningioma in the United States. Using metic- intracranial lesions.16 These studies also reported a male
ulous aseptic technique in a 2-hour operation, he extracted rather than female predominance and found that 20% of
an 88-g, left frontotemporal tumor from a 26-year-old car- meningiomas occurred in the second decade of life.2 This
riage maker. The patient, who had a history of head trauma high incidence of meningiomas in Africa may be relative and
at the age of 3 and presented with headaches, seizures, and can be explained by a lower incidence of gliomas rather than
partial blindness, recovered and lived over 30 years after an absolute increase in meningiomas. However, a popula-
the operation. The turn of the century marked an tion-based survey in Los Angeles, California, also reported
improvement in the outcome of neurosurgical procedures a higher incidence of meningiomas (3.1 per 100,000) in
primarily due to aseptic principles, localization of cerebral African Americans than whites (2.3 per 100,000), thereby
function, and better surgical techniques.4 suggesting a higher incidence in some populations.17
Meningiomas in children account for 1% to 2% of all
intracranial neoplasms. These tumors have a male predom-
EPIDEMIOLOGY inance (71%) and present at a mean age of 10.9 years—
higher than that observed for other childhood brain
A review of six large neurosurgical series accounting for tumors. The incidence of intraventricular (17%), posterior
18,171 tumors found meningiomas to constitute approxi- fossa (19%) locations is higher for childhood meningiomas
mately 20% of all intracranial neoplasms.11 In 1938, than their adult counterparts.18 Childhood meningiomas
Cushing and Eisenhardt reported that 13.4% of 2203 are more likely to be malignant. In one study of 51 menin-
brain tumors were meningiomas.3 Multiple series since giomas in patients younger than 21 years of age, a higher
then have estimated meningiomas to comprise 13% to incidence of the papillary variant, a histologically aggressive
26% of all primary brain tumors, with a total annual inci- subtype, was observed. Approximately 24% of these tumors
dence of approximately 6 per 100,000 people.12 These fig- were associated with neurofibromatosis type 2 (NF2).2
ures include incidence data from hospital-based as well as
population-based studies, which include meningiomas
found incidentally at autopsy. Since the majority of menin- ETIOLOGY
giomas are benign lesions that remain asymptomatic dur-
ing life, they represent over 30% of incidental tumors Radiation
found at autopsy. In symptomatic patients, however, the
incidence for benign meningiomas is 2.3 per 100,000 and Although head trauma, viruses, and gender are all hypoth-
0.17 per 100,000 for malignant meningiomas.13 In study of esized as causal factors in meningioma development,
the incidence of primary intracranial neoplasms in radiation exposure is the only unequivocal risk factor
Rochester, Minnesota, from 1935 through 1977, autopsies identified in the genesis of these tumors. In fact,
794 SURGICAL NEUROTOLOGY

meningiomas are the most common radiation-induced an overwhelmingly male predominance in individuals
neoplasms of the central nervous system (CNS). Radiation treated with low-dose radiation for tinea capitis.20
is thought to introduce single- and double-stranded breaks Radiation-induced meningiomas present with an aggres-
in deoxyribonucleic acid (DNA) strands. These errors, sive histologic growth pattern: high cellularity, cellular
when permanently incorporated into genes regulating the pleomorphism, and an increased number of giant cells.18 In
cell cycle, may lead to tumor formation.19 Although, most a study of seven radiogenic meningiomas identified at the
animal models have shown the induction of sarcomas and Mount Sinai Hospital, three were characterized as atypical.20
gliomas with radiation, few have shown the development In another series of 10 high-dose radiation-induced menin-
of spinal meningiomas. An example can be found in the giomas, 4 of 8 tumors examined histologically were con-
rabbit model. When rodents are exposed to cobalt-60 sidered atypical and had a high bromodeoxyuridine (BrdU)
implanted under the dura, meningiomas develop.20 labeling index. In general, radiogenic meningiomas follow-
Radiogenic meningiomas can be divided into two major ing low-dose radiation to the head have a high recurrence
categories based on the dose of radiation administered: low- rate of 18.7%, even after complete surgical removal.23
dose are defined as less than 10 Gy radiation-induced menin-
giomas. They are discovered years after treatment of Trauma
nonneoplastic diseases of the head and neck such as tinea
capitis. High-dose is defined as less than 20 Gy radiation- Berlinghieri, an Italian surgeon from Pisa, Italy, was the
induced meningiomas that appear after treatment for head first to consider trauma as a cause of meningiomas in
and neck tumors, most frequently medulloblastoma in child- 1813.4 Although head trauma has been suggested as
hood. A third category, recently proposed, includes a small another cause of meningiomas, the evidence for such an
group of meningiomas that were induced in patients sub- association remains unconvincing. In a review of 295
jected to intermediate doses of radiation between 10 and patients by Cushing and Eisenhardt, 94, or 30%, had a
20 Gy to the head and neck, application of radium to the skin history of head trauma that appeared to be related to the
for vascular nevi, or Thorotrast myelography (visualization of development of meningiomas. A scar, previous swelling, or
the CNS using thorium dioxide, a radiopaque substance).20 depressed fracture was noted in 24 of these patients, thus
The first case of a high-dose radiation-induced menin- supporting trauma as for a cause of meningiomas.3 Reports
gioma was reported by Mann and colleagues in 1953. It of tumors associated with skull fracture lines, a retained
involved a 4-year-old boy who received 65 Gy to the orbit intracranial foreign body, and dural scarring have been
for an optic nerve glioma. Four years after treatment, he found in the literature.24 A recent case-controlled study of
developed a histologically malignant, supraorbital menin- 189 women with meningiomas also found a higher
gioma.21 Meningiomas developing in high-dose irradiated incidence of patient-reported trauma than either of the
fields have been described in the subsequent literature, but control groups.18 In a 2002 population-based case-control
only represent approximately 10% of radiation-induced study of 200 case and 400 control subjects, Phillips and
meningiomas.22 The overwhelming majority of these coworkers found an increased risk of meningioma forma-
meningiomas arise in patients treated with low-dose radi- tion with head trauma. This statistically significant corre-
ation for tinea capitis (ringworm of the scalp). In a study of lation was found to be especially significant for head
10,834 children in Israel treated with radiation doses of 1 to trauma occurring 10 to 19 years prior to the diagnosis of
2 Gy for tinea capitis between 1948 and 1960, 19 patients a meningioma.25 One theory suggests that release of
developed meningiomas. The average latency period from bradykinin, histamine, and arachidonic acid during trauma
radiation exposure to diagnosis was 20.7 years.15 Results may increase the permeability of the blood-brain barrier
also showed that 89% of the meningiomas could be attrib- (BBB), thereby allowing the passage of harmful substances
uted to radiation exposure that these patients received dur- that may lead to the development of meningiomas.18
ing childhood. A retrospective review of these children In 1971, Boldrey commented that, “It is certainly no
revealed that the incidence of meningiomas in the irradi- compliment to our civilization that a tumor more com-
ated children was 4 per 10,000 compared with the inci- monly encountered in women than in men should be
dence of 1 per 10,000 observed in nonexposed subjects.18 regarded to have trauma as a major etiologic factor.”16
Radiation-induced meningiomas are often multiple and Several studies have not supported an association between
more likely to occur over the convexities. Eighty percent head trauma and meningioma formation. In one such study
of radiogenic meningiomas were found over the convexi- of 2953 patients at the Mayo clinic with a 29,859 person-
ties compared with 46% of spontaneously occurring year follow-up, an increased risk of meningioma formation
meningiomas. The average patient age at presentation for was not found in individuals who sustained head trauma, a
low-, moderate-, and high-dose radiation-induced menin- skull fracture, or post-traumatic amnesia.26
giomas was 45, 32.3, and 34.2 years, respectively. The
average time interval from radiation exposure to tumor Gender
discovery was 35.2, 26.1, and 19.5 years, respectively. In
general, increasing doses of radiation are associated with The female predominance in patients with meningiomas
shorter latency periods and a younger patient age at tumor suggests a role for sex hormones in the growth and devel-
presentation.23 A female predominance, with a male to opment of these tumors. An association between breast
female ratio of 1:1.2 and 1:1.6, was also found in moder- cancer and meningiomas, the presence of estrogen and
ate- and high-dose radiation-induced meningiomas. Low- progesterone receptors on meningiomas, and evidence that
dose radiation-induced tumors, however, were found to meningiomas increase in size during pregnancy further
have a male to female ratio of 1.2:1. This was attributed to support this hypothesis. A population-based case-control
 Meningiomas of the Posterior Fossa and Skull Base 795

study of adult brain tumors demonstrated a reduced Although a majority of benign meningiomas exhibit a
relative risk (RR) for meningiomas in postmenopausal diploid karyotype or monosomy 22, a significant number
women (RR = 0.59; 95% confidence limits = 0.18 − 1.94). have been found to harbor additional mutations. The loss of
Oophorectomy-induced menopausal patients also exhib- additional chromosomes or hypodiploidity is associated
ited a reduced relative risk for meningioma development with progression of benign (grade I) meningiomas to atypi-
(RR = 0.12; 95% confidence limits = 0.01 − 1.30).18 Other cal (grade II) or even to anaplastic (grade III) meningiomas.
case-control studies have shown an increase in menin- This is in contrast to the hyperdiploidity encountered in the
gioma size during pregnancy. The presence of estrogen progression toward increasing malignancy of most other
receptors in 30% of patients and progesterone receptors solid tumors.27 Atypical meningiomas often contain allelic
in 70% of patients in a study of 330 meningiomas support losses of chromosomes 1p, 6q, 10q, 14q, 17p, and 18q. The
the theory that varying levels of estrogen may contribute above-mentioned aberrations as well as frequent losses of
to meningioma growth.15 chromosomes 6q, 9p, 10, and 14q are typically found in
anaplastic meningiomas. High-grade meningiomas are also
Viruses found to have chromosomal gains specifically for chromo-
somes 20q, 12q, 15q, 1q, 9q, and 17q.12 Demonstration of
Several types of adenoviruses, a few polyoma viruses, and these genetic and chromosomal alterations, specifically the
a subgroup of papovaviruses have produced CNS tumors frequently observed deletion of chromosomes 1p and 14,
in laboratory animals. A papovavirus antigen, as well as BK may lead to the establishment of a molecular diagnostic tool
viral DNA, SV-40, and adenovirus DNA have been found for meningioma grading and prognostication.31
in human meningiomas. Although these findings suggest a
role of viruses in meningioma induction and growth,
further investigation will be necessary to establish a causal
relationship.18 PATHOLOGY
Gross Pathology
MOLECULAR PATHOGENESIS Meningiomas are derived from arachnoidal cap cells, the
external layer of the arachnoid membrane. These tumors
The overwhelming majority of meningiomas are sporadic are firm, rubbery, and well-circumscribed, with an uneven
tumors, but approximately 2% are hereditary and associ- nodular or smooth surface. Meningiomas can be differen-
ated with a number of familial cancer syndromes.27 Most tiated into three overall macroscopic appearances: the exo-
of these hereditary tumors occur in association with NF2, phytic tumor, the “en plaque” tumor causing expansion of
an autosomal-dominant disorder in which patients have a the meninges over a wide area, and a third variant associ-
propensity to develop multiple meningiomas, vestibular ated with bony hyperplasia.22
schwannomas, and, infrequently, ependymomas. Approxi- Classically, meningiomas have a broad and firm attach-
mately 35% of NF2 patients have meningiomas.28 Heredi- ment to the dura. En plaque meningiomas are sheetlike
tary tumors are also found with an increased frequency in tumors that expand within the meninges. These tumors
Werner’s syndrome, Gorlin’s syndrome, and Cowden’s syn- are commonly associated with hyperostosis and frequently
drome. However, the association of meningiomas with these seen at the sphenoid ridges. Irregular, dumbbell-shaped
syndromes is less well defined.12 meningiomas are observed to originate from the meninges
Meningiomas were among the first solid tumors in separating compartments of the cranial cavity. Examples
which a distinctive cytogenetic alteration was identified. include falcine meningiomas that penetrate the falx and
Abnormalities of chromosome 22 in human meningiomas occupy the frontal lobes and tentorial meningiomas that
were discovered in 1972 and later verified in 61% to 80% may expand into both the posterior and middle fossae.2,22
of all meningiomas.29 Early molecular studies reported The consistency of meningiomas is associated with their
the loss of heterozygosity (LOH) for all sequences on intratumoral contents. Calcific psammoma bodies (often
chromosome 22 in meningiomas. Soon thereafter, the found in smaller growths and spinal meningiomas) give
NF2 gene was located by linkage analysis on chromosome these tumors a characteristic “gritty” texture (Fig. 47-1).
22 and subsequently cloned. Recent studies have identified Advanced mucoid or fatty degeneration, edema, and
mutations in the NF2 gene on the long arm of chromo- necrosis can soften the consistency of a tumor. Occasion-
some 22 as an important aberration in the development of ally, tumors are fluctuant to palpation secondary to the
meningiomas. NF2 mutations are detected in approxi- presence of cysts lying near the periphery. In addition,
mately 30% to 35% of all meningiomas and 40% to 60% osseous changes in meningiomas can also result from
of sporadic meningiomas.30,31 The majority of these muta- metaplasia within the tumor.2,16,33
tions are small insertions and deletions or nonsense Meningiomas have a pinkish gray color, which changes
mutations, which alter splice sites and cause frameshifts to grayish white after fixation in formalin. Recent or old
or create stop codons. These modifications alter the hemorrhages, which occur in highly vascularized tumors,
production of a protein called merlin, which serves as a can cause a reddish brown discoloration. Also, lipid accu-
structural link between the cytoskeleton and several mulation in the cells may change the appearance of the
proteins in the cytoplasmic membrane.12 Merlin is thought tumor to yellow.2,22
to be a tumor suppressor, so that when inactivated in Significant changes to the surrounding parenchyma,
the mouse by targeted mutagenesis, a variety of malignant bone, and neurovascular structures can accompany menin-
tumors with a high rate of metastasis arise.32 gioma growth. Pressure atrophy of adjacent parenchyma,
796 SURGICAL NEUROTOLOGY

Figure 47-1. Large psamomma bodies are prevalent in this transitional Figure 47-3. Microcystic meningioma with prominent pale vacuoles
meningioma (H&E, ×200). (H&E, ×200).

invasion of the venous sinuses, and encasement of intracra- extensive histologic classification, which included nine
nial vasculature are not common findings. In contrast, types and 22 variants.3 Since then, several additional
frank invasion of neural tissue; infiltration of arterial walls; classification systems have been proposed. Controversy
and extension into extracranial compartments such as the persists because the histology of these tumors has gener-
pericranium, petrous bone, and orbit are rarely observed ally shown poor correlation with tumor topography and
(Fig. 47-2). Hyperostosis, an osteoblastic process at the clinical behavior. However, overall histologic categoriza-
base of the tumor, is observed in approximately 25% of tion of these tumors has aided in determining their prog-
meningiomas.34 Direct bony involvement and increased nosis. In addition, altered histologic changes in a recurrent
subperiosteal bone formation secondary to reduced blood meningioma have been useful in identifying anaplastic
supply are both thought to contribute to this phenomenon. transformation.
A recent study showed that meningiomas associated with In 1992, a landmark study of 1799 meningiomas from
hyperostosis were found to have a threefold increase in 1582 patients defined three histologic subtypes: classic,
alkaline phosphatase.2 atypical, and anaplastic, which established a clear clinical
correlation to a histologic type.35 The current classifica-
tion scheme of the World Health Organization (WHO)
Microscopic Pathology defines groups of meningiomas on the likelihood of recur-
rence and grade. Grade I tumors are benign and include
The enormous diversity of meningioma histology has meningothelial, fibrous (fibroblastic), transitional (mixed)
defied simple, well-integrated classification. In 1938, (see Fig. 47-1), psammomatous, angiomatous, microcystic
Cushing and Eisenhardt were the first to propose an (Fig. 47-3), secretory (Fig. 47-4), lymphoplasmacyte-rich,

Figure 47-2. Atypical meningioma with brain invasion. Note the many
well-defined nests of meningioma invading the bland neural tissue Figure 47-4. Secretory meningioma features pseudopsamomma bodies that
(H&E, ×100). exhibit epithelial differentiation (H&E, ×100).
 Meningiomas of the Posterior Fossa and Skull Base 797

Figure 47-5. Clear-cell meningioma is found most often in the posterior Figure 47-6. Chordoid meningioma may be confused with a chordoma
fossa. The clear cells are filled with glycogen. Also note the long collagen (H&E, ×400).
bundles in this section (H&E, ×100).

and metaplastic subtypes. These tumors constitute 90% of psammoma bodies are uncommon in these tumors but are
meningiomas and have a low risk of recurrence and aggres- poorly formed when present. These tumors also have a
sive growth. Grade II tumors are atypical and include the propensity to bleed.
atypical (see Fig. 47-2), clear cell (intracranial) (Fig. 47-5), Fibrous (fibroblastic) tumors are formed by predomi-
and chordoid (Fig. 47-6) variants. These tumors comprise nantly spindle-shaped, fibroblast-like cells that form parallel
7% of meningiomas and are associated with a higher like- and interlacing bundles, rich in collagen and reticulin.
lihood of recurrence and aggressive behavior. Grade III Whorls and psammoma bodies are infrequent, and
tumors are anaplastic and include the rhabdoid, papillary, meningothelial features are often present.
and anaplastic (malignant) subtypes, as well as tumors Transitional (mixed) tumors contain features of both the
of any grade with a high proliferation index with or with- meningothelial and fibrous variants (see Fig. 47-1). Lobules
out brain invasion. These aggressive tumors comprise and fascicles are found in close arrangements. Tight con-
3% of meningiomas and have the greatest likelihood of centric whorls and psammoma bodies are frequently seen
recurrence (Table 47-1).33 in this subtype.
Psammomatous tumors possess a plethora of psammoma
bodies, which may become confluent and form irregular
Grade I Meningioma Histopathology calcified and sometimes ossified masses. Occasionally, these
tumors are completely replaced with psammoma bodies.
Common Benign Subtypes They typically occur in the thoracic spine and are typically
Meningothelial, fibrous, and transitional tumors are the seen in middle-aged women.
most common histologic subtypes of meningiomas. Angiomatous tumors contain blood vessels that are
Meningothelial tumors are characterized by uniform, dominant in the background of a typical meningioma. The
polygonal (arachnoid-like) tumor cells forming lobules majority of blood vessels are small, thin-walled structures
defined by thin collagenous septae. These cells have oval and may obscure the histopathology of the tumor. Unlike
nuclei with an even chromatin pattern that often show hemangiopericytomas, these meningiomas are not aggres-
central clearing secondary to glycogenation. Whorls and sive tumors. The size of the meningiomatous vessels may

TABLE 47-1. WHO Histopathologic Classification for Meningiomas

Recurrence/
WHO Grade Incidence Histologic Subtype Aggressiveness

Grade I—Typical Common Meningothelial, fibrous, transitional, Low

psammomatous, angiomatous
Rare Secretory, microcystic, lymphoplasmacyte- Low
rich, metaplastic
Grade II—Atypical Atypical, clear-cell, chordoid Low
Grade III—Anaplastic Anaplastic, papillary, rhabdoid High
Tumors with high proliferation
index or brain invasion

From Louis DN, Scheithauer BW, Budka H, et al: meningiomas. In Kleihues P, Cavenee WK (eds.): Pathology and Genetics of Tumors of the Nervous
System. Lyon, IARC Press, 2000, p 314.
798 SURGICAL NEUROTOLOGY

be helpful in distinguishing these tumors from vascular preferred locations for these tumors which are associated
malformations and capillary hemangioblastomas. with aggressive behavior, particularly when discovered at
these sites.
Rare Benign Subtypes Chordoid tumors consist of lobules of eosinophilic,
Secretory tumors are characterized by focal epithelial vacuolated chordoid cells in a myxoid matrix (see Fig. 47-6).
differentiation with glandular lumina containing keratin These lesions can mimic the histologic appearance of
and staining potential for periodic acid-Schiff (PAS) and chordomas, with the exception of the following features:
carcinoembryonic antigen (CEA) (see Fig. 47-4). The absence of typical physaliphorous cells, whorl formation,
surrounding meningothelial cells are positive for cytoker- positive staining for vimentin and epithelial membrane
atin. These tumors may be associated with marked peritu- antigen (EMA), and absence of cytokeratin staining.
moral edema. Chronic inflammatory cells are often present, and peritu-
Microcystic tumors consist of cells with elongated moral and intratumoral lymphoplasmacellular infiltrates
processes on a loose mucinous background (see Fig. 47-3). are prominent in younger patients. Few of the patients
This histology gives the tumor an appearance of small with these tumors have hematologic conditions, such as
cysts. Pleomorphic cells are abundant in this subtype. Castleman’s disease. These tumors are also associated with
Lymphoplasmacyte-rich tumors are a rare subtype a high rate of recurrence after a subtotal resection.
composed of extensive chronic inflammatory cells on a
background of meningothelial cells. This variant is associ- Grade III Meningioma Histopathology
ated with polyclonal gammopathies or anemias. Diagnosis
of these meningeal-based hematologic conditions must be Anaplastic meningiomas have more than 20 mitoses per
considered with this tumor. hpf and features of frank malignancy which include
Metaplastic tumors exhibit prominent focal mesenchymal whorls, banding, onion skin features, an increased nuclear-
differentiation. Meningothelial, fibrous, and transitional to-cytoplasmic ratio, increased cellularity, increased rate of
tumors may show osseous, cartilaginous, lipomatous, mitoses, micronecroses, increasing proliferation fraction
myxoid, and xanthomatous changes. of cells, and spider cell tumors. Patients with these tumors
have a median age of survival of less than 2 years. Invasion
of the brain is insufficient to make the diagnosis, and the
Grade II Meningioma Histopathology cytology can be similar to that of sarcomas, carcinomas, or
Atypical meningiomas have greater than or equal to malignant melanoma.
4 mitoses per high-power field (hpf) and satisfy three Papillary tumors are a rare meningioma variant that
or more of the following: increased cellularity, small cell tends to occur in children. They are aggressive lesions
population with an increased nuclear-to-cytoplasmic defined by perivascular psuedopapillary pattern formation
ratio, prominent nucleoli, uninterrupted patternless or in at least part of the tumor. Local and parenchymal inva-
sheetlike growth, foci of spontaneous or geographic necrosis, sion, tendency to recurrence, and metastases occur in 75%,
and brain invasion (Fig. 47-7). These tumors have moder- 55%, and 20% of these lesions, respectively.36
ately high proliferation-associated antigen-labeling (MIB-1) Rhabdoid tumors are a recently described entity
indices and correlate with a higher rate of recurrence. composed of rhabdoid cells with the following features:
Clear-cell tumors are characterized by patternless rounded cells, eccentric nuclei, prominent nucleoli, and
polygonal cells with few classic meningioma features (see inclusion-like eosinophilic cytoplasm composed of whorled
Fig. 47-5). The tumor cells are PAS-positive and have a intermediate filaments. These cells may be present only
clear and vacuolated cytoplasm, rich in glycogen. The at the time of recurrence. These tumors display anaplas-
cerebellopontine angle (CPA) and cauda equina are tic signs, including a high mitotic rate and elevated
MIB-1 labeling indices. This meningioma variant has
an aggressive clinical course and carries an unfavorable
prognosis.

Immunohistochemistry
The immunohistochemistry of meningiomas is reflective
of their dual mesenchymal and epithelial nature. Positive
staining for vimentin, a cytoskeletal protein in intermedi-
ate filaments, is found in 98% of them.22 An equally
significant percentage of meningiomas, approximately
95%, display a membranous pattern of immunoreactivity
for EMA. Positive staining for EMA is more prominent in
the meningothelial and transitional subtypes, meningioma
variants with greater epithelial differentiation. EMA
staining is less consistent for atypical and anaplastic
meningiomas. In addition, gliomas (except for low-grade
ependymomas) and hemangiopericytomas do not stain for
EMA, making this stain a useful tool in differentiating
Figure 47-7. Darkly staining atypical mitotic nucleii (H&E, ×400). between these tumors.37
 Meningiomas of the Posterior Fossa and Skull Base 799

Staining for S-100, a nuclear antigen, can be used to reduction in the caloric response in 12 of 18 (67%) patients,
distinguish between schwannomas and meningiomas. and Aiba and coworkers noted the same in 9 of 12 (75%)
Strong positive staining for S-100 is seen in 100% of cases.38,42 Baguley and colleagues also found no significant
schwannomas, whereas a patchy and weak reaction is relationship between tumor size and abnormal results for
found in only 41% of meningiomas.22 Secretory menin- audiometry, speech audiometry, and caloric testing.38
giomas strongly stain for CEA, an immunostain primarily The ABR is a useful noninvasive screening technique for
seen in the pseudopsammoma bodies of these lesions. diagnosing lesions of the CPA and IAC. Not surprisingly,
These tumors are also known to be associated with an ABR better reveals evidence of retrocochlear pathology in
elevated circulating level of CEA. Cytokeratin positivity is CPA meningiomas than does basic audiometry.43 Baguley
also often seen in secretory meningiomas, with far less and colleagues noted an abnormal ABR in all 18 patients
staining seen in the meningothelial and transitional tested. This abnormal result was also found in patients
subtypes. Overall, approximately 20% of meningiomas who had exhibited a normal PTA and SDS. This led the
stain for cytokeratins, and 4% stain for CEA.12,22 authors to conclude that ABR is more sensitive to disten-
tion or compression of the eighth cranial nerve (CN) than
basic audiometry. Noting a predominance of larger
DIAGNOSIS meningiomas in their series, Baguley and colleagues also
suggested that ABR testing may not be sensitive to small
CPA lesions and could also miss meningiomas not imping-
Audiovestibular Testing ing on the auditory pathway.38 In a study comparing the
Audiovestibular findings have been studied in only a few clinical characteristics of rare CPA lesions, Aiba and
series of CPA meningiomas. Basic audiometric data, coworkers noted an abnormal ABR in 8 of 10 (80%) CPA
primarily in the form of pure tone average (PTA) and meningiomas. The authors found a relatively low frequency
speech discrimination scores (SDS), have not been of ABR and ENG abnormalities in CPA meningiomas
reported in a majority of patients. Audiometric brainstem compared with vestibular schwannomas.42 In 1995, Hart
response (ABR) and electronystagmography (ENG) have and Lillehei reported an abnormal ABR in five of seven
been studied in even fewer patients. Although abnormal (71%) cases.39 Granick and colleagues and Laird and
audiologic findings were found in patients harboring CPA coworkers found the same in 100% of their patients.40,41
meningiomas, none of these series made any definitive Although ENG and ABR testing is useful, they are neither
conclusions on the topic. Furthermore, only a small specific nor sensitive in discriminating meningiomas from
percentage of patients in each series underwent compre- vestibular schwannomas or any other CPA tumors.
hensive audiovestibular testing and therefore were perhaps
not representative of the entire series. Since CPA and IAC
meningiomas have no clear and distinctive audiometric
Radiology
features, most authors agree that audiovestibular testing is The first radiologic diagnosis of a meningioma was made
a useful but not necessary adjunct to the radiologic inves- with plain radiography by Mills and Pfahler in 1902. The
tigation of these tumors.38,39 tumor was localized with a radiograph that showed a
In a 1997 series of 25 patients, Baguley and colleagues shadow between the frontoparietal suture and posterior
reported normal hearing in 5 of 25 (20%) patients, a low- meningeal artery.9,44 A more consistent and methodical
frequency hearing loss in 3 of 25 (12%), a flat loss in 9 of approach to the radiologic diagnosis of meningiomas,
25 (36%), a midfrequency hearing loss in 3 of 25 (12%), using plain radiography, was introduced by Sosman and
and a profound hearing loss in 5 of 25 (20%). In contrast, Putnam in 1925. Their analysis of 95 intracranial menin-
the authors found normal audiometry in only 1.9% of 361 giomas showed that 49% of these tumors had characteris-
patients with vestibular schwannomas.38 Furthermore, tic changes on radiographs. These alterations included
none of the patients with CPA meningiomas exhibited the sclerosis, bone destruction, spicule formation, enlarged
characteristic high-frequency hearing loss seen in vestibu- vascular channels, calcification, and pneumosinus dilatans, a
lar schwannomas.34,38 Granick and coworkers in a study dilation of the paranasal sinus.45 Ventriculography and
of 32 patients, of which audiometric data was available pneumoencephalography, two diagnostic techniques intro-
for only 23, reported normal hearing in 6 of 32 (26%), a duced by Dandy in 1918 and 1919, respectively, enhanced
mild hearing loss (20 to 45 dB) in 2 of 32 (9%), a moder- the localization of meningiomas. However, tumor diagno-
ate hearing loss (50 to 80 dB) in 7 of 32 (30%), and a pro- sis of meningiomas with these techniques remained elusive.
found hearing loss (>85 dB) in 8 of 32 (35%) patients.40 An For example, differentiating extra-axial from intra-axial
abnormal SDS was noted in approximately 50% of lesions was difficult in the absence of additional findings,
patients.38,39 In 1985, Laird and colleagues noted an abnor- such as hyperostosis or increased vascularity.44,46
mal SDS in 57% of patients, a slightly higher percentage Cerebral angiography was initially described by Moniz
than in other series. The authors of this series reported a in 1927. Two years later, he reported the first angiographic
median SDS of 76%, compared with 8% for vestibular features of meningiomas with Pinto and Lima. An extensive
schwannomas.41 characterization of the angiographic features of 125 tumors,
ENG abnormalities have been found in over 90% of 20 of which were meningiomas, was conducted by List
patients with CPA meningiomas. Laird and colleagues and Hodges in patients undergoing cerebral angiogra-
reported decreased vestibular responses in 9 out of 10 phy. The development of computed tomography (CT)
patients, and Granick and coworkers noted the same in 19 by Hounsfield in 1973 and subsequent introduction of
of 20 (95%) patients.40,41 Baguley and colleagues found a intravenous (IV) contrast agents improved the extra-axial
800 SURGICAL NEUROTOLOGY

localization, detection, and characterization of menin- nature of the arterial blood supply (dural, pial, or mixed),
giomas. Soon thereafter, MRI was pioneered by Lauterbur overall tumor vascularity, patency of vessels, venous drainage
and offered extraordinary anatomic detail using magnetic pattern, and the degree of displacement or encasement of
field gradients and multiplanar imaging. The development arteries and veins. Definitive knowledge of the vasculature
of IV contrast agents further enhanced the diagnosis of involved with the meningioma can greatly aid its resection.
brain tumors, making MRI a superior technique for Furthermore, preoperative embolization can decrease the
meningiomas.45,46 overall vascularity of the tumor to diminish operative
blood loss and facilitate resection of the tumor.49
Cerebral angiography was extensively employed in the
Plain Radiography
past to make the diagnosis of a meningioma. In a study
The advent of newer imaging modalities such as CT addressing the utility of angiography, this technique made
and MRI have made plain radiography obsolete for the a specific diagnosis of a meningioma in 83% of cases; it was
diagnosis of meningiomas. However, characteristic find- uncertain or negative in a mere 8% of patients.48 Yet, some
ings of meningiomas found incidentally on a radiograph of the literature argues that the pattern of tumor vascular-
taken for different reasons can lead to a tumor diagnosis.47 ity is nonspecific for meningiomas and does not help to
X-ray films are also helpful in defining the extent of a pre- differentiate between other hypervascular tumors.50 Imaging
vious surgical procedure or in planning a surgical approach techniques such as MRI, and more recently magnetic reso-
in a patient who previously underwent a craniotomy or nance angiography (MRA), offer a safe, noninvasive, and
metallic cranioplasty.11 Hyperostosis, the most common highly sensitive and specific modality for the diagnosis of a
finding of meningiomas on plain radiograph, has an inci- meningioma. Although, a recent meta-analysis of cerebral
dence of 38% to 61%. It is most easily visualized when it angiography found a 0.07% risk of a permanent neurologic
involves the cranium or sphenoid bone. Blistering, a deficit and a 0.6% risk of an adverse non-neurologic
pathognomonic finding in meningiomas of the paranasal outcome, the complication rate remains higher than for
sinuses, is defined by hyperostosis of the planum sphe- the noninvasive imaging technologies available today.49
noidale, as seen on plain radiography.47 Angiography is also seldom requested by surgeons for the
Increased vascularity is the second most common finding preoperative planning of small- or moderate-sized tumors,
for meningiomas on radiographic imaging. A widening of which can be removed without significant blood loss.
grooves created by meningeal vessels on the inner table of
the skull is commonly associated with convexity menin-
giomas. Broadening of the foramen spinosum is also asso- Computed Tomography and Magnetic
ciated with meningiomas. However, this feature may also Resonance Imaging
be seen with arteriovenous malformations and prolonged
Detection
carotid occlusive disease.48 Prior to the introduction of CT,
calcification was seen in 3% to 18% of meningiomas on CT and MRI have not only improved the detection and
plain radiography at initial presentation. It is a rare finding diagnosis of meningiomas, but also enhanced the surgical
and usually presents in a diffuse, fine, or nodular pattern.47 planning and follow-up treatment of these tumors.
Although MRI is the modality of choice for the diagnosis
and evaluation of meningiomas, CT remains an important
Angiography
imaging technique for several reasons, including its capac-
Cerebral angiography is often used for the surgical plan- ity to identify intracranial processes (hemorrhage, hydro-
ning and preoperative embolization of a meningioma. cephalus, and mass effect) requiring urgent therapeutic
Although imaging techniques such as CT and MRI have intervention and its ability to exclude nonneoplastic
better sensitivity and specificity, angiography is still used in pathology. CT also remains an excellent initial screening
circumstances of diagnostic uncertainty. Meningiomas tool, given its wide availability in hospitals, good tolerance
classically have a “sunburst” or “spokeswheel” appearance to patient motion, easier access to acutely ill patients
on angiography. This pattern represents a radial arrange- during imaging, and lower cost.48,50
ment of meningeal vessels that enter at the hilum or dural Initial studies comparing CT with MRI showed that
attachment of the tumor. Dural branches supplying blood small tumors with minimal mass effect or edema were
to the tumor are large, tortuous vessels that usually arise more easily detected with CT. Approximately 10% of
from meningeal branches of the external carotid system. lesions were found to be undetectable by MRI and were
Typically, the blood supply arises from the vasculature that easily visualized by CT. However, the introduction of IV
perfuses the anatomic location where the tumor develops. contrast agents such as gadolinium diethylenetriamine
Large meningiomas may also parasitize pial vessels to pentaacetic acid (Gd-DTPA) enhanced the ability of MRI
supply the periphery of the tumor. A delayed capillary to detect even the smallest tumors.47 Recent improvements
blush is also a classic angiographic feature of a menin- in the magnetic field strength, acquisition time, slice thick-
gioma that is caused by the contrast that persists into the ness, and software associated with MRI systems have
late venous phase. Meningiomas of the CPA and skull base reduced the diameter of detectable intracranial lesions to
often stain poorly on angiography.48,49 less than 3 mm with or without contrast enhancement.49
Preoperative planning for the resection of a meningioma Excellent delineation between anatomic structures, multi-
may be enhanced by information gleaned from angio- planar imaging, and three-dimensional computer-generated
graphic features of the tumor. Angiography can provide reconstructions have made MRI the premier diagnostic
information about the size and location of arterial feeders, imaging tool.
 Meningiomas of the Posterior Fossa and Skull Base 801

Morphology demonstrate mild to moderate hypodensity on CT,

The morphology of intracranial lesions, particularly menin- hypointensity on T1WI, and hyperintensity on T2WI.47
giomas, plays an important role in their radiologic diagnosis. Flocculent and peripheral curvilinear hyperdensities
Meningiomas usually present as well-circumscribed, extra- can be seen in 20% to 30% of meningiomas on CT.47
axial, sessile lesions with a broad dural attachment. These Approximately 84% of meningiomas exhibit a mottled or
tumors are usually smooth, but are often lobulated when sit- speckled heterogeneity on T2WI. This heterogeneity is
uated adjacent to a rigid anatomic structure. Pedunculated suspected to be secondary to tumor vascularity, cysts, and
lesions commonly originate from the edge of the falx and calcification. In addition, hypointense punctate or curvi-
have a narrow dural base. En plaque meningiomas are linear shapes representing tumor vessels can be visualized
uncommon lesions that usually present at the base of on T1WI and T2WI.48 A majority of meningiomas
the brain as a narrow band of tissue. Even rarer are intra- enhance brightly with Gd-DTPA. Dense calcification and
ventricular meningiomas, which present in the lateral cystic lesions present in some meningiomas prevent their
ventricles, and fissural meningiomas, which are completely homogeneous enhancement.47 The enhancement with
surrounded by brain parenchyma and often mistaken for Gd-DTPA is more sensitive than that seen with iodinated
intra-axial tumors.47 contrast on CT. Thus, MRI is the preferred imaging tech-
Since most meningiomas are primarily extra-axial, nique for visualizing small or multiple meningiomas, the
differentiating between intra-axial and extra-axial lesions is latter most often seen in patients with NF2.46,50
an important clue in their diagnosis. Multiplanar imaging Contrast enhancement of meningiomas with Gd-DTPA
and the elimination of beam-hardening artifact on MRI on MRI often reveals a “dural tail,” a flat layer of enhanc-
have improved the visualization of the dural base of any ing dura that extends a few millimeters away the base of
lesion, regardless of its location. Coronal and parasagittal the lesion (Fig. 47-8). Although, once thought to be
imaging can differentiate superficial intra-axial lesions pathognomonic for meningiomas, recent studies have
from meningiomas of the high convexity, tentorium, and shown its presence in a number of lesions, including super-
parasellar region. Metastatic lesions, low-grade astrocy- ficial intra-axial masses, dural metastases, and vestibular
tomas, and exophytic masses may also grow intra-axially, and schwannomas. Dural tails have also been found in inflam-
spread along the dural surface, thereby mimicking extra- matory processes, as well as aneurysms. Pathologic
axial lesions.47 examination and electron microscopy have concluded that
An interface seen between the lesion and cortex is although a dural tail may indicate tumor infiltration, it
another morphologic feature helpful in establishing an could also represent a nonneoplastic reactive change.
extra-axial location. Displaced arteries and veins, including These could include hyperemia, tissue proliferation,
pial vessels found on the periphery of meningiomas, are hypervascularity, increased permeability to contrast, or
hypointense on all pulse sequences. T1-weighted images dilation of dural vessels.46,48,49 In one histopathologic study
(T1WI) best identify the interface between a hypointense of 54 patients with meningiomas, 31 (57%) were observed
tumor and hyperintense edema surrounding the lesion. to have a meningeal tail on MRI. Tumor invasion was
Arachnoid cysts, which often overshadow meningiomas, detected in 20 (65%) patients, thereby arguing for wide
have a low density on CT, a low intensity on T1WI, and a resection of the tumor to reduce the risk of recurrence.52
high intensity on T2-weighted images (T2WI). White Bone Changes
matter buckling and “arcuate bowing of adjacent cortical
gyri in an accordian-like manner” also suggest an extra- Changes in adjacent bone are seen in 15% to 25% of
axial tumor.48 Although an extra-axial location may be meningiomas. These changes can present as a mild “reactive
appreciated on CT, MRI is better at perceiving subtle mor- process” or direct tumor infiltration of the bone. Minor
phologic characteristics indicative of a meningioma.

Density, Intensity, and Enhancement

Meningiomas appear isodense (25%) or slightly hyper-
dense (75%) to brain parenchyma on nonenhanced CT
scans.48 These tumors usually undergo intense, homoge-
nous enhancement following administration of IV iodinated
contrast agents. These compounds enhance meningiomas
by accumulating in the interstitial spaces of the tumor after
passing through an abnormal blood-brain barrier found in
most extra-axial lesions.51 On MRI T1-weighted (short
repetition time/echo time [TR/TE]) images, meningiomas
are isointense (60%) or mildly hypointense (30%) to gray
matter. On T2-weighted (long TR/TE) and proton density
(long TR/short TE) images, these neoplasms are isoin-
tense (50%), mildly to moderately hyperintense (40%), or
hypointense (10%) relative to the cortex.48 About 10% to
Figure 47-8. Axial T1WI postgadolinium MRI scan revealing a small
15% of meningiomas display atypical densities and inten- meningioma on the posterior surface of the porus acousticus, demonstrating
sities. Most of these meningiomas are hyperdense on CT a dural tail found at the transition of the tumor mass with the normal
and hypointense on MRI. Less than 5% of meningiomas meninges posterior to it.
802 SURGICAL NEUROTOLOGY

bony changes on CT include minimal hyperostosis, blister- Edema

ing, and mild erosion secondary to direct pressure of the Peritumoral edema is found in 46% to 92% of menin-
tumor or dilated vasculature. Gross invasion of bone is giomas.48 Approximately 66% of patients with symptomatic
marked with striking hyperostosis or bone destruction.48 meningiomas are estimated to have a varying degree of
Extensive hyperostosis is associated with larger menin- surrounding edema.49 The amount of peritumoral edema
giomas, especially those located near the sphenoid bone. is variable and can range from unremarkable to massive.
Hyperostosis may also be the principal manifestation of a On CT, edema appears as a low-density area surrounding
en plaque meningioma.49 Osseous changes associated with the lesion. On MRI, edema is hypointense on T1WI and
meningiomas are better appreciated on CT with the use of hyperintense on T2WI. T2WI is the preferred diagnostic
bone windows, specific settings used to enhance the visu- modality for detecting and measuring the amount of peri-
alization of these findings.48 tumoral edema.48 The cause of edema formation remains
Subtle bony changes are better delineated by CT than uncertain, although, blood vessels within meningiomas are
MRI. CT is therefore the favored imaging modality for this known to have endothelial fenestrations. Gap junctions are
purpose. However, severe hyperostosis, bone destruction, also known to exist between vessels.11 Venous obstruction,
tumor invasion, and obliteration of the diploic spaces can be although never proven, has also been suggested as a possi-
distinguished on MRI. Tumor infiltration is best appreci- ble cause of edema formation.51
ated on T1WI as hypointense signals taking the place of the Tumor size, location, histology, blood supply from pial
normally hyperintense fat in the bone marrow. Hyperostosis arteries, degree of parenchymal infiltration, and duration
is also seen as a hypointense signal on T1WI.46 of symptoms have been shown to correlate with the pres-
Calcification ence of peritumoral edema.11,49 Convexity, falx, parasaggi-
tal, sphenoid wing, and frontobasal meningiomas are often
Calcification is present in 15% to 20% of meningiomas associated with edema. In contrast, suprasellar, posterior
(Fig. 47-9). It is easily visualized on noncontrast CT and is fossa, and intraventricular meningiomas have little to no
found in a variety of forms: punctate (psammomatous), dif- edema. Meningothelial and transitional meningiomas are
fuse, rimlike, chunky, or nodular.48 Punctate calcifications also known to be associated with peritumoral edema.48
are most common and give the meningioma a fine speck- Secretory meningiomas have also recently been shown to
led appearance on CT. Central areas of hyperdensity often have a significant amount of surrounding edema. Although
represent dense calcifications, which can prevent contrast numerous studies have established factors correlating with
enhancement of a meningioma.51 Calcification, often con- the presence and amount of edema, other studies have
fused with hemorrhage, can be differentiated with density found few, if any, associations.12
measurements or by studying bone windows.48 Although
small punctate or rimlike calcifications are undetectable on Vascular
MRI, large nodular calcifications can be easily visualized.
Calcium is usually hypointense on T1WI and T2WI, with Displacement, encasement, narrowing, or occlusion of
the latter being more sensitive in the detection of vascular structures can be caused by meningiomas.
calcium.46 Vascular compromise by meningiomas is typically caused
by encasement of arteries and direct compression of dural
venous sinuses. CT is rarely able to visualize the vascular
supply to meningiomas, given similar densities of the
vessels and brain parenchyma before or after contrast
administration. Dynamic CT, a technique in which a bolus
of contrast enhances the arteries before accumulating in
the lesion, can be useful in defining the vascular supply to
the tumor.51 MRI, however, is far better at evaluating vas-
cular compromise than CT for several reasons. A differ-
ence in signal intensity between blood flow in the vessels
and soft tissue in the tumor provides superior anatomic
detail. Also, multiplanar imaging and the absence of bone
artifact help to clearly define the relationship between
the tumor and adjacent vasculature.47 In addition, flow-
sensitive techniques can also be introduced to resolve
difficult cases.48

Atypical Characteristics
About 15% of meningiomas present with unusual imaging
features, including necrosis, hemorrhage, cystic change,
and lipomatous degeneration. Rapid tumor growth may
lead to foci of necrotic tissue within the meningioma,
which appears hypodense to surrounding tissue on CT. On
MRI, these areas have a low attenuation on T1WI and a
Figure 47-9. Axial CT scan of the head revealing a calcified left petroclival high attenuation on T2WI.48 Necrotic areas do not enhance
meningioma. on contrast administration. Occasionally, meningiomas
 Meningiomas of the Posterior Fossa and Skull Base 803

undergo complete necrosis and present as ring-enhancing influence the decision for surgery.11,34 Minimal morbidity
lesions, thereby widening the differential to include from a surgical procedure is expected in a young patient
abscesses, thrombosed aneurysms, and intra-axial tumors, with a good functional status and minimal or no comor-
in particular glioblastomas. Morphologic features can help bidities. The size, location, vascularity, sinus involvement,
to distinguish meningiomas from many intra-axial lesions. and extent of a tumor are important factors in determining
Hemosiderin deposited in the walls of aneurysms seen its resectability. Large vascular meningiomas infiltrating into
with MRI can also help to differentiate between these vas- the dura, bone, and sinuses, as well as those compressing the
cular malformations and meningiomas.51 neurovasculature, are difficult lesions to resect and are
Hemorrhage is seen in 5% of meningiomas. The imag- expected to cause considerable impairment. In general,
ing characteristics vary depending on the age of the young symptomatic patients with a good functional status
blood.48 On CT, an acute hemorrhage is isodense or afflicted with a growing tumor causing progressive neuro-
hyperdense to surrounding tissue and may be confused logic symptoms are the most suitable candidates for surgery.
with calcification. Two to 3 weeks later, after liquefaction Patients with a strong preference for removal of a tumor
of the clotted blood, hemorrhage appears isodense to brain that is likely to become symptomatic in the future are also
parenchyma and after 4 weeks is hypodense to surround- good surgical candidates.55
ing tissue.51 On MRI, hemorrhage appears hyperintense The basic goals of any surgery are to prolong life and
on T1WI and hypointense or hyperintense on T2WI. preserve function. To meet these objectives, a surgical pro-
Multiple bleeds over days may produce variable densities cedure must maximize tumor resection without causing
and intensities. In addition, massive hemorrhage into the damage to the neurovasculature or intra-axial structures.56
subdural or subarachnoid spaces can complicate or obscure The decision to perform a total or subtotal resection rests
the diagnosis.47 once again on the functional status of the patient and
Cystic meningiomas represent only 2% to 4% of all tumor characteristics. A complete resection of the tumor
meningiomas. Cysts present as nonenhancing, hypodense including a dural margin and removal of any infiltrated
areas on CT. On MRI, they are hypointense on T1WI bone remains the objective. Petroclival meningiomas,
and hyperintense on T2WI. Cysts on the periphery of especially those with cavernous sinus involvement, are the
the tumor may represent secondary arachnoid cysts. most difficult to completely resect. In the event that only a
The differential diagnosis of cystic meningiomas also subtotal resection is feasible, the goals must be modified to
includes hemangioblastomas, gangliogangliomas, and cys- entail the procurement of an accurate tissue diagnosis and
tic gliomas.48 Diffusion weighted imaging (DWI) is a tech- reduction of the mass effect caused by the lesion.53 Prior to
nique that may help to differentiate between solid and cystic surgery, the surgeon must select the approach, review the
tissue. Cystic areas have a low signal intensity as opposed relevant intracranial anatomy, and study the images dis-
to tissue, which has a high signal intensity on DWI. playing the relationship of the neurovascular structures
Lipomatous degeneration, which involves replacement of with the tumor. The approach must be selected not only
tissue with fat, is a rarely found in meningiomas. These based on the anatomic location of the tumor but also the
areas are hypodense on CT, hyperintense on T1WI, and individual patient. Elderly patients with multiple comor-
hypointense on T2WI.50 bidities may not tolerate the discomfort and hospitaliza-
tion mandated by the certain approaches, even though
they may be ideal candidates for complete resection.56
GENERAL SURGICAL PRINCIPLES Unexpected and unforeseen intraoperative emergencies
such as brain swelling, damage to venous sinuses, and
Skull base meningiomas pose significant surgical chal- significant arterial bleeding must be anticipated for every
lenges due to their ability to invade dura and bone, compress, surgical procedure.11
and encase critical neurovascular structures. The decision The relationship of a meningioma to the adjacent cranial
to operate is at least partially based on the balance between nerves is much less predictable than for a vestibular
the morbidity of tumor removal versus the natural history schwannoma. To optimize the functional outcome, it is
of the untreated tumor. The anticipated risk of short-term important for the surgeon to understand the anatomic
impairment must be weighed against the probability of a relationship between the cranial nerves and the tumor. A
similar or worse ultimate outcome if the surgery is not premeatal (anterior to the IAC) meningioma displaces the
performed. The patient’s lifestyle and occupation should facial nerve over its posterior aspect. In contrast, the most
also be taken into account.53 The surgeon should discuss common course for the facial nerve in the case of a vestibu-
the surgical goal, expected results, and anticipated lar schwannoma is anterior. In the case of CPA menin-
morbidity with the patient. If the patient is asymptomatic giomas, CN VII often lies between the surgeon and the
with a small tumor and a surgical intervention is deferred, meningioma, making it more vulnerable to surgical
the patient should be available for regular clinical and radi- trauma. Retromeatal (posterior to the IAC) meningiomas
ologic follow-up and understand the risks of deferring displace the facial nerve anteriorly, thereby placing the
treatment.54 tumor directly between a surgeon’s instruments and the
Patient factors as well as tumor characteristics play a cranial nerve.57,58
significant role in predicting the morbidity of a surgical Hearing preservation should be attempted with the sub-
procedure. A patient’s age, estimated life expectancy, pre- occipital/retrosigmoid or petrosal approach for all patients
operative Karnofsky performance score, neurologic status, with retromeatal meningiomas with good preoperative
and associated medical conditions such as uncontrolled hearing. The suboccipital/retrosigmoid approach, in par-
hypertension, diabetes, bleeding disorder, or infection ticular, provides good access for tumors located posterior
804 SURGICAL NEUROTOLOGY

to the porus acousticus with a minimal risk of significant of dexamethasone every 6 hours).34 These agents improve
morbidity. Multiple authors have suggested using this intracranial compliance and protect the brain from the
approach to maximize hearing preservation even for patients trauma of surgery. Treatment with anticonvulsants for the
with large tumors and poor preoperative hearing.59,60 Cases prevention of seizures is controversial. Most surgeons
in which hearing is to be safeguarded, tumors involving administer anticonvulsant therapy prior to the surgery so
the IAC may be approached with a middle fossa or that therapeutic concentrations may be achieved before
extended middle fossa approach. Patients with large the patient is taken to the operating room. Although these
meningiomas of the IAC with evidence of bony invasion medications protect against seizures, they are sometimes
and poor hearing may be treated with a translabyrinthine associated with lethargy, confusion, and, rarely, an allergic
approach.34 Tumors of the lateral IAC with invasion of the response. In addition, surgeons often question the need for
inner ear have been reported. Resection of the inner ear anticonvulsant therapy in the absence of preoperative
has been proposed in these cases to prevent recurrence.61 seizures.11,53 Antibiotic coverage is also recommended for
Meningiomas may also involve other basal foramina, such a period of 24 hours to protect against infections. Several
as Meckel’s cave, the jugular foramen, and the foramen medications and techniques may be used to reduce brain
magnum, which may necessitate the use of alternative edema and shrink the intra-axial structures. These include
approaches. hyperventilation (CO2 level of 25 mEq/L), administration
of an osmotic diuretic such as mannitol (1 to 1.5 g/kg as a
20% solution), and placement of a lumbar drain in antici-
PREOPERATIVE CONSIDERATIONS pation of a prolonged brain retraction for skull base
lesions.11,56
Given the differential diagnosis of the CPA and IAC, a Neuromonitoring plays an important role in preserving
preoperative evaluation should include an effort to deter- function in meningioma surgery. Cranial nerve monitor-
mine the specific type of tumor present. As stated previ- ing, especially facial nerve monitoring, is routinely
ously, CT and MRI remain the premier noninvasive tools conducted for meningiomas in the CPA and IAC. The
for detecting and diagnosing specific lesions in the CPA and trigeminal nerve and recordings from the extraocular mus-
IAC. These imaging techniques provide specific anatomic cles are also monitored during surgery for meningiomas
information such as length and width of the IAC, precise involving Meckel’s cave and the cavernous sinus. The
location of the semicircular canals and jugular bulb, and cochlear nerve is often monitored in cases selected for
the extent of pneumatization of the petrous and mastoid hearing preservation. Electrodes may also be placed in the
bones. This information is especially helpful for the sur- tongue, neck, pharynx, trapezius, or sternocleidomastoid
geon planning the details of the procedure. The amount muscles for monitoring the lower cranial nerves (IX
and direction of tumor extension may also be gleaned from through XII) when the meningioma extends to the jugular
these data. In cases of hearing loss, hearing tests may also foramen.34,63 Repetitive, irregular, high-frequency discharges
be performed; the loss of discrimination is a more sensitive on spontaneous electromyography (EMG) recordings
index than hearing threshold for detecting a neural origin alert a surgeon that a cranial nerve is being acutely
of a hearing disorder. High-resolution cochleomeatal stretched or compressed. Specific stimulation of a cranial
scanning (CMS) of the IAC may be performed to detect nerve using electrical stimuli can not only confirm the
the presence of tumor in the canal as well as ascertain the identity of a particular nerve but also reassure the surgeon
position of basilar vessels rostrally and the jugular vein that the pathway is intact from the point of stimulation to
caudally.62 the muscles generating the recordings.63
Angiography was extensively used in the past for diag-
nosing meningiomas. Today, however, it is rarely used,
given the availability of noninvasive imaging techniques POSTERIOR FOSSA MENINGIOMAS
such as CT and MRI. It may be indicated in meningiomas
of the cavernous sinus and in evaluation of the Posterior fossa meningiomas account for 9% to 10% of all
intrapetrous carotid to determine the patency and feasi- intracranial meningiomas and represent 7% of all posterior
bility for resection by balloon occlusion testing. cranial fossa tumors.64–68 In Olivecrona’s series of 4185 brain
Angiography can also be used to determine the patency of tumors, posterior fossa meningiomas made up 8.45% of all
any dural sinuses involved with tumor. These tests may intracranial meningiomas and 1.7% of all brain tumors.69
rarely cause complications, so they must be selected after Meningiomas are the second most common tumor of the
weighing their benefits and risks. Preoperative emboliza- posterior cranial fossa after vestibular schwannomas.39
tion of the external carotid contributions to the tumor’s Prior to the advent of modern neuroradiologic (CT, MRI,
blood supply may be selected by the operating surgeon. angiography) techniques, diagnosis of these tumors was dif-
Embolization reduces blood loss intraoperatively and ficult due to conflicting signs and symptoms.64 Early man-
may soften the tumor due to tissue necrosis so that the agement of these rare lesions was also challenging due to
tumor may be removed by the cavitron ultrasonic suction the inability of surgeons to identify their precise location
aspirator (CUSA).34 preoperatively.64,65,70 Early series reported high morbidity
Blood should be available and cross-matched before sur- and mortality rates for the surgical resection of these
gery. This is especially important for large, hypervascular lesions. The operative mortality rates ranged between
meningiomas located in close proximity to significant vas- approximately 20% and 30%, and the perioperative mor-
cular structures. Meningiomas causing significant cerebral tality rate ranged from 0 to 15.7%.64,65 The slow growth
edema should be treated with perioperative steroids (4 mg rates of these lesions posed a dilemma for the surgeons
 Meningiomas of the Posterior Fossa and Skull Base 805

who had to weigh the significant morbidity of surgical supply to these tumors. The lesions were divided into five
removal against progressive functional deterioration of groups: CPA meningiomas, meningiomas of the cerebellar
the patient due to an increasing tumor size.65 The intro- convexity, tentorium cerebelli meningiomas, peritorcular
duction of modern neuroradiologic techniques, skull base meningiomas, and clival meningiomas. CPA meningiomas
approaches, and microsurgical techniques have lessened included lesions attached to the posterior ridge of the
the morbidity and mortality associated with the surgical petrous bone that derived their blood supply from the
resection of these tumors.64–66,71 meningeal branches of the vertebral artery. Meningiomas
Cushing and Eisenhardt proposed one of the first classi- of the cerebellar convexity originated from the dura cover-
fication systems for posterior fossa meningiomas in 1938.3 ing the cerebellum and obtained their vascular supply from
They divided posterior fossa meningiomas into tumors of the vertebral and occipital arteries. Tentorium cerebelli
the basilar groove, posterior cerebellar convexity, the meningiomas extended both supratentorially and infraten-
acoustic foramen, and the lateral recess. Since then, several torially and were supplied by the IAC, the middle meningeal
different classification schemes have been proposed to artery, the occipital artery, and terminal branches of the
organize posterior fossa meningiomas. In 1953, based on basilar artery. The meningeal branches of the vertebral
their radiologic and postmortem examinations of 71 pos- artery, the middle meningeal artery, and occipital arteries
terior cranial fossa meningiomas, Castellano and Ruggerio provided blood supply to peritorcular meningiomas. Clival
divided these tumors into five groups. These groups con- meningiomas obtained their blood supply primarily from
sisted of tumors arising from the cerebellar convexity, tento- the meningeal branches of the IAC and vertebral artery.66
rium, posterior petrous region, clivus, and foramen magnum The aforementioned classification schemes illustrate the
and were classified on the basis of the tumor’s site of dural two primary methods, namely, site of dural attachment and
attachment (Fig. 47-10). The posterior petrous ridge was location, that have been used to subdivide posterior fossa
the most common site of dural attachment (42%) followed meningiomas. Creation of these groupings is necessary to
by the tentorium (30%), clivus (11%), cerebellar convexity compare surgical morbidity and mortality. Both methods,
(10%), and foramen magnum (4%).72 Russell and Bucy, on however, have limitations that complicate the objective com-
the other hand, classified posterior fossa meningiomas parison of surgical data. Despite the availability of sophisti-
according to their location within the posterior cranial cated, multiplanar imaging techniques, the primary site of
fossa, not their site of origin. The CPA was the most com- dural attachment is difficult to determine preoperatively. In
mon location for these tumors according to these authors.73 addition, the size and location of the tumor make this deter-
Yasargil and Mortara proposed yet another classification mination challenging even intraoperatively.69 Yasargil and
system, which divided meningiomas of the posterior cra- Mortara cautioned, “at time … even with close observation
nial fossa into CPA, foramen magnum, clival, petroclival, through the operating microscope, a precise origin cannot be
and sphenopetroclival regions based on his intraoperative ascertained.”74 Classifying meningiomas based on their loca-
findings.74 tion is also problematic, given the frequent extension of
In a 1983 study of 38 posterior fossa meningiomas, tumors into different areas of the posterior cranial fossa.
Martinez and coworkers divided these tumors based on This lack of a consistent and unified classification scheme has
their site of dural attachment and also detailed the vascular made accumulation, integration, and comparison of surgical
data for posterior fossa meningiomas difficult.
A more recent classification scheme introduced by
Sekhar and colleagues divides posterior fossa meningiomas
into six groups based on their site of dural attachment:
(1) cerebellar convexity and lateral tentorial (type I), (2) lat-
eral petrous ridge and CPA (type II), (3) jugular foramen
(type III), (4) petroclival (type IV), (5) foramen magnum
(type V), and (6) unclassified (type VI). Type I meningiomas
include lesions originating from the cerebellar dura, tento-
rium, or transverse, sigmoid or straight sinuses. Type II
meningiomas are tumors that arise from the lateral petrous
ridge dura, lateral and posterior to the IAC meatus, with
or without extension into the canal. Tumors cropping up
from the dura in the jugular foramen region or cerebel-
lomedullary angle, with or without extracranial extension,
are classified as type III meningiomas. Type IV menin-
giomas are petroclival meningiomas that arise from the
petrous apex, medial petrosal ridge, or upper two-thirds
of the clivus, with or without extension into the cavernous
sinus or Meckel’s cave. Type V meningiomas are lesions
that originate from the dura of the foramen magnum,
lower one-third of the clivus, or C1–2 area. And finally,
Figure 47-10. A view of potential sites of origin of posterior fossa type VI meningiomas are unclassified tumors.65 Although
meningiomas including the cerebellopontine angle, petroclival region,
cerebellar convexity, and the jugular foramen. (Used with permission from
plagued with the same imperfections mentioned for
Jackler RK: Atlas of Neurotology and Skull Base Surgery. Philadelphia, other classification schemes, this is a comprehensive and
Mosby, 1996.) detailed scheme that may further the accurate collection,
806 SURGICAL NEUROTOLOGY

interpretation, and comparison of surgical morbidity This particular patient had a meningioma that arose from
and mortality. the anterior lip of the IAC. The other six patients did not
fare as well and had an average postoperative survival of
only 20 months.3 In 1934 and 1936, De Martel and
CEREBELLOPONTINE ANGLE Guillaume described the removal of a CPA tumor.
MENINGIOMAS Postoperatively, the patient experienced an improvement
in hearing, a significant accomplishment given the absence
Introduction of modern magnification and surgical techniques.77 In
1953, Castellano and Ruggerio reviewed Olivecrona’s
The term cerebellopontine angle (CPA) was introduced in series of 71 meningiomas, 29 of which were classified as
1902 by Henneberg and Koch when they found two CPA tumors. Approximately 79% of the lesions underwent
patients with bilateral vestibular schwannomas (acoustic complete excision but this was accompanied by an
neuromas) in a location they called kleinhirnbruchenwinkel appalling mortality rate of 43%. The mortality rate for the
(kleinhirn = cerebellum, bruchen = pons or bridge, winkel = total resection of CPA meningiomas remained dismal until
angle).75 The CPA is most simply defined as the space 1980 when Yasargil and Mortara reported complete
bound by the cerebellum, pons, and petrous temporal removal for 30 of these tumors with a nearly 0% mortal-
bone. It is traversed by multiple neurovascular structures ity.74 Since then, multiple series have reported excellent
entering or exiting the cranial vault.76,77 It is a large surgical excision for CPA meningiomas with minimal or
intracranial basal cistern filled with cerebrospinal fluid no mortality.
(CSF) that has a meningeal lining. The CPA is bounded
posteriorly by the flocculus and petrosal surface of the Epidemiology
cerebellum. Anteriorly, it is enclosed by the posterior sur-
face of the petrous pyramid and lateral aspect of the clivus. Although, the CPA is the eighth most common site of
The lateral aspect of the tentorium marks the superior involvement for all intracranial meningiomas, it is the
limit of the CPA. Inferiorly, this cistern extends along the most common location for meningiomas in the posterior
lateral surface of the medulla. The lateral limit of the CPA fossa.78,79 Approximately 8% to 18% of all intracranial
is approximated by the posterior aspect of the petrous meningiomas and 30% to 58% of all posterior fossa
pyramid and internal acoustic meatus (IAM). The medial meningiomas are found in the CPA. Meningiomas account
limit of this space is defined by the pons.77 Important neu- for only 3% to 12% of CPA tumors, making them the
rovascular structures that reside in the CPA cistern are the second most common tumor in the angle.34,40,41,76,80–83
CN VII through VIII nerve complex; the anterior inferior These tumors tend to occur most frequently in middle-
cerebellar artery (AICA) and its branches; the posterior infe- aged females. In one of the larger series of CPA menin-
rior cerebellar artery (PICA); and numerous veins draining giomas, Matthies and coworkers reported that meningiomas
the petrosal surface of the cerebellum, the pons, and comprised 18% of tumors in the CPA, a much higher fig-
medulla, which empty into the superior petrosal vein.76,77 ure than other series.84 Although meningiomas represent a
noteworthy pathology in the CPA, the most common
lesion remains the vestibular schwannoma, which makes
History up almost 90% of all lesions in the angle.41,75,78,83
The first CPA meningioma was reported by Rokitansky
in 1855.77 Soon thereafter in 1863, Virchow described a Origin
“psammoma” originating from the posterior lip of the
IAC.7 Although multiple surgical excisions were attempted, Meningiomas originate from the arachnoid lining cells
the first successful removal of a meningioma was described found in clusters at the tips of arachnoid villi, which serve
in 1894 by Charles Ballance. Although the author reported as the sites of CSF absorption. Arachnoid villi are finger-
the tumor to be a vestibular schwannoma (acoustic neu- like projections of the arachnoid mesothelium that pro-
roma), evidence reviewed by Cushing suggested that he trude into the sinus wall.85 Intracranially, meningiomas are
was one of the first of many who have confused the identity found along the dural sinuses, their large tributary veins, as
of the two tumors.34 Cushing considered the broad dural well as the exit foramina for vessels and cranial nerves.78,85
attachment of the tumor and the absence of auditory In the CPA, meningiomas are thought to arise from arach-
symptoms to strongly suggest that the tumor removed by noid villi that are associated with large and small venous
Ballance was more likely a meningioma.3 Henshen went channels surrounding the petrous portion of the temporal
on to give an account of three CPA meningiomas in 1910 bone.83 These tumors are typically situated near the sigmoid
and also reviewed the literature on these specific tumors.77 sinus, jugular foramen, torcula, and superior and inferior
The history of CPA meningioma surgery continued petrosal sinuses. Concentrations of arachnoid cells found
when Olivecrona detailed the removal of two posterior within the IAC, the jugular fossa, the geniculate ganglion,
petrous pyramid meningiomas in 1927 and 1929, with only and along the greater and lesser superficial petrosal nerves
the latter being associated with a good outcome.77 In a may also give rise to meningiomas.34,78,85
1938 report on 23 meningiomas, which accounted for
2.4% of his surgical series, Cushing detailed the manage- Classification
ment of 7 CPA meningiomas. Only one of those patients,
however, was reported to have a favorable outcome and Akin to the classification schemes for posterior fossa menin-
was reported to be alive and well 9 years after the operation. giomas, the site of dural attachment as well as location of
 Meningiomas of the Posterior Fossa and Skull Base 807

the tumor are the basis for many of the methods devised posterior fossa meningiomas classified as clival tumors by
for defining and cataloging CPA meningiomas. Castellano Yasargil and Mortara would have been characterized by
and Ruggerio defined CPA meningiomas on the basis of Sekhar and Jannetta as CPA meningiomas. Since clival
their dural attachment to the posterior petrous ridge in tumors have an increasing likelihood of morbidity and
1953. In a report of 30 posterior fossa meningiomas in mortality depending on the degree of resection, they are
1975, Grand and Bakay defined CPA meningiomas as all often only partially excised. Meningiomas in the CPA with
lesions that arise from the face of the petrous bone.64 Since a significant clival or tentorial extension, which were more
then, several authors, including Yasargil and Mortara74 likely to be incompletely resected, were cataloged as CPA
widely accepted this definition and classified CPA menin- meningiomas by Sekhar and Jannetta. This dissimilarity in
giomas on the basis of the tumor’s primary site of dural classification may explain a significant discrepancy in the
attachment. This definition of CPA meningiomas, how- resection rates between the two series.80
ever, excluded meningiomas growing in close proximity to Another example of the difficulty associated with the
the posterior petrous pyramid, but not actually originating lack of an all encompassing classification scheme was illus-
from it, including, for example, meningiomas with a dural trated in a recent series of 41 CPA meningiomas by Thomas
origin in the lateral clivus or undersurface of the tentorium and King. These authors defined petroclival meningiomas
cerebelli.77 In addition, the precise point of dural attach- as those lesions arising from the apex of the petrous bone
ment is often difficult to determine despite the most between the superior and inferior petrosal sinuses.69
favorable imaging techniques and surgical exposure. A Bricolo and coworkers, however, considered this anatomic
classification scheme for CPA meningiomas should not region to only include tumors with an origin medial to the
only consider the dural surfaces involved but also take into trigeminal nerve.86 Given the high morbidity and mortal-
account the location and anatomic extensions of the ity rates associated with petroclival meningiomas, Thomas
tumor. A CPA meningioma should be considered as such and King reported a higher resection rate with a lower
when its bulk lies in the CPA or IAC.34 likelihood of morbidity and mortality for these tumors
One of the simplest classification schemes for CPA compared with their Italian counterparts. The variability
meningiomas divides these tumors into lesions anterior of inclusion criteria in virtually all series on CPA menin-
(medial) and posterior (lateral) to the IAC. Samii and giomas makes a comparison of surgical outcome data
Ammirati demonstrated a difference in the clinical presen- between them particularly tricky.69
tation, tumor extension, and surgical morbidity and mortal-
ity based on a meningioma’s location medial or lateral to the Clinical Presentation
porus acousticus.77 In a series of 22 CPA meningiomas in
1984, Sekhar and Jannetta used a similar scheme to describe Hearing loss, dysequilibrium, and tinnitus are the most
tumor extension.80 Given the importance of location as a common symptoms reported in patients with CPA menin-
determinant of approach and outcome, Thomas and King giomas (Table 47-2).40,41,66,78,87,88 In 1985, Granick and
introduced a more comprehensive classification scheme that colleagues studied the clinical manifestations and diagnosis
subdivides CPA meningiomas into six anatomic groups of CPA meningiomas in a series of 32 patients. The authors
namely lateral, midpetrosal, petroclival, Meckel’s cave, infe- found hearing loss (75%), vertigo or imbalance (59%), and
rior, and IAC. The lateral group includes meningiomas aris- tinnitus (34%) to be the most common symptoms reported
ing in a region defined by the sigmoid sinus laterally, the by patients at the time of their initial evaluation.
superior petrosal sinus superiorly, the IAC medially, and the Trigeminal nerve dysfunction was also reported to be
jugular foramen inferiorly. Midpetrosal meningiomas arise
from the bone immediately above the IAC stretching to the
superior petrosal sinus. The petroclival region lies medial to TABLE 47-2. Clinical Presentation of CPA Meningiomas
the IAC between the superior and inferior petrosal sinuses. Sign or Symptom Frequency References
This area is the most common site for CPA meningiomas.
Meningiomas of Meckel’s cave comprise lesions arising Hearing loss 60% to 75% 40, 41, 64, 69, 74, 79, 84
from the dura of Meckel’s cave extending into the CPA. Imbalance, dysequilibrium 50% to 66% 40, 41, 69, 79, 84
Tinnitus 43% to 66% 41, 64, 79, 80, 84, 88
Inferior meningiomas come from the narrow stretch of Ataxia 6% to 81% 40, 64, 69, 72, 74, 79, 88
bone between the jugular foramen and IAC. Finally, IAC Decreased corneal reflex 50% to 60% 41, 72, 74
meningiomas are defined as tumors that arise from and are Headache 22% to 58% 40, 41, 74, 87, 90, 95,
centered on the IAC.69 100, 104
Facial numbness 19% to 64% 40, 41, 72, 74, 79, 88
Although a number of classification methods have been Trigeminal neuralgia 7% to 31% 40, 41, 64, 72, 74, 79, 84
proposed for CPA meningiomas, the lack of a unified and Facial spasm 6.7% to 36% 72, 79, 80
consistent classification scheme has made the comparison Facial weakness 3% to 53% 40, 41, 64, 72, 74, 79, 80,
of surgical outcome data problematic. Given the paucity of 82, 84
large series of CPA meningiomas, even subtle variations in Dysarthria 10% to 25% 41, 64
Dysphagia 5% to 19% 40, 41, 64, 72, 79, 84
cataloging CPA meningiomas by various authors alters the Papilledema 5% to 26% 41, 64, 66, 69, 79, 80, 82
data on surgical resection, morbidity, and mortality. For Dementia 13% to 14% 64, 80
example, Sekhar and Jannetta suggested that the primary Diplopia 8% to 25% 41, 64, 72, 79
reason for a difference in the resection rate between their Hemiparesis 5% to 16% 40, 64, 66, 72, 80, 84
Otalgia 5% to 16% 40, 41
series of 22 CPA meningiomas (64%) and Yasargil and Abducens paresis 3% to 18% 40, 66, 80, 84
Mortara’s series of 30 (100%) was more than likely due Visual disturbances 2.7% to 19% 40, 64, 66, 79, 84
to a minor variation in classification. Some of the large
808 SURGICAL NEUROTOLOGY

frequent in these patients; an alteration in facial sensation nerve irregularities in 47% of their patients.66 Facial weak-
was described in 25%, and trigeminal neuralgia was ness was reported as a symptom in multiple series ranging
reported in 16%.40,87 Lower cranial nerve abnormalities from 3% to 53%. On further examination, this large range
were noted in 13% of patients. Less common symptoms of frequencies can be separated into three distinct group-
were headache (22%), visual changes (19%), limb weak- ings: 3% to 7.5%,40,41,79,84 18% to 25%,64,80,82 and 50% to
ness (9%), otalgia (6%), and facial weakness (3%). On 53%.72,74 The difference in the involvement of the facial
physical examination, common otologic and neurologic nerve based on the location of the majority of tumors
findings were nystagmus (50%), decreased facial sensation in each series was most likely the cause of the variance.
(44%), ataxia (41%), reduced hearing (28%), and facial The authors of three separate studies found a difference in
weakness (28%).40,87 Overall, cranial nerve dysfunction the frequency of facial weakness reported by the patient
and cerebellar deficits were the most prominent signs and versus that noted on neurologic examination. Granick and
symptoms among patients with CPA meningiomas. colleagues found only 3% of patients complaining of facial
Impairments of multiple cranial nerves are some of the weakness. On exam, however, he noted that 28% of
earliest clinical signs and symptoms seen in CPA menin- patients had mild to moderate facial weakness.40 Laird and
giomas. Vestibulocochlear nerve dysfunction is the most colleagues noted a similar difference, in which only 5% of
frequently reported symptom in multiple series of CPA patients mentioned facial weakness, but 15% were found
meningiomas. In one of the earliest series, Grand and to have the sign on physical exam.41 Matthies and cowork-
Bakay reported on 30 posterior fossa meningiomas, ers found the two frequencies to be 3% and 11%.84 Facial
noting eighth nerve dysfunction in 94% of patients with spasm was noted in three different studies to be 6.7%,
CPA meningiomas.64 The frequency of hearing loss 12.5%, and 36%.72,79,80
ranged from approximately 60% to 75% in a majority of Lower cranial nerve (IX, X, XI, XII) abnormalities were
studies.40,41,64,69,74,79,84 In a retrospective review of reported in 13% to 25% of patients in multiple
Olivecrona’s 71 CPA meningioma cases, Castellano and series.40,41,64,66,72,74,79,80,84 Dysarthria was reported in 10% of
Ruggerio reported hearing loss as an initial symptom in patients by Laird and colleagues. Grand and Bakay noted
57% of their patients.72 In a series of 30 CPA menin- 25% of patients complaining of dysarthria, but 19% men-
giomas, Yasargil and Mortara described hearing loss as a tioned it on physical examination. The frequency of dys-
clinical sign on admission in 67% of their patients.74 phagia was found to be between 5% and 19% in multiple
Sekhar and Jannetta, however, found a significantly lower studies on CPA meningiomas.40,41,64,72,79,84 Cerebellar signs
incidence of hearing loss (14%) in their series of 22 CPA were also frequently noted on physical exam for patients
meningiomas. In contrast, these authors reported a far with CPA meningiomas. Ataxia was noted on neurologic
higher incidence of trigeminal nerve dysfunction (73%).80 exam with a frequency of 6% to 81%.40,64,69,72,74,79,88 Non-
Martuza suggested that a difference in referral patterns, specific symptoms such as headache, nausea, emesis, and
specifically Jannetta’s interest in trigeminal neuralgia, was dizziness were also reported with varying frequencies in
more than likely the reason for this discrepancy.80,87 multiple series. Akin to many brain tumors, headache is
Dysequilibrium, which included imbalance and vertigo, one of the earliest clinical symptoms reported by patients
had a more variable presentation, with a large number with CPA meningiomas.66 Papilledema was noted in 5% to
of series reporting frequencies ranging from 50% to 26% of patients, signifying an increase in intracerebral
66%.40,41,69,79,84 Yasargil and Mortara and Minor and pressure.41,64,66,69,79,80,82 Sekhar and Jannetta noted postpa-
colleagues noted low incidences of dysequilibrium at 36% pilledemic optic atrophy in 5% of their patients.80
and 37%, respectively.74,88 Castellano and Ruggerio as Several uncommon signs and symptoms noted for
well as Sekhar and Jannetta reported even lower incidences patients with CPA meningiomas in a small subset of
of dysequilibrium at 27% and 32%, respectively.72,80 series were visual disturbances (2.7% to 19%), diplopia (8%
Tinnitus was also reported in an unpredictable pattern in to 25%), sixth nerve irregularities (3% to 18%), dementia
a majority of series, with frequencies ranging from 43% (13% to 14%), hemiparesis (5% to 16%), and otalgia (5%
to 66%.41,64,79,80,84,88 to 6%). Yasargil and Mortara reported subarachnoid hem-
Trigeminal nerve dysfunction is another commonly orrhage as an interesting and unusual presenting symptom
reported symptom for patients with CPA meningiomas. in 6.6% of their patients with CPA meningiomas.74
Sekhar and Jannetta described trigeminal neuralgia in 64% The mean time from the onset of symptoms to diagno-
and facial numbness in 9% of patients in their series.80 sis of a CPA meningioma has been reported in multiple
This reported incidence of facial pain is significantly series to range from 4 to 6 years. Martinez and coworkers
higher than that in other series, which found frequencies found a lower mean time of 3.5 years in their series.
ranging from 7% to 31%.40,41,64,72,74,79,84 Facial hypesthesia Granick noted the mean time between the onset of symp-
was reported to be present in 25% of patients by Laird and toms to the first time the patient consulted a physician to
colleagues.41 Facial numbness was found in 19% to 64% of be 6 years, with a range of 1 month to 34 years. The largest
patients in a majority of series.40,41,72,74,79,88 This range time lapse between the first consultation with a physician
excluded the low incidence of 9% reported by Sekhar and to the actual diagnosis of a CPA meningioma was 18 years,
Jannetta. On physical exam, a decreased corneal reflex was with a mean time of approximately 4 years. The authors of
noted in 50% to 60% of patients.41,72,74 this study found this delay to be the direct result of a mis-
Facial nerve abnormalities, which included weakness, diagnosis in 55% of cases.40,87 Yasargil and Mortara also
and facial spasm were noted by Grand and Bakay in 44% noted a mean interval of 4 years from the first medical
of their patients.64 Martinez and coworkers, in a study of evaluation to the diagnosis of a CPA meningioma. The
19 CPA meningiomas, found a similar incidence of seventh time between the first onset of symptoms to the diagnosis
 Meningiomas of the Posterior Fossa and Skull Base 809

ranged from 1 year to 18 years. This author also noted a 18 of which were meningiomas.42 Significant clinical dif-
gender-specific delay that ranged from 3 years for women ferences found between meningiomas and vestibular
and 7 years for men.74 Samii and Ammirati found the time schwannomas were hearing loss 44% versus 57%, tinnitus
between the onset of symptoms to diagnosis to depend on 39% versus 51%, and trigeminal neuralgia 6% versus 1%,
the location of the tumor. The mean interval for menin- but also vertigo 28% versus 9%, facial dysthesia 33%
giomas posterior to the IAM was 10 months (2 weeks to versus 1%, and headache 28% versus 2%. In contrast,
2 years) with a median of 1 year. For meningiomas anterior dysequilibrium, facial numbness, and headache were found
to the porus acousticus, the mean interval was 4.3 years in equal frequencies by Laird and colleagues.41,42 Neverthe-
(5 weeks to 5 years) with a median of 3 years.77 less, there was significant agreement between the two stud-
The mean age at the time of presentation for CPA ies, suggesting an important role for a thorough clinical
meningiomas has been reported by many authors to lie history and physical examination in making the preoperative
between 50 to 57 years.40,64,79,84 Granick and colleagues diagnosis of a CPA lesion. Although minor variations in
found the mean age of presentation to be 55.3 years with the clinical presentation of a CPA lesion may help with the
a wide age range of 19 to 84 years. However, approxi- preoperative diagnosis, newer, readily available imaging
mately 20 of the 32 (63%) of the patients were between the modalities are more likely to provide a definitive verdict.
ages of 45 to 65 years.40 The median has been noted to
range between 52 to 53.5 years in a smaller number of
studies.69
Diagnosis
Given that meningiomas and vestibular schwannomas Multiple diagnostic tests are available for the diagnosis of
have very similar clinical presentations, distinguishing CPA lesions. These include physiologic tests such as
between them based solely on clinical presentation is diffi- audiometry, electronystagmography, brainstem evoked
cult if not impossible.87 However, subtle differences may response, and blink reflex testing, as well as imaging stud-
help to differentiate between these two tumors in the CPA. ies such as polytomography, myelography, angiography,
In a study conducted by Laird and colleagues in 1985, the CT, and MRI. Although the physiologic diagnostic
clinical presentation as well as audiovestibular results and tests are useful for detecting CPA masses, they are not
imaging studies of 20 patients with CPA meningiomas was helpful in the specific diagnosis of a CPA meningioma.
compared with 131 patients with vestibular schwannomas. Myelography and angiography were used extensively
At initial presentation, a significantly larger percentage of before the advent of noninvasive imaging technology.40
meningiomas (35%) than vestibular schwannomas (18%) Angiography is rarely used today except in cases of diag-
were greater than or equal to 4.1 cm.41 Noteworthy differ- nostic uncertainty or for preoperative embolization of the
ences in the clinical presentation of meningiomas and tumor to decrease blood loss during surgery.
vestibular schwannomas were found with respect to hear- CT and MRI are the primary means for diagnosing
ing loss 60% versus 98%, tinnitus 50% versus 70%, lesions of the CPA (Fig. 47-11). Bone erosion or invasion,
trigeminal neuralgia 15% versus 0%, and lower cranial and tumor calcification are more easily detected on CT.
nerve (IX, X, XI, XII) dysfunction 15% versus 0%.41
Hearing loss for similar-sized lesions was greater for
vestibular schwannomas than meningiomas.80 Vestibular
schwannomas had a higher incidence of vestibulocochlear
nerve dysfunction than meningiomas, but displayed no
signs of trigeminal neuralgia or lower cranial nerve dys-
function such as dysphagia or dysarthria in this study.41
Dysequilibrium was found in two-thirds of patients with
both tumors. Patients with CPA meningiomas displayed a
range of symptoms from positional vertigo to gait instabil-
ity but not episodic vertigo. Neurologic deficits such as
facial numbness, facial palsy, otalgia, and loss of taste
occurred in both groups of patients with nearly equal
frequencies.41 Nonspecific symptoms such as headache,
nausea, emesis, and diplopia also were found in a similar
percentage of patients with both tumors. No significant
differences in physical examination were noted except for
a decreased corneal reflex in meningiomas (50%) versus
vestibular schwannomas (33%). This was most likely
secondary to the compression of the trigeminal nerve in
both groups.41
The clinical comparison between meningiomas and
vestibular schwannomas presented by Laird and colleagues
is in agreement with the data presented in another study
comparing the clinical presentation of both tumors.41 Aiba
and coworkers compared the clinical and audiovestibular Figure 47-11. Axial T1-weighted gadolinium-enhanced MRI scan revealing a
findings between 141 patients with vestibular schwanno- right cerebellopontine angle meningioma. Note its broad sessile base and the
mas and 43 patients with nonacoustic lesions in the CPA, absence of widening of the internal auditory canal.
810 SURGICAL NEUROTOLOGY

On the other hand, MRI is better at detecting tumor vas- In a study of 56 patients with temporal bone menin-
cular or neural involvement and extension into the IAC, giomas in 1992, Arriaga and colleagues reported the use of
petrous apex, Meckel’s cave, IAC, petroclival region, and six surgical approaches: the (1) retrosigmoid, (2) translaby-
jugular foramen. MRI is also more reliable in differentiat- rinthine, (3) transcochlear, (4) retrolabyrinthine, (5) infra-
ing meningiomas from vestibular schwannomas. Although temporal, and (6) middle fossa approaches. The authors
both lesions appear isointense to hypointense on T1WI, studied the use of these surgical approaches with respect to
with a variable presentation on T2WI, vestibular schwan- the tumor location, morbidity associated with the proce-
nomas enhance significantly with gadolinium administra- dure, and long-term functional outcome. The translaby-
tion compared with meningiomas.89,90 rinthine approach was employed in 43% of patients, the
transcochlear approach in 27%, and the middle fossa
approach in 16%. Less often used were the retrosigmoid
Surgical Management approach in 9% of cases, the infratemporal fossa approach
CPA meningiomas have posed a challenge for surgeons, in 4%, and the retrolabyrinthine approach in 2%. Total
given their close proximity to neurovascular structures and excision of the tumor was accomplished in 86% of cases.93
their predisposition to attain massive sizes prior to clinical In a series of 22 CPA meningiomas in 1984, Sekhar and
diagnosis. The likelihood operative morbidity and mortal- Jannetta used the retrosigmoid craniectomy in 19 cases,
ity has been high ever since Cushing reported the first achieving a complete removal of tumor in 12 patients. The
successful removal of a CPA meningioma (Table 47-3).80 authors employed a subtemporal approach in the remaining
These tumors are particularly difficult to excise because of three patients and were successful in total excision of the
their hypervascularity and attachment to large sinuses lesion in two patients.80 In a series of 41 CPA meningiomas
in the subtentorial space.91 The difficulties with resecting in 1996, Thomas and King divided these tumors based on
these tumors also include their variable origin and unpre- their anatomic location. They used the retrosigmoid
dictable growth extension.84 The introduction of the new approach in 10 patients with tumors in close proximity to
skull base approaches, the operating microscope, and the IAC and the translabyrinthine approach for midpet-
microsurgical techniques have dramatically improved the rosal and IAC lesions. Complete resection was realized in
rate of resection, minimized postoperative complications, all groups except for petroclival meningiomas, which are
and preserved functionality. The outcome for patients with discussed in the next section.69 In a more recent study of
CPA meningiomas depends on the patient’s preoperative 40 CPA meningiomas in 2000, Voss and coworkers used a
condition, the location of the tumors, degree of tumor petrosal approach in 18 of 40 (45%) patients, a suboccipital/
resection, tumor histology, and the use of adjunctive modal- retrosigmoid approach in 11 of 40 (27%), and a translaby-
ities.92 In addition, postoperative imaging has also improved rinthine approach in 7 of 40 (17%). The transcochlear and
the detection of small asymptomatic recurrences.80 middle fossa approaches were employed in the remaining

TABLE 47-3. Cerebellopontine Angle Meningiomas—Series (1938–2002)

Author Year Total Cases Mortality CPA TR Mortality PR/SR Mortality

Cushing and Eisenhardt3 1938 23 22% 7 14% 0% 86% 14%

Cambell and Whitfield 1947 5 30% 5
Petit-Dutaillis and Daum 1949 41 29% 21 10% 0% 90% 35%
D’Errico91 1950 10 20% 7
Castellano and Ruggerio72 1953 71 30% 29 79% 43% 17% 60%
Russell and Bucy73 1953 15 33% 10 20% 0% 50% 40%
Markham et al.110 1955 29 28% 15 67% 30% 33% 40%
Hoffman et al. 1957 12 12 58% 29% 42% 0%
Lang et al. 1967 7 57% 5
Lecuire et al. 1970 114 27% 98
Obrador 1971 42 10
Scott82 1972 20 10% 8 50% 0% 50% 0%
Grand and Bakay84 1975 30 16
Yasargil and Mortara74 1980 50 4% 30 100% 0% 0% 0%
Laird et al.41 1982 20 20 80% 20%
Martinez et al.66 1983 38 16% 19 84% 26% 16% 0%
Sekhar and Jannetta80 1984 22 0% 22 64% 0% 36% 0%
Granick et al.40 1985 32 32
Samii and Ammirati77 1991 56 0% 56 95% 0% 5% 0%
Schaller et al.92 1995 13 8% 13 92% 8%
Matthies et al.84 1996 230 134 95% 5%
Thomas and King69 1996 41 0% 41 73% 20%
Cudlip et al.68 1998 52 0% 18 78% 0% 22% 0%
Paterniti et al.71 1999 139 12% 21 81% 19%
Voss et al.79 2000 41 5% 41 82% 18%
Roberti et al.65 2001 161 0% 9 100% 0% 0%
Batra et al.159 2002 21 0% 21 90% 0% 10% 0%

TR, total resection; PR, partial resection; SR, subtotal resection.

 Meningiomas of the Posterior Fossa and Skull Base 811

few cases. Total resection of the meningioma was achieved in problems. Only 15% of these patients developed postop-
82% of cases, with a subtotal excision in 18% of patients.79 erative facial nerve paresis. CSF leaks were reported in 9 of
The primary reasons for an incomplete resection were 40 (23%) patients, necessitating four wound revisions and
brainstem invasion, cavernous sinus extension, and stub- two lumbar-peritoneal shunt placements.79
born adherence of the tumor to the neurovasculature.79,80 In the study of 56 temporal bone meningiomas, Arriaga
and colleagues reported facial nerve preservation in 92%
of patients postoperatively. Patients with meningiomas
Complications originating from the petrous ridge, petroclival region, or
Cranial nerve palsies and CSF leaks are the two most tentorium had a worse long-term facial nerve function
common complications following surgery for CPA menin- than those with tumors located in the region of the sig-
giomas. Bacterial meningitis, aseptic meningitis, wound moid sinus, IAC, or jugular foramen. Similarly, patients
infection, hydrocephalus, and hemorrhage are less com- approached with a transcochlear or infratemporal
monly seen complications. Dysfunction of CN V, VII, and approach that involved direct manipulation of the facial
VIII, and, less commonly, CN IX, X, and XI are often nerve had the worst long-term facial nerve function. The
noted after surgery for CPA tumors.94 CSF leaks usually retrolabyrinthine and retrosigmoid approaches, although
result from the incomplete obliteration and sealing of the used in only a handful of patients, were successful at
mastoid or petrous apex air cells after a craniectomy for preserving a HB (House-Brackmann) grade of I or II in
the surgical approach to a CPA meningioma. Increased 100% of patients after more than a year of follow-up. The
intracranial pressure, hydrocephalus, or infection can translabyrinthine approach used in 11 patients was
often initiate or exacerbate a CSF leak. Drainage of clear successful in doing the same in 64% of patients. Other
fluid into the middle ear, through the eustachian tube, into complications reported included postoperative ataxia in
the pharynx or nose that worsens with a Valsalva’s maneu- 35%, long-term ataxia in 27%, CSF leaks in 12%, and
ver is suggestive of a true CSF leak. Management initially meningitis in 7%. More than 90% of patients returned to
includes placement of a lumbar drain. CSF leaks may also their preoperative functional status after surgery.93
be observed at the wound site secondary to poor wound
healing, hydrocephalus, and infection.94
In 2000, Voss and coworkers reported multiple postop- INTERNAL AUDITORY CANAL
erative cranial nerve deficits in their series of CPA menin- MENINGIOMAS
giomas. These included facial nerve dysfunction in 12 of
40 (30%) of patients, trigeminal neuropathy in 6 of 40 The majority of meningiomas found in the IAC originate
(15%), and vestibulocochlear nerve dysfunction in 5 of 40 from outside the canal, typically arising from the posterior
(13%). Neuropathies of CN IV, VI, as well as IX and X face of the petrous bone and prolapsing slightly into the
were noted in 8%, 5%, and 8% of patients, respectively. canal. Completely intracanalicular meningiomas are
Not surprisingly, the authors noted a significant difference extremely rare. Less than 15 well-documented cases have
in the frequency of postoperative cranial nerve dysfunction been reported in the literature (Table 47-4).38,61,81,83,95–103
based on the location of the CPA meningioma with respect These tumors arise from the meningeal lining of the IAC
to the porus acousticus. Seven of 10 (70%) patients with and are completely centered on the canal wall. Meningiomas
meningiomas with an origin anterior to the IAC and 6 of with a significant component in the IAC usually have a broad
8 (75%) patients with an origin inferior to the IAC dis- base along the posterior petrous bone, thus making the
played new cranial nerve deficits after surgery. Postopera- determination of the origin particularly difficult.61
tive facial nerve paresis in these patients was 60% and The first meningioma of the IAC was reported by
50%, respectively. In contrast, only two of eight (25%) Virchow, who noted a histologically proven meningioma
patients with meningiomas arising posterior to the IAC arising from the porus internus.3 The next intracanalicular
and two of seven (28%) patients with meningiomas origi- meningioma was reported more than a hundred years later
nating superior to the IAC developed new cranial nerve in 1975 when Singh and colleagues described a patient

TABLE 47-4. Clinical Presentation, Approach, and Outcome in IAC Meningiomas

Author Year Case Age Gender Size (cm) Presentation Approach Resection Outcome

Singh et al.99 1975 14 Male HL, CN VII palsy MF CN VII paresis

Brookler et al.100 1980 70 Female 0.2 HL, TI, dizziness T 100% CN VII intact
Langman et al.61 1990 Case 1 52 Male 2.0 × 2.5 HL, transient TI T CN VII intact
Case 2 54 Male Bilateral HL T 100% CN VII intact
96
Bohrer and Chole 1996 Case 1 52 Male Unilateral TI MF CN VII & VIII intact
Case 2 66 Female HL, vertigo T CN VII intact
Zeitouni et al.98 1997 60 Female AF, dysequilibrium T 100% CN VII intact
Caylan et al.101 2000 Case 1 42 Male AF, HL, vertigo T CN VII intact
Case 2 46 Male HL T CN VII intact
Martinez et al.103 2001 48 Female 1 HL, TI unsteadiness T CN VII HB Grade V
Magliulo et al.102 2002 Case 1 50 Male 1.1 × 0.5 Bilateral HL T 100% CN VII HB Grade I
Case 2 56 Female 1.2 × 0.5 TI R 100% CN VII & VIII normal

MF, middle fossa; T, translabyrinthine; R, retrosigmoid; HL, hearing loss; TI, tinnitus; AF, aural fullness.
812 SURGICAL NEUROTOLOGY

with complete facial palsy and deafness with a tumor in the tinnitus, fullness, vertigo, and facial palsy. PTA demon-
lateral end of the IAC that also involved the ampullated strated a unilateral hearing loss in 9 of 12 (75%) patients and
end of the lateral semicircular canal.99 Another case involv- was normal in 3 of 12 (25%).61,96,99,101–103
ing the posterior semicircular canal, vestibule, and IAC
was reported by Brookler and coworkers in 1980.100 Since
then multiple authors have reported meningiomas of the CLIVAL AND PETROCLIVAL
IAC in the literature.61,96,98,101–103 Nager and Masica noted MENINGIOMAS
the tendency of intracanalicular meningiomas to invade
deeper portions of the temporal bone via the lateral end of Introduction
the IAC.85 These tumors were seen to grow along the
nerve fibers into the cochlea, vestibule, and semicircular Clival and petroclival meningiomas are some of the most
canals. Infiltration of the perilabyrinthine tracts has also difficult skull base lesions to manage, given their close prox-
led to the involvement of the middle ear and mastoid por- imity to critical neurovascular structures.104,105 Due to their
tions of the temporal bone.61 Given the deeper involve- location and insidious growth pattern, these tumors may
ment of intracanalicular meningiomas, if the lateral end of present with significant brainstem compression, involve-
the IAC is involved, exenteration of the cochlea and the ment of multiple cranial nerves, and encasement of arteries
semicircular canal should be considered.34,61 arising from the vertebrobasilar system. Clival and petrocli-
IAC meningiomas are most common during the fourth to val meningiomas are usually detected after they have
sixth decades of life. They occur more frequently in women attained an enormous size, as their insidious early growth
than men, with a ratio of 5:2.3.102 Their clinical presenta- often occurs in the absence of significant signs and symp-
tions are related to compression of the vestibulocochlear toms.105 The surgical resection of these lesions is made even
nerve complex rather than parenchymal involvement. Akin more difficult with their propensity to extend to the petrosal
to CPA tumors, these lesions become symptomatic as they and cavernous sinuses, middle cranial fossa, parasellar area,
increase in size within the bony IAC.61,98,101 The advent of Meckel’s cave, IAC, and foramen magnum.86,104,106–110 Given
high-resolution CT and MRI has permitted the diagnosis of their depth of location within the skull and anterior rela-
small intracanalicular lesions before irreversible cranial tionship to the posterior cranial fossa nerves, the skull base
nerve damage has occurred.96 In 12 well-documented cases surgeon is relegated to dissecting these tumors between the
of IAC meningiomas, 9 (75%) had unilateral hearing loss, often attenuated and displaced cranial nerves (Fig. 47-12).57

TUMOR
Figure 47-12. A surgeon’s view of a left
prepontine petroclival tumor. Draped on the
lateral aspect of tumor are CN VII, VIII, and V, JB
limiting direct exposure to the tumor. Access
is via a “picket fence” approach working
between cranial nerves, which is somewhat
limiting. (Used with permission from Jackler
5
RK: Atlas of Neurotology and Skull Base
Surgery. Philadelphia, Mosby, 1996.)
7 8

Ch F1
 Meningiomas of the Posterior Fossa and Skull Base 813

Prior to the availability of the operating microscope, micro- 41 clival meningiomas, Sekhar and colleagues, in 1990,
surgical techniques, skull base approaches, advanced imag- divided the clivus into three parts: the upper clivus (region
ing, and intraoperative monitoring, the surgical resection of above the trigeminal nerves), the middle clivus (region
these tumors was associated with significant morbidity and between the trigeminal nerves and the glossopharyngeal
mortality.106 Although recent series report a dramatic nerves), and the lower clivus (region between the glos-
increase in complete resection of these meningiomas sopharyngeal nerves and foramen magnum). Only 7 of 41
accompanied by a decline in postoperative neurologic (17%) patients had single involvement of the upper, middle,
impairment, considerable morbidity is still associated with or lower clivus, whereas the majority of cases, specifically
the surgical management of these tumors. In a study of 33 24 of 41 (59%) patients, had involvement of two regions of
petroclival meningiomas, Bricolo and colleagues in 1992 the clivus. Only 10 of 41 (24%) patients were found to
stated that “In nearly all cases, the patient is in a worse clin- have tumors in all three regions of the clivus. In the same
ical and neurological condition after surgery than before, study these clival meningiomas had various intracranial
and therefore requires constant and meticulous assis- extensions: the tentorial notch in 32 of 41 (78%) patients,
tance.”86 In a review of petroclival meningiomas, Sekhar and the cavernous sinus in 21 of 41 (51%), the petrous ridge in
coworkers believe that although improvements have been 19 of 41 (46%), Meckel’s cave in 18 of 41 (44%), the sella
made in the management of these tumors, the temporary turcica in 12 of 41 (29%), the IAC in 9 of 41 (22%), and
and permanent postoperative morbidity after surgical resec- the middle cranial fossa in 7 of 41 (17%). Cranial and
tion remains underreported.104 extracranial extensions to the petroclival bone were found
in 16 of 41 (39%) patients, to the sphenoid sinus in 5 of 41
Origin and Classification (12%), to the infratemporal fossa in 4 of 41 (10%), and the
C1–2 area in 3 of 41 (9%).113
Akin to other posterior fossa meningiomas, clival and
petroclival meningiomas have undergone changes in defi-
nition over time. Comparisons between series of patients
Clinical Presentation
with clival and petroclival meningiomas have been limited The average age at presentation for a patient with a clival
due to the inconsistencies in the classification of these or petroclival meningioma is in the middle of the fifth
tumors.111 In 1953, using postmortem examinations to decade of life, with an age range of 5 months to 69
localize the site of the tumor, Castellano and Ruggerio years.105,106 Females are affected twice as often as males in
defined clival meningiomas as tumors arising from the a majority of studies. Mayberg and Symon reported that
superior part of the clivus displacing the pons posteriorly.72 females constituted 64% of their series versus males who
Hakuba and colleagues, in 1977, also adopted this defini- made up 36%. The authors also found females to be
tion in a report of six meningiomas of the clivus.112 In afflicted at an earlier age of 47 years, versus 54 years for
1963, Dany and Mortara described clival meningiomas as the males.111 In contrast, Castellano and Ruggerio in 1953
tumors originating from any part of the anatomic clivus and Hakuba and coworkers in 1977 reported an equal inci-
growing anterior to the basilar artery.106 This definition, dence of males and females. The duration between the
however, excluded rare cases in which the meningioma onset of symptoms to diagnosis was reported to average
rests between the basilar artery and the pons. Based on from 3 to 5 years, with a range from 1 month to 17 years
their intraoperative observations in 1980, Yasargil and in a majority of series.72,112
Mortara defined clival meningiomas as tumors “attached The incidence as well as the order of symptoms and
at any of the lateral sites along the petroclival borderline, signs are variable and inconsistent among series. In a
where the sphenoid, petrous, and occipital bones meet.”74 review of 44 cases in 1977, Hakuba and coworkers
Despite the attempts of these authors to describe and clas- reported a constellation of clinical signs and symptoms,
sify these tumors, a precise definition for clival and petro- which included increased intracranial pressure (70%),
clival meningiomas remains undecided. However, most cerebellar involvement (70%), CN V palsy (68%), hearing
authors agree that clival tumors arise from the upper two- loss (64%), facial nerve palsy (57%), involvement of the
thirds of the clivus, whereas petroclival tumors originate corticospinal tract (57%), CN VI palsy (40%), involve-
from the petrous ridge anterior to the IAC or the upper ment of CN IX and X (34%), CN III palsy (27%), nuchal
two-thirds of the clivus. As previously mentioned, other rigidity (25%), nystagmus (25%), sensory impairment in
authors, particularly Bricolo and coworkers, consider the limbs (16%), and psychological disturbance (1%).112
petroclival tumors to have an origin strictly medial to the In a later study of 35 meningiomas of the clivus and
trigeminal nerve.86 Sekhar and colleagues argue that petrous bone in 1986, Mayberg and Symon reported dis-
although these definitions aid the surgeon, they fall short turbance of gait and imbalance to be the most common
of helping to plan the operative approach or gauge the complaints on admission. These were followed by headache,
technical difficulties associated with a particular tumor. diminished auditory acuity, and facial pain. Vomiting,
For example, a soft petrous middle clival tumor poses a dysarthria, dysphagia, and somatic motor and sensory dis-
very different intraoperative challenge from a hard, vascu- turbances occurred later in the course of the disease.
lar, middle clival tumor encasing the basilar artery and Cranial nerve deficits were noted in more than 90% of
multiple cranial nerves.104 patients. CN V, VII, and VIII were most frequently involved.
The authors also noted a surprising lack of palsies of CN
III, IV, and VI, despite their frequent and intimate involve-
Extension ment with the tumor. The authors did not find any signif-
Clival and petroclival meningiomas often extend and grow icant correlation between the clinical signs and symptoms,
into various regions of the posterior fossa. In a study of duration of disease, or abnormal physical findings and
 Meningiomas of the Posterior Fossa and Skull Base 815

intervention is deferred may be conducted with regular

clinical examinations and imaging.108

Approach Selection
A plethora of approaches have been developed for the resec-
tion of clival and petroclival meningiomas. This is
in no small measure due to the extreme difficulty associated
with their complete removal. These approaches include the
frontotemporal (pterional), occipitotranstentorial, subtem-
porotranstentorial, suboccipital, combined subtemporal and
suboccipital, combined subtemporal and translabyrinthine,
transpetrososubtemporal, transcochlear, combined suboc-
cipital-translabyrinthine, transclival, transphenoidal, and
extradural transbasal approaches.107,108,118,119 In 1990,
Sekhar and colleagues used the retrosigmoid (suboccipital)
approach in 20 of 41 (49%) of patients and the frontotem-
poral/orbitozygomatic/transcavernous approach in 18 of 41
(44%).113 Bricolo and coworkers also preferred the
retrosigmoid approach in 23 of 33 (20%) patients. The
remaining patients were approached equally with the fron-
totemporal (15%) or petrosal (15%) approaches.86
The retrosigmoid approach was used more often in
patient’s with medium-sized tumors.86,113 This approach is
used for petroclival meningiomas that are located centro-
laterally and have minimal involvement of the upper clivus
and tentorial notch. Advantages of this approach include
expeditious access to the tumor. Disadvantages include the
position of cranial nerves between surgeon and tumor,
cerebellar retraction, and difficulty in accessing the brain- Figure 47-13. Axial view of a prepontine petroclival tumor approached via a
stem when it is compressed by the tumor (Fig. 47-13). The suboccipital retrosigmoid craniectomy. Note the lengthy distance from the
frontotemporal/transcavernous approach is used for craniectomy opening to the tumor and the cerebellar retraction necessary for
tumors involving the cavernous sinus and the upper and exposure. (Used with permission from Jackler RK: Atlas of Neurotology and
Skull Base Surgery. Philadelphia, Mosby, 1996.)
middle clival area. This approach allows the surgeon to
access the upper clival area through the middle cranial
fossa with less retraction of the temporal lobe. The disad-
vantage is the increased morbidity associated with working
in the cavernous sinus.104,113 death.3,72,106,111 Early series reported an operative mortality
In a study of 46 patients with large clival and petroclival rate of over 50% for these lesions. Prior to 1970, only 10
tumors extending below the tentorial incisura, Spetzler and of 26 (38%) patients survived surgery for clival menin-
coworkers in 1992 used three variations of combined giomas, and only one case of successful total removal was
approaches—the retrolabyrinthine, translabyrinthine, and reported.106,111 It was these dismal results that led Castellano
transcochlear—to approach these lesions (Figs. 47-14 & and Ruggerio in 1953 to conclude that clival and petroclival
47-15). These approaches offer better visualization of the meningiomas were “inoperable.”72
arachnoid plane between the brainstem and tumor, and In a review of 29 clival meningiomas, reported in the
minimal cerebellar retraction, with excellent superior expo- literature until 1966, Cherrington and Schneck noted that
sure to the anterior brainstem, middle fossa, and foramen clival meningiomas had a 1-year survival rate after diagno-
magnum.115,120 Several factors determine the selection of an sis of 25%.121 In a 1977 review of 44 cases of clival and
approach for clival and petroclival meningiomas: tumor petroclival meningiomas, Hakuba and coworkers noted
size, clival and petroclival region involved, extent and shape that out of 31 patients who received surgery, 17 (55%) died
of brainstem compression, degree of vertebrobasilar arte- within 26 days, 3 (10%) died within 3 months after biopsy
rial encasement, tumor vascularity, source of the tumor or partial removal of tumor, and 1 died 50 days after
blood supply, venous anatomy, patient’s preoperative neu- complete resection of the tumor. At the time of the report,
rologic status, goal of the operation (total versus subtotal), seven patients were still living after partial or subtotal
and finally the surgeon’s personal experience and prefer- removal. Only three patients survived after complete
ence. Large and extensive tumors require complex removal of the meningioma. However, two of them had
approaches, which often require staged operations.104 significant postoperative neurologic deficits.106,112,122 In a
series of six patients with completely resected clival tumors
in 1977, Hakuba and coworkers reported the death of only
Surgical History one, a significant achievement, given past results in the
The natural history of clival and petroclival meningiomas literature.112 Since then, multiple series have reported
is one of relentless progression and eventual patient much improved results.
816 SURGICAL NEUROTOLOGY

GG

JV
7
7
Figure 47-14. A left translabyrinthine Ca
approach to the cerebellopontine angle.
JB
Note that this is a anterosigmoid exposure I S
allowing excellent visualization of the jugular V V
foramen, CN IX, X, XI, the internal auditory
canal, CN VII and VIII, and CN V. Ca, cochlear
aqueduct; Cb, cerebellum; Ch, choroid
plexus; D, dura; Fl, flocculus; GG, geniculate 11 10 9 SPS
ganglion; IV, inferior vestibular nerve; JB,
jugular bulb; JV, jugular vein; SPS, superior
7 8 6
petrosal sinus; SS, sigmoid sinus; Ch 5
SV, superior vestibular nerve; TS, transverse F1
sinus; T, tentorium. (Used with permission
from Jackler RK: Atlas of Neurotology and Cb
Skull Base Surgery. Philadelphia, Mosby,
1996.)
SS T

D
TS

Resection Although gross total resection is preferred, subtotal

resection has been associated with a good functional out-
Gross resection of clival and petroclival tumors has come followed by long periods of survival. In 1986, Mayberg
markedly improved within the span of little more than a and Symon reported that only 4 of 26 (15%) patients
decade. The rate of complete resection of clival and petro- demonstrated tumor progression and subsequently died.111
clival tumors has ranged from 26% to 85% in a majority of In a series of 22 petroclival meningiomas in 1986, Sekhar
series (Table 47-6).74,86,105–108,111,113,115,117,119,123 With the and Samii104 found only 1 of 5 (20%) patients had clinical
exclusion of two of the early series by Yasargil and col- symptomatology suggestive of tumor growth after a subto-
leagues and Mayberg and Symon as well as a recent one by tal resection. Samii and coworkers113 also reported no
Jung and coworkers, the percentage of total resection varied reoperations on patients known to have residual tumor.
between 68% to 88%. In a recent meta-analysis of six sepa- Residual tumor was most likely to be found in the
rate studies on clival and petroclival meningiomas totaling cavernous sinus or in the clivus.104,113 In 2000, Jung and
298 patients, complete resection was possible in 68% of coworkers noted that during a mean follow-up of 47.5
cases.57 Yasargil and Mortara pointed to the extradural inva- months, tumor progression occurred in 16 of 38 (42%)
sion of bone as the primary factor in preventing complete patients who had a subtotal resection of tumor. The
removal of tumor, a feat accomplished in only 35% of authors also reported that during a follow-up period ranging
patients.74 Fierce adherence of the meningioma to the from 6 months to 141 months (mean 47.5 months), 33 of 38
neurovasculature, invasion of the cavernous sinus, and (87%) patients with subtotal resections had a Karnofsky
extradural spread to bone were some of the reasons reported performance score of more than 80. Although postopera-
by Mayberg and Symon for subtotal resection of tumors in tive cranial nerve deficits were observed in 12 of 38 (32%)
1986.111 In a more recent study of 38 petroclival menin- patients, the degree of impairment was mild.105
giomas in 2000, Jung and coworkers noted several reasons
for incomplete resection of tumor: a difficulty in dissecting
the tumor from the brainstem in 13 of 38 (34%) patients,
adhesion of the tumor to cranial nerves in 9 of 38 (24%),
Mortality and Quality of Life
cavernous sinus invasion in 6 of 38 (6%), hypervascularity of Prior to 1970, the cumulative mortality rate in a majority
the tumor in 4 of 38 (11%), encasement of major vessels in of series was greater than 50%.57,111 With the introduction
3 of 38 (8%), and inadequate exposure in 3 of 38 (8%).105 of microsurgical techniques, Yasargil amd Mortara in 1980
 Meningiomas of the Posterior Fossa and Skull Base 817

Figure 47-15. A transcochlear approach to a

CA prepontine petroclival tumor. There is a short
ET distance from the surface of the craniectomy to
the tumor. Minimal cerebellar retraction is
needed and direct access to the tumor is
afforded without intervening cranial nerves after
the facial nerve has been rerouted. CA, carotid
artery; ET, eustachian tube. (Used with
permission from Jackler RK: Atlas of
Neurotology and Skull Base Surgery.
Philadelphia, Mosby, 1996.)

TABLE 47-6. Clival and Petroclival Meningiomas—Review of Series (1977–2000)

Author Year Total Cases Mortality Postop CN Deficit Gross Resection

Hakuba et al.112 1977 6 17% 100%

Yasargil and Mortara74 1980 20 10% 50% 35%
Mayberg and Symon111 1986 35 9% 54% 26%
Al-Mefty et al.78 1988 13 0% 31% 85%
Samii et al.108 1989 24 0% 46% 71%
Nishimura et al.124 1989 24 8% 91%
Sekhar et al.113 1990 41 2% 22% 78%
Spetzler et al.115 1992 18 0% 39% 78%
Bricolo et al.86 1992 33 9% 76% 79%
Samii et al.107 1992 36 0% 75%
Sekhar et al.117 1994 75 0% 60% 60%
Couldwell et al.123 1996 109 4% 33% 69%
Zentner et al.109 1997 19 5% 34% 68%
Jung et al.105 2000 64 1.5% 34% 41%

CN, cranial nerve.

818 SURGICAL NEUROTOLOGY

and Habuka and colleagues in 1977, reported operative University, 16 were noted to be Meckel’s cave menin-
mortality rates of 17% and 15%, respectively.74,112 giomas, also giving an incidence of 1%.129 In 1992, only
Mayberg and Symon in 1986 reported a postoperative 70 cases of Meckel’s cave meningiomas had been reported
mortality rate in 3 of 35 (9%) patients within 6 months of in the literature, with few other reports noted in the
surgery and in 4 of 35 (11%) patients after 6 months of English literature since then.129
surgery.130 The vast majority of recent series on clival and
petroclival meningiomas have reported a mortality rate of
less than 10%.68,86,105,107,113,123,124 In addition, many studies
Origin and Classification
demonstrate a significant number of patients sustaining Meckel’s cave meningiomas originate from the dura
new neurologic deficits after surgical resection of petrocli- mater of Meckel’s cave and compress the trigeminal gan-
val meningiomas. The majority of these deficits involved glion, which lies in the posteromedial portion of the mid-
injury to cranial nerves and affected approximately 35% of dle cranial fossa.126 These tumors may invade the middle
patients.57 or posterior cranial fossa, and may infiltrate into the
In 1977, Hakuba and coworkers reported six cases of cavernous sinus, or surround the internal carotid artery
total removal of petroclival meningiomas. Two patients and the cranial nerves.127 In a retrospective review of 12
were in excellent condition postoperatively, three patients meningiomas of Meckel’s cave in 1975, Nijensohn and
had mild to minimal impairment, and one died.112 In 1980, coworkers divided these tumors into three groups on the
Yasargil and colleagues reported 20 cases of clival and basis of their clinical presentation and prognosis. The first
petroclival meningiomas. Eleven (55%) patients experi- and largest group of patients (group I) experienced typical
enced a good recovery, five had a fair recovery, and two trigeminal neuralgia only; the second group of patients
had a poor functional status postoperatively.74 Mayberg (group II) had a history of atypical trigeminal neuralgia
and Symon assigned patients preoperatively and postoper- without any neurologic deficits, and the third group (group
atively to one of five clinical grades based on physical III) experienced trigeminal symptoms as well as other
examination and functional status. These grades were cranial nerve deficits. The authors noted an excellent
defined as follows: grade I (no deficit), grade II (neurologic prognosis (no tumor recurrence, and resolution of pain)
deficit but able to work or manage household), grade III after complete removal of tumor for patients in group I. In
(unable to work but able to care for self ), grade IV contrast, the authors observed a high incidence of tumor
(requires nursing care), grade V died of disease. Approxi- recurrence due to subtotal removal, and a return of
mately 57% of patients were assigned a worse clinical intractable pain for patients in the group III. Patients in
grade in the immediate postoperative period. The majority the group II had an intermediate rate of tumor recurrence
of these patients, however, showed improvement within a and trigeminal pain.128
month.111 In their series of 24 patients with petroclival In their series in 1992, Delfini and colleagues did not
meningiomas, Samii and colleagues reported that 12 (50%) note a significant difference between patients with typical
patients were able to return to their preoperative level of and atypical neuralgia, with or without other trigeminal
activity, 8 (33%) were independent but were unable to nerve impairment. These authors divided Meckel’s cave
function as they previously had, and 4 (17%) required meningiomas into two instead of three groups. Patients in
nursing assistance.108 group I had a history of typical or atypical trigeminal neu-
ralgia with all physical abnormalities limited to facial
hypoesthesia. These tumors were small meningiomas
MECKEL’S CAVE MENINGIOMAS confined to Meckel’s cave. Group II patients experienced
symptoms of trigeminal dysfunction combined with
impairment of other cranial nerves.129 These were larger
Epidemiology tumors originating from Meckel’s cave and extending
Lesions of Meckel’s cave comprise less than 0.5% of beyond. Delfini and colleagues defined group I patients
all brain tumors.125–128 A wide range of lesions are found not only on their distinct clinical characteristics but also
in this region, including meningiomas, chordomas, lipo- noted that these individuals had small globular menin-
mas, arachnoid cysts, schwannomas, cholesteatomas, giomas measuring less than 3 cm that only involved
malignant melanotic schwannomas, metastatic carcinomas, Meckel’s cave. Patients in group II were afflicted with
sarcomas, melanocytomas, amyloidomas, cylindromas, neu- larger tumors no longer confined to Meckel’s cave.129 In
roepitheliomas, fibrous xanthomas, and cysticercosis.125,129 two separate comments following the report by Delfini
Although several pathologic entities may occupy Meckel’s and colleagues, Sekhar and Sen considered the larger
cave, schwannomas and meningiomas are the most com- meningiomas in group II to be cavernous sinus menin-
mon tumors in this region.126,129 Primary meningiomas of giomas. Sekhar suggested that these tumors may have
Meckel’s cave are rare tumors that comprise approximately originated in the cavernous sinus or petroclival region and
1% of all intracranial meningiomas.127 In their series of subsequently extended to Meckel’s cave. Both authors
295 intracranial meningiomas in 1938, Cushing and agreed that determining the origin is difficult despite
Eisenhardt noted only 5 meningiomas arising from information garnered from MRI. No clinical or radiologic
Meckel’s cave.3 Among 1454 intracranial meningiomas evidence of recurrence was found in any patients in group
studied at the Mayo Clinic from 1914 to 1960, only 14 I, with an average follow-up of 6.1 years. Four of 8 (50%)
were found to be in Meckel’s cave, yielding an incidence patients in group II showed evidence of recurrence with an
of 1%.128 Of the 1511 intracranial meningiomas undergo- average follow-up of 4.5 years. Three of 8 (38%) patients
ing surgery at the Neurosurgical Department of Rome in group II were reported to have tumor progression.129
 Meningiomas of the Posterior Fossa and Skull Base 819

Figure 47-16. Meckel’s cave meningiomas

may (A) reside primarily in the middle
fossa, (B) reside primarily in the posterior
fossa and extend into Meckel’s cave, or
(C) have a significant posterior and middle
fossa component bridged by Meckel’s cave.
(Used with permission from Jackler RK:
Atlas of Neurotology and Skull Base
Surgery. Philadelphia, Mosby, 1996.)

A B C

Samii and coworkers reclassified his series of 21 Meckel’s common symptom of meningiomas located in Meckel’s
cave meningiomas into four groups based on tumor loca- cave is a deficit of the fifth cranial nerve.129 Typical and
tion and extension. Type I meningiomas were confined to atypical trigeminal neuralgia has been noted in approxi-
Meckel’s cave. Types II and III meningiomas originated in mately 65% of all published cases.126,129 In one large study
Meckel’s cave and extended into the middle fossa and pos- on meningiomas of Meckel’s cave in 1992, typical or atyp-
terior fossa, respectively, without any infiltration into the ical trigeminal neuralgia was noted in 10 of 16 (63%)
cavernous sinus. Type IV meningiomas were dumbbell- patients. Cranial nerve impairment was found in 7 of 16
shaped tumors that arose in Meckel’s cave and extended (44%) patients in this series.129 In 1997, Samii and colleagues
into the middle and posterior fossae with or without infil- noted trigeminal nerve impairment as the earliest sign in
tration into the cavernous sinus. The authors excluded 15 of 21 (75%) patients, with hearing loss mentioned as the
meningiomas that had a dural attachment close to Meckel’s next most common symptom. The authors also reported
cave or those that involved it secondarily (Fig. 47-16).127 trigeminal pain and hypesthesia as the main symptoms of
types I and III meningiomas.127
In their series in 1975, Nijensohn and coworkers noted
Clinical Presentation that patients in group I described their facial pain as super-
Meningiomas are more common in women than in men. ficial, intense, brief, and paroxysmal—typical symptoms of
Multiple authors have found this is also true for patients trigeminal neuralgia. This pain was observed to be limited
with Meckel’s cave meningiomas. Of the 12 patients in to some part of the trigeminal nerve distribution. In addi-
their series reported in 1975, Nijensohn and coworkers tion, most of these patients reported trigger points at some
noted that 9 were women and 3 were men, with a mean age time during the course of their disease. Patients in group II
of 56 years and an age range of 35 to 71 years.128 In an reported atypical facial pain that was described as constant,
analysis of 30 cases in 1983, Butti and coworkers also burning, and deeper than that experienced by patients in
found that meningiomas were more common in women group I. Patients in group III experienced atypical facial
(22 cases) than men (8 cases). The author noted an average numbness and pain. These patients also had other cranial
age of 52 years, with a range of 22 to 71 years.126 In a series nerve involvement. One patient had ipsilateral optic atro-
of 16 Meckel’s cave meningiomas, Delfini and colleagues phy and a decreased sense of smell as well as partial CN III
noted a female-to-male ratio of 1.6 to 1. The mean age at and IV palsies. Another patient experienced hearing loss
diagnosis was 41.6 years, with the age range between 22 to with intact labyrinthine function.128
60 years. The mean duration of symptoms was 2.7 years, In 1967, Kerr proposed that the progressive breakdown
with a range of 1 month to 20 years. The authors also of the myelin sheaths due to degenerative changes second-
noted a difference in the mean age between group I and II ary to tumor growth was the probable cause of trigeminal
to be 34.5 years and 57.7 years, respectively. The mean neuralgia.128 In their series, Beck and coworkers noted that
duration of clinical symptoms for group I was 11 months the three patients with facial pain had lesions that extended
and 4.1 years for group II.129 In the series of 21 Meckel’s into the posterior fossa, compressing the root entry zone
cave meningiomas, Samii and coworkers noted a mean of the fifth nerve.125 In contrast, patients with tumors that
patient age of 46.5 years, with an age range of 17 to 72 years. remained confined to the Meckel’s cave had no CN V dys-
The average time of onset of symptoms to diagnosis was function. These findings are in agreement with current
3.3 years.127 Tumors of Meckel’s cave are most often asso- theories on the causes of trigeminal neuralgia.
ciated with dysfunction of the fifth cranial nerve.125 In a
study of 12 patients with lesions of Meckel’s cave, of which Imaging
4 were meningiomas, Beck and Menezes noted that 9 of 12
(75%) patients presented with CN V deficits. Trigeminal CT and MRI are the diagnostic modalities of choice for
neuralgia was noted in only three patients. Two of these lesions involving Meckel’s cave. Precise information on the
patients were found to have histologically proven menin- size, location, and nature of the lesion may be obtained
giomas. Seven of 12 (58%) patients experienced other with the use of CT multiplanar high-resolution imaging.
cranial nerve involvement.125 Not surprisingly, the most CT is particularly useful for detecting bony changes and
820 SURGICAL NEUROTOLOGY

approach combined with the Kawase approach. In addition

to providing good exposure of the tumor and its exten-
sions, this technique reduces retraction of the temporal
lobe, vein of Labbé, and cerebellum. Recently introduced
preoperative techniques, such as balloon occlusion testing,
can help the surgeon assess the collateral circulation in the
event that the ipsilateral carotid artery needs to be occluded
temporarily for resection of the tumor.
In a series of 21 Meckel’s cave meningiomas in 1997,
Samii and coworkers varied their surgical approach based
on the tumor location and extension. For type I (restricted
to Meckel’s cave) and type II (middle fossa extension)
meningiomas, the authors used the pterional transsylvian
approach. Type III (posterior fossa extension) meningiomas
were removed with a suboccipital retrosigmoid approach,
and type IV (middle and posterior fossae extension)
meningiomas were excised with a combined subtemporal-
suboccipital approach.127

Surgical Management
Several factors must be considered prior to the surgical
removal of Meckel’s cave meningiomas. These include
extension of the tumor into the surrounding structures
(especially the CPA and middle fossa), cavernous sinus
infiltration, carotid artery encasement, petrous apex ero-
sion, and cranial nerve impairment.127 In a series of 12
Figure 47-17. T1-weighted gadolinium-enhanced axial MRI scan revealing a Meckel’s cave lesions in 1987, Beck and Menezes noted
meningioma of Meckel’s cave extending toward the posterior aspect of the that although the CN V palsies persisted after surgery,
cavernous sinus.
ocular motor muscle palsies were alleviated. Impairment
of CN V remained in 9 of 12 (75%) patients, despite com-
plete tumor removal in 11 of 12 (92%) patients.125 In 1975,
intratumoral calcification. MRI is useful for identifying Nijensohn and coworkers reported that patients in group I
tumor invasion into cavernous sinus and for accurately had small, friable tumors, which were easily removed and
identifying trigeminal nerve compression (Fig. 47-17). did not recur. These patients also reported complete alle-
Postoperative gadolinium-enhanced MRI images are able viation of their trigeminal neuralgia after surgical resec-
to delineate the extent of tumor resection. Delfini and col- tion of the tumor and a trigeminal sensory rhizotomy.128
leagues also believe that cerebral angiography is necessary In one of the largest series of Meckel’s cave menin-
for detailing the precise anatomic relationship between the giomas, Delfini and colleagues reported a Simpson grade I
tumor and surrounding vascular structures, especially the (macroscopically complete resection of tumor and its dural
carotid artery.129 and bony attachments) removal in 7 of 8 (88%) patients in
group I and a grade II removal in the eighth patient. No
recurrences were reported, and facial pain was alleviated
Surgical Approach in all eight patients. In addition, no new neurologic deficits
Small tumors localized to Meckel’s cave may be were present postoperatively. In contrast, grade I removal
approached with the subtemporal intradural approach. was accomplished in only 1 of 8 (13%) patients in group II.
Delfini and colleagues used this approach in 12 of 16 (75%) A Simpson grade II (macroscopically complete resection of
patients, the majority of whom had small, globular menin- tumor with endothermy coagulation of its dural attach-
giomas measuring less than 3 cm confined to the postero- ment) removal was reported in five patients (63%), and a
medial portion of the middle cranial fossa.129 Compared Simpson grade III (macroscopically complete resection of
with the intradural approach, the extradural approach pro- tumor without coagulation of its extensions) removal was
vides the surgeon with a better exposure and reduces the noted in two patients (25%). One patient died intraopera-
risk of damage to the superficial petrosal nerve damage. tively and another succumbed after recurrence of the
However this approach is inadequate for patients with meningioma. This difference in outcome was reflective of
tumor extension into the cavernous sinus (see Fig. 47-17). the large and extensive tumors present in group II
Delfini and colleagues used a frontotemporal craniotomy patients.129 In the most recent series in 1997, Samii and
followed by a superior or lateral approach to cavernous coworkers reported radical surgical removal in 76% of
sinus for tumors involving the cavernous sinus. Tumors their patients with complete excision of all type I and III
with extension into the posterior cranial fossa can be meningiomas. Subtotal resection (Simpson type III or IV )
approached with a combined subtemporal-suboccipital was noted in the single type II meningioma and 4 of 5 (80%)
approach. Two skull base approaches with excellent expo- type IV meningiomas due to cavernous sinus invasion. Facial
sure include the petrosal approach and the subtemporal pain was alleviated in all patients after surgical removal,
 Meningiomas of the Posterior Fossa and Skull Base 821

but trigeminal hypesthesia was resolved in only 35% of Classification

patients. Immediate postoperative complications included
cranial nerve impairment, hemiparesis, and diplopia.127 Tumors of the jugular foramen may be divided into
Radiotherapy has been used as adjuvant treatment of primary and secondary lesions.133 In a review of 55 lesions
subtotally resected or unresectable meningiomas of of the jugular foramen, Samii and Bini noted that 25
Meckel’s cave. It may also be used in elderly patients with a tumors were located in the jugular foramen and were
poor preoperative functional status and short life expectancy defined as primary tumors, whereas 30 tumors involved
who have large tumors with a high risk of operative and the foramen but did not arise from it and were defined as
postoperative mortality. secondary tumors. Two-thirds of secondary tumors were
meningiomas.130 Primary intrinsic jugular foramen
meningiomas are exceedingly rare lesions that arise from
the arachnoid cells located within the jugular foramen
JUGULAR FORAMEN MENINGIOMAS associated with the jugular bulb and in close association
with the lower cranial nerves (Fig. 47-18).85 These tumors
Introduction are centered on the jugular foramen and may erode into
The jugular foramen is a depression on the medial and the hypotympanum, infralabyrinthine temporal bone,
inferior surface of the petrous bone formed at the interface and middle ear. Larger primary jugular foramen menin-
of the temporal and occipital bones. It measures approxi- giomas often have simultaneous intracranial or extracra-
mately 15 mm × 10 mm. In two-thirds of cases, the right nial extensions.133,134
jugular foramen is larger than the left.130–132 The antero- Secondary extrinsic jugular foramen meningiomas
medial aspect of the foramen is occupied by the inferior are intracranial lesions that can extend to the jugular fora-
petrosal sinus and CN IX, X, and XI. The jugular bulb and men from above or arise inferiorly in the upper neck
internal jugular vein are found in the posterior aspect of (Fig. 47-19).133,135 These lesions are typically large CPA or
the foramen.130,133 Three major tributaries, the inferior petroclival meningiomas. Small tumors, however, posi-
petrosal sinus, the condylar vein, and the sigmoid sinus, tioned in the lower clivus or along the medial and inferior
empty into the jugular bulb.130,133 The sigmoid sinus has portions of the posterior petrous bone may also extend to
a constant drainage pattern into the jugular bulb, whereas the jugular foramen directly or by invading and destroying
the inferior petrosal vein and condylar vein are more vari- the temporal bone. The degree of jugular foramen involve-
able. The jugular bulb is separated from the carotid artery ment may vary from minor tumor invasion to extensive
by a dense fibrous band and a thin plate of bone called extracranial extension into the neck. Jugular foramen
the carotid crest. The three most common tumors in the meningiomas may directly invade the internal jugular vein
jugular foramen include glomus jugulare tumors (paragan- and upper neck and extend through the adjacent occipital
gliomas), schwannomas, and meningiomas. Paragan- bone to the foramen magnum. Meningiomas of the jugu-
gliomas are the most common lesions of the jugular lar foramen can encase individual cranial nerve filaments
foramen followed by schwannomas of CN IX, X, and XI. and spread into the sheaths surrounding the nerves at the
Chondrosarcoma, invasive squamous cell carcinoma, chor- skull base. In contrast, the lower cranial nerves are usually
doma, and metastatic disease from renal or thyroid carci- compressed against the surface of glomus jugulare
noma are rarer lesions of the jugular foramen.130,132–134 tumors.133,135

IAC

Figure 47-18. A sagittal view of a jugular

foramen meningioma with both intracranial
and extracranial extension. IAC, internal
auditory canal; HC, hypoglossal canal.
(Used with permission from Jackler RK:
Atlas of Neurotology and Skull Base
Surgery. Philadelphia, Mosby, 1996.)

HC
822 SURGICAL NEUROTOLOGY

manifestations were present in three of eight (37%)

patients. Molony and coworkers found all their patients
were women between the ages of 19 to 52 years, with a
mean age of 40 years.134
Similar signs and symptoms were reported in two large
series on patients with extracranial meningiomas of the
temporal bone. In one such series in 1983, Reitz and
colleagues reported hearing loss in 83% of patients. An
equal distribution of mixed, conductive, and sensorineural
hearing loss was found among these patients. A middle ear
mass or changes in the tympanic membrane was found in
74% of patients. Tinnitus and otalgia were noted in 42%
of patients. The study also reported facial paresis in 32%
of patients and the presence of other cranial neuropathies
in only 11%.133,136 In a study of 56 patients with extracra-
nial meningiomas of the temporal bone in 1992, Nassif
and coworkers noted that an overwhelming majority of
patients (85%) exhibited otologic complaints. Hearing loss
was found in 54%. Tinnitus, vertigo, and dizziness were
some of the other presenting symptoms.133,137
Figure 47-19. Coronal view of a T1-weighted gadolinium-enhanced MRI scan
revealing extension of a posterior fossa meningioma into the jugular Diagnosis
foramen.
A preoperative histologic diagnosis is usually not obtained
due to the relative inaccessibility of the jugular foramen
region. However, a detailed radiologic study of a suspected
lesion in the jugular foramen is necessary to suggest a diag-
Clinical Presentation nosis, determine the extent of the disease, and formulate a
The clinical signs and symptoms of patients with menin- therapeutic strategy. CT, MRI, and angiography are the
giomas of the jugular foramen vary due to their proximity primary diagnostic modalities for assessing meningiomas
to the lower cranial nerves. Hearing loss, pulsatile tinnitus, of the jugular foramen. The characteristic findings of
hoarseness, and dysphagia have been reported as the most meningiomas on CT, MRI, and angiography have been
common symptoms for these tumors.131,134,136 In a com- previously described. High-resolution CT images with
prehensive chapter on meningiomas of the jugular foramen, bone detail in multiple planes are required to adequately
Thompson and Cass reviewed the clinical manifestations visualize meningiomas of the temporal bone. Mild hyper-
for 19 primary jugular foramen meningiomas reported in ostosis and destruction of bone may be seen well beyond
the literature. Mixed conductive and neurosensory-type the cortex of the jugular foramen, given the propensity of
hearing loss was reported in 15 of 19 (79%) patients. A vis- these meningiomas to spread locally. In contrast, glomus
ible middle ear mass was noted in 11 of 19 (58%) patients. jugulare tumors exhibit far greater bony changes, typically
Tinnitus was noted in 9 of 19 (47%) patients with pulsatile in the form of irregular bony destruction of the jugular
tinnitus present in 5 of 9 (55%). Cranial nerve deficits fossa. When these changes are present on CT, the
(V through XII) were noted in 10 of 19 (53%) patients, surrounding bone is commonly described as looking
with CN IX and X neuropathies reported in 5 of 10 (50%) “moth-eaten.” The difference in the degree of bone
patients each. Six of 19 (32%) patients were reported to destruction may help to differentiate between these two
suffer from multiple cranial neuropathies.133 Patients with tumors. The intense signal enhancement of the jugular bulb
meningiomas of the jugular foramen commonly present on postinfusion images sometimes prevents identification of
with multiple cranial nerve deficits; a combination of CN the jugular foramen meningiomas. However, menin-
IX, X, and XI neuropathies is known as Vernet’s syndrome giomas with significant intratympanic or extracranial
and a combination of neuropathies of CN IX, X, XI, and extension can be easily discovered with enhancement.133
XII is known as Collet-Sicard syndrome.130,131 Headache, MRI remains the preferred imaging modality for detect-
facial pain, visual loss/diplopia, vertigo, and ataxia are ing intracranial and extracranial extension of jugular fora-
additional symptoms noted in patients with jugular fora- men meningiomas. Identifying tumor extension into the
men meningiomas. nose, nasopharynx, paranasal sinuses, middle ear, mastoid,
In contrast, Thompson and Cass noted that secondary parapharyngeal space, infratemporal fossa, and cervical
jugular foramen meningiomas were more likely to present region is important in the preoperative evaluation of the
with a neurosensory hearing loss, a weak voice, and dys- tumor. Angiography with preoperative embolization may
phagia, due to their involvement of multiple cranial nerves. be considered for a highly vascular jugular foramen
In one of the larger series on jugular foramen menin- meningioma. When a meningioma is limited only to the
giomas, Molony and coworkers noted that hearing loss jugular foramen, it may not be easily visible with angiog-
accompanied with a middle ear mass was present in 7 of 8 raphy. Angiography, however, may be useful for differenti-
(88%) patients. Six of eight (75%) patients complained of ating meningiomas from glomus jugulare tumors, which
tinnitus, which was pulsatile in four. Lower cranial nerve demonstrate an intense arterial flow with early venous
 Meningiomas of the Posterior Fossa and Skull Base 823

return.133 Preoperative embolization is used to prevent infratemporal approach to provide a large exposure of the
excessive blood loss for highly vascular lesions.134 tumor.130,133,134,138
Given the presence of otologic symptoms in a major-
ity of patients with jugular foramen meningiomas, Surgical Management
audiometry is often performed to determine the type and
degree of hearing loss. Conductive hearing loss suggests As with the treatment of all meningiomas, complete surgi-
involvement of the ossicular chain or the tympanic mem- cal excision of jugular foramen meningiomas is preferred.
brane, whereas sensorineural hearing loss suggests This is difficult given the propensity of these lesions to
involvement of the otic capsule structures, CN VIII, or infiltrate into the surrounding bone and encase the neuro-
the brainstem. The precise involvement is important vasculature. Wide surgical margins are also required to
when considering hearing preservation surgery. Auditory prevent tumor progression and recurrence. Subtotal resec-
brainstem evoked potentials may also be useful for reveal- tion, however, is often necessary, especially if involvement
ing vestibulocochlear involvement. Vestibular testing is of the local cranial nerves has occurred. Preservation is
usually not performed due to the frequent absence of especially important if only mild cranial nerve dysfunction
vertigo in patients with jugular foramen meningiomas. is present prior to surgery, given the risk of severe mor-
However, vocal cord function, laryngeal and pharyngeal bidity with surgical procedures attempting complete resec-
sensation, and swallowing function should be evaluated tion in this region. Aggressive surgical excision of the
in all patients with a lesion of the jugular foramen.133 tumor may be performed if severe cranial dysfunction is
In a comprehensive review of 34 jugular foramen menin- present preoperatively.134 Elderly patients with increasing
giomas, Lustig and Jackler noted a preoperative dys- symptoms accompanied by evidence of tumor progression
function of the lower cranial nerves in approximately combined with a poor preoperative functional status and a
35% of cases (CN IX 38%, CN X 41%, CN XI 32%, CN short life expectancy may be treated with radiation ther-
XII 35%).135 apy. Stereotactic radiation therapy may also be used for
patients who fail surgical resection of the tumor.
Multiple cranial nerve deficits have been reported
Surgical Approach following the surgical removal of jugular foramen menin-
The surgical approach is primarily determined by the giomas. The tumor location, degree of neurovasculature
tumor location and extent of disease. The approach may
be modified based on the size of the lesion, the likelihood
of total resection, and possibility of cranial nerve preserva-
tion. Jugular foramen meningiomas with a significant
intracranial component must be approached with an
intracranial approach. A suboccipital craniotomy provides an
excellent exposure to the CPA and jugular foramen. Limited
intracranial extension may be addressed with a retrolab-
yrinthine approach. If the patient has a profound sen-
sorineural hearing loss secondary to a sizable intracranial
tumor component, hearing ablation surgery is justified,
and the tumor may be managed with a translabyrinthine
approach. The transcochlear approach can be used for large
anteriorly based meningiomas, which require a wider
exposure.
Meningiomas extending to the foramen magnum may
be approached with a far or extreme lateral approach
necessary for exposure of the tumor as well as adequate
control of the vertebral artery (Figs. 47-20 and 47-21).
Jugular foramen meningiomas extending anteriorly may
be approached with a subtemporal-infratemporal approach
combined with a transjugular approach. This is necessary
to ensure adequate tumor exposure as well as control of the
carotid artery. Meningiomas with an extensive intracranial
component as well as temporal bone invasion may be
approached with a complete petrosectomy and may result
in a greater likelihood of complete tumor removal and a
decreased chance of recurrence.133 An infratemporal fossa
or transpetrosal approach with a transdural extension may
also be used for resection of jugular foramen menin-
giomas. Molony and colleagues used this approach in a
majority of their patients to obtain exposure of the lesion Figure 47-20. The skin incision used for the far lateral approach begins
above the ear, extends inferiorly in the postauricular region before turning to
and its origin in the jugular bulb. The juxtacondylar the midline over the posterior processes of the vertebral bodies. (Used with
approach, which provides an inferior and posterior access permission from Jackler RK: Atlas of Neurotology and Skull Base Surgery.
to the jugular foramen, may be used to complement the Philadelphia, Mosby, 1996.)
824 SURGICAL NEUROTOLOGY

Figure 47-21. A view of the bony exposure JV

of the far lateral approach. The posterior
aspect of the sigmoid sinus defines the
anterior superior border of the suboccipital
craniectomy. Drilling is performed down to
the region of the occipital condyle and in
this example a C1 and C2 laminectomy
have been performed. JV, jugular vein;
VA, vertebral artery. (Used with permission
from Jackler RK: Atlas of Neurotology
and Skull Base Surgery. Philadelphia,
Mosby, 1996.)

VA

encasement, infiltration of the lesion, and extent of resec- venous complex early in their growth. Complete excision
tion influence the morbidity associated with surgical exci- of meningiomas arising in the medial aspect of the jugular
sion. In a review of 25 patients with jugular foramen foramen are associated with a high risk of CN IX, X, and
meningiomas, Thompson and Cass in 1996 reported the XI injury.135 Meningiomas deeply penetrating the dural
following postoperative cranial nerve neuropathies: CN X envelope of the jugular foramen, however, are always asso-
in 14 of 25 (56%) patients, CN IX in 13 of 25 (52%), CN ciated with a high risk of injury to the cranial nerves,
XI in 7 of 25 (28%), CN XII in 7 of 25 (28%), and CN VII regardless of their origin. Sudden injury to CN X may
in 6 of 25 (24%). CSF leaks were reported in 3 of 25 (12%) leave the patient with an incompetent larynx and require
patients, and hemiparesis was noted in 1 patient (4%).133 that the patient undergo a tracheostomy and gastrostomy
The complex relationship between the tumor and the for airway protection and nutrition.
local nerves and vessels in the jugular foramen makes the
surgical resection of tumors in this region particularly
challenging. Within the jugular foramen, tumors may FORAMEN MAGNUM MENINGIOMAS
originate laterally with the jugular vein and bulb, medial to
the inferior petrosal sinus, or centrally along the fibro- Introduction
osseous partition on which the cranial nerves lie. Lustig
and Jackler noted a unique and consistent relationship The foramen magnum lies within the occipital bone.
between the neurovasculature and each of the three most Multiple structures lie in close proximity to this foramen,
common tumors of the jugular foramen, namely, glomus including the caudal medulla, rostral spinal cord, cerebel-
jugulare (paragangliomas), schwannomas, and menin- lar tonsils, inferior vermis, fourth ventricle, and the lower
giomas. Knowledge of the jugular foramen anatomy com- cranial and upper cervical nerves. The spinal cord is
bined with characteristic tumor growth patterns help the attached to the lateral dura by the dentate ligaments, the
surgeon assess the risk of cranial nerve injury and accord- most rostral of which serves as an important landmark in
ingly plan the degree of tumor resection leading to the the surgery of tumors of the foramen magnum. The lateral
best possible functional outcome.135 aspect of this ligament is in close association with the ver-
Meningiomas are much more variable in their relation- tebral artery where it enters the dura with the posterior
ship to the lower cranial nerves and vasculature in the spinal artery and dorsal root of C1. After entering the
jugular foramen than glomus tumors. Meningiomas origi- dura, the vertebral artery gives rise to the posterior infe-
nating in the lateral aspect of the jugular foramen lend rior cerebellar artery (PICA) superior to the foramen mag-
themselves to excellent neural preservation since the num. The vertebral artery continues superiorly to merge
tumor lies between the surgeon and cranial nerves. In with the contralateral vertebral artery to form the basilar
addition these tumors also occlude the jugulosigmoid artery.139,140
 Meningiomas of the Posterior Fossa and Skull Base 825

The lower cranial nerves arise from the anterolateral 1941, Dandy agreed with the classification and felt that it
medulla and spinal cord. These nerves are usually affected was important for planning an operative approach.139 In
by tumors of the foramen magnum since they lie in close 1953, Castellano and Ruggerio proposed their classification
proximity to this region. Cranial nerves IX through XI of posterior fossa meningiomas based on their site of dural
arise as rootlets from the anterior medulla and spinal cord attachment. Given this criterion, only meningiomas aris-
and exit the skull base though the jugular foramen. A con- ing from the foramen magnum were considered foramen
tribution to CN XI passes through the foramen magnum magnum meningiomas, not meningiomas arising else-
from C2.139,140 where that extended through the foramen magnum.72
Recent authors have proposed that all meningiomas pass-
ing through the foramen magnum be classified as foramen
Epidemiology magnum meningiomas.139 Comparing outcomes between
Meningiomas represent the majority of tumors originating series of foramen magnum meningiomas has been diffi-
at the foramen magnum, yet they are exceedingly rare cult, given their scarcity as well as wide variations in their
lesions. In 1953, in a review of Olivecorona’s series of classification.
posterior fossa meningiomas, Castellano and Ruggerio
noted only three foramen magnum meningiomas.72 In Clinical Presentation
1971, Lecuire and Dechaume studied a series of 240 pos-
terior fossa meningiomas, only 20 of which were foramen A wide range of clinical signs and symptoms have been
magnum meningiomas.82 In 1980, Yasargil and Mortara observed for patients with foramen magnum menin-
reported only three foramen magnum meningiomas in a giomas. In 1953, Castellano and Ruggerio stated that “the
large series of posterior fossa meningiomas.74 In a chapter possibility of a meningioma of the foramen magnum
review of multiple series of foramen magnum menin- should always be considered in the presence of a capricious
giomas in 1991, Scott and Rhoton found these tumors to clinical history with long remissions and illogicalness.”72
account for approximately 1.8% of all intracranial menin- In a series of 102 benign extramedullary tumors of the
giomas, 6% to 7% of all posterior fossa meningiomas, and foramen magnum, Meyer and colleagues found that 40%
8% to 9% of all spinal meningiomas.139 A more recent of patients had a normal neurologic exam at initial evalua-
paper by Pirotte and coworkers in 1998 reported that fora- tion.143 The clinical presentation of these tumors has fre-
men magnum meningiomas account for 0.2% of all quently simulated and been diagnosed as cervical
intracranial tumors, 1% of all intracranial meningiomas, spondylosis, multiple sclerosis, demyelinating disease, sev-
and 5% of posterior fossa meningiomas.141 Meningiomas eral degenerative diseases, and even occasionally hyste-
represent approximately 70% of all benign tumors arising ria.140 A high degree of suspicion is required to make the
from the foramen magnum and are the most common diagnosis of a meningioma before the tumor has grown to
tumor entity at this location.140,142 cause significant impingement of the neural axis. In a study
Akin to all other intracranial meningiomas, foramen of 16 benign extramedullary tumors of the foramen mag-
magnum meningiomas are more common in females than num, half of which were meningiomas, Akalan and cowork-
in males. Multiple series have noted a female-to-male ratio ers reported that only five cases were diagnosed within 6
of approximately 2:1 to 3.6:1.140 Although the age at pres- months of their initial symptoms. Patients with symptoms
entation varies from the fourth to the sixth decade, the age that began at least a year before admission had multiple
range ranges from 4 to 88 years.140 Meyer and colleagues incorrect diagnoses prior to their final diagnosis and
reported patients’ ages to range from 12 to 81 years, with appropriate treatment.144
an average of 49 years. The average interval from the first Initially, patients often complain of a deep, aching pain
symptoms to diagnosis was between 2.5 to 4 years in most in the suboccipital and cervical regions. This pain is often
series.143 exacerbated by neck movement, coughing, and straining.
This symptom is thought to result from tumor involve-
ment of the first three cervical nerves, which innervate the
History and Classification dura covering the anterior aspect of the posterior
In 1929, Elsberg and Strauss reported the first successful fossa.139,140 Several sensory and motor deficits develop with
removal of a foramen magnum meningioma in a 36-year-old an increasing growth of the tumor. The deficits often sim-
patient with Brown-Sequard syndrome.140 In 1938, ulate the relapsing-remitting pattern of multiple sclerosis
Cushing and Eisenhardt defined foramen magnum menin- and therefore are very difficult to diagnose. Cold or burn-
giomas as those tumors located on the margin of the fora- ing dysthesias have been described as some of the most
men magnum.3 Castellano and Ruggerio defined them as common sensory changes in patients with foramen mag-
tumors involving the lower third of the clivus.72 Cushing num meningiomas. These dysthesias often progress to
and Eisenhardt divided foramen magnum tumors into two hypesthesias, diminished temperature sensation, and loss
anatomic groups: craniospinal and spinocranial. Cran- of tactile or position sense. Trigeminal sensory loss in an
iospinal meningiomas arise in the basilar groove anterior “onionskin” pattern, hyperesthesia, and trigeminal neural-
or anterolateral to the spinal cord projecting inferiorly gia have also been reported as signs of foramen magnum
to the foramen magnum. Spinocranial meningiomas meningiomas.139
originate posterior or posterolateral to the medulla and Progressive spastic quadriparesis or asymmetrical
projecting superiorly to the cerebellar cistern. The authors pyramidal quadriparesis has been described as a common
made this distinction primarily based on the clinical pres- clinical presentation in patients with foramen magnum
entation and on the difficulty of surgical excision.3,140 In meningiomas. This symptomatology begins with weakness
826 SURGICAL NEUROTOLOGY

and spasticity in the arm, progressing to the ipsilateral leg,

followed by the contralateral leg, and then the arm. This
pattern of quadriparesis is observed with anterolaterally
growing lesions and has been noted to be more severe on
the ipsilateral side. Atrophy and weakness of the stern-
ocleidomastoid and trapezius muscles due to involvement
of the spinal accessory nerve have been noted in 25% to
44% of patients.140 Atrophy of the distal upper extremity
and intrinsic hand muscles has also been noted in these
patients secondary to venous outflow obstruction and sub-
sequent infarction of the spinal cord.140 In cases in which
the tumor has progressed to large dimensions, compres-
sion of the medulla has resulted in development of a spas-
tic or ataxic gait, sphincter disturbances, and respiratory
dysfunction.
Patients with foramen magnum meningiomas also
exhibit slow and athetotic-like movements of their arms,
hands, and particularly fingers when they close their eyes
and hold their arms outstretched. This phenomenon, also
known as “piano-playing fingers” has been reported in as
many as a third of patients with extramedullary foramen A
magnum tumors.145 In conclusion, signs and symptoms of
foramen magnum meningiomas include unilateral neck
pain aggravated by coughing, Lhermitte’s sign in the
absence of multiple sclerosis, CN XI dysfunction, sensory
dyesthesias, progression of motor and sensory deficits, and
atrophy of intrinsic hand muscles.130

Diagnosis
CT and MRI are the primary modalities for diagnosing
foramen magnum meningiomas as well as determining
their size, extent, and neurovascular involvement. Guidetti
and Spallone found the overall diagnostic accuracy of CT
without intrathecal contrast to approach 75%.145 In a
series of 102 benign extramedullary tumors of the foramen
magnum, including meningiomas, Meyer and colleagues
found CT with IV contrast to be diagnostic in 75% and
suggestive in another 20% of these tumors.143 MRI, how-
ever, is widely considered to be the superior noninvasive
B
imaging modality. MRI provides better delineation of the
tumor relationship to the surrounding structures, espe- Figure 47-22. A, Coronal T1-weighted gadolinium-enhanced MRI scan
cially the brainstem, upper spinal cord, and neurovascula- revealing a large foramen magnum meningioma compressing the medulla
and spinal cord. B, Sagittal view.
ture (Fig. 47-22).146,147 MRI also aids in providing a better
definition of the surrounding vasculature as well as exclud-
ing aneurysms of the vertebral artery and its branches. The
absence of bony artifacts on MRI also provide a better
delineation of the tumor.146
Surgical Approach
Angiography is useful for revealing the vascular supply The displacement of the medulla and spinal cord, supe-
to the tumor and defining the position of major vessels rior-inferior extent of the tumor, size of the tumor, and
surrounding or intimately involving the tumor. These size of the dural attachment are all considered in deter-
vessels include the anterior spinal artery, posterior spinal mining the optimal approach for resecting foramen mag-
artery, PICA, and vertebral artery. Preoperative emboliza- num meningiomas. A large number of approaches are
tion may be used to decrease the risk of severe intraop- designed to access the anterior rim of the foramen mag-
erative hemorrhage of highly vascular meningiomas. num by removing functionally less important portions of
Angiography is also helpful in elucidating the venous the skull base.148 Only 20% of these lesions occur posteri-
drainage pattern and the dominance and degree of venous orly or posterolaterally. The most common location of
involvement by the tumor. This is especially important if these tumors is anterolaterally in the foramen magnum.
sacrifice of the sigmoid sinus or jugular vein is considered Anterior routes, such as the transoral and transcervical
necessary intraoperatively.139,140 Angiography may also routes, as well as posterior routes via the suboccipital and
exclude the possibility of an aneurysm in the posterior retrosigmoid approaches have been taken to resect menin-
circulation.139 giomas of the foramen magnum.140
 Meningiomas of the Posterior Fossa and Skull Base 827

Preliminary results for the transcervical and transoral of foramen magnum meningiomas can be resected
approaches were dismal due to injury of the lower cranial with a lateral suboccipital approach with microsurgical
nerves and brainstem during tumor removal, resulting in a techniques.142
poor functional outcome for the patient. Although large
anterior or anterolaterally located tumors that displace the
brainstem may provide enough room for excision of a
Surgical Results
tumor through posterior routes, the outcomes with these Dismal results have been reported for the surgical resec-
approaches have also been disappointing. The far and tion of foramen magnum meningiomas. In several early
extreme lateral approaches were designed through modifi- series multiple lower cranial nerve deficits and brainstem
cations of the posterior approaches to obtain a better expo- injuries were reported for the surgical excision of foramen
sure for anteriorly placed lesions. These approaches have magnum meningiomas. These patients were often left
had better success at visualization of the foramen magnum with severe postoperative deficits, including labile hyper-
and may be combined with a variety of transpetrosal tension, aspiration, and respiratory arrest.139,140 Patients who
approaches (Fig. 47-23).140,149 Some authors have also pro- survived surgery were often left with brainstem and lower
posed the use of a dorsolateral transcondylar approach for cranial nerve deficits that often required a tracheostomy
ventral or ventrolateral meningiomas of the foramen mag- and feeding gastrostomy.
num with little or no additional neurologic impairment or In a chapter review on foramen magnum meningiomas
craniospinal instability.148,150 In a recent paper studying in 1991, George reported an overall mortality rate of 13%
the role of occipital condyle resection in the far lateral for 161 foramen magnum tumors. Approximately 68% of
approach, Nanda and coworkers found that this was not patients had good results, 10% had fair results, and 9%
necessary for the safe and total resection of anterior had poor results.146 In one of the earliest series of 74 fora-
intradural foramen magnum meningiomas.151 men magnum meningiomas in 1941, Love and coworkers
In a recent report on 17 foramen magnum menin- reported 34 perioperative deaths due to complications.152
giomas, Goel and colleagues took a conventional poste- In 1980, Yasargil and Mortara reported an overall mortality
rior suboccipital approach with a midline incision and rate of 13.2% for these meningiomas in a review of 114
extension of the craniectomy laterally toward the side of surgically treated cases. The overall neurologic outcome
the tumor. With a tumor size ranging from 2.1 to 3.8 cm, was described as good in 79 of 114 (69.3%) patients, fair in
and a majority of lesions displacing the brainstem posteri- 9 of 114 (7.9%), and poor in 11 of 114 (9.6%).74 In 1988,
orly, complete tumor resection was achieved in 14 of Guidetti and Spallone also noted an operative mortality
17 (82%) patients and a subtotal resection was performed rate of 11%.139 In a series of 102 benign intradural
in the other 3. No significant postoperative complications extramedullary foramen magnum tumors in 1984, Meyer
occurred in the majority of patients, with an average follow- and colleagues reported an operative mortality rate of 5%
up of 43 months. The authors concluded that a majority and a 5% mortality rate from recurrence within 3 years.

Figure 47-23. A sagittal view of the region

of the foramen magnum. Posterior foramen
magnum tumors are directly accessible
from a posterior approach, whereas anterior
foramen magnum tumors that are intradural
are best accessed through a far lateral
FM approach. A, anterior; C, clivus;
FM, foramen magnum; O, odontoid;
P, posterior. (Used with permission from
C1 Jackler RK: Atlas of Neurotology and Skull
Base Surgery. Philadelphia, Mosby, 1996.)
C

C1
C2

O
828 SURGICAL NEUROTOLOGY

Results were excellent in 75% of patients, mildly impaired the collection and analysis of hearing preservation data
in 12%, and poor in 13%.143 particularly difficult.
In a recent series of 40 foramen magnum meningiomas The Committee on Hearing and Equilibrium guidelines
in 1996, George and coworkers achieved complete of the American Academy of Otolaryngology has estab-
removal (Simpson grade I or II) in 86% of these lesions lished a classification system by which preoperative and
and 94% of intradural tumors. The posterolateral approach postoperative audiometric data can be reported (Table 47-7).
was used in 31 of 40 (78%) patients. Subtotal resection This classification scheme is similar to one proposed by
(Simpson grade III) was accomplished in 11% of cases. Shelton and Hitselberger in 1991. Class A hearing is
Significant intradural extension and bony invasion were defined as socially useful hearing with a PTA (500 Hz and
the primary reasons for an incomplete resection.153 1, 2, and 4 kHz) of less than 30 dB and an SDS of greater
Clinical improvement, defined by the authors as a better than 70%. Class B is described as serviceable hearing with
postoperative than preoperative functional status was a PTA of less than 50 dB and an SDS of greater than 50%.
reported in 90% of patients, with worsening noted in Class C hearing is defined as any measurable hearing loss,
7.5% of patients. Three patients died as a result of surgery, and class D hearing is equivalent to the absence of any
and no recurrences were noted with a mean follow-up of measurable hearing.158 In a series studying the preopera-
4.8 years.153 tive and postoperative auditory function in patients with
In another recent series of 40 craniocervical junction CPA meningiomas, Schaller and coworkers proposed a
meningiomas in 1996, Samii and colleagues reported com- slightly different classification system: Classes I and II
plete removal in 63% and subtotal removal in 30% of correspond exactly to classes A and B of the prior classifi-
patients. The authors noted that an intracranial origin, cation scheme. Class III was more specifically defined as a
infiltrative or en plaque growth, and encasement of the PTA between 51 dB and 90 dB and an SDS between 5%
vertebral artery were independent predictors of incom- and 49%. Class IV was described as a PTA ranging from
plete tumor removal.154 Complications from surgery were 91 dB to 100 dB with an SDS between 1% to 4%. Class V
reported in 30% of patients. Postoperative tracheostomies was defined as a PTA and SDS with no response, corre-
were necessary in four patients, and gastrostomies were sponding to class D. The combination of classes III and IV
required in three. Aspiration secondary to lower cranial hearing corresponds to class C.92
nerve dysfunction was noted in four patients, two of whom Hearing classification schemes have been used by some
died after developing pneumonia, resulting in an overall authors and not by others. Samii and colleagues in 1985,
mortality of 6%.154 Other complications included transient reported measurable hearing in 11 of 15 (73%) patients
worsening of caudal cranial nerve function, facial nerve postoperatively, but they provided no information regard-
palsies, and temporary gait ataxia. Three recurrences were ing the quality of the postoperative hearing.62 In a series of
reported in this series, two of which were noted in patients 12 patients in 1992, Nassif and coworkers reported an
8 years after an incomplete removal of meningiomas. overall hearing preservation in 11 of 12 (92%) patients, with
Although preoperative cranial nerve deficits remained 8 of 12 (67%) patients retaining class A or B hearing.137
postoperatively, sensory changes, dysesthesias, pain, and Approximately 75% of patients in this series preserved their
gait ataxia improved during the first year following preoperative hearing after the surgical excision of a CPA
surgery. The average Karnofsky score also improved from meningioma.137 In 1995, Schaller and colleagues also
63 ± 17 to 73 ± 12 after surgery.154 reported favorable hearing preservation data in their series
of 13 patients. The authors reported total hearing preser-
vation in 9 of 13 (69%) patients, with 100% of patients
HEARING PRESERVATION maintaining a class A or B level of hearing postopera-
tively.92 Like Nassif and colleagues,137 Schaller and col-
Hearing preservation after the surgical removal of a CPA leagues92 also reported a similar percentage (69%) for
meningioma has been reported in multiple series to vary preservation of preoperative hearing. In 1996, in a study of
between 33% and 100%.41,92,137,155–159 The variation in the 16 patients, Grey and coworkers reported a hearing
rate of hearing preservation is due to the unpredictability preservation in 8 of 16 (50%) patients. However, if serv-
of the tumor site in the CPA, the different degrees of audi- iceable hearing or better (class A or B) was present preop-
tory nerve involvement as well as the scarcity of literature eratively, 8 of 11 (73%) patients achieved preservation of
on hearing preservation, and the inadequate reporting of their hearing. Class A hearing, or socially useful hearing,
preoperative and postoperative audiometric data.92,137 In was maintained in 6 of 9 (67%) cases.158 In the most recent
addition, the absence of a universal classification scheme study by Batra and coworkers in 2002, hearing preserva-
and specific inclusion criteria for hearing results has made tion was attained in 10 of 11 (91%) patients, and 9 of

TABLE 47-7. Hearing Classification of the American Academy of Otolaryngology

Hearing Class Description Pure Tone Average (PTA) Speech Discrimination Score (SDS)

Class A Good PTA ≤ 30 dB SDS ≥ 70%

Class B Serviceable PTA ≤ 50 dB SDS ≥ 50%
Class C Measurable Any measurable hearing loss
Class D “Dead ear” Absence of any measurable hearing

PTA, average of 500 Hz and 1, 2, 4 kHz.

 Meningiomas of the Posterior Fossa and Skull Base 829

TABLE 47-8. Hearing Preservation for CPA Meningiomas—Series (1982–2002)

Preoperative Hearing Postoperative Hearing Hearing Preservation
Author Year Total Class A + B Total Class A + B Total Class A + B

Laird et al.41 1982 18 6 33%

Nedzelski and Tator155 1984 3 3 100%
Samii et al.62 1985 15 11 73%
Nassif et al.137 1992 12 12 11 8 92% 67%
Cohen et al.156 1993 8 3 38%
Prasad et al.157 1993 3 2 1 1 33% 50%
Schaller et al.92 1995 13 8 9 8 69% 100%
Grey et al.150 1996 16 11 8 8 50% 73%
Batra et al.159 2002 11 10 10 9 91% 90%

10 (90%) achieved a class A hearing status after surgery a wide exposure for the removal of posteriorly but not
(Table 47-8).159 None of the patients in these studies expe- anteriorly based meningiomas. The middle fossa approach
rienced an improvement in hearing after surgery except allows for resection of tumors in the IAC as well as the
those in Schaller and colleagues’s study, who reported an middle cranial fossa. Anteriorly located lesions as well as
improvement in 2 of 13 (15%) patients.92 meningiomas with a significant component in the CPA can
The ability to preserve hearing is based on multiple fac- be resected with an extended middle fossa approach. Grey
tors: the level of preoperative hearing, quality of hearing and coworkers reported that 6 of the 16 patients required
in the contralateral ear, location of the tumor, extent of additional exposure with the retrolabyrinthine and middle
cochleovestibular nerve involvement, size of the tumor, cranial fossa approaches. Although this indicated the
age, and general health of the patient.158,160 Hearing increased size of the tumors and the difficulty encountered
preservation surgery is usually performed via the suboc- in their removal, four of the six patients (66%) retained
cipital/retrosigmoid, petrosal, middle fossa, extended mid- their preoperative hearing. The authors suggest that addi-
dle fossa approach, or the petrosal approach (Figs. 47-24, tional bony removal did not result in a significant loss of
47-25, and 47-26).155 The retrosigmoid approach provides auditory function.158 Maurer and Okawara recommended
a suboccipital/retrosigmoid craniotomy to maximize the
possibility of hearing preservation.59 Maniglia and cowork-
ers also suggested the use of the suboccipital approach if
patients with a preoperative hearing loss were to have a
chance of hearing preservation or full restoration.60
Hearing ablative surgery, on the other hand, is performed
through the translabyrinthine and transcochlear approaches
in patients with nonserviceable hearing.
The location of a meningioma has been shown to be the
most important determinant in the preservation of hear-
ing. A comparison between retromeatal (posterior to the
IAC) and premeatal (anterior to the IAC) meningiomas in
several studies showed that the prognosis for hearing
preservation is markedly worse when the tumor rests
medial to the porus acousticus.57,158 Schaller and colleagues
noted a difference in the clinical presentation as well as
surgical approach, operative resection, and morbidity and
mortality of premeatal versus retromeatal menin-
giomas.92,161 The authors reported a preservation of class I
(class A) hearing in four of six (66%) patients with
retromeatal meningiomas. In contrast, all the patients with
Figure 47-24. Surgeon’s view of the floor of the middle cranial fossa. The premeatal tumors had a class IV or V hearing preopera-
temporal lobe dura has been retracted, and the superior petrosal sinus can tively.92 The authors considered these patients as having
be seen medially. The triangle region over the internal auditory canal nonserviceable hearing preoperatively and therefore
designates a safe region of drilling where the superior semicircular canal excluded them from being considered for hearing preserva-
posteriorly and the basal turn of the cochlea anteriorly would not be entered.
The wide anterior posterior identification of the internal auditory canal can be
tion surgery. In the series by Batra and coworkers, hearing
performed medially at the level of the porus acousticus. Drilling should be preservation surgery was attempted in 10 patients with
performed directly over the internal auditory canal when progressing retromeatal tumors. Class A hearing was preserved in eight
medially to laterally to avoid entering the otic capsule structures. Also note a of nine (90%) patients, with one patient relegated to class B
quadrangular region anteriorly known as Kawase’s quadrangle of the petrous hearing. Another patient with a class B hearing achieved a
apex. Drilling in this quadrangle allows for the exposure of the ventral portion
of the cerebellopontine angle and posterior fossa. (Used with permission class C hearing status postoperatively. Ten of the 11 patients
from Jackler RK: Atlas of Neurotology and Skull Base Surgery. Philadelphia, with premeatal tumors did not have serviceable hearing pre-
Mosby, 1996.) operatively, and therefore hearing preservation surgery was
830 SURGICAL NEUROTOLOGY

Figure 47-25. The surgeon’s view of a

transtentorial combined middle and posterior VL
fossa anterosigmoid petrosal approach. The
vestibular apparatus has been kept intact. The
superior petrosal sinus has been divided,
exposing a combined view of the
cerebellopontine angle and the middle
cranial fossa floor. The inferior aspect of the
dissection is the region of the jugular bulb.
The trochlear nerve and trigeminal nerve are
well visualized superiorly. The brainstem can
be accessed over a large area. (Used with
permission from Jackler RK: Atlas of
Neurotology and Skull Base Surgery.
Philadelphia, Mosby, 1996.)

VL

not attempted in these individuals. Only one patient with a

premeatal tumor with class A hearing retained a similar level
of auditory function postoperatively.159
The explanation offered for the difference in the hear-
ing preservation between premeatal and retromeatal
meningiomas is the hindrance of the CN VII–VIII com-
plex in the line of dissection. Given this intimate relation-
ship, stretch or inadvertent damage to these nerves may
occur even in the hands of the most experienced surgeons
as the premeatal meningiomas displace the facial-cochlear
nerve complex posteriorly.92,161 Grey and coworkers also
agreed that stretching of nerves during dissection of the
tumor could lead to worse hearing preservation for tumors
anteromedial to the IAM.158 In contrast, retromeatal tumors
are typically separated from the nerves by an arachnoid
layer and therefore are less likely to invade or compress the
neurovascular structures of the IAC (Fig. 47-27). Since a
good tissue plane can usually be found between
retromeatal tumors and the CN VII–VIII nerve bundle,
and since the tumor is not obstructed by these cranial
nerves, a favorable outcome is expected.57,92
Multiple studies have shown that the size of a CPA
meningioma does not appear to affect the preservation of
hearing after surgical removal.92,158,159 In a study of 16
patients, Grey and coworkers reported that although two of
three patients (66%) with meningiomas less than 2.5 cm
retained their preoperative hearing classification, only 6 of
13 patients (46%) with meningiomas greater than 2.5 cm
Figure 47-26. The petrosal approach may be further enlarged by resecting did the same. Although this may seem like a noteworthy dif-
the bone of the middle fossa floor primarily in Kawase’s quadrangle. This is ference, the authors did not find this result to be statistically
still a hearing conservation approach as the cochlea, labyrinthine apparatus,
and the internal auditory canal are kept intact. (Used with permission from
significant (p = 0.54, Mann-Whitney U test).158 Schaller and
Jackler RK: Atlas of Neurotology and Skull Base Surgery. Philadelphia, colleagues also did not find an association between tumor
Mosby, 1996.) size and preservation of preoperative hearing. In their study
 Meningiomas of the Posterior Fossa and Skull Base 831

phenomenon when total hearing loss may be caused by a

small nidus of tumor resulting in vascular compro-
mise.92,158 Batra and coworkers reported six of eight (75%)
patients with purely extracanalicular tumors to have class
A hearing postoperatively. In the same series, three
patients had intracanalicular tumors, but all of them
retained their class A hearing postoperatively.159
Dramatic improvements in patients with poor preoper-
ative hearing have been reported after removal of CPA
meningiomas.59,60,92,155,160,162,163 In 1950, Baker and
Christoferson reported the first case of a 44-year-old female
who experienced a return to normal hearing after removal
of a CPA meningioma despite a completely dysfunctional
acoustic nerve for more than 2 years.164 Maurer and Okawara
recently reported the case of a 32-year-old female who pre-
sented with a 1-year history of deafness in her right ear.
Audiometry demonstrated a profound retrocochlear hearing
loss, and CT showed a 3.2-cm enhancing lesion of the
right CPA. The authors used a suboccipital approach to
remove the lesion, which was confirmed to be a menin-
gioma on histopathology. By the seventh postoperative
day, the patient was routinely using her right ear for tele-
phone conversations. Audiometry revealed a normal hear-
ing threshold with an SDS of 100%.59 Similar case reports
have been found in the literature. Goebel and Vollmer
reported yet another case of hearing improvement of 10 dB
in speech reception threshold (SRT) and a remarkable
return of SDS from 0% to 86%.160 Nedzelski and Tator
Figure 47-27. Axial T1-weighted gadolinium-enhanced MRI scan revealing a reported similar preoperative and postoperative hearing
large posterior petrous face meningioma, which is posterior to the cranial results for all three of their patients with CPA menin-
nerves. Despite the size of this tumor, it is easily accessible since arachnoid giomas. In particular, they described a dramatic hearing
planes separate the anterior portion of the tumor from the left-sided posterior improvement in one patient 6 months after surgery.155
fossa cranial nerves.
Magnilia also reported preservation or improvement in
hearing in 3 of 14 (21%) patients who had experienced
some preoperative hearing loss.60 Schaller and his col-
of 13 patients, all 3 patients with meningiomas less than 2 leagues, who recommended not pursuing a hearing preser-
cm and the 1 patient with a tumor between 2 cm and 3 cm vation approach for patients with less than a class A
retained their preoperative hearing classification. In con- hearing status, themselves reported an improvement in
trast, only six of nine patients (66%) with meningiomas postoperative hearing in two (15%) of their patients with a
larger than 3 cm maintained their preoperative hearing sta- poor preoperative hearing status.92 Goebel and Vollmer
tus.92 However, this difference also did not achieve statisti- mention that even when patients have poor preoperative
cal significance. Multiple authors including Nassif and auditory function, a hearing preservation approach should
coworkers have not found any relationship between hearing be attempted.160 Maurer and Okawara go so far as to rule
preservation and the size of the a CPA meningioma.137 out the use of a translabyrinthine approach given the
Several investigators have also studied the effect of possibility of hearing preservation.59 In a study of CPA
tumor extension into the IAC and hearing status. Grey and meningiomas in 2000, Voss and coworkers suggested that
coworkers discovered that the likelihood of having class D a retromeatal meningioma, with minimal IAC involve-
hearing preoperatively was directly related to the presence ment, and absence of inner ear invasion on temporal bone
of tumor in the IAC. If tumor involvement was present in CT scans should prompt hearing preservation surgery despite
the IAC, the chance of profound hearing loss was 45% a poor preoperative hearing status.79 Although several authors
versus 5% if no involvement was present.158 The authors agree in part with this assessment, Batra and coworkers
noted that the preoperative hearing class was maintained correctly point out that more data are required before
in 2 of 3 (66%) cases when the meningioma occupied the hearing conservation surgery can be recommended for all
IAC, 1 of 3 cases when the tumor entered the porus patients regardless of their preoperative hearing loss.159
acousticus, and 5 of 10 cases when the tumor did not enter Two theories have been offered for the cause of vestibu-
the IAC. In agreement with the data presented by Grey locochlear dysfunction even in the presence of an anatom-
and coworkers, Schaller and colleagues also demonstrated ically preserved CN VIII. Vascular compromise of the
that extensive tumor infiltration in the IAC is associated labyrinth or the nerves themselves is believed to be the
with class D hearing.92 Furthermore, they found that the most likely cause of auditory and vestibular dysfunction.158
amount of tumor in the IAC does not necessarily correlate Intraoperatively, the vascular compromise is thought to
with the presence of hearing. The authors proposed that result from a spasm of the labyrinthine arteries induced
tumor involvement of the IAC may be an “all or none” by mechanical irritation of the neurovascular bundle or
832 SURGICAL NEUROTOLOGY

coagulation of the labyrinthine vessels in the event of a A comprehensive clinical examination including the assess-
persistently bleeding tumor.92 Belal and coworkers pre- ment of cerebellar ataxia, dysdiadochokinesis, Romberg’s
sented evidence that postoperative hearing loss was due to test, walking along a line with eyes open (WALEO), and
compromise in vascular supply. Stretching and trauma to walking along a line with eyes closed (WALEC) were con-
the nerve have also been postulated to play a lesser role in ducted to assess the cerebellar and vestibular function of
the loss of function.158 The use of evoked otoacoustic emis- each patient. Improvement was noted for patients with all
sions may help to differentiate between the above-men- tests except the WALEC, signifying the importance of the
tioned causes of CN VIII dysfunction since emission loss visual system compensation in patients with vestibular dys-
is encountered only with disruption of vascular supply to function.158
the cochlea and not retrocochlear nerve damage. Grey and Given the possibility of hearing preservation for menin-
coworkers reported that only one of their patients with giomas and the poorer relative hearing results associated
class D hearing had evoked emissions preoperatively, and with vestibular schwannomas, it is imperative to obtain an
so attributed the profound hearing loss to vascular com- accurate preoperative diagnosis of any CPA lesion.92 The
promise in the rest of their patients.158 availability of modern imaging techniques has not only
Recent reports have shown the preservation of hearing assisted in making the diagnosis of a CPA meningioma but
even after surgical removal of a large meningioma suspected also identifying the precise location of the tumor. The
to have caused significant vascular compromise to the preoperative identification of a meningioma may alter the
labyrinth. A hypothesis for the remarkable postoperative surgical strategy since the factors influencing the risk of
hearing in some patients was recently suggested by damage to the CN VII–VIII nerve complex are different
Buchheit. The blood supply to the cochlea is usually from those for vestibular schwannomas.92 The position of
derived from the internal auditory artery, a branch of the the meningioma also helps to plan the surgical approach as
basilar artery. Buchheit believes that some collateral circu- well as set realistic expectations for hearing and vestibular
lation to the cochlea is provided by the stylomastoid artery, nerve preservation. Although imaging techniques are still
a branch of the posterior auricular artery. This is not, how- in their infancy, the knowledge collected in these studies
ever, a universally held belief. Thus, even in cases of severe serves as encouragement for surgeons to plan and expect
damage to the internal auditory artery, blood flow would to preserve the CN VII–VIII nerve complex.158
be maintained by the collateral circulation, thereby result-
ing in hearing preservation. The author lends additional
weight to this hypothesis by pointing out the infrequency FACIAL NERVE PRESERVATION
of hearing preservation in difficult cases even with the
most experienced surgeons.59 Satisfactory preservation of the facial nerve has been noted
Although current opinion given case studies of dramatic in most series in the literature. Facial nerve preservation
hearing improvement suggests that hearing preservation defined as an absent to moderate postoperative impair-
surgery should be attempted even in patients with poor ment after removal of a CPA meningioma was recently
preoperative hearing, some authors suggest a hearing abla- noted in two large series to be 69% and 94%.92,159 Similar
tive approach such as the translabyrinthine or transcochlear to the results available for hearing preservation, minimal
approach if the lateral two-thirds of the IAC or vestibule preoperative and postoperative data exist for facial nerve
are extensively involved or if massive IAC involvement or function in the literature. The location, and the size of the
encasement by the tumor of the vestibulocochlear complex meningioma play a role in the postoperative function of
occurs.160 However, a good level of preoperative hearing facial nerve. The degree of tumor involvement in the
and questionable status of the contralateral ear may also region of the IAC may also affect facial nerve preservation.
prompt the surgeon to attempt hearing preservation sur- In contrast to the data accumulated for hearing preserva-
gery at the expense of reduced exposure and increased oper- tion, however, surgeons have, of late, consistently used the
ative time.160 Grey and coworkers disagreed with Schaller facial nerve grading system introduced by House and
that hearing preservation surgery should be reserved for Brackmann to quantify postoperative CN VII function.165
patients with class A hearing only. These authors felt that In a recent study, the facial nerve was anatomically pre-
class B hearing is still serviceable, whereas Schaller and served in 11 of 13 (85%) patients. Schaller and colleagues
colleagues believe that preservation of a classes B or C reported an HB grade I preservation in 6 of 10 (60%)
hearing is of little functional importance.92,158 patients. The other four patients who had no preoperative
The preservation or recovery of clinical vestibular deficits were noted to have a postoperative CN VII dys-
function after surgical removal of CPA meningiomas was function of HB grade II, 20%, HB grade III/IV, 10%, and
reported by Prasad and colleagues in 1993.157 All three HB grade VI, 10%. All three patients with a preoperative
patients in the study experienced an improvement in functional weakness (HB grade II–VI) had a total facial
clinical vestibular function after surgery, despite an absent nerve deficit (HB grade VI) immediately after surgery.92 A
or minimal caloric function. The vestibular results reported similar percentage of normal facial nerve function was
by Grey and coworkers158 also suggested improvement recorded by Batra and coworkers, who reported an HB
following surgical resection. Eight of 13 patients com- grade I preservation in 11 of 17 (65%) patients in their
plained of imbalance preoperatively, whereas only 1 of series of 21 patients, 17 of whom had facial nerve preser-
16 experienced unsteadiness postoperatively. However, vation data available. Two of 17 (11.5%) patients each
six patients were found to be unsteady postoperatively retained an HB grade II and III, respectively, and 1 of 17
when the vestibular system was stressed with tests that (6%) patients each maintained an HB grade IV and VI,
required the patient to walk in the dark or turn rapidly. respectively. Overall, 13 of 17, 76%, of patients maintained
 Meningiomas of the Posterior Fossa and Skull Base 833

an HB grade I or II postoperatively. The facial nerve for grade III in two patients, HB grade IV in one patient, and
the patient with a postoperative HB grade VI had to be HB grade VI in the final patient.159
transected due to encasement of the nerve in tumor. One The causes for the dismal rate of facial nerve preserva-
patient with a preoperative HB grade of VI improved to an tion in meningiomas located anteromedial to the IAM are
HB grade IV after tumor removal (Table 47-9).159 Given similar to those reported for poor hearing preservation for
these reasonable results, the facial nerve dissection should these tumors after surgery. The intimate relationship
be attempted in every CPA meningioma case. between premeatal tumors and the neurovascular bundle
Size does not appear to have a significant effect on as well as the presence of the CN VII–VIII complex
the postoperative CN VII function. Schaller and col- between the surgeon and the tumor are the primary rea-
leagues noted a preoperative and postoperative total facial sons for the poor facial nerve preservation during dissec-
nerve paralysis (HB grade VI) in patients with large tion of a premeatal meningioma.57,158 Preoperative facial
tumors. One of three (33%) patients with meningiomas nerve paresis has also been noted as a risk factor for post-
less than 2 cm had a worsening of facial nerve function operative CN VII dysfunction. Schaller and colleagues
compared with none of the patients with tumors between reported that all three patients with preoperative facial
2 and 3 cm and three of nine (33%) patients with tumors nerve weakness ended up with HB grade VI postopera-
greater than 3 cm. The facial nerve was transected in 2 of tively.92 Batra and colleagues described one patient with
11 (15%) patients with large meningiomas, leading the HB grade III before surgery declining to HB grade VI
author to conclude that the risk of poor facial nerve func- after tumor removal. However, the authors also noted the
tion increased in large tumors due to a difficult intraoper- improvement of CN VII function from HB grade VI to
ative dissection.92 Batra and coworkers also noted that grade IV.159
size did not statistically influence the postoperative facial
nerve function. Two of five (40%) patients with tumor
sizes less than 2 cm, 7 of 10 (70%) patients with tumor RECURRENCE
sizes between 2 and 4 cm, and one of two patients (50%)
had normal CN VII function postoperatively. Based on the Although surgical excision is the definitive therapy for the
data, tumor size was not found to statistically affect the treatment of meningiomas, recurrence and progression of
postoperative facial nerve function using the Fischer exact disease have plagued surgeons for decades, despite the
test ( p = 0.52).159 seemingly complete removal of these tumors.166 Multiple
Akin to hearing preservation, continuity of CN VII has factors influencing recurrence have been recognized ever
been reported to vary based on the site of a meningioma. since Cushing began operating on patients for the surgical
Facial nerve dysfunction was noted to be higher in tumors resection of meningiomas.167 In his series of 295 patients,
located anterior to the IAM, thereby displacing the nerve 43 required reoperation for “actual or symptomatic” recur-
posteriorly, partially obstructing tumor resection primarily rence. In addition, 76 patients died due to an incomplete
due to a difficult intraoperative dissection of nerve. Schaller removal of the meningioma. Although Cushing did not
and colleagues reported a grade I through IV preservation report a recurrence rate, an analysis of his data by Simpson
of the facial nerve in all eight meningiomas located poste- suggests that it was more than 15%. In 1957, Simpson
rior to the IAM. However, only one of five (20%) patients reemphasized the role of the extent of resection, location,
with premeatal meningiomas retained grade I through IV and histology of the tumor in influencing the recurrence
facial function.92 The authors reported a preservation of of meningiomas.168 Since then, several authors have
HB grade I in six of eight (75%) patients with retromeatal attempted to elucidate the factors hastening tumor recur-
meningiomas. In contrast, a HB grade I was not seen in rence in order to initiate close follow-up and early postop-
either of the two patients (0%) with premeatal tumors.92 erative treatment (e.g., radiotherapy) in patients with an
Batra and coworkers also reported a statistically significant increased risk of tumor growth and progression.166
difference ( p = 0.025) in the preservation of postoperative Few papers in the literature have addressed the incidence
facial nerve function and retromeatal tumors. All 10 of 10 and causes of recurrence extensively. One of the reasons is
patients (100%) with retromeatal tumors treated with a that meningiomas are benign tumors that grow slowly and
retrosigmoid approach retained their HB grade I facial therefore lend themselves to retrospective study. In addi-
function. In contrast only one of seven patients (14%) with tion, several early papers oversimplified the statistical
premeatal tumors maintained HB grade I facial function analysis required for calculating the recurrence rate. In
postoperatively. The CN VII function in the rest of their many cases recurrence was calculated as a proportion of all
patients was as follows: HB grade II in two patients, HB patients treated without considering the follow-up period,
resulting in a gross underestimation of the true recurrence
rate.169 Recent papers employ a statistical method used to
TABLE 47-9. Facial Nerve Results for CPA Meningiomas— correct for the differences in the follow-up period known
Five Series; 35 Cases as life-table analysis.166,169 However, this method cannot
correct for the quality of postoperative follow-up, which
Preoperative Postoperative varies tremendously among studies. In many studies,
patients are not followed until clinical recurrence has
HB Grade I–II 30 23
HB Grade III–IV 1 6
occurred. Also, the rate of late recurrence for menin-
HB Grade V–VI 4 6 giomas is unknown because few patients are followed for
periods of 15 to 20 years.169 Furthermore, the methods
Data taken from references 59, 61, 112, 178, and 182. used for detecting recurrence have varied; in early series
834 SURGICAL NEUROTOLOGY

recurrence was defined by a return of clinical symptoms, TABLE 47-10. Simpson’s Grading Scheme for Extent
whereas in others recurrence was measured with modern of Tumor Resection
imaging techniques. Finally, subjective data such as the Simpson’s Grade Degree of Removal
functional status of a patient is rarely used as a criterion to
measure recurrence after surgery; consideration of only Grade I Macroscopically complete removal of the tumor
objective data such as radiologic evidence or the need for with excision of its dural and bony attachments
a second operation for assessing recurrence result in an Grade II Macroscopically complete removal of the tumor
underestimation of the survival and recurrence rates.166 and its extensions with endothermy coagulation
of its dural attachments
In 1957, Simpson defined recurrence as the reappearance of Grade III Macroscopically complete resection of tumor without
symptoms due to tumor growth after a period of sympto- removal or coagulation of its extradural extensions
matic relief.168 In 1983, Adegbite and coworkers introduced Grade IV Partial removal leaving intradural tumor in situ
the term progression, which implied a “continuance in Grade V Simple decompression of the tumor
growth” subsequent to incomplete tumor removal.167 With
From Simpson D: The recurrence of intracranial meningiomas after surgical treatment.
the advent of modern imaging techniques, the definition of J Neurol Neurosurg Psychiatry 20:20–39, 1957.
recurrence was modified. Mirimanoff and colleagues in 1975
considered patients to have a recurrence if after a period of
time, radiologic studies detected the presence of tumor removal of tumor experienced recurrence in this study.170
despite complete excision.166 These authors defined the pro- Simpson noted recurrence rates of 9%, 19%, 29%, and
gression as an increase in tumor size after subtotal removal, 40% at 10 years for patients with a grades I, II, III, and IV
confirmed with imaging studies. Using this definition of resection, respectively.168 In a more recent series using life-
recurrence, Melamed and coworkers calculated an overall table analysis, Mirimanoff and colleagues noted a 5-, 10-,
recurrence rate of 29% in a series of 126 patients in 1979. and 15-year recurrence-free survival rate of 93%, 80%,
This figure was calculated without life-table analysis.170 In and 68%, respectively, following complete tumor removal.
contrast, in 1986 Jaaskelanian estimated the overall recur- In contrast, after a subtotal excision for the same period,
rence rate to be 19% at 20 years using life-table analysis in a the authors reported a progression-free survival rate of
series of 657 patients.169 In a study of 225 patients in 1985, 63%, 45%, and 9%, respectively. This difference was
Mirimanoff and colleagues reported an absolute 5-, 10-, and highly statistically significant ( p < 0.0001) when assessed
15-year survival probability of 83%, 77%, and 69%, respec- with the Mantel-Haenszel test. In addition, patients with
tively.166 In 1983, Adegbite and coworkers noted similar subtotally excised meningiomas had a high likelihood of a
recurrence-free rates of 80% at 5 years, 70% at 10 years, second operation at 5, 10, and 15 years (25%, 44%, 84%)
and less than 50% at 20 years in their report on 114 when compared with 6%, 15%, and 20% for patients with
patients.167 In the most recent study of 286 patients with completely resected meningiomas.166
intracranial meningiomas in 1999, Ayerbe and coworkers Adegbite and coworkers also noted the grade of the ini-
reported recurrence rates of 14%, 37%, and 61% at 5, 10, tial surgery to have a statistically significant influence on
and 15 years, respectively. All these patients were followed recurrence. In their series, the percentage of patients free
with either CT or MRI from 3 to 17 years since the initial of recurrence 5 years after a grade I, II, III, and IV surgi-
surgery.171 cal excision were 86%, 82%, 100%, and 48%, respectively.
A classification scheme for measuring the degree of sur- The number of patients with a grade III removal were too
gical excision was proposed by Simpson in 1957. The author few for an accurate statistical analysis. Nevertheless, the
introduced five distinct grades of surgical resection: Grade I trend suggested that a higher degree of tumor removal was
is defined as a macroscopically complete excision of tumor associated with a lesser likelihood of recurrence. The dif-
including its dural attachments and abnormal bone. This ference in results between patients with a grade I and II
includes removal of the sinus wall if infiltrated with tumor. surgical removal versus those with a grade IV excision was
A grade II resection is described as resection of the tumor statistically significant.167 In an analysis of 53 patients,
and its extensions with coagulation of its dural attach- Marks and coworkers found a recurrence rate of 9.5%
ments. Grade III is defined as a resection of the intradural after complete resection of tumor versus a rate of 18.4%
tumor without removal or coagulation of its dural attach- after subtotal removal.172 In a study of 257 patients, simi-
ments. A grade IV resection is described as an incomplete lar results were noted by Chan and Thompson in 1984,
tumor removal, and a grade V excision is a simple decom- who reported a frequency of tumor recurrence after a
pression with or without a biopsy (Table 47-10).168 grade I, II, III, IV, and V removal to be 11%, 22%, 50%,
The extent of surgical resection has been reported to 37%, and 100%, respectively. A difference of 3.3 years was
play a major role in the recurrence rate of meningiomas. found in the average survival time between patients with
Multiple studies in the literature have noted a higher inci- complete removal versus those with partial removal of the
dence of recurrence/progression with an incomplete or tumor.173 Given these data, a surgeon must balance the
partial resection. In an early series of 126 patients, extent of resection with the likelihood of recurrence and
Melamed and coworkers noted that two-thirds of patients postoperative functional status of the patient.
with a radical excision of the tumor remained recurrence- The likelihood of recurrence or progression of a menin-
free. The authors defined radical excision as either the gioma has also been reported to vary based on the location
complete removal of the tumor with resection of the of the tumor. Parasagittal meningiomas were noted by
meninges and invaded bone or total tumor removal with Simpson and Melamed and coworkers to have a high rate
or without cauterization of the meninges. In contrast, of recurrence.168,170 Melamed and coworkers suggested
nearly one-half (44%) of patients with an incomplete that this was most likely due to invasion of the superior
 Meningiomas of the Posterior Fossa and Skull Base 835

sagittal sinus wall.170 Waga and colleagues, on the other survival, however, remains the preoperative clinical condi-
hand, found meningiomas of the convexity to be associated tion of the patient.
with the highest rates of recurrence.167 However, the In a study of 124 intracranial meningiomas in 1989,
authors noted that when malignant tumors were excluded, Kajiwara and colleagues reported an association between
meningiomas of the falx were found to recur most often.167 meningioma recurrence and the age of the patient, with
Contradicting these findings, Mirimanoff and colleagues the majority of recurrences found in patients younger than
reported low recurrence and progression rates at 5 and age 60 years. A particularly high recurrence rate was found
10 years for meningiomas of the convexity (3% and 25%) in individuals younger than age 40. In addition, the mean
and parasagittal area (18% and 24%).166 In an analysis of age of patients with recurrent tumors was younger than
risk factors for recurrence, Ayerbe and coworkers found that for patients with no recurrences.174 In contrast, several
tumors at the petroclival and parasaggital locations to cor- other studies do not report an association between a
relate with a high degree of recurrence.171 patient’s age or gender with an increased rate of recurrence
Posterior fossa meningiomas were reported to have a and progression. In the 34 cases of recurrence, Melamed
high risk of recurrence by Melamed and coworkers in and coworkers in 1979 reported a male-to-female ratio of
1979. These tumors showed a recurrence of 54.5% in one 3:2, equal to that found in the entire group of 126
of the earliest series studying the recurrence of intracranial patients.170 In 1985, Mirimanoff and colleagues found no
meningiomas. The authors attributed this high rate of association between recurrences or progression of the
recurrence to the incomplete removal of these tumors due tumor with such factors as the age, gender, or duration of
to their close proximity to critical neurovascular struc- symptoms. The recurrence or progression-free survival
tures.170 In the series by Mirimanoff and colleagues in 1985, rates at 5 and 10 years for females (83% and 68%) and
complete excision was noted in only 10 of 31 (32%) poste- males (84% and 66%) were nearly identical. There was
rior fossa meningiomas, with a subtotal resection in the also no difference in the rates at 5 and 10 years between
other 68% of these tumors. The lesions displayed overall patients younger than 50 years (83% and 61%) and indi-
5- and 10-year recurrence rates of approximately 20% and viduals older than 50 years old (84% and 75%).166 In
40%, respectively.166 In a study of 257 patients in 1984, addition, the time from the onset of symptoms to surgical
Chan and Thompson reported an overall recurrence rate resection was less than 6 months in 59 patients, 6 months
of 20% for posterior fossa meningiomas. They reported to a year in 54 patients, 1 to 2 years in 60 patients, and
no recurrence for patients with a grade I resection 0/7 more than 2 years in 52 patients. The recurrence- or
(0%) and only one recurrence for a patient with a grade II progression-free rates of 76%, 63%, 65%, and 71% were
resection. However, 8 (42%) recurrences were noted in similar in all four groups at 10 years.166
the 19 patients that underwent a grade IV or V removal.173 Melamed and coworkers in 1979, reported no correla-
Due to the low rate of total excision in the posterior fossa, tion between the consistency of the meningioma defined
meningiomas in this location were associated with inter- as hard, friable, “suckable,” necrotic, or vascular and the
mediate to high rates of recurrence when compared with rate of recurrence.170 In contrast, in a study of 657 patients
tumors in other locations. in 1986, Jaaskelanian reported soft consistency of the
In contrast to these data, Adegbite and coworkers tumor to strongly and independently correlate with recur-
reported no significant influence of location on recur- rence (p < 0.01). The author reported that 15 of the 79
rence. Although differences in the percentage of tumor meningiomas had been soft and “suckable” during surgery,
recurrence were observed between convexity, parasagittal, resulting in a recurrence rate of 34% at 20 years. The
sphenoid wing, and posterior fossa meningiomas among author suggested that soft meningiomas tended to recur
others, this variation was not statistically significant.167 because they were more apt to tear and be left behind in
However, given that the location of a meningioma deter- the tumor bed during surgical removal. In addition to soft
mines the extent of resection which in turn influences consistency of the tumor, the author also found simple
the rate tumor recurrence, the site of a meningioma may coagulation of the tumor base and invasion of bone to be
be considered an indirect factor in tumor recurrence and risk factors for recurrence. Approximately 34% to 56% of
progression. patients with two of the three risk factors, 15% to 24% of
The complete removal of tumor also resulted in a longer patients with one of the three risk factors, and 11% with
observed survival time as well as an improved quality of life no risk factors experienced a recurrence within 20 years.169
compared with partial tumor excision. Given the difficulty Specific histologic types of meningiomas have been
of complete tumor resection, posterior fossa meningiomas noted to correspond to a higher rate of recurrence. In 1970,
had the lowest observed average survival period of 5.9 years Crompton and Gauthier-Smith suggested that syncytial
compared with parasagittal, falcine, convexity, olfactory meningiomas are most likely to recur, whereas fibroblastic
groove, and sphenoidal ridge meningiomas.173 Further- meningiomas are least likely to do so.175 However, recent
more, patients with gross total removal of recurrent tumor studies have not found a statistically significant correlation
had a significantly longer duration of subsequent survival between a particular histology and the duration to recur-
with good functional status than those with partial tumor rence. Simpson in 1957 and Melamed and coworkers in
resection. A longer period of survival was also found in 1979 found no correlation between any particular histology
patients with meningiomas smaller than 4.5 cm in diame- and an increased rate of tumor recurrence.168,170 Adegbite
ter.173 Patients with smaller meningiomas did not have and coworkers did not find any relationship between
longer survival rates than individuals with larger menin- recurrence and the three most common histologic groups
giomas but led a better quality of life after tumor removal. for meningiomas, namely, the syncytial, transitional, and
The most important factor for determining postoperative fibroblastic subtypes.167 The authors did, however, find a
836 SURGICAL NEUROTOLOGY

5-year recurrence-free survival rate of only 32% for studied the role of fractionated external beam radiotherapy
angioblastic and malignant meningiomas. However, the (5000 to 5500 cGy) in treatment of subtotally resected
small sample size of these tumors did not allow for a sta- (Simpson grade IV) meningiomas. Approximately 5 years
tistically significant comparison.167 Chan and Thompson after treatment, the authors found a recurrence rate of 29%
reported that the average survival of 3.6 years for patients in the irradiated group versus 74% in the nonirradiated
with malignant tumors was not significantly different from group.179 In a more recent study of 135 meningiomas not
that for benign meningiomas.173 localized to the posterior fossa, Barbaro and coworkers in
Although no specific histology is associated with an 1987 noted a similar difference in the recurrence rates
increased recurrence, high cellularity is often observed in between meningiomas receiving and those not receiving
recurrent meningiomas. Two early studies by Skullerud and radiation treatment. Of the 51 patients who underwent a
Loken in 1974 and Jellinger and Slowik in 1975 found an complete resection and did not receive radiation therapy,
increased cellularity and mitotic rate in recurrent tumors.176 only 2 (4%) had a recurrence. Among the 84 patients in the
Waga and coworkers also noted histologic malignant study who underwent an incomplete resection, a recurrence
changes in 6 of 19 recurrent meningiomas.167 Crompton rate of 60% was noted in the 30 patients who did not receive
and Gautier-Smith believed that an increased number of radiation treatment, whereas the 54 patients who were given
mitoses, greater extent of necrosis within the tumor, and radiotherapy had a recurrence rate of 32%. The authors also
infiltration of the tumor into adjacent brain predicted a reported a longer median time to recurrence in the irradi-
greater chance of recurrence.175 Melamed and colleagues, in ated versus the nonirradiated group, with a 125-month hia-
agreement with these authors, also found that cerebral infil- tus in irradiated patients versus 66 months in patients who
tration, numerous mitoses, and cellular pleomorphisms did not receive irradiation, (p < 0.05). This large series con-
were associated with a higher rate of recurrence.170 The tained 23 posterior fossa meningiomas, 21 of which under-
study by Adegbite and coworkers in 1983 noted that 6 of went subtotal resection. Of these 21 posterior fossa
the 21 recurrent meningiomas displayed a greater degree of meningiomas, 16 did not receive radiation treatment.180
cellularity or increased mitotic figures.167 Marks and col- A more recent study of benign partially resected menin-
leagues in 1986 also noted mitoses and areas of focal necro- giomas by Miralbell and colleagues in 1992 compared the
sis to correlate with a higher recurrence rate.172 In a review recurrence rates between 36 patients treated with surgery
of 82 cases in 1986, De la Monte and coworkers noted and radiation therapy versus those in 79 patients treated
the following histopathologic factors were associated with with surgery alone. The authors found a recurrence rate of
recurrence: hypervascularity, hemosiderin deposition, 12% for patients treated with subtotal resection and radi-
growth of tumor in sheets, prominent nucleoli, mitotic fig- ation therapy (5000 to 6000 cGy). This compared with a
ures, single cell or group necrosis, nuclear pleomorphism, rate of 52% for patients treated only with a subtotal resec-
and an atypical or malignant tumor grade.177 All these stud- tion. The paper did not reveal the anatomic distribution of
ies suggest a more aggressive cellular histology for recurrent meningiomas in this study.181 All these studies suggested
tumors. In a study of 286 patients in 1999, Ayerbe and that radiotherapy is beneficial as adjunctive therapy for
coworkers found atypical and malignant histologic types, incompletely resected benign meningiomas. However,
nucleolar prominence, and the presence of greater than 2 additional studies need to be performed to prove an
mitoses/hpf to correlate with a higher rate of recurrence.171 unequivocal benefit in these patients.34 Patients with
The assessment of DNA has also been used to predict malignant meningiomas, however, have been determined
meningioma recurrence. A high proliferation index deter- to greatly benefit from radiation therapy. Radiation ther-
mined by flow cytometry analysis has been associated with apy may also be used for the palliation of inoperable and
recurrent meningiomas.178 In a study by May and colleagues recurrent tumors.167
in 1989, a higher proliferation index was observed in recur- Stereotactic photon-beam radiosurgery (gamma knife),
rent meningiomas than in nonrecurring ones. The two which was initially used for a limited number of patients, is
groups of patients with recurrent and nonrecurring tumors now being used with greater frequency. Patients with subto-
were matched for age, gender, and length of follow-up. tally resected meningiomas, individuals with recurrent
A greater number of mitoses and areas of focal necrosis tumors in locations associated with unacceptable surgical
were noted in the recurrent group. Foci of necrosis were morbidity, and elderly patients with poor functional status
seen in four of the nonrecurring tumors compared with are some of the groups that have benefited from stereotac-
seven of the recurrent ones. In addition, mitotic figures were tic radiosurgery. In a study of 50 patients with intracranial
seen in 4 of nonrecurring tumors compared with 12 for the meningiomas, which included six posterior fossa menin-
recurrent group.178 Flow cytometry may play a role in pre- giomas, Kondziolka and colleagues reported a 2-year tumor
dicting the clinical behavior and therefore recurrence in growth rate control of 96%.182 Some of the complications
these cases. This study concluded that a proliferative index with this treatment modality were reported by Al-Mefty and
of greater than 20% in any tumor suggests that it may coworkers in a series of 58 patients who received an aver-
recur, despite complete resection and a benign histology. age 5000 cGy with a follow-up of 8 years. Complications,
including visual deterioration, pituitary dysfunction, brain
necrosis, and one case of radiation-induced clival menin-
RADIATION THERAPY gioma, were noted in 19% of patients.183 Brainstem and
cerebellar necrosis was also noted by Miralbell and col-
The benefit of radiotherapy as an adjunctive treatment leagues in their series of meningiomas.181 The role of
for meningiomas has been established in a few limited stud- stereotactic radiation therapy is expected to increase in the
ies. In a study of 58 patients in 1975, Wara and coworkers treatment of meningiomas in the near future.
 Meningiomas of the Posterior Fossa and Skull Base 837

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 Epidermoid Cysts of the
Cerebellopontine Angle

Outline
Introduction Surgical Treatment Antonio De la Cruz, MD
Embryology Unusual Compllcalions of Karen Jo Doyle, PhD, MD
Pathology CPA Epidermoid Cysts
Clinical Signs Spontaneous Meningitis Stephanie Moody Antonio, MD
Diagnosis Lumbar Arachnoiditis
Computed Tomography Squamous Cell Carcinoma
Magnetic Resonances Imaging Summary

INTRODUCTION CPA epidermoid cysts are to be differentiated from

extradural (cranial or diploic) epidermoid cysts and from der-
Congenital cholesteatoma, or epidermoid cyst of the tem- moids. Intradiploic epidermoid tumors are slow-growing
poral bone, may occur in the middle ear, the mastoid, the masses that present as a painless swelling of or defect of the
petrous apex, or in the cerebellopontine angle (CPA). cranium.'! These tumors probably develop from indusion
Cruveilhier' in 1829 was among the earliest to identify of ectodermal elements during closure of the neural
intracranial epidermoid tumors. After his descriptions of groove.f-!' Dermoid tumors contain hair follicles and
three cases, they were called Cruveilhier's pearly tumors in gland tissue and tend to occur in the midline" and are four
the literature for the next 100 years. Muller2 first used the to nine times less common than epidermoid cysts.'?
word cholesteatoma in reference to three cases he reported,
because they contained cholesterol crystals. Virchow! pre-
ferred to use the name pearly tumors because cholesterol EMBRYOLOGY
was not always present in the four cases he presented. In
1897, Bostroem" outlined the embryology of these tumors In 1854, Von Remak first advanced the view that epider-
and dubbed them epidermoid. By 1943, Rand and Reeves' moid cysts arise from epithelial cell rests early in embry-
found about 200 cases in their review of the world litera- onic development.l" Bostroem" also leaned toward an
ture and added 21 cases of their own. epithelial origin of epidermoid cysts, suggesting that they
Epidermoid cysts comprise 0.2% to 1.5% of all intracra- arose from embryonic epithelial rests at a fairly late stage
nial tumors, and the posterior fossa is the most frequent of fetal development. Bostroem regarded dermoids as
intracranial site for their appearance." In the CPA, epider- developing from a younger and more primitive cell layer
moid cysts are the third most common lesion, constituting that may give rise to epithelial and mesothelial tissues,
4.6% to 14% of all tumors in this region.Y Other locations unlike epidermoid cysts, which are composed of deriva-
by decreasing frequency include the parasellar area, clival tives of epithelial tissue only." Scholtz'! described the
area, lateral recess of the fourth ventricle, and petrous inclusion of ectodermal elements at the time of the closure
apex." Mahoney!" analyzed 142 cases of cranial and of the neural groove during the third to fifth week of
intracranial epidermoid cysts and found 53 (37%) in the embryonic life, when the neural ectoderm separates from
CPA Yamakawa and colleagues II reported the location of the cutaneous ectoderm; he surmised that these misplaced
45 intradural epidermoid cysts: 46% CPA, 15% middle cells give rise to dermoid or epidermoid tumors in the
fossa,.15% cerebral hemisphere, 9% suprasellar, 9% third midline. Later, other authors added to the epithelial rest
ventricle, and 6% fourth ventricle. Nager" reviewed the theory, hypothesizing that epidermoid cysts layaway from
literature and concluded that 30% to 40% of epidermoid the midline as a result of epithelial misplacement during
cysts are found in the CPA, where they account for 6% to development of the secondary otic and optic cerebral vesi-
7% of all CPA tumors. The tumors extend linearly along cles in the forebrain and metencephalon during the fourth
planes of least resistance to the middle fossa, foramen or fifth week of development.S'? Fleming and Botterel'?
magnum, and to the contralateral CPA; enveloping neu- hypothesized that epidermoid cysts formed from the
rovascular structures along the way.9,12 Multiple epidermoid proliferation of multipotential embryonic cell rests located
cysts almost never occur." CPA epidermoid cysts appear in more laterally than the neural tube closure site. Migratory
any age group, but the majority are identified in the third properties of CPA epidermoid cells were observed in
and fourth decades.V They present with progression of vitro, similar to acquired cholesteatomas of the middle ear
symptoms after a long period of slow growth. 8 and mastoid. Because this migratory ability is unique to
841
842 SURGICAL NEUROTOLOGY

epithelium derived from the first branchial groove (no inferior cerebellar artery. Superior extension across the
other epithelium in the head and neck shares this prop- tentorium results in middle fossa involvement. Finally,
erty), the authors suggest a first branchial groove site of tumor may extend medially into the foramen of Lushka
origin for CPA epidermoid cysts.l" into the fourth ventricle.i! Yasargil and colleagues-" found
that of 22 CPA epidermoid cysts in their series, 5 were
directed posterocaudally through the foramen of Luschka
into the fourth ventricle, 3 extended anterorostral through
PATHOLOGY the incisura into the parasellar cisterns, and 4 appeared to
be supratentorial tumors extending back to the posterior
Bailey'? gave an almost poetic description of the macro-
fossa. Samii'? reported the location and extension of CPA
scopic appearance of epidermoid tumors:
epidermoid cysts in 40 patients: 15 were confined to the
CPA, 3 had transtentorial extension, 5 had middle fossa
"Grossly the tumors resemble startlingly mother-of-pearl both
in tint and luster. The surface is smooth, silky, with irregular
extension, 9 had extension to the foramen magnum, and
pea-sized or larger elevations and peels away easily from the 8 had both transtentorial and foramen magnum extension.
surroundings. The surface layers are tough, with about the The only change to the brain produced by an epider-
malleability of heavy tin foil. From the surface, with a knife blade, moid is local atrophy attributable to the pressure exerted
flakesmay easily be separated which show beautifully the charac- by the expanding cyst. 20 Ganglion cells disappear, and fre-
teristic luster." quentlya mild degree of gliosis occurs. No inflammatory
reaction is typically seen.
Microscopically, epidermoid cysts are covered by strati-
fied squamous epithelium overlying a thin layer of connec-
tive tissue. The capsule may contain foci of calcification. CLINICAL SIGNS
The superficial layers are usually cornified, and intercellular
bridges are occasionally seen.i? Epidermoid cysts contain Posterior fossa epidermoid cysts, because they are very
keratin debris and frequently, cholesterol crystals. This slow-growing, may be asymptomatic for years. Before
debris is the result of progressive desquamation and break- imaging techniques became available, patients could exhibit
down of keratin from the epithelial lining of the cyst, form- symptoms for decades before diagnosis. In 1964, Ulrich!'
ing concentric lamellae. The interior of the epidermoid is recorded patients with intracranial epidermoid cysts whose
usually soft, white, waxy material. Sometimes the contents durations of symptoms were as long as 29 and 53 years.
are thick, viscid, and dark brown or gray. They are devoid of Even with the advent of modern imaging techniques, diag-
blood supply, but often are in surface contact with arteries." nosis may be delayed more than 20 years. 9,12,26-28
To further differentiate epidermoid cysts and dermoids, der- The symptoms of CPA epidermoid cysts include hear-
moids contain other elements of normal skin, such as sweat ing loss, tinnitus, dizziness, and gait disturbance. 12,23
glands, sebaceous glands, hairs, or hair follicles, whereas Hearing loss and tinnitus are the usual initial symptoms in
epidermoid cysts have only squamous and sometimes basal 80% of patients, and gait disturbance and headache are the
epithelium present. initial complaints in 20%.29 Other less common presenting
Montgomery and Finlayson/? presented an interesting symptoms are intention tremor, tic douloureux, facial numb-
case of a tumor involving the middle fossa as well as the ness, facial spasm, facial palsy, impaired taste, impaired
posterior fossa. The middle fossa portion had dermoid fea- lacrimation, dysarthria, dysphagia, tongue deviation, nau-
tures (sebaceous glands and hair follicles), whereas the sea and vomiting, and loss of consciousness." Nager"
posterior fossa part exhibited more epidermoid character- reported that 50% to 75% of patients with epidermoid cysts
istics. They argued that this was evidence that epidermoid of the CPA complained of progressive sensorineural hearing
cysts and dermoids were the same tumor, but this is the loss, tinnitus, unsteadiness, and facial nerve symptoms. He
only case of its kind in the literature. also found that 25% to 50% of tumors manifested as atyp-
The growth rate of epidermoid cysts is linear, like nor- ical trigeminal neuralgia (atypical because it was of longer
mal skin, unlike the exponential growth demonstrated by duration and might, not have trigeminal nerve impair-
most neoplasrns.P This linear rate of growth is expected of ment). Samii summarized potential mechanisms for tic
tumors derived from a single layer of basal germinal cells douloureux: direct compressive effect, indirect pressure
spread out over a surface area. The slow growth rate by causing vascular compression, or local irritation from
enables adjacent structures to adjust gradually, and epider- cyst content seepage.V The most common cranial nerve
moid cysts spread with finger-like projections along pre- abnormalities are VIII (50% to 55%), VII (18% to 45%),
formed clefts and spaces. They tend to engulf nearby blood V (25% to 43%), and VI (10% to 30%).9,12
vessels and cranial nerves and spread along the crevices of
the brainstem and cerebellar and cerebral hernispheres.Vr"
Ulrich/! described the gross spread of epidermoid cysts as DIAGNOSIS
"multilobulated masses that adapt themselves to the avail-
able space between the skull and the brain." There are four Before the advent of computed tomography (CT) and
possible routes of spread from the CPA. Anteriorly tumor magnetic resonance imaging (MRI), the diagnosis of
may spread to the prepontine cistern, engulfing or displac- intradural epidermoid cysts was difficult. Presenting symp-
ing the basilar artery, and toward the contralateral side. toms and signs pointed to CPA tumor, but it was impossible
Inferior extension toward the foramen magnum risks the to predict the pathology preoperatively because acoustic
lower cranial nerves, the vertebral artery, and the posterior neuroma, meningioma, arachnoid cysts, and other lesions
 Epidermoid Cysts of the Cerebellopontlne Angle 843

behave similarly. Plain radiographs, which showed diploic

epidermoid cysts as radiolucent areas in the cranium, were
of little use in diagnosing CPA epidermoid cysts." In
Braclanann and Anderson's series-" of CPA cholesteatoma,
9 of 13 patients had normal internal auditory canals (IACs)
on petrous pyramid plain films. "Without a tumor large
enough to produce hydrocephalus, a pneumoencephalo-
graph was frequently read as normal. 30 In the pre-CT era,
the Pantopaque myelogram was used, on which CPA
cholesteatoma exhibited the characteristic appearance of a
lobulated or scalloped border, in contrast to the round or
smooth contour of meningioma or acoustic neuroma."
Braclanann and Anderson performed lumbar puncture as a
part of the myelogram and reported that 9 of 10 patients
hada normal cerebrospinal fluid (CSF) protein level, despite
largeCPA epidermoid cysts, unlike other CPA neoplasms,
whichare associated with elevated CSF protein levels.i" Figure 48-2. Normal right lAC.

Computed Tomography (80 to 120 Hounsfield units), with two of them demon-
In the 1970s, CT permitted a more reliable radiologic strating scattered peripheral densities consistent with
diagnosis of CPA epidermoid cysts. In a study of nine calcification (140 to 160 Hounsfield units). They could
patients with CPA epidermoid cysts comparing earlier find no histologic reason for the increased CT density
imaging techniques to C'I, skull radiographs were normal and termed the lesions dense epidermoid cysts. Nagashima
in four patients and nonspecific in five, radionucleotide and colleagues-" identified four patterns of CT findings:
brain scans were normal in seven, and angiography was (1) homogeneous low density, (2) homogeneous low den-
nondiagnostic in every case. CT detected the lesion in sity with calcification or small dense nodules, (3) isodense,
eight of nine cases." and (4) homogeneous high density. They were able to find
On CT, CPA epidermoid cysts are homogeneous and a pathologic correlate in that the low or isodense epider-
low density (low absorption values from -22 to +18 moid cysts were pearly appearing containing a white, waxy
Hounsfield units: 500 scale) (Fig. 48-1). Bone erosion may material rich in cholesterol, whereas the high-density
be demonstrated (Figs. 48-2 and 48-3). By C'I, a CPA epi- epidermoid cysts were cystic and contained brown, viscous
dermoid may be difficult to distinguish from a subarach- fluid with saponification of the debris. Dunn and cowork-
noid cyst, which is also homogeneous and of low density, ers" described another CT dense posterior fossa epider-
but the subarachnoid cyst usually has a sharply defined, moid cyst where the tumor contained a viscous brown fluid.
rounded margin compared with the irregular periphery of They also pointed out that all reported cases of dense
the epidermoid tumor. 12,32 Enhancement of the capsule is epidermoid cysts have occurred in the posterior fossa of
uncommon.12,33 females. Another interesting finding reported by Laster and
The appearance of epidermoid cysts may vary on CT. colleagues was of freely movable fatty material within the
Increased density has been reported for some epidermoid ventricles and subarachnoid space seen in association with
tumors. Braun and coworkers'? reported three cases of a CPA epidermoid, with negative absorption values by CT
posterior fossa epidermoid cysts with increased density scan within the CSF space." The authors suggested that this

Figure 48-3. Bone program axial CT of leftCPA epidermoid, with extension

Figure 48-1. CT examination of leftCPA epidermoid (arrow); demonstrates to and erosion of petrous bone involving the left lAC (arrow). Compare with
characteristic homogeneous lowdensity without enhancement. normal right lAC in Figure 48-2.
844 SURGICAL NEUROTOLOGY

probably represented rupture of the cyst in to the subarach-

noid space, occurring spontaneously or postsurgically."

Magnetic Resonance Imaging

Epidermoid tumors have a characteristic appearance
on MRI. Generally, they have long Tl recovery times
(low signal intensity) and prolonged T2 decay time (high
signal intensity) (Figs. 48-4 and 48-5).J7-40 New MRI tech-
niques have provided a better means of differentiating
epidermoid from arachnoid cysts, which have identical
MRI characteristics. On fluid-attenuated inversion recov-
ery (FLAIR), an arachnoid cyst will be hypointense (simi-
lar to CSF), but an epidermoid cyst will be hyperintense
(indicating protein content)."! Diffusion-sequence MRI
can also be useful in distinguishing these two lesions as the
solid nature of the epidermoid leads to a high signal
(white) compared with the low signal (black) of the arach-
noid cyst."
Vion-Dury and colleaguesf highlighted variability in
MRI findings among different cases of CPA epidermoid
cysts. In their review of the literature, they found that 57% Figure 48-5. MRI of leftCPA epidermoid. Demonstrates typical T2-weighted
of epidermoid cysts are characterized by an increase and appearance (high intensity). This large CPA epidermoid has extended
about 15% by a decrease of T2 relaxation time; and in anteriorly to surround the pons.
26% the T2 relaxation time is not different from that of
the surrounding parenchyma." Other authors have found
some variability in the Tl-weighted appearances of epi- on T2 images.t" Steffey and coworkers'! emphasized the
dermoid cysts.9, 12,43 Horowitz suggested cystic epidermoid variability of consistency on MRI of five epidermoid
tumors with dense capsules had bright signal in Tl images tumors: four of the five showed heterogeneous internal
due to high lipid content, whereas classical pearly tumors signal intensity; the fifth was homogeneous yet different
were hypointense on T'I images.t! Another study demon- from brain and CSF. They felt that this variability did not
strated that 4 of 20 surgically verified epidermoid cysts preclude the use of MRI to distinguish epidermoid cysts
exhibited hvperintensitv on Tl images and hvpoinrensitv from subarachnoid cysts, which have the same signal inten-
sity as CSF on both Tl- and T2-weighted images.
Arriaga and Brackmann'" stressed the importance of
obtaining both CT and MRI to work up petrous apex
lesions and to differentiate epidermoid from cholesterol
granuloma. These two imaging modalities have added a
great deal to the preoperative planning of surgical treatment
of CPA epidermoid cysts, with MRI having an advantage
in locating the full anatomic extent of tumor for preoper-
ative planning.f? Postoperatively, MRI with its greater
anatomic detail is the preferred imaging technique for
monitoring residual or recurrent epidermoid tumor." The
new MRI techniques will likely playa strong role in pre-
operative diagnosis.

SURGICAL TREATMENT
The history of surgery for epidermoid tumors is long.
Bailey'? in 1920 described successful surgical removal of
intracranial epidermoid cysts using the suboccipital
approach. In 1943, Rand and Reeves' reported five epider-
moid cysts involving the CPA, including one with prepon-
tine origin and spread to both CPAs. They found two
tumors at autopsy and attempted removal of three others
by the suboccipital approach. Two patients died postoper-
atively, and the third did well after a second operation in
which all tumor was successfully removed. They felt that
Figure 48-4. MRI of leftCPA epidermoid. Typical T1-weighted appearance complete removal of tumor was out of the question when
(low intensity). the capsule was intimately involved with cranial nerves or
 Epidermoid Cysts of the Cerebellopontine Angle 845

the circle of Willis. In their 1950 paper, Grant and Austen'" translabyrinthine and transcochlear procedures. The trans-
outlined treatment of 22 epidermoid cysts, including 4 of labyrinthine operation permits direct access to the CPA
the CPA. They removed these tumors subtotally, via sub- without cerebellar retraction, via extended mastoidectomy,
occipital craniotomy, but emphasized that their patients did labyrinthectomy, and removal of the bone surrounding
not require further operations. The mortality rate from the lAC. A translabyrinthine approach is attempted when
their entire series was 23 %, and they did not offer separate hearing preservation is not an option and provides good
mortality figures for the CPA epidermoid cysts. MacCarty exposure to tumor in the prepontine cistern, contralateral
and coworkers 5a reported 24 intracranial epidermoid cysts side, and foramen magnum." In cases with tumor involve-
treated before 1959, 8 of which were located in the CPA. ment of the area anterior to the brainstem, the opposite
Four patients had surgery, and three tumors were com- CPA, and the carotid artery, the transcochlear approach is
pletely removed. One patient died, one was lost to follow- used. The facial nerve is rerouted posteriorly after the
up, and two were alive with some neurologic problems and translabyrinthine approach is carried out, and bony
facial paralysis. removal of the cochlea to the internal carotid artery is
Surgeons continue to employ the suboccipital craniotomy, completed.51 This enables access to the midline structures,
but have added other surgical approaches to the armamen- including the clivus, basilar artery, vertebral arteries, cra-
tarium for removal of CPA epidermoid cysts, including nial nerves V through XI, and the opposite lAC.
the translabyrinthine, middle fossa, and transcochlear With microdissection techniques, mortality, morbidity,
approaches. The choice of approach is based on the hear- and recurrence rates have improved. Generally, intracra-
ing, cranial nerve symptoms, and extent of the tumor, nial epidermoid cysts should be treated by complete surgi-
including presence of contralateral or middle fossa exten- cal excision. However, complete removal can be limited by
sion. The retrosigmoid or suboccipital approach provides the encasement of neurovascular structures and the risk of
access to the prepontine region with adequate exposure of increased morbidity with sacrifice of functioning cranial
cranial nerves V to XI. It may allow hearing preservation. nerves. In these cases, it may be preferable to perform an
Any extension superiorly over the tentorium will require a incomplete removal, since recurrence may occur slowly and
middle fossa approach. With the middle fossa approach, reoperation may not be required for many years. 8, 12 Despite
division of the superior petrosal sinus and tentorium careful technique, postoperative cranial nerve deficits are not
further widens the operative field." Larger lesions involv- uncommon. Mohanty and colleagues reported 40% of their
ing the posterior and middle fossa may be approached patients had postoperative deterioration in cranial nerve
with a combined extended middle fossa (exposing petrous function. 52 It must be kept in mind, however, that rates of
ridge to clivus) and retrolabyrinthine/retrosigmoid preoperative dysfunction may also be high,9,l2,52 and some
approach, called the petrosal approach. Wide access to the patients may experience an improvement in function, espe-
middle fossa, lAC, and posterior fossa is obtained while cially notable for cranial nerve V l2
still preserving the otic capsule and, hence, hearing. Table 48-1 summarizes the published surgical results
Transtemporal approaches to CPA epidermoid cysts are the from the treatment of CPA epidermoid cysts, from the

TABLE 48-1. Operations and Surgical Results for the Treatment ofCPA Epidermoid Cysts inthe
Premicrosurgical and Microsurgical Eras
Second
Patients Total Subtotal Operation Deaths
Rand and Reeves5 SO 3 2 1 1 2
Grant and Austin 49 SO 4 0 4 0 N
MacCarty et also SO 4 3 1 N 1

Total Premicrosurgical 11 5 6 3
Guidetti and Gagliardi SO 78 7 3 4 0 1
Brackmann and Anderson 28 TL 13 5 8 3 2
Hamel et al. 79 SO 11 8 3 0 2
De la Cruz 55 TC 6 6 0 N 1
Berger and Wilson 27 SO 13 0 13 0 0
Sabin etal. 80 SO 10 1 9 2 1
Yamakawa et al." SO 15 7 8 2 2
De Souza et al. 53 SO, MF 30 0 27 2 1
Yasargil et al. 26 SO 22 22 N 0 0
Lunardi et al. 54 SO 16 5 11 3 2
Altschuler et al 4 8 SO 11 2 9 4 0
Samii et al. 12 SO 40 30 10 3 0
Mohanty et al,52 SO 25 12 13 0 2
Talacchi et al. 9 SO, ST 28 16 12 7 1
Moffat et al. 25 SO, MF, TL 15 12 3 1 0
Total Microsurgical 262 129 130 27 15

SO, suboccipital; TL, translabyrinthine; Te, transcochlear; MF, middle fossa; ST, subtemporal; N, data not given.
846 SURGICAL NEUROTOLOGY

premicroscopic and microscopic eras. From this table it Brackmann and Andersorr" reported results of 12
is noteworthy that subtotal resection remains a common patients who had translabyrinthine removal from 1964 to
occurrence. Second operations are required in 0 to 36% of 1977. Eight tumors were removed subtotally due to adher-
patients. The mortality rate has substantially improved. ence of the capsule to brainstem or vessels. Three patients
Yamakawa and colleagues!' surgically treated 15 cases of required additional surgery for recurrences. Two postop-
CPA epidermoid cysts from 1963 to 1988. Seven patients erative deaths occurred, one due to bleeding and one from
had total tumor removal, six were subtotal, and two, sub- postoperative infection.
capsular. There were two deaths, and three patients needed De la Cruz! reported the use of the transcochlear
at least one additional operation. Excellent postoperative approach for seven CPA cholesteatomas. Total tumor
functioning was reported for 71 % of the patients ("excel- removal was achieved in all patients. One patient with dia-
lent function" was not defined in the study). betes died postoperatively of pyelonephritis, and autopsy
De Souza and coworkers 53 reported surgical results of revealed no residual tumor. Three patients had permanent
patients with 30 CPA epidermoid cysts from 1966 to 1986 facial paralysis, one patient had persistent headaches, and
in India. The suboccipital approach was used in 27 patients, one had ongoing facial pain. None had evidence of recur-
and the middle fossa was used or added in 4. Incomplete rence from 2 to 5 years postoperatively.
removal was the rule. One patient died, three developed In 2002, Moffat and colleagues'! reported a series of
meningitis, and four patients had postoperative facial paral- 15 patients treated with retrosigmoid, retrolabyrinthine,
ysis. Two patients were reoperated on for recurrence. Six transotic, or translabyrinthine approaches combined with
patients had bipolar coagulation of the epithelial remnants, middle fossa as needed. They based the surgical manage-
and none of these developed symptoms or signs of recur- ment on a new classification stage of disease extent.
rence by 3 years after surgery.