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NEUROTOLOGY ISBN: 0-323-01830-0

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

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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
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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

In the early 1990s, the first edition of this text helped to
define the body of knowledge encompassed by neurotol-
ogy, which was then a relatively new field. Over the past
decade, major strides have been realized on a number of
fronts. In terms of specialty organizations, the American
Neurotology Society has grown to over 500 members.
Across the Atlantic, neurotology has been organized through
the European Academy of Otology and Neurotology, an
active group of some 300 members.
Perhaps no aspect of neurotology has undergone a greater
degree of maturation than training. In the United States, two-
year post-residency fellowships are now formally accredited
by the American Council of Graduate Medical Education.
As of early 2004, approximately 20 fellowship programs
are active, 10 of which have completed the accreditation
process. In a major milestone, neurotology has become the
first subspecialty of Otolaryngology–Head and Neck Surgery
to achieve board certification by the American Board of
Otolaryngology.
In the clinical realm, a sizable and ever increasing num-
ber of practitioners are focusing their professional efforts
in neurotology. In the operating room, microsurgical tech-
nology continues to evolve with improved microscope and
drill systems, image guidance, and more capable neuro-
physiologic equipment to mention just a few advances. In
tumor surgery, the emphasis continues to be on develop-
ment of minimally invasive techniques that maximize
tumor control while optimizing neural preservation.
Innovative radiotherapy methods, particularly stereotactic
techniques, have developed a role in selected neurotologic
tumors. In the vestibular field, numerous new therapies
have been devised for BPPV and entire new diagnoses,
such as superior semicircular canal dehiscence, have been
introduced.
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
2004—a large fraction of which is dedicated to investigation
Preface
of the ear and auditory nervous system. Among the numer-
ous fruits of this investment are over 60,000 cochlear
implant devices placed worldwide and the continued
refinement of the auditory brainstem implant. Programs
have been initiated in the development of a vestibular pros-
thesis. In genetics, over 100 genes for hereditary hearing
impairment have been localized, a significant portion of
which have been cloned. In neurotologic tumors, great
strides have been made in understanding the molecular
genetic basis for acoustic neuroma, NF-2, paragangliomas,
and papillary adenocarcinomas of the endolymphatic sac.
Functional imaging, in which the chemical processes
within the brain and other tissues are mapped, also has a
promising future. Looking forward a few decades, it seems
probable that the first human sense to be directly coupled
with implanted digital devices on a routine basis will be the
ear. It can be envisioned that man-machine interaction
with computers and communication devices will revolu-
tionize how the ear is used.
The companion surgical atlas to this text, promised in
the preface of the first edition, was published in full color
in 1996 (Jackler RK: Atlas of Neurotology and Skull Base
Surgery. St. Louis, Mosby, 1996). A second edition is being
contemplated at present. With the digital publishing revo-
lution currently in full force, it can be envisioned that
future editions of these works will appear primarily on the
internet.
Over the last few decades, neurotology has achieved
critical mass as a field, both through the number of scientists
and clinicians engaged in it as well as through the steady
accumulation of new knowledge and clinical capabilities.
The editors hope that this comprehensive resource, as the
primary textbook in the field, will serve to foster excellence
and stimulate innovation in neurotology.
Robert K. Jackler, MD
Derald E. Brackmann, MD
vii

Kedar K. Adour, MD
Director of Research, Senior Consultant, Kaiser-Permanente
Medical Center, Oakland, California; Emeritus President
and Founder, Sir Charles Bell Society, San Francisco, California
Sumit K. Agrawal, BSc, MD
Resident, Department of Otolaryngology, University of
Western Ontario; Resident, London Health Sciences Centre;
London, Ontario, Canada
Stephanie Moody Antonio, MD
Assistant Professor, University of Maryland School of Medicine,
Baltimore, Maryland
John R. Arrington, MD
Professor of Radiology, University of South Florida College
of Medicine; Attending Neuroradiologist, HL Moffitt Cancer
and Research Center; Tampa, Florida
Yasmine A. Ashram, MD, D ABNM
Lecturer, Neurophysiology Division, Department
of Physiology, University of Alexandria, Alexandria, Egypt
Robert J. Backer, MD
Division Chief, Neurological Surgery, St. John’s Mercy Medical
Center, St. Louis, Missouri
Thomas J. Balkany, MD
Hodgkiss Professor and Chairman, Department
of Otolaryngology; Professor, Department of Pediatrics;
Professor, Department of Neurosurgery; Chief, Department
of Neurotology; University of Miami School of Medicine; Chief
of Service, ENT, Jackson Memorial Hospital; Miami, Florida
Loren J. Bartels, MD, FACS
Clinical Professor, Department of Otolaryngology, University
of South Florida College of Medicine; Immediate Past Chief
of the Medical Staff, Tampa General Hospital; Tampa, Florida
Nikolas H. Blevins, MD
Assistant Professor, Department of Otolaryngology–Head &
Neck Surgery, Stanford University of Medicine, Palo Alto,
California
Dennis I. Bojrab, MD
Michigan Ear Institute, Farmington Hills, Michigan
Contributors
Derald E. Brackmann, MD, FACS
Clinical Professor of Otolaryngology–Head and Neck Surgery
and Clinical Professor of Neurosurgery, University of Southern
California School of Medicine; President, House Ear Clinic;
Board of Directors, House Ear Institute; Los Angeles, California
Sujana S. Chandrasekhar, MD
Associate Professor of Otolaryngology, Mount Sinai School
of Medicine; Director of Otology/Neurology and Director,
Cochlear Implant Program, Mount Sinai Medical Center;
New York, New York
Wileen Chang, MS
Audiologist, University of California-San Francisco,
San Francisco, California
Douglas A. Chen, MD
Clinical Associate Professor, University of Pittsburgh;
Co-Director, Hearing and Balance Center, Allegheny General
Hospital; Pittsburgh, PA
Steven W. Cheung, MD
Associate Professor-in-Residence, Otology, Neurotology
and Skull Base Surgery, Department of Otolaryngology–Head
and Neck Surgery, University of California-San Francisco,
San Francisco, California
Sung J. Chung, MD
Private Practice, ENT Surgical Consultants, Ltd, Joliet, Illinois
Harold V. Clumeck, PhD
Lecturer, Department of Communication Sciences and
Disorders, California State University, Hayward, California;
Section Chief, Speech Pathology, VA Medical Center,
San Francisco, California
Newton J. Coker, MD
Professor, Bobby R. Alford Department
of Otorhinolaryngology and Communicative Sciences,
Baylor College of Medicine; Attending Physician,
Otorhinolaryngology, The Methodist Hospital; Attending
Physician, Otorhinolaryngology, Michael E. DeBakey Veterans
Affairs Medical Center; Attending Physician,
Otorhinolaryngology, Harris County Hospital District
(Ben Taub); Attending Physician, Otorhinolaryngology,
St. Luke’s Hospital; Houston, Texas
ix
x CONTRIBUTORS
Hugh D. Curtin, MD
Professor of Radiology, Harvard Medical School; Chief
of Radiology, Massachusetts Eye and Ear Infirmary; Boston,
Massachusetts
Edward J. Damrose, MD
Assistant Professor of Otolaryngology, Stanford University,
Stanford, California
C. Phillip Daspit, MD, FACS
Clinical Professor of Surgery (Otolaryngology), University
of Arizona; Chief, Section Neurotology, Department
of Neurosurgery, Barrow Neurological Institute; Chairman,
Institute Review Board, St. Joseph’s Hospital;
Phoenix, Arizona
J. Diaz Day, MD
Associate Professor of Neurosurgery, Drexel University College
of Medicine, Philadelphia, Pennsylvania; Allegheny General
Hospital, Pittsburgh, Pennsylvania
Antonio De la Cruz, MD
Clinical Professor of Otolaryngology/Head and Neck Surgery,
University of Southern California; Director of Education,
House Ear Institute; Active Staff, St. Vincent Medical Center;
Active Staff, LAC/USC Medical Center; Los Angeles,
California; Active Staff, Torrance Memorial Hospital, Torrance,
California
Manuel Don, PhD
Head, Electrophysiology Department, House Ear Institute,
Los Angeles, California
Christopher F. Dowd, MD
Clinical Professor of Radiology, Neurological Surgery,
Neurology and Anesthesia and Preoperative Care;
Interventional Neuroradiology, The Neurovascular Medical
Group; University of California, San Francisco School
of Medicine, San Francisco, California
Karen Jo Doyle, MD, PhD
Associate Professor, Department of Otolaryngology, Head and
Neck Surgery, University of California, Davis Medical Center,
Sacramento, California
Colin L. W. Driscoll, MD
Assistant Professor, Mayo Clinic College of Medicine;
Consultant, Department of Otorhinolaryngology, Mayo Clinic
and Mayo Foundation; Rochester, Minnesota
David R. Edelstein, MD
Clinical Professor of Otorhinolaryngology, Weill Medical
College of Cornell University; Chairman, Department of
Otolaryngology–Head and Neck Surgery, Manhattan Eye,
Ear and Throat Hospital; New York, New York
Bruce M. Edwards, AuD
Senior Audiologist, University of Michigan Health System,
Department of Otolaryngology–Head and Neck Surgery,
Division of Audiology and Electrophysiology, Ann Arbor,
Michigan
Adrien A. Eshraghi, MD, MSc
Assistant Professor of Otolaryngology, University of Miami
School of Medicine; Attending Physician and Surgeon, Jackson
Memorial Hospital, Miami Veterans Administration Hospital,
and University of Miami Ear Institute; Miami, Florida
Grace Fan, MD
Diagnostic Radiology, Kaiser Permanente Oakland Medical
Center, Oakland, California
Laurel M. Fisher, PhD
House Ear Institute, Los Angeles, California
David R. Friedland, MD, PhD
Assistant Professor, Division of Otology and Neuro-otologic
Skull Base Surgery, Department of Otolaryngology
and Communication Sciences, Medical College of Wisconsin;
Attending Physician, Froedtert and Medical College Hospital;
Milwaukee, Wisconsin
Rick Friedman, MD, PhD
Associate Research Scientist, House Ear Institute, Los Angeles,
California; Active Staff, Chapman Medical Center, Orange,
California; Active Staff, St. Vincent Medical Center; Cedars-
Sinai Medical Center; USC Medical Center; Los Angeles,
California
Richard R. Gacek, MD, FACS
Professor of Otolaryngology, Department
of Otolaryngology–Head and Neck Surgery, University
of Massachusetts Medical Center, Worchester, Massachusetts
Bruce J. Gantz, MD, MS
Professor and Department Head, University of Iowa,
Iowa City, Iowa
Sanjay Ghosh, MD
Neurosurgeon, Senta Medical Clinic, San Diego, California
Gerard Gianoli, BSE, MD
Clinical Associate Professor, Departments of Otolaryngology
and Pediatrics, Tulane University Medical School,
New Orleans, Louisiana; North Oaks Hospital, Hammond,
Louisiana; The Ear and Balance Institute, Baton Rouge,
Louisiana
Joel A. Goebel, MD, FACS
Residency Program Director and Professor
and Vice Chairman, Washington University School
of Medicine, St. Louis, Missouri
Robert A. Goldenberg, MD
Professor and Chief, Department of Otolaryngology, Wright
State University School of Medicine, Centerville, Ohio;
Associate Clinical Professor, University of Cincinnati School
of Medicine, Cincinnati, Ohio
John Grant, MB, FRCS(C), FACS
Associate Professor of Neurosurgery, University
of Missouri-Kansas City; Children’s Mercy Hospital
and Clinics; Kansas City, Missouri

John H. Greinwald Jr, MD
Associate Professor, Department of Otolaryngology, University
of Cincinnati; Assistant Director, Center for Hearing
and Deafness Research, Cincinnati Children’s Hospital Medical
Center; Cincinnati, Ohio
A. Julianna Gulya, MD, FACS
Clinical Professor of Otolaryngology, George Washington
University, Washington, DC
Van V. Halbach, MD
Clinical Professor of Radiology, Neurological Surgery,
Neurology, and Anesthesia and Preoperative Care;
Interventional Neuroradiology, The Neurovascular Medical
Group; University of California, San Francisco School
of Medicine, San Francisco, California
Courtney D. Hall, PhD
Assistant Professor, Department of Rehabilitation Medicine,
Emory University, Atlanta, Georgia; Research Health Scientist,
Rehabilitation Research and Development Center, Atlanta
VAMC, Decatur, Georgia
Hal L. Hankinson, MD
Neurosurgical Associates, Albuquerque, New Mexico
Lee A. Harker, MD
Deputy Director, Boys Town National Research Hospital;
Vice Chairman, Department of Otolaryngology and Human
Communication, Creighton University School of Medicine;
Omaha, Nebraska
Richard E. Hayden, MD
Department of Otolaryngology–Head and Neck Surgery,
Mayo Clinic, Scottsdale, Arizona
Carl B. Heilman, MD
Associate Professor, Department of Neurosurgery, Tufts
University School of Medicine; Tufts New England Medical
Center; Boston, Massachusetts
Susan J. Herdman, PhD
Professor, Departments of Rehabilitation Medicine and
Otolaryngology–Head and Neck Surgery, Emory University,
Atlanta, Georgia; Research Health Scientist, Rehabilitation
Research and Development Center, Atlanta VA Medical Center,
Decatur, Georgia
Randall T. Higashida, MD
Clinical Professor of Radiology, Neurological Surgery,
Neurology, and Anesthesia and Preoperative Care;
Interventional Neuroradiology, The Neurovascular Medical
Group; University of California, San Francisco School
of Medicine, San Francisco, California
Barry E. Hirsch, MD, FACS
Professor, Departments of Otolaryngology, Neurological
Surgery, and Communication Sciences and Disorders; Director,
Division of Otology, Department of Otolaryngology; University
of Pittsburgh School of Medicine and School of Physical
Medicine and Rehabilitation; Pittsburgh, Pennsylvania
Contributors xi
William E. Hitselberger, MD
Neurosurgeon, St. Vincent’s Hospital; House Ear Clinic;
Los Angeles, California
Annelle V. Hodges, PhD
Associate Professor of Otolaryngology, University of Miami
School of Medicine, Miami, Florida
Ronald A. Hoffman, MD
Professor of Clinical Otolaryngology, Albert Einstein College
of Medicine, Bronx, New York; Director of Otology, Beth Israel
Medical Center, New York, New York
Karl L. Horn, MD
Ear Associates, PC; Presbyterian Ear Institute; Albuquerque,
New Mexico
Michael M. Hovsepian, MD
Staff Radiologist, Fullerton Radiology Medical Group, Inc.,
Fullerton, California
Timothy E. Hullar, MD
Assistant Professor, Department of Otolaryngology–Head
and Neck Surgery, Washington University School of Medicine,
St. Louis, Missouri
Robert K. Jackler, MD
Sewall Professor and Chair, Department of
Otolaryngology–Head and Neck Surgery,
Professor, Departments of Neurosurgery and Surgery,
Stanford University School of Medicine, Stanford, CA
Alexis H. Jackman, MD, BA
Resident in Otolaryngology, New York University School
of Medicine, New York, New York
Michael J. Kaplan, MD
Professor of Otolaryngology, Professor of Head and Neck Surgery,
Stanford University School of Medicine, Stanford, California
Collin S. Karmody, MD, FRCSE
Professor of Otolaryngology, Tufts University School of
Medicine, New England Medical Center, Boston, Massachusetts
Robert W. Keith, PhD
Professor, Departments of Otolaryngology and Communication
Sciences and Disorders, University of Cincinnati; Director,
Division of Audiology, University of Cincinnati Medical
Center; Cincinnati, Ohio
Kevin E. Kelly, MD
Family Practice Program, Phoenix Baptist Hospital, Phoenix,
Arizona
Paul R. Kileny, PhD
Professor and Director, Division of Audiology
and Electrophysiology, Department of Otolaryngology,
University of Michigan Health System, Ann Arbor, Michigan
Louis J. Kim, MD
Resident, Neurological Surgery, Barrow Neurological Institute,
St. Joseph’s Hospital and Medical Center, Phoenix, Arizona
xii CONTRIBUTORS
Karen Iler Kirk, PhD
Associate Professor and Psi Iota Xi Scholar, Department
of Otolaryngology–Head and Neck Surgery, Indiana University
School of Medicine, Indianapolis, Indiana
G. Robert Kletzker, MD, FACS
Clinical Assistant Professor, Department
of Otolaryngology–Head and Neck Surgery, Washington
University School of Medicine; Active Staff, St. John’s Mercy
Medical Center; Barnes Jewish Hospital; Missouri Baptist
Medical Center; Associate Staff, St. Luke’s Hospital;
St. Louis, Missouri
John F. Kveton, MD
Clinical Professor of Otolaryngology/Surgery and
Neurosurgery, Yale University School of Medicine; Attending
Surgeon, Yale New Haven Hospital; New Haven, Connecticut
Anil K. Lalwani, MD
Mendik Foundation Professor and Chairman, Department of
Otolaryngology and Professor of Physiology and Neuroscience,
New York University School of Medicine, New York, New York
Paul R. Lambert, MD, FACS
Professor and Chair, Department of Otolaryngology–Head
and Neck Surgery, Medical University of South Carolina,
Charleston, South Carolina
Michael J. LaRouere, MD
Clinical Assistant Professor, Department
of Otolaryngology–Head and Neck Surgery, Wayne State
University, Detroit, Michigan; Chairman, Department
of Otology, Neurotology, and Skull Base Surgery, Providence
Hospital, Southfield, Michigan; Attending Neurotologist,
Michigan Ear Institute, Farmington Hills, Michigan
John P. Leonetti, MD
Professor of Otolaryngology–Head and Neck Surgery, Loyola
University, Stritch School of Medicine, Chicago, Illinois;
Director, Loyola Center for Cranial Base Surgery, Loyola
University Medical Center, Maywood, Illinois
Robert E. Levine, MD
Clinical Professor of Ophthalmology, University of Southern
California, Keck School of Medicine; Co-Founder
and Co-Director, Center for Facial Nerve Function,
House Ear Clinic; Los Angeles, California
Charles J. Limb, MD
Assistant Professor, Department of Otolaryngology–Head
and Neck Surgery, Johns Hopkins University School of
Medicine; Assistant Professor, Otology, Neurotology, and Skull
Base Surgery, Johns Hopkins Hospital; Baltimore, Maryland;
Staff Physician, National Institute on Deafness and Other
Communication Disorders, National Institutes of Health,
Bethesda, Maryland
William W. M. Lo, MD
Clinical Professor of Radiology, University of Southern California,
Keck School of Medicine; Section Chief, Neuroradiology,
St. Vincent Medical Center; Los Angeles, California
Larry B. Lundy, MD
Assistant Professor of Otolaryngology–Head and Neck Surgery,
Mayo School of Graduate Medical Education, Jacksonville,
Florida
Lawrence R. Lustig, MD
Associate Professor, Department of Otolaryngology–Head and
Neck Surgery, Johns Hopkins University, Baltimore, Maryland
William M. Luxford, MD
Clinical Professor, University of Southern California, Keck
School of Medicine; Associate, House Ear Clinic; Los Angeles,
California
Alexander S. Mark, MD
Associate Clinical Professor of Radiology and Neurosurgery,
George Washington University Medical Center; Director
of MRI, Washington Hospital Center; Washington, DC
Angela D. Martin, MD
Chief Resident Associate and Instructor in Otolaryngology,
Mayo Clinic College of Medicine and Mayo Foundation,
Rochester, Minnesota
Michael W. McDermott, MD, FRCSC
Departments of Neurological Surgery and Radiation Oncology,
University of California at San Francisco, San Francisco,
California
John S. McDonald, DDS, MS, FACD
Volunteer Professor, Department of Anesthesia, and Volunteer
Associate Professor, Department of Pediatrics, Division
of Pediatric Dentistry, University of Cincinnati College
of Medicine, Cincinnati, Ohio
Arnold H. Menezes, MD
Professor of Neurosurgery and Vice Chairman, Department
of Neurosurgery, Roy and Lucille Carver College of Medicine,
University of Iowa Hospitals and Clinics, Iowa City, Iowa
Ted A. Meyer, MD, PhD
Fellow in Neurotology, University of Iowa, Iowa City, Iowa
Anand N. Mhatre, PhD
Assistant Professor, Department of Otolaryngology, New York
University School of Medicine, New York, New York
Dawna Mills, AuD
Adult Cochlear Implant Coordinator, House Ear Clinic,
Los Angeles, California
Lloyd B. Minor, MD, FACS
Andelot Professor and Chairman, Department
of Otolaryngology–Head and Neck Surgery, The Johns
Hopkins University School of Medicine, Baltimore, Maryland
Richard T. Miyamoto, MD, MS
Arilla Spence DeVault Professor and Chairman, Department
of Otolaryngology–Head and Neck Surgery, Indiana University
School of Medicine; Co-Chief, Otolaryngology–Head
and Neck Surgery, Clarion; Indianapolis, Indiana

Aage R. Møller, PhD
Professor, MF Johnson Endowed Chair, University of Texas
at Dallas, Dallas, Texas
Edwin M. Monsell, MD, PhD
Professor of Otolaryngology–Head and Neck Surgery, Wayne
State University School of Medicine, Detroit, Michigan
Jean K. Moore, PhD
Emeritus Scientist, House Ear Institute, Los Angeles, California
Karsten Munck, MD
Resident, University of California, San Francisco,
San Francisco, California
Haruka Nakahara, MD
Assistant Professor, Department of Otolaryngology–Head and
Neck Surgery, Tokyo University Medical School, Tokyo, Japan
J. Gail Neely, MD
Professor and Director, Otology/Neurotology/Base of Skull
Surgery, Department of Otolaryngology–Head and Neck Surgery,
Washington University School of Medicine, St. Louis, Missouri
Steven A. Newman, MD
Professor of Ophthalmology, University of Virginia,
Charlottesville, Virginia
Thomas Nikolopoulos, MD, DM, PhD
Assistant Professor, Athens University Medical School,
Athens, Greece
John K. Niparko, MD
George T. Nager Professor, Otolaryngology–Head and Neck
Surgery, The Johns Hopkins School of Medicine; Director,
Division of Otology, Neurotology, Johns Hopkins Hospital;
Baltimore, Maryland
Michael A. Novak, MD
Clinical Assistant Professor of Surgery, University of Illinois,
School of Medicine at Urbana-Champaign; Chairman, Division
of Otolaryngology, Carle Clinic Association; Urbana, Illinois
Gerard M. O’Donoghue, MD, FRCS
Professor, Department of Surgery, University of Nottingham;
Professor, Department of Otolaryngology, Queens Medical
Centre, University Hospital; Nottingham, United Kingdom
John S. Oghalai, MD
Assistant Professor, Department of Otorhinolaryngology
and Communicative Sciences, Baylor College of Medicine,
Houston, Texas
Michael J. O’Leary, MD, FACS
Clinical Assistant Professor, Uniformed Services University
of the Health Sciences, Bethesda, Maryland; Chief,
Neurotology, Skull Base Surgery Division, Senta Medical
Clinic, San Diego, California
Vincent B. Ostrowski, MD
Midwest Ear Institute, Indianapolis, Indiana
Contributors xiii
Steven R. Otto, MA
Advanced Research Associate, House Ear Institute,
Los Angeles, California
Dennis Pappas, MD
Pappas Ear Clinic; Director of Neurotology, Healthsouth
Medical Center; Birmingham, Alabama
Lorne S. Parnes, MD, FRCSC
Professor and Chair, Department of Otolaryngology,
University of Western Ontario; Chief, Department of
Otolaryngology, London Health Sciences Centre; London,
Ontario, Canada
Ian F. Parney, MD, PhD, FRCSC
Neuro-Oncology Service, Department of Neurological Surgery,
University of California at San Francisco, San Francisco,
California
Myles L. Pensak, MD
Professor Otolaryngology–Head & Neck Surgery and
Neurologic Surgery, University of Cincinnati, Cincinnati, Ohio
Markus H. F. Pfister, MD
Visiting Assistant Professor, Department of Otolaryngology–
Head and Neck Surgery, Stanford University School of
Medicine, Stanford, California
Lawrence H. Pitts, MD
Professor, Neurosurgery and Otolaryngology, University of
California at San Francisco, San Francisco, California
Curtis W. Ponton, PhD
Senior Scientist, Compumedics Neuroscan, El Paso, Texas
Steven D. Rauch, MD
Associate Professor, Otology and Laryngology, Harvard
Medical School; Surgeon, Department of Otolaryngology,
Otology Service, Massachusetts Eye and Ear Infirmary; Boston,
Massachusetts
Miriam I. Redleaf, MD
Assistant Professor of Surgery, University of Illinois Hospitals,
University of Illinois, Chicago, Illinois
Grayson K. Rodgers, MD
President/Director, Birmingham Hearing and Balance Center,
Birmingham, Alabama
Seth I. Rosenberg, MD, FACS
Clinical Assistant Professor, Department of
Otorhinolaryngology, University of Pennsylvania, Philadelphia,
Pennsylvania; Active Staff, Sarasota Memorial Hospital; Active
Staff, Cape Surgery Center; Active Staff, Surgery Center of
Sarasota; Vice President, Silverstein Institute; Vice President,
Ear Research Foundation; Sarasota, Florida
Edwin W Rubel, PhD
Professor, Department of Otolaryngology–Head and Neck
Surgery, University of Washington, Seattle, Washington
xiv CONTRIBUTORS
Christina L. Runge-Samuelson, PhD
Assistant Professor, Division of Otology and Neuro-otologic
Skull Base Surgery, Department of Otolaryngology
and Communication Sciences, Medical College of Wisconsin;
Children’s Hospital of Wisconsin/Froedtert Hospital;
Milwaukee, Wisconsin
Tammy S. Schumacher-Monfre, MSN, APNP
Instructor, Department of Otolaryngology and Communication
Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
Mitchell K. Schwaber, MD
Clinical Associate in Otolaryngology, Vanderbilt University;
Medical Director, St. Thomas Neuroscience–Hearing and
Balance Center, St. Thomas Hospital; Nashville, Tennessee
Dietrich W. F. Schwarz, MD, PhD
Professor, Department of Surgery (Otolaryngology), University
of British Columbia, Vancouver, British Columbia, Canada
Samuel H. Selesnick, MD
Professor and Vice Chairman, Department
of Otorhinolaryngology, Weill Medical College of Cornell
University; Attending Otolaryngologist, Weill Cornell Center
of New York Presbyterian Hospital; New York, New York
Robert V. Shannon, PhD
Adjunct Professor, Biomedical Engineering, University of
Southern California; Head, Department of Auditory Implants
and Perception, House Ear Institute; Los Angeles, California
Neil T. Shepard, PhD
School of Medicine, University of Pennsylvania; Director
of Audiology, Speech Pathology, and the Balance Center,
University of Pennsylvania Health System, Hospital
of the University of Pennsylvania; Philadelphia, Pennsylvania
Herbert Silverstein, MD, FACS
President, Silverstein Institute, Sarasota, Florida
Ameet Singh, MD
Resident, Department of Otolaryngology, Strong Memorial
Hospital, University of Rochester Medical Center, Rochester,
New York
Aristides Sismanis, MD, FACS
Professor and Chairman of Otolaryngology–Head and Neck
Surgery, Virginia Commonwealth University Medical Center,
Richmond, Virginia
William H. Slattery III, MD
Clinical Professor, Department of Otolaryngology, University of
Southern California; Director, Clinical Studies Department and
Associate, House Ear Institute and Clinic; Los Angeles, California
Peter G. Smith, MD, PhD
Clinical and Assistant Professor of Otolaryngology–Head
and Neck Surgery, Washington University School of Medicine,
St. Louis, Missouri
Eric E. Smouha, MD, FACS
Associate Professor of Surgery and Clinical Neurosurgery, State
University of New York at Stony Brook, Stony Brook, New York
Robert W. Sweetow, PhD
Clinical Professor of Otolaryngology and Director
of Audiology, University of California San Francisco,
San Francisco, California
Mark J. Syms, MD
Otologist/Neurotologist, Section of Neurotology, Department
of Neurosurgery, Barrow Neurological Institute; Attending
Otologist/Neurotologist, Phoenix Children’s Hospital;
Phoenix, Arizona
Thomas A. Tami, MD, FACS
Professor of Otolaryngology, University of Cincinnati,
Cincinnati, Ohio
Steven A. Telian, MD
John L. Kemink Professor of Neurotology, University
of Michigan, Ann Arbor, Michigan
Fred F. Telischi, MEE, MD
Professor of Otolaryngology, University of Miami School
of Medicine; Attending Physician and Surgeon, Jackson
Memorial Hospital; Director, University of Miami Ear
Institute; Miami, Florida
R. David Tomlinson, PhD
Associate Professor, Department of Otolaryngology,
University of Toronto, Toronto, Ontario, Canada
Debara L. Tucci, MD
Associate Professor, Duke University Medical Center, Durham,
North Carolina
P. Ashley Wackym, MD
John C. Koss Professor and Chairman, Department
of Otolaryngology and Communication Sciences, Medical
College of Wisconsin; Chief, Otolaryngology–Head and Neck
Surgery, Froedtert and Medical College Hospital; Chief,
Pediatric Otology, Children’s Hospital of Wisconsin;
Milwaukee, Wisconsin
Robert A. Williamson, MD
Fellow in Otology/Neurotology, The Bobby R. Alford
Department of Otorhinolaryngology and Communicative
Sciences, Baylor College of Medicine, Houston, Texas
Charles Yingling, PhD, D ABNM
Otolaryngology/Head and Neck Surgery, Stanford University,
Stanford, California
Nancy M. Young, MD
Associate Professor, Northwestern University Feinberg School
of Medicine; Head, Section of Otology and Neurotology,
Children’s Memorial Hospital; Chicago, Illinois
Kenneth C. Y. Yu, MD
Staff Surgeon, Department of Otolaryngology–Head and Neck
Surgery, United States Air Force Base, Elmendorf Air Force
Base, Alaska

THE NEUROTOLOGY SAGA:
A PERSONAL PERSPECTIVE
During the past few years, I have heard myself introduced
on occasion as the “Father of Neurotology.” If this is true,
then it is also true in my case that being this kind of a
father is not something that was planned; it just happened.
In looking back, I realize now that it all started during
my third and last year of ear, nose, and throat (ENT)
residency at Los Angeles County Hospital. The year was
1955. I was 31 years old. By then June and I had been
married for 10 years, and Karen was 8 and David 7. I had
completed dental school, served 2 years in the Navy as a
dentist, finished medical school, and taken the ENT resi-
dency so that I could become a plastic surgeon. June was
helping to hold the household together by working part
time in my brother Howard’s office as an RN.
ENT was not a sought-after residency at that time
because it was widely believed that penicillin was eliminat-
ing the sinus, mastoid and tonsil, and adenoid problems
that occupied the eye, ear, and nose specialists. In fact, we
had so few residents that I was obliged to be on-call at the
hospital every other night. Fortunately, the library was well-
stocked so I had time to read the latest ENT literature.
There was no full-time ENT faculty, but there was usually
an attending physician to help in the clinics and in surgery
several times a week. As I look back, I can now call the resi-
dency a learning residency instead of a teaching residency.
During the last year of my residency much of my learning
came through Howard, who (being 15 years older than I) had
finished the 2-year Los Angeles County residency in 1939
and had established a large practice that was 95% otology.
He was doing seven or eight fenestration operations a
week; this included Saturday morning surgery. In addition
to this, he usually had two or three ENT doctors taking a
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.
I would often help in the morgue, and Howard encouraged
me to do cadaver head and neck dissection and surgical
procedures. On Saturdays, I often observed his surgery.
Howard also introduced me to a very remarkable, older
ENT practitioner, Gilbert Roy Owen. He had become
very interested in temporal bone and sinus x-ray. As time
permitted I would go to his office, and he would take me
through his remarkable collection of x-ray pathology. One
of the things he repeatedly showed me was the enlarged
Foreword
internal auditory canal of acoustic tumors. I remember
going to the library and reading as much as I could find on
acoustic tumors. The recurring theme was that these were
serious, although benign, lesions that should be operated
on as early as possible.
During the last few months of my residency, a remark-
able event occurred that was to change my life. Howard
had heard of some interesting work going on in Germany
called “tympanoplasty.” He visited Dr. Wullstein in
Wurtsburg and for the first time saw the Zeiss microscope.
He immediately ordered a microscope (I believe for the
large sum of $2,000) and invited Dr. Wullstein to come to
Los Angeles to demonstrate his techniques. It was my job
to chauffeur the doctor to his demonstrations. The film
that he showed of temporal bone surgery through the
microscope were astounding to me in terms of what you
could see of the temporal bone structures over what we
had been seeing with the headlight and loops. He took
these films by working to a point in the tympanoplasty and
then swinging in a microscope with a camera mounted on
one eyepiece. While he worked through the other eyepiece,
he filmed the procedure.
When Howard’s microscope arrived he began using it
in the new stapes mobilization procedures, and I would
take the microscope to the morgue at night to explore the
wonders of the temporal bone.
On completion of my residency in July 1956, I joined
Howard in his office. By then I had become fascinated with
otology, and—because of Howard’s practice—I was able to
spend all my time in otology. The first few hours of each
day were spent making the rounds of several Los Angeles
hospitals to change the dressings of Howard’s numerous
fenestration patients. The remainder of the day was spent
in the office cleaning fenestration cavities and seeing a
never-ending stream of otology patients.
STARTING PRACTICE
AND DEVELOPMENT OF THE FACIAL
RECESS APPROACH
It was an exciting time to be starting an otology practice.
Wulstein and Zolner had introduced “tympanoplasty”
surgery using a Zeiss microscope a few years earlier, and
Howard was doing a few skin grafts to the middle ear at the
time of mastoid surgery. John Shea (whom I had gotten to
know during my residency because he had spent some time
xix
xx FOREWORD
with Howard learning fenestration surgery) had boldly
introduced stapedectomy because so many of the stapes
mobilization procedures that had been introduced by
Rosen a couple of years before were refixing. Howard,
who for years had been doing 10 or 12 fenestrations a
week, asked John to come to Los Angeles and demonstrate
his revolutionary stapes removal operation. As the word
spread of the remarkable results these stapedectomy
patients were getting, the patients came flocking to
Howard’s office. I was immediately busy working up these
patients and getting them on Howard’s surgery schedule.
It soon became apparent that Howard had no time for
anything else except otosclerosis surgery. No one wanted
the kid brother to do their stapes surgery. Many of the
patients, hoping to get their hearing restored by this new
miracle surgery, turned out to be chronic ear patients.
After all, antibiotics except for sulfa drugs had only been in
widespread use for 10 years. Howard was more than will-
ing to turn these patients over to me and encouraged them
to have me do their mastoid surgery.
During my residency, the goal of radical and modified
radical mastoid surgery was to open the mastoid to allow it
to drain rather than back up into a brain abscess. Antibiotics
and tympanoplasty procedures using the microscope were
challenging these concepts that had been the standard of
practice for the past 75 years. The microscope made it
possible to see the facial nerve more clearly and, therefore,
allowed much more complete removal of cholesteatoma
and granulation from the middle ear rather than leaving
it wherever the facial nerve might be. Indeed, I remember
my instructors during my residency telling me that if
you so much as touch the facial nerve, it will become
paralyzed.
Tympanoplasty procedures were now advocating graft-
ing over the middle ear with skin and, thus, violating the
leave open for drainage principle. It was soon found that
grafting over infected granulation even with vigorous
postoperative antibiotics was unsuccessful. It became
obvious to me that if all the middle ear granulation and
cholesteatoma was to be removed it was necessary to know
where facial nerve was and treat it as a friendly landmark.
The microscope made this possible through identifying
the horizontal canal and lifting the granulation to locate
the facial nerve in the tympanic segment. Visualization was
also enhanced by developing continuous irrigation suction
where the amount of water flow and suction were con-
trolled by rotating the thumb over the suction hole. Until
then, mastoid surgery had been done by drilling using two
hands on the drill as taught by Lempert; then irrigating
and suctioning. This was a slow, tedious process, and
I remember taking 3 or 4 hours to do a mastoid in the
laborious way. However, using one hand on the drill and
one hand on the suction was sometimes viewed as reckless
surgery. However, Howard let me do it and often came to
my defense in discussions with colleagues.
The principle of chronic ear surgery thus changed to
remove the disease and cure the infection. The tym-
panoplasty grafts were now much more successful, but
there were still problems. Mastoid cavities are subject
to accumulation of debris and recurrent infection. It was
discouraging to see a nice tympanoplasty result, with some
improvement in hearing, be wiped out by a recurrent
infection that destroyed the graft. To overcome this prob-
lem, many different mastoid obliteration procedures such
as swinging in muscle from the temporalis, and various
plastic and tissue inserts were advocated. I tried all of these
procedures and found them all to be wanting.
It became obvious to me that the best answer was to
avoid creating a cavity. After all, we were no longer simply
opening things for drainage; we were now after a cure for
the infection. But if we left the posterior boney ear canal
intact, could we see well enough to remove all the infected
tissue in the middle ear? The answer was “no,” so it was
back to the dissection lab again. I had seen Wullstein on
his type I tympanoplasties, that is, those with an intact
ossicular chain drill a “control hole” and was able to visu-
alize through this disease in the middle ear. This was done
quite blindly, and it frightened me because I could visual-
ize a good chance of hitting the mastoid part of the facial
nerve. In the dissection lab, I learned how to skeletonize
the mastoid part of the facial just inferior to the horizontal
canal and open the area widely for good visualization of
the stapes incus and posterior part of the middle ear. The
chorda tympani nerve and the annulus of the ear drum
were used as landmarks. I named this the “facial recess
approach” because I wanted to emphasize the facial nerve
as the basic landmark.
Fortunately, this approach is now widely used and has
become the standard in cochlear implant surgery. However,
leaving the canal wall intact led to new problems. Wullstein
had advocated four types of tympanoplasty. Type 1 would
now be called a myringoplasty because the ossicular chain
is intact. Type 2 was a graft to the head of the stapes. Type
3 was a graft to the promontory to leave the oval window
open if the stapes superstructure was gone. Type 4 was
fenestration of the horizontal canal if the oval window
was obliterated. It is obvious that these procedures were
designed to avoid reconstructing the ossicular chain.
Leaving the canal wall intact made it necessary to recon-
struct the ossicular chain since the graft was now in the
location of the previous ear drum. As intact canal wall pro-
cedures became more widely used, a number of otologists,
including myself, devised a number of prosthetic recon-
struction procedures.
Such reconstruction of the ossicular chain led to another
problem. If the middle ear did not become aerated, the
hearing result was poor and the graft would adhere to
the promontory. There would also be a retraction of the
graft into the attic and a new cholesteatoma formation.
I tried a number of procedures to avoid this retraction,
including placing wire mesh in the attic to prevent the
retraction. I called the procedure the “iron curtain proce-
dure.” Months later, to my horror, if the middle ear did not
aerate I saw the skin retract through the mesh and, thus,
become a worse problem than the original cholesteatoma.
I learned that aeration, not obliteration, is essential for
successful chronic ear surgery.
I told the story of my experience with the development
of chronic ear surgery in a book dedicated to neurotology
to illustrate how temporal bone surgery had developed
after the microscope was introduced. The use of amplifi-
cation, continuous suction irrigation, and use of the facial
nerve as a landmark allowed us to develop temporal bone
procedures to move through the temporal bone with

dispatch and, thus, develop the next generation of tempo-
ral bone surgery. The retrolabyrinthine, translabyrinthine,
transcochlear, and middle fossa approaches would not
have been possible before today’s chronic ear surgery was
developed.
DEVELOPMENT OF THE MIDDLE
FOSSA APPROACH
Obviously, otosclerosis has been a big part of my life. To
find out more about it, I read a two-volume series of arti-
cles on otosclerosis that had been collected by the
American Otologic Society. One of the articles that caught
my eye was a study that detailed how otosclerosis lesions
commonly occurred around the cochlea above the internal
auditory canal and compressed the cochlear nerve. This
was theorized to be a possible cause for the sensorineural
loss that I was frequently seeing in otosclerotic patients. It
seemed logical to me that if you could drill away the oto-
sclerosis and relieve the pressure on the eighth nerve, you
might reverse some of the hearing loss.
I have always been an early riser, and I remember sitting
one morning and looking at a dissected skull that my
father had given me in dental school. There was a yellow
line for the greater superficial petrosal nerve, and it
occurred to me that this might be the key to follow back to
the geniculate ganglion and then on along the labyrinthine
part of the facial to the internal auditory canal.
By this time we could afford a babysitter, so June and
I started going to the morgue to see if I could get to the
internal auditory canal without damaging the hearing or
the facial nerve. Because of my experience with diamond
burrs and irrigation in dentistry, I had already adapted these
procedures to my work in chronic ear surgery. June would
set up the microscope and instruments and act as the scrub
nurse to facilitate the dissection. Since the approach called
for elevation of the temporal lobe, I recruited the help of a
young neurosurgeon, Ted Kurze, and after a number of dis-
sections I felt we were ready for our first case.
For this case, I selected an attorney who had changed
careers to become an accountant after he went completely
deaf. His medical records clearly showed that he had oto-
sclerosis. On August 1, 1958, June’s birthday, we did the
first middle fossa decompression at St. Vincent Hospital in
Los Angeles. I was very honored and not a little scared that
Dr. Carl Rand, the dean of Los Angeles neurosurgery,
Cushing’s last resident, and Dr. Kurze’s associate, came to
watch the surgery.
As far as I know, this was the first intracranial procedure
in which the operating microscope was used. During the
procedure, using the old Jordan Day drill with belt-driven
engine arm and hand-piece, enough static electricity
developed that it caused frequent stimulation of the facial
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
to me, but I was already so nervous that I came very close
to aborting the procedure.
Fortunately, the patient recovered well, with no facial
weakness. I remember his wife telling me how sexy she
thought he looked with his completely shaved head.
Foreword xxi
Unfortunately, he did not recover any hearing. Some years
later he was to become one of my first cochlear implant
patients.
DEVELOPMENT OF ACOUSTIC
NEUROMA SURGERY
My discouragement because the operation did not recover
any hearing was offset by my realization that the middle
fossa approach had a number of other possibilities, such as
vestibular nerve section and identification of the facial
nerve during acoustic tumor surgery.
Early in practice I had seen a very handsome young fire-
man with a unilateral hearing loss. I sent him to Dr. Owen
for x-rays. The report came back that he had an enlarged
internal auditory canal. I referred him to Dr. Kurze who
concurred with my diagnosis of an acoustic neuroma. He
told me that he did not want to operate at that time
because the patient would trade a little hearing loss and
tinnitus for certain facial paralysis and possibly ataxia.
Within 2 years he had developed facial numbness and early
papilledema. I attended the surgery, which was performed
with the patient in the sitting position and took some
hours. Unfortunately, the patient stopped spontaneous
respiration and died several days later. In a later discussion
with Dr. Kurze, we both agreed that he had done all he
could. I will never forget what he said, “You have to real-
ize we were dealing with a large tumor.”
I realized in the aftermath of the loss of this patient that
the key to early acoustic tumor surgery was preservation of
the facial nerve. I remember that I dreaded seeing and
evaluating patients with unilateral hearing loss because
I felt that if a diagnosis of acoustic neuroma was established
the patient’s doom was sealed.
June and I continued our sessions in the morgue. I was
trying to work out an approach to the cerebello-pontine
angle through the middle fossa. The concept was to iden-
tify the facial nerve at the beginning of the procedure and
then to dissect the acoustic tumor away from it. I had
never operated on a acoustic tumor, but I teamed up with
a young neurosurgeon, Jack Doyle, who had just finished
his residency at the Mayo Clinic. We did our first acoustic
in January 1960, using the microscope, with the patient in
the sitting position. Drilling out the labyrinth and internal
auditory canal down to the jugular bulb using a slow
Jordan Day drill is a long and very tedious procedure. Jack
Urban, a fantastic engineer who died some years ago and
whom I still miss very much, helped me develop a special
retractor and a seat with arm rests. It was a partial removal.
The patient had some facial weakness but recovered well.
During the next 3 years, we were to do another 20 tumors
this way. The histories and the results are chronicled in
our first monograph.
DEVELOPMENT OF THE
TRANSLABYRINTHINE APPROACH
Operating in the sitting position and removing the
labyrinth through the middle fossa was very onerous to me.
My experience with mastoid surgery, with the patient
xxii FOREWORD
prone on the table, seemed to present some interesting
possibilities. So it was back to the dissection lab and to
investigations on how to remove the labyrinth and open
the internal auditory canal using mastoid procedures.
I soon found that the facial nerve could be skeletonized,
the labyrinth removed, and the internal auditory canal
opened, without having to retract any brain or drill away
any bone with the dura open.
Fortunately at this time, Bill Hitselberger came into my
life and, for the first time, I could work with a neurosur-
geon who really wanted to learn temporal bone surgery
and be able to apply the expertise of neurosurgery to the
problems of acoustic neuroma surgery. We soon recog-
nized that it was safer and much easier to operate with the
patient in a supine position and to approach the angle
through the mastoid and the labyrinth. This eliminated
the constant worry of air embolism and considerably
shortened the dissection down to the angle.
By now, I too, had begun teaching in Howard’s courses,
and many students wanted to learn the temporal bone
approaches. One of these students was Frank Ellis from
Sydney, Australia. During each night of dissection, I would
emphasize that the key to establishing the exact location of
the facial was to identify it at the beginning of the tumor
dissection at the point where it entered the fallopian canal
at the lateral end of the internal auditory canal. I would
say, “Frank you’ve got to see that bar of bone (the vertical
crest) at the end of the canal.” It was Frank who dubbed it
Bill’s bar, a name that has stuck. It is the key to saving the
facial nerve and making early acoustic neuroma removal
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
differently or return to the morgue for a new look at a
particular part of the surgery. We were backed up by Jack
Urban who often observed surgery and developed instru-
mentation, microscope viewing tubes, and camera and
television equipment. It seemed like he could do it all, if it
involved engineering.
Over the next few years, we did a number of acoustic
neuroma surgeries using the translabyrinthine approach.
After 50 cases, we decided it was time to publish our
results. I was very impressed with Cushing’s volume, pub-
lished in 1917. Each patient that he had operated on up to
that time was documented in detail and in sequence. I tried
to emulate this example by publishing each of my cases in
the same way. Fortunately, Dr. George Shambaugh, who
was at that time the editor of the Archives of
Otolaryngology, suggested that we devote an entire issue
of the journal to these cases. This issue was the first sig-
nificant recognition of this work, and I shall always be
grateful to him. It set forth clearly the value of micro-
surgery in acoustic tumor surgery. This heralded a very
significant change in intracranial surgery and was not met
with enthusiasm by the neurosurgical community.
It was through television equipment, starting with the
black and white sets, that we were able to teach many
students. These students have established neurotology
programs and greatly advanced neutotologic procedures
worldwide. I remember Dr. Wullstein saying in one of his
lectures, “If a man develops a procedure that lasts for 3 years
unchanged he has done a very outstanding piece of work,
if it is unchanged in 10 years the man was a genius, but if the
work is unchanged for 20 years he is working in a dead
field. There is no question that neurotology is not a dead
field. Like any father I am very proud of my many neuro-
tology sons and daughters.”
William F. House, M.D.
Staff Otologist
Hoag Memorial Presbyterian Hospital
Private Practice
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
indivisibly linked that I cannot even conceive of one without the
other.”
Theodor Billroth (1829-1894), Über das Lehren und Lernen der medicin-
ishen Wissenbschaften, as translated by Lesky.1
INTRODUCTION
When did the subspecialty of neurotology and skull base
surgery begin? Was it at the first attempt to operate on the
facial or hearing nerves in the 19th century? Are its origins
dated to the first operation on a vestibular schwannoma in
the late 1800s? Was it founded with the introduction of the
operating microscope toward ear surgery in the 1920s?
Was it when otologists and neurosurgeons first combined
their expertise to tackle complicated skull base lesions in
the 1960s? Or was it at the founding of societies devoted
to solely neurotology or skull base surgery? The closer one
examines the question, the quicker one realizes that there
really is no specific point in time when neurotology and
skull base surgery “became” an independent subspecialty.
Rather, it has slowly emerged out of a confluence of inter-
related disciplines and technologies over the past century
to become the field that we know of today as “neurotology
and skull base surgery.” Its formation required the marriage
of neurosurgery and otology; the introduction of the oper-
ating microscope; and advances in surgical technique,
anesthesia, and radiology. Along the way, the field also began
involving specialists within ophthalmology and craniofa-
cial and plastic and reconstructive surgery. Lastly, and
perhaps most importantly, the formation of neurotology
and skull base surgery required pioneering surgeons laden
with confidence, daring, and foresight, who were willing
to push the boundaries of their training, sometimes under
the ridicule or scorn of the medical establishment. This
historical review is a salute to these pioneers’ efforts.
It is undeniable that the field of neurotology and skull
base surgery is in a period of rapid transition, whose his-
tory is still being written. Thus, rather than wade into the
academic debate on matters of primacy of current tech-
niques that makes the practice of surgery so enlivening
(and is the focus of this textbook), this historical overview
will focus on the origins of the specialty up through the
last quarter century, ignoring the myriad strides and
accomplishments made within the past 25 years. Long
before the first skull base or neurotology fellow was trained,
before the operating microscope came into use, and before
the first vestibular schwannoma resection was performed,
the seeds of our specialty were being sewn by visionaries
in the anatomic, physiologic, and surgical sciences.
MEDICAL THOUGHT PRIOR TO THE
EUROPEAN RENAISSANCE
If the underpinnings of neurotology and skull base surgery
are otologic and neuroanatomy and otologic physiology,
then the origins of the specialty can be considered to
date back to antiquity. In the age of the Romans, human
society, including medicine, had advanced to new heights.
Of all the ancient Roman scientific scholars, the most
influential was undeniably Claudius Galen of Pergamum
(c. 129–200 AD). For 1500 years the main source of European
physician’s knowledge about the human body came from
the writings of Galen. As one of the most prolific writers
of antiquity, Galen was said to have produced more than
500 treatises on physiology, rhetoric, grammar, drama, and
philosophy. Mostly, though, Galen is best known for his
prolific treatises on anatomy. Since Roman custom forbade
dissection of the human body, Galen performed all his
dissections on monkeys for external anatomy and used pigs
for internal anatomy. Predictably, this led Galen to many
inaccurate conclusions. However, as the Roman empire
waned, and Christianity, with its belief in the resurrection
of the human body, subsequently dominated the middle
ages, Galen’s inaccuracies would remain buried until the
Renaissance.2 However, Arabic and Byzantium medicine
flourished, based on the ancient Hellenic and galenic
traditions. It was during this time that Aëtius of Amida of
the Byzantine school wrote a comprehensive description
of ear diseases.3 Unfortunately, due to religious restric-
tions like those that existed in Europe, anatomic dissection
was forbidden, limiting the potential medical advances of
these great civilizations.
By the 13th century, the potential benefits of human
cadaveric dissection began to be realized by some enlight-
ened leaders throughout Europe. Emperor Frederick II,
who founded the universities at Padua and Naples (and
incidentally fought continuously with the Church over the
extent of its authority) decreed that all physicians in his
domain were to learn anatomy by studying the human

body, and be required to provide proof of such training.4
With the arrival of the Black Death in 1348, limited
necropsy was allowed by the Church in the hopes of find-
ing the cause. However, the papacy continued its general
prohibition against necropsy and only slowly relaxed its
restrictions over the following 200 years. It was not until
1537 that Pope Clement VII, following the example of the
leading universities at that time, finally endorsed teaching
by anatomic dissection.4 This official sanction paved the
way for a new anatomic revolution. Although Italian artists
such as Leonardo da Vinci subsequently became known for
precise and exquisite anatomic drawings during the time,
this new paradigm shift in anatomy came by way of Brussels,
the birthplace of Andreas Vesalius.
SIXTEENTH CENTURY—THE VESALIAN
REVOLUTION
Born in Brussels in 1514 as the son of the apothecary
to the emperor Charles V, Andreas Vesalius (1514–1564)
(Fig. I-1) received the best medical education of his time at
the University of Paris, where he studied under Professor
Sylvius, the celebrated champion of Galen’s writings.
As professor at the University of Padua, in conducting
his required “anatomy” (from the Greek anatome, for
“cutting up”) he departed from the usual custom of staying
seated high in the professorial cathedra (chair) while a
barber-surgeon pulled out organs from the cadaver below.
Instead, Vesalius himself handled the body and dissected
the organs. While teaching from Galen’s text, Vesalius
noted many instances where Galen’s description was not
found in the human body. He soon realized that Galen’s
Figure I-1. Andreas Vesalius (1514–1564). (From Politzer A: A History of
Otology, Part I, 1904.)
The History of Neurotology and Skull Base Surgery 3
anatomy was really only a compendium of statements about
animals in general. Vesalius insisted that his students see,
feel, and decide for themselves about the inaccuracies of
Galen’s anatomy. His subsequent anatomic studies culmi-
nated in perhaps the most influential textbook of anatomy
ever written. De Humanis Corporis Fabrica5 (The Structure
of the Human Body) was published in 1543, the same year
as Copernicus’ De Revolutionibus, and was destined to be as
equally influential. Amazingly, the treatise was completed
before Vesalius was 28 years old.
Vesalius’ revolutionary approach helped bring anatomy
from the realm of guesswork and superstition into the
domain of science. As the darkness of the Middle Ages
waned and coalesced into the Renaissance, the necessity of
human dissection became obvious and widely accepted.
Renaissance artists like Leonardo, Raphael, and Titian had
broadcast a new realism in the palaces and churches of
Europe, while architects such as Brunelleschi and Alberti
were leading a reexamination and reinterpretation of the
ancient Roman texts and traditions. What Vesalius said was
unimportant compared with the path he opened for future
students to learn about all organs of the body. Vesalius
firmly placed anatomy on the foundations of observed facts
and demonstration. Within a scant half-century, vesalian
anatomy prevailed in European medical schools, and the
study of anatomy would never be the same.2,4 By paving
the way for a generation of otologic and neuroanatomists,
Vesalius was instrumental in establishing a method for under-
standing the anatomy of the ear and skull base, a critical
step in the formation of the specialty of neurotology and
skull base surgery.
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-
most anatomists of his era. Living from approximately
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
Otology, Part I, 1904.)
anatomist and physician, but also as a philosopher and a
linguist. He was a professor at the Sapienza hospital, the
same hospital da Vinci had been denied access to only a few
decades earlier for performing dissections there. As a pro-
fessor, Eustachio was a fanatical supporter of Galen’s
anatomic ideas. As a result, he and Vesalius became natural
antagonists. Eustachio vehemently criticized Vesalius’
description of the organ of hearing, going so far as to say
that Vesalius’ entire work failed to contain a shred of truth.6
He was critical of Vesalius’ description of the course and
ramifications of the facial and acoustic nerves and of his
superficial description of the organ of hearing. Given
Vesalius’ lack of interest in the anatomy of the ear, and this
being Eustachio’s field of expertise, these charges may have
held some truth.7
Eustachio’s principle work was the Opuscula Anatomica,
written in 1564.8 Its beautiful copper plate illustrations
Figure I-3. Bartholommeo Eustachio (1520–1574). (From Politzer A:
A History of Otology, Part I, 1904.)
were entrusted to an assistant, but somehow became lost.
They were rediscovered 160 years later in the Vatican Papal
Library by Lancisi, Pope Clement XI’s personal physician.
On the advise of Morgagni, Eustachio’s illustrations were
published with Lancisi’s own notes in 1714.9
Although he is known for his otologic discoveries,
Eustachio’s findings span the entire field of anatomy. He
described the tensor tympani and was the first to establish
that the chorda tympani is intimately associated with the
lingual nerve. Eustachio’s writings contain cross sections
of the petrous portion of the temporal bone, the ossicles,
and the vestibule (Fig. I-4). He described the turns of the
cochlea, the osseous and membranous spiral lamina, and
the modiolus. His greatest contribution to otology,
however, lay in providing a precise description of the shape
and course of the tubular structure bearing his name,
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

Figure I-5. Gabrielle Fallopio (1523–1562). (From Politzer A: A History of
Otology, Part I, 1904.)
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-
tive, and largely untested, beliefs. Invasive surgery was of
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
in poverty in 1736 in Ruvo, near Naples, diligent study and
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
smallest, work, De Aquaeductibus Auris Humanae Internae
Anatomica Dissertatio18 (Figs. I-13 and I-14). In this land-
mark treatise, Cotugno was the first to establish that fluid
Figure I-13. Title page to Cotugno’s work, De Aquaeductibus Auris Humanae
Internae Anatomica Dissertatio, 1775.
completely fills the cavities of the labyrinth, debunking
an idea that had been around since the time of Galen, that
air fills the inner ear. Cotugno achieved success where
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

Figure I-12. Domenico Cotugno (1736–1822). (From Politzer A: A History of
Otology, Part I, 1904.)
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
of Bologna. Gradually, Scarpa became well versed in all
disciplines of medicine and surgery, becoming Morgagni’s
10 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY
most revered student. It is said that Morgagni died in
Scarpa’s arms.6 He continued his education by traveling to
the leading medical centers of Europe. His first book, De
Structura Fenestrae Rotundae (Fig. I-16), asserted that sound
is transmitted to the labyrinth both by way of the ossicular
chain and by way of air in the middle ear to the round
Figure I-15. Antonio Scarpa (1747–1832). (From Politzer A: A History of
Otology, Part I, 1904.)
Figure I-14. Illustration from
Cotugno’s work, demonstrating
his anatomical preparations of the
temporal bone and bony labyrinth.
window.21 His greatest contribution came in1789 with the
publication of Disquisitiones Anatomicae de Auditu et Olfactu,
where he presented his discovery of the membranous
labyrinth and the spiral cochlear duct, filled with fluid later
called Scarpa’s fluid, or endolymph.22 His studies, outlined
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
(It has been speculated that it was not Petit, but the pio-
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
years prior to this description, on the King of France,
François II. However, though technically capable, Paré in
all likelihood did not attempt the surgical procedure.)25
The Prussian military surgeon Jasser also reportedly
operated on a soldier for coalescent mastoiditis, postauric-
ular swelling, and aural discharge in 1776. His technique
involved fitting the tip of a syringe into the mastoid
and vigorously irrigating. After his initial success, and
supported by further cadaveric studies, he subsequently
made a small hole in the mastoid cortex with a trocar and
again successfully cured a patient by repeated irrigations.26
Despite the successes of Petit and Jasser, however, mastoid
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
heard of Petit’s success with the mastoid trephination pro-
cedure, though perhaps not completely understanding the
correct indications for the operation, persuaded a surgeon to
operate on his own mastoid to relieve his tinnitus and hear-
ing loss. Bergen’s well-publicized tragic and painful death
12 days later literally doomed the procedure for a hundred
years, until it was again successfully reintroduced by Herman
Schwartze in the late 1800s.26
THE NINETEENTH CENTURY
Despite limited surgical successes in the mastoid and cranial
cavity, the progress in otologic knowledge through the 18th
century was primarily concerned with anatomic discoveries,
with only a few advances in pathophysiology. At the begin-
ning of the 19th century, the dissection of cadavers was
widely accepted and an integral part of medical education.
As a result, in the early 1800s the demand for cadavers
increased dramatically. This lead to body shortages, fueling
illegal body acquisitions, and in some cases murder, to
obtain cadavers for dissection!4 However, by the mid-19th
century the study of gross anatomy was legally standardized
throughout European medical schools and has changed little
until the present.
Yet, despite Valsalva’s emphasis of the importance of
pathologic correlation with disease states a century before,
knowledge in this area was still limited, and clinical diagno-
sis hadn’t changed appreciably during the previous 300 years.
Ear exams were still performed with available sunlight as
they were before the Renaissance, and surgery of the ear was
limited to a few operations of the external auditory meatus
and auricle, despite soaring advances in other surgical areas.
As already mentioned, the early “mastoidectomy” or mastoid
trephine was nearly abandoned in the late 1700s, though not
completely, being condemned by ear surgeons in the medical
literature as late as 1870.27 Neurosurgery still primarily con-
sisted of operations on the skull itself; trephination for infec-
tions, and the management of head trauma. The two primary
clinical otologic advances during the 18th century were
catheterization of the eustachian tube by E. G. Guyot in
1724, and paracentesis of the drum, popularized by Sir Astley
Cooper in 1800.28,29 Interestingly, Guyot was the postmaster
of Versailles who was said by von Tröltsch to have relieved
his own deafness by injecting his eustachian tube using a
curved tube introduced through his mouth.30
It is not until the 19th century that a significant under-
standing of otologic disease and advances in neurotology
and neurosurgery finally take place. Great strides in
histology, pathology, and physiology in the early 1900s led
to the development of the new branch of laboratory
medicine in the second half of the 19th century.31 Though
this pathologic-anatomic revolution began in Paris in the
early part of the century with Cruveilhier, it was quickly
superseded by advancements in what is now Germany and
Austria.32 Germany was at the forefront of this revolution
because they had developed a large body of full-time sci-
entists, while in the rest of Europe, research and teaching
still depended mainly on the work of practicing physicians.
In German universities, the organization of teaching and
research careers became centralized around the professor,
enabling the gradual introduction of new specialties that
incorporated the scientific advances occurring simultane-
ously.32 This academic organization eventually became
the model for American universities. (The influential von
Tröltsch later credited the “critical German spirit” for the
gradual intellectual shift from England to Germany and
eastern Europe during this time period.30)
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
medicine, but rather as a dynamic science that incorpo-
rated pathology and functionality, anatomic teaching
began to be viewed as the foundation of surgical training.
With this new emphasis on anatomic and pathologic
education, it is no coincidence that many operations, such
as the appendectomy and hysterectomy, were successfully
described for the first time during the late 1800s and early
1900s.33,34 Furthermore, the numerous European wars of
the 18th and 19th centuries provided most surgeons ample
trauma experience, establishing the careers of such notable
surgeons as John Bell (1763–1820) and his younger
brother Charles Bell (1774–1842), John Abernathy
(1764–1831), and Sir Astley Cooper (1768–1841).
Additionally, the physics of sound and acoustical science
was advancing at a rapid pace, thanks to the works of
Laplace, Jean-Daniel Colladon (1802–1893), and Félix
Savart (1791–1841). All these simultaneous anatomic,
physiologic, and surgical developments crystallized the
understanding of the ear and skull base during the 19th
century and would lead to the independent creations of
otology and neurosurgery, the twin pillars of neurotology
and skull base surgery.
Sir Charles Bell and Cranial
Nerve Physiology
Sir Charles Bell (Fig. I-18) is now most commonly remem-
bered for the clinical facial palsy bearing his name.
Yet Bell’s contributions to medical science were infinitely
greater. In the early part of the 19th century, Bell would
conduct a series of investigations that would radically change
our understanding of neuroanatomy and neurophysiology.
Charles Bell was born in 1774 in Fountainbridge, a
suburb of Edinburgh. It was during his high school years
that the young Charles began to assist his older brother
John, a lecturer at the Anatomy School in Edinburgh,
where Charles also began attending medical lectures.35
By 1799 at the precocious age of 23, the younger Charles
had already displayed a surgical and anatomic skill akin to
that of his master and older brother. By 1814, while prac-
ticing in London as the surgeon to the Middlesex
Hospital, Charles Bell had already achieved a formidable
reputation, having published A System of Dissections in
1798, contributed to his brother John’s Anatomy of the
Human Body, and completed his masterful, Essays on the
Anatomy of Expression in 1806. This later, magnificent
four-volume publication revealed Bell not only as an expert
anatomist, but as one contemporary put it, one possessed of
the “. . . most exquisite taste and feeling for sculpture and
painting.”35 John Flaxman (1755–1826), one of the greatest

Figure I-18. Sir Charles Bell (1774–1842), whose research led to a
revolutionary conception of the anatomy and physiology of the cranial and
spinal nerves. His discovery that individual nerves have a defined course
from the brain to the periphery, that different nerves have quite
distinct functions, and that the roots of the spinal nerves have distinct,
compartmentalized functions has been hailed as epoch-making as Harvey’s
discovery of the circulatory system.
of English sculptors, later said that the book had done
more for the arts than anyone of the age.36
These contributions alone would have merited Bell’s
inclusion into the pantheon of great physicians. However,
Bell would accomplish much more. In the preface to his
now classic work, The Nervous System of the Human Body
(Fig. I-19),37 in which his papers originally read to the
Royal Society through the 1920s were reprinted, Bell
summarized the prevailing attitude toward neurology at
the start of his investigations:
“In the period immediately preceding the publication of these
papers in the Philosophical Transactions, there was a singular
indifference to the study of the nerves; and an opinion very gen-
erally prevailed that as the notions of the ancients had descended
to us uncontroverted and unimproved, the subject was entirely
exhausted. The hypothesis that a nervous fluid was derived from
the brain, and transmitted by nervous tubes, was deemed
consistent with anatomical demonstrations, and there was no
hope for improvement.”
Despite the anatomic knowledge, physiology of the cranial
and spinal nerves was limited, and the concept that separate
nerves would transmit sensory and motor information was
occasionally speculated about, but never proven. It was
generally accepted that a nervous fluid circulated along the
nerves, indifferently one way or the other, acting both for
motion and sensation. The function of the ganglia of the
spinal nerves and of the large ganglion related to the poste-
rior root of the trigeminal nerve was still a mystery.
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.
Ten years later Bell read a series of papers to the Royal
Society37 in which he proposed a classification of nerves
into two broad groups: those involved in “respiration”
(including the facial, vagus, spinal accessory, phrenic, and
long thoracic nerves), and another group that included
all the other “symmetrical” nerves that Bell felt were
necessary for “life and motion.” Bell also made several crit-
ical observations in the living donkey that clearly estab-
lished separate roles for the facial nerve (motion) and
trigeminal nerve (sensation). In support of these obser-
vations, Bell quoted several of his clinical cases. Among
other findings, these experiments allowed Bell to clearly
differentiate a more potentially serious central facial palsy
from a less serious peripheral injury and allowed him
to admonish surgeons to be watchful of the facial nerve
when operating in this area. Interestingly, nearly all of
Bell’s cases of facial palsy that accompanied this pioneering
work resulted from tumors, purulent infection, or iatro-
geny, and not from what we today would consider Bell’s
palsy.
Based on the innovative work of Bell, François
Magendie (1783–1855) in France was able to subsequently
solve the riddle of the ganglion in the spinal cord. While
Bell and Magendie were initially quite friendly, their
relationship turned sour when each claimed primacy in
the discovery of the separate function of the nerve roots.
The debate turned rather rancorous at times.35 History
has been kind to both scientists, however, giving neither
sole credit for the discovery. It is now known as the
Bell–Magendie rule, which in medical literature is used to
indicate the direction of conduction in the spinal nerve
roots. For a long time it also had the double entendre of
signifying a compromise between the points of view of the
older type of anatomist who arrived at function by way of
inference and the physiologically minded investigator who
insists on experimental verification.
14 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY
Early 19th-Century Advances
in Vestibular Science
The understanding of disorders of balance would also
undergo major advances in the 19th century. The nearly
universal belief that vertigo was primarily due to a central
pathology persisted well into the 19th century. Erasmus
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.)
Darwin, grandfather of Charles Darwin and a famous
physician in his own right, made an association between
vertigo and tinnitus in 1794, but owing to the state of
knowledge of the time, was limited to observation of the
phenomena only.39,40 It was well known that the inner ear
mediated sound perception, and a variety of competing
theories sough to explain how hearing actually takes place.

The semicircular canals were felt to be an extension of the
auditory apparatus, also mediating the sensation of sound.
Autenrieth was probably the first to propose that the
semicircular canals mediated a sensation other than pure
hearing, proposing in 1802 that they were used in deter-
mining the direction from which sound came.41 J. E. Purkyne
(1787–1869) described opticokinetic nystagmus in 1820
and classified at least five types of vertigo. Yet he believed,
as did the other physicians of his time, that the senses of
motion and acceleration were mediated by cutaneous
pressure receptors or alterations in blood flow and that all
vertiginous disorders were due to cerebral or cerebellar
pathology.42,43 These misconceptions would undergo a
radical change over the course of the 19th century, spurred
in part by the monumental changes that were occurring
throughout the medical community.
Vestibular Semicircular Canal
Physiology: Flourens
Working within the flourishing European scientific envi-
ronment of the early 1800s, Marie-Jean Pierre Flourens
(1794–1867) (Fig. I-20) provided the first scientific clues
that the semicircular canals were intimately involved in the
regulation of balance. As a professor of comparative
anatomy in Paris, Flourens published a series of experi-
ments pertaining to the function of the inner ears, first in
1824, and again in 1842 and 1861.6,44,45 In these remark-
able series of studies, Flourens demonstrated in pigeons
that lesions in the horizontal semicircular canals caused
the animal to turn on its vertical axis, while posterior
canal lesions caused the birds to roll over backwards. From
his experiments, Flourens observed that even after the
Figure I-20. Marie-Jean Pierre Flourens (1794–1867). (From Politzer A:
A History of Otology, Part I, 1904.)
The History of Neurotology and Skull Base Surgery 15
operation, the animals could still hear, and that the direc-
tion of the movements was exactly the same as that of
the canal that had been divided. Interestingly, Flourens
concluded from his results that the semicircular canals
influenced the directional movements of pigeons, rather
than being the organ of equilibrium.46 Furthermore,
Flourens did not make the scientific leap separating the
vestibular and auditory functions of the inner ear, believ-
ing still that both mediated sound perception, with the
cochlea being the more essential of the two.41
Flourens’ observations only slowly permeated into the
medical community. Yet it provided the first scientific clue
that vertiginous disorders were not of a central nervous
origin, spurring others to study this newly emerging topic.
In 1836, for example, Nicholas Deleau pointed out that
too often diseases of the ear (though he supposed the mid-
dle ear) were mistaken for diseases of the brain, and
included vertiginous attacks simulating prodromes of
“apoplexy.”47 Over the following 30 years, many other
investigators reproduced and partially confirmed the results
obtained by Flourens, including Harless, Brown-Sequard,
and Czermak. However, none of these men provided revo-
lutionary breakthroughs (though Brown-Sequard did dis-
cover labyrinthine calorics without realizing the full
significance of his finding).41,46
The State of Otology and the
Neurosciences in the Mid-19th
Century
The middle third of the 19th century was a time of great
scientific advancement, and medicine and surgery were
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
changed by the great English otologic anatomist-patholo-
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.

otosclerosis, and invented an artificial eardrum made of a
disc of India-rubber sandwiched between two small silver
plates.51 This artificial drum was a design standard for
nearly 100 years, until replaced by tympanoplasty by Zöllner
and Wullstein in the 1950s. (Toynbee was not, however,
the first to propose of an artificial tympanic membrane—
this concept dates back at least as early as 1640.)52
The Vienna Medical School
In the second half of the 19th century the Vienna Medical
School (Fig. I-24) was home to the greatest medical minds
of the day, a concentration of physicians and scientists
unequaled in the annals of medicine until then. These
included such notable figures as Billroth, Kaposi, Chiari,
Rokitansky, Czermak, Hyrtl, Skoda, Politzer, Barany,
Alexander, Zuckerkandl, Ludwig, Gruber, and Brauer.
According to Henry Hun, a neurologist and author of a
guide for American medical students training in Europe at
that time, “. . . there is, undoubtedly, no place where a stu-
dent can attend so many excellent clinics with so little loss
of time, or where he can so well train his eyes and hands in
methods of diagnosis and treatment, as in Vienna.”53 More
directly, Lesky stated that during this seminal time period,
“Vienna medicine had become world medicine.”1
Much of this reputation and brilliance centered on
a pathologist named Karl Rokitansky (1804–1878).
Rokitansky’s three-volume Handbuch der Pathologischen
Anatomie, first published in 1842, was the most extensive
pathologic-anatomic text ever written and was referred to
by Heyfelder of Erlangen as “. . . one of the noblest prod-
ucts of medical literature.”1 Virchow, champion of the cel-
lular theory and the father of modern physiology, would
later base his life’s work on many of the principles founded
by Rokitansky. Utilizing the wealth and variety of material
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.)
The History of Neurotology and Skull Base Surgery 17
available to him in Vienna, Rokitansky’s ambition was clear
and comprehensive:
“First . . . sorting the facts scientifically on a purely anatomical
basis and thereby creating the subject of general pathological
anatomy which would justify its separate existence as such . . . sec-
ond, demonstrating the applicability of the facts and their utiliza-
tion for diagnosis in live patients . . .”
(Rokitansky, as translated by Lesky)1
Slowly through the mid-1800s Rokitansky’s work
permeated almost every branch of medicine, helping to
provide a pathologic-anatomic basis for specialty after spe-
cialty, including neurology, dermatology, ophthalmology,
pediatrics, and obstetrics. Otology was spared until
Toynbee obtained Rokitansky’s text and proceeded to
model his studies after Rokitansky’s teachings. Until
Toynbee laid these scientific foundations, otology could
not advance past the back-alley of medicine it inhabited.
According to Anton Friedrich von Tröltsch (1829–1890)
(Figs. I-25 and I-26), “. . . Toynbee contributed most to this
change (in otology) . . . by his numerous sections of the audi-
tory apparatus, as well as by various contributions to our
anatomical and physiological knowledge of aural disease.”30
Thus, by the 1860s, Rokitansky’s teachings were firmly
in place in otologic medicine. “I need not speak to you,
gentleman, of the importance of pathologic anatomy, for
medical science, any more than I need to tell you that the
sun illuminates the earth over which it shines. We have
already seen how late it was in the history of aural medicine
and surgery before pathological investigation of the ear was
undertaken, and that the slow and late development of this
part of our science resulted as it necessarily must, from this
neglect of the appearances of the organ on the cadaver,”
wrote von Tröltsch in 1869.30 After Toynbee’s immense
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
solely to the ear, Archiv für Ohrenheilkunde, in 1863 along
with von Tröltsch and Politzer. Schwartze eventually suc-
cumbed to a nervous condition of restlessness, vertigo, and
delusions, dying of heart failure at the age of 73.
It was Schwartze’s mentor, von Tröltsch, who was respon-
sible for urging Schwartze to fully develop a method of
treatment for suppurative processes of the temporal bone.
In 1863, Schwartz published his influential work on the
indications for the mastoid operation and his success
with the use of specifically designed chisels and gouges (see
Fig. I-33).64 According to Whiting, an American otologist
in 1911, through this publication Schwartze had,
“. . . clearly enunciated the technical and symptomatic
principles upon which are based the steps of the modern
mastoid operation as performed to-day (sic), and however
much we may modify our practice the innovations result in
a little more or a little less than Schwartze’s operation . . .”65
Later, in 1889 Stacke and subsequently Zaufal in 1890
described the radical mastoid operation.23
The Pathophysiology of Coalescent
Mastoiditis: Friedrich Bezold
It was also during this seminal time period that Friedrich
Bezold (1842–1908) (Fig. I-34) published his findings per-
taining to coalescent mastoiditis leading to an abscess.66
Bezold was born in Rothenburg an der Tauber (in modern
day Bavaria). He studied medicine throughout the
Germanic states, including München (Munich), Würzburg,
Figure I-34. Friedrich Bezold (1842–1908), the German otologist who
thoroughly described the complications of suppurative mastoiditis, including
the “Bezold’s abscess,” a coalescent mastoiditis with extension into the neck.
and Erlangen, graduating in 1866. Although initially an
ophthalmologist, training under the great, pioneering eye
surgeon von Graefe, he subsequently studied pathologic
principles under the direction of Virchow. From 1866
onward, he lived and taught in Munich under the tutelage
of von Tröltsch where he studied the ear while practicing
ophthalmology.32 Von Tröltsch was so influential to the
young Bezold, that he is repeatedly cited in Bezold’s text.
According to Bezold, von Tröltsch’s text was the “codex” of
otology. “. . . There is hardly a part of our branch which
v. Tröltsch did not enrich with new and fruitful views.”67
In 1878, Bezold published his findings pertaining to coa-
lescent mastoiditis leading to an abscess.66 The manuscript
itself described in intricate detail the ways in which a
coalescent mastoiditis could spread beyond the mastoid.
In the introduction of this manuscript, Bezold outlined the
prevailing lack of clinical information on the topic: “It used
to be that the diseases of the mastoid were exclusively seen
as in association with diseases of the tympanum. Because of
this there is little in the otologic literature concerning
the pathology of mastoid disease as a primary process.” He
then went on to describe a case of a 6-year-old boy, who
developed a coalescent mastoiditis from a cholesteatoma
(which he termed an epidermoid mass) 16 years after his
original presentation. Additionally, he reviewed the world
literature up to that time on disease processes of the mas-
toid that spread to contiguous areas. Bezold would later
describe the course of mastoid inflammation and infection.
However, it was not until 3 years later in 1881 that he
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
behind a legacy still felt today.69,70 Macewen was born on
the Scottish Island of Bute, the youngest of 12 children. As
the son of a master mariner, the young Macewen learned

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
bone.
to use tools and to work with his hands at an early age. He
joined the Glasgow Medical Faculty in 1865 and began his
surgical work the same time Joseph Lister carried out his
revolutionary antiseptic research. Lister was Macewen’s
premier influence as a young faculty member and was
instrumental in Macewen’s pioneering work in surgical
antisepsis.
In his now classic, Pyogenic Infective Diseases of the Brain
and Spinal Cord, Macewen outlined his technique of treat-
ing otogenic intracranial complications.71 His results were
so extraordinary for the era, they were unequaled until the
era of computed tomography and have been deemed,
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.)
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
lifetime.75
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
invited to become the chair of surgery at the newly estab-
lished Johns Hopkins Medical School in 1889, but an
agreement was not reached and Halstead was ultimately
appointed instead. Macewen died after a severe case of
pneumonia in 1924 at the age of 76.70,76,77
Victor Horsley and the Birth
of Neurosurgery
It wasn’t just otology that had defined itself as a unique
subspecialty in the later half of the 19th century.
Neurosurgery, the second pillar of neurotology and skull
24 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY
base surgery, also saw its nascent beginnings during this
time. The National Hospital for Nervous and Mental
Diseases, located on Queen’s Square in London, is consid-
ered by most to be the birthplace of neurologic surgery.
Although Macewen was clearly one of the stars of this
emerging field, his practice in distant Glasgow limited his
influence among his contemporaries. The National
Hospital hosted such luminaries as Charles-Édouard
Brown-Séquard, John Hughlings Jackson, and Sir William
Gowers, making it the center for neurologic studies in
the world at that time. However, the most famous surgeon
to grace the hospital staff was also credited with the found-
ing of modern neurologic surgery: Sir Victor Horsley
(1857–1916) (Fig. I-37). A contemporary of Macewen’s
and also credited with some of neurosurgery’s earliest
successes, it was Horsley’s, “. . . indefatigable physiological
experimentation in addition to his clinical and pathologi-
cal experiments,” that has led to his inclusion in neuro-
surgery’s pantheon.72 Horsley was also the first surgeon
ever to devote a majority of his efforts to neurosurgery. His
contributions to neurosurgery included the first laminec-
tomy for a spinal neoplasm, the first carotid ligation for
aneurysm, the first transcranial approach to the pituitary,
pioneering intracranial trigeminal nerve sectioning for
neuralgia, and the use of bone wax to stem bleeding from
bone, to name but a few of his many accomplishments.78
According to Cushing, after Horsley was appointed surgeon
to the, “. . . National Hospital for the Paralyzed and
Epileptic, Queen Square, the birth of modern neurologic
surgery may properly be assumed to have taken place.”79
Victor Horsley was present at what is widely considered
the first modern brain tumor surgery. In 1884, Rickman
Godlee at the Hospital for Epilepsy and Paralysis in
Figure I-37. Sir Victor Horsley (1857–1916), the father of neurologic
surgery. (From Paget S: Sir Victor Horsley. New York, Harcourt, 1920.)
London operated on a tumor that had been diagnosed and
localized to the right motor cortex by the neurologist
Alexander Bennett.75,80 Although brain tumors had been
removed previously, Bennett’s localization of the tumor
and Godlee’s first use of antiseptic technique during tumor
surgery made the case quite extraordinary. Using Bennett’s
knowledge of neuroanatomy and pathophysiology, Godlee
was able to plan his craniotomy directly over the tumor,
and easily remove the tumor, which turned out to be a
glioma. The patient survived the immediate operation, but
succumbed to purulent cerebritis a month after surgery.
The case is noteworthy for overcoming the third most
challenging obstacle, following anesthesia and asepsis, that
faced the development of neurosurgery; tumor localiza-
tion. With this obstacle overcome, employing the help of
neurologists such as Bennett, neurosurgical advances
accelerated. Godlee’s case is noteworthy also from the
standpoint of who attended the operation: the neurologist
Hughlings Jackson, the neurosurgeons Victor Horsley and
David Ferrier, and Joseph Lister (Godlee’s uncle) were
reported to be there.75
Sir Charles Ballance: Pioneering Skull
Base Surgeon
Along with Victor Horsley, Sir Charles Ballance (1857–1936)
(Fig. I-38) was another of the pioneering British neuro-
logical surgeons. Neurotology and skull base surgery can
also claim Ballance as one of its instrumental founders as
well, based on his landmark surgical advances within the
temporal bone. Born in Middlesex, England, Ballance
entered medical school in 1875 at St. Thomas’ Hospital in
London. As one of the stars of his medical school class,
Figure I-38. Sir Charles Ballance, a pioneering neurotologist and skull base
surgeon. (From Shambaugh GE: Surgery of the Ear. Philadelphia,
WB Saunders, 1967, with permission.)
26 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY
be predicted that as the mastoidectomy became popular for
treating mastoid suppuration after its introduction by
Schwartz,64 the number of iatrogenic facial nerve injuries
also rose, providing a further spur to facial nerve surgery
repair. It is no coincidence that the first report of a facial
nerve crossover repair was reported by Drobnik in 1879,
only 6 years after Schwartz’s publication.89 As noted by
Duel in 1933 in his historical retrospective, “. . . unskilled
surgery of the temporal bone brought with it an ever
increasing number of cases of accidental paralysis.”90 Sir
Charles Ballance had tremendous influence on facial nerve
surgery during this time, with his introduction of a spinal
accessory-facial nerve crossover anastomosis in 1895, as
well as the first reported attempt at rerouting the facial
nerve intratemporally.26,91 Several other surgeons also
attempted facial nerve crossover operations during this
time, including Faure, Kennedy, and Cushing.89 Over the
course of the next 25 years, nearly all the lower cranial
nerves would be used as possible crossover grafts to the
facial nerve, and controversy surrounded whether to per-
form end-to-end versus end-to-side anastomoses, issues
which are still debated today.
Scientific Advancement in Vestibular
Physiology in the late 19th Century:
Prosper Mèniére and the First
Description of Ménière’s Disease
In one of the first great advances in understanding vestibu-
lar physiology in the later portion of the 19th century,
Prosper Mèniére (1799–1862) (Fig. I-40) described for
Figure I-40. Prosper Mèniére (1799–1862), the first to establish that the
combination of vertigo, hearing loss, nausea, and vomiting has as their basis
an inner ear pathology. (From Politzer A: A History of Otology, Part I, 1904.)
the first time the disease that now bears his name. Born in
the southwest of France, Mèniére completed his medical
studies at the Hotel-Dieu in Paris, where he was closely
influenced by Guillaume Dupuytren and later by Itard,
one of the leading otologists in Europe at that time. After
receiving his doctorate in 1828, he took up a position as
assistant professor of the Paris Faculty of Medicine, later
to become a fellow of the university. In 1848, Mèniére
began a French translation of a German textbook on hear-
ing loss by Kramer.92,93 Within this translation, Mèniére
added a footnote that mentioned a case of labyrinthine
hemorrhage resulting in sudden deafness.94 This was, in
fact, the same case report he would describe 13 years later
in his now classic description of endolymphatic hydrops.
In 1861, in a series of reports before the Paris Academy
of Medicine, Mèniére described a group of patients with
the symptoms of vertigo, nausea, and vomiting, and
sought, “. . . to attribute vertigo and falling to lesions dif-
ferent from those which have their site exclusively in the
brain, and as a consequence to institute a rational treat-
ment for these affections, for too long a time confused
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
sometimes bilateral, mostly the occurrence was unilateral.
He noted that the ear exam was nearly always normal, and
that the symptoms of tinnitus, vertigo, nausea, and vomit-
ing stopped when the hearing was completely lost, typi-
cally after many years. He also reported worsening of the
condition with quinine. To illustrate his basic point that
vertigo, nausea, and vomiting may be due to an inner ear
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
Goltz (1834–1902) (Fig. I-41), a scientist from Strasbourg,
took the next large step to change this, ushering in the next
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-
rosurgeons, mortality for these operations was 78%, and
most survivors had serious disability.106 However, these
statistics would be radically changed by the most influen-
tial neurosurgeon of the 20th century, Harvey Cushing.
Harvey Cushing: The Founder
of Modern Neurosurgery
There is perhaps no one in the annals of neurologic sur-
gery about whom more has been written than Harvey
Cushing (1869–1939) (Fig. I-42), a man whose name is
synonymous with the field. His personality and accom-
plishments are the stuff of legend.
Born the youngest of 10 children in a long line of physi-
cians, Cushing followed his father, grandfather, great-grand-
father, and great-great-grandfather’s path into medicine.
After an undergraduate education at Yale, he studied med-
icine at Harvard Medical School. He subsequently went to
Johns Hopkins University to train under the pioneering
surgeon Halsted, where he was also exposed to the other
medical icon of that era, Sir William Osler. From Johns
Hopkins and later at Harvard, Cushing would revolution-
ize the field of neurosurgery. He introduced the concept of
meticulously documented anesthesia records and the use of
continuous intraoperative blood pressure monitoring. He
was perhaps the first surgeon to make regular use of the
new technology of x-rays, including making the emulsions
and developing the films himself. He described the
“Cushing response,” the physiologic changes induced by a
rise in intracranial pressure. He performed pioneering
work in balanced salt solutions that led to modern intra-
venous therapy. He pioneered transsphenoidal pituitary
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-42. The “father” of modern neurological surgery, Harvey Cushing.
(Courtesy of the Alan Mason Chesney Medical Archives, Johns Hopkins
University.)
decisions to operate, rather than relying on medical physi-
cians or neurologists.107 Cushing made meticulous, ana-
tomically based surgical technique fashionable, rather than
reliance on speed. Of course, this was made possible by his
improved technical advances such as hemostasis and insis-
tence on superior anesthesia. So pervasive was his instruc-
tion, that to this day, nearly all American-trained neurologic
surgeons can somehow trace their legacy back to Cushing.
Cushing’s advances within the field of skull base surgery
are equally monumental, particularly with regard to the
treatment of acoustic neuromas. After realizing that the
tumors could not be completely removed by current stan-
dards, he advised intracapsular removal of the tumor and
subtotal resection (Fig. I-43).109 Combined with his other
technical advances, this approach enabled Cushing to reduce
surgical mortality from near 90% to 20%, as noted in his
classic monograph, Tumors of the Nervus Acusticus and the
Syndrome of the Cerebello-Pontine Angle, published in 1917.110
By 1920, Cushing had redefined the specialty of neuro-
logic surgery, with its emphasis on a strong foundation
of neurologic training. According to Greenblatt, “. . . with
further demonstration of his successes in training, in ther-
apeutic results, and in research productivity, the Cushing
model became the world model.”108
Nylén, Holmgren, and the Birth
of the Operating Microscope
While Cushing was laying the foundations for modern
neurologic surgery in America, two unassuming Swedish
surgeons were developing a technology that would ulti-
mately revolutionize the fields of otology, neurotology,
skull base surgery, and neurosurgery.
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,
leaving the tumor capsule intact. (From Cushing H: Tumors of the Nervus
Acusticus and the Syndrome of the Cerebello-Pontine Angle. Philadelphia,
WB Saunders, 1917.)

The operating microscope evolved out of the optics of
the microscope originally pioneered by Robert Hooke and
Anton van Leeuwenhoek in the mid-1600s. Yet it was the
inherent constraints of ear surgery that led to development
of a microscope uniquely suited to the operating room.
Otology and neurotology were uniquely poised for this
transition because of the difficulties imposed by the micro-
scopic anatomy of the inner ear, limiting what ear surgeons
could do by unmagnified eyesight alone. Furthermore, with
the development of improved anesthesia at the beginning
of the 20th century, the need for more precise surgical
technique within otology, as championed by Cushing in
neurosurgery, became paramount.
Carl-Olaf Nylén (Fig. I-44) was an assistant in the
University Otolaryngology Clinic in Stockholm under the
chief Gunnar Holmgren in the early 1920s. Prompted by
Maier and Lion’s report of endolymph movements in
the living pigeon using a low-power microscope,111 Nylén
began work on a higher power microscope that could be
used during ear surgery. Such a device would have direct
relevance to Nylén’s primary clinical interest of study—
labyrinthine fistulas.112
Nylén’s first monocular microscope was developed by
the Brinnell-Leitz factory (see Fig. I-44, right). Nylén later
recalled his initial use of the microscope,
“The idea of using a larger magnification than had previously
been employed, occurred to me early in 1921 when I was exper-
imenting with labyrinthine fistula operations on temporal bone
preparations from human beings and in living animals. . . . In
November 1921 I used the Brinell microscope for observations
and operations in two cases of chronic otitis with labyrinthine fis-
tulas, and in one case with bilateral pseudo-fistula symptoms.”113
Nylén later modified the scope with the help of his
friend and engineer Persson so it could more easily mount
on the patient. These results were reported in 1922 at the
Figure I-44. Carl-Olaf Nylén (left)
and his first monocular microscope
(right). (From Dohlman GF,
Arch Otolaryngol 90:161–165, with
permission.)
The History of Neurotology and Skull Base Surgery 29
meeting of the Swedish Otolaryngologic Society and again
in Paris in July of that same year.114
Unfortunately, after his initial contribution of the
monocular operating microscope, Nylén found himself
unable to continue to develop the instrument in the clinic
of his chief, Gunnar Holmgren (Fig. I-45), where tradition
and custom dictated that the chief alone could carry out
the new, and still experimental otosclerosis surgery, one of
the primary applications of the new “otomicroscope.”
Holmgren was already known for having introduced the
operating loupes to ear surgery and thus already had a sub-
stantial appreciation for the need of magnification during
these procedures. After seeing his assistant Nylén use the
operating microscope, Holmgren immediately recognized
the added advantages of the microscope over loupes
during these cases. However, Holmgren didn’t simply
copy Nylén’s idea—he significantly advanced it and gave
ample credit for the idea to his assistant. In one of his
publications, he stated, “. . . following a good idea of my 1.
Assistant surgeon Dr. Nylén I tried a microscope and
found the Zeiss binocular microscope a very suitable
instrument . . .”115 To the Zeiss binocular, ophthalmologic
scope, Holmgren added a light source and support suitable
for the operating theater and began using it that same year,
in 1922 (Fig. I-46).115 Compared with Nylén’s monocular
scope, Holmgren had developed an entirely new and revo-
lutionary binocular operating microscope.
In his initial description of the uses of the operating
microscope in the temporal bone, Holmgren enthusiasti-
cally presaged its benefit in ear surgery, stating that the
advantages of using the microscope for radical operations
on otitis, “. . . are indeed so obvious that no operator, who
has had experience of the lens will give it up when doing
this operation.”115 Holmgren’s words are prescient indeed,
as any current otologic, neurotologic, skull base surgeon
or neurosurgeon will attest! Additionally, Holmgren
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.
(From Shambaugh GE: Surgery of the Ear. Philadelphia, WB Saunders, 1967,
with permission.)
employed what he termed, “. . . a little circular cutting file,
viz., one driven by a little electro-motor of the type which
is often used by dentists, armed with the very smallest
drills obtainable, which are sufficiently small to make it
possible that even very delicate bone operations can be
carried out in the utmost safety under the guidance of the
eye.”116 This was perhaps the first application of the drill
for aural surgery and has to be regarded as a seminal event
in the history of neurotology and skull base surgery.
Figure I-46. Gunnar Holmgren is shown using binocular operative
microscope, from his 1922 monograph, “Operations on the temporal bone
carried out with the help of the lens and the microscope.” (From Holmgren G:
Operations on the temporal bone carried out with the help of the lens and the
microscope. Acta Otolaryngol 4:383–393, 1922.)
Figure I-47. Walter Dandy (1886–1946). (Courtesy of the Alan Mason
Chesney Medical Archives, Johns Hopkins University.)
Walter Dandy
At approximately the same time Nylén and Holmgren
were introducing the operating microscope to aural sur-
gery, one of Cushing’s protégé’s was carrying on the trans-
formation of neurosurgery started by his mentor. Walter
Dandy (1886–1946) (Fig. I-47), perhaps Cushing’s most
accomplished student, is clearly responsible for ushering in
the next great leap in neurotologic, neurosurgical, 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-
rologic surgery, Dandy would nearly rival his teacher’s
accomplishments while at Johns Hopkins. Perhaps Dandy’s
greatest accomplishment came while he was still in his
training years. In 1918 he reported on ventriculography by

the injection of air into the cerebral ventricles.118 The
effect on the field of neurosurgery was enormous, for it
allowed the direct localization and size estimation of brain
tumors for the first time. According to Horrax, “It brought
immediately into the operable field at least one third more
brain tumors than could be diagnosed and localized previ-
ously by the most refined neurological methods.”72 One
year later he introduced pneumoencephalography.
Dandy’s influence upon neurotology and skull base sur-
gery was equally profound. In 1917 he reported on the first
successful total excision of an acoustic neuroma.119,120
Whereas Cushing had advocated leaving the capsule intact
to minimize surrounding brain injury, bleeding, and facial
paralysis, Dandy recommended total excision (Fig. I-48).
This departure from his former teacher’s doctrine reportedly
left Cushing infuriated.117,121 Reports extending into the
1940s followed Dandy’s subsequent practice of the suboccip-
ital approach for complete acoustic neuroma resection.122
Dandy’s influence on neurotology and skull base sur-
gery would not end with his achievements in vestibular
schwannoma resection. As discussed later on, his influence
on the treatment of Ménière’s disease was equally important.
However, to better understand the import of these advances,
it is necessary to understand the advances that were simul-
taneously occurring in the vestibular sciences in the early
part of the 20th century.
Advances in Vestibular Science
in the Early 20th Century
Even with the rapidly accumulating data on the structure
and function of the vestibular apparatus, at the turn of the
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.)
The History of Neurotology and Skull Base Surgery 31
century, knowledge of Ménière’s disease had progressed
little since Ménière’s original description nearly 40 years
earlier. Many vertiginous disorders were still confusingly
grouped together, and therapy was based on empiricism
and anecdotal reports. For example, Crockett in 1903
attempted to remove the stapes in two patients with
Ménière’s disease, which lead to complete deafness. A year
later Lake opened the semicircular canals in a Ménière’s
patient and instilled an antiseptic solution.123,124 This lack
of a rational approach to Ménière’s disease was in part due
to the poor state of vestibular diagnosis. This would be
radically changed by the eminent physician-scientist
Robert Bárány (1876–1936) (Fig. I-49). Barany fundamen-
tally advanced our understanding of vestibular physiology
during the first part of the century. Bárány initially trained
under Adam Politzer. Working at the University of Vienna,
Barany introduced into the clinical exam caloric testing,
rotational testing, galvanic testing, and the air-fistula test.46
He correlated various forms of nystagmus with vestibular
pathologies and explored the relationship between the
semicircular canals and the central nervous system. His
new methods of examination enabled the clinician to
differentiate between eighth nerve tumors, vestibular
neuronitis, and other forms of nystagmus. Much of this
work was outlined in his classic work, “Untersuchengen
über den vom Vestibularapparat des Ohres reflektorisch
ausgelosten rhythmischen Nystagmus und seine Begleiter-
scheinungen,” published in volume 40 of the Monatschrift für
Ohrenheilkund.46,125 For his achievements, Bárány received,
among numerous other international awards, the Nobel
Prize in medicine 1915. Tragically, due to professional
jealousy and religious prejudice, he was accused by his
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
simple step, and the transmastoid labyrinthectomy quickly
became the preferred method for treating patients with
Ménière’s disease, surpassing the vestibular nerve section
championed by Dandy. With the subsequent rise of the
operating microscope in the 1960s, this debate between
the superiority of the labyrinthectomy versus the vestibu-
lar nerve section would again rage within the surgical
community, and in some circles, is still being debated.
Neurotologic Surgery Advances in the
1930s and 1940s: Maurice Sourdille,
Julius Lempert, and the Fenestration
Operation
Pioneering efforts to restore hearing to patients with oto-
sclerosis has undeniably benefited the development of
neurotology and skull base surgery. For the operation to
succeed required improvements in both aural operative
technique and surgical microscopy, advances that were
ultimately incorporated into neurotologic and skull base
surgery. During the 1940s, two figures stand prominent in
the development of an effective surgical treatment for oto-
sclerosis: Maurice Sourdille (1885–1961) (Fig. I-53) and
Julius Lempert.
Though the lesser known of the two men, Maurice
Sourdille’s influence on the surgical treatment of otosclerosis
is perhaps nearly as important. After studying at the
University of Paris in 1911, he eventually became a pupil of
Lermoyez, one of the most prominent otolaryngologists in
France at that time. It was under Lermoyez’s tutelage that
Figure I-53. Maurice Sourdille (1885–1961), a pioneering French surgeon for
otosclerosis. Sourdille developed the three-stage fenestration operation that
would later become the basis for Lempert’s famed fenestration operation.
(From Shambaugh GE: Surgery of the Ear. Philadelphia, WB Saunders, 1967,
with permission.)
Sourdille developed his passion for hearing preservation
surgery.137 Following World War I, Sourdille traveled to
Sweden where he studied with Holmgren and Bárány. There
he witnessed firsthand the spectacular, though often short-
lived, labyrinthine fenestration results with the microscope
that Holmgren was achieving on patients with otosclerosis.
The high incidence of deafness eventually led Bárány and
Holmgren to abandon the procedure.
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
cadaver, Sourdille developed a three-stage procedure. He
decided that the horizontal canal was the most accessible,
and he closed the fistula with a thin cutaneous flap from
the external auditory canal, which came to be known as
“Sourdille’s flap.”137 Not only were his hearing results supe-
rior, but the auditory improvement lasted. After Sourdille
presented his results in 1929 to the French Academy of
Medicine, word quickly spread throughout Europe and the
Americas, leading both otologists and patients from around
the world to seek out Sourdille. He eventually came to
North America in 1937, lecturing in several cities about his
new, improved technique. Ultimately, however, Sourdille’s
technique would lose favor to one devised by an American
sitting in the audience of one of these lectures.
As Shambaugh later recollected, Julius Lempert was
present in the audience at the New York Academy of
Medicine, where Sourdille was speaking at the invitation
of Edmund Fowler.138 Afterward, Lempert reportedly
invited Sourdille to dinner where he obtained further details
of the new procedure. It would be a meeting that Sourdille
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
Joachim Heermann, the German physician who had first
described the procedure.138
Regardless of the controversy surrounding the primacy of
the procedure, Lempert’s one-stage fenestration operation

Figure I-54. Julius Lempert, the highly influential surgeon who popularized
the fenestration operation for otosclerosis, and performed pioneering
neurotologic and skull base surgery. (From Shambaugh GE: Surgery of the
Ear. Philadelphia, WB Saunders, 1967, with permission.)
rapidly took hold and revolutionized otologic surgery in
the United States. Surgeons and patients from all over
the world soon flocked to Lempert’s private office in
New York, while Sourdille slipped into relative obscurity.
Sadly, when Lempert’s operation was ultimately sup-
planted by the stapes mobilization procedure, and later the
stapedectomy, it would be Lempert who would refuse to
change, ultimately slipping into obscurity himself.
Glomus Jugulare Tumors—
Harry Rosenwasser
There is no doubt that glomus tumors have played a
pivotal role in the development of neurotology and skull
base surgery. The innovative infratemporal fossa skull base
approaches that have been developed and refined over the
years have their origins in surgery for glomus tumors.
As has been noted by Schuknecht, perhaps the first com-
plete description of a glomus body tumor was in 1937 in the
Dutch literature by J. Lubbers.142 However, it was in 1941
when Stacy Guild was credited with the first description of
a glomus jugulare tumor in the English literature.143 It was
just a year later when Harry Rosenwasser, a surgeon at
The Mount Sinai Hospital in New York City operated on
a patient with a vascular mass protruding from his ear and
extending into the mastoid (though not reported until
1945).144 In this report, Rosenwasser credited Guild with
the first report of a glomus tumor. It was most likely
Rosenwasser and Guild’s lack of access to the Dutch liter-
ature that led to the historical confusion on primacy of the
description of glomus tumors. Following these initial
reports, however, a new understanding was brought to
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-
pally remembered for three advances: the stapedectomy
operation, the modern tympanoplasty, and the develop-
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
advances.
After Nylén’s, and subsequently Holmgren’s, descrip-
tion of the operating microscope, its adaptation by the
general otologic community was slow. George Shambaugh
Jr. was the first to apply the binocular microscope to
Lempert’s one-stage fenestration operation in the 1940s.
With the assistance of the operating microscope, as well as
the first use of continuous irrigation to help wash away
bone dust, Shambaugh was able to demonstrate signifi-
cantly better surgical results, highlighting the utility of the
microscope during ear surgery.147 During the same period,
Cawthorne in London was popularizing the microscope
for transmastoid labyrinthectomy and for operations on
the facial nerve, Tullio began applying the microscope to
mastoid surgery, and Simpson-Hall began using the
microscope for Sourdille’s earlier fenestration operation in
Europe.112
Despite these reports, however, there was still some
general resistance to the use of the “otomicroscope” for
several reasons. First, there were cost issues; these micro-
scopes were custom built and quite expensive. Second,
Lempert preferred the loupes for ear surgery along with a
headlamp, probably because of the microscope’s limita-
tions, and his technique dictated much of what was done in
operating rooms of the United States during the 1940s.148
Last, and perhaps most important, were the microscope’s
technical limitations—each of the previously mentioned
surgeons, and many others, had their own, unique micro-
scope design, which were slightly modified and improved
versions of the original operating microscopes of
Holmgren and Nylén, and which incorporated better
working distances, maneuverability, and lighting.113
36 THE HISTORY OF NEUROTOLOGY AND SKULL BASE SURGERY
Figure I-55. The Zeiss OpMi-1 binocular dissecting microscope, also known
as the Opton microscope. This scope would revolutionize neurotologic and
skull base surgery through its ease of use and widespread availability.
(From Mudry A: The History of the Microscope for Use in Ear Surgery. Am J
Otol 21(6):877–886, with permission.)
Then in 1951, the Zeiss company, under the direction of
Hans Littmann, produced the OpMi-1 binocular dissect-
ing microscope (Fig. I-55), also known as the Zeiss-Opton,
which simultaneously incorporated many of the advances
that had occurred over the previous decade.113 This device
would revolutionize microsurgery. Of particular importance,
the microscope included illumination that entered the
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.
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-
tion of antisepsis, asepsis and anesthesia.”148
With Zöllner and Wullstein’s landmark work on surgery
for chronic ear disease, the utility of the microscope became
obvious and was quickly adapted for nearly every type of
otologic surgery. Rosen developed the stapes mobilization
procedure,151 while Shambaugh, Derlacki, Heermann, and
House simultaneously advanced and independently adapted
it toward stapes surgery, along with specially designed
instruments for use under the microscope (Fig. I-56).152–154
These instruments are all still routinely used during otologic
and neurotologic surgery, and homage is paid every time a
surgeon asks their scrub nurse for an instrument such as the
“Rosen knife.”
 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
When the operating microscope was first introduced into
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
acoustic neuroma resection, he faced an uphill battle. That
his prescience and perseverance led to his ultimate triumph
over the neurosurgical establishment of the day has earned
him a revered spot in the pantheon of great ear surgeons.
The 1960s were a time of tremendous social change. It
saw the birth of the free-speech movement, a countercul-
tural revolution, and an entire generation questioning the
values and morays of their parents and society at large.
Otology and neurosurgery were not spared the changes
happening in the broader social context. It was perhaps the
social trends of the day that enabled surgeons such as House
to openly question and challenge the way surgery was per-
formed, particularly by another field such as neurosurgery.
After completion of his residency, William House joined
his brother Howard in a private otology practice in the
flourishing Los Angeles of the 1950s. William House soon
developed an interest in the treatment of diseases of the
inner ear. It was House’s interest in sensorineural hearing
loss from otosclerosis and the possibility of restoring
hearing by drilling out the internal auditory canal that
ultimately led him to attempt a middle fossa approach.157
After a series of experiments on cadavers in his local
morgue, he attempted the middle fossa approach using the
operative microscope, along with the neurosurgeon Kurze
on a patient with cochlear otosclerosis.158,159 The patient
did not regain hearing, nor did the two subsequent
patients on whom the operation was attempted. According
to House, when he presented the operative approach at a
symposium, he was publicly ridiculed not only for the
results, but for the approach itself.157
It was several years subsequent to this that House revived
the translabyrinthine approach to the cerebellopontine
Figure I-57. William House, the “father” of modern skull base surgery.
(From House W: Monograph: Transtemporal bone microsurgical removal of
acoustic neuromas. Arch Otolaryngol 80:597–756, 1964, with permission.)
angle for resection of vestibular schwannomas. House,
along with William Hitselburger, thus introduced the
operating microscope and otologic surgical technique to
neurosurgery.160 The operative approach was immediately
recognized for its importance within the otolaryngologic
community. George Shambaugh Jr. wrote in the foreword
to House’s highly influential 1964 monograph that his
work was, “. . . destined to become a second milestone in
the surgical approaches through the temporal bone made
possible and practical by microsurgical temporal bone
techniques.”161 In fact, the first milestone that Shambaugh
was referring to was Cushing’s work nearly 50 years prior.
Shambaugh also noted in his foreword the not so subtle
manner in which House patterned his monograph exactly
as Cushing laid out his classic work in Tumors of the Nervous
Acusticus in 1917.110
Despite the enthusiastic reception of the work within
otolaryngology, the opposition that House and Hitselburger
faced from the neurosurgical community, which had
traditionally cared for these tumors, was fierce.139,157 The
squabble at House’s own institution would ultimately be
mirrored across the country on numerous other hospital
staffs as similar turf wars would play themselves out
between neurosurgeons and otologists. However, soon the
advantages of House and Hitselberger’s microscopic tech-
nique became obvious, and the microscope quickly spread
to other fields, including neurosurgery itself. Both otology
and neurosurgery gradually came to realize that by
combining their individual expertise toward the resection
of vestibular schwannomas, the ultimate benefactor was
the patient. Once the acoustic neuroma obstacle had been
cleared, collaboration on resection of other skull base
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-
ogy over acoustic neuromas had occurred in the late 1960s
and early 1970s, the field of skull base surgery was born.
House’s influence on neurotology was profound. He went
on to develop additional, expanded approaches to the skull
base, including the extended middle fossa and transcochlear
approaches. His pioneering work on cochlear implants was
far ahead of its time and again initially met with great oppo-
sition from within otology’s own elite establishment.162
Clearly, one of House’s laudatory attributes as a person is his
perseverance in the face of misdirected opposition. In each
case, he appears to have won, convincingly. As noted by
Glasscock, “Had William F. House not had such a strong
personality, had he not been so determined, then neuro-
otology would not exist as we know it today.”139
Electrical Stimulation of the Auditory
Nerve—The Birth of Cochlear Implants
The 1960s were notable for another milestone in neuro-
tology, the birth of the cochlear implant. As the first true
prosthetic device that enables the restoration of a lost
sense, the cochlear implant surely has to be ranked as one
of the greatest achievements of medical science. Fittingly,
cochlear implants arose out of uncoordinated international
efforts, replete with individuals who persisted in their
work despite fierce criticism within the academic and med-
ical communities.
Attempts to electrically stimulate the ear date as early as
1790, when Alexander Volta, professor of natural philoso-
phy at the University of Pavia, was experimenting with the
relatively new phenomenon of electricity. He inserted a
metal rod into each of his ears, connected a 50-volt battery
between them, and heard a noise similar to the boiling of
a viscous liquid.163 In the mid-18th century, two prominent
otolaryngologists introduced the idea of electrical stimula-
tion to medicine by advocating it for the diagnosis and
treatment of many ear diseases. This short-lived field of
“electro-otiatrics” was abandoned by the start of the 20th
century, however, and remained dormant for the following
30 years.164,165
The idea that sound could be artificially created through
electrical stimulation of the ear was resurrected by two
events in the early 20th century. In 1925 radio engineers
discovered that sound could be produced by stimulating
electrodes in the near vicinity of the ear, and in 1930 Weaver
and Bray discovered a phenomenon known as the “cochlear
microphonic,” an electrical potential arising from the
cochlea as a result of acoustic stimulation.166 Shortly before
World War II, a group of scientists at MIT, the prominent
psychophysicist S. S. Stevens, and a group of Soviet scien-
tists, began independently investigating the concept of elec-
trical stimulation of the eighth nerve.167–169 Each of these
groups tried to stimulate the cochlea from within the mid-
dle ear to create sound. With only primitive electronics such
as vacuum tubes, however, this proved to be too great a
technical feat. Each group encountered difficulty with the
dynamic range of their devices and couldn’t create sound
without causing pain or stimulating the facial nerve.
However, their early, rigorous scientific endeavors were
instrumental in setting the stage for successful stimulation
of the eighth nerve within the following two decades.
Djourno and Eyries published their first data on direct
stimulation of the cochlear nerve in a totally deaf person in
1957. During a reoperation for facial paralysis and deafness
in a 50-year-old man, an electrode was placed into the
region of the cochlear nerve stump and a current was
passed. The patient heard sounds like “crickets” or a
“roulette wheel.”170,171 The researchers never followed up
their results, however, and their work remained obscure for
a number of years.
In 1961 William House and James Doyle designed a few
implantable cochlear-stimulating devices based on the work
of the scientists at MIT and in the Soviet Union and tested
them in human patients. Due to poor construction and the
toxic nature of the implant material, however, the devices
had to be removed after 3 weeks. Despite this setback and
the use of a nonphysiologic stimulating current, House and
Doyle’s initial results indicated that patients could perceive
the rhythm of speech and music and were aware of a variety
of environmental sounds.172 The technical difficulties they
encountered, however, discouraged them from continuing
further with cochlear implants for a number of years.
The most widely acclaimed implantation in the 1960s
occurred under the direction of Blair Simmons at Stanford
University.173 He placed an implant in the cochlea of a
terminally ill, congenitally deaf patient and showed that
the patient could perceive sound. Ironically, because the
patient could not understand speech, Simmons concluded
in his landmark paper that, “. . . the chances are small indeed
that electrical stimulation of the auditory nerve can
ever provide a uniquely useful means of communication.”
A colleague of Simmons, Robin Michelson, would ulti-
mately leave Simmons to begin his own program at the
University of California San Francisco.
In 1973 the First International Conference on Cochlear
Implants was held at the University of California San
Francisco. By this time, House had preformed a total of
22 implants, Michelson and his colleagues had done seven
with some published results, and Simmons had done two.
Additional cochlear implant development programs were
well underway in Melbourne, Australia, and Innsbrück,
Austria, each making landmark strides on their own.
However, Merle Lawrence summed up the prevailing
attitudes of a large segment of the medical and scientific
community when he implied at the conference assembly
that there is no way, “. . . of the number of channels or
electrode points . . .” by means of which one can get tono-
topic or specific frequency stimulation by attempting to
stimulate first order neuron dendrites in the cochlea, and
all that would be produced would be “noise.”174 Harold
Schuknecht, another conference participant, was more
direct when he flatly stated at the conference’s conclusion,
“. . . I will admit that we need a new operation in otology
but I am afraid this is not it.”174
Much of the criticism of the implants at this point
centered on the belief that it was immoral to proceed in
humans until sufficient animal work had been done,
combined with the prevailing belief that the device itself
would simply never work because of the extensive and irre-
versible neural damage already present in deaf individuals.
Beyond these concerns, extravagant claims surfacing in the
public, including testimonials about “. . . hearing the chirp-
ing of mockingbirds once again (and) enjoying symphony

music . . .” further alienated the scientific community and
made research in cochlear implants a pariah of audiologic
research.175
However, a pivotal year for the advancement of the
cochlear implant came in 1977, when the National Institutes
of Health began an independent, multicenter study of
patients with cochlear implant devices. Led by Dr. Bilger at
the University of Pittsburgh, the study concluded that the
device was a definite aid in communication.176 Bilger, who
was skeptical of cochlear implants, was actually converted to
a modest supporter by the results of his own report: “It . . .
(the report) . . . put to rest some of the wilder claims about
the benefits of . . . implants and it substantiated that for some
individuals there were benefits in lip reading, environmental
awareness and voice modulation control.”175 What is more
important, the study provided substantial scientific evidence
for the benefits of cochlear implantation and gave credibility
to the emerging technology.
The Creation of the American
Neurotologic Society
By the mid-1960s, the multitude of advances in the hearing,
vestibular, and neurosciences, as well as in otologic and
skull base surgery were stirring the restive members of the
American Academy of Ophthalmology and Otolaryngology.
There was a concept of “neurotology” as an independent
subspecialty that was slowly growing and gaining consen-
sus. As later recalled by Marcus,177 the growing array of
diagnostic tests and surgical approaches, as well as advances
in the basic understanding of the inner ear and central
nervous system led Nicholas Torok and Richard Marcus to
form “the Neurotology group,” in 1965. The goals of the
group were twofold: (1) to exchange and disseminate infor-
mation about the physiology, pathology, and clinical
management of the sensorineural systems of audition and
equilibrium; and (2) to stimulate education and basic and
clinical research relating to these systems. In 1974, the
group changed its name to the American Neurotologic
Association.177 With its formation, neurotology can thus be
said to have “officially” begun.
CONCLUSION
In many ways, this current textbook, Neurotology, is the
triumph of the goals of the “Neurotology group,” that orig-
inally formed in 1965. However, in so many more ways,
neurotology and skull base surgery are the continuation of a
tradition of the pioneering spirit of the clinician, the
surgeon, and the scientist, often wrapped up in the same
individual, dating back to the Renaissance and beyond. The
past 25 years, though not covered by this historical review,
has seen the emergence of revolutionary forms of technol-
ogy, such as computed tomography and magnetic resonance
imaging, each of which have had no less of a revolutionary
effect on our specialty. It is without doubt that future
generations will write on our own time as a new kind of
renaissance; not one of art and anatomy, but one of genet-
ics, neuroscience, computers, and biotechnology. It is pre-
cisely the appreciation of our historic origins that enables
each of us to revel in our specialty’s own great achievements.
The History of Neurotology and Skull Base Surgery 39
Eighty years ago, Sir Charles Ballance, the pioneering
skull base surgeon, eloquently acknowledged what each of
us owes to our teachers and predecessors, and his senti-
ments remain relevant today as we look forward to the next
millennium:
“Every man is a debtor to his profession. A vast field of our art
and science still remains unmapped and unexplored. I trust that
succeeding generations of surgeons . . . will devote time to
research work. Research adds zest and satisfaction to life, and
gives the promise of that thrill of delight which accompanies the
first perception, the slow unfolding of some new truth or princi-
ple. Thus may we surgeons rightly forge new weapons against
disease and death” (Sir Charles Ballance, 1922).12
It is only through such dedication to clinical and surgical
advances and basic neurotologic research that tomorrow’s
leaders, as great and revolutionary as those in our historical
past will emerge, and neurotologic and skull base history
will continue to advance.
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eighth cranial nerve. Arch Otolaryngol 80:388–391, 1964.
163. Volta A: On the electricity excited by the mere contact of conducting
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164. Neftel WB: Galvano-Therapeutics. New York, Appleton, 1871.
165. Shah SB, Chung JH, Jackler RK: Lodestones, quackery, and sci-
ence: Electrical stimulation of the ear before cochlear implants.
Am J Otol 18:665–670, 1997.
166. Wever EG, Bray CW: The Nature of the Acoustic Response: The
Relation Between Sound Frequency and Frequency of Impulses in
the Auditory Nerve. J Exp Psychol 13:373–387, 1930.
167. Stevens SS, Jones RC: The mechanism of hearing by electrical
stimulation. J Acoust Soc Am 10:261–269, 1939.
168. Simmons B: Electrical stimulation of the auditory nerve in man.
Arch Otolaryngol 84:2–54, 1966.
169. Andreef AM, Gersuni GV, Volokhov AA: Electrical stimulation of
the hearing organ. J Pysiol USSR 17, 1934.
170. Eisen MGR: Djourno and Eyries and the first stim of the VIIIth
nerve. Otol Neurotol, in press.
171. Djourno A, Eyries C: Prothese auditive par excitation electieque a
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172. Doyle JH, Doyle JB, Turnball FM: Electrical stimulation of the
eighth cranial nerve. Arch Otolaryngol 80:388–391, 1964.
173. Simmons FB: Electrical stimulation of acoustic nerve and inferior
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174. Lawrence M: In Merzenich MM, Schinder RK, Sooy FA (eds.):
Proceedings of the First International Conference on Electrical
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175. Simmons B: In Schindler RA, Merzenich MM (eds.): Cochlear
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Otol Rhinol Laryngol (Suppl) 38:3–10, 1977.
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Otolaryngol Head Neck Surg 104:1–4, 1991.
178. Paget S: Sir Victor Horsley. New York, Harcourt, 1920.
179. Shambaugh GE: Surgery of the Ear. Philadelphia, WB Saunders,
1967.

The Human Brainstem
Auditory System
Outline
Brainstem Topography
Generation of Evoked
Potentials
Information Processing in the
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
human central auditory pathway. Next, it considers how
brainstem structures act as generators of evoked auditory
potentials, information that may be useful in distinguish-
ing peripheral and central pathology. It then considers the
manner in which information from the cochlea is analyzed
and altered as it passes through brainstem centers. Finally,
it reviews what is currently known about the type and
degree of central degenerative change that occurs subse-
quent to hearing loss.
BRAINSTEM TOPOGRAPHY
An overview of the brainstem auditory pathway in lon-
gitudinal section, based on serially sectioned human brain-
stems,1 is presented in Figure 1-1. As shown in this figure,
the brainstem auditory pathway begins at the pontomed-
ullary junction, at the point where the cochlear nerve enters
the brainstem and terminates in the cochlear nuclei. The
cochlear nuclear complex consists of two components, a
dorsal nucleus and a ventral nucleus. The dorsal cochlear
nucleus is a flattened structure that curves around the infe-
rior cerebellar peduncle on the dorsolateral surface of the
brainstem. The ventral nucleus is a compact structure that
extends laterally along the caudal edge of the middle cere-
bellar peduncle. The cochlear nerve enters the center of
the ventral cochlear nucleus, and its axons radiate to inner-
vate both the dorsal and ventral nuclei. The pathway
carrying most of the ascending auditory information to
higher centers originates in the ventral nucleus, and its
axons leave the nucleus as the trapezoid body, a broad
pathway that crosses the brainstem. Within the brainstem,
the superior olivary complex lies a short distance medial
and rostral to the cochlear nuclei. The medial olivary
Chapter
1
Inferior Colliculus Jean K. Moore, PhD
Descending Pathways
Effects of Hearing Loss
Conclusions
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
form a column of cells extending almost a centimeter
rostrally through the brainstem. At the point where the
pons is no longer covered laterally by the middle cerebel-
lar peduncle, the auditory pathway swings laterally to
become a flattened, superficial band of axons, the lateral
lemniscus. A few clusters of small cells scattered through-
out the lemniscus are vestiges of the lower lemniscal nuclei.
The dorsal lemniscal nucleus is a distinct cell group that
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
to the contralateral colliculus through the collicular
commissure.
Previous comparisons of the human and cat brainstem1
have shown that their auditory centers are approximately
the same size, but because of the overall size of the human
brainstem, human auditory centers are strung out along a
considerably longer pathway. An accurate measurement of
the length of the human brainstem auditory pathway has
been obtained from a computer reconstruction based on
a series of digitized histologic sections.2 The reconstruc-
tion shows that the distance the axon of a neuron in the
human ventral cochlear nucleus travels to reach the ipsi-
lateral superior olivary complex is approximately 10 mm;
to reach the contralateral superior olivary complex is about
25 mm; to reach the upper level of the contralateral lateral
lemniscus is about 40 mm; and to reach the center of the
contralateral inferior colliculus is roughly 45 mm. Thus a
response in the human brainstem to a transient stimulus
will consist of waves of action potentials passing along
myelinated axons for a total distance of up to 4.5 cm. In the
cat, by comparison, the total distance from the center of
the cochlear nuclei to the center of the contralateral infe-
rior colliculus is less than 2 cm.
45
46 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 1-1. Overview of the brainstem auditory pathway as seen in
longitudinal section. Spatial relationships and dimensions are based on
reconstructions from serially sectioned human brainstems. Auditory nuclei
(solid outlines) are labeled in the lower half of the figure and tracts
(dotted outlines) are labeled in the upper half. AS, acoustic stria; BIC,
brachium of inferior colliculus; CIC, commissure of inferior colliculus;
DCLL, dorsal commissure of lateral lemniscus; DCN, dorsal cochlear
nucleus; DNLL, dorsal nucleus of lateral lemniscus; IC, inferior colliculus;
LSO, lateral superior olivary nucleus; MCP, middle cerebellar peduncle;
MSO, medial superior olivary nucleus; PO periolivary region; TB, trapezoid
body; VCN, ventral cochlear nucleus; VNLL, ventral nucleus of lateral
lemniscus; VIIIc, cochlear nerve. (Modified from Moore JK: The human
auditory brainstem as a generator of auditory evoked potentials. Hear Res
19:33–43, 1987.).
GENERATION OF EVOKED POTENTIALS
Evoked auditory brainstem responses (EABR) are gener-
ally regarded as reflecting synchronized discharges in
groups of axons. However, it is difficult to apply the results
of animal investigations when attempting to identify the
generators of potentials evoked from the human brainstem
because the human cochlear nerve and brainstem pathways
are much longer than those in other species. More relevant
information can be obtained from studies done in human
subjects. In contrast to lower mammals, in which only a
single wave is generated by the cochlear nerve, there is evi-
dence that the human cochlear nerve generates
the two earliest potentials of the EABR, waves I and II.
Intrasurgical recordings, made with a wire electrode placed
directly on the auditory nerve,3,4 concluded that wave I is
generated within the cochlea, presumably by activation
of the peripheral nerve processes contacting cochlear hair
cells. Wave II was localized to the cochlear nerve at the
level of the internal auditory meatus. Similarly, dipole
localization studies5 concluded that wave II is generated as
the wave of action potentials following a click stimulus
crosses the conduction boundary between the temporal
bone and the intradural space. This interpretation is
supported by clinical findings in a case of Gaucher’s
disease with marked brainstem gliosis,6 in which EABR
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
axonal conduction velocity.2 The most reasonable conduc-
tion velocity, one closely matching the known conduction
velocity of eighth nerve axons, was obtained by assuming
that waves IV and V were generated at the level of the
superior olivary complex contralateral to the stimulated
ear, presumably by the bend in the axonal pathway occur-
ring at that point (see Fig. 1-1). The idea that waves IV
and V are generated at the level of the olivary complex,
rather than higher in the brainstem, is supported by the
fact that both waves are intact after destructive lesions of
the inferior colliculus.9,10
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
they traverse the trapezoid body and lateral lemniscus,
these axons do not encounter any synaptic junction.
Alternatively, some pathways to the inferior colliculus
synapse in the intermediate brainstem nuclei, such as the
medial and lateral olivary nuclei and the periolivary cell
groups.12 It has been suggested that the closely spaced
waves IV and V reflect activity in parallel asynaptic and
monosynaptic pathways. Passing though a single synaptic
junction would delay the wave of action potentials by
approximately 0.7 msec, which is, in fact, the interval sep-
arating waves IV and V. Additional support for the idea
that waves IV and V are generated by parallel pathways
comes from EABRs recorded during placement of an
auditory brainstem implant device on the cochlear nuclei.13
Because tumor removal interrupts the continuity of the
eighth nerve, the peripheral generators of the EABR are
missing and the electrical stimulus acts directly on
cochlear nucleus neurons. This direct activation of axons
leaving the cochlear nuclei bypasses cochlear mechanics,
the synapses at the level of the hair cells, and the synapses
in the cochlear nuclei, all of which normally precede
wave III. In these recordings, peaks are recognizable that
correspond in time to waves III, IV, and V of the acousti-
cally evoked ABR. When the stimulus rate is increased
from 100/sec to 200/sec, the peak corresponding to wave
IV is unaffected, but the peak corresponding to wave

V shows rapid attenuation. This implies that the two peaks
are generated by different pathways, rather than by
sequential structures in a single pathway, and that wave V
is rate-sensitive because its generator contains a synaptic
junction.
INFORMATION PROCESSING
IN THE BRAINSTEM
Cochlear Nuclei
The activity of the cochlea is carried as a single represen-
tation in the auditory nerve. Upon entering the nerve root
in the center of the ventral cochlear nucleus, its axons
bifurcate to form ascending and descending branches. In
humans, as in other species, fascicles of ascending
branches of the cochlear nerve fill the anterior half of the
ventral nucleus, and similar fascicles of descending
branches penetrate the posterior part of the nucleus and
then continue into the dorsal nucleus.14 The ventral
nucleus is very densely innervated, but in the dorsal
nucleus synaptic terminals are much more sparsely scat-
tered. The tonotopic sequence of axons in the auditory
nerve identified in the monkey15 is identical to that of
other mammalian species, with high-frequency informa-
tion carried by fibers bifurcating in the tip of the nerve
root, and an orderly sequence of progressively lower fre-
quencies extending down to axons bifurcating at the base
of the nerve root. Frequency information should therefore
be represented in the human ventral cochlear nucleus as
stacked sheets of eighth nerve axons, with the highest
frequency input in the most dorsal sheets and lowest fre-
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
planes run parallel to the surface of the nucleus.14
Neurons in the cochlear nuclei do not simply relay pitch
information to higher auditory centers. Instead, the nuclei
are a point of transformation of the pattern of activity
carried in the auditory nerve. Each individual auditory
nerve axon, as it runs through the nuclei, passes through
areas of different cell types.1,14 Distinct types of synapses
are formed on each class of neuron, with the synapses vary-
ing from expanded calyces surrounding the cell body to
scattered small boutons located mainly on dendrites.16 As
a result, the transformation of impulses across the synapse
results in a distinctive pattern of activity in each postsyn-
aptic cell group.
An additional factor in the transformation of the pattern
of information originally carried by the cochlear nerve is
the presence of many synaptic terminals containing the
inhibitory transmitters γ-aminobutyric acid (GABA) and
glycine. Several types of inhibitory systems have been
described in nonprimate mammals, but two systems are
particularly well developed in the baboon17 and, by analogy,
in humans. The first system is a very precise, tonotopically
specific system projecting from the dorsal nucleus to the
ventral nucleus. The origin of this system is a population
of glycine- and GABA-positive cells in the central dorsal
cochlear nucleus that are characterized by dendritic arbors
flattened in the isofrequency planes of the nucleus. Their
The Human Brainstem Auditory System 47
axons form tightly bundled fascicles penetrating the central
area of the ventral nucleus. Studies in mouse slice prepara-
tions have shown that these dorsal nucleus cells project to
bands of neurons in the ventral nucleus that are innervated
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
nucleus.
The point-to-point nature of these dorsal-to-ventral
nucleus connections stands in contrast to a much more
widespread projection pattern of commissural axons. The
commissural projection arises from relatively large glycine-
positive cells scattered throughout the cochlear nuclei.
Their large-diameter axons come together to form a dis-
tinct bundle, the commissural stria, and form a plexus of
axons in the contralateral nuclei.19 Within the contralateral
cochlear complex, commissural axons branch widely and
distribute their inhibitory terminal very broadly.20 This
glycine-positive commissural projection is undoubtedly
responsible for the short-latency crossed inhibition shown
in recordings in the cat21 and presumably plays a role in the
balance of level of activity of the cochlear nuclei on the two
sides of the brainstem.
It is apparent that by the time auditory information has
passed through its first central synapse in the cochlear
nuclei, it has been acted on by modulatory influences.
First, a recoding of the pattern of activity in the auditory
nerve occurs during the interaction of the presynaptic
axons and the postsynaptic neuron. Second, there is an
interplay of that excitatory activity with intrinsic inhibitory
systems. These factors combine to ensure that a unique
pattern of activity is carried in each of the pathways leaving
the cochlear nuclei.
Superior Olivary Complex
One basis for complexity in brainstem information pro-
cessing is the fact that the cochlea, unlike the retina or
body surface, does not directly encode the spatial locus
of a stimulus. Instead, the spatial dimension of a sound
stimulus must be recreated by the central auditory system.
Behavioral studies in cats have implicated the superior
olivary complex in this process. Animals with lesions at or
above the level of the superior olivary complex are unable
to locate a sound source in the spatial field contralateral to
the lesion, while lesions below the level of the olivary com-
plex cause more diffuse deficits.22 A very similar deficit has
been seen in a human subject with an extensive midline
pontine lesion that eliminated crossed input to the supe-
rior olivary complex on both sides.23 The subject could
detect frequency and amplitude modulation and had no
general deficit in detection of auditory temporal informa-
tion, but was unable to determine, by sound alone, the
location and direction of motion of objects in the envi-
ronment, such as ringing telephones and passing trains.
Collectively, these findings imply that the central repre-
sentation of auditory space is first organized at the level of
the superior olivary complex and that the process of orga-
nization occurs similarly in humans and other mammals.
Physiologic studies carried out in animals have long
indicated that time and intensity cues to spatial location
are analyzed separately in the superior olivary complex,
48 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
and dipole studies carried out in human subjects24 suggest
that the same is true in humans. The human dipole studies
involved recordings of the binaural interaction component
of the EABR, which is obtained by subtracting the
response to a binaural stimulus from the algebraic sum
of the right and left ear monaural responses to the same
stimulus. The reduction in total activity in the binaural
response is presumed to reflect the fact that the binaural
response involves convergence of activity from the right
and left ears on some subset of brainstem auditory neurons
that process information from both ears. When the binau-
ral interaction component was determined for a variety of
interaural time and intensity differences, the dipoles for
interaural time versus intensity differences had slightly dif-
ferent locations in the brainstem, suggesting that time and
intensity cues are processed by two separate structures.
The system that uses interaural time differences has
long been believed to be the medial olivary nucleus. This
nucleus is a laminar structure, with long primary dendrites
extending medially and laterally from a central column of
cell bodies. The laterally directed dendrites are innervated
by the ventral cochlear nucleus on the same side of the
brainstem, and the medially directed dendrites are inner-
vated by the nucleus on the contralateral side.12 Thus, each
neuron receives frequency-matched input from both ears.
The discharge rate of cells in the medial nucleus is influ-
enced by interaural time differences, including phase
disparities, and shows phase-locking to both monaural and
binaural stimuli.25,26 These response properties allow the
neurons to create a map of interaural time differences
along the rostrocaudal axis of the nucleus. Because time
disparities are most useful for low-frequency sound, and
phase cues are unambiguous only below 1500 Hz, the
medial nucleus is biased toward low-frequency information,
with most of its neurons having best frequencies of less
than 3 to 4 kHz.27 Given that the human range of audible
frequencies is quite low by general mammalian standards,
it is not surprising that the human medial olivary nucleus
is twice as large as that of the cat and several times larger
than those of most other species.28 Because large head size
increases the range of frequencies that can be used for
interaural phase difference cues, both human head size and
low-frequency hearing range may account for the promi-
nence of the medial olivary nucleus in our binaural hear-
ing system.
Stimulus intensity cues are generally believed to be
processed by the lateral olivary nucleus. Single unit record-
ings have shown that lateral nucleus neurons respond to
interaural intensity differences and also to monaural ampli-
tude fluctuations.29,30 Because intensity cues can be used
across a broad range of frequencies, the mammalian lateral
olivary nucleus has an orderly representation of best
frequencies spanning the entire audible range.27 The
nucleus is large in carnivores that are sensitive to frequen-
cies from 20 Hz to 40 kHz and is extremely large in echolo-
cating species, such as bats and porpoises, whose range
extends above 100 kHz.28 Possibly because our range of
usable frequencies is restricted to those at the low end of
the mammalian spectrum, the human lateral nucleus is a
relatively small nucleus, much smaller than that of the cat
and similar in absolute size to the nucleus in rodents and
insectivores.28
The medial and lateral olivary nuclei are surrounded by
a separate component of the olivary complex, the perioli-
vary region. Human periolivary cells are roughly grouped
into medial, lateral, and dorsal periolivary nuclei. A unique
feature of the human periolivary system is a rostral column
of cells that extends up to 8 to 10 mm through the pons.
Periolivary neurons are a heterogeneous population that
forms ascending and descending projections to a number
of diverse targets. The hypertrophied rostral cell group is
composed of a type of periolivary neuron that, in the cat,
forms a projection to the inferior colliculus31 and thus may
represent the main ascending pathway from the periolivary
region to the midbrain. Other periolivary neurons form
descending pathways and are discussed in the section on
the descending auditory system.
Lemniscal Nuclei
In most species, the lower part of the lemniscus contains
two sizable nuclei, the ventral and intermediate lemniscal
nuclei. These nuclei are prominent in the cat and are
extremely large in echolocators such as the porpoise and
bat, suggesting that they are related to some aspect of
high-frequency acoustic processing. In humans, these nuclei
are represented only by cell clusters scattered along the
course of the lateral lemniscus.1 Thus the comparative devel-
opment of the lower lemniscal nuclei across mammals
suggests that their reduction in the human brainstem, like
that of the lateral olivary nucleus, is related to our com-
paratively low-frequency range of hearing.
In contrast, the dorsal lemniscal nucleus is a prominent
cell group, very similar in size and morphology to the cor-
responding nucleus in the cat.1 In mammals, afferent input
to the dorsal nucleus comes mainly from the medial and
lateral superior olivary nuclei,32 meaning that its input
is related primarily to spatial localization. The dorsal
nucleus projects directly to the adjacent inferior colliculus
and through its commissure to the dorsal lemniscal
nucleus and inferior colliculus on the opposite side.33
Because the dorsal nucleus consists mainly of neurons that
use GABA as a neurotransmitter,34 this symmetrical and
reciprocal projection is inhibitory and must influence the
level of activity in the inferior colliculus bilaterally. It is
likely that the dorsal lemniscal nucleus plays a role in the
balance of ipsilateral and contralateral activity related to
spatial mapping in the inferior colliculus.
Inferior Colliculus
Essentially all the axons in the lateral lemniscus terminate
in the inferior colliculus, with greatest density in its central
nucleus. Thus the central nucleus receives overlapping
input from the dorsal and ventral cochlear nuclei, the medial
and lateral olivary nuclei, periolivary cell groups, and the
lemniscal nuclei, particularly the dorsal lemniscal nucleus.
The overlap of the ascending projections to the central
nucleus does not occur in a random manner, but rather in
an organized fashion related to the laminar organization of
the nucleus. As axons enter the central nucleus, they form
bands running from ventrolateral to dorsomedial. These
axonal bands run parallel to cellular planes formed by neu-
rons with flattened, disc-shaped dendritic fields, producing

a laminar architecture of alternating bands of axons and
flattened cells. Studies of evoked activity and 2-deoxyglu-
cose labeling in primates have shown that the laminae rep-
resent frequency-specific planes of the central nucleus.35,36
The tonotopic planes are curved and tipped at about 20 to
30 degrees from the horizontal, with a regular progression
of best frequencies from low dorsally to high ventrally.
Some projections, such as those from the ventral cochlear
nucleus and the lateral olivary nucleus, span the entire
tonotopic spectrum, while the medial olivary nucleus is a
major source of afferents to the low-frequency region of
the central nucleus.
Tonotopy is not the only organizing principle within the
inferior colliculus. Recordings in the cat show that neurons
in the central nucleus respond to simulations of natural
combinations of interaural time and intensity differences
and to spectral cues indicating location of a sound source.37
Most cells are sensitive to stimulus location along the hor-
izontal azimuth, and about half of the neurons tested
are sensitive to elevation. This suggests that at the level of
the colliculus, pathways representing spatial localization,
that is, those from the medial and lateral olivary nuclei
and dorsal lemniscal nucleus, are integrated into a single
spatial map. Overall, it seems safe to assume that multiple
parameters of auditory stimuli, including frequency spec-
trum, loudness, time patterning, and spatial location, are
correlated within the central nucleus to produce an inte-
grated neural representation of the stimulus.
Information from the central nucleus of the colliculus is
passed on to the forebrain by axons that form the brachium
of the inferior colliculus. Brachial axons continue forward
on the surface of the brainstem, lateral to the superior
colliculus, to reach the medial geniculate complex of the
thalamus. This ascending pathway from the inferior col-
liculus is the route for essentially all information ulti-
mately reaching the thalamic and cortical levels. However,
the inferior colliculus is also the source of descending
auditory pathways, which are discussed in the following
section. One descending projection ultimately reaches the
acousticomotor centers involved in head and eye orienta-
tion to sound. A second descending system is the purely
auditory pathway to lower brainstem auditory centers and,
through the olivocochlear projection, to the cochlea itself.
In sum, it appears that the inferior colliculus is a point of
convergence for a series of parallel brainstem pathways, but
also a point of divergence from which integrated auditory
information is sent up to auditory cortex, back down the
brainstem through feedback pathways, and to centers con-
cerned with motor responses to sound stimuli.
Descending Pathways
The central nucleus of the inferior colliculus is surrounded
by a relatively large pericentral zone. The rostral half of
this zone is notable for being an area of multisensory
convergence. This region has been called the external cor-
tex and is also termed the intercollicular area because it
forms a bridge, anatomically and functionally, between the
inferior and superior colliculi. In addition to auditory
input from the central nucleus of the colliculus, it receives
visual input via the optic tract38 and somatosensory input
from the spinal trigeminal nucleus and the dorsal column
The Human Brainstem Auditory System 49
nuclei.39 Electrophysiologic studies of the external cortex
show that many cells are influenced by both auditory and
somatosensory stimuli, and most have relatively nonspe-
cific response fields, reflecting broad frequency ranges and
large areas of the body.40 An organized map of auditory
space has been demonstrated in this region,41 and behav-
ioral studies have shown that lesions here cause deficits in
the ability to orient to sound.22 Neurons in the intercollic-
ular area project to the deep layers of the superior collicu-
lus, where the auditory map is aligned with the map of
visual space. In turn, output from the multimodal neurons
in the deep layers of the superior colliculus plays a major
role in control of the motor nuclei for head and eye turn-
ing. Thus the external cortex of the inferior colliculus is
the beginning of a process of integration of auditory input
with visual and somatosensory information, leading to
creation of a multisensory spatial map and, ultimately,
direction of head and eye position by that map.
The caudal half of the pericentral region of the inferior
colliculus is often called the dorsal cortex because it is
a multilayered structure, with neurons segregated into
several layers and cells becoming progressively larger in
the deeper layers. This area is a way station for relaying cor-
tical influence to the brainstem. Many of the axons descend-
ing from cortex bypass the thalamus and travel to the
inferior colliculus, where they end in the dorsal cortex.42,43
Efferent axons from the dorsal cortex project down to the
level of the superior olivary complex, where they terminate
exclusively in the periolivary region.44 The periolivary cells
that receive these projections form the olivocochlear path-
way that travels in the vestibular nerve to reach the cochlea.
Recent work has provided a clearer picture of the
human olivocochlear system. Immunostaining for choline
acetyltransferase (ChAT), the synthesizing enzyme for
acetylcholine, has been used to identify olivocochlear
neurons in the human brainstem45 and efferent terminals
on hair cells in the human cochlea.46 In addition, immuno-
staining has made it possible to identify two subdivisions
of the human efferent system. One division, the medial
olivocochlear system, is known to form synaptic terminals
contacting outer hair cells, and occasionally, their afferent
fibers. This subsystem appears as a population of large mul-
tipolar cells, scattered throughout the periolivary region,
that are immunopositive only for ChAT. The other subdi-
vision, the lateral olivocochlear system, forms synaptic
terminals contacting afferent fibers from inner hair cells
and, in some cases, inner hair cell somata. These are pre-
dominantly small oval cells, located in or near the lateral
olivary nucleus. They colocalize a variety of neuropeptides
with the cholinergic enzymes and can be visualized by
their reactivity for both ChAT and calcitonin gene-related
peptide (CGRP). The most significant difference between
the human olivocochlear system and that of other mam-
malian species is the relative size of the two subdivisions.
In mammals generally, the lateral efferent component is
consistently the largest portion of the olivocochlear system,
making up approximately 75% of the system in the cat
and monkey, 85% to 90% in rodents, and 90% to 100% in
bats. In contrast, the human lateral olivocochlear system
makes up at most one-third to one-half of the total
number of efferent axons. Despite anatomic differences,
the behavioral influence of the human olivocochlear system
50 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
can be demonstrated in subjects in whom vestibular
neurectomy has disrupted the efferent projection to the
cochlea. These subjects have no detectable change in hear-
ing in quiet surroundings, but in the presence of noise,
there is increased subjective loudness and worsened inten-
sity discrimination in the deafferented ear.47
EFFECTS OF HEARING LOSS
Prosthetic stimulation, provided at the level of the ear, the
cochlea, or the brainstem, requires some structural foun-
dation in the central auditory system to process the input.
Thus one question to be considered is the possibility of
degenerative change in brainstem auditory centers subse-
quent to hearing loss. Some insight into this question can
be obtained from investigations of changes in the human
brainstem subsequent to adult-onset, bilateral profound
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,
duration of deafness, and hearing assessments. Postmortem
examination of the temporal bones provided histopatho-
logic evaluation and counts of the number of surviving
cochlear ganglion cells. In the brainstems of these pro-
foundly deaf subjects, neuronal size was measured by
digitizing the cross-sectional area of cells in the cochlear
nuclei, superior olivary complex, and inferior colliculus.
A reduction in neuronal size was observed in all of the sub-
jects. The change was primarily a reduction in the volume
of cell cytoplasm, with little change in size of the cell
nucleus, and it was accompanied by marked reduction in
cell staining. Because protein production occurs in the
cytoplasmic compartment of cells, smaller size reflects a
lesser volume of the subcellular machinery needed to sup-
port this activity. Reduction in stainable cytoplasmic Nissl
substance (rough endoplasmic reticulum, RNA) also
reflects lower levels of protein synthetic activity. One con-
sistent observation was that, in any given subject, all of the
auditory centers were affected equally, that is, the same
degree of size reduction and pallor was seen in neurons of
the cochlear nucleus, which are directly innervated by the
cochlear nerve, and in the higher brainstem nuclei. This
indicates that the factors that produce cellular degenera-
tion in the central nervous system operate across several
synaptic levels of the central pathway.
The size of central auditory neurons in these profoundly
deaf subjects varied from near normal to only 50% of nor-
mal, despite the fact that all of the subjects ultimately
experienced the same degree of hearing loss. One poten-
tial factor in the differential central degeneration appeared
to be duration of deafness. Not surprisingly, the best pre-
servation of central neurons was seen in a case in which
onset was sudden and the duration of deafness was only
1 year. The excellent survival of central auditory neurons in
this case could be explained by the fact that this subject had
maintained a near normal population of ganglion cells,
since cochlear nerve axons are generally believed to have a
tonic effect on the central auditory system. Degenerative
change was consistently greater in the subjects who had
died 7 to 30 years after the onset of deafness and whose
populations of cochlear ganglion cells were reduced to less
than one-third of normal. However, there are indications
that ganglion cell survival is not the only factor in central
neuronal survival, and that causal factors play a prominent
role in determining the degree of central degenerative
change. On the one hand, excellent preservation of central
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-
tion of cochlear ganglion cells acting on the brainstem to
effectively zero. In addition, among the subjects with
reduced populations of ganglion cells, neuronal degenera-
tive change was significantly greater in those with deafness
due to bacterial meningitis or adult-onset cochleosaccular
degeneration (Scheibe’s degeneration). Additionally, there
was some evidence for a direct effect of genetic mutation
on the central nervous system, as one subject with Scheibe’s
degeneration showed changes in other eighth nerve-related
brainstem nuclei.50
CONCLUSIONS
Information from the ear undergoes significant reorganiza-
tion as it passes through the brainstem, with an interplay of
excitation and inhibition, and changing patterns of activity
in successive populations of neurons. The present protocol
for placement of the auditory brainstem implant adjacent to
cochlear nuclei takes advantage of the ability of brainstem
centers to process and modify the artificial electrical stim-
uli. If it becomes technically feasible to implant electrode
arrays higher in the auditory pathway, consideration will
have to be given to the issue of sacrificing the brainstem’s
contribution to stimulus resolution and perception. How-
ever, it is also true that much of the complexity of stimulus
processing in the brainstem relates to recreation of the
auditory spatial field, a factor that will not be significant in
use of a central prosthetic device. Thus, at the present time,
optimal device placement is still an open question.
It is clear that profound deafness ultimately causes
degenerative changes within the auditory pathway, but
these changes did not appear to occur immediately after
hearing loss and complete loss of central neurons was
never observed. The pronounced central degeneration in
subjects with genetically and meningitis-induced deafness
suggests that cause of deafness is at least as important as
severity and duration of hearing loss. Thus etiology may
provide at least a partial explanation of differences in
performance among those who have suffered hearing loss.
The fact that profound loss of auditory input over decades
did not appear to cause complete degeneration of the
central auditory structures gives reason for optimism and
allows for an expectation that even the most severely
affected cases will maintain a population of neurons poten-
tially responsive to stimulation from a prosthetic device.
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 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
Sound Conduction to the
Cochlea
Frequency Analysis in the
Auditory System
The Cochlea as a Frequency
Analyzer
Representation of Frequency
in the Auditory Nerve
Basis for Frequency
Discrimination in the
Auditory System: Temporal
or Place Representation?
The Auditory Nervous
System
Pathways
Cochlear Nucleus
Superior Olivary Complex and
Binaural Hearing
Inferior Colliculus
Medial Geniculate Body
Auditory Cortex
Nonclassical Ascending
Pathways
Efferent System
Olivocochlear Bundle
Centrifugal Pathways to
the Cochlear Nucleus and
Higher Centers
Neural Plasticity
Parallel Processing and
Stream Segregation
Connections to Other
Nonauditory Parts of the Brain
Evoked Potentials Generated
by the Ear and the Auditory
Nervous System
The Ear
Electrocochleographic
Potentials
Evoked Potentials from the
Auditory Nervous System
Brainstem Auditory Evoked
Potentials
Acoustic Middle Ear Reflex

INTRODUCTION system. Understanding the role of the nonclassical audi-

Many of the disorders confronting the neurotologist are
related to the auditory nervous system. Therefore, neuro-
tologists need to comprehend the physiologic processes
that occur in the ear as well as those arising from the
auditory nervous system. Initially, understanding of the
processing that occurs in the ear and the auditory nervous
system was mainly limited to academic interest. Now the
development of cochlear and brainstem implants has made
understanding of the function of the processing that
occurs in the ear and the auditory nervous system of direct
clinical importance. Therefore the function of both the ear
and the central auditory system will be covered here. The
representation of the frequency of sounds in the auditory
nervous system is of particular importance and it is dis-
cussed separately in this chapter.
The physiologic processes involved in coding and trans-
formation of complex sounds are important because most
natural sounds not only have a broad spectrum but a more
or less rapidly varying frequency or spectral composition.
The intensity of natural sounds such as speech sounds also
varies more or less rapidly. Having an understanding of
how sounds such as pure tones are processed by the audi-
tory system is not sufficient to understanding how complex
sounds such as speech sounds are processed by the ear and
the various nuclei of the auditory system. During recent
years much information has been gained about processing
in more central parts of the auditory system, and the
importance of parallel processing and stream segregation
has become evident. It has also become evident that neural
plasticity is important for the functioning of the auditory
52
tory pathways has progressed over the years, and the
importance of connections from the auditory pathways to
nonauditory parts of the brain have been explored. Studies
in animals that have provided important information about
the way the auditory nervous system codes and transforms
complex sounds will also be discussed in this chapter.
Current knowledge about the function of the auditory
nervous system is based primarily on recordings made from
single nerve fibers and cells in animals. Because it is not
technically feasible to record from single nerve cells or
nerve fibers in the human auditory system, it is important
to know how results obtained from animal experiments can
be applied to understanding the human auditory system.
Recording of evoked potentials, either from electrodes
placed on the scalp or from electrodes placed intracranially
in patients undergoing neurosurgical operations, has been
the most common method of studying the physiology of
the human auditory system. Such studies have contributed
to understanding the pathophysiology of disorders that
affect the ear and the auditory nervous system.
Auditory evoked potentials are used in the diagnosis of
pathologies of the human ear and auditory nervous system
and also in intraoperative monitoring. Interpretation of
evoked potential tests such as brainstem auditory evoked
potentials (BAEP, also known as AEP or ABR) requires
neurotologists to understand how neural activity in the
auditory nerve and auditory nuclei and fiber tracts is
reflected in the BAEP, as well as how changes in function
are reflected in these potentials and what those changes
mean in terms of pathologic processes. In many applications
of the BAEP, it is important to know the neural generators

of the different components of these potentials. This chap-
ter describes the generation of sound-evoked electrical
activity in the ear, the auditory nerve, and the various audi-
tory nuclei of the ascending auditory pathway. The trans-
formation of these near-field potentials into far-field
potentials that can be recorded from electrodes placed on
the scalp is also discussed. The neural generators of the
BAEP are described on the basis of auditory evoked poten-
tials that were recorded from humans. Auditory evoked
potentials recorded from animals are different from those
recorded from humans because of anatomic differences.
The neural generators of the human BAEP can therefore
not be directly deduced from studies of animals.
More recently, magnetoencephalography (magnetic
evoked potentials, MEP), a measure of the magnetic field
that is created by electrical currents in the central nervous
system (CNS), has come into use for studies of the response
to sensory simulation. Functional imaging methods such as
functional MRI (fMRI), positron emission tomography
(PET), and single-photon emission computed tomography
(SPECT) are other means of detecting activation of neural
structures due to sound stimulation for research purposes
and are beginning to find clinical applications. These meth-
ods all measure small changes in blood flow and the use
of such methods are based on the assumption that increased
neural activity is associated with increased blood flow.
However, this assumption has been challenged.
This chapter describes the basic functions of the ear and
the auditory nervous system. The role of the cochlea as a
frequency analyzer and the representation of frequency in
the nervous systems are discussed, followed by a discussion
of neural processing of complex sounds. Contemporary
knowledge and understanding of higher-order processing
in the auditory nervous system is described as assessed
using different experimental methods in studies of animals
as well as in a few studies in humans. Parallel processing
and stream segregation are described, and their impor-
tance in central processing of auditory information is dis-
cussed. The role of neural plasticity in the normal function
of the auditory system and as a cause of symptoms of
pathologies is discussed. The anatomy and physiology of
the acoustic middle ear reflex is examined in view of its
importance in neurotologic diagnoses.
THE EAR
The following description of the function of the ear is
divided into that of the sound conductive apparatus and
that of the cochlea. The description of the function of the
cochlea focuses on its ability to separate sounds according
to their frequency (frequency analysis).
Sound Conduction to the Cochlea
The ear canal and the middle ear conduct sound to the
cochlea, where the sensory cells are located. The ear canal
and the acoustic effects of the head as an obstacle in a
sound field modify the sound that reaches the cochlea.
The ear canal acts as a resonator that is tuned to a fre-
quency of approximately 3 kHz depending on the length
of the canal (average 2.8 kHz).1 The sound pressure at the
Physiology of the Ear and the Auditory Nervous System 53
entrance of the ear canal is different from that measurable
without the person being present because the head acts as
an obstacle that disturbs a free sound field. When sound
reaches an observer from a source that is located in front
of the observer, the sound pressure at the entrance of the
ear canal is higher than it would be in that place if the
person were not present. Together with the effect of the
resonance in the ear canal, the total gain is approximately
15 dB in the frequency range between 2 and 5 kHz.2,3
The sound pressure at the entrance of the ear canal
depends on the direction to the sound source. Therefore,
the sound pressure at the two ears is different except when
sound reaches the observer from directly in front of or
behind the observer. The difference depends on the
frequency of the sounds. There is also a difference in the
arrival time of sounds at the two ears that is a direct func-
tion of the azimuth. The arrival time difference together
with the difference between the sound pressure at the two
ears are the physical bases for directional hearing.
Sounds that reach the tympanic membrane set it into
motion, and this motion is conducted to the fluid of
the cochlea by the three ossicles of the middle ear. The
middle ear functions as an impedance transformer, which
improves the transmission of sound to the cochlear fluid.
This improvement in transmission is mainly the result
of the large ratio between the area of the tympanic mem-
brane and that of the stapes footplate.2,4 The improvement
of sound transmission varies with its frequency. The
increase is between 25 and 30 dB. This also means that the
middle ear causes a large difference between the amount
of sound that reaches the two windows of the cochlea.
This difference between the force at the two windows sets
the fluid in the cochlea into motion. The improvements
of sound transmission to the cochlea by the action of
the middle ear compared with a situation when an equal
amount of sound reaches both windows is thus much
greater than the aforementioned 25 to 30 dB; patients
without the middle ear can experience hearing impairment
on the order of 50 dB.2
Various pathologies can affect the function of the mid-
dle ear.2,4 For example, the sound transmission through
the middle ear changes (decreases) when the air pressure
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
parts of it.2 Tympanometry, which involves measuring the
ear’s acoustic impedance (or admittance or compliance)
while the air pressure in the sealed ear canal is varied, can
determine the pressure in the middle ear cavity noninva-
sively.2,5 Disorders such as otosclerosis impair hearing by
adding stiffness to the middle ear. A perforation of the
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
Two small muscles that are attached to the ossicles can
affect sound transmission through the middle ear. One, the
tensor tympani, is innervated by the trigeminal nerve and
pulls the tympanic membrane inward when it contracts,
thus causing the tympanic membrane to be stretched and
thereby attenuating sound transmission for low-frequency
sounds. The other muscle, the stapedius muscle, is
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.
The stapedius muscle is innervated by the facial nerve, and
its contraction also decreases the middle ear’s ability to
conduct low-frequency sounds. In humans the stapedius
muscle contracts as an acoustic reflex in response to a
strong sound. (See the section on Acoustic Middle Ear
Reflex near the end of this chapter.)
Contraction of the stapedius and the tensor tympani
muscles increases the ear’s acoustic impedance.2,5,7 The
contractions of the stapedius muscle can therefore be
recorded by measuring changes in the ear’s acoustic
impedance. This technique is noninvasive. Unlike a con-
traction of the tensor tympani muscle, which causes the
tympanic membrane to move inward, a contraction of the
stapedius muscle does not cause any noticeable movement
of the tympanic membrane.2,7
Frequency Analysis
in the Auditory System
The cochlea separates sounds according to their frequency
(or spectrum*) before the sounds are converted into a neu-
ral code by the inner hair cells. The frequency selectivity of
auditory nerve fibers and cells in the nuclei throughout the
ascending auditory pathways including those of the audi-
tory cerebral cortex is based on the frequency selectivity of
the cochlea. However, that frequency selectivity is trans-
formed in various ways as the information ascends in the
auditory nervous system. Much of our knowledge about the
function of the frequency analysis in the cochlea has been
achieved by studies of the responses from single auditory
nerve fibers but valuable information has also been
obtained by recordings from single hair cells and from
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
simple sounds such as pure tones or trains of impulses, while the proper-
ties of complex sounds should be described by their spectrum which
represents the distribution of energy as a function of the frequency.
decreases until the wave motion becomes extinct. The
distance that the wave travels before it reaches its peak
amplitude is a direct function of the frequency of the
sound that has initiated the motion. Thus, the vibration
amplitude of the basilar membrane in response to low-
frequency sounds is highest near the apex of the cochlea,
while high-frequency sounds give rise to maximal vibra-
tion of regions of the basilar membrane at the base of the
cochlea. Each point of the basilar membrane vibrates
with the greatest amplitude for a certain frequency, and
each point can be regarded as possessing frequency selec-
tivity, that is, being tuned to a certain frequency (Fig. 2-1).
A frequency scale can be laid out along the basilar mem-
brane with respect to the highest vibration amplitude, low
frequencies at the apex and high frequencies at the base of
the cochlea. This also means that the basilar membrane
separates sounds according to their spectral contents, and
the different spectral components of a complex sound are
separated along the basilar membrane.
Once technologic advances made it possible to measure
the vibration amplitude of the basilar membrane in living
animals at sound intensities within or just above that of
normal sounds,10 and later down to threshold values11–13
(see Fig. 2-1), it became evident that the motion of the
basilar membrane was nonlinear. Its frequency selectivity
depended on the sound intensity.
The vibration of the basilar membrane activates sensory
cells (inner and outer hair cells) that are located along the
basilar membrane. The hair cells are therefore activated
according to the frequency (spectrum) of sounds. The
outer hair cells are morphologically similar to inner hair
cells, but they have a purely mechanical function in that
they act as “motors” that amplify the motion of the basilar
Figure 2-1. Basilar membrane vibration amplitude as a function of frequency
for different sound levels in a guinea pig. (Adapted from Johnstone BM,
Patuzzi R, Yates GK: Basilar membrane measurements and the traveling
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
that the mechanical tuning curves of the basilar membrane
in living animals were nearly identical to the FTCs
obtained by measuring the responses from single auditory
nerve fibers12,13 (Fig. 2-5). There was no longer a need of
Figure 2-4. Tuning properties of a single auditory nerve fiber in a rat
estimated from the responses of a single auditory nerve fiber to
pseudorandom noise of different intensities (given in dB SPL). (Adapted
from Møller AR: Frequency selectivity of phase-locking of complex sound in
the auditory nerve of the rat. Hear Res 11:267–284, 1983.)
Figure 2-5. Frequency selectivity of the basilar membrane (Thick line:
isovelocity; thin line: isodisplacement) determined at sound levels near the
threshold of hearing, compared with a FTC (dashed line) of the auditory
nerve. Both measurements were done in anesthetized guinea pigs. (Adapted
from Sellick PM, Patuzzi R, Johnstone BM: Modulation of responses of spiral
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
sounds in the auditory nerve become apparent when more
complex sounds are used. The tuning curves shown in
Figures 2-2 and 2-3 were obtained by probing with a single
tone, the frequency and intensity of which was changed, to

Figure 2-6. Effect of anoxia on the frequency threshold curves of a single
auditory nerve fiber in a guinea pig. (Adapted from Evans EF: Normal and
abnormal functioning of the cochlear nerve. Symp Zool Soc Lond
37:133–165, 1975.)
determine the least intensity necessary to produce a notice-
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
Fig. 2-7).22 Note that there are two such inhibitory areas,
one on each side of the response area of the fiber depicted
in Figure 2-7. This is typical for auditory nerve fibers, and
this two-tone inhibition has been studied extensively.22
Figure 2-7. Inhibitory areas of a typical auditory nerve fiber (cross hatched)
in a cat together with the frequency threshold curve (filled circles).
The inhibitory areas were determined by presenting a constant tone (CTCF )
together with a tone, the frequency and intensity of which were varied to
determine the threshold of a small decrease in the neural activity evoked by
the constant tone (CTCF ). (Adapted from Sachs MB, Kiang NYS: Two-tone
inhibition in auditory nerve fibers. J Acoust Soc Am 43:1120–1128, 1968.)
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
occur in fibers of the auditory nerve for pure tones,27 but
later it was shown to occur also for more complex sounds
such as those that consist of more than one sinusoid28
(Fig. 2-9), including broadband sounds such as vowels29
and broadband noise.19,20
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
Arthur RM, Pleiffer RR, Suga N: Properties of “two tone inhibition” in
primary auditory neurons. J Physiol 212:593–609, 1971.)
Figure 2-9. Period histograms of discharges in a single auditory nerve fiber
of a squirrel monkey to stimulation with two tones of different frequencies
that were locked together with a frequency ratio of 3:4 and an amplitude ratio
of 10 dB. The different histograms represent the responses to this sound
when the intensity was varied over a 50-dB range. (Modified from Rose
JE, Hind JE, Anderson DJ, Brugge JF: Some effects of stimulus intensity on
response of auditory fibers in the squirrel monkey. J Neurophysiol
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

medial geniculate body (vMGB) (Fig. 2-10). The fiber
tract of the lateral lemniscus (LL) crosses the midline
while connecting the CN with the ICC. The brachium of
the IC (BIC) connects the ICC with the vMGB, which
projects to the primary (and secondary) auditory cerebral
cortices (AI, AAF, PAF). Other nuclei, such as those of the
superior olivary complex (SOC), the dorsal and ventral
nuclei of the lateral lemniscus (DNLL and VNLL) inter-
rupt some ascending information (see Fig. 2-10).
A colliculus; ICC, central nucleus of the
Physiology of the Ear and the Auditory Nervous System 59
All these nuclei have complex internal networks of neu-
rons that process auditory information, although the FTCs
of neurons in the cochlear nucleus, the nuclei of the supe-
rior olivary complex, and the nucleus of the inferior
colliculus are rather similar to those of fibers of the auditory
nerve16 (Fig. 2-11). Whereas the representation of the fre-
quencies of simple sounds such as pure tones seems consis-
tent throughout the ascending auditory nervous system,
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
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
A superior colliculus (SC), which receives auditory input from
B auditory nerve innervates each of the three main divisions
C neurons in the CN have tuning curves of different shapes,
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
complex sounds such as sounds the frequencies or intensi-
ties of which vary at different rates. The response patterns
of the auditory nerve fibers and of cells of the various nuclei
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
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
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
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
Figure 2-12. Tonotopical organization in the cat cochlear nucleus. Pv,
posterior ventral; Av, anterior ventral; Dc, dorsal cochlear nucleus. (Adapted
from Rose JE, Galambos R, Hughes JR: Microelectrode studies of the
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)
while MTF of auditory nerve fibers have cut-off frequen-
cies of approximately 1 kHz.25 Neurons in the cochlear
nucleus thus selectively modulate the frequency of a tone
(or noise) as well as the frequency of a tone stimulus.
At the “best” modulation frequency, the discharges of neu-
rons in the cochlear nucleus may be modulated nearly 100%
when the amplitude of the sound is modulated by only a few
decibels.2,36,49,50,54 The response of cells in the cochlear
nucleus is also different from that of auditory nerve fibers in
that cells in the CN respond better to the modulation wave-
form than do auditory nerve fibers.47,48,54,55
Although the vast majority of nerve cells in the cochlear
nucleus receive input from only the ipsilateral ear, some
neurons respond to contralateral sounds,56–58 either by
increasing their discharge rate (excitatory) or by decreasing
it (inhibitory). Sound-driven activity from the ipsilateral ear
can also, in a few nerve cells, be inhibited by delivering
sound, in a specific frequency range, to the opposite ear.
Superior Olivary Complex and Binaural Hearing
The superior olivary complex (SOC) (see Fig. 2-10) con-
sists of a series of nuclei scattered in the brainstem. The
anatomic organization of the SOC in humans versus that
in small animals is the most different of all the ascending
auditory nuclei of the brainstem.59 The possible physio-
logic effects of these differences are difficult to assess, but
caution should be exercised when drawing conclusions
from the results of studies in animals about the function of
the various groups of neurons in the SOCs of humans.
Figure 2-15. Modulation transfer functions obtained in a single auditory
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
compared with cells in the cochlear nucleus. Acta Physiol Scand
98:157–167, 1976.)
The SOC is usually regarded as the most peripheral
level at which the ascending auditory pathway crosses from
one side to the other. However, there are also connections
between the two cochlear nuclei, as mentioned earlier.
When hearing acuity is nearly equal in both ears, the
direction of a sound can be determined with great accuracy
and, perhaps more importantly in humans, binaural hearing
helps to discriminate sound on the basis of the location of its
source in space. When listening to speech in an environ-
ment with more than one speaker, or in a noisy environ-
ment, binaural hearing improves the ability to distinguish
one speaker from another. The use of binaural hearing for
this purpose is known as the “cocktail party phenomenon.”
The ability to discriminate from which direction a
sound is coming is based on the difference in arrival time
and intensity of the sound that reaches both ears. When a
sound is located directly in front of the head, or exactly
behind the head, the sound will arrive at both ears at pre-
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
sound source. The value of this time difference is a direct
function of the azimuth to the sound source (and the prop-
agation velocity of the sound), which is constant. Jeffress60
presented a hypothesis that describes how interaural time
differences can be detected by a neural circuit that consists
of coincidence detectors and variable delay lines.
Experimental evidence has been presented that such a
circuit exists in the medial superior olivary (MSO) nucleus
of the SOC.61
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
nucleus (ICX), and the dorsal cortex (DC).41,62 The neurons
of the ICC are the midbrain relay nucleus of the classical
ascending auditory pathways.63 The cells of the ICC receive
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
ipsilateral ear through the nuclei of the lateral lemniscus.
The ICX and DC belong to the nonclassical auditory path-
ways, and these nuclei receive their auditory input mainly
from neurons in the ICC.
It is generally assumed that all auditory information is
interrupted by synaptic contacts in neurons of the ICC.
However, considerable differences may exist among
species, and there are indications that in the chimpanzee
some cochlear nuclear axons may bypass the IC.41 Similar
findings have been made more recently showing connec-
tions between neurons in the DCN and the medial division
of the MGB.65
Also, neurons in the central nucleus of the IC are tono-
topically organized,41,66 similar to more peripheral nuclei.
Neurons in the central nucleus of the IC exhibit frequency
selectivity similar to that of neurons in the auditory nerve
and the cochlear nucleus, but again the variations in the
widths and shapes of the tuning curves of these neurons
are greater than that of neurons of more caudally located
nuclei41,67 (Fig. 2-16).
Some neurons of the ICC respond with a sustained dis-
charge when stimulated with continuous sounds or tone
bursts, whereas others respond only to the onset or the off-
set of tone bursts.41 In this connection, keep in mind that
the response pattern may be affected by the level and type
of anesthesia used. Responses in unanesthetized animals
tend to have more complex patterns than those from
anesthetized animals. This is true also for more peripheral
levels of the auditory system. Although responses from the
auditory nerve and the ventral portion of the cochlear
nucleus are generally assumed not to be affected by anes-
thesia, a noticeable effect of anesthesia on the dorsal
cochlear nucleus has also been demonstrated.68
Many neurons in the central nucleus of the IC respond
in a nonmonotonic fashion, which means that the discharge
rate first increases when the stimulus level is increased
from threshold levels and then, at a certain stimulus inten-
sity, the rate begins to decrease, reaching very low values
at the highest stimulus levels.41
Studies have shown that development of a normal
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
When 2-day-old gerbils underwent ablation of the cochlea
on one side, responsiveness of the ipsilateral ICC was
greatly enhanced 6 months after birth compared with the
response in normal animals. Apparently, sound deprivation
caused reorganization of the ascending auditory pathways.
Deprivation of sound70 and hearing loss due to auditory
overstimulation (in adult cats) have been shown to result in
a decrease in temporal integration of the IC.71 This change
may reflect hypersensitivity of the IC to sound.
Experimental evidence for involvements of the ICC in
directional hearing have been presented, and neurons in
the ICC have been shown to specifically respond to differ-
ences between the ears in the intensity of a sound.72 The
physical properties of the head provide the interaural
intensity differences that are related to the azimuth of a
sound source. The modification of the spectrum of sounds
by the physical properties of the head also contribute to
the perception of space (stereophonic sound).43
Almost all neurons in the ICC respond to contralateral
sound stimulation, whereas fewer than 40% of the neurons
are excited by ipsilateral sound stimulation.41 There are sev-
eral anatomic bases for binaural interaction in the auditory
midbrain. One is the commissure of the IC, which is a large
fiber bundle that connects the two ICCs. The lateral lem-
niscus and the ICC are also connected via the DNLL and
VNLL. The commissure of Probst connects one of the dor-
sal nuclei of the lateral lemniscus with the corresponding
nucleus on the other side as well as the contralateral ICC.
Directional information from the auditory system is
integrated with that from the visual system in the SC to
achieve a perception of space.73,74 Some neurons in the SC
thus respond to sound, although this nucleus does not
function as a relay nucleus for auditory stimuli.41
The IC is a reflex center that passes on auditory infor-
mation to motor systems, for example, to the spinal cord
and to the SC, which activates the extraocular muscles.
The IC is not involved in the acoustic middle ear reflex.75
Medial Geniculate Body
The medial geniculate body (MGB) is the thalamic relay
nucleus of the auditory pathway. On anatomical grounds,
the MGB in the cat has been divided into ventral, dorsal,
and medial divisions,76 and physiologic studies have shown
that the response patterns of neurons in these three divi-
sions are different. The ventral MGB (vMGB) belongs to
the classical ascending auditory pathways, and the dorsal
and medial portions of the MGB belong to the nonclassical
pathways. All information from the ICC is conducted to the
vMGB through the brachium of the IC (BIC), where all
information is interrupted by synaptic connections before it
reaches the cerebral cortex. The neurons in the vMGB are
sharply tuned, and they project to the primary auditory cor-
tex.77 There is a considerable projection from the auditory
cortex to the vMGB78,79 as well. No known connections
exist between the vMGB of the two sides.
Auditory Cortex
The primary auditory cortex (AI) receives its input from
the vMGB.77,80 Other auditory cortical areas are the anterior
and posterior auditory fields (AAF and PAF), which
receive input from the AI. Neurons in the AI on one side
connect to neurons in similar areas on the other side
through the corpus callosum.81,82 Single nerve cells in the
AI cortical area respond to sounds in a more stereotypical
fashion than do neurons in the more caudally located
nuclei of the ascending auditory pathway, but cortical
neurons have more complex frequency tuning than that of
cells in the nuclei at more caudal levels of the ascending
auditory pathways.83 Nerve cells in the primary auditory
cortex usually respond to stimulation of both ears, and
they are distinctly sensitive to the time interval between
stimulation of the two ears.83,84 Responses of the nerve
cells of the auditory cortex to pure tones indicate that
these nerve cells are organized according to the frequency
to which they are tuned. Cells in the AI and the AAF
cortex respond well to amplitude-modulated sounds, but
the range of modulation frequencies is much lower than
that of neurons at more peripheral levels.85,86
Animal experiments in which sounds have been applied
to both ears have shown that cortical neurons are orga-
nized in bands where neurons respond with excitation
from the contralateral and ipsilateral ear (EE). These
bands alternate with bands where neurons are excited from
the contralateral ear but inhibited from the ipsilateral ear
(EI).87 Also, recent animal experiments have revealed a
high degree of neural plasticity of cortical neurons caused
by deprivation88 and prior stimulation with various kinds
of sounds.86
The auditory cortex in humans is located deep in the
lateral fissure of the temporal lobe, in the superior tempo-
ral gyrus (Heschel’s gyrus)77,83 (Brodmann’s area 41), and it
is therefore not easily accessible for studies using physio-
logic methods. Only a few studies of the physiology of the
human auditory cortex have been published.
Penfield and Rasmussen89 showed that electrical stimula-
tion of the primary auditory cortex in their patients who
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
patients undergoing neurosurgical operations, has shown
that sounds are represented bilaterally in the human cortex.
These somewhat contradictory findings call into ques-
tion the level that should be assigned to the primary audi-
tory cortex. Is the cortex the end point in the auditory
system, the point at which we actually perceive and
interpret natural sounds, such as speech sounds, to which
we are normally exposed? When viewed in one way, the
primary auditory cortex may be regarded as just another
stage of the ascending auditory pathway where consider-
able information processing occurs, as indicated by the
response patterns of single cortical neurons being more
complex than that of neurons in the lCC and the vMGB.
The primary auditory cortex may thus be just another com-
mon pathway in the ascending auditory pathway leading
toward higher brain centers (association cortices) where
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, and modern imaging techniques, such as
CT and MRI can delineate most lesions that affect the
auditory cortex. Before these techniques were available,

low-redundancy speech was used in tests designed to iden-
tify the location, and perhaps the nature, of lesions in this
part of the auditory nervous system.91,92
Nonclassical Ascending
Pathways
The main anatomic differences between the classical
and the nonclassical ascending auditory pathways are that
the nonclassical pathways are interrupted by synaptic con-
tacts with neurons in the medial and dorsal part of the
MGB whereas the classical pathways use the ventral por-
tion of the MGB (Fig. 2-17). Neurons in the dorsal and
medial MGB project to secondary cortices and association
cortices,41,93 and those in the ventral part project to pri-
mary auditory cortex (AI). There is a direct connection
from neurons in the dorsal and medial MGB to the lateral
nucleus of the amygdala.94 This connection provides a fast
route through which little processed information can
reach the amygdala. Another important difference
between the classical and nonclassical auditory systems is
Figure 2-17. Schematic drawing of the ascending nonclassical auditory
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
other structures. Efferent input from the cerebral cortex and connections to
the DC and ICX from the somatosensory system (dorsal column nuclei)
and from the opposite IC are not shown (for more details see Fig. 9-1).
AAF, anterior auditory field; AI, primary auditory cortex; AII, secondary
auditory cortex; D, dorsal division; M, medial division; OV, ovoid part of the
MGB; PAF, posterior auditory field; SAG, sagulum; V, ventral division.
(Adapted from Møller AR: Sensory Systems: Anatomy and Physiology.
Amsterdam, Academic Press, 2003.)
Physiology of the Ear and the Auditory Nervous System 65
that the nonclassical auditory pathways receive input from
other sensory systems, most noticeably the somatosensory
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
(for a more detailed description of the nonclassical path-
ways see Chapter 9, and Møller, 2003.35). Some neurons in
the ICX receive input from the somatosensory system
(mainly cutaneous tactile), and approximately 10% of the
neurons in the ICX receive both somatosensory and audi-
tory input.41,63 The main auditory input to the DC and
ICX is from the ICC, but some evidence indicates that
auditory input may also arise from the auditory cortex.41
Animal studies have confirmed that somatosensory
input can interact with the responses to auditory input
from neurons in the ICX and DC41 and evoked responses
from the surface of the IC.99 Interaction between sensory
modalities has been demonstrated at several levels of
sensory pathways.100
The tonotopic organization seems to be less prominent
in the ICX and DC compared with that in the ICC. These
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-
tem and a polysensory system.103
Efferent System
The auditory pathways include abundant descending sys-
tems. Traditionally, the efferent pathways have been
described as separate systems, and two main efferent sys-
tems have been identified: one the olivocochlear bundle
that terminates in the ear and one that terminates in vari-
ous nuclei of the ascending auditory system. However, it
66 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
may be more appropriate to regard the descending systems
as being reciprocal pathways to the ascending pathways,
because most of the neurons that receive ascending input
also send descending fibers to the same nuclei from which
they receive ascending input (and often also other nuclei of
the auditory pathways).
Olivocochlear Bundle
The olivocochlear bundles consist of the crossed olivo-
cochlear bundle (COCB) that originates in the medial
superior olivary nucleus (MSO)104,105 and the uncrossed
olivocochlear bundle (UOCB) that originates in the lateral
superior olivary complex (LSO). The COCB fibers mainly
terminate on outer hair cells, whereas the UOCB fibers
mainly terminate on axons of inner hair cells. The efferent
fibers have sharp frequency tuning and about the same
sensitivity as auditory nerve fibers.106
Early animal experiments have shown that activation of
the COCB results in a decrease of stimulus-driven neural
activity in fibers of the auditory nerve,107,108 but more
recently it has become evident that neural activity in these
fibers can also affect the mechanical properties of the
cochlea. This effect is mediated by the termination of
efferent fibers on the cell bodies of outer hair cells and is a
consequence of the fact that the outer hair cells are an
integral part of the mechanical system of the cochlea.14
This means the medium that transmits the stimulus to the
receptors (inner hair cells) is controlled from the
CNS.109,110 Neural activity in the COCB can be elicited by
(contralateral) sound stimulation. The mechanical proper-
ties of the cochlea can therefore be affected by contralat-
eral sound stimulation, which can be detected by recording
otoacoustic emissions from the ear.111,112
The functional importance of the OCB is not yet under-
stood, but some studies indicate that its stimulation
reduces masking in auditory nerve fibers.113 Other behav-
ioral studies, performed in patients who had undergone
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
on such patients have not revealed any specific effects of
severing the OCB except a better ability to detect signals
at unexpected frequencies, and that was interpreted as an
impaired ability to focus attentions in the frequency
domain.114 It has been reported that the OCB offers pro-
tection against noise-induced hearing loss.115 It is difficult
to believe that such an effect should be the primary func-
tion of this system because noise-induced hearing loss was
probably not a factor that influenced an animal’s survival
during evolution.
Centrifugal Pathways to the Cochlear Nucleus
and Higher Centers
The descending systems of the central auditory pathways
are abundant.78,116 The number of fibers that connect
cortical cells with cells in the MGB is several times larger
than that of the fibers that ascend from the MGB to the
auditory cortex.117 The cells of the auditory cortex also
send connections to the ICC.78,116 There is also an abundant
descending system from the ICC to neurons in the dorsal
cochlear nucleus bilaterally.118
Generally, little is known about the physiology of the
descending auditory systems. It has been shown that elec-
trical stimulation of the auditory cortex affects sound-
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
MGB as well as the ICC were tuned.120
Neural Plasticity
Neural plasticity is usually regarded as a process that cause
changes in the nervous system in response to altered
demands or which shifts function from one region of the
CNS to another after injuries. Neural plasticity is assumed
to involve establishment of new connections or elimina-
tion of connections (synapses and axons or dendrites) or by
changes in synaptic efficacy. Morphological changes can
be altered as a result of the firing pattern of neurons121 and
that is the basis for activity induced plasticity. Recent
studies have shown that neural plasticity is much more
extensive than earlier assumed and it is not always bene-
ficial to the organism. For example, neural plasticity can
cause symptoms and signs of disorders such as pain and
tinnitus.122,123
Studies of the auditory cortex have shown that extensive
alterations in processing may occur as a result of deprivation
of input or exposure to specific kinds of sounds.88,124–127 The
nucleus basalis128 (an acetylcholine pathway) is important
for many functions such as memory, arousal, and facilitation
of neural plasticity of the auditory cortex that are caused
by prior sound stimulation.129 The functional changes in
the response of neurons in the AI cortex caused by prior
sound stimulation are facilitated by electrical stimulation
of the nucleus basalis as well as by application of acetyl-
choline to the cortex.129 These changes involve the tuning
of cortical neurons and of their response to temporal
information.86,129
Higher-Order Processing
The primary auditory cortex may be regarded as one of
the final common pathways to higher CNS centers.
Connections from the primary auditory cortices (AI) reach
secondary auditory cortices such as the anterior (AAF) and
posterior auditory fields (PAF) and from there, auditory
information can reach larger regions of association
cortices. Neurons in the auditory AI cortex respond only
to sound, but some neurons in secondary cortices respond
to other sensory modalities. Such multimodal responses
are common in neurons in the association cortices,
where information from different sensory modalities is
integrated.
Parallel Processing and Stream Segregation
Considerable processing of auditory information occurs in
the association cortices, and there is evidence that the
same information is processed in different populations
of neurons (parallel processing) and that different types
of information is processed in different populations of

neurons (stream segregation). Although parallel process-
ing is prominent throughout the ascending auditory
pathways beginning in the cochlear nucleus, stream segre-
gation seems to be mainly present in the cerebral cortex.
Stream segregation has been studied to the greatest extent
in the visual system, where it has been demonstrated that
spatial information (“where”) and object information
(“what”) is processed in two different regions of associa-
tions cortices (dorsal and ventral regions, respectively).130
Although the basis for parallel processing is obvious
from the anatomy of the auditory systems, stream segrega-
tion has only been demonstrated in the auditory system
relatively recently.131–134 One form of stream segregation in
the auditory system is based on projections of two differ-
ent kinds of information from the vMGB to the supertem-
poral plane in addition to the more commonly known
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
respond to the spatial location of a complex sound,
whereas neurons in the lateral surface of the superior
temporal gyrus respond best to complex sounds such as
species-specific communication sounds. Auditory stream
segregation has been demonstrated in monkeys,131,133
where it has been shown that certain populations of
neurons respond to complex sounds, whereas others
preferentially respond to pure tones.134 Little is known
about stream segregation of auditory information in asso-
ciation cortices.
Connections to Other Nonauditory
Parts of the Brain
Similar to other sensory systems, the auditory system has
ample connections to parts of the brain that are not usually
associated with sensory functions.35 Connections between
the auditory system and motor systems are evident from
such phenomena as the startle response and the acoustic
middle ear reflex. There are also connections to speech
motor centers from the auditory system.
Connections from the auditory system to structures of
the limbic system are important under normal conditions
and in pathologies of the auditory system such as severe
tinnitus123 (see Chapter 9). It is especially true of nuclei of
the amygdala, which are important to the auditory sys-
tem.35,94 Auditory information can reach the nuclei of the
amygdala through mainly two routes. One route involves
the primary auditory cerebral cortex, secondary cortices,
and association cortices, which connect to the lateral
nucleus of the amygdala.135 That route is known as the
“high route,”94 and it carries highly processed informa-
tion. The other route known as the “low route,”94 is
shorter and faster and consists of direct connections to the
lateral nucleus of the amygdala from the dorsal and
medial parts of the MGB. The low route thus carries
information from the nonclassical auditory pathway while
the high route carries information from the classical audi-
tory pathways. This information is likely to be subjected
to modulation by other sensory input and intrinsic infor-
mation from different parts of the CNS. The low route
carries information that is little processed and less
affected by other (intrinsic of extrinsic) neural activity.
Physiology of the Ear and the Auditory Nervous System 67
The lateral nucleus of the amygdala connects to the baso-
lateral group of nuclei, which in turn connect to the cen-
tral nucleus of the amygdala. That nucleus connects to
many parts of the brain, such as the hippocampus and var-
ious endocrine centers.35,94 It also connects to the nucleus
basalis, which is important for neural plasticity94 and con-
trolling arousal.
The nonclassical pathways that provide input to the
amygdala through the low route may not be active in
adults, but there are indications that it is active in young
children102 and in some patients with tinnitus101 (see
Chapter 9). The fast path between the dorsal and medial
auditory thalamus and the amygdala may explain why
sounds can evoke emotional reactions and why tinnitus can
evoke fear and phonophobia and cause other affective
symptoms such as depression.35,136
EVOKED POTENTIALS GENERATED
BY THE EAR AND THE AUDITORY
NERVOUS SYSTEM
Evoked potentials from the ear and the auditory nervous
system are important diagnostic tools. They have provided
some insight in the differences between the human auditory
system and that of the animals commonly used in studies
of the function of the auditory system.
The Ear
Several different types of evoked potentials can be
recorded from the cochlea and its vicinity in response to
sound. The earliest of such potentials is the cochlear
microphonic (CM), which, as the name indicates, is a
potential that has the same waveform as the sound. When
recorded from the round window membrane, the CM
potential is assumed to be generated by outer hair cells.137
Neural activity in the auditory nerve gives rise to evoked
potentials (action potentials, APs) that can be recorded
from the round window.
When recorded from animals, these potentials are
known as CM, summating potentials (SP), and AP
(Fig. 2-18), and when recorded from the promontorium of
the cochlea in humans they are known as electrocochleo-
graphic (ECoG) potentials (Fig. 2-19). When recorded
from the round window in small animals, the AP consists
of two negative peaks, the first generated in the cochlea by
neural transduction processes and the second generated by
the cochlear nucleus138 and conducted to the recording
site by electronic conduction. Whereas the CM can best
be visualized in response to continuous pure tones of
low frequency, the AP is best visualized in response to a
transient sound. This potential is a slow potential that
follows the envelope of a sound and, like the CM, it is
generated by hair cells.137 The SP is best visualized in
response to tone bursts. The polarity of the SP can be
either negative or positive, depending on the condition of
the cochlea and the way the SP is recorded.139 By choosing
a tone burst stimuli of a not-too-high frequency, all three
potentials can be visualized in the same recording2
(see Fig. 2-18).
68 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 2-18. Recording from the round window of a rat showing cochlear
microphonic (CM ) and action potentials (AP ) (N1N2). The stimulus was a
5-kHz tone burst. The summating potential (SP ) is represented by the
baseline shift during the tone burst. The sound is shown at the bottom of
the graph. (Adapted from Møller AR: Auditory Physiology. New York,
Academic Press, 1983.)
Electrocochleographic Potentials
The neural components of the ECoG potentials recorded
in humans are different from the APs recorded in small
animals in that the AP consists of two distinct peaks and
the neural component of the ECoG normally consists of
one peak140,141 (see Fig. 2-19). The reason for this differ-
ence between the response in humans and that in small
animals is that potentials generated in the cochlear nucleus
in small animals are conducted effectively to the recording
site (the cochlea) due to the small distance between the
cochlea and the cochlear nucleus. In humans, potentials
that are generated in the cochlear nucleus are attenuated
because of the much longer distance from the recording
site (the cochlear capsule) to the cochlear nucleus (the
length of the auditory nerve in small animals is 5 to 8 mm,
whereas in humans it is 25 mm.142
The SP can also be identified in the ECoG recordings.
ECoG potentials are often elicited by click sounds, which
provide distinct AP components but less distinct CM and
SP responses. If the purpose of recording ECoG is to
obtain CM and SP responses, it is advantageous to use
tone bursts as stimuli.2
Figure 2-19. Typical electrocochleographic (ECoG) recording from the
promontorium of an individual with normal hearing in response to click
stimuli (arrow). (Adapted from Eggermont JJ: Electrocochleography. In
Keidel WD, Neff WD [eds.]: Handbook of Sensory Physiology, vol 3,
chap 15, New York, Springer Verlag, 1976.)
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
kinds of myogenic potentials144 that can be recorded from
electrodes placed on the scalp. These potentials, including
the MLR and the ERP, have little importance in neuroto-
logic diagnosis, and their generators are not known in any
detail. We will therefore limit the discussions to the BAEP.
Brainstem Auditory Evoked Potentials
These potentials are generated by the auditory nerve and
the fiber tracts and nuclei of the ascending auditory path-
way of the brainstem. Recorded in the conventional way,
differentially between electrodes that are placed on the
vertex (Cz) and on the mastoid (or earlobe) on the side that
is being stimulated, the BAEPs are characterized by five to
seven vertex-positive peaks.145 The first five peaks of the
BAEP are relatively constant (although peak IV may at
times be difficult to identify), but the peaks beyond peak V
are variable. Some investigators prefer to display the
BAEP with the vertex-positive peaks pointing upward;
others show them pointing downward. The common way
of displaying neuroelectric potentials is with the negative
potential of the active electrode giving a downward deflec-
tion (Fig. 2-20). Only the vertex-positive peaks are labeled
(with Roman numerals), whereas both positive and nega-
tive peaks of other evoked potentials are usually labeled.
The spectral filtering used in connection with recording
BAEP alters its waveform depending on the settings of the
filters and the kinds of filters. Different investigators use a
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
irritation of the auditory nerve, such as may occur in
patients with tinnitus148 and in patients with a particular
form of vestibular disorder (disabling positional vertigo,
DPV)149 and inflammatory processes that affect the

A including nonhuman primates.
B those of peaks I and II. Peaks I and II only have contribu-
C midline157 and that the SOC is most likely an important
Figure 2-20. BAEP obtained in an individual with normal hearing. A, Vertex-
positive peaks shown as upward deflections. B, Vertex-positive peaks shown
as downward deflections. C, BAEP after filtering.
auditory nerve. A prerequisite for the use of BAEPs in
differential diagnosis in neurotology is a determination of
which neural structures generate the different components
of these potentials. In the following section, the sources of
these potentials are discussed.
Neural Generators of Brainstem Auditory
Evoked Potentials
Earlier studies of the neural generators of the BAEP used
information from animal research to identify the sources
of BAEP peaks, but the differences between the small
animals used in such studies and humans made it difficult
to draw conclusions about the neural generators of the
human BAEP on the basis of animal studies. The animals
commonly used for auditory research only have four
distinct peaks in their BAEP compared with the five in
humans.150 Intracranial recordings from the auditory nerve
in patients undergoing neurosurgical operations revealed
that the auditory nerve is the generator of the first two
peaks (I and II) in humans,151–153 whereas in animals only
peak I is generated by the auditory nerve and peak II is
generated by the cochlear nucleus.150,154 The explanation
for these differences is that the human auditory nerve is
much longer than that of the animals commonly used in
studies of the auditory system. The auditory nerve in
humans is approximately 2.5 cm long,142,155 and it is only
0.8 cm in the cat. Even the monkey has a much shorter
auditory nerve than humans.154 This difference in length
of the eighth cranial nerve in humans and the animals used
in studies of the auditory system is partly the result of
humans having larger heads than these animals and partly
the result of the much larger subarachnoidal space of the
Physiology of the Ear and the Auditory Nervous System 69
cerebellopontine angle in humans compared with animals,
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
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
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
IC but the results of intracranial recordings in patients
undergoing neurosurgical operations have indicated
that the sharp (vertex-positive) portion of the peak is gen-
erated by the lateral lemniscus where it terminates in the
IC.157–159 The slow (vertex-negative) deflection that
follows the sharp part of peak V (SN10)160 most likely rep-
resents dendritic potentials from the IC.161 Animal experi-
ments, however, indicate that the IC does not produce any
noticeable far-field potentials,154 despite the fact that a
very clear (slow) response can be obtained by recording
directly from the nucleus both in animals154 and in
humans.158,159 The failure of the IC to produce any notice-
able far-field potentials is assumed to be related to nearly
random organization of the dendrites of the cells of the IC,
which causes the electrical field produced by the nuclei to
decrease rapidly with distance from the nucleus (known as
a closed field).162 However, the SN10 of some individuals is
very large, suggesting a large individual variation of the
anatomy of the IC.
The fact that only vertex-positive peaks of the BAEP are
labeled has diverted the interest from the vertex-negative
peaks. Most studies of the neural generators of the BAEP
have focused on the vertex-positive peaks despite the fact
that the negative peaks may have distinct generators,157 as
does the vertex-positive peaks, and these vertex-negative
peaks may be of diagnostic value. Figure 2-21 shows a sim-
plified summary of the neural generators of the BAEP in
humans.163
The generation of evoked potentials from the nervous
system is often represented by dipoles. The amplitude of
the recorded potentials depends on the orientation of such
(fictive) dipoles in relation to a line through the two
recording electrodes. The greatest amplitude is obtained
when the orientation of the dipoles is parallel to the line
between the recording electrodes, and small potentials are
recorded when the orientation of a dipole is perpendicular
70 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 2-21. Neural generators of the human BAEP. DCN, dorsal division of
the cochlear nucleus; LL, lateral lemniscus; MG, medial geniculate body;
SO, superior olivary complex; VCN, ventral division of the cochlear nucleus.
(Adapted from Møller AR, Jannetta PJ: Simultaneous surface and direct
brainstem recordings of brainstem auditory evoked potentials (BAEP ) in
man. In Cracco RQ, Bodis-Wollner I [eds.]: Evoked Potentials, chap 20,
New York, Alan R Liss, 1986.)
to a line through the recording electrodes. The dipoles of
the generators of peak I and II are nearly horizontal,
whereas the source of peak V is nearly vertical and the
orientation of the dipole of peak III is approximately
30 degrees from the horizontal plane.164 This means that
the conventional electrode placement (between the mas-
toid and the vertex) is not ideal for recording peak I, II,
and V but nearly ideal for recording peak III. This is the
reason that some investigators have chosen to record
BAEP in two channels, with one pair of electrodes placed
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
of the different components of the BAEP vary among
individuals. The effectiveness of different electrode place-
ments also varies from one individual to another.
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).
Direct connections also exist between the ventral cochlear
nucleus and the facial motonucleus. In addition, numerous
indirect pathways exist, but little is known about these.
The inferior colliculus does not seem to be involved in the
acoustic middle ear reflex.75 The population of neurons in
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
causes contractions of only the stapedius muscle. In the
animals commonly used in auditory research, the tensor
tympani muscle is also involved, although it has a some-
what higher threshold than the stapedius muscle. The
reflex arc for the acoustic tensor tympani reflex that is
active in animals involves the cochlea, the auditory nerve,
the ventral cochlear nucleus, the superior olivary complex,
and the motonucleus of the fifth cranial nerve.75 In
humans, the tensor tympani can be made to contract by
stimulating the skin around the eye, for instance by an air
Figure 2-22. Reflex arc of the acoustic stapedius reflex. N VIII, Auditory
nerve; N VII, facial nerve; VCN, ventral cochlear nucleus; SO, superior olive;
n VII, facial motonucleus. (Adapted from Møller AR: Auditory Physiology.
New York, Academic Press, 1983.)

puff.168 This response is not an acoustic reflex, but a
trigeminal reflex similar to the blink reflex.
When only one ear is stimulated, the reflex response is
bilateral. In humans, ipsilateral stimulation elicits a stronger
contraction than the same level of contralateral stimulation,
and the threshold for ipsilateral activation is slightly lower
than it is for contralateral activation.169 Bilateral stimulation
is about 3 dB more effective than ipsilateral stimulation
(Fig. 2-23). The threshold of the middle ear reflex for
contralateral stimulation is about 85 dB above hearing
threshold in the frequency range of 500 to 4000 Hz.2,170
The strength of the stapedius muscle contraction
increases with increasing stimulus intensity.165,169 A low-
frequency continuous tone or noise elicits a sustained con-
traction of the stapedius muscle, but the reflex adapts after
a few seconds when elicited by tones of frequencies higher
than about 1500 Hz. (For more detail about the physiol-
ogy of the acoustic middle ear reflex, see Møller, 20002.)
Because the branch of the facial nerve that innervates
the stapedius muscle exits the main trunk of the facial
nerve at a point between the brainstem and the stylomas-
toid foramen, testing for the middle ear reflex response
can help determine the anatomic location of injury to the
facial nerve. When the facial nerve regenerates from a
central location, the acoustic middle ear reflex response
returns before contractions of the facial muscles. This
means that the acoustic middle ear reflex test is a predictor
of facial recovery in patients with facial palsy such as
Bell’s palsy. Return of the acoustic middle ear reflex
Figure 2-23. Response of the acoustic middle ear reflex, recorded as
changes in the ear’s acoustic impedance, to 500-ms tone bursts (1450 Hz)
at different intensities. Recordings were made in both ears while the stimulus
tone was applied to one or both ears. Solid lines show the response to
ipsilateral stimulation, and dashed lines show the response to contralateral
stimulation (when both ears were stimulated, the solid line is from the right
ear). (Adapted from Møller AR: The acoustic reflex in man. J Acoust Soc Am
34:1524–1534, 1962.)
Physiology of the Ear and the Auditory Nervous System 71
response means that the facial nerve is in the process of
regenerating, and although no facial muscle activity is yet
present, this return of the reflex is a good indication that
facial function will also return. The ipsilateral response
returns sooner than the contralateral response and should
therefore be used as a test of regeneration of the facial nerve.
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 Chapter
Anatomy of the Central
Vestibular System

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

75
76 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 3-1. The two types of mammalian vestibular hair cell and their
innervation.
potential difference that exists between endolymph and the
sensory cell (approximately 120 mmol), causing intracellular
depolarization and an increase in the frequency of the action
potentials in vestibular nerve fibers. Conversely, deflection
of the cilia away from the kinocilium results in intracellular
hyperpolarization and a decrease in the vestibular nerve
action potentials. Since most vestibular neurons have a rest-
ing neural discharge, an opportunity exists to either increase
or decrease the neural activity.
Type I and type II hair cell distribution in the vestibular
sense organs is characteristic for the type of sense organ.9 In
the crista ampullaris all hair cells are similarly oriented so
that the kinocilium is on the same side of the stereocilia. In
the crista of the lateral canal the kinocilium is located closest
to the utricle, whereas in the vertical canals the kinocilium is
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
posterior and anterior canals of the contralateral labyrinth.
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
the semicircular canals and the utricle receive an approxi-
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
utricular nerve has approximately 3500 nerve fibers. The
saccular nerve has slightly fewer than 3000 nerve fibers.
These first-order vestibular neurons terminate in all four
major vestibular nuclei and in three minor nuclei.
The dendrites of the neurons supplying the cristae of the
three semicircular canals are located in both the inferior and
the superior vestibular divisions but their axons are located
in the rostral half of the vestibular nerve as it enters the
brainstem (see Fig. 3-3). The neurons supplying both
the utricular and saccular maculae occupy the caudal half
of the vestibular nerve before entering the brainstem. The
differential localization of the canal and macular fibers pre-
dicts a different termination within the vestibular nuclei.
The canal neurons terminate in the superior and medial
vestibular nuclei primarily, although the macular input
Figure 3-2. Schematic summary of the polarization of hair cell cilia in the
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 3-5. Photomicrograph of a transverse section through the superior
vestibular nucleus showing the distribution of large, medium, and small
cells (cresyl violet stain). RB, restiform body; BC, brachium conjunctivum;
IV, fourth ventricle; V, vestibular nerve root.
of the nucleus, while small neurons predominate laterally
and medially (Fig. 3-5). The medium-sized cells are multi-
polar or pear shaped. Clusters of larger multipolar cells,
which are dispersed among the medium-sized cells, are
present in the central portion of the nucleus. The dendrites
of the cells in the superior nucleus radiate in different
directions. Some dendrites are directed medially and ventral
laterally. In the peripheral region of the nucleus, dendrites
are arranged tangential to the nuclear border. By and large
the dendritic trees of these neurons remain within the con-
fines of the nucleus, but in the ventral region some dendrites
may extend into the adjacent reticular formation. The larger
neurons in the central portion of the nucleus are strung out
in a ventral lateral to dorsal medial direction and separated
by bundles of nerve fibers representing the incoming
vestibular nerve. The large and medium-sized neurons are
primarily those that represent vestibulo-ocular projections
and vestibulocerebellar projections. The small neurons rep-
resent commissural neurons.24 The peripheral input to the
superior vestibular nucleus is entirely from the semicircular
canals, while the efferent projections are vestibulo-ocular,
vestibulocerebellar, and commissural.
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
from a lateral aspect and are seen to radiate in a fanlike
pattern within the limits of the nucleus. A prominent
Figure 3-6. Transverse section through the dorsal (DL) and ventral (VL)
divisions of lateral vestibular nucleus and the rostral extension of medial
nucleus (M). RB, restiform body; DAS, dorsal acoustic stria; V, descending
trigeminal root; VII, facial nerve genu; VI, abducens nucleus.
projection of myelinated fibers enters the nucleus from a
dorsal aspect to supply the dorsal division. These represent
cerebellar vestibular afferents. However, collateral
branches from the descending rami of canal neurons also
terminate in cells of the ventral division. The dorsal divi-
sion of the lateral nucleus receives its primary input from
the cerebellar cortex, particularly from the hemisphere,
flocculus, and paraflocculus. The primary output of the
large multipolar neurons of the lateral nucleus is in a
descending direction to the anterior horn cells of the spinal
cord. These neurons form the lateral vestibulospinal tract.
The medial vestibular nucleus is the longest rostracau-
dally of the major vestibular nuclei and has a main body
that extends from the caudal end of the lateral vestibular
nucleus caudal to the facial nerve nucleus, where it tapers
to its caudal end. The medial border of the nucleus is
formed by the floor of the fourth ventricle; laterally, it
interfaces with the descending vestibular nucleus. The
medial vestibular nucleus has a narrow rostral extension
that extends medial to the dorsal acoustic stria and blends
in with the caudal portion of the superior vestibular
nucleus (see Figs. 3-6 and 3-7). The cells of the medial
Figure 3-7. Transverse section through the caudal part of the lateral
nucleus and the midportion of medial (M) nucleus. The group Y nucleus is
also seen at this level.

Figure 3-8. High-power photomicrograph of the medial nucleus showing
the large vestibulo-ocular neurons (to abducens nucleus) and smaller
commissural neurons.
vestibular nucleus are large, medium, and small with most
of the small neurons located in the rostral extension
(Fig. 3-8), whereas in the wider caudal section or body of the
medial nucleus, large and medium-sized cells predominate
(see Fig. 3-7). The large and medium cells in the body of
the medial vestibular nucleus represent the primary terminus
of first-order neurons terminating by way of the descending
rami of incoming nerve fibers. These neurons represent
input from the semicircular canals, the utricle, and to a
smaller extent, the saccule. These neurons project contralat-
erally as the vestibulo-ocular pathway, and in a descending
fashion down the medial longitudinal fasciculus as the
medial vestibulospinal tract. A small number of neurons in
the medial vestibular nucleus also project rostrally in the
lateral tegmental field as a separate vestibulo-ocular pathway
(ascending tract of Deiters), which terminates in the ipsi-
lateral portion of the oculomotor nucleus that serves the
medial rectus eye muscle.25 The larger neurons in the ros-
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
vestibular nuclei.23 The group Y nucleus is comprised of
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
and elongated parallel to the vestibular root fibers.
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
projecting from the semicircular canals (see Fig. 3-4).
The rostral division receives the input from the canals of the
superior vestibular division (lateral and anterior), while the
caudal receives those of the posterior canal.18 The efferent
projection of the NIV is not precisely known, although it
has been observed to label when horseradish peroxidase
(HRP) is injected into the contralateral vestibular nuclei,
which suggests a commissural connection.24
The group L nucleus is a small subset of medium-sized
lateral vestibular nucleus multipolar neurons that lies
between the lateral vestibular nucleus and the restiform
body (see Figs. 3-6 and 3-7). These cells have abundant
branching dendrites, which are oriented parallel to the
fibers of the restiform body. It is considered part of the
lateral nucleus and sends fibers to spinal cord levels.23
Because it is regarded as part of the lateral nucleus, the
afferent input to this minor nucleus is from the utricular
nerve.
Figure 3-9. Transverse section through the caudal portions of the medial (M)
and descending (D) vestibular nuclei.
80 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
A their efferent and afferent projections are unknown and
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
retrograde labeling techniques. A, Infracerebellar division to the
oculomotor nucleus. B, Commissural neurons of group Y.
Group F is a collection of closely packed relatively large
cells near the descending vestibular nucleus. Ventrolaterally,
it is related to the spinal trigeminal tract and nucleus, and
the cells have short, richly branched dendrites that do not
extend far from the cell bodies. This group does not receive
primary vestibular fibers but does send fibers to the cerebel-
lum and therefore is considered a part of the vestibular
nucleus complex. The group does receive input from the
cerebellum by way of the hook bundle.
Group X is another very discrete small-cell group that is
located lateral to the caudal end of the descending nucleus
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
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-
posterior canal input terminates more caudally and cen-
trally in the superior nucleus, while the cristae of the supe-
rior division terminate rostrally and laterally. The superior
and lateral canal afferents terminate by short collaterals in
the rostral division of the NIV, while the posterior canal
afferents similarly terminate in the caudal division of the
NIV. Descending vestibular nerve rami of the superior and
lateral canal rami are more ventrally located than those
belonging to posterior canal fibers. The termination of these
two groups in the medial nucleus remains ventrodorsal.
These canal afferents all converge in the medial vestibular
nucleus with the utricular and saccular macular fibers.
Input from the utricular macula is primarily to the ventral
division of the lateral vestibular nucleus and to the medial
and descending vestibular nuclei (Fig. 3-12). The input

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
vestibular nucleus and the medial nucleus. However, the
saccule has a unique input to the group Y nucleus, which
differentiates it from utricular fibers. Neither utricular nor
saccular macular fibers terminate primarily in the cerebel-
lum, but they do project to the vestibular cerebellum by
way of second-order neurons in the medial and descending
nucleus and possibly the reticular formation.
Four physiological types of second-order vestibular
neurons have been described in the major vestibular
nuclei. Type I neurons are the most numerous; they make
Figure 3-12. Summary of the central termination of the vestibular neurons
that supply the otolith sense organs.
Anatomy of the Central Vestibular System 81
up approximately 90% of the active second-order neurons.
Type I neurons are those that respond in the same directional
pattern as first-order afferents. The next most common are
the type II neurons, which exhibit an opposite response pat-
tern to that seen in the first-order neurons providing
input. Types III and IV are extremely uncommon and show
both increased and decreased activity during rotations in
both directions. The majority of type I and type II second-
order neurons are located in the rostral portion of the
medial vestibular nucleus and the superior nucleus, where
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
medial and descending nuclei, contain second-order neurons
that project abundantly to the anterior and posterior lobes
82 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
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.
of the vermis and to the vestibulocerebellum.28 The ves-
tibulocerebellar projections can be primary or secondary.
Primary vestibulocerebellar fibers represent the continua-
tion of vestibular nerve axons that terminate in the vestibu-
lar nuclei and then continue on to the vestibulocerebellum.29
(MLF)
Figure 3-14. Summary of the reflex projections of the utricular macula.
MVST, medial vestibulospinal tract; LVST, lateral vestibulospinal tract;
MLF, medial longitudinal fasciculus.
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.
Primary vestibulocerebellar fibers have been described
in both submammalian and mammalian animal forms to
terminate in the flocculus and nodulus of the cerebellum
ipsilaterally. This is a heavily ipsilateral pathway, which
includes the paraflocculus and the caudal folia of the uvula.
The bundles of primary vestibulocerebellar fibers have
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
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-
ents. Second-order neurons in the caudal vestibular nuclei,
especially those receiving input from the maculae, also form
projections to the cerebellum. In a reciprocal way, the

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
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-
jections (Fig. 3-17). The effect of commissural activity is
largely inhibitory and because it involves primarily the
superior, descending, and medial vestibular nuclei, this
activity is provoked mainly by input from the semicircular
canals. It is thought that commissural inhibition initiated
by canal activity may potentiate the inhibition of the con-
tralateral complementary canal, therefore representing an
effective mechanism for differential activity in complemen-
tary or coplanar canals. The primary mechanism for this
differential coplanar canal activity is afforded by the oppo-
site polarization of hair cells in the cristae. Because the
maculae have an opposite polarization of the hair cells in
the two halves of the sense organs, commissural projec-
tions may not be necessary to produce a differential effect
from activation of this sense organ.
Vestibulospinal Projections
Vestibulospinal reflexes constitute one of the most important
reflex activities of the vestibular system. These projections
Figure 3-16. Summary of the commissural projections of the vestibular
nuclei.
Anatomy of the Central Vestibular System 83
Figure 3-17. Retrograde label demonstrating the commissural neuron
population of the medial vestibular nucleus. See Figure 3-8.
are divided into lateral (LVST) and medial vestibular
spinal tracts (MVST) (see Figs. 3-13, 3-14, and 3-15). The
LVST is an ipsilateral projection originating from the
neurons of the lateral vestibular nucleus.32 The fibers of
the LVST proceed ventrally and somewhat medially after
leaving the vestibular nuclei and then turn in a caudal
direction, where they are located dorsal medial to the
nucleus of the facial nerve and dorsal lateral to the inferior
olive and lateral to the hypoglossal nerve. On leaving the
medulla, the fibers continue into the spinal cord where
they are found largely in the ventral half of the lateral
funiculus, while other fibers pass in the lateral part of the
ventral funiculus.33 Fibers terminate in the anterior horn
cells of the spinal gray matter terminating in lamina VIII
and lamina VII. A few fibers terminate in lamina IX, which
contains alpha as well as gamma motoneurons.
Physiologic studies indicate that the vestibulospinal
fibers exert a monosynaptic excitatory influence on extensor
motoneurons, but a polysynaptic pathway through inter-
nuncial neurons in laminae VII and VIII is also possible.
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
activated by input from proprioceptive impulses in the
somatosensory system (joints, muscle tendons, etc.), which
84 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
arrive by way of the spinovestibular tracts. The peripheral
input to the ventral portion of the lateral vestibular nucleus
is from all the sense organs, but particularly from the
maculae of the utricle and saccule. Therefore, the LVST to
the upper levels of the spinal cord, that is the cervical and
thoracic levels, are tightly connected to the otolith organs.
The MVST is not as extensive as the LVST and projects
bilaterally over the medial longitudinal fasciculi to the cer-
vical and upper thoracic cord levels36 (see Figs. 3-13, 3-14,
and 3-15). The medial vestibulospinal tract course is along
the medium raphe, where it terminates on the anterior
horn gray matter in laminae VIII and VII. The pathway is
bilateral and some of the fibers, especially those coming
from the medial vestibular nucleus, dichotomize and send
a branch ascending in the medial longitudinal fasciculus as
well as a descending ramus, which forms the MVST.32 The
MVST originates from the medial, lateral, and descending
vestibular nuclei and performs both excitatory and
inhibitory functions. Its peripheral input is from the canals
and to a lesser extent the utricle. The vestibulospinal tracts
arising from the caudal levels of the vestibular nuclei are
activated primarily by gravity receptors (utricle, saccule).
However, there is also a pathway for cervical muscle acti-
vation from canal input by way of connections to the
caudal vestibular nuclei.
Vestibulo-Ocular Projections
In mammals, a very prominent vestibular reflex associated
with the labyrinth function is the vestibulo-ocular reflex.14
The vestibulo-ocular second-order neurons are located
in the superior and medial vestibular nuclei, the ventral
Figure 3-18. Summary of the vestibulo-ocular neuronal network serving
horizontal eye movements. MR, medial rectus subgroup of III nucleus;
ATD, ascending tract of Deiters; MLF, medial longitudinal fasciculus;
NPH, nucleus prepositus hypoglossi.
portion of the lateral vestibular nucleus, and in the infrac-
erebellar division of the group Y nucleus. There is evi-
dence that some first-order vestibular neurons projecting
from the utricle also connect directly to the ipsilateral
abducens nucleus.37 The efferent projection pathways
of these vestibular neurons are the medial longitudi-
nal fasciculus (MLF), the ascending tract of Deiters, retic-
ular formation, and the brachium conjunctivum. The
vestibulo-ocular projections that are responsible for hori-
zontal eye movement differ from those that elicit vertical
or oblique eye movements. The medial and lateral rectus
muscle groups innervated by the oculomotor and abducens
nuclei are responsible for horizontal eye movements
(Fig. 3-18), while the superior and inferior recti and
superior and inferior oblique muscles are responsible for
oblique and rotatory eye movements. These muscles
are innervated by the oculomotor and trochlear nuclei
(Fig. 3-19).
The cranial nerve nuclei serving the extraocular muscles
are three, four, and six. The third or oculomotor nucleus is
the most complex and is located in the floor of the mid-
brain and near the aqueduct of Sylvius. This nucleus serves
the innervation of four eye muscles, the medial and inferior
recti, the inferior oblique, and the superior rectus. The
organization of this nucleus, demonstrated by retrograde
axonal tracers, indicates that the nucleus comprises rostra-
caudally oriented cell columns, which are contained in two
halves of the nucleus38 (Fig. 20A and B). In the rostral half
of the nucleus, the main subnuclei are those innervating
the medial rectus and the inferior rectus, with the medial
rectus being located dorsally while the inferior rectus is
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 3-19. Summary of the vestibulo-ocular neuronal network for
vertical and rotatory eye movements. BC, brachium conjunctivum;
IFC, infracerebellar nucleus; MLF, medial longitudinal fasciculus;
NPH, nucleus prepositus hypoglossi.

B Figure 3-21. Horizontal section through the abducens nucleus showing
Figure 3-20. A, B, The oculomotor nucleus showing the arrangement
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.
Additional oculomotor neurons are located outside the
confines of the nucleus in between the muscle bundles
of the MLF and also in the reticular formation ventral to
the MLF. These neurons belong to the subgroup that sup-
plies the inferior rectus muscle.38
The trochlear nucleus is the smallest of the extraocular
nuclei, is located immediately caudal to the oculomotor
nucleus, and is a spherical nucleus that indents the dorsal
surface of the MLF. The majority (approximately 90%) of
neurons in the trochlear nucleus innervate the contralateral
superior oblique muscle; approximately 10% innervate the
ipsilateral superior oblique muscle.38
The sixth cranial nerve or abducens nucleus is located in
the brainstem (medulla oblongata) immediately ventral to
the genu of the facial nerve root. The multipolar neurons
in this nucleus are larger than those in the other two cranial
nerve nuclei, are compactly arranged, and primarily inner-
vate the ipsilateral lateral rectus muscle. Approximately
50% to 65% of neurons project into the abducens nerve to
the lateral rectus muscle. The remaining 25% to 50% are
small fusiform neurons, which project contralaterally by
way of the MLF to the medial rectus subgroup of the
oculomotor nucleus (Fig. 3-21).39,40
The vestibulo-ocular neurons supplying vertical and
oblique eye muscle neurons arise primarily from the supe-
rior nucleus and rostral portions of the medial nucleus.41,42
The superior nucleus projects ipsilaterally and the medial
nucleus contralaterally via the MLF to the trochlear
nucleus and subgroups of the oculomotor nucleus.41–44
The ipsilateral vestibulo-ocular pathway rising from the
superior nucleus is inhibitory while the contralateral pro-
jection from the medial nucleus is excitatory. Neurons
in the dorsal portion of the superior nucleus are driven
by the anterior canal and project by way of the brachium
Anatomy of the Central Vestibular System 85
labeled interneurons that project to the medial rectus subgroup of IIIN.
MLF, medial longitudinal fasciculus; 7, facial nerve.
conjunctivum to reach the third and fourth nuclei.45 Large
cells in the infracerebellar division of group Y nucleus also
project to the fourth nucleus and some subgroups of the
third nucleus. Since the saccule projects to this nucleus,
group Y provides a pathway for vertical eye movements
from saccular input.29
The vestibulo-ocular projections providing horizontal
eye movements are provided by the lateral rectus and
medial rectus subgroups (see Fig. 3-18). The second-order
neurons projecting to the ipsilateral and contralateral
abducens nuclei are located in the medial vestibular nucleus,
particularly in its most rostral portion.37,46 Excitation is pro-
vided to the ipsilateral abducens nucleus and inhibition to
the contralateral abducens nucleus to provide synchronized
eye movement. Interneurons in the abducens nucleus proj-
ect contralaterally through the MLF to the medial rectus
subgroup, thereby providing a tight connection from the
ipsilateral lateral rectus and contralateral medial rectus
motor neurons. Some neurons in the medial vestibular
nucleus, together with those in the ventral portion of the
lateral nucleus, give rise to the ascending tract of Deiters,
which projects outside of the MLF to the ipsilateral medial
rectus subgroup to provide it with an excitatory input.
This neuronal network provides projections to the
abducens and medial rectus neurons that can be activated
by both utricular and canal afferents. In addition to these
more traditional pathways, vestibulo-ocular projections
can occur through the reticular formation. However,
anatomic verification of such connections is lacking.
Efferent Vestibular Pathway
An efferent vestibular pathway projecting from the brain-
stem to the vestibular sense organs has been known for more
than 40 years.47,48 The small cells of origin of this pathway
86 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 3-22. Summary of the efferent vestibular pathway (solid line). Efferent
cochlear pathway shown as stippled bundle.
are located lateral to the abducens nuclei and provide each
labyrinth with a bilateral and approximately equal projection
from the groups of neurons in the efferent vestibular
nucleus49 (Fig. 3-22). Although the number of efferent
neurons is considerably smaller than the afferent (approxi-
mately 400 to 500 efferent neurons in the cat), the peripheral
innervation of sensory epithelium by way of vesiculated
terminals is rich because of a complex branching pattern in
each efferent neuron. The efferent vestibular neurons
travel with the efferent cochlear bundle in the vestibular
nerve and reach the peripheral sense organs scattered
among afferent fibers in the individual vestibular nerve
branches. Both of these efferent systems are associated
with high levels of acetyl cholinesterase, which can be used
in histochemical preparations to differentiate them from
afferent fibers.50
These nerve fibers terminate as small vesiculated endings
on both type I and type II hair cells in all vestibular sense
organs (see Fig. 3-1). However, their mode of termination
on the two types of hair cell varies. The efferent terminals
contact the calyx type terminal on type I hair cells, while
they make direct contact with the hair cell membrane of
type II hair cells. It is therefore possible that activation of
the efferent component produces different physiologic
effects at the sensory epithelium level. Both excitation and
inhibition51–53 of the vestibular nerve response have been
demonstrated following excitation of the efferent vestibular
pathway. However, inhibition has been the predominant
effect demonstrated and may provide a mechanism by
which self-stimulation of the vestibular system can be pre-
vented or at least controlled. It may also be possible that
either excitation or inhibition can be used to modulate the
resting activity in individual vestibular neurons, thereby
modifying the range over which they can be altered by
peripheral end organ excitation.52
Vestibuloreticular Projections
Connections between the vestibular nuclei and the reticular
formation have been sparsely studied, but the major segment
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-
mation split off ventrally to terminate in the contralateral
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
nucleus reticularis pontis caudalis and the nucleus reticularis
giganto cellularis. Some of the commissural fibers of supe-
rior vestibular nucleus continue into the descending and
medial nuclei and also give off terminal branches to the
rostral part of the nuclei reticularis giganto cellularis and
parvi cellularis.
After lesions in the lateral vestibular nucleus, fibers pass
through the ventral part of the superior nucleus and course
ventrally to the ipsilateral nucleus reticularis pontis caudalis.
However, the majority of fibers passing to the reticular for-
mation leave the lateral nucleus and pass ventromedially
toward the midline and terminate in the contralateral
nucleus reticularis pontis caudalis.
The evidence thus accumulated indicates that the lateral
and superior nuclei are associated with the reticular forma-
tion nuclei that project to the cerebellum. These are the
lateral reticular nucleus and nucleus reticularis tegmenti
pontis. In turn, the lateral and superior nuclei receive
abundant fibers from the cerebellum and are, therefore,
interrelated in a circuit through the cerebellum, reticular
formation, and vestibular nuclei. Those regions of the
reticular formation that give rise to fiber connections of
the spinal cord receive projections from the superior, lateral,
and descending vestibular nuclei, that is, nuclei that have
also a close relationship to spinal cord mechanisms.
OTHER AFFERENT PROJECTIONS
TO THE VESTIBULAR NUCLEI
In addition to the vestibular nerve input, there are two major
afferent projections to the vestibular nuclei, as discussed in
the following sections.
Spinal Vestibular Projections
Direct spinal vestibular fibers are distributed only to
the portions of the vestibular nuclei that do not receive
primary vestibular afferents.54 Degeneration studies have

indicated that the spinal vestibular projection (which is
modest compared to the descending vestibulospinal projec-
tion) originates from the lumbar and sacral portions of the
cord. The projection is entirely ipsilateral and ascends in
the dorsal portion of the lateral funiculus. Its termination
is in the caudal vestibular nuclei, that is, the descending
and medial nuclei, with a small portion also in the dorsal
caudal portion of the lateral nucleus. The minor cell
groups X and Z also receive input from the spinal vestibular
pathway.55
Vestibulocerebellar Projections
Input to the vestibular nuclei from the cerebellum forms
the largest complement of afferent fibers in the system.
This projection may be divided into a projection from the
vestibular portion of the cerebellar cortex and the other
from the spinal cerebellar cortex.56
The cerebellovestibular projection originates from the
cortex of that portion of the cerebellum supplied by
the projection from the primary vestibular neurons and
the uvula and paraflocculus. A portion of the lateral cere-
bellar nucleus is also included. This projection is entirely
ipsilateral, with a projection from the flocculus that sup-
plies the superior and medial nuclei and a second bundle,
which is more lateral than the first, that gives off fibers
to all four vestibular nuclei and group F. The terminations
in the vestibular nuclei occupy discrete portions of the
nuclei. The paraflocculus does not have a projection in the
vestibular nuclei.
The nodulus projection terminates in the peripheral
portion of the superior nucleus, the caudal and medial por-
tions of the medial nucleus, and the ventral caudal portion
of the descending nucleus as well as group F and group X.
The uvula projects to the peripheral portion of the superior
nucleus, to the caudal portion of the descending nucleus,
and to group X. As mentioned earlier, the projection of the
different portions of the vestibulocerebellum are to rather
discrete portions of the vestibular nuclei, which suggests
that there are some functional differences between the
lobules of cortex in the vestibulocerebellum.
The projection from the spinal portion of the cerebellum
(vermis) to the vestibular nuclei is generally considered the
termination of spinal afferents to the cerebellum.57 This
projection is further broken down into a direct projection
from the spinal cerebellum to the vestibular nuclei and an
indirect projection, which relays in the fastigial nucleus.
The direct spinal vestibular projection terminates primarily
in the dorsal rostral portion of the descending nucleus and
the dorsal portion of the lateral nucleus. The experiments
of Walberg and Jansen57 demonstrated that the projection
from the vermis of the anterior lobe to Deiters nucleus is
somatopically arranged with the fore limb portion projecting
to the rostral dorsal portion of the lateral nucleus and the
hind limb to the caudal dorsal portion.
The indirect projection from the spinal portion of the
cerebellum relays through the fastigial nucleus.58,59 The
first link in this pathway, that is, the cerebellar fastigial
projection, is organized so that the vermal cortex projects
to the fastigial nucleus, the intermediate portion of the
cerebellar cortex to the nucleus interpositus, and the lateral
hemispheres onto the lateral or dentate nucleus. This
Anatomy of the Central Vestibular System 87
organization is also demonstrated in the projection of the
vermal cortex to the fastigial nucleus.60 The fore and hind
limbs of the vermis, that is, the lobules 1 through 5, project
to the rostral end of the fastigial nucleus with the fore limb
located behind the hind limb terminus in the fastigial
nucleus. The caudal, vermal lobules (VIII and IX) terminate
in the caudal portion of the fastigial nucleus, with the fore
limb being located rostral to the hind limb.
The fastigiovestibular projection forms the final link in
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
portions of the superior nucleus, the dorsal half of the lateral
nucleus, and the dorsomedial portion of the descending
nucleus and medial nuclei. The crossed or contralateral
fastigiovestibular projections form the final link in the pro-
jection from the caudal vermal cortex. These fibers termi-
nate in the peripheral portion of the superior nucleus, the
ventral portion of the medial ventral half of the lateral
nucleus, the ventral lateral portion of the descending
nucleus, and groups F and X. These two projections termi-
nate in different portions of the major vestibular nuclei, and
this is particularly well demonstrated in the dorsal division
of the lateral nucleus where the ipsilateral cortical fastigial
vestibular projection terminates ipsilaterally and the posterior
or caudal vermal projection terminates in the contralateral
lateral vestibular nucleus.
HIGHER CENTRAL VESTIBULAR
CENTERS
Nuclei concerned with higher projections of the vestibular
pathway exist both in the midbrain and in the thalamus
and cortex. In the midbrain the two nuclei that receive the
most rostral termination of the vestibulo-ocular projec-
tions from the major vestibular nuclei are the interstitial
nucleus of Cajal (INC)61 and the nucleus of Dankschewitz
(ND) (see Fig. 3-13). These nuclei are adjacent to the MLF
in the mesencephalon and have been little studied over the
years. However, recent physiologic as well as anatomic
retrograde tracing techniques have revealed some of their
connections. Both nuclei consist of small cells, fairly com-
pactly arranged in nuclei that have indistinct borders.
More is known about the functions and connections of the
INC.62,63 These studies have demonstrated that the INC
projects to the oculomotor nucleus and to several other
centers in the midbrain and the thalamus. In addition to
projections from the major vestibular nuclei by way of the
MLF, the INC receives input from the group Y nucleus.
The majority of functional studies have indicated that this
nucleus is concerned with the neural integration of verti-
cal eye movements in response to vestibular stimulation.
By way of its aforementioned projections, this rather
unique function can be understood.
The ND is somewhat less studied physiologically, but the
anatomic connections have demonstrated that it receives
projections from the frontal eye field as well as the thala-
mus.64 It projects to both the anterior and posterior lobes of
the cerebellum by way of the accessory olivary nucleus.
Some studies have suggested that projections from group Y
nucleus as well as some of the major vestibular nuclei
88 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
provide input to the ND. A proposed functional pathway
from the ND is one that conveys information for eye
movement from the frontal eye fields in the cortex to the
cerebellum for ultimate projection to the oculomotor
nuclei.
CORTICAL VESTIBULAR PROJECTION
The existence of a cortical representation of the vestibular
system has been suggested by many and is based particu-
larly on two observations: (1) the demonstration by Walzl
and Mountcastle65 of evoked potentials in the cerebral cor-
tex between the auditory area and the somatic sensory area
following stimulation of the labyrinth in the laboratory
animal, and (2) the demonstration by Penfield66 in experi-
ments on humans where direct stimulation of the tem-
poral lobe cortex often elicited sensations of vertigo and
dizziness.
The two animal models that have been used to demon-
strate this sensory representation are the cat and the
monkey. Walzl and Mountcastle65 demonstrated in the cat
by the evoked potential method under barbiturate anes-
thesia that the area of evoked potentials was located in
the anterior sylvian sulcus posterior to the face zone of the
somatosensory field anterior to the auditory cortex. The
projection was bilateral but strongly contralateral.67
Mickle and Ades68 found an overlap of the vestibular rep-
resentation with the somatic afferents. The location of the
cortical area in the cat left some doubt as to whether the
projection was more associated with the auditory cortex
in the temporal lobe or with the somatosensory portion of
the parietal lobe.
In the rhesus monkey the primary cortical vestibular
projection has been demonstrated in the postcentral gyrus
at the lower end of the intraparietal sulcus, near the face
level of the first somatosensory field.69 In Brodmann’s clas-
sification this is area 2 but because of differences in the
cytoarchitecture and the different senses represented in
somatic area 2, it has been called area 2V. Neurons in area
2V respond strongly to caloric and galvanic stimulation of
the labyrinth. The physiology of the neurons in this area
is left for a different discussion. Suffice it to say that the
physiologic demonstration has been confirmed repeatedly.
Anatomic demonstration of this projection with the newer
axonal tracers has not been produced. The location of the
vestibular sensory area in humans has been speculated to
be located in the anterior portion of the interparietal sul-
cus, which would correlate with the location of 2V in the
monkey and the cat. This speculation about this location
has been based on direct stimulation experiments.66 A sec-
ond vestibular cortical projection area designated in area
3 may represent the projection from the somatosensory
arm field.70 Therefore this portion of the projection prob-
ably represents a projection from the somatic afferents
involved in balance. These projections would appear to
integrate labyrinthine and somatic proprioceptive signals
in order to provide the subject with an awareness of body
orientation.
The pathway by which vestibular signals reach the cortex
is not well known. It is suggested that a pathway may take
place through the thalamus, particularly the ventral posterior
region of the thalamus.71 Demonstration of this linkage
in the ascending pathway will require careful use of intra-
axonal tracers.
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 Chapter
Physiology of the Vestibular System

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

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
constraints of this chapter nor is it desirable. An attempt
has been made to refer to review articles as much as possi-
ble so that the interested reader can find additional infor-
mation if desired. Such reviews are cited at the beginning
of each section where possible. The most important
general text is the book by Wilson and Melvill Jones.1
More detailed references to the older literature can be
found in the handbook edited by Kornhuber.2 Finally, an
excellent overview of the vestibulo-ocular reflex and its
associated pathologies can be found in Leigh and Zee.3
The material in this chapter concentrates on areas of clinical
relevance. Thus more emphasis is placed on peripheral and
vestibulo-ocular physiology. Undoubtedly, the importance
of the vestibular system on spinal, cortical, cerebellar, and
autonomic physiology will increase as our knowledge of
these systems increases.
DEVELOPMENT OF THE LABYRINTH
The labyrinth is derived from the skin during early
embryogenesis. Lateral ectoderm, destined to become the
inner ear (placode), invaginates to form an otic pit, which
eventually buds off to become the otic cyst, representing
the primordial endolymphatic space lined by ectodermal
epithelium. The labyrinth and its sense organs (semicircular
canals, utricle, saccule, and cochlea) develop from the otic
cyst by further growth and differentiation. The physician
must realize that the endolymphatic space corresponds
originally to the exterior environment of the organism.
The original vertebrate hair cell probably evolved in
aquatic animals before the evolution of terrestrial verte-
brates. Its function was, as it is now in many species, to
monitor water currents relative to the body surface. The
apical portions of the hair cell, equipped with stereocilia
and kinocilia, were exposed to the water, whereas the
basolateral cell membrane was contacted by extracellular
fluid. Because of the differences in ionic concentration
between the exterior water, the intracellular milieu, and
the extracellular space, continuous ionic currents existed.
Deflection of the cilia could alter those currents. The ionic
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
space by encapsulation of the inner ear space so that the
ionic composition could be controlled. Another advantage
was that the physical forces deflecting the cilia could be
selected very precisely by the evolution of accessory struc-
tures such as the semicircular canal system, the otolithic
91
92 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
system, and vibration-sensitive structures (cochlea, papilla
basilaries, and so forth).
LABYRINTH FLUID SPACES
If ear development is considered from a teleologic perspec-
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
species available in the exterior water, the receptor current
through the apical end of the hair cell had to be carried by
a variety of cations. Contrary to widespread belief, regular
extracellular fluid (perilymph) can mediate the mechano-
electric transduction as long as the hair cell remains vital.
Because the predominant extracellular (and perilymphatic)
ion is sodium, a constant Na+ current would have to flow
through the hair cell. As a result, the Na+ and K+ electro-
genic pumps in the hair cell membrane would be rapidly
overburdened, and the cell would die. This problem does
not exist for the second most common cation, K+. Thus
having the K+ concentrated at the apical end of the hair cell
and the Na+ removed from this location is advantageous.
The dark cell is specialized for this task. Dark cells are
strategically located on the slopes of the semicircular canal
cristae and close to the utricular maculae as well as in the
stria vascularis of the cochlea. Labeled Na+ and K+ have
been demonstrated to move through these cells in a direc-
tion opposite to their gradients.4 The basal portion of these
cells, directed toward the basement membrane and capil-
laries, is characterized by extensive indentations, which serve
to increase the surface area. Dark cells contain an unusual
concentration of mitochondria, testifying to high meta-
bolic activity. Their apical cell membrane bears villi much
as other secretory cells. Quite possibly, other cells sur-
rounding the hair cells are also responsible for the high K+
concentration in the endolymph.
Because the ionic concentrations within the mammalian
endolymph and hair cell intracellular space are similar,
little ionic gradient is available to drive a K+ receptor
current. The existence of a positive electric charge within
the endolymphatic space, with respect to the perilymph,
compensates for this deficit. A corresponding potential is
to be found in the cochlea and is known as the endolym-
phatic potential. In the vestibular labyrinth, this potential
appears to be concentrated over the relatively small
patches of sensory epithelium (cristae ampullares, otolithic
maculae). The positive potential increases when a record-
ing electrode is moved from the endolymph into either the
cupula or the otolithic membrane and is greatest just above
the apical surface of the hair cells. In areas far from these
sites, the endolymphatic potential becomes small. The
regional differences in this potential illustrate clearly that
the high K+ concentration in the endolymph and the
positive endolymphatic potential are independent of one
another. This point has been proven experimentally in the
cochlea where a positive charge over the stria vascularis
can be recorded after removal of all K+ from the endolym-
phatic space.5 Both the positive endolymphatic potential
and the high extracellular K+ concentration at the apical
surface of the hair cell appear to be fundamental for the
hair cell transducer function. In lateral line organs with
limited access to seawater, a K+-rich milieu is maintained,
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
force supporting the K+ current through the hair cell. The
intensity of this current is modulated by deflection of the
stereocilia.
HAIR CELLS
The two hair cell (HC) types found in the human labyrinth
are illustrated in Figure 4-1A. The phylogenetically ori-
ginal type II HCs (right) have cylindrical shapes and are
contacted by afferent dendritic nerve terminal boutons as
well as efferent axon boutons. Type I HCs (left) are more
recent and are concentrated in the central portions of the
sensory epithelia, that is, on the cristae crests and within
the striolae of the maculae. They are flask-shaped, and a
calyx-shaped dendritic afferent terminal surrounds most of
their basolateral membrane. Thus efferent terminals can
only contact the neural calyx membrane of type I HCs, not
the cell membrane itself.
The “hairs” of these cells, the cilia, extend from the apical
surface and greatly increase the membrane surface area.
Vestibular hair cells typically have 40 to 200 stereocilia and
one kinocilium. The kinocilium is located at the end of the
stereocilia bundle (Figs. 4-1A and C). Thus the hair cell is
morphologically polarized. Deflection of the cilia bundle
toward the kinocilium depolarizes the cell membrane and
leads to afferent nerve fiber activation, whereas deflection
in the opposite direction has the opposite effect (Fig. 4-1B).
Thus a functional polarization exists as well. Cilia deflec-
tion is effective only along this polarization axis. At other
angles of deflection, the response amplitude, measured as
either membrane potential, receptor current, or spike rate
change in the afferent neuron, drops off according to a
cosine function (Figs. 4-1C, D, and E).
As the name implies, the kinocilium is capable of active
motion. As with other mobile cilia, it is equipped with the
typical nine-plus-two axoneme of microtubules that distin-
guishes mobile cilia in the respiratory tract, sperm cells,
and elsewhere. Mammalian vestibular hair cell kinocilia
are longer than the longest stereocilia and extend into the
gelatinous substance of the cupula or otolithic membrane,
thus mediating displacement of these structures relative
to the epithelial surface. The kinocilium tip is typically
bulb-shaped and connected to the longest stereocilia by
fine filaments. The kinocilium appears to store free calcium
ions, perhaps to safeguard receptor current changes when
stereocilia are deflected.
Transducer function of the HC appears to depend criti-
cally on stereocilia deflections. Their displacement toward
the kinocilium causes the resting membrane current
through the apical membrane to increase, presumably by
opening membrane ion channels. Stereocilia are arrayed
with the longer ones standing at the excitatory pole adja-
cent to the kinocilium, their length gradually decreasing
toward the inhibitory pole. This length gradient may be
important for transduction. With a diameter of 0.2 μm,
they are slightly thinner than the kinocilium (0.25 μm).
In contradiction to the classic belief, stereocilia are stiff,

A move in response to an electrical polarization stimulus.
B C
D E
Figure 4-1. Hair cells and their mechanoelectric transduction. A, Schematic
drawing of type 1 and type 2 hair cells. B, Plot of receptor potential or
receptor current (y axis) against cilia deflection (x axis). Excitatory deflection
causes much greater response than inhibitory deflection. C, Schematic top
view of one hair cell. Viewing direction indicated by arrow in A. The + and −
arrows represent excitatory and inhibitory deflections, respectively. Arrows
labeled 30, 60, and 90 degrees indicate deflections yielding corresponding
response amplitudes in D. Relative size of receptor potential for various
angles of deflection (top) for same deflection amplitude (bottom).
E, Receptor potential amplitudes drop with deviation of deflection direction
from polarization vector according to cosine function.
the result of a skeleton of actin filaments. The actin fila-
ments penetrate into the cuticular plate just below the stere-
ocilia (see Fig. 4-1A). When the stereocilia are deflected,
they do not bend but rather lean over like sticks, moving
the cuticular plate with them.7 Stereocilia are stiff enough
to exhibit resonant oscillations, the preferred frequency
being a function of the cilia length.8 Although this charac-
teristic serves as an auditory tuning mechanism in some
reptilian ears,9,10 it also underlies the need to dampen such
oscillations within the mammalian vestibular apparatus by
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
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-
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
for cations at the apical cell membrane. The term apical is
particularly appropriate in this context, because the maxi-
mal receptor current change has been measured at the
location of the stereocilia tips. The current itself is nor-
mally carried by K+ because of its high concentration in
the endolymph, but Li+, Na+, Rb+, Cs+, NH4+, and to a
lesser extent Ca++, as well as tetramethylammonium,
acetylcholine, choline, and other cations can also con-
tribute. Apparently charge carrier molecules must not
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
amounts of Ca2+ in the endolymph, and at this location
calcium can be replaced by strontium (Sr2+) and blocked by
magnesium, cobalt, and barium (Mg2+, Co2+, Ba2+ ) ions
and other compounds. Other systems have shown that one
ionic channel accounts for a conductance of about 50 ps.
A measured peak conductance of some 2 to 5 ns at the
stereocilia tips would imply the existence of about one
channel per stereocilium.
The maximal response current is about 200 pA, leading
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
is decreased to at most −40 mV. Stereocilia deflection in
the opposite inhibitory direction yields a maximal polar-
ization change of about one-fifth the excitatory response,
that is, a hyperpolarization to about −64 mV. The HC
therefore is a rectifying transducer, dramatically overem-
phasizing the excitatory response (see Fig. 4-1B). Note,
however, that this asymmetry in the excitatory and
inhibitory responses is much larger than that seen in the
afferent nerve. The membrane resistance is voltage-
dependent: the input resistance of some 200 to 300 MΩ
drops to about 6 MΩ after depolarization to −50 mV or
less. This reflects an increased K+ conductance. Similarly,
Ca2+ conductance is voltage-controlled at the basolateral
membrane of the HC. Depolarization results in Ca2+ influx
toward the synaptic region of the HC, which is necessary
to induce fusion of synaptic vesicles with the cell mem-
brane and trigger release of the synaptic transmitter.
Synaptic activity thus depends on the receptor current.
A constant apical K+ current provides for synaptically
mediated resting activity in the primary vestibular neuron.
Modulation of the receptor current, through membrane
conductance changes, induces synaptic modulation of the
resting discharge rate.
Thus the transduction theory Davis proposed many years
ago has been supported by the rigorous studies in the labo-
ratories of Flock, Hudspeth, and others.7,15–17 In this theory,
the high potential between the endolymph and the HC was
considered to be a battery driving a current through the cil-
iated apical membrane, which acted like a variable poten-
tiometer capable of controlling the receptor current and
potential.
VESTIBULAR SENSORY ORGANS
Semicircular Canals
The three coplanar (complementary) canal pairs act recip-
rocally.1 Because these canal pairs are connected via the
brainstem commissures, the reciprocal arrangement is the
basis for functional symmetry, compensating for the asym-
metrical responses of the individual canals. All HCs in one
canal are activated by rotation in the same direction:
toward the ipsilateral side for the lateral canal, during
forward and ipsilateral bending of the head for the anterior
canal, and during backward and ipsilateral head flexions
for the posterior canal. Thus the three coplanar canal pairs
are both lateral canals and each of the two ipsilateral ante-
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
canal vertically. The canal position, however, is kept approx-
imately horizontal during normal behavior.
Hydrodynamics
The canal responses exhibit two time constants, the short
time constant T1 reflects the time taken for the cupula to
deflect when stimulated with a step of head velocity while
the long time constant T2 describes the time taken by the
cupula to return to its rest position.
The long cupular time constant T2 is of diagnostic
significance in Bárány’s classic rotation test, in which a
velocity step is applied, usually from 0 degrees/sec to some
value between 10 and 100 degrees/sec (Fig. 4-2). The cupula
deflects almost instantly (because the Tl time constant is so
short) and then reverts back to its rest position with a time
constant of T2. Postrotatory cupular deflections in the
opposite direction follow an identical time course. In addi-
tion, T2 dominates the caloric test; however, diagnostic
determination of T2 cannot be recommended using caloric
stimuli since the time course of temperature conduction is
highly variable and unknown for each patient.
Although the time constant of the cupula, T2, lies in the
range of 5 to 10 sec, the time constant of the nystagmus
that follows step changes in head velocity is much longer.
Postrotatory nystagmus, in normal subjects, exhibits a time
constant of 18 to 30 sec, or approximately three times that
of the cupula. This difference is the result of brainstem
and cerebellar circuits that act to perseverate the activity
generated by the afferent nerve. The precise topography
of these circuits (sometimes called the velocity storage
system) is not yet fully understood, but they are known to
be related to the optokinetic system. Unilateral peripheral
vestibular lesions result in a reduction of the nystagmus
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
well above normal following lesions involving the cerebel-
lar nodulus. These issues are dealt with in more detail later.
Human Semicircular Canal
The canal time constant T1 depends heavily on the narrow
canal diameter. About one-quarter of the semicircular canal
circumference is occupied by the membranous utricle,
which has a much larger diameter. For this portion, the
viscous drag becomes negligible. The greater utricular
volume would probably also increase the moment of inertia
because of the greater endolymph mass. Thus the real canal
time constant T1 is probably greater than the calculated
one, but it should still only be a few milliseconds.
Figure 4-2. Cupular displacement induced by velocity step. Cupula is
deflected immediately with short time constant and returns to midposition
with long time constant (top) during step in rotation velocity (bottom).

Perilymph fluid dynamics probably do not play an
important role in vestibular function. Because blood ves-
sels and trabeculae in the perilymphatic space are highly
variable, as is the volume of that space, protecting the HCs
from this undoubtedly real fluid movement would be
advantageous. Nonetheless, experiments by Rabbitt and
Damiano18 have demonstrated that semicircular canal
dynamics are more complex than would be expected from
the old torsion pendulum model and as a result canals
remain able to respond at high frequencies even after
plugging. However, these responses are only significant at
frequencies above those involved in normal human head
movements and thus are of little clinical significance.
The considerations discussed here explain the semicir-
cular canal’s function as an angular accelerometer. During
the years many researchers discussed the possibility that
the canals might also be sensitive to linear forces. Guedry
kindled interest in this possibility when he observed that
there is a maintained compensatory nystagmus generated
when the subject is placed horizontally and rotated about
his or her longitudinal axis (“barbecue spit” nystagmus19).
In this situation the labyrinth is exposed to a constantly
changing gravity vector. This nystagmus is now known to
be generated by the combined action of many otolithic
afferents.
No conclusive evidence for canal sensitivity to linear
accelerations exists under normal circumstances, although
almost everyone has experienced linear canal sensitivity
under slightly unusual circumstances. Positional alcohol
nystagmus and vertigo is caused by slow alcohol diffusion
into the endolymph, starting at the well-vascularized
crista-cupula region. The cupula density is thought to be
decreased as a result, becoming sensitive to changing grav-
ity vectors. Heavy water, resulting in the opposite density
change, has been shown to cause nystagmus and vertigo in
the opposite direction. An appropriate cocktail of alcohol
and heavy water can prevent nystagmus and vertigo, as
well as the alcohol-induced nausea, which can be interpre-
ted as being related to motion sickness.20
Another example of linear canal sensitivity is benign
paroxysmal positional nystagmus. Otolith debris is believed
to fall through the endolymph and cause currents much
like a stone falling through water will. These currents
would activate the HC for the time required for the debris
to reach the bottom of the canal. Any series of head move-
ments that moved the debris out of the canal lumen would
alleviate the problem.
The best known canal response to linear acceleration
occurs during caloric stimulation. The amplitude and
direction of caloric stimulation of the lateral canal should
change according to a cosine function when the canal is
tilted away from the proper vertical position. This is clin-
ically important because it implies that misalignment of
the head by 10 to 20 degrees should have very little effect
on the nystagmus amplitude (1.5% to 6%). The caloric
stimulus is also known to exert a small direct temperature
effect on the sensory epithelium such that cooling causes
a direct decrease in afferent firing, whereas warming has
the opposite effect. This will result in a slightly faster nys-
tagmus slow phase than would be predicted based on the
convection currents alone.
Physiology of the Vestibular System 95
Afferent Neurons
A clear concept of primary neuron activity is fundamental
to both clinical diagnostic studies and physiologic theory.
All primary vestibular neurons are active at rest.21 This
spontaneous activity ranges from about 10 to 200 spikes
per second with a mean of around 90. This resting dis-
charge rate is probably caused by the resting receptor
current already described and is a prerequisite for bidirec-
tional sensitivity. Canal rotation in the excitatory direction
leads to an increased firing rate, and rotation in the oppo-
site direction simply results in a spike rate reduction with-
out the need for any synaptic inhibition. The spontaneous
rate also eliminates the need for a definable threshold.
Stimulus detection depends not so much on a minimal
spike rate modulation amplitude as on the signal-to-noise
ratio. This ratio is severely limited by the binary nature of
pulse rate coding for stimulus intensity in a single neuron,
but is enormously improved by averaging over the entire
neuron population. Thus very sensitive vestibular trans-
ducers must be equipped with many neurons.
Since the two classes of HCs are defined mainly by their
innervation pattern, it is not surprising that two classes of
primary afferents have been found: regular and irregular
neurons. In general, regular units, with narrow ranges of
interspike intervals, have thin axons with low conduction
velocities, and they innervate predominantly the slopes
of the cristae where mainly type II HCs are found.
Conversely, irregular firing patterns are associated with
thick axons having high conduction velocities. These
axons innervate predominantly the crest of the cristae
where mainly type I HCs are found. This functional clas-
sification is not as distinct as the morphologic HC classifi-
cation. Experiments have determined three different
morphologic categories of afferent axons based on the
synaptic contacts that they make with the HCs: calyx, bou-
ton, and dimorphic. Calyx-ending axons only synapse on
type I HCs and are only found on the crests of the cristae;
they have relatively low sensitivity but are irregular in their
discharge pattern. Bouton-ending axons are only found in
the periphery of the sensory epithelium innervating type II
HCs; they exhibit regular firing patterns and are also
rather low in sensitivity. Finally, axons with dimorphic
endings innervate both type I and type II HCs and are
found in all parts of the cristae. They exhibit a clear
relationship between their degree of regularity and their
sensitivity, with low-sensitivity units exhibiting regular
firing patterns and vice versa.
Regular and irregular neurons differ in their responses
to rotatory stimuli. In general, the more regular the neu-
ron’s firing rate, the more accurately it will encode angular
head velocity in its firing pattern. If a rotatory stimulus of
long duration is applied (Figs. 4-3A and B), then regular
neuron spike rates encode angular velocity quite accurately
(Figs. 4-3C and D), although the excitatory response is
greater than its inhibitory counterpart.
In contrast, the spike rate of irregular neurons peaks
earlier and adapts exponentially with an adaptive time
constant of about 30 sec, which is reminiscent of the HC
adaptation already discussed. This adaptive behavior
accounts for the apparent inhibition after termination of
96 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 4-3. Relationship of head rotation stimulus (A and B) to cupular
deflection. (C) and primary canal afferent signals (D and E). A, Rotatory head
velocity (Q ). B, Rotatory head acceleration (Q̈). C, Cupular deflection
following slow time constant. D, Response of regular neuron (firing rate
versus time). E, Response of an irregular neuron. RD, resting discharge;
Sp/sec, spikes per second; °/sec, degrees per second.
excitation (undershoot) and the overshooting rebound
following an inhibitory stimulus (Fig. 4-3E).
The rapid rise time of the response in Figure 4-3E
reflects a lead element,22 which is best studied using the
Bode plots of Figure 4-4. The gain curve (Fig. 4-4A) for
irregular neurons follows the theoretical mechanical fluid
movement reasonably well at low frequencies. At higher
frequencies, above 1 Hz, however, a dramatic gain increase
occurs. The phase behavior of irregular neurons is charac-
terized by a consistent lead throughout the frequency
range, with an enormous difference between the fluid
movement and the neuron firing rate evident in the higher
frequency range (Fig. 4-4B). Although much more limited,
a similar difference for high-frequency phase and gain is
seen in regular neurons. As mentioned previously, irregu-
lar neurons tend to be more sensitive than regular neurons.
In the middle frequency range where gain is nearly constant,
the average sensitivity of nonadapting regular neurons is
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
difference because semicircular canal neuron behavior is
virtually unchanged when anesthetized and alert animals
are compared.
Figure 4-4. Relationship between canal dynamics (solid line) and response
encoded in regular (dotted line) and irregular (dashed line) neurons. A, Gains
(discharge rates per velocity). B, Phases.
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
tilted backward and downward by 25 to 30 degrees and
laterally upward by about 10 degrees, just as in the hori-
zontal semicircular canals. Since normal head position tilts
the stereotactic plane by about 25 degrees with the chin
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
that maximum differential sensitivity would be obtained
while the subject is in the supine or prone position. The
saccular macula is oriented almost at right angles to both
utricular portions, with its lower end deflected laterally by
about 18 degrees. Its maximal horizontal sensitivity would
occur while lying on one ear. Also shown in Figure 4-5 are
the HC orientation vectors for the saccular macula (A) and
the utricular macula (C). Although probably not physio-
logically significant, HC orientation vectors (and thus
kinocilia) are always directed away from the striola in the
saccule and toward the striola in the utricle. More impor-
tantly, both maculae contain HC orientation vectors in all
directions. The striolae in both maculae are the central
areas containing a greater density of smaller calcite
otoliths on the otolithic membrane than on more periph-
eral areas. They are equipped with more type I HCs and
are innervated by thicker axons, conducting spikes at
greater velocities.
Adequate Stimulus
The calcite crystals constituting the otoconia (statoconia)
have a specific gravity of about 2.7 and are moving in
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 4-5. Position of utricular and saccular maculae relative to stereotactic
horizontal plane. Deflection angles are given in A and B, and hair cell
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
Labyrinthine HCs are innervated not only by the postsyn-
aptic afferent dendrites, but also by presynaptic terminals
that contact the HC membrane in type II HCs and the
calyx of the afferent ending at type I HCs. These terminals
contain spherical vesicles, much as has been described in
cholinergic terminals elsewhere in the body, and are derived
from a small, distinct axon bundle within the vestibular
nerve that is strongly cholinesterase-positive.23 Cells of
origin for the efferent bundle do not appear to degenerate
following transection of the vestibular nerve and therefore
have only been discovered since the development of retro-
grade tracer techniques.
Most efferent cell bodies in mammals are clustered in a
small group, termed group E, which is dorsolateral to the
nucleus of the abducens nerve and adjacent to the genu of
the facial nerve.24 In birds25 and lower vertebrates, the
efferent cells are scattered in the caudal pontine reticular
nucleus, where some of these cells are also found in
rodents.26 Only a few hundred of these cells exist, distrib-
uting their axons to some 20,000 HCs in the periphery.
Thus many collaterals issue from each efferent cell, and
each cell innervates several semicircular canals or otolithic
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-
sive efferent collateralization, electrical stimuli of one
ampullary nerve can produce trans-synaptic responses in
other subdivisions of the vestibular nerve. These responses
are simply axon reflexes and do not indicate peripheral
interconnections between various labyrinthine sensors.
It has been suggested that if the efferent system is acti-
vated in anticipation of movement, then it could be used to
switch the vestibular system from a postural mode to a
volitional mode by inhibiting units that could be saturated
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.
VESTIBULO-OCULAR REFLEX
No brain function is as well understood and as thoroughly
studied as the vestibulo-ocular reflex (VOR).1,28–30 There
are several reasons for this:
1. Detailed knowledge is available about the input from
the vestibular labyrinth and the signals required to
drive the eye.
2. Input and output are linked by only one brainstem
neuron.
3. Signal transformation within the brain are well under-
stood.
In contrast to many reflexes used in clinical diagnostic
studies, the VOR’s purpose is understood completely.
Thus VOR analysis is a particularly useful diagnostic tool,
directly assessing the patient’s functional capacity.
The VOR’s purpose is to stabilize images on the retina
during head movements. The reader can immediately ver-
ify how critically important this reflex is by attempting to
read this text while shaking the book through a small angle
a few times per second. Reading will become impossible
because the visual tracking reflexes are far too slow to
guarantee satisfactory visual stability when the visual target
is moving at such frequencies. If, however, the book is kept
still and the head is gently shaken, reading is easy because
now the relative movements between the visual target and
the head are compensated for by the VOR, which drives
the eyes at the same velocity as the head but in the opposite
direction. It is possible, however, to exceed the dynamic
performance of even the VOR by vigorous head shaking,
thus causing the print to blur.
The dynamics of the human VOR have been studied in
some detail. Recent experiments have demonstrated that
human subjects are able to generate vestibular eye move-
ments that compensate for the head movements up to
350 degrees/sec. For velocities higher than this, the gain
(eye velocity/head velocity) is seen to decrease and the
maximum eye velocities observed were about 500 degrees/
sec. Since the entire reflex pathway only requires a total of
three neurons, it is not surprising that the latency (the time
from the beginning of a head movement to the onset of the
eye movement) is very short. Although there has been some
disagreement as to the actual value, most authors now
believe the latency of the human VOR to be 10 to 12 msec.
VOR PATHWAYS
Strictly speaking, the VOR is defined as any compensatory
eye movement resulting from stimulation of labyrinthine
receptors by a head movement. It is more practical, how-
ever, to consider such eye movements as a combination of
several separate reflexes that can be studied in isolation
and that are transmitted via separate brainstem pathways.
These reflex pathways are labeled according to their site of
origin within the labyrinth.
Horizontal Canal VOR
The horizontal canal VOR, which only compensates for
horizontal head rotation, should not be confused with the
horizontal VOR, which must also compensate for lateral
linear motion of the head and is mediated by otolithic
receptors. To avoid confusion, the canal-based VOR has
recently been renamed the angular VOR, or aVOR, to
distinguish it from the otolith-mediated linear VOR.
Electric stimulation of one horizontal canal nerve causes a
pure horizontal deviation of both eyes toward the con-
tralateral side, which is mediated via the three-neuron
reflex arc summarized in Figure 4-8. The excitation from
the horizontal canal afferents is fed through excitatory
interneurons in the vestibular nuclei to the contralateral
abducens nucleus, resulting in excitation of lateral rectus
(LR) muscle motor units. A second group of excitatory
vestibular interneurons sends its axons up through the
ascending tract of Deiters (ATD) to terminate on ipsilateral
medial rectus (MR) muscle motor units in the oculomotor
nucleus. Although the ipsilateral MR and contralateral LR
muscles contract simultaneously, the corresponding
vestibular nucleus (VN) neurons do not send axon collat-
erals to both motoneuron groups. Strict separation of
these pathways permits separate regulation of muscle

Figure 4-8. Direct neuron connections of horizontal VOR. Arrows in eye
indicate direction of evoked eye movement. IS, Interstitial nucleus of
vestibular nerve; S, L, D, and M, superior, lateral, descending, and medial
vestibular nuclei, respectively; PH, nucleus prepositus hypoglossi; III, ocular
motor nucleus; VI, abducens nucleus.
contraction to combine vergence movements with the
VOR while fixating targets at various distances. These
connections suggest that the VOR gain to the separate hor-
izontal eye muscles might be adjusted by vergence signals
within the vestibular nuclei. These excitatory VN cells are
scattered around the border between the medial, lateral,
and descending vestibular nuclei, which casts some doubt
on the functional significance of these cytoarchitectonic
borders.
Because the eyes are always moved in a push-pull fashion,
the antagonist eye muscles are relaxed simultaneously by
two separate inhibitory pathways. Inhibitory interneurons
excited by the lateral canal nerve project directly to the ipsi-
lateral abducens nucleus and thus cause a relaxation of 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
to the ipsilateral abducens nucleus.
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
recurrent collaterals back into the VN, which might be
partly responsible for the integration process discussed in
the following sections.
Anterior Canal VOR
Electrical stimulation of the anterior canal nerve results in
a conjugate upward deviation of both eyes along with
counterrolling such that the upper poles of both eyes move
toward the contralateral side (i.e., the ipsilateral eye intorts
and the contralateral eye extorts) (Fig. 4-9). When the eye
is at primary position, elevation is more pronounced in the
ipsilateral eye, whereas counterrolling is more pronounced
in the contralateral eye. Both elevation and counterrolling
are produced by a contraction of the ipsilateral superior
rectus (SR) and the contralateral inferior oblique (IO)
muscles. In contrast, the antagonists of these muscles, the
ipsilateral inferior rectus (IR) and contralateral superior
oblique (SO) muscles, are relaxed by inhibition of their
motoneurons in the ipsilateral trochlear nucleus and the
Figure 4-9. Anterior canal VOR connections. Symbols and abbreviations as
in Figure 4-8.
100 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
IR subdivision of the ipsilateral oculomotor nucleus. The
inhibition is mediated by one class of interneurons on the
superior VN, innervating both of these motoneuron pools
via axon collaterals.35 The contraction of the ipsilateral SR
and the contralateral IO is mediated by one type of excita-
tory VN interneuron, also located in the superior VN,
which innervates both motoneuron pools within the con-
tralateral oculomotor nucleus. Remember that the SR and
SO muscles have their motoneurons located contralaterally
in the brainstem, whereas all other extraocular muscles are
innervated ipsilaterally, thus the innervation of the vertically
acting extraocular muscles is arranged so that the muscles
that cause intorsion of the eye have their motoneurons
located on the contralateral side of the brainstem, while
muscles that cause extorsion are innervated ipsilaterally.
The wiring diagram for the anterior canal VOR is sim-
pler than that for the horizontal canal VOR because there
are only two classes of VN cells involved as can be seen in
Figure 4-9.
Posterior Canal VOR
Electrical stimulation of the posterior canal nerve (Fig. 4-10)
causes counterrolling in the same direction as does ipsilat-
eral anterior canal stimulation. The rotatory component is
stronger in the ipsilateral eye and the additional downward
deviation is more apparent in the opposite eye. These
movements are caused by contraction of the ipsilateral SO
and contralateral IR. The corresponding motoneuron pools
receive excitatory input from a single class of VN neurons
located in the medial vestibular nucleus, which sends axon
collaterals to both the trochlear nucleus and the IR subdi-
vision of the oculomotor nucleus, both on the contralateral
side. These axons travel up and down the MLF to contact
cells in a variety of other areas including the pretectal
areas, the interstitial nucleus of Cajal, the nucleus of the
facial nerve, and neuron groups in the reticular formation
around the abducens nucleus. In addition, axon collaterals
Figure 4-10. Posterior canal VOR connections. Symbols and abbreviations
as in Figure 4-8. PrT, Pretectum; IC, interstitial nucleus of Cajal; IV, trochlear
nucleus; VII, facial nucleus.
are seen to ramify within the medial and lateral vestibular
nuclei and in the PH nucleus.36 Most of these cells send
a prominent axon branch down into the spinal cord,
although excitatory secondary vestibular neurons without
such vestibulospinal connections also exist.
The antagonist muscles are relaxed by inhibition of their
motoneurons in the ipsilateral oculomotor nucleus. This
inhibition is mediated by inhibitory neurons located in the
superior VN that form synaptic contacts with both SR and
IO motoneurons. The SR motoneurons then send their
axons across the midline to innervate the contralateral eye.
These inhibitory vestibular neurons form less extensive
collateralizations outside of the oculomotor complex and
only appear to contact reticular formation neurons close to
the midline. The final ascending axons appear to project
beyond the midbrain to some higher centers.
Excitatory VN cells in all of the canal VOR pathways
exhibit extensive collateralization within their target ocular
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-
bility to the approach of using a single quantitative equa-
tion to describe the signal carried by that cell group.
Figures 4-9 and 4-10 clearly show that all vertical canals
participate in the vertical VOR as well as in the counter-
rolling torsion reflex (tVOR). The discrete connection of
certain eye muscles with specified canals in the schemes
already described must not be viewed as a complete
description of the canal-based VOR (aVOR). Rather, the
antagonist muscle pairs connected with each canal can only
be regarded as the prime movers, since all extraocular mus-
cles are always involved in all vertical eye movements. The
reasons for this are as follows:
1. Canal pairs are not exactly coplanar, thus during any
head movement more than two canals are stimulated.
2. About 40% of the secondary vestibulo-ocular neu-
rons receive afferents from two canal pairs and 16%
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
target is viewed, then the required tVOR gain for clear
vision becomes much greater; indeed, the required gain is
a function of target distance (Fig. 4-11A). Thus if tVOR

Figure 4-11. A, When the head is displaced laterally through a distance X,
the required compensatory eye movement, θ, can be calculated from the
formula θ = arctan (X/D ) where D is the distance to the target; thus when the
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
is located closer to the head than the axis of rotation R, then the eye
movement required to compensate for a rotation through an angle A is B + C.
Note that the eye movement required is in the same direction as the head
rotation; thus if the head rotates to the right, the eyes must also rotate to the
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.
gain is measured during linear acceleration while viewing
a near target, the gain is found to be very significant and,
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
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
gain, and even the direction of movement, of the eyes during
the tVOR needs to be a function of both eye position and
vergence angle (Fig. 4-12). For example, if the head is moved
in the nasal-occipital direction toward a target that is in line
with one eye, then the required tVOR should produce no
movement in the eye in line with the target, but an adduc-
tion of the other eye (see Fig. 4-12). This is, indeed, just what
is observed.40,41
Many second-order canal neurons also receive input
from the otoliths.42 The latency of the three-neuron arc on
which the aVOR is based has been measured and found to
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
conceivable directions of movement. Thus stimulation of
these nerves produces eye movements of no functional
significance. For example, stimulation of the whole utric-
ular nerve causes torsional movements of the eyes with
intorsion of the ipsilateral eye and extorsion of the con-
tralateral eye. In addition, the ipsilateral eye elevates
and adducts while the contralateral eye depresses and
abducts. If small areas of the utricular macula are stimu-
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
movement, and stimulation of the lower area causes
downward movement.
Spinal Influences
The diagrams summarizing the semicircular canal VOR
pathways (Figs. 4-8, 4-9, and 4-10) suggest that vestibulo-
ocular neurons are the source of at least part of the medial
vestibulospinal tract. This is largely true for excitatory
second-order cells, whereas the inhibitory neurons tend to
be kept separate for ocular and spinal function. Generally,
vestibulo-ocular neurons use γ-aminobutyric acid (GABA)
as a transmitter substance (blocked by picrotoxin), whereas
vestibulospinal neurons tend to be glycinergic (blocked by
strychnine). Spinal cervical proprioceptive afferents in turn
can influence the activity of second-order vestibulo-ocular
neurons, which implies that the normally weak neck-to-eye
102 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
reflex is at least partly funneled through VOR pathways.
It is presumably through this pathway that the effects of
neck injury on balance and eye movements are mediated.
The corresponding afferent pathways are not as well
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
vestibular nuclei as well as into the intercalated (Staderini)
nucleus, which is a caudal extension of the PH nucleus
(D. W. F. Schwarz and I. E. Schwarz, unpublished obser-
vations). None of these areas receives primary vestibular
afferents, nor do they contain secondary VOR neurons.
The neck proprioceptive afferent influence on the VOR
thus must be polysynaptic.
CEREBELLAR LOOP
Primary vestibular axon collaterals terminate in the caudal
vermis of the cerebellum on granule cell (GC) dendrites
within the granular layer of the cortex (Fig. 4-13). In addi-
tion, axon collaterals convey the same information to the
fastigial nucleus. Rather surprisingly, the flocculus, a por-
tion of the cerebellum that projects directly to the VN,
does not appear to receive as many direct inputs from
the vestibular nerve. GC axons, the parallel fibers, excite
Purkinje cells (PCs), which are the only output of the
cerebellar cortex. These PCs send inhibitory GABA-
ergic axons into the VN, which terminate on VOR neu-
rons. Part of the GC excitation within this loop is derived
from VN neurons rather than primaries. This is particu-
larly true of the flocculus, which receives a substantial
input from the VN. Such vestibulocerebellar inhibition is
available for all coplanar semicircular canal pairs but not
for all secondary VOR neurons. For the horizontal canal
system, only the VN cells terminating in the ipsilateral
abducens nucleus are so inhibited; in the vertical canal
system only secondary cells connected to the anterior
semicircular canals have this inhibitory control, not those
responding monosynaptically to posterior canal stimula-
tion. For each canal-specific eye movement plane, a special
microzone of the floccular cortex is responsible for this
direct inhibition.
As indicated in Figure 4-13, the cerebellar loop is closed
at the ocular output side. Retinal slip signals carried via the
accessory optic tract and relayed in the nuclei of the optic
tract are carried to these same cerebellar PCs via their
second afferent type, the climbing fibers (CFs). All cere-
bellar CFs originate in the inferior olivary nucleus.
Figure 4-13. Schematic diagram of visual and cerebellar influence on VOR.
VN, Vestibular nucleus; GC, granule cells; PF, parallel fibers; PC, Purkinje
cells; CF, climbing fibers; RF, reticular formation; IO, inferior olivary nucleus;
AOT, accessory optic tract; NAOT, nuclei of accessory optic tract.
Activity of the CFs is thought to be able to modulate the
efficacy of the parallel fiber-PC synapse, and this type of
modulation is thought to be responsible for the adjustment
of motor signals during trained movement coordination.43
SIGNAL TRANSFORMATION
If the VOR input and output signals are known, the signal
processing that must take place within the brain can
be deduced. The semicircular canal input has already
been discussed and has been well characterized by a num-
ber of investigators.44–46 The output elements are the ocu-
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.
Although several types of muscle fibers can be identified
both histologically and functionally, all the motoneurons
behave in much the same fashion. Some of the moto-
neurons have low recruitment thresholds (i.e., they are
recruited into the active pool when the eye is still far in the
off direction of the muscle), and these units tend to have
low velocity sensitivity as well, resulting in a behavior that
is more tonic in nature. Others have high thresholds and
tend to have higher velocity sensitivity and thus might be
described as being more phasic in their firing patterns. In
spite of these differences, all motoneurons are involved in
all types of eye movements. Even those with the lowest
thresholds show some phasic behavior, and those with the
highest thresholds exhibit tonic firing during fixation if the
eye is deviated far enough. Thus they all exhibit both
phasic and tonic firing patterns and so can be classified as
burst-tonic (BT) cells.
The ocular motor apparatus (often called the plant if the
motoneurons are included) is simpler than that for skeletal
joints for a number of reasons. First, the forces resisting
muscle contraction are almost totally due to the viscous
drag and elastic tension within the eye muscles, with a
small contribution from the other orbital contents. Thus
the system does not have to deal with variable and unpre-
dictable external loads. Second, the eye muscles insert
tangentially to the globe and “peal off ” as the eye rotates.
Thus their insertion angles, and corresponding mecha-
nical advantage, are essentially constant. The result is that
over most of its operating range, the eye represents a
completely predictable load.
Given the mechanical simplicity of the system, it is not
surprising that the behavior of the motoneurons can be
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
needs to have parameters related to these two variables
along with a description of the eye position at which the
neuron is recruited into the active pool. If we define E as

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′
which means that the average motoneuron is firing at
about 100 spikes per second when the eye is aimed straight
ahead. Thus the eye muscles exhibit a remarkable amount
of cocontraction. As the fixation position of the eye moves
in the pulling direction of the muscle, the motoneuron fir-
ing rate will on average increase by 4 spikes per second for
each degree of rotation. In addition, the firing rate will
increase further if the eye is moving (rather than fixating a
stationary target). This phasic increase will generate an
additional 0.95 spikes per second for each degree per sec-
ond of eye velocity. Finally, the time constant of the system
should be 0.95/4 or about 240 msec, a value close to what
has been measured under deep anesthesia.
Equation 4-1 demonstrates that the oculomotor
neurons exhibit both an eye position and an eye velocity-
related discharge. The signal coming from the semicircu-
lar canals is only related to head velocity. Its amplitude and
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-
related part of the signal still needs to be generated in
some fashion. Because, in the mathematical sense, position
can be derived from velocity through the process of inte-
gration, it has been deduced that a neural integrator must
exist that generates the eye position signal by integrating
the eye velocity signal. This turns out to be true for all eye
movements, not just the VOR; a controller (for saccades
or quick phases, for example) generates an eye velocity
command, which is sent to both the integrator and to the
motoneurons. The integrator output is then also sent
to the motoneurons so that they receive the correct
mixture of eye position and velocity inputs (Fig. 4-14).
Experiments have strongly suggested that there is a single
integrator for all types of eye movements. This integrator
was originally thought to be located between the VN and
the motoneurons (see Fig. 4-14A), because in anesthetized
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
made that secondary VOR neurons already possessed an
eye position signal, and so the situation must be closer to
that illustrated in Figure 4-14B. The exact location of the
integrator is still not clear. Lesions of the cerebellum
greatly degrade integrator function, but do not eliminate
it. Recently, lesions involving the VN and PH in primates
Physiology of the Vestibular System 103
Figure 4-14. A, Convergence of the vestibular velocity and integrated
position signals on ocular motoneurons as originally proposed by Skavenski
and Robinson. B, Corrected version of the same diagram. Note that a portion
of the eye position signal is already present on the secondary vestibular
neurons. OMN, Ocular motoneurons; VN, vestibular nuclear neurons:
INT, integrator.
have succeeded in completely eliminating integrator func-
tion. Whether the integrator is located in PH or in VN is
still not completely clear, and the most likely explanation
for the experimental data is that they involve interconnec-
tions among VN, PH, and the cerebellum. Note, however,
that one integrator is not sufficient; instead, separate inte-
grators are required for each eye movement direction (up,
down, left, and right). Because the integrator is required to
maintain the eye in eccentric positions, lesions that affect
its performance (most commonly lesions of the posterior
cerebellum) will result in an inability to hold eccentric
gaze. The nystagmus that results has been termed gaze
paretic nystagmus.
CENTRAL VOR NEURONS
Figure 4-15 illustrates the oculomotor neuron firing that
would result from an idealized VOR eye movement caused
by a rapid head rotation while viewing a stationary target.
The motoneuron discharge rate following the termination
of the movement shows a step increase relative to that
before the onset of the movement that reflects the new eye
position (as manifested by the kE term in Equation 4-1).
During the actual movement, the rE′ results in a further eye
velocity-related increase in the discharge rate. Thus the BT
activity is manifest as a pulse-step of activity in the spike rate
versus time plot of Figure 4-15B, a terminology Robinson46
introduced to describe similar events during saccadic eye
movements. During a movement of this type, the burst
would result from semicircular canal activity while the step
would be the result of the integrator output.
Burst-Tonic Cells
Qualitatively, the same signal as that found on the
motoneurons has been found in the vestibular nuclei, the
PH nucleus, the paramedial pontine reticular formation
(PPRF), the interstitial nucleus of Cajal, and the mesen-
cephalic reticular formation. The function of these cells
is unclear; they may be premotor cells, they may subserve
104 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 4-15. Neuronal pulse-step response of a burst-tonic (BT) cell during
idealized VOR eye movement. A, Head and eye position. B, Spike rate versus
time, indicating combination of pulse (B, burstlike spike activity, bottom) and
S, step (tonic rate increase, bottom).
an efference copy function, or they may be involved in
oculomotor control in some other fashion. Since many of
the BT cells in the vestibular nuclei project into the MLF,39
it seems likely that at least this subgroup may provide some
drive to the motoneurons.
BT neurons carry both eye velocity and eye position
signals. Although the eye position signal is generally
independent of the oculomotor system moving the eyes
(saccades, VOR, smooth pursuit, etc.), the amount of eye
velocity modulation is often not.
Second-Order Vestibular Neurons
The neurons in the vestibular nucleus are diverse and are
named based on the types of signals they convey. These
cells include (1) position-vestibular-pause (PVP) neurons,
(2) burst-tonic (BT) cells, (3) eye-head velocity (EHV)
neurons, (4) floccular target neurons (FTN) (although
these may be the same as EHV), (5) vestibular-only (VO)
cells, and (6) vestibular pause cells.39,47–54 The firing rate of
PVP cells is proportional to angular head velocity and eye
position when the head is stationary and ceases during a
saccade. It is thought to be the second neuron in the three-
neuron arc of the angular VOR.39,53 Evidence for this
comes from the finding that PVP cells involved in gener-
ating horizontal eye movements project directly to the
contralateral abducens nuclei and that afferents have been
shown to monosynaptically activate PVP cells.34,53 PVPs
also can make inhibitory connection to the ipsilateral
abducens (11% of the population53). There are also PVPs
that make monosynaptic connections to the oculomotor
(third) nucleus and participate in vertical eye move-
ments.39,55 Eye and head velocity signals converging onto
PVP cells act synergistically, since eye position sensitivity
is in the opposite direction to head velocity sensitivity.51,53
This is true for both type I and type II PVPs, where type I
indicates an increase in the firing rate in response to ipsi-
lateral head velocity and contralateral eye velocity and type
II is just the opposite. In general, the sensitivity of PVP
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-
rally directed.58-61
VO neurons fire during translation and rotation of the
head and have no eye position on them.39,53,54,62 Their
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-
ment and combined eye-head gaze shifts,62 leading to the
hypothesis that efference copy of the neck motor com-
mand suppresses the activity of these cells. These neurons,
especially those in the LVN, MVN, and IVN (but not in
the SVN) project to the spinal cord via the lateral vestibu-
lospinal tracts (LVST), the medial VST (MVST), and the
caudal VST (CVST).63,64 In addition, these cells project to
the rostral fastigial nucleus in the rhesus monkey where
most of the neurons also exhibit a combined canal and
otolith input.65 Indeed, the rostral fastigial nucleus
receives extensive input from the vestibular nucleus66 and
minor input from vestibular afferents, making the cerebel-
lum the most likely target of these vestibular neurons. The
exact function of these cells is unknown although there do
exist some hypotheses. For example, they could be a part
of a preprocessing circuit for the VOR,54 or more likely
they contribute to vestibulospinal reflexes as suggested by
their projections to the fastigial nucleus.67
VO neurons are ideal for the study of convergence of
rotational and translational signals. Given that natural head
movements are composed of a combination of translation
and rotation,68 then elucidating the types of interactions
between these signals is paramount for the understanding
of vestibular reflexes. Both these stimuli have been intro-
duced simultaneously by using eccentric rotation (rotation
around an axis removed from the interaural line).30,69,70
Linear techniques have been applied to PVP, FTN, and
VO cells in order to calculate the sensitivity of the various
individual signals converging onto them. Experiments
using the previously mentioned method calculated the
translational sensitivity of the VO cell by subtracting the
linearly calculated rotational contribution to the firing
rate. Specifically, an animal would be rotated on-axis
(about an axis centered on the interaural line so that no
translational acceleration exists) while the response of a
neuron is being recorded. Given the rotational attributes,
such as velocity or acceleration, the sensitivity of the cell
to the stimulus can then be easily calculated. Then, the
animal is shifted off-axis, so that eccentric rotation can be

applied introducing a tangential acceleration. Note that
the rotational stimulus does not change during the eccen-
tric condition since the semicircular canals continue to
sense the same rotational acceleration. The total forces
during this condition do change though, as tangential
and centripetal accelerations, which are dependent on the
distance of the head from the axis of rotation are intro-
duced. Given that the rotational sensitivity has been calcu-
lated, then the rotational contribution to the response of
the cell during eccentric rotation was removed, leaving
behind a residual signal. Since translational accelerations
represented the additional stimuli during eccentric rota-
tion, then the additional signals recorded (the residual)
were assumed to be otolith in origin. This methodology
makes the bold assumption that the interaction between
the rotational and translational contribution to the firing
rate is linear.
No proof of linear behavior exists in the vestibular
nucleus although there may be linear interaction between
vestibulo-ocular reflexes. Sargent and Paige,71 by studying
the VOR during eccentric rotation, have suggested that
signals from different end organs sum linearly. The assump-
tion of linearity in the vestibular nucleus was necessary
since it was the only way to obtain an estimate of the otolith
sensitivity. Assuming linearity, the otolith response was
obtained by subtracting on-axis responses from eccentric
responses.51,72,73 This method has been applied to cells
in the vestibular nucleus with and without eye position
sensitivity.
The head velocity command is forwarded to the
motoneurons by secondary vestibular neurons that behave
in a manner similar to vestibular primaries during head
movements, but exhibit firing patterns related to other eye
movements (saccades, smooth pursuit, and optokinetic nys-
tagmus) as well. Experiments have shown that FTNs exhibit
large changes in firing behavior when the VOR gain is
changed as a result of wearing magnifying or minifying
lenses, while PVP change very little. As a result, many
experimenters currently believe that the VOR is based on
two parallel pathways: a PVP pathway that is relatively fixed,
and an FTN pathway that is highly modifiable. It is likely
that the FTN pathway is largely responsible for the com-
pensation that occurs following unilateral peripheral lesions.
Burst Neurons
Burst neurons are found in the pontine reticular formation
near the abducens nucleus (horizontal “on” directions) and
in the mesencephalic reticular formation near the midline
and anterior to the oculomotor nucleus (vertical “on” direc-
tions). These neurons fire an intense burst of spikes begin-
ning just before the onset of saccades and quick phases but
are otherwise silent. They supply the saccadic pulse to the
motoneurons. Several types of burst neurons exist.
Discharges of short-lead burst neurons start 4 to 16 msec
before the onset of the saccade. They can be further subdi-
vided into inhibitory burst neurons (IBNs) and excitatory
burst neurons (EBNs). For the horizontal system the IBNs
are located just caudal and deep to the abducens nucleus, and
the EBNs are located in reticular formation just rostral to the
abducens nucleus. The vertical burst neurons are located in
a nucleus in the mesencephalic reticular formation called the
Physiology of the Vestibular System 105
rostral interstitial nucleus of the MLF (riMLF). Consider the
horizontal system as an example: The short-lead IBNs are
inhibitory to contralateral abducens motoneurons, and the
EBNs are excitatory to the ipsilateral abducens. Thus these
two neuron pools are responsible for the bursts and pauses
seen in the motoneurons during saccades and quick phases.
During light sleep, burst neurons are seen to fire irregularly
even though no saccades are occurring. If the animal is
rotated under these conditions, burst neurons fire in phase
with head velocity and thus must receive a vestibular input.
Although the function of this vestibular input is unknown, it
may be related to the problem of eye-head coordination,
which is treated later.
Since the burst neurons are responsible for the premo-
tor drive signal during all saccades and quick phases, it is
not surprising that lesions in medial reticular regions can
result in slow or absent saccades.
Pause Cells
Although many cells have been demonstrated to pause dur-
ing saccades, there is one discrete group for which experi-
mental data suggest a functional role. These cells are found
close to the midline anterior to the abducens nucleus. They
exhibit a regular firing rate except that they pause during
all nystagmus quick phases and saccades. They have been
shown to be monosynaptically inhibitory to the EBNs74
and IBNs.75 They are believed to function as part of a latch
circuit that prevents neural noise from causing random
saccades. Thus they must be inhibited in order to initiate
a quick phase or saccade. Furthermore, stimulation of the
pause neuron area results in the complete inhibition of all
saccades and quick phases for the duration of the stimulus.
Tonic Cells
The PPRF and PH nucleus also contain cells that encode
only eye position by their firing. These cells have been
termed tonic cells and are thought to represent the output
of the neural integrator. Other cells behave in a manner
similar to tonic cells except they have a weak eye velocity
signal as well and thus may represent an intermediate step
in the integration process.
COMMISSURAL CONNECTIONS
Virtually all type I (excited by ipsilateral head rotation) VN
neurons involved in the VOR send axon collaterals into a
commissural system that connects both VN complexes
(Fig. 4-16). BT cells monosynaptically excite type II
(excited by contralateral head rotation) cells of the oppo-
site side, which in turn inhibit BT cells there. In addition,
type II neurons are monosynaptically inhibited by
contralateral IBNs and BT cells excited by ipsilateral
EBNs. A proposal has been made that the positive feed-
back loop that results from the connections between the
BT neurons and the type II neurons might be subject to
gain control and time constant modulation via the burst
neurons. Galiana and Outerbridge76 have suggested that
the commissural system functions as a type of oculomotor
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.
few data exist to support this view, especially since recent
lesion studies have implicated the VN and the PH complex
in the integration process.
Certain statements concerning the commissures, however,
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.
Specifically, they are excited by the ipsilateral canal and
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-
half of its normal level (due to the loss of contralateral
disinhibition). As a result, following a unilateral peripheral
lesion, the brain needs to compensate for both the unequal
activity in the VN on the two sides (resulting in sponta-
neous nystagmus) and the reduced sensitivity, which results
in a subnormal VOR gain.
NEURON ACTIVITY DURING
NYSTAGMUS
Intermediary Neurons
Because of the fact that the canals are arranged in comple-
mentary pairs, the two vestibular nuclei fire reciprocally
during rotation and its resulting nystagmus.77 Thus the firing
rate increases in the ipsilateral (relative to the rotation
direction) type I neurons and a parallel decrease results in
the contralateral type I cells. The various different cell
types found in the VN exhibit characteristic behavior dur-
ing nystagmus. During a slow phase directed toward the
contralateral side (which occurs with ipsilateral rotation),
VP cells maintain a steady discharge rate proportional to
slow-phase, or head, velocity (Fig. 4-17A). The reciprocal
pattern of concerted cell firing during excitatory (contra-
lateral) quick phases and inhibitory (ipsilateral) movements
is exemplified in Figures 4-17A to D. The behavior of all
of the different cell types during nystagmus is simply what
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,
and VP cells (bottom). C, Inhibitory slow phase. Eye position (top); dis-
charge rate of TVP (tonic vestibular pause) cells (bottom). D, Inhibitory quick
phase. Eye position (top); firing rates of TVP cells and inhibitory burst (IB)
cells (bottom).
would be predicted based on their activity during saccades,
periods of fixation, and sinusoidal rotation.
Motoneurons
Activation during both excitatory quick and slow phases in
all extraocular motoneurons is caused by a combination of
EPSPs (excitatory postsynaptic potentials) and a simulta-
neous release from synaptic inhibition (disinhibition). The
opposite situation occurs during slow and quick phases
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.
A notable exception to this is medial rectus motoneurons,
which do not exhibit IPSPs during nystagmus.
VISUAL VESTIBULAR INTERACTION
The primary function of the VOR is to stabilize images on
the retina during head movements. There are three other
eye movement systems with which the VOR must inter-
act.78,79 The optokinetic system (OK) stabilizes images
whenever the entire visual world (or at least a large part of
it) moves. The smooth pursuit system (SP) functions to
stabilize images of smoothly moving foveal targets (e.g., a
bird flying through the air). The saccadic system is used to
move a target from the peripheral retina onto the fovea.
The first two of these, the OK and SP systems, are dis-
cussed here. Interactions between the saccadic system and
the VOR are considered later in the section on Eye-Head
Coordination. Both of these visual following mechanisms
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
identical to the neuronal time constants (see Figs. 4-18B
and F), and the combined vestibular and OK responses
generate a faithful replica of the stimulus in the nystagmus
slow-phase velocity profiles when the rotation occurs
in the light (see Fig. 4-18H). The optokinetic response,
however, is complicated by the fact that both the OK and
SP systems contribute to the overall visual response
(see Fig. 4-18G). We can see in Figure 4-18G that an ini-
tial rapid rise in slow-phase eye velocity occurs followed
by a slow increase until finally eye velocity matches drum
velocity. The pattern shown here is commonly seen in
nonhuman primates. Human subjects, however, exhibit a
slightly different pattern in that there is not normally a
slowly increasing part to the response. Instead, eye veloc-
ity jumps immediately to drum velocity and then stays
there. Other experiments have demonstrated that during
the course of the maintained response, the SP system is
generating almost all of the nystagmus immediately after
the start of the stimulus, but this contribution subseque-
ntly drops as the OK system increases its contribution (the
slowly increasing part of the monkey response in
Fig. 4-18G). When the lights are then switched off, the SP
component decreases very rapidly to zero. As a result, the
residual nystagmus after the lights are extinguished starts
at a lower velocity (due to the lack of any SP component)
and is a result of the OK system. It is termed optokinetic-
after-nystagmus (OKAN). This OKAN declines with a time
constant of about 25 sec, approximately the same as that
of postrotatory nystagmus, and its initial value reflects the
contribution of the OK system immediately prior to turning
out the lights. Thus, the fact that both the SP and OK
systems contribute to optokinetic nystagmus (OKN),
whereas OKAN is driven only by the OK system, means
that only measurements of OKAN reflect OK systems
behavior. Indeed, OKN could theoretically be normal even
with a completely nonexistent OK system; the nystagmus
would be purely a result of smooth pursuit of the moving
stripes.
OKAN has some function in the diagnostic assessment
of vestibular function.81 Although its usefulness is limited by
the fact that it exhibits considerable test-to-test and subject-
to-subject variability. OKAN is lost following bilateral
labyrinthectomy, and after loss of only one labyrinth, it is
stronger toward the intact side. Again, following unilateral
lesions, the time constant of OKAN is reduced when the
slow phase is directed toward the intact side as is the time
constant of the VOR. Together with the second-order
neuron data (see Fig. 4-18C), all of these observations sug-
gest that some form of neural velocity storage mechanism
is shared by both the OKN and VOR pathways. This is
believed to be the same mechanism that prolongs the time
constant of the vestibular system from that of the cupula to
that seen during postrotatory nystagmus.
In animals with laterally positioned eyes and no fovea
(e.g., the rabbit), there is no SP system. Thus, during OK
stimulation, the velocity of the slow phases of the nystag-
mus does not exhibit a sudden initial jump as it does in
primates. Instead, the velocity is seen to build slowly until
it reaches drum velocity.
Up to about 60 degrees/sec the OKN system exhibits a
gain of about 0.8. (Gain here is defined as eye velocity
divided by drum velocity.) For drum velocities greater than
this value, the gain begins to decrease until the system
saturates for drum velocities in excess of 120 degrees/sec,
and further increases in stimulus velocity result in lower,
rather than higher, eye velocities.
Horizontal vestibular nystagmus can be driven by either
the horizontal canals, or, under exceptional circumstances,
by the otoliths (during barbecue spit rotation, for example).
During normal rotations, the horizontal canal activity con-
tributes to the nystagmus in the following two ways:
1. Modulation of firing rates in the primary afferents
caused by cupular deflection is responsible for rotatory
and postrotatory vestibular nystagmus; the slow-phase
velocities quickly approach head velocity and then
decay with a time constant of about 20 sec.
2. The background activity in the lateral canal fibers is
essential for normal function of the velocity storage
mechanism in the VOR and OKN pathways. Thus
the slow decay in OKN after the drum lights are
extinguished, OKAN, is present if the canal’s mechan-
ical responsiveness is eliminated by canal plugging,
but disappears if the lateral canal nerve is cut.
If a subject is tilted and then rotated about the new tilted
axis, which might be earth horizontal (barbecue spit
nystagmus82) or merely at some intermediate angle (off
vertical axis rotation [OVAR]),19 the resulting nystagmus
endures for the duration of the stimulus and does not
decay as it does when the rotation axis is vertical. If the
lateral canals are plugged, the enduring nystagmus is still
present but disappears when the utricular nerve is sec-
tioned. If, however, the lateral canal nerve is sectioned and
the utricular nerve is left intact, the nystagmus cannot be
elicited. Thus, although this type of nystagmus seems to
be driven by the otoliths, it requires a certain amount of
activity in the lateral canal nerve. The most reasonable
explanation for these findings is that the otolith informa-
tion responsible for generating OVAR nystagmus is fed
through the velocity storage system, which depends on
lateral canal nerve activity to function. Thus if OVAR
nystagmus is elicited clinically with any kind of rotating
chair (which, of course, must be able to be tilted) then the
responses can be used to check lateral canal, otolith, and
velocity storage system functions.
The velocity storage mechanism can be discharged, or
“dumped,” by changes in head orientation. For example,
if, during postrotatory nystagmus, the head is suddenly
pitched forward, the nystagmus decay time constant sud-
denly drops from the normal value of 20 sec to that of the
cupula (about 6 sec). Thus this procedure greatly reduces
the duration of the postrotatory response. This is believed to
be caused by a sudden tilt-induced discharge of the activity
in the velocity storage circuits and is often termed dumping.
This dumping is dependent on the integrity of the cere-
bellar nodulus. Thus patients with lesions involving the
nodulus do not dump their postrotatory nystagmus when
they tilt their heads.
A similar simple diagnostic avenue exists for the vertical
canals. If horizontal rotation is maintained about the
normal vertical axis, then the nystagmus will also be main-
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
test in the dark or in a visually unstructured but illuminated
environment, the VOR gain drops with decreasing stimu-
lus frequency, indicating that at low frequencies the VOR
alone is not adequate to generate accurate compensatory
eye movements. Clearly, visual tracking mechanisms must
make greater contributions at lower frequencies. This low-
frequency compensation is accomplished mainly by the OK
system. Indeed, since the optokinetic signal is fed through
the vestibular nuclei, it is often useful to think of the OK
system as part of the VOR even though its input does not
come from the labyrinth. Many people believe that canal
function can be measured reliably by rotating the patients
in darkness so as to exclude visual input. This, however, is
incorrect, since imaginary visual tracking in total darkness
can have large effects on VOR gain.87
At high frequencies (>2.5 Hz) the VOR gain rises with
increasing frequency to values greater than 1, just as the
gain of the primary afferents rises at high frequencies. This
increase, however, is observed only when a randomized,
unpredictable stimulus is employed. When predictable
waveforms are used or during active high-frequency head
shaking,88 the gain remains close to the ideal value of 1,
presumably because of the contribution of predictive motor
programs. Indeed, if a subject rapidly shakes his or her head
while viewing a distant target, the target appears to move
in the opposite direction to the head movement, thus indi-
cating that the VOR gain must be slightly less than 1 under
these conditions. Because high-frequency gains during
unpredictable rotations are reduced to the appropriate
value of unity as long as the test is performed in light, visual
tracking mechanisms must be able to make small contribu-
tions even at these high frequencies. Under these condi-
tions, retinal slip velocities appear to remain low enough
for the pursuit system to largely overcome them. Thus
at high frequencies, visual tracking mechanisms have the
opposite effect on VOR gain when compared with low
frequencies (see Fig. 4-19B).
The level of visual acuity during head shaking is a sensi-
tive measure of VOR function since even small deviations
from a gain of 1 will result in visual blurring. This fact is
of substantial clinical importance because it means that
if a patient’s head is taken in the hands and gently shaken
through a few degrees in an unpredictable fashion while
the patient attempts to read a Snellen chart, then VOR
deficiencies are easily uncovered. Normal people do not
lose more than two lines (relative to their score with the
head still), and a loss of more than this can be viewed as a
sign of vestibular dysfunction. Although this test does not
yield information about the site of the lesion, it requires no
equipment, is more sensitive than the caloric test, and can
quickly alert the clinician to a potential problem.
When fixating a visual target that is moving with the
head during random rotation, the subject is attempting to
suppress the VOR, and consequently VOR gain is reduced
at low frequencies although no suppression is seen at
high frequencies. The mechanism responsible for VOR
suppression, or cancellation as it is often called, is unclear.
It was initially believed to be a function of the SP system
because cancellation and pursuit exhibit similar frequency
response curves and show parallel decreases in performance
following lesions of the cerebellum. Recently, however,
this view has been called into question. Tomlinson and
Robinson39,89 demonstrated that the behavior of many
cells in the VN was inconsistent with the notion that the
pursuit was used to cancel the VOR. In addition,
Lisberger90 and Cullen and colleagues91 have both demon-
strated that under certain circumstances the cancellation
system has a much shorter latency than smooth pursuit
(<30 msec versus 100 msec). Thus the current view is that
two separate mechanisms cooperate to cancel the VOR, a
short latency system that is probably independent of visual
feedback and thus may be viewed as parametric in nature,
and a second, longer latency system that probably corre-
sponds to smooth pursuit. Finally, there are now reports of
patients who exhibit different degrees of deficit in their SP
and cancellation systems.92 Given this information, it
would seem that clinical testing should involve tests of
both SP and VOR cancellation since the two systems may
exhibit differential deficits.
ADAPTIVE VOR PLASTICITY
A disadvantage of the very short latency of the VOR
(about 12 msec) is that there is no time for visual feedback
control. (Note, however, that increasing the latency of the
reflex would destroy its usefulness because visual blurring
would occur during head movements.) The eyes need to
move too quickly for the long transneuronal delays in the
retina and central visual pathways to supply adequate visual
slip information. Since such feedback does not exist, the
VOR is an open-loop system and VOR eye velocity (E′)
will depend only on the concurrent head velocity (H′),
with its size depending only on the value of the parameter
k in the following equation:
E′ = k × H′ (4-2)
The parameter k represents the efficacy of the signal
transduction. It can be adjusted over a slow time course
if gaze is not sufficiently stable during head move-
ments.93,94 Thus the VOR, lacking closed-loop feedback
control, represents an open-loop system that is subject to
parametric control, that is, the value of k can be adjusted.
There is an obvious necessity for such parametric
control. It is unlikely that synaptic efficacy would remain
constant throughout a lifetime without some means of
periodic adjustment. In addition, both the degree of ocular
mobility and the efficiency of the mechanoelectric trans-
duction in the labyrinth are likely to vary due to disease or
aging. Common eyeglasses will change visual distances
by about 3% per diopter and thus will require a parallel
change in VOR gain (for example, 2 × lenses cause objects
to apparently move twice as much as the head moves
and thus require a VOR gain of 2.0). This required recali-
bration of VOR gain partly explains the disorientation
associated with a new prescription. Spectacle wearers can
easily confirm these facts by fixating a stationary target
while shaking their heads and the repeating the procedure
after removing their glasses. If they are myopic, the
target will appear to move in the direction of the head

movement; if they are hyperopic, the apparent motion will
be in the opposite direction. Of course, this only works
for people who have rather large corrections, because
small inaccuracies (a few percent) in VOR gain cannot be
detected. These gain changes are referred to as parametric
adjustments (the parameter k is being changed) and are
maintained for long periods of time.
Because of the general applicability of such control to a
wide range of brain functions, this phenomenon has been
extensively studied in a variety of laboratories.43,93–96 Since
visual acuity is maintained provided the retinal image does
not drift at a velocity greater than a few degrees per sec-
ond, the VOR gain is normally kept within 3% of unity,97
at least in subjects with normal vision. If retinal image
slip increases during head movements, the VOR gain will
slowly change so as to minimize the slip. Thus if a subject
wears telescopic goggles with a magnification factor of 2,
the VOR gain will slowly change during a period of days
until it approaches this value. Similarly, if 0.5 × goggles
are worn, the VOR gain will drop to about one-half of its
normal value. Such gain changes only occur in the plane in
which slip occurs. Indeed, the VOR can even be “twisted”
if vertical slip is induced during horizontal head movements.
The result is that, after adaptation, horizontal head move-
ments will produce oblique eye movements. Experiments
by Lisberger and colleagues96,98 have demonstrated that
the modified VOR has a different latency than the unmod-
ified VOR. Thus when a sudden head movement is made,
the eyes always follow the same trajectory for the initial
short period of 12 msec; however, the eye trajectories
obtained at different VOR gains depart from one another
about 19 msec after movement onset. Thus it would
appear that the three-neuron arc always has the same gain
(and a latency of about 12 msec), but other modifiable
pathways act to change the VOR gain and have an addi-
tional latency of 7 msec.
The variable gain mechanism is thought to involve
modifiable synapses. Since VOR gain plasticity does not
survive cerebellar lesions, this was initially thought to be
the site of the modifiable synapse. This assumption is now
less certain. Demer and Robinson95 demonstrated that if
the climbing fibers (CF) carrying retinal slip information
from the inferior olive to the cerebellum were reversibly
lesioned with lidocaine, then the VOR gain immediately
changed to a default value that was essentially independent
of the state of adaptation of the VOR. These experiments
imply that the cerebellum may be necessary for plastic
modification of the VOR, but it is not sufficient; some
other structures must also be involved. When the lesion is
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
maintained at its adapted value but subsequent modifica-
tion becomes impossible. Thus the CF-cerebellum circuit
seems to be necessary to maintain gain changes that are
established outside of the cerebellum and to establish new
gains. Indeed, Paige and Sargent99 have demonstrated that
elderly patients with poor cerebellar function exhibit
reduced ability to modify their VOR gain. Since such
patients would also exhibit reduced ability to compensate
for unilateral vestibular lesions, testing the ability of a
Physiology of the Vestibular System 111
patient to modify VOR gain in response to reversing
prisms might be of diagnostic value.
The adaptive process normally requires both visual and
vestibular inputs because the gain remains at its adapted
level if the animal is kept in the dark (no visual input) or
has its head immobilized (no vestibular input).
However, if a subject is rotated in darkness for several
hours while attempting to fixate an imaginary target that
is also moving, the VOR gain drops. This had been attri-
buted to VOR plasticity.
A number of factors appear to contribute to parametric
modification of VOR gain. If the gain is followed over a
period of weeks in animals fitted with telescopic lenses or
reversing prisms (which require a reversal of the VOR), the
gain change is seen to exhibit two time constants; there is
an initial rapid change in gain with a time constant of about
10 h, followed by a slower change with a time constant of
about 1 week. Thus it seems likely that at least two mech-
anisms are involved.
The latency data of Lisberger have demonstrated that
the plastic change in VOR gain is not accomplished
through a simple change in the three-neuron arc. Other
evidence also supports this conclusion. If the VOR is
adapted during prolonged rotation at a single frequency,
then although the gain change is seen at all frequencies, it
is greatest at the frequency of the adapting stimulus.100,101
Frequency-specific adaptation has been cited to explain the
well-known habituation of figure skaters to high rotational
velocities, as opposed to that of sailors to low-frequency
movements of their ships. However, habituation is most
likely a different phenomenon from plastic gain changes.
In addition, predictive mechanisms seem also to play a role
because greater adaptation is seen if the testing is done with
predictable sinusoidal stimuli rather than randomized stim-
ulation profiles.102 Finally, adaptation is more complete
when gains are measured in the light and with active head
movements than with passive rotation in darkness.
Animals without previous visual experience (reared in
complete darkness) cannot adjust their gain at all, although
the VOR and its cancellation by visual fixation of a target
moving with the head are intact in these animals.103 Gain
adaptation is possible in animals reared under stroboscopic
illumination, although visual motion processing by the
visual cortex and superior colliculus is absent in these
animals. This suggests that the accessory optic system
must supply the critical visual input as it does for the opto-
kinetic system. The location of the modifiable synapses
still remains elusive in spite of repeated efforts by many
laboratories.
EYE-HEAD COORDINATION
During normal behavior, targets located more than
20 degrees from the line of sight are acquired with a stereo-
typed combined eye and head movement called a gaze
saccade (Fig. 4-20A). In this situation, gaze is defined as
the direction of the visual axis and is therefore the sum of
eye-in-head plus head-in-space. The actual movement can
be broken down into two parts: the saccade, during which
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
by the VOR as the head continues to rotate. The head move-
ment takes longer to execute than the eye saccade because of
the greater mass of the head and its slower dynamics. At the
end of the movement, the head will be nearly aligned with
the target and thus the eye will be near the center of the orbit
(at its primary, or straight ahead, position). This normal pat-
tern is altered in predictable fashion if the VOR gain has
been adapted to a new value. If the VOR gain has been
increased by wearing 2 × lenses (see Fig. 4-20B), the com-
pensatory rollback of the eyes is too great, necessitating a
series of corrective saccades. If, on the other hand, the VOR
gain is too low, the compensatory rollback is inadequate and
again a corrective saccade is required (see Fig. 4-20C). This
latter pattern is also seen if the VOR gain has been reduced
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
and the use of predictive eye movements, presumably driven
by the motor program responsible for moving the head.
The mechanism for adjusting the amplitude of the eye
saccade to compensate for variable head contributions
has recently been the focus of renewed interest. It has
previously been proposed that the saccadic command was
summed linearly with the VOR. Thus, if a 40-degree
saccade were called for, the saccadic system would pro-
gram a 40-degrees saccade and if the head moved during
the saccade, the VOR would effectively subtract the head
contribution. This simple view is now known to be incor-
rect. Instead, VOR gain is substantially reduced during
large saccades, allowing the head to contribute to the
Figure 4-20. Head-eye coordination. Solid line, Gaze curve; dashed line, eye
movement; dotted line, head movement. A, Normal subject. B, Subject after
plastic VOR adaptation to 2 × telescopic goggles. C, Subject after plastic
adaptation to 0.5 × goggles.
change in gaze position. Accuracy is maintained, however,
by the fact that the saccadic system programs the saccade
in gaze (eye-in-space) rather than eye (eye-in-head) coor-
dinates.104–107 Thus the saccadic system must use informa-
tion from the labyrinth to tell it how much the head moved
during the course of the saccade.
Disorders of this system could theoretically result in
patients with normal saccades with their heads still, normal
VOR, and abnormal gaze saccades. Such patients might
find quick head movements disorienting because the eyes
would not be on target after the rapid head movement of a
gaze saccade. Whether such a possibility might account for
complaints of disorientation during rapid head movements
in certain patients with normal vestibular and oculomotor
examination results is unknown at present.
HABITUATION
In the previous section, the term adaptation was used to
describe the adjustment of the VOR to altered conditions
(e.g., 2 × spectacles) with the purpose of optimizing the reflex
performance. In contrast, the term habituation is applied to
describe the gradual decline of the response to a normal
stimulus. These definitions are not identical to those used in
classical sensory physiology in which adaptation is normally
used to describe response decline during a stimulus, whereas
habituation is used to indicate the response attenuation that
occurs with repeated stimulus presentations.
Habituation of vestibular nystagmus is diagnostically
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-
ing the following:
1. The head and body tilt toward the side of the lesion.
This tendency may be so strong that an animal such

as a rat can induce active rolling about its longitudi-
nal axis until it is exhausted.
2. Spontaneous nystagmus toward the contralateral side.
3. Reduced VOR gain for rotations toward the ipsilateral
side.
4. Circular locomotion toward the ipsilateral side.
Immediately following the lesion, VOR gain is reduced
for rotations in both directions with the greatest reduction
for high-velocity rotations directed toward the side of the
lesion. A reduction in the time constant to about 6 sec and a
brisk spontaneous nystagmus are also seen. This decrease in
time constant results in the phase shift during low-frequency
rotations that is commonly seen during rotation testing of
patients with unilateral lesions. Over time, these symptoms
are alleviated.110–112 The spontaneous nystagmus is greatly
reduced within a few days. This nystagmus results from an
inequality between the firing rates in the two vestibular
nuclei, creating a sense of rotation toward the side contralat-
eral to the lesion. The recovery from spontaneous nystagmus
has been demonstrated to not require vision, but does
depend on the integrity of the cerebellum. The recovery of
VOR gain is much slower and has been demonstrated to
require several months. Gain recovery, however, is never
complete, particularly for high rotational velocities where
the gain exhibits a permanent reduction, particularly for
rotations toward the side of the lesion.38,110 Since this gain
reduction is much more modest when low-velocity stimuli
are used (<100 degrees/sec), it is often not seen during con-
ventional rotational testing. Paige38 evaluated the perform-
ance of the VOR in patients following unilateral vestibular
ablation surgery by using a range of different stimulus veloc-
ities, up to 300 degrees/sec. Although he only followed the
patients for 4 months following the surgery, he found that
performance approached normal values when using a 0.25-
Hz stimulus and a peak velocity of 50 degrees/sec. However,
when the peak velocity was increased to 300 degrees/sec, the
patient gains were less than half of those recorded in normal
controls. In addition, a large gain asymmetry was present
during high-velocity stimuli that was not present at lower
velocities. Although substantial improvement in function
was seen over the 4-month period when low-velocity stimuli
were used, very little recovery was seen with high-velocity
stimuli. He concluded from his studies that high-velocity
stimuli were more likely than other more conventional
methods to identify and lateralize even subtle vestibulopathy.
Halmagyi and his coworkers113 have demonstrated that
sudden impulsive movements of the head (accelerations of
>2000 degrees/sec) are accompanied by a very marked and
permanent VOR gain reduction when the movement is
directed toward the side of the lesion. This same group114
has also demonstrated that unilateral lesions result in
marked ocular torsion, presumably due to asymmetric
otolith input, but this sign disappears with time.
Although some improvement is seen in VOR gain fol-
lowing unilateral lesions, this improvement is dependent
on retinal slip occurring during activation of the reflex.
Thus, although elimination of vision does not disrupt the
resolution of the spontaneous nystagmus, it does prevent
improvement in VOR gain. Although the evidence is not
conclusive at this time, prevention of retinal slip during
head movements, which can be accomplished either by
Physiology of the Vestibular System 113
preventing vision or preventing head movements, seems to
result in a reduction in the amount of recovery that even-
tually occurs. This result argues strongly in favor of mobi-
lizing patients as quickly as possible following unilateral
lesions because the recovery process will be delayed if they
do not move their heads. This may in turn result in a
reduction in the degree of recovery ultimately achieved.
If the second labyrinth is lesioned following compensa-
tion for the first labyrinthectomy, a mirror image of the
original symptoms is observed (Bechterew’s phenomenon).
For example, the head is tilted toward the side of the
second lesion and a spontaneous nystagmus develops that
beats toward the side of the first lesion. This, of course, is
the result of the compensation for the first lesion. In the
course of the compensation for the original lesion, the
background activity in the two vestibular nuclei was equal-
ized. The second lesion now results in a depression of
activity levels in the ipsilateral nucleus and the resulting
inequality results in the new symptoms. This is a demon-
stration of the fact that it is not an inequality between the
firing in the two vestibular nerves that is important, but
rather an inequality between the two nuclei.
Although some researchers originally believed that
denervation hypersensitivity of VN neurons on the side of
the lesion accounted for the compensation for unilateral
vestibular loss, this explanation seems unlikely. Following
unilateral lesions, both the excitatory and inhibitory
commissural connections originating on the intact side
and terminating on the VN cells on the lesioned side have
been shown to exhibit an enhanced synaptic connectivity,
with the resulting postsynaptic potentials having lower
thresholds, faster rise times, and higher amplitudes. Also,
electron microscopic evidence has shown new synapse
formation in the denervated VNs.115,116 Transection of the
commissural system between the two VN prevents com-
pensation and the development of Bechterew symptoms.
Nonetheless, the commissural system alone is clearly
insufficient for the compensatory process because com-
pensation can be prevented by cerebellar lesions. In addi-
tion, cerebellar lesions in animals that have compensated
for a previous unilateral loss result in the reappearance of
symptoms for which no compensation is possible. Thus
care must be taken when contemplating a surgical solution
for unstable peripheral lesions (e.g., Ménière’s disease). If
the patient has compromised cerebellar function, compen-
sation for labyrinth destruction will not occur and the
symptoms may get worse instead of better.
Although the commissural system and the cerebellum
seem to be particularly important for recovery from
unilateral lesions, other brain systems must contribute as
well. Furthermore, since different symptoms seem to
resolve with different time courses, different pathways
must be involved, at least to some extent. Sensory experi-
ence during active locomotion undoubtedly plays an
important role.117 Such compensation largely depends on
information from the intact labyrinth. For example, com-
pensation for the head tilt is accomplished much faster
when the gravitational force is enhanced in a centrifuge.
Even the remnants of the VN on the side of the lesion
may contribute because dendrites regrow into the periph-
ery118 and the deafferented nerve develops background
activity.119
114 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
If a critical role of the vestibular commissural system in the
compensation process is accepted, it should not be surprising
that commissurotomy causes an immediate and complete
decompensation; that is, all primary symptoms reappear.
Varying degrees of decompensation, however, are also seen
after many other CNS lesions, including spinal cord transec-
tion, hemispherectomy, bilateral fastigial nucleus lesions,
inferior olive lesions, and cerebellectomy. Lesions of the lat-
eral reticular nucleus decompensate the skeletal motor
symptoms more than the oculomotor effects. All of these
structures have connections with the vestibular nuclei and
therefore can influence the dynamics of the commissural
loops. Galiana, Flohr, and Melvill Jones120 assume that this is
also possible by much more general changes in brain activity,
such as that induced by certain drugs.121 For example, gen-
eral depressants, such as barbiturates and chlorpromazine,
retard the compensation process, and a decompensation is
seen after administration of ether, alcohol, and muscimol
(a GABA agonist). Indeed, even moderate doses of barbitu-
rates can produce nystagmus in some people, which may be
the result of decompensation of minor peripheral inequali-
ties. The physician must realize that drugs, especially alcohol,
can cause symptoms associated with long-past pathologic
events for which complete compensation has occurred.
The central cholinergic system plays an important role in
compensation. Cholinesterase inhibitors such as physostig-
mine, paraoxon (E600), parathion (E605), and diisopropyl
fluorophosphate (DFP, or isoflurophate), when applied sys-
temically, can cause an immediate dose-dependent decom-
pensation. This is also seen after use of cholinomimetics,
such as nicotine, muscarine, and oxotremorine. This
decompensation occurs at much lower dosages if the drugs
are applied into the cisterna magna, suggesting localized
effects in the brainstem. Cholinolytics, such as atropine and
scopolamine, have a direct antagonistic effect and can cause
overcompensation, such as spontaneous nystagmus and
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
to occur with an accelerated time course. Similarly, when a
unilateral lesion is produced not in one but in several
successive subtotal surgical procedures, the presence of
repeated new symptoms induces an accelerated and more
complete final compensation.
VESTIBULOSPINAL SYSTEM
In addition to the VOR, the vestibular sensory input pro-
vides the drive to a series of reflex systems capable of
affecting almost all of the skeletal muscles that contribute
to the stability of the body with respect to gravity.1,122
Obviously, direction of the gravity vector with respect to
the otolithic maculae changes with head position. In addi-
tion, the net vector sensed by the otoliths will be a func-
tion of both the head position (with respect to gravity) and
any linear accelerations that the head is undergoing. It is
equally obvious that the reflex changes in muscle force
necessary for the maintenance of any particular body pos-
ture will differ if the whole body moves relative to what is
required when only the head moves. For example, tilting
the head to one side (in the roll plane) requires a different
postural adjustment in order to maintain an upright posture
than does a tilt of the whole body. Since the vestibular
labyrinth is located in the head, it is unable to distinguish
between tilting of the body and tilting of the head. Given
this situation, it is not surprising that the vestibular nuclei
require information from other sensory systems than
the labyrinth in order to make the appropriate postural
adjustments.
The two most important sensory systems contributing
to the resolution of this problem are the visual system,
which provides information concerning the relationship
of the body to the visual surround, and the somatosensory
system (particularly proprioceptors), which provide infor-
mation about the postural state of the body. Continuing
with the same example cited previously, if information
from neck proprioceptors, signaling head-on-body position,
is combined with information from the otoliths, signaling
head-in-space position, then the relationship of the body
to the gravity vector can be calculated. The major function
of the vestibulospinal reflexes is to keep the head and body
stable in space. This task is far more complex than the
oculomotor analogue, the VOR, for two main reasons:
1. Vestibulospinal reflexes act on many joints and the
required muscle tension at any joint must depend on
the forces acting on other relevant joints (including
forces external to the body, such as weights carried in
the hands). Thus an analytic treatment of the VOR
action on any single joint is an extremely complex
task.
2. Although labyrinthine head stabilization reflexes serve
to prevent head movement, the head must move to
induce these reflexes. This head movement becomes
the error signal of a negative feedback control system,
perhaps best illustrated by the vestibulocollic reflex
(VCR).
VESTIBULOCOLLIC REFLEX
If a subject is suddenly and unexpectedly rotated with the
head free to move, the head tends to maintain its original
position in space. This is partly the result of the inertia of
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
of the head, this reflex is slower than the VOR. When sub-
jects are rotated at constant velocity in darkness, they may
execute head and eye nystagmus in the same direction
without necessarily being aware of either. In this situation,
saccadic repositioning of the eyes and head occurs almost
simultaneously and the VCR and VOR both contribute to
the overall gaze stabilization.
Rotatory head perturbations in the vertical plane will
result in a head tilt and will therefore activate both the
otolithic maculae and both semicircular canals. In this
situation, the canal input is primarily responsible for the
high-frequency component of the VCR, bringing the head
back quickly, while the maculae are more important for low-
frequency corrections and thus maintain the long-term head
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
AND NECK REFLEXES
When higher motor control is removed by decerebration
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
about the neck joints while the head is maintained stable in
space so as to result in neck bending but no change in
vestibular input, the tonic neck reflexes can be demon-
strated (Fig. 4-21, N reflex pattern). For example, if the neck
is bent toward one side, a reflex flexion of the ipsilateral
limbs results, as well as an extension of the contralateral
limbs. Thus the tonic neck reflexes tend to compensate for
surface support tilt when the head is kept in the upright
position with respect to gravity. The patterns of flexion
and extension are changed with different directions of
neck flexion so as to compensate for all directions of tilt.
For example, when the neck is flexed upward in a
labyrinthectomized animal, the hind limbs flex and the
forelimbs extend, with the opposite occurring for down-
ward neck flexion.
If neck afferent input is prevented by the use of a cast
(thus preventing the neck from bending) or deafferenta-
tion of the upper cervical segments, the tonic labyrinth
reflexes can be demonstrated. These reflexes again func-
tion to stabilize body position on a tilting platform (see
Fig. 4-21, L reflex pattern). Note that the tonic labyrinth
reflexes act in exactly the opposite direction to the tonic
neck reflexes, resulting in limb extension on the side
toward which the head is tilted and flexion on the
contralateral side. Because the two reflexes induce oppo-
site effects, if the head is simply tilted to one side without
Figure 4-21. Tonic neck and labyrinth reflexes and dynamic labyrinth reflex.
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
extension and contralateral flexion.
any movement of the body, the two effects cancel and no
reflex change in limb position results (see Fig. 4-21, N + L
reflex pattern). This is of course precisely what is necessary
because there is no danger of loss of balance in this situa-
tion. Thus these two reflex systems cooperate to produce
always the correct change in body support musculature
for any change in head and body position.
The maintained limb position of the tonic labyrinthine
reflexes is derived from the otolithic maculae. More rapid
stabilization adjustments in the same directions depend
on canal input. For example, if all of the semicircular canals
of a cat are inactivated by plugging, the animal is still able
to compensate for slow platform tilts, but is thrown off
balance by rapid tilts that would be easily handled by the
normal animal. Following complete labyrinthectomy,
however, both slow and rapid tilts result in loss of balance.
The effect of rapid linear translation on the limbs appears
to be quite different from that of the tonic labyrinthine
reflexes. For example, rapid linear translation to the left of
a mobile platform results in ipsilateral (left) limb extension
and contralateral flexion, the exact opposite to that
induced by the tonic reflexes generated by the same direc-
tion of utricular hair cell deflection (see Fig. 4-21). Mayne123
and Nashner124 have therefore proposed that tonic gravi-
tational reflex actions are processed separately from dynamic
linear signals within the CNS. Nonetheless, the complex-
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.

can be gated by other motor areas. For example, when
Deiters’ nucleus is electrically stimulated during different
phases of the step cycle in the decerebrate cat, a facilitation
of gastrocnemius muscle activity can be seen only during
the extension phase and not during flexion. Thus these
reflexes can be modulated according to the circumstances.
Not all LVST neurons receive monosynaptic
labyrinthine input because vestibular afferents are con-
centrated in the ventral portion of the nucleus. As the
antigravity function of this system would predict, most
vestibular input arises from the otolithic maculae, includ-
ing the saccular macula. Neurons whose axons project
exclusively to the cervical segments tend to exhibit an
alpha response to tilting (excitation when the ipsilateral
eye is tilted down and inhibition for tilts in the opposite
direction). Cells with axons directed to the lower spinal
segments more frequently exhibit a gamma response
pattern (excitation for tilts to both sides). Tilt-sensitive
neurons do not receive commissural inhibition from the
contralateral side, although the less common canal driven
LVST neurons do. An indirect input to Deiters’ nucleus
travels via the fastigial nucleus of the cerebellum, as well
as through the posterior vermis and anterior lobe of the
cerebellar cortex. Deiters’ nucleus could be considered a
cerebellospinal relay rather than a strictly vestibular struc-
ture since most LVST neurons receive cerebellar input,
and many neurons, particularly in the dorsal half of the
nucleus, do not exhibit monosynaptic inputs from the
vestibular nerve.
Deiters’ cells receive somatic sensory input via the
spinocerebellar tracts as well as through the mossy fiber
(MF) inputs derived from the reticular system and the
climbing fiber (CF) system originating in the inferior
olive. All this somatic sensory input does not appear to be
somatopically organized, and modalities include muscle
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)
(see Fig. 4-22) since all Purkinje cells (PC), which termi-
nate on Deiters’ neurons or elsewhere are inhibitory.
Removal of the anterior lobe of the cerebellar cortex,
which projects to Deiters’ nucleus, results in increased
extensor tonus and opisthotonos, which disappears after
ipsilateral labyrinthectomy. In the intact cat, Deiters’ cells
often respond to tilt in a phasic fashion, that is, only dur-
ing the tilting movement. However, after cerebellectomy
these neurons exhibit the typical static response seen in
otolithic afferents. Many Deiters’ neurons are strongly
modulated when a cat walks on a treadmill, with activation
coinciding with the stance phase. After cerebellectomy, the
spontaneous firing rate of the cells is seen to increase but
the modulation during locomotion is lost.
Medial Vestibulospinal Tract
The medial vestibulospinal tract (MVST) descends bilat-
erally in the MLF and terminates mainly in the cervical
spinal cord, with its most caudally directed afferents ter-
minating in thoracic segments. Cells of origin are located
within the same VN area that contains VOR neurons, that
is, a region around the borderline between the medial,
descending, and lateral vestibular nuclei. Examination
Physiology of the Vestibular System 117
of the collateralization patterns for VOR neurons (see
Figs. 4-8 and 4-10) reveals that some cells in this area
belong to both the VOR and the MVST systems. In con-
trast to the LVST, the MVST contains many inhibitory
fibers that mediate monosynaptic IPSPs in many neck
motoneurons. These IPSPs can be blocked by strychnine,
indicating that the transmitter is glycine rather than GABA.
Excitatory MVST fibers, however, also make monosynaptic
contacts with cervical motoneurons. Polysynaptic excitation
and inhibition mediated via this tract are also seen. Most
MVST neurons are second-order vestibular cells, which are
monosynaptically activated by semicircular canal afferents.
Characteristically, type 1 or type 2 canal responses are rare;
however, many vestibulospinal neurons exhibit type 3
response patterns (excitation with rotations in both direc-
tions). Evidence also suggests utricular input. MVST neu-
rons with canal input receive commissural inhibitory
connections, just as VOR neurons do. Although only a few
MVST neurons do not receive direct labyrinthine input,
even those are driven by vestibular stimuli via interneurons.
MVST neurons in Deiters’ nucleus are subject to cere-
bellar control, but the functional relationship between the
vestibulocerebellum and MVST neurons is not well under-
stood. Nonetheless, it is known that fastigial nucleus neurons
can excite type 1 MVST neurons bilaterally.
Fredrickson, Kornhuber, and Schwarz125 observed a
strong somatosensory input to the VN region containing
MVST neurons. This input did not appear to be organized
somatotopically since the neurons were typically activated
by a coordinated joint movement pattern involving several
proximal joints. In keeping with the MVST action, the
strongest input was derived from the neck.
MVST cells can also be influenced by stimulation of
the rostral brainstem, particularly the interstitial nucleus
of Cajal.
Caudal Vestibulospinal Tract
The caudal vestibulospinal tract is a newly discovered
pathway originating from the most caudal aspects of the
medial and descending vestibular nuclei and projecting as
far down as the lumbar spinal cord. Its functional signifi-
cance is still unknown. However, the most caudal portions
of the descending and medial vestibular nuclei, as well as
the intercalated (Staderini’s) nucleus, receive direct input
from peripheral cervical nerves (D. W. F. Schwarz and
I. E. Schwarz, unpublished observations). Proprioceptive
afferents from the most rostral cervical segments are
known to play an important role in the maintenance of
balance. In cats, denervation of the first two segments, or
merely severing cervical muscle tendons at their insertion,
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
concerned with movement sensation within the central
vestibular system.
Some vestibulospinal neurons with canal input also
respond to a comparable neck flexion.127 Movement of the
body with respect to the fixed (in space) head can even
induce a sensation of rotation if the movement is slow.128
At higher velocities, trunk movement is perceived. Clinical
neurotologists are familiar with the fact that neck injury
118 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
can cause severe vertigo, and even nystagmus, without any
indication of vascular impairment. Thus the preponder-
ance of evidence certainly indicates that the vestibular
nuclei utilize information from a variety of sources in
order to estimate the movements of the body.
PROJECTION TO FOREBRAIN
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
been found to be specifically and exclusively dedicated to
vestibular input; rather, vestibular signals appear to blend
into the representation of other senses. Early evoked
potential studies, as well as cortical stimulation in alert
human subjects, had suggested the existence of at least one
specific vestibular cortical field in the parietal lobe.
Subsequent single-unit investigations, however, have
revealed that vestibular responses can be found over wide
areas of the somatic parietal fields (areas 3a, 2, and 5). This
input is derived from thalamic cells located in the ventral
posterior complex (ventroposterolateral nucleus [VPL], its
oral portion [VPLo], and the ventroposteroinferior
nucleus [VPI]), which in turn receive axon terminals from
the contralateral lateral and medial vestibular nuclei. It is
not clear how much of this sensory convergence is simply
the consequence of the convergence already present in the
VN. It is known, however, that thalamic neurons transmit-
ting vestibular information to the parietal lobe also carry
somatic sensory signals, usually from proximal joints and
muscles. Because all secondary vestibular neurons with
canal input also receive visual information from the OK
system, this signal must also be present. Thus the vestibu-
lar system is unique among sensory systems because its
estimates of head angular velocity are based on informa-
tion from a variety of sources including the labyrinth, the
retina, and joint and muscle proprioceptors.
The visual cortex also appears to receive vestibular
input. Researchers have shown that the orientation of
certain visual cortical receptive fields can be changed by
otolithic stimulation. Reinis and colleagues130 also showed
that semicircular canals stimulated with heavy water can
influence visual cortical background firing rates as well as
the size of complex visual cortical receptive fields.
The superior temporal gyrus has been suspected to con-
tain a specific vestibular projection field ever since Penfield
evoked sensations of rotation and imbalance from this
general area by electrical stimulation in human subjects.
However, no confirmation of this finding using neurophys-
iologic methods has been made.
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-
ment of the body, whether the stimulus affects the somato-
sensory system, the visual system, or the vestibular system.
The illusion of rotation, circular vection, created by caus-
ing the entire seen world to rotate, is in no way different
from the sensation of rotation induced by a rotatory stim-
ulus acting on the labyrinth. As a result, going through life
without ever being aware of the vestibular sense organs is
quite possible.
Vestibular input is certainly necessary for spatial orien-
tation. Children or rats without functional labyrinths
cannot remember a path through which they have been
passively transported. Such egocentric orientation capabil-
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
cannot find their way back to a location from which they
have been passively transported.
MOTION SICKNESS
Clinically, the most important vestibular sensations are
dizziness and vertigo associated with autonomic reactions
such as sweating, salivating, and vomiting.132 This syn-
drome can be elicited by a variety of different peripheral
and central vestibular lesions and is undoubtedly related to
motion sickness. A prerequisite for motion sickness is
labyrinthine input that conflicts with a central representa-
tion of a stable world. After bilateral labyrinthectomy,
motion sickness does not occur; however, an OK stimulus
can evoke the syndrome in healthy subjects. The visual
stimulus needs to be a smooth retinal image slip, since
motion sickness caused by visual direction reversal (pro-
duced by wearing spectacles fitted with reversing prisms)
does not occur under conditions of stroboscopic illumina-
tion. Visual fixation on a steady-reference horizon can be
used effectively to prevent sea and car sickness.132
Conversely, car sickness is exacerbated by attempting to
read in a moving vehicle.
For the past 40 years, researchers believed that motion
sickness depended on activity in the vestibulocerebellum
and on secretion of a humoral mediator to the emetic trigger
zone in the area postrema. Cats, however, are still suscepti-
ble to motion sickness after posterior cerebellectomy134
or ablation of the area postrema. If the aqueductus cerebri
(sylvian aqueduct) is blocked, and thus the flow of the puta-
tive humoral mediator from the third ventricle to chemore-
ceptors further caudally, motion sickness apparently does
not occur.135 If the emetogenic compound is secreted into
the third ventricle, it must be derived from very caudal
structures lining its wall, since motion sickness can be
evoked in decerebrate animals. Conceivably, not one but a
variety of natural brain chemicals can mediate the emetic
response. Interestingly, a number of external poisons
(pilocarpine, lobeline, L-dopa, and apomorphine) will no
longer cause emesis after bilateral labyrinthectomy.136
These somewhat conflicting findings show that a coherent
physiologic framework for those vestibular sensations that
bring many patients to their physicians is not yet available.
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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
Anil K. Lalwani, MD
Inheritance Patterns
Autosomal-Recessive
Inheritance
Autosomal-Dominant
Inheritance
X-Linked Inheritance
Variations on Mendelian
Principles
Linkage and Recombination
Mitochondrial Inheritance
X Chromosome Inactivation
Genomic Imprinting
Trinucleotide Repeat
Expansion
Multifactorial Inheritance
Epidemiology of
Nonsyndromic Hereditary
Hearing Loss
Connexin 26
Pendrin
Myosins
Molecular Genetics of
Vestibular Schwannomas
and Glomus Tumors
Neurofibromatosis Type 1
Neurofibromatosis Type 2
Familial Paragangliomas
Genetic Mapping of the PGL
Loci and Identification of
the PGL1 Gene
PGL2, PGL3, and PGL4
Transmission and Loss
of Heterozygosity
Intracochlear Transgene
Expression and Its Potential
Therapeutic Application
Animal Models and Gene
Transfer Vectors
Intracochlear Gene Delivery
Modalities
Preclinical Applications
Risks and Limitations
Summary

INTRODUCTION provides a critical assessment of the intracochlear gene trans-

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,”
encoding a wide variety of protein products with differing
biologic roles. Each of these “deafness genes” represents a
genetic tool or a probe for deciphering the molecular patho-
physiology of hearing loss precipitated by the mutant allele
and thus contributing toward our understanding of the
molecular circuitry responsible for hearing. The immediate
clinical impact of these discoveries includes the development
and deployment of genetic tests for molecular diagnosis of
hearing loss in the general population, thus affecting their
care and management. The long-term clinical impact
includes the development and application of gene-based
therapy that can correct certain forms of inherited and
acquired hearing loss.
The objective of this brief review is to inform the neuro-
tologist of the progress in hearing research, its impact upon
our understanding of hearing loss, and its application to
current and future clinical practice. The review begins with a
brief overview of Mendelian genetics, illustrated through
analysis of inherited disorders and their inheritance patterns.
This is followed by a review of molecular genetic analysis and
genetic epidemiology of nonsyndromic hereditary hearing
loss. Genetics and genetic analysis of vestibular schwannomas
and glomus tumors are also described. Finally, the review
122
fer studies that are directed toward treatment of hearing loss.
INHERITED DISORDERS AND THEIR
INHERITANCE PATTERNS
Roughly half of the observed severe hearing loss seen in
childhood has been attributed to genetic factors.
Approximately one in every 1000 children is born with a
severe hearing loss with the estimated prevalence of genetic
hearing loss around 1 in 2000.1 Of these cases, approximately
75% exhibit an inheritance pattern that is consistent with an
autosomal-recessive trait, 23% exhibit autosomal-dominant
inheritance, 2% appear to be X-linked, and less than 1% are
caused by deleterious mutations in the mitochondrial
genome.
Autosomal-Recessive Inheritance
An autosomal-recessive trait is characterized by having
two unaffected parents who are heterozygous carriers for
mutant forms of the gene in question but in whom the
phenotypic expression of the mutant allele is masked by
the normal allele. These heterozygous parents (A/a) can
each generate two types of gamete, one carrying the
mutant copy of the gene (a) and the other having a normal
copy of the gene (A). Of the four possible combinations of

these two gamete types from each parent, only the offspring
that inherits both mutant copies (a/a) will exhibit the trait.
Of the three remaining possibilities, all will have a normal
hearing phenotype but two of the three will be heterozygous
carriers of the mutant form of the gene, similar to the carrier
parents.
Although relatively uncommon, it is permissible for
more distant relatives such as first or second cousins to
marry and have children. This practice, known as consan-
guineous mating, greatly increases the potential to produce
a child affected by a recessive disorder. Figure 5-1 illustrates
the inheritance pattern of an autosomal-recessive trait in
offsprings of consanguineous mating in a pedigree spanning
several generations. A consanguineous mating of first cousins
can generate a risk of 1 in 64 for having a child affected
with an autosomal-recessive disorder from unaffected
parents with a common grandparent. With approximately
1 in 2000 children born having a genetic form of hearing
loss and 75% of these due to autosomal-recessive inheri-
tance, a generalized risk of having such an affected child is
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
1:64 divided by the frequency of autosomal-recessive hearing
loss in the general population (random mating) 1:2700.
This represents a 42-fold increase over the odds of two
unrelated individuals giving rise to a child with autosomal-
recessive hearing loss.
Autosomal-recessive deafness is extremely heterogeneous,
as inferred from frequent examples of families where both
parents are deaf while their children have normal hearing.
Thus, the generalized risk of having such an affected
child is a simplification based on an assumption of a single
causative locus and consequently an overestimate. It is
possible that individuals with a mutant phenotype whose
Figure 5-1. A pedigree pattern illustrating transmission of autosomal-
recessive trait. The affected individuals (shaded) have parents who are first
cousins as well as carriers of the recessive trait. The double horizontal line
between the parents of the affected children indicates that this is a
consanguineous mating between first cousins. When the recessive allele is
rare, it is more likely to become homozygous through inheritance from a
common ancestor than from parents who are completely unrelated.
Molecular Genetics in Neurotology 123
expression is consistent with autosomal-recessive inheri-
tance in fact possess mutations in two distinct genes that
are in trans to each other. Such noncomplementary double
heterozygotes, or digenic individuals, have been identified
in retinitis pigmentosa within several families in which
mutations in unlinked photoreceptor-specific genes ROM1
and peripherin/RDS were identified.2 Only the double
heterozygotes were observed to develop retinitis pigmen-
tosa. These cases represent the first example of digenic
inheritance in human disease. Potential double heterozy-
gotes have also been identified in nonsyndromic hearing
loss within the Ashkenazi Jewish population. The affected
individuals possess a common mutation 167delT in the
GJB2 gene in trans to a major deletion spanning the GJB3
gene, thus suggesting digenic mode of inheritance.3
However, the effect of the deletion upon transcription of
the adjacent GJB2 gene remains to be determined. If the
deletion adversely affects transcription of GJB2, then
the deletion effectively represents another example of
recessive mutation.
Autosomal-Dominant Inheritance
For autosomal-dominant disorders, the transmission of a
rare allele of a gene by a single heterozygous parent is
sufficient to generate an affected child. A heterozygous
parent can produce two types of gamete. One gamete will
carry the mutant form of the gene of interest, and the
other the normal form. Each of these gametes then has an
equal chance of being used in the formation of a zygote.
Thus, the chance that an offspring of an autosomal-
dominant affected parent will itself be affected is 50%. Equal
numbers of affected males and females are expected for an
autosomal-dominant trait and roughly half of the offspring
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.
Also the ratio of affected males to affected females appro-
aches unity and male-to-male transmission of the hearing
loss phenotype is observed, thus ruling out X-linked
inheritance. All affected offsprings developed bilateral
sensorineural hearing loss greater than 80 dB by their
mid-thirties to early forties and had normal intelligence
124 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
A between dominant inheritance with reduced penetrance
B
Figure 5-2. A, A pedigree pattern illustrating transmission of autosomal-
dominant trait (shaded). The autosomal-dominant trait is transmitted
from the affected parent to the offsprings, who have 50% probability of
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
pattern illustrating transmission of autosomal-dominant trait with incomplete
penetrance. Not all carriers of the mutant gene are affected, indicating
incomplete penetrance of the mutant allele.
and fertility. Thus, the penetrance of the mutant allele was
shown to be complete in older individuals. However, the
age of onset of the hearing loss was variable. All affected
individuals were born with normal hearing followed by
degeneration of their hearing ability beginning between
the ages of 6 to 16 years and continuing into their third
decade of life, when the rate of hearing loss plateaus. The
initial linkage analysis of this family excluded children
younger than 16 years to avoid problems of misdiagnosing
carriers of the mutant allele who had not yet expressed
the phenotype. The gene for this nonsyndromic hearing
loss was mapped to chromosome 5q31 by genetic linkage
analysis and the locus was identified as DFNA1, denoting
mapping of the first nonsyndromic deafness gene with
autosomal-dominant mode of inheritance.4 The DFNA1
gene was subsequently determined to be diaphanous
(DIAPH1) several years later through the identification of
a splice-site mutation, leading to a frameshift in the
DIAPH1 mRNA in only the affected members of the
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
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
that are inherited in an autosomal-recessive, X-linked
recessive, and X-linked dominant manner.
Variable expression of different aspects of syndromes,
including hearing loss, is common. Some aspects may be
expressed in a range from mild to severe, or different
combinations of associated symptoms may be expressed in
different individuals carrying the same mutation within a
single pedigree. An example of variable expressivity is seen
in families transmitting autosomal-dominant branchio-
oto-renal (BOR) syndrome. For BOR syndrome, aplasia or
stenosis of the lacrimal duct is reported in approximately
10% of cases; diagnosed structural anomalies of the renal
system occurs in 12% to 20% of cases; branchial cysts or
fistulas are present in approximately 60% of cases; anom-
alies of the inner ear occur in 30% to 60% of reported
cases; and hearing loss is found in approximately 75% of
reported cases. Of the hearing loss seen in BOR syndrome
cases, 50% is mixed, 30% is conductive, and 20% is
sensorineural loss. All three forms of hearing loss have
been seen in affected members of the same family. In
several individuals the type of hearing loss appears to dif-
fer between the two ears. Positional cloning approach led
to the identification of EYA1 as the disease gene responsi-
ble for the BOR syndrome and has been shown to be the
human homologue of the Drosophila eyes absent gene
(EYA).6 Analysis of its murine orthologue, EYA1, suggests
a role in the development of the inner ear and the kidney.
The range of variation observed in dominant disorders
is generally wider than in recessive disorders. A major

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
phenotype, despite the presence of a normal allele, as
observed in transmission of dominant disease traits, can
occur via several mechanisms. These in turn depend on
the nature of the protein encoded by the gene and the
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
the available product by a half. This pathologic reduction
in total amount of the active product is referred to as hap-
loinsufficiency. For example, PAX3 is considered to encode
a transcription factor and its haploinsufficiency resulting
from a mutant allele is postulated to cause the expression of
the disease phenotype, the dominantly transmitted type I
Waardenburg’s syndrome. Another group of genes that can
cause expression of the disease phenotype are those that
encode structural proteins or membrane proteins that phys-
ically interact to yield functional product. Mutations within
genes that encode collagens or connexins represent exam-
ples of such dominantly inherited disorders.7,8 However,
not all mutations in genes whose products are part of an
oligomeric assembly are dominant. For example, both
dominant and recessive forms of a disease can result from
different mutations of the same gene. This has been demon-
strated for autosomal-dominant and -recessive forms of
Stickler’s syndrome, a syndromic sensorineural deafness that
results from different mutations within COL11A2 gene.
X-Linked Inheritance
In humans, females have 22 pairs of autosomes and a pair
of X chromosomes (46,XX); males have 22 autosomes, 1 X
chromosome, and 1 Y chromosome (46,XY). Accordingly,
males always receive their Y chromosome from their
father and their X chromosome from their mother, and
females receive one of their X chromosomes from each
parent. Because males have one copy of the X chromosome,
they are hemizygous for genes on the X chromosome and
the X chromosome is active in all their nucleated cells. In
general, only one of the two X chromosomes carried by a
female is active in any one cell, while the other is rendered
inactive by a natural process known as lyonization. This
random inactivation process makes all females, who are
heterozygous for X-linked traits, mosaic at the tissue level,
resulting in variable expression of the mutant gene.
Diseases that are rarely expressed clinically in heterozygous
females are called X-linked recessive. In female tissues,
various proportions of cells may exist in which one or the
other of two alleles for an X-linked locus is expressed.
Occasionally, a carrier female manifests some symptoms of
an X-linked-recessive disorder due to this mosaicism if she
Molecular Genetics in Neurotology 125
Figure 5-3. A pedigree pattern illustrating transmission of an X-linked
recessive trait (shaded). The affected males inherit the X-linked recessive
disease allele from their unaffected carrier mother. The X-linked trait is
characterized by absence of male-to-male transmission; all daughters of the
affected male are heterozygous or carriers for the disease allele.
by chance has an abundance of cells with the mutant allele
being expressed. Transmission of an X-linked-recessive trait
in a pedigree is illustrated in Figure 5-3.
The X-linked diseases were some of the first well-
documented genetic disorders in humans because of their
unique inheritance patterns. Hemophilia A is one the most
well known X-linked human diseases resulting from defi-
ciency in a blood-clotting factor, factor VIII, encoded by
its gene located on the X chromosome. While comprising
only approximately 2% of cases, X-linked transmission of
alleles involved in inherited hearing loss is significant.
Examples of such disorders include Norrie’s syndrome,
X-linked congenital sensorineural hearing loss, and X-linked
high-frequency sensorineural hearing loss. In pedigrees
exhibiting X-linked-recessive traits, many more males are
affected than females because males have only one X chro-
mosome. Thus, a recessive allele for hearing loss is not
masked in males. Females have two X chromosomes, allow-
ing the masking of a recessive allele on one X chromosome
by a normal allele of the gene on their other X chromo-
some. Females who express a true X-linked-recessive trait
have inherited a mutant form of the gene from both
parents. Approximately half of the sons are affected and
half are unaffected when a female carrier of an X-linked-
recessive gene has children with a normal male. No affected
offspring will result from the mating of a male affected by
an X-linked-recessive disorder with a homozygous normal
female; however, all of his daughters will be carriers. The
absence of father-to-son transmission is a unique charac-
teristic of all X-linked traits because males always receive
their X chromosome from their mother.
DFN3 represents one of the most frequent forms of
X-linked deafness. Affected males have conductive hearing
loss (as a result of stapes fixation) and progressive sen-
sorineural deafness. The DFN3 gene has been cloned and
is referred to as POU3F4, a member of a multigene family
that encodes nuclear transcription factors.9 POU3F4
represents the first cloned gene whose mutant allele was
identified in individuals with nonsyndromic deafness.
Variations on Mendelian Principles
Mendel established the two fundamental principles of
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
refers to separation of homologous genes, representing the
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
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.
These variations and their underlying principles have
increased our understanding of genetic etiology of disease.
Linkage and Recombination
Not all genes assort independently of each other. Thomas
Hunt Morgan initially identified this variation on the
Mendelian principle in fruit flies through analysis of trans-
mission of selected traits. Experiments showed inheritance
of a specific pair of alleles in a combination not present in
the parental phenotype. This new combination of alleles
was considered to result from crossover and exchange of
genetic material between two homologous chromosomes,
known as homologous recombination, yielding the new com-
bination of alleles not present in the original parental
chromosomes. Analysis of recombination frequencies
between two traits considered to be controlled by genes
residing on the same linkage group (i.e., the same chro-
mosome) provided two essential concepts that led to the
development of the genetic map: Genes are arranged in a
linear order and the frequency with which two alleles are
inherited together is a function of the relative physical
distance from each other. Thus, the closer the two genes,
the greater the chance that they will remain linked post
meiosis. The relative chromosomal positions of genes may
be readily mapped through the application of these princi-
ples of linkage and recombination to generate genetic
maps. The genetic distance between two linked genes as
measured through frequency of recombinants between the
two alleles is measured in centimorgans (cM). These two
loci are one cM apart on the genetic map if there is a 1%
chance of a recombination between them in meiosis. Thus,
genes that are far apart on a chromosome will assort in an
apparent independent manner and genes that are close will
tend to remain linked post meiosis. Applying the principles
of genetic linkage, Morgan and his colleagues were able to
order more than several hundred genes in D. melanogaster
via recombination analysis by the year 1922.
Mitochondrial Inheritance
Not all genes are inherited equally from both parents. The
extranuclear genome is inherited solely through the
mother. Male mitochondria are not contributed to newly
formed zygotes. This inheritance pattern, illustrated in
Figure 5-4, gives rise to pedigrees in which all the children
of an affected mother may be affected and none of the
children of an affected father will be affected. In practice,
the expression of mitochondrially inherited disorders is
often variable and may be incompletely penetrant. This
1 2 3 4
I
II 1 2 3 4
III 1 2 3 4
Figure 5-4. A pedigree pattern illustrating mitochondrial inheritance of the
disease trait (shaded). The disease trait is transmitted maternally, through its
mitochondrial genome, to both male and female offsprings.
observation is possibly due in part to the fact that a popu-
lation of mitochondria, which can itself be genetically
heterogeneous, is actually transmitted by the mother. If all
of the mitochondria transmitted by the mother are of the
same genotype, it is called homoplasmia; if there are genetic
differences between them, it is call heteroplasmia.
Despite its small size relative to the nuclear genome,
1:200,000, mutations of the mitochondrial genome are a
significant contributor to human disease. This is in part
due to the 10-fold higher mutation rate that is associated
with the replication of mitochondrial genome relative to
the nuclear genome and that it consists of proportionately
far less noncoding sequence. To date there are 326 syn-
dromes, disorders, and peculiar phenotypes associated with
mutations in the mitochondrial genome.10 Twenty-one of
these disorders have some involvement with sensorineural
hearing loss, which indicates that the requirement for a
healthy population of mitochondria is very important to
the cells involved in normal hearing.11–14 One of the most
striking examples of a mitochondrially inherited trait whose
expression is environmentally affected is the hearing loss
caused by hypersensitivity to aminoglycosides.12 Hyper-
sensitivity to aminoglycosides phenotype is the result of a
single base transition of A to G at position 1555 in the
mitochondrial 12S rRNA. This mutation causes a portion of
the 12S rRNA transcript structure to closely resemble the
binding site of aminoglycosides to bacterial rRNA. When
an aminoglycoside such as streptomycin is administered to
patients who carry this mutation, it binds to the mutant
12S rRNA and prevents it from functioning in the transla-
tion of mitochondrially transcribed genes. This results in
the loss of mitochondria that may lead to cell death or loss
of their normal function. Screening for this mutation
before initiation of aminoglycoside therapy may reduce
the incidence of ototoxicity.
X Chromosome Inactivation
The chromosome can be identified in nondividing cells of
females (within the interphase nuclei) as a darkly staining
mass called the Barr body attached to nuclear membrane.
The Barr body represents the X chromosome that has
been inactivated and thus appears as a condensed mass
(heterochromatization). This X-chromosome inactiva-
tion in females is also known as lyonization, named after

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
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-
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-
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
Some genetic disease occur more often if inherited from
the fathers than from mothers or vice versa. This occurrence
is considered to result from “genomic imprinting.”15 This
phenomenon runs counter to the teachings of Mendelian
genetics, which emphasize equal contribution from paternal
and maternal genes, with the obvious exception of genes
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
when inheritance of that disorder depends on the sex of
the parent that transmits the mutant gene.
The gene-specific imprinting, as with the X-chromosome
inactivation, is presumed to be the consequence of reversible
“epigenetic” modification of the parental allele during game-
togenesis, leading to its differential expression. The precise
mechanism of imprinting and its evolutionary significance
remain unknown. Imprinting is considered to be established
prior to or during gametogenesis and is known to persist sta-
bly throughout somatic cell divisions. Hypermethylation of
the imprinted gene represents one possible mechanism. This
process involves the covalent addition of a methyl group to
the C5 position of the cytosine ring. The role of methylation
for mediating the imprinting process is supported by the
observations that all of the imprinted sequences that have
been analyzed are methylated. It is possible that methylation
of the imprinted gene is secondary to a prior imprinting step
and its role may be stabilizer of the imprinted signal.
The gene-encoding IGF-II, a potent growth factor and
a mitogen, was the first identified example of an autosomal-
imprinted gene.16,17 The expression of IGF-II was shown
to be restricted to its paternal allele, the maternally derived
allele was transcriptionally silent. Several other imprinted
loci or genes have been identified in humans based on
inheritance patterns of familial disorders that are consistent
with imprinting phenomenon. These include the Prader-
Willi syndrome, where the affected gene is maternally
imprinted, and the Angelman syndrome, where the affected
gene is paternally imprinted. A pedigree transmitting
a maternally imprinted disease gene is illustrated in
Figure 5-5. An example of genomic imprinting at the
level of a specific gene has also been identified in familial
cases of nonchromaffin paragangliomas, benign tumors of
the paraganglionic cells. Although benign, their enlarge-
ment can cause deafness and facial palsy. Familial cases of
Molecular Genetics in Neurotology 127
2
I 2 3 4 5 6 7 8 9
II 2 3 4 5 6 7 8
III 1 2
Figure 5-5. A pedigree pattern illustrating transmission of autosomal-
dominant trait (shaded) that is genomically imprinted. A pedigree
demonstrating a maternally imprinted autosomal-dominant transmission of a
disease allele. Individuals are affected only if they receive the mutant allele
through paternal and not maternal transmission. Furthermore, the affected
carrier male who has received the mutant allele through maternal inheritance
can then transmit the allele.
paragangliomas (glomus tumors) have shown an autosomal-
dominant inheritance with genomic imprinting of the
maternal allele. Thus, the transmission of the disease occurs
via the affected paternal allele and not the maternal allele.18,19
The genetic basis of the head and neck paragangliomas
and the observed parent-specific transmission pattern are
discussed in greater detail in a later section.
Trinucleotide Repeat Expansion
Another type of deviation from Mendelian genetics has
been identified through analysis in six neurologic disorders
that are characterized by increased severity or an earlier
onset of the disease in successive generations. This phe-
nomenon, unique to these disorders, is termed anticipation.
These include the fragile X syndrome (FRAXA), spinal
and bulbar muscular atrophy (SBMA), Huntington’s disease
(HD), and muscular dystrophy (MD). Analysis of mutation
in the affected individuals has revealed a pathologic expan-
sion of a region of DNA, known as trinucleotide repeats,
beyond the normal range observed in the unaffected,
within genes linked to disorders characterized by anticipa-
tion. A progressive increase in the size of these trinu-
cleotide repeats is correlated with the increased severity
and/or age of onset of the disease. The mechanism of
pathophysiology caused by this dominantly inherited
pathologic mutation remains relatively unknown.
In patients affected by fragile X syndrome, the syndrome
can be transmitted not only by heterozygous female carriers
but also by unaffected (hemizygous) males. The “carrier
males” possess expanded repeat numbers of 60 to 230, rela-
tive to normal controls who express an average repeat
number of 29. The unaffected paternal carriers of X-linked
disorders or the phenomenon of anticipation associated
with trinucleotide repeat expansion could not have been
predicted from principles of Mendelian genetics.
128 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Multifactorial Inheritance
An expression of a phenotype whose outcome is determined
by a single gene is termed a Mendelian trait. Its pattern of
transmission within a pedigree can be readily discerned in
most cases, as described in previous sections. On the other
hand, most common human diseases and traits show irreg-
ular inheritance patterns. These traits are considered to be
determined from action of multiple genes and nongenetic
factors. A phenotype that is an outcome of both genetic
and environmental factors is called a multifactorial, or com-
plex, trait. The low proportion of Mendelian traits relative
to number of multifactorial traits in humans is better illus-
trated by considering the proportion of total number of
Mendelian traits known, approximately 6,000 according to
McKusiak,20 to the total number of genes that are estimated
to exist, approximately 30,000. It should be emphasized
that classification of Mendelian traits as being determined
by single genes is an oversimplification. As more Mendelian
disorders are identified and their phenotypes investigated,
the phenotypic variability and complexity of each Mendelian
trait is becoming increasingly clear and concomitantly its
distinction from complex or multifactorial trait is becoming
increasingly blurred. Phenotype variability or variable expres-
sion seen in a single gene disorder such as Waardenburg’s
syndrome may reflect interaction of that major gene, such
as PAX3, with “modifier” genes. Identification of these
modifier genes has important implications for understanding
and treatment of the Mendelian disorders with variable
expressivity.
One of the clearest examples of interaction of other genes
and their products (termed epistatic effects) or nongenetic
factors during development of a particular Mendelian
phenotype is provided by the large variation of the clinical
phenotype observed in individuals with an identical muta-
tion in a given gene. A classical example of a single mutant
allele yielding a varying phenotype is the hemoglobin βS
mutation that results in substitution of valine or glutamine
at position six of the β-globin chain. In the homozygous
state, this mutation usually causes sickle cell anemia of
varying clinical severity. The identity of the modifying
genetic factors that interact to yield the variable clinical
severity in sickle cell anemia remain as yet undetermined.
Such phenotypic heterogeneity despite the identity of
mutation has been described in number of disorders
including Waardenburg’s syndrome (WS), cystic fibrosis,
phenylketonuria (PKU), Duchenne’s muscular dystrophy
(DMD), retinitis pigmentosa (RP), and Marfan syndrome,
as well as XY gonadal dysgenesis ( XYGD). Thus, muta-
tion analysis alone is insufficient in predicting the clinical
phenotype of the affected individual. Conversely, the pheno-
typic outcomes do not depend on the nature of mutations
only. As seen in the examples cited, the primary structural
change in the DNA sequence can result in spectrum of
consequences depending on the individual’s genotype or
genetic background. This can range from complete blocking
of the pathway to complete compensation of the defect,
depending on interactions with other genes and their
products and their relative influence for the specific
process or the role that is mediated by the mutant gene.
The relatively irregular mode of inheritance that char-
acterizes a multifactorial trait is presumed to result from
interaction of multiple genes (polygenic).21 This interaction
is apparently distinct from that presumed for Mendelian
traits. But this distinction may be at a quantitative rather
than qualitative level. For example, instead of a predominant
influence or effect of one gene upon expression of the
phenotype, the multifactorial trait is characterized by a
number of genes with equivalent influence or effect. The
genetic component of multifactorial traits is referred to by
terms such as increased risk, predisposition, and susceptibility.
Because of their complexity, the factors that contribute to
the multifactorial traits are poorly defined. Several well-
studied diseases that are classified as multifactorial include
cardiovascular conditions, diabetes, and distinct behavioral
disorders. Influence of nongenetic factors, such as environ-
mental agents and stochastic processes during developmen-
tal outcome of variety of traits, is also clearly illustrated in
the studies of identical twins.
GENETICS AND GENETIC EPIDEMIOLOGY
OF NONSYNDROMIC HEREDITARY
HEARING LOSS
Hearing loss is the most common form of sensory loss in
humans. Nearly 10% of the U.S. population, or 30 million
Americans, have significant auditory dysfunction. For some,
the hearing loss is present at the beginning of life. The
prevalence of permanent, moderate to severe sensorineural
hearing loss (SNHL) is estimated to be between 1 and 3 per
1000 live births.1 Historically, infectious disorders such
as otitis media, maternal rubella infections, and bac-
terial meningitis, as well as environmental factors such as
intrauterine teratogenic exposure and ototoxic insult were
the dominant causes of congenital and acquired hearing
losses. The introduction of antibiotics and vaccines and
the increasing awareness of teratogens has led to a decline
in hearing loss resulting from infectious and environmental
agents. Currently, more than half of childhood hearing
loss is thought to be hereditary.22
Genetic analysis of hereditary hearing loss has benefited
significantly from the development of critical resources
and techniques. The development of a high-resolution
map of the human genome characterized by closely spaced
genetic markers (1 centimorgan or 1 megabase separation)
and the application of the polymerase chain amplification
(PCR) technique for rapid characterization of these
genetic markers (genotyping) has enabled the localization
and identification of genes responsible for variety of inher-
ited disorders in humans. This genetic approach has also
been applied toward determining the genetic basis of
syndromic and nonsyndromic hereditary hearing loss. In
syndromic hearing loss, more than 100 genes have been
identified since 1990, showing a large heterogeneity even
within a single type of syndromic hearing loss [e.g., Usher
syndrome type Ia-f with 6 different genetic loci (Table 5-1)].
In nonsyndromic hearing loss, as of January 2004, 51 auto-
somal-dominant, 39 autosomal-recessive, 8 X-linked,
1 modifier, and 2 mitochondrial loci have been mapped on
the human genome. From these 101 mapped loci, 37 genes
have been identified (Table 5-2).23
The 37 “deafness genes” that have been identified
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
products include the following: cytoskeletal proteins
important in maintaining cellular structure, division, and
intracellular transport; transcription factors that regulate
the expression of other genes; ion channels important
in transport of sodium, potassium, chloride, and iodine;
developmental genes that regulate morphogenesis; and
proteins involved in intercellular communications such as
gap junctions and tight junctions.
Genetic analysis of hearing loss has profoundly altered
conventional notions of the relationships between genes,
mutations, and the corresponding disease phenotype.
Numerous examples illustrate that distinct mutations within
a single gene have a differing effect upon the encoded
protein, thus affecting the mode of inheritance and/or the
clinical phenotype associated with the disease gene. Thus,
mutation of the gene-encoding myosin VIIA can cause either
dominant or recessive forms of nonsyndromic deafness.24,25
This phenomenon has also been documented for connexin
26: Different mutations of CX26 are associated with dom-
inant and recessive mode of transmission.8,26 The dominant
or recessive mode of inheritance for a specific mutation is
considered to reflect the disruptive effect of the mutant
protein upon functional integrity of the multimeric assem-
blies formed by the individual subunits. Syndromic and
nonsyndromic deafness associated with mutations of
132 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
TABLE 5-3. Gene Transfer Vectors
Insert
Vector Genome Size Site Efficiency
AAV ssDNA 4.5 kB Genome Variable
Retrovirus RNA 6–7 kB Genome Low
Adenovirus dsDNA 7.5 kB Episome Moderate
Herpesvirus dsDNA 10–100 kB Episome Moderate
Plasmid RNA/DNA Unlimited Episome Very low
Liposome RNA/DNA Unlimited Episome Very low
myosin VIIA, an intracellular motor protein, represents an
excellent example of differing clinical phenotypes due to
mutations in a single gene. Similarly, mutant alleles of
pendrin, encoding a solute transporter, can cause either
Pendred’s syndrome or isolated (nonsyndromic) large
vestibular aqueduct.
The patient’s genetic background is a critical factor in
determining the clinical phenotype that results from a
specific mutation. The genetic background represents other
genes that interact with the mutated gene via its protein
products. These genes are known as modifier genes and
their interactions can determine the clinical severity of the
disease trait predicated by the mutant allele. For example,
affected individuals within a family carrying an identical
mutation in PAX3 gene, associated with Waardenburg’s
syndrome type I, can display a clinical phenotype of varying
severity, corroborating the important contribution of
differing genotypes in determining the phenotype.27
Several of the genes whose mutant alleles have been
causally linked to nonsyndromic deafness are especially
important in clinical otology on the basis of their prevalence
or their associated histopathology. These include gene-
encoding connexins, PDS, and the myosins. Each of these
is discussed here.
Connexin 26
Connexin 26 is a member of a family of proteins that are
involved in the formation of gap junctions. Connexins are
transmembrane proteins that form channels to allow
transport of ions or small molecules between adjacent
cells. Each connexin subunit contains three intracellular
domains and two extracellular domains, crossing the
plasma membrane four times. The second intracellular
domain (IC2) contains the cytoplasmic loop. The other
two intracellular domains consist of the N terminus and
C terminus. Six connexin subunits join to form a connexon.
A pair of connexons, one in each adjacent cell, comes
together to form an intercellular channel.
The connexin gene family plays an important role in
normal hearing; mutations in several members of the family
are associated with hearing loss. To date, mutations in five
members of the connexin gene family—CX26, CX30,
CX31, CX32, and CX4—have been implicated in hearing
loss.28 Among them, mutations of CX26 are the most com-
mon and represent a major cause of inherited and sporadic
nonsyndromic deafness.29–31 Specifically, CX26 mutations
Cell
Division Expression Advantages Disadvantages
Not required Permanent No human Difficult to
disease produce
Required Permanent Suited for Insertional
neoplastic cells mutagenesis
Not required Transient Ease of Inflammatory
production response
Not required Transient Neural tropism Human disease
Not required Transient Safe, easy Low
production transfection
Not required Transient Safe, easy Low
production transfection
are responsible for both recessive (DFNB1) and dominant
(DFNA3) forms of HHL.8,26 Several studies have demon-
strated prevalence of CX26 mutations in 50% of individuals
with recessive deafness with a carrier rate as high as
4%.32,33 Given the large genetic heterogeneity of HHL,
evidenced by the 93 distinct loci that have been mapped,
the predominance of a single gene’s being responsible for
the majority of the hearing loss in the general population
is a surprising outcome with significant implications for
screening and clinical management.
Studies investigating physiologic role of CX26 in the
cochlea suggest that it serves as the structural basis for
recycling of potassium ions back to the endolymph of the
cochlear duct after stimulation of the sensory hair cells.34
Dysfunction of CX26 is believed to affect homeostasis of
potassium ions in the cochlear duct, thus affecting
mechanotransduction and resulting in hearing loss.
Currently, more than 60 mutations have been identified.28
Two single base pair deletions account for nearly half of all
mutations in this gene: 35delG and 167delT.32,33 The
35delG mutation has been found to be common in several
populations, accounting for up to 70% of CX26 mutant
alleles in families from the United Kingdom, France,
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.
The 35delG mutation leads to frameshift and early termina-
tion of the nascent protein and a nonfunctional intracellular
domain in the protein. Alternatively, this mutation may
lead to an unstable RNA, leading to its early degradation
or absence of its translation into protein. Clinically, homo-
zygous patients with the 35delG mutation show a variable
phenotype, ranging from mild to profound hearing loss.
However, most patients with homozygous 35delG muta-
tion show a severe to profound phenotype. The differences
in the worldwide populations are also reflected in the vary-
ing prevalence of the common CX26 mutant alleles. Thus,
although common in most populations, the 35delG muta-
tion is much less frequent in the Japanese populations in
which 235delC is the prevalent CX26 mutation.35,36
Likewise, in the Ashkenazi Jewish population, the 167delT
mutation has been found to be more common than the
35delG mutation with a carrier rate of 4%.33
The high frequency of mutant CX26 alleles associated
with recessive forms of hearing loss, presence of a single
coding exon of a relatively small size, and predominance of
two mutations collectively represent attributes of an ideal

gene for mutation screening. Correspondingly, screening
for the two common CX26 mutations is now available at
numerous medical centers and laboratories; however, its
role in the diagnosis and management hearing loss in
children needs to be determined. We have recently screened
154 individuals with SNHL for mutations in CX26 by
DNA sequencing and identified 34 patients with mutations
for an overall incidence of 22% in the study population.37
Of all CX26 mutations, the 35delG mutation accounted for
26%. The 35delG mutation was present in a homozygous
state in only 4 individuals (each of the two chromosomes
harbored the 35delG mutation) and heterozygous in 6
individuals (only one chromosome had the 35delG muta-
tion). Herein lies the fundamental problem with screening
for only 35delG: only 4 of 34 individuals (12%) with CX26
mutations, or 154 individuals in total (3%), had homozygous
mutation that would be required to clearly implicate CX26
as the causative gene. The identification of a single copy of
35delG mutation does not implicate this gene in deafness
and may simply reflect the high carrier rate in the popula-
tion. In this case, the rate of identifying the cause of child-
hood SNHL by genetic testing is significantly less than
that of radiologic imaging. Therefore, genetic testing for
35delG and 167delT mutation only, without sequencing
the entire CX26 gene, is inadequate.
Pendrin
Mutations of the SLC26A4 ( PDS) gene are the pathogenic
cause of isolated large vestibular aqueduct, the most
common radiologic abnormality associated with childhood
deafness, as well as Pendred’s syndrome. The SLC26A4
( PDS) gene on chromosome 7q31 consists of 21 exons and
encodes an 86 kDa polypeptide known as pendrin that is
expressed in the kidney, thyroid gland, and cochlea.38
Comparative sequence analysis indicated that this gene is a
member of a gene family that is involved in sulfate transport.
However, functional studies have shown this transmembrane
protein to be an energy- and sodium-independent trans-
porter of iodide and chloride ions, primarily.39 In the mouse
inner ear, pendrin localizes to the endolymphatic duct and
sac, distinct areas in the utricle and saccule, and the external
sulcus region within the cochlea, implicating a possible
role in endolymph resorption and/or homeostasis. How-
ever, the specific substrate and the biological role of
Pendrin in the inner ear remain undetermined.
It has been estimated that mutations of SLC26A4 may be
responsible for as much as 10% of HHL and thus represents
the most common cause of syndromic HHL.40,41 Two fre-
quent missense mutations of SLC26A4, L236P (707 T to C),
and T416P (1246 A to C) were initially identified40; subse-
quently, a third common mutation, E384G (1151 A to G)
has also been identified. Although the gene is too large for
screening by direct sequencing, identification of common
mutations opens the opportunity for screening for these iso-
lated mutations. Goiter that is associated with Pendred’s
syndrome results from the reduced ability of the thyroid
gland to organify iodine into the thyroid hormone.42
However, goiter is not considered to be a specific marker
of the Pendred syndrome due to its variable expression and
phenocopies. The hearing loss is usually congenital and
profound. However, there are reports of a milder or pro-
gressive hearing loss. Investigation of the role of pendrin in
Molecular Genetics in Neurotology 133
hearing and its dysfunction has led to the generation of
knockout mice carrying null allele of SLC26A4.43 These
knockout mice (Slc26a4–/Slc26a4–) have both auditory and
vestibular dysfunction. However, goiter or other abnormal-
ities of thyroid function are absent.
SLC26A4 mutations are also responsible for nonsyn-
dromic hearing loss associated with the large vestibular
aqueduct. Isolated presence of a large vestibular aqueduct
(LVA) is one of the most common forms of inner ear anom-
alies. Genetic studies of families with LVA disorder identi-
fied a recessive nonsyndromic locus, DFNB4 that also
mapped to the same region as the PDS gene. This led to the
evaluation of PDS gene and the subsequent identification of
seven PDS mutations responsible for LVA with nonsyn-
dromic HHL.44 Like Pendred’s syndrome, different muta-
tions, V480D, V653A, I490L, and G497S, have been found
to be commonly associated with LVA. In review of our expe-
rience at the University of California–San Francisco, LVA
was the most common imaging abnormality detected in
children with nonsyndromic SNHL.45 At least 40% of chil-
dren with LVA will develop profound SNHL. Patients with
LVA are at risk for progressive hearing loss after minor head
trauma. Identifying this anomaly influences parent counsel-
ing with respect to the dangers of incidental head trauma.
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
development and in the normal functioning of the inner
ear and thyroid. Screening for mutations may play an
important role in the diagnosis and management of a child
as well as siblings with hearing loss.
Myosins
The importance of myosins in inner ear function is widely
recognized by the growing list of unconventional (non-
class II) myosin-heavy-chain genes pathogenically linked
to HHL. These disease genes encode the heavy chains of
myosin IA, IIIA, VI, VIIA, and XV. Myosin VIIA was the
first of the unconventional myosins that was causally linked
to hereditary hearing loss in both rodents and humans.
Mutations in the gene-encoding myosin VIIA are respon-
sible for mouse shaker 1, human Usher syndrome type 1,
human nonsyndromic hearing loss DFNB2 and DFNA11.
Shaker 1 mice are deaf and have vestibular defects. Mice
that are homozygous for mutant shaker 1 allele display
progressively disorganized stereocilia. Myosin XV is the
largest of all myosin-heavy chains, having a molecular weight
of 395 kDa. Mutations in myosin XV have been pathogen-
ically linked to DFNB3 in humans and the shaker 2 phe-
notype in mice. Myosin VI was initially identified as the
deafness gene in a mouse model of inherited hearing loss;
the cochlear and vestibular neurosensory epithelium in
this mouse model, known as Snell’s waltzer, degenerates
soon after birth. A mutant allele of myosin VI is consid-
ered to be responsible for the DFNA22, the human non-
syndromic, form of hereditary hearing loss. Mutant alleles
of myosin IA and IIIA have also been recently identified as
responsible for DFNA48 and DFNB30, respectively.
Expression of these unconventional myosins is not limited
to the cells and tissues of the inner ear. Yet, the expression
of their dysfunction is largely restricted to hearing loss.
The unconventional myosins are distributed throughout
134 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
the mechanosensory hair cells. Moreover, histopathology
of mouse models of myosin XV dysfunction has been
valuable for understanding the consequences of myosin
dysfunction upon the sensory hair cells. Myosin VI is local-
ized in the actin-rich cuticular plate and in the rootlet actin
filaments that descend from stereocilia into the cuticular
plate, suggesting a role in stabilizing the basal attachment of
stereocilia.46,47 Myosin VIIA is localized in the stereocilia and
cell body of hair cells.47 Postulated roles for myosin VIIA
include maintaining stereocilia integrity and membrane traf-
ficking in the inner hair cells. Histopathology of the inner
ears of mouse models of myosin XV dysfunction revealed
significantly shortened stereocilia in the sensory hair cells,
demonstrating the importance of myosin XV in the mainte-
nance of hair cell structure and thereby its function.
A mutation in a conventional or class II myosin, MYH9,
resulting in nonsyndromic has also been described. The
class II myosins, broadly expressed in skeletal, cardiac, and
smooth muscles as well as nonmuscle tissues, consist of a
pair of heavy chains, a pair of light chains, and a pair of
regulatory light chains.48 The N-terminal motor domain is
the most highly conserved region of the myosin heavy
chain and contains the ATP and actin binding sites. The
apparent molecular weight of the class II myosin heavy
chain is 200 kDa. The myosin that mediates skeletal muscle
contraction, also known as the sarcomeric myosin, repre-
sents the most well characterized representative of class II
myosin family. Cardiac and smooth muscle cells also
express isoforms of class II myosin, distinct from the sar-
comeric myosin that mediate contraction in these muscle
cells. Mutation in MYH9, a conventional nonmuscle myosin,
was described in an American family with autosomal-
dominant nonsyndromic hereditary hearing loss (DFNA17)
associated with cochleosaccular degeneration.49,50 The
affected members of the DFNA17 family exhibit progressive,
postlingual onset of hearing loss, a pattern that is observed
in the majority of nonsyndromic autosomal-dominant
HHL. The cosegregation of the mutant MYH9 with non-
syndromic hearing loss illustrates a biologically significant
role for MYH9 in hearing and an organ-specific pathology
associated with the mutant allele.
Two other myosin genes have been predicted to have an
important role in hearing. Myosin V is an abundant protein
of afferent nerve fibers that innervate both inner and outer
hair cells.51 Myosin Iß has been implicated as an effector of
adaptation of the hair cell transduction apparatus.52 The
diverse classes and subtypes of myosins whose dysfunction
can result in hearing loss is not surprising given the varying
forms of actin filament systems in the inner ear.53
MOLECULAR GENETICS
OF VESTIBULAR SCHWANNOMAS
AND GLOMUS TUMORS
Neurofibromatosis Type 1
Neurofibromatosis 1 (NF1), also known as von Reckling-
hausen’s disease, is one of the most common Mendelian
diseases that affects the nervous system. NF1 is characterized
by autosomal-dominant inheritance with complete penetrance
but extremely variable expression. The most common tumor
seen in NF1 is the neurofibroma and the second most com-
mon tumor is the optic pathway glioma. The diverse pheno-
type associated with NF1 is the consequence of mutations
within a single gene located on chromosome 17q11.2, which
was identified in 1990 through positional cloning and desig-
nated NF1.54–56 The gene spans 350 kilobases of genomic
DNA, contains 60 exons, and encodes a large cytoplasmic
protein product known as neurofibromin, a member of a
family of proteins known for their GTPase activation.56
Mutations of NF1 have been identified throughout the
gene. Most studies have not found an obvious relationship
between particular NF1 mutations and resulting clinical
manifestations in a patient. However, attempts at genotype-
phenotype correlation in NF1 are confounded by the
effect of age, which increases the frequency of disease
manifestations and the likelihood of serious complications
in all patients. In addition, there is no consensus regarding
how to define NF1 severity. While some mutations recur
in different families, no true “hotspots” have been found in
NF1. The most frequently recurring alteration is a nonsense
mutation in exon 31 (R1947X), which accounts for 1% to
2% of NF1 mutations identified. The wide variability of
the NF1 phenotype, even in individuals with the same NF1
gene mutation, suggests a contribution of other protein
products in determining the clinical manifestations.
Screening of individuals with a hereditary form of NF1
has linked them to the single NF1 locus at 17q11.2. This
finding negates genetic heterogeneity of NF1 or mutations
at more than one locus/gene responsible for the tumor
phenotype. Due to absence of locus or genetic heterogeneity
of NF1, frequency of mutant NF1 genes can directly be
inferred from the incidence of the disease at birth, esti-
mated to be 1 in 2500. Thus, the mutant gene frequency is
approximately 1 in 5000, or half of the estimated prevalence
of NF1 at birth. It is estimated that about half of all NF1
patients represent new mutations since a positive family
history is confirmed in half of all NF1 cases and penetrance
is presumed to be complete. Thus, the rate of new NF1
mutations is estimated to be as high as 1 per 10,000 gametes,
representing one of the highest single-locus mutation rates
known in humans. Interestingly, more than 80% of new
mutations are considered to be of paternal origin. However,
the predominance of paternal mutations in NF1 has not
yielded a significant correlation between risk of sporadic
NF1 and paternal age.
The loss-of-function results suggest that neurofibromin
acts as a tumor suppressor. The proposed tumor suppressor
function is supported by the findings of somatic “second hit”
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
neuronal cell types as well as in the gonadal tissue and the
white blood cells, histopathologic and molecular analysis of
the NF1-associated tumors has shown that the neoplastic
cell of origin in the neurofibromas is the Schwann cell.57,58
The molecular factors that contribute to the loss of regu-
latory control in the Schwann cell with the mutant NF1
allele remain to be determined. The physiologic role of neu-
rofibromin has been investigated though analysis of mouse
models deficient in NF1 and drosophila NF1 mutants. These
studies indicate that defects in neurofibromin function affect
diverse signaling pathways in different cell types.59

Neurofibromatosis Type 2
Neurofibromatosis 2 (NF2) is characterized by autosomal-
dominant inheritance that predisposes the carriers to nerv-
ous system tumors in their second and third decades of life.
The hallmark central nervous system tumor in NF2 is the
schwannoma, which affects the eighth cranial nerve and
results in bilateral vestibular schwannoma (VS), also referred
to as acoustic neuroma. Continued growth of the vestibular
schwannomas leads to deafness and balance problems. In
addition to the eighth cranial nerve, schwannomas can occur
on other cranial or peripheral nerves throughout the body.
Ninety percent of patients with NF2 also have ocular abnor-
malities, causing blurred or loss of vision. Patients with NF2
who have bilateral vestibular schwannomas represent 2% to
4% of all occurrences of vestibular schwannomas, which in
turn represent approximately 8% of intracranial tumors.
The majority of vestibular schwannomas are sporadic and
unilateral, presenting in the fifth decade.
The incidence of NF2 is estimated to be between
1:33,000 and 1:50,000,60 or approximately 10-fold less
than the frequency of NF1. In approximately 50% of cases,
there is no family history and these patients are considered
to carry new germline mutations.61 The genetic differentia-
tion of NF1 and NF2 as distinct disease entities did not
occur until 1987. Molecular genetic analysis of these disor-
ders localized the disease gene for NF1 near the proximal
long arm of chromosome 17. At the same time, the gene
responsible for NF2 was localized to chromosome 22.62 In
1993, the NF2 gene, designated merlin or schwannomin,
was isolated by two groups working independently.63,64
The NF2 gene is spread over approximately 100 kB on
chromosome 22q12.2 and contains 17 exons. The coding
sequence of the messenger RNA is 1785 base pairs in
length and encodes a protein of 595 amino acids. Compara-
tive sequence analysis has led to classification of merlin as
a member of the protein 4.1 subfamily, which includes
ezrin, radixin, and moesin (ERM proteins). These proteins
are involved in linking cytoskeletal components with the
plasma membrane and are located in actin-rich surface
projections such as microvilli. Like other ERM proteins,
merlin binds to actin and is associated with actin cytoskele-
ton. However, a distinct role of merlin relative to the ERM
proteins is emphasized by its unique subcellular distribution
in the peripheral nerve Schwann cells.
The NF2 gene has been hypothesized to function as a
growth regulator or a tumor suppressor. Support for this
role is derived from studies demonstrating germline muta-
tions in the NF2 gene in patients with NF2 and biallelic
inactivation of NF2 in NF2-associated tumors, including
schwannomas, ependymomas, and meningiomas. Support
for the tumor-suppressing role of NF2 is derived from in
vitro studies that include the demonstration of growth
suppression as a consequence of NF2 gene expression in
merlin-deficient meningiomas and schwannoma cells.
Expression of NF2 mutant allele encoding dysfunctional
merlin had no effect on growth in these cell lines. The
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
predominantly within the Schwann cells. Dissection of the
potential mechanism of action of Merlin is also being
Molecular Genetics in Neurotology 135
addressed through development of transgenic mouse
models. Mice homozygous for the NF2 null allele die during
early embryonic development as a consequence of their
inability to induce mesoderm formation.65 Mice that are
heterozygous for the NF2 null allele are viable but develop
malignant sarcomas, tumors that are not seen in humans
affected with NF2. To be able to assess the biologic effect
of the loss of merlin within the glial cells, a conditional
knock-out was generated where merlin expression was
specifically interrupted in the Schwann cells. These condi-
tional knock-outs developed schwannomas that histologi-
cally resemble human schwannomas.66 Thus, the conditional
knock-outs support the hypothesis that the loss of merlin is
sufficient for the onset of schwannomas.
To date more than 200 mutations of the NF2 gene have
been identified, including single-base substitutions, inser-
tions, and deletions. Most mutations lead to truncation of
the C-terminal end of the protein as only 13 missense
mutations have been identified. Ruttledge and colleagues67
have found that mutations in the NF2 gene that result in
protein truncation are associated with a more severe clinical
presentation of NF2 and missense and splice-site muta-
tions are associated with a milder form of the disease.64
Similarly, Parry and colleagues68 have reported that retinal
abnormalities were associated with the more disruptive
protein truncation mutations of the NF2 gene.68 Both
studies showed intrafamilial variability of phenotypic
expression. The more severe phenotype in patients with
mutations that result in protein truncation may be due
to the dominant negative effect of the mutant protein,
negating the biologic function of the protein product of
the wild-type allele.
Mutations involving the NF2 gene have also been
observed in 22% to 59% of patients with sporadic vestibular
schwannomas. Included in this group are individuals with
de novo germline mutations as well as those with somatic
mutations that are detected in the DNA of their tumor
tissue. The large fraction of the sporadic cases of NF2 who
are negative for NF2 mutation suggests a non-NF2 etiology.
However, no evidence exists that substantiates or contests
genetic homogeneity of NF2. To date, only mutation in
the NF2 gene has been identified as the causal event in
schwannoma formation. Defects of the NF2 gene have also
been detected in other malignancies including meningiomas,
malignant mesotheliomas, melanoma, and breast carci-
noma. These findings suggest that the NF2 gene may also
be the critical tumor suppressor in these sporadic tumors.
The precise mechanism by which merlin regulates cellular
proliferation within the cell types that are tumor-prone
(i.e., Schwann cells) remains to be determined.
The identification of the gene responsible for NF2 has
significantly advanced our understanding of the molecular
pathology as well as factors responsible for the clinical het-
erogeneity among patients with NF2. Understanding of
the function of merlin may lead to the development of
novel therapies that may eventually alleviate the suffering
associated with NF2.
Familial Paragangliomas
Paragangliomas (PGLs) are rare tumors of the paraganglia,
an assembly of neuroendocrine tissues and small organs
136 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
distributed throughout the body. The tumors are identified
within two major sites, the carotid body of the head and
neck and the adrenal medulla. The carotid body is the
largest of all paraganglia and is considered to function as
an oxygen sensor. Genetic analysis of hereditary paragan-
glioma has served to disclose its molecular etiology and
provided an insight into its underlying pathophysiology.
Currently, three genes have been identified whose mutant
alleles have been pathogenically linked to hereditary para-
ganglioma. All of these genes encode distinct subunits of a
hetero-oligomeric protein known as the mitochondrial
complex II. This heteromeric protein consisting of four
separate subunits is a component of the mitochondrial
ETC and the Krebs cycle. Dysfunction of the mitochon-
drial complex II is considered to result in malfunction of
the oxygen-sensory apparatus and thus activate the patho-
physiologic pathway that leads to the development of
paragangliomas. Identification of the disease genes and the
protein that they encode has enabled us to address and
understand some of the questions and paradoxes raised by
genetic analysis of familial PGL.
Genetic Mapping of the PGL Loci
and Identification of the PGL1 Gene
Unraveling the genetic basis of the hereditary PGL followed
a well-established pathway for finding disease genes,69,70
which begins with the identification of affected families and
determination of the mode of inheritance of the disorder.
This is followed by two-point linkage analysis to localize the
disease gene to a chromosomal locus. The resolution of the
locus may vary from 1 to 12 centiMorgans in genetic dis-
tance or equivalent to 1 to 12 megabase pairs. Localization
and resolution of the disease locus sets the stage for the end
game. Identifying the disease gene within the linked locus
can be the most challenging stage of the genetic study of the
affected family. The difficulty of this task is demonstrated by
the presence of several hundred genes that can potentially
occupy the linked locus, many of which remain to be cloned
and characterized. Further compounding the difficulty of
the task is that the pathogenic sequence alteration can be as
subtle as a single-base pair change within a gene whose
sequence length can span several thousand nucleotides. A
sequence alteration in the candidate gene affecting the
coding sequence or splice signals can then be considered
pathogenic if it is shown to cosegregate with or be inher-
ited by the affected and not the unaffected in a family that
is under study.
Genetic linkage analysis of a large Dutch family with
hereditary PGL mapped the disease locus to the short arm of
chromosome 11, 11q22–q23 in 1991.18 This disease locus,
designated PGL1, was further resolved to approximately 11
megabase region at 11q23.71 This finding was later con-
firmed in several North American families and the critical
region was further resolved to a 2-megabase interval through
the presence of informative individuals displaying a recom-
bination event in the linked locus and the use of new poly-
morphic markers.72 Both the Dutch and the North American
families that mapped to the PGL1 locus were shown to carry
an identical haplotype, or set of markers, indicating that
these apparently unrelated families likely carried an identical
mutation that had occurred in a distant ancestor.
Following genetic mapping, the disease locus was then
physically mapped to identify the set of genes present.
Thus, the linked locus defined by genetic recombination
events is isolated in overlapping large- and small-capacity
cloning vectors. Physical mapping of the overlapping
clones, or the contig, includes determining their size in base
pairs and localization of various polymorphic markers such
as short sequence repeat polymorphisms (SSRPs) and
nonpolymorphic markers such as sequence tag sites
(STSs), anonymous sequences that serve as landmarks and
expressed sequence tags (ESTs), short sequences that are
identified from cDNA libraries. The physical map facilitates
subdivision of the contig and thus aids in the identification
of candidate genes spanning the cloned region. This strategy
of physically mapping the linked locus is also referred to as
positional cloning.69
Physical mapping of the PGL1 identified a minimum of
10 distinct genes within the linked locus. Based on their
physical locations, all of these genes are considered posi-
tional candidates for PGL1. Screening of all of these genes
for a pathogenic mutation would have represented a mon-
umental, labor-intensive task. A critical factor in hunting
for disease genes is to determine which of the positional
candidates might have a role in the etiology of the disease
on the basis of function. Although intuitive, this principle
is very difficult to apply since histopathologic analysis of
the disorder does not by itself enable determination of the
underlying molecular pathophysiology. Under these cir-
cumstances, the gene hunter must be highly resourceful in
searching for parallel cases that may provide clues concern-
ing the molecular etiology of the disease under study.
Identification of the PGL1 gene represents an excellent
illustration of this principal. Baysal and colleagues72
focused their search on a single candidate gene on the basis
of an insight derived from study of the histopathology of
the PGL and its similarity to carotid body tumors found in
people living at high altitudes.73 In these tumors, the
observed hyperplasia of the carotid body chemoreceptor
cells was inferred to be the result of their sustained stimu-
lation by chronic hypoxia. The observed link between
hypoxic stress and carotid body tumors and the physio-
logic role of the carotid body in oxygen sensing led to the
hypotheses that chronic stress upon the oxygen-sensory
apparatus or a mutation in its molecular components
causing its malfunction can both serve to trigger its hyper-
plasia. Supporting evidence for this hypothesis included
enlargement of carotid body in rats exposed to hypoxic
conditions.73
Thus, the 10 candidate genes were evaluated on basis of
their potential role in oxygen sensing and signaling. The
candidate gene selected encoded SDHD, a small subunit
of cytochrome b in the mitochondrial complex II, one of
the five protein assemblies or complexes that form the
electron transport chain. Through its production of reactive
oxygen molecules, the electron transport chain was consid-
ered to play a pivotal role in the signaling and detection of
oxygen tension. The gene encoding SDHD consists of
4 exons and yields 159 amino acid polypeptides. Screening
of the families with hereditary PGL identified various
mutations of the SDHD gene that segregated with the
disease.74 These mutations were subtle alterations of the
gene sequence, affecting post-transcriptional processing of

the transcript or the amino acid sequence of the primary
polypeptide. None of the pathogenic sequence alterations
were detected in more than 100 normal individuals.
The predisposition of the PGL due to inheritance of a
single mutant allele is consistent with the predicated role
of the SDHD as a tumor-suppressor gene that is subjected
to “two-hit inactivation.” The classification of PGL1 as a
tumor suppressor was initially based on the observation
that the genome of the tumor cells from affected individuals
did not reveal the expected heterozygosity for a genetic
marker at their PGL1 locus.75 This loss of heterozygosity
(LOH) was inferred to be due to deletion or other muta-
tional event within the normal allele that renders the cell
either hemizygous (one deleterious allele and one deleted
allele) or homozygous for the deleterious allele. The
occurrence of somatic mutation leading to LOH can cause
complete inactivation of SDHD within the cell type. This
cell type carrying the two “hits” will no longer possess reg-
ulatory growth control due to loss of both alleles encoding
SDHD as a consequence of germline and somatic muta-
tions and will no longer behave normally. Thus, the “second
hit” catapults the cell on the biologic pathway toward
hyperplastic and neoplastic proliferation. The “two-hit”
paradigm has also been used to explain the occurrence of
certain sporadic tumors. Unlike the inherited predisposition
to the tumors, the sporadic tumors are considered to be
caused by two independent somatic mutations inactivating
the two wild-type alleles of the tumor-suppressor genes.
This proposed mechanism is consistent with the relatively
rare occurrence of sporadic tumors and has been validated
by genetic analysis of sporadic cases of NF1 and retino-
blastoma.76,77 The sporadic occurrence of paragangliomas
without family history is also observed. Genetic studies
have yet to determine if mutation of the SDHD gene also
accounts for sporadic cases of paragangliomas.
PGL2, PGL3, and PGL4
Given that SDHD is a subunit of a the mitochondrial
respiratory chain complex II, it was inferred that mutation
in the other subunits can also cause dysfunction of the
complex II and the onset of neoplasia. This hypothesis has
been validated for two of the three subunits, SDHC and
SDHB, through identification of mutations in their genes
that are causally linked to hereditary PGL.78,79 SDHC
located on chromosome 1q21 was found to be within the
PGL3 locus that was mapped using a German PGL family.
Mutation analysis of SDHC, consisting of six exons and
yielding a polypeptide of 169 amino acids, identified the
pathogenic sequence alteration in the affected German
family. Unlike the mapping studies that were used for
selecting SDHD and SDHC for mutation screening, muta-
tions in SDHB, consisting of eight exons and yielding a
polypeptide of 280 amino acids, were identified in small
families in which linkage analysis was not possible due to
their limited numbers. Linkage analysis in an extended
Dutch family has also linked a distinct locus on chromo-
some 11q13 cosegregating with familial PGL.80 However,
the responsible gene within this locus, designated PGL2,
remains to be identified.
Mutations of SDHB, SDHC, and SDHD linked to the
head and neck tumors localized to the carotid body have
Molecular Genetics in Neurotology 137
also been associated with paragangliomas in the adrenal
medulla, conventionally referred to as phaeochromocy-
tomas.81,82 Although, they differ in their anatomic location,
innervation, and specific function, both the paraganglia of
the head and neck region and the adrenal medulla are
linked by their common embryologic origin, their similar
morphology, and their general role in responding to acute
alterations in the surrounding environment. Thus, it is not
surprising that specific mutations of SDHB and SDHD
result in familial forms of head and neck paraganglioma as
well as phaeochromocytoma.79 However, in general, muta-
tions of these three subunits are linked with either the
head and neck paraganglioma or the phaeochromocytoma.
Pathogenic mutations have also been identified in
SDHA. However, germline mutations in this subunit of
complex II do not result in paragangliomas. The clinical
phenotype characterized by mutations in SDHA result in
optic atrophy, ataxia, myopathy, and Leigh syndrome.83
The dissimilar clinical phenotype suggests a distinct role
for the SDHA subunit and its apparent separation from the
task of oxygen sensing and signaling that is linked to
SDHB, SDHC, and SDHD. The mechanism of this
dichotomy remains to be determined.
Identification of several of the genes underlying
hereditary PGL has led investigators to assess their preva-
lence among both familial and sporadic cases of PGL in
which the affected individuals have no family history of
this tumor. These studies have been carried out using
population samples in the United States84 and in the
Netherlands.85 Germline mutations in SDHD, SDHB, and
SDHC have been identified in the majority of patients with
positive family history. Amongst these three candidate
genes, mutations of SDHD are most common. Molecular
epidemiologic studies of hereditary head and neck para-
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
affected individuals who are positive for this mutation are
linked through their common ancestry. In contrast to the
Dutch population, the common SDHD mutation in the
U.S. sample is P81L. However, this particular site is con-
sidered to be a mutational hotspot and hence not all indi-
viduals carrying P81L are considered to share common
ancestry. The presence of SDHB mutations among the
affected with positive family history is considerably lower
than that of SDHD, accounting for up to 20% of the sam-
ple population. No mutations of SDHC were identified.
Up to 30% of the familial HNP samples in the U.S. study
were negative for mutations in the candidate genes.
Contribution of noncomplex II genes, including the PGL2
gene, toward etiology of familial HNP represents a valid
explanation for this outcome.
In the absence of positive family history, the association
of complex II gene mutations is significantly less. The
Dutch study identified founder mutations of SDHD in the
germline of 36% of the affected while the U.S. study iden-
tified germline mutations of SDHD or SDHB in 8% of
nonfamilial samples. The presence of germline mutations
of the complex II genes in the apparently sporadic PGL
cases may be explained by variable penetrance or imprinting
of the mutant allele or an occurrence of a de novo muta-
tion. Both of these alternatives attempt to account for the
138 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
absence of positive family history despite the presence of
a germline mutations associated with familial PGL. These
alternatives may be verified through genetic analysis of
family members of the affected individual. Mutation
screens of the candidate genes in the DNA from sporadic
tumors did not detect mutated alleles of the complex II
genes that were not present in the germline, thus eliminating
the contribution of somatic mutation.
Parent-Specific Transmission
and Loss of Heterozygosity
Hereditary PGL has generally been observed to follow the
autosomal-dominant inheritance pattern. However, a vari-
ation on this pattern is observed for families with mutation
in the SDHD. In these families, the disease phenotype
is transmitted only through the fathers; the mothers do
not transmit the disease.86 The sex-specific transmission
pattern is an example of the phenomenon referred to as
genomic imprinting. The mechanism of imprinting remains
unknown but its effect is to silence the expression of the
imprinted allele.
The SDHD mutations have provided an excellent case
study for assessing and deciphering the molecular basis of
parent-specific gene expression pattern. Analysis of SDHD
expression in various tissues has shown expression of both
the maternal and the paternal alleles.74 These results argue
against a widespread silencing of the maternal allele but
do not exclude imprinting of SDHD limited to the para-
ganglionic tissue. The inference of maternal imprinting
specifically within the paraganglion is at odds with the
observation of preferential deletion of the maternal SDHD
allele in the tumor DNA, as determined through LOH
analysis.75 This leads one to question the mechanism of
maternal imprinting that is put forward to explain the
observed parent-specific (paternal) transmission of PGL.
Thus, if the onset of tumor is believed to be initiated by
inactivation of the normal allele through somatic mutation
in accordance with the two-hit pattern of tumor initiation,
then the mechanism is yet unknown by which the children
of an affected mother carrying one mutant SDHD allele are
refractory to developing tumors, since they already have
one inactive copy in their germline. This paradox remains
to be resolved. There is no evidence for parent-specific
disease transmission in families with SDHC and SDHB
mutations.
INTRACOCHLEAR TRANSGENE
EXPRESSION AND ITS POTENTIAL
THERAPEUTIC APPLICATION
Concurrent with the enlarging list of deafness genes is a
steady progress in the development of intracochlear gene
transfer technology. The simple and powerful objective of
this technology is to introduce a “therapeutic gene” (e.g.,
a normal version of the defective gene) into appropriate
target cells of the affected individual. Expression of the
exogenous therapeutic gene would then alter the target
cell and the clinical phenotype. In the absence of effective
conventional therapy for most types of hearing disorders
and the rapid advances in therapeutic applications of gene
transfer in various diseases, including cancer, intracochlear
gene therapy represents a promising treatment modality
that is under development.
Much of the experimental data to date addresses the
utility of various gene transfer vectors for expression of
marker genes within the cochlea and the vestibular end
organs. These studies have demonstrated that the transgene
can be expressed in the inner ear and that the transfer vector
and the mode of its delivery represent the critical determi-
nants of tissue or cell specificity and duration of the trans-
gene expression.87 Despite the promising advances, much
work remains to be carried out before application of intra-
cochlear gene transfer can be clinically applied to specific
forms of hearing loss.
Animals Models and
Gene Transfer Vectors
Preliminary studies in intracochlear gene transfer used the
guinea pig as the animal model because of the relatively
large size of its cochlea compared to mice and rat and the
ease of surgical manipulation in this species. Subsequent
studies have shifted their focus to using a mouse as the
model organism. The mouse genome is the most extensively
characterized of all mammalian model organisms. The
intrinsic value of the mouse as a model organism in hear-
ing research is the availability of a number of mutant mice
with inherited hearing loss.88 These mutant mice have
been well characterized and the genetic basis of their hear-
ing loss identified. In addition, a number of transgenic
mice have been generated to assess the effect of specific
candidate genes whose mutant alleles have been linked to
nonsyndromic and syndromic hearing loss.89 Both the
mutant and the transgenic mice represent excellent animal
models to assess the utility and efficacy of intracochlear
gene therapy.
Both viral and nonviral vectors have been used to transfer
and express genes in the inner ear of animal models. A
major advantage of nonviral vectors is the lack of immuno-
genic components. However, the nonviral vectors are still
in a developmental state and in competition with viral
vectors, which have the advantage of having developed
through evolution. Thus, individual virions represent a
highly efficient means of introducing the viral genome
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
by altering their genome so that they can no longer repli-
cate within the transduced cell and lead to cellular lysis.
These replication-defective viruses are engineered to func-
tion solely to introduce the desired gene into the nuclei of
target cells. Viral vectors have been developed from both
DNA (e.g., adeno, adeno-associated, and herpes) and RNA
(e.g., retro and influenza) viruses.
Feasibility of intracochlear gene therapy was initially
demonstrated through intracochlear transgene expression
using the guinea pig as an animal model.90 A viral vector
derived from the adeno-associated virus (AAV ) capable of
transducing nondividing cells and considered to be safer
than other viral vectors, in view of its nonimmunogenicity
 Molecular Genetics in Neurotology 139

and nonpathogenicity, was used to deliver a marker trans-
gene to the cochlea via steady-state infusion using an
osmotic minipump. Based on expression of the marker
transgene encoding a bacterial enzyme β-galactosidase,
AAV vector was found to transduce the spiral limbus, spiral
ligament, spiral ganglion, and the organ of Corti. The
marker gene expression was shown to be present up to
24 weeks after osmotic minipump mediated infusion of the
AAV-βgal.90 Subsequent studies investigating intracochlear
gene transfer have characterized a variety of vectors for
their efficacy and safety as well as their mode of introduction
into the cochlea.
The adenoviral (Ad) vector represents one of the well-
characterized vectors used for intracochlear gene transfer.
The attributes of adenoviral vector for gene transfer
include its capacity to carry large transgenes (8 kB) and
that it can be generated at high titer and can transduce
both dividing and nondividing cells. However, the Ad vector
has been reported to elicit a strong immune response, thus
contravening its attributes.91 A lentiviral vector, based on
the human immunodeficiency virus (HIV ), can integrate
into the chromosome of both dividing and nondividing or
mitotically quiescent cells, leading to a potentially stable,
long-term expression of a transgene spliced into the viral
vector. Thus, the postmitotic cochlear neuroepithelia and
the spiral ganglion neurons represent suitable targets for
a stable long-term transgene expression via lentivirus-
mediated gene transfer. Infusion of the lentiviral vector
carrying a marker transgene into a guinea pig cochlea
has revealed a highly restricted fluorescence pattern
limited to the periphery of the perilymphatic space.92
Transduction of spiral ganglion neuron (SGN) and glial cells
by lentivirus in vitro but not in vivo suggests limited dis-
semination of the viral vector from the perilymphatic
space. Restricted transduction of cell types confined to the
periphery of the perilymphatic space by the lentivirus is
ideal for stable production of gene products secreted into
the perilymph.
In addition to viral vectors, cationic lipid vesicles, or
liposomes, have also been used for intracochlear gene
transfer. The liposomes coupled to the transgene integrated
within a plasmic vector bind to the plasma membrane of
the target cells, releasing the DNA into the cytoplasm,
where it is eventually incorporated into the host genome.
Liposome vectors are nonimmunogenic and easy to produce.
Furthermore, the DNA introduced into the host cell is
incorporated by recombination, so there is little risk of
insertional mutagenesis. The drawback of liposome vectors
is a low transfection rate compared with other vectors.
The feasibility of inner ear gene transfer with liposome
vectors has been demonstrated by several in vivo studies.93
The attributes of the gene transfer vectors that have been
used in intracochlear gene transfer are summarized in
Table 5-3. These parameters provide a guide for assessing
suitability of a given vector for a specific objective. Thus,
if a transgene expression is required for a short period
only, then an adeno-associated or adenoviral vector may be
suitable. However, if sustained gene expression is required
that replaces a nonfunctional mutant gene product, then a
retroviral vector will be more suitable because the transgene
carried by the retroviral vector will be stably integrated
into the genome.
The cochlear expression of the transgenes mediated by
the transfer vectors described in Table 5-3 is summarized
in Table 5-4. The different cell types and tissues transduced
by these expression vectors likely reflect the unique property
of individual transfer vectors, each being similarly intro-
duced within the cochlear perilymph and carrying marker
genes driven by strong viral promoters. The variability in
the transgene expression pattern is likely a consequence of
number of factors including the size of the viral particle,
presence or absence of viral receptors, and mode of delivery.
Inspection of the table allows some generalization about
the ability of various viral vectors in transfecting cochlear
tissues. The spiral ganglion cells, spiral ligament, and
Reissner’s membrane were transfected by every virus
tested. On the other hand, only adenovirus demonstrated
transgene expression within the stria vascularis. Immune
response was present in the cochlea following transfection
with adenovirus, HSV, and Vaccinia virus.
Intracochlear Gene Delivery
Modalities
Local gene transfer to the inner ear is feasible because of
its relatively closed anatomy. However, developing a deliv-
ery method for genetic vectors to the inner ear without
causing local destruction and concomitant hearing loss is a
significant obstacle. The general strategy behind these
delivery modalities is to introduce the transgene-carrying
vector into the inner ear circulation, enabling its diffu-
sion to the surrounding tissues. Most of the delivery meth-
ods introduce the gene transfer into the perilymphatic
circulation. These methods include microinjection via
the round window membrane (RWM), microinjection or
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.
Gene transfer vectors have also been introduced into the
endolymphatic circulation through injection into
endolymphatic sac94 or into the scala media following
cochleostomy.95
Introduction of viral vector via infusion with a minios-
motic pump was characterized by evidence of trauma at the
basal turn adjacent to the cochleostomy associated with an
inflammatory response and connective tissue deposition.
Carvalho and colleagues96 demonstrated preservation of
preoperative ABR thresholds in the lower frequencies
(1 to 2 kHz), mild postoperative elevation of thresholds
(<10 dB) in the mid frequencies (4 to 8 kHz), and marked rise
(>30 dB) in ABR thresholds at higher frequencies (>16 kHz)
after miniosmotic pump infusion via a cochleostomy.96
However, in general, cochleostomy has been shown to cause
histopathologic alterations (including localized surgical
trauma and inflammation) and may lead to hearing loss.
A much less traumatic alteration to cochleostomy is the
direct microinjection through the RWM without causing
permanent hearing loss or tissue destruction. Histolog-
ically, cochleae microinjected through the round window
demonstrated intact cochlear cytoarchitecture and an
absence of inflammatory response 2 weeks after microinjec-
tion. Further, microinjection through the round window
membrane did not cause permanent hearing dysfunction.97
To avoid hearing loss associated with the direct manipulation
of the cochlea, gene transfer vectors have also been delivered
through the vestibular apparatus via canalostomy.98 This
delivery modality yielded transgene expression mainly in
the perilymphatic space with the preservation of cochlear
function.
The potential for surgical trauma, inflammation, and
hearing loss associated with these infusion or microinjection
techniques has led to the investigation of a less invasive
delivery method. Jero and colleagues99 investigated the
potential to deliver a variety of vectors across an intact
RWM by loading vectors onto a Gelfoam patch that was
placed in the round window niche. Adenovirus and lipo-
some vectors, but not the AAV vector, effectively infected
inner ear tissues, as evidenced by detection of reporter
genes. Thus, diffusion across the RWM has been shown to
be an effective, atraumatic, but vector-dependent method
of delivery for gene transfer vectors.99
An effective test of the delivery modality as well as the
transfer vector will have to await the generation of a mouse
model with inherited hearing loss that can potentially be
corrected with the introduction of a normal gene.
Preclinical Applications
The preclinical applications for gene transfer in the inner
ear have focused on protective effects of various neu-
rotrophins and growth factors against ototoxic agents,
including noise, aging, and aminoglycoside-based antibi-
otics. These neurotrophins and growth factors, including
brain-derived neurotrophic factor (BDNF), neutroophin-3
(NT3), and glial cell line–derived neurotrophic factor
(GDNF), have been expressed within the cochlea as trans-
genic products and have served to protect sensory hair
cells and the primary auditory neurons against atrophy and
degeneration.
Staecker and colleagues100 used a herpes simplex virus-1
(HSV-1) vector to deliver BDNF to the inner ear and
assessed its protective effect against neomycin. The gene
therapy group demonstrated a 94.7% salvage rate for SGNs,
in contrast to a 64.3% loss of SGNs in control animals
(without the BDNF transgene). Interestingly, BDNF
expression was ubiquitous in inner ear tissues, but this was
not the case for the reporter gene, β-galactosidase. This
reporter gene was detected in only 50% of the cells, thus
identifying the cells specifically transduced by the HSV-1
vector. This transduction rate was sufficient to affect
cochleawide BDNF distribution and ensure 95% SGN
survival. The authors speculate that SGNs must require
only a small number of BDNF-producing cells to ensure
the survival of the entire ganglion.100
Lalwani and colleagues used both in vitro and in vivo
models to test the protective effect of AAV-mediated
BDNF expression.101 They found a significant survival rate
of SGN in cochlear explants transduced with AAV-BDNF
and challenged with aminoglycoside relative to controls.
Although direct expression of transgenic BDNF could not
be recorded, the vector’s ability to salvage SGNs was
tested against a gradient of known BDNF concentrations
applied directly to the cochlear explants. They found that
the vector system was able to achieve the same protective
effects as 0.1 ng/mL of BDNF. However, this protective
effect is subtherapeutic, as the most efficient dose was
determined to be 50 ng/mL, a concentration of BDNF
that results in almost total SGN protection. In the in vivo
experiment, animals infused with AAV-BDNF with an
osmotic minipump displayed enhanced SGN survival. The
protection from AAV-BDNF therapy was region-specific;
there was protection at the basal turn of the cochlea but
not at the middle or apical turn. The authors propose that
this regional selectivity is a pharmacokinetic phenomenon.101
Neurotrophin-3-mediated protection against cisplatin-
induced ototoxicity has been documented using an HSV-1
derived viral vector. Chen and colleagues102 established that
efficacy of the vector in an in vitro study, where HSV-
1-mediated transfer of NT-3 (demonstrated by production
of NT-3 mRNA proteins and by reporter gene expression)
conferred increased survival to cochlear explants after
cisplatin exposure.102 Bowers and colleagues103 confirmed
these effects in an in vivo model, where HSV-1-mediated
transfer of NT-3 to SGNs suppressed cisplatin-induced
apoptosis and necrosis. The authors suggest that these
findings may not only be useful to prevent cisplatin-related
injury, but may also provide preventive treatment for hearing
degeneration due to normal aging.103
Several studies have established the efficacy of an
Ad vector carrying the GDNF gene (Ad.GDNF) to protect
against a variety of ototoxic insults. When administered
prior to aminoglycoside challenge, Ad.GDNF significantly
protects cochlear104 and vestibular105 hair cells from cell
death. Pretreatment with Ad.GDNF also provides signifi-
cant protection against noise-induced trauma.106 Finally,
Ad.GDNF enhances SGN survival when administered 4
to 7 days after ototoxic deafening with aminoglycosides.107
The studies described here have assessed the therapeu-
tic efficacy of gene transfer against chemically or physi-
cally induced ototoxicity in animal models. The results of
these studies are promising as preventive countermeasures

in preservation of spiral ganglion neurons following loss
of sensory hair cells. In addition, these results provide
proof of the principle of therapeutic efficacy of gene ther-
apy. However, correction or amelioration of hearing dys-
function in mouse models with hereditary hearing loss
through the use of gene transfer technology remains to be
addressed. Replacement or correction of a defective gene
underlying inherited hearing loss that results in a signifi-
cant change in the animal’s ability to hear will represent a
defining test for the therapeutic application of intra-
cochlear gene therapy.
Risks and Limitations
Major risk factors associated with the introduction of a
gene transfer vector into the inner ear are twofold: damage
to the cochlear structure and function as a consequence of
delivery modality and the relative safety of the gene transfer
vector. Delivery modalities that prevent damage to the
cochlear structure or function are described in the section
Intracochlear Gene Delivery. The safety of the gene transfer
agent is determined by assessing its immunogenicity and
toxicity. Unwanted dissemination of the therapeutic agent
outside the target region also represents a risk factor.
Using AAV as the gene therapy vector, Lalwani and
colleagues91 observed transgene expression within the
contralateral cochlea of the AAV-perfused animal, albeit
much weaker than within the directly perfused cochlea.
Subsequently, Stover and colleagues demonstrated transgene
expression in the contralateral cochlea using adenovirus.108
Expression of the transgene away from the intended target
site (i.e., within the contralateral cochlea) raises concern
about the risks associated with dissemination of the virus
from the target tissue. The appearance of the virus distant
from the site of infection may be due to its hematogenous
dissemination to near and distant tissues. However, this is
unlikely due to the absence of the viral vector in near and
distant tissues.109 Other possible explanations include
migration of AAV via the bone marrow space of the tempo-
ral bone or via the cerebrospinal fluid (CSF) space to the
contralateral ear.109 The perilymphatic space into which
the virus is perfused is directly connected to the CSF via
the cochlear aqueduct; transgene expression within the
contralateral cochlear aqueduct has been demonstrated
following introduction of the viral vector in the ipsilateral
cochlea. Collectively, these results suggest possible routes
for AAV dissemination from the infused cochlea via the
cochlear aqueduct or by extension through the temporal
bone marrow spaces. Subsequent investigations have
shown that dissemination outside the target cochlea can
largely be eliminated by using microinjection or round
window application of a vector and avoiding the infusion
technique.
Although transgene expression within the inner ear has
been well established, several limitations of the gene transfer
vector are evident. These include cell-target specificity of
the gene transfer agent and the sustained or regulated
expression of the transgene by the transduced cell. These
concerns are currently being addressed through the devel-
opment of vectors that carry cell-specific receptors and
the use of promoters from genes with cell-specific and
cell-selective expression.
Molecular Genetics in Neurotology 141
SUMMARY
Identification of deafness genes and the determination of
their prevalence in the human population have had a sig-
nificant impact on diagnosis and treatment of HHL. Thus,
it is critical to practicing otologists and neurotologists to
understand the principles of molecular genetics so that
they may selectively apply the appropriate diagnostic tests
and therapeutic interventions and judiciously interpret
their results.
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 Chapter
Pathologic Correlates in Neurotology
6 Outline
A. Julianna Gulya, MD, FACS Vestibular Schwannomas
(Acoustic Neuromas)
Neurofibromatosis
Meningiomas
Glomus Tumors
Metastatic Tumors
Auditory Implants
Pacchionian Bodies
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
encountered in neurotologic practice. Such information
should be sought in the chapters focusing on the particu-
lar pathologic process of interest. Instead, this chapter
concentrates on the intradural pathologic correlates to
neurotologic symptomatology, as well as the pathologic
features of neurotologic entities that have implications in
the medical and surgical treatment of the patient.
VESTIBULAR SCHWANNOMAS
(ACOUSTIC NEUROMAS)
Vestibular schwannomas give rise to symptoms such as
sensorineural hearing loss (SNHL), tinnitus, disequilib-
rium, and other neurologic symptomatology through the
direct effects of the tumor, namely, compression and
destruction of neural structures,1–3 as well as by indirect
effects. Studies of the pathology of the vestibular schwan-
noma can be divided into two groups: those that use the
tumor or nerve specimen obtained at the time of surgery
and those that make use of the temporal bone specimens
harvested at the time of the patient’s death. Tumor-nerve
specimens obtained at the time of surgery allow for elec-
tron microscopic and immunohistochemical studies,
which in turn facilitate the analysis of the tumor-nerve
interface with respect to both the cochlear and vestibular
nerves, as well as analysis of neural integrity.
Neely and colleagues4–6 have presented detailed studies
of three small vestibular schwannomas completely resected
by the translabyrinthine approach. Considering nerve VIII
as a unit, they4 identified two types of tumor interface
simultaneously coexisting in the same tumor at different
locations; the first constituted a distinct separation of the
tumor and the nerve, whereas the other was described as a
144
Facial Nerve Patterns
of Degeneration
Internal Carotid Artery
Serpentine Aneurysms
Vascular Loops
Dural Arteriovenous
Malformations
Jugular Bulb
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-
face in some instances.
In subsequent studies, Neely and Hough5 focused on
cochlear nerve involvement with small schwannomas. In
the evaluation of a superior vestibular nerve schwannoma, a
separation of the tumor from the cochlear nerve was main-
tained throughout its length. With schwannomas of inferior
vestibular nerve origin, however, Neely and Hough5 found
that the cochlear nerve, initially separate from the tumor,
rotated about and progressively became more tightly
applied to and incorporated within the tumor as evaluation
progressed laterally. Cochlear nerve fiber incorporation
progressed, with loss of expected fiber orientation, until
no identifiable cochlear nerve fiber aggregates remained.
Paradoxically, the superior vestibular nerve schwannoma,
which had the greater number of cochlear nerve fibers, was
associated with poorer hearing than the inferior vestibular
nerve schwannoma.
Ylikoski and associates,9 based on a similar study encom-
passing larger, predominantly inferior vestibular nerve-
derived tumors, described three stages of tumor growth
(Fig. 6-1). In stage I, the tumor only invades its nerve of
origin and displaces the facial nerve and the remainder of
the eighth cranial nerve. In the second stage, the tumor
invades the adjacent cochlear nerve and compresses both
the superior vestibular nerve and the facial nerve, while the
third stage involves tumor invasion of all components of
the eighth cranial nerve and extensive compression of the
facial nerve. They10 also found a gradual transition from
tumor to cochlear nerve, with no correlation between the
number of preserved fibers and auditory function as mea-
sured by standard clinical audiologic techniques.
Because auditory function fails to reflect the remaining
cochlear nerve fiber population,11 it has been suggested
that a cochlear nerve “conduction block” exists, stemming
 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
Hough6 have presented histologic evidence supportive of
the conduction block idea with the demonstration of
“onion bulbs”—concentric layers of Schwann cell processes
among which are interspersed an increased number of
collagen fibers. The onion bulbs are thought to result
from repetitive demyelination and remyelination, and are
manifested in a marked decrease in the conduction veloc-
ity of the affected fiber.
These pathologic correlates have at least theoretic impli-
cations in the concept of total tumor removal with attempt
at hearing preservation. First, the degree of cochlear nerve
involvement with the tumor is not reflected by auditory
function, although the auditory brainstem response (ABR)13
may be able to prognosticate to some extent the likelihood
of successful hearing preservation. Second, the lack of a
clear interface between cochlear nerve and tumor implies
that in some proportion of cases, tumor inevitably will be
left behind in the hearing preservation attempt.14 One fac-
tor playing a role in the lack of a clear interface between the
cochlear nerve and the vestibular schwannoma may relate
to the infiltrative tendency of the vestibular schwannoma,
but it may also derive from the fact that in 25% of normal
eighth nerves15 no cleavage plane is evident between the
cochlear and vestibular components in the cerebellopon-
tine angle, with vestibular fibers imperceptibly blending
into the substance of the cochlear component.16 Practically
speaking, such microscopic remnants do not inevitably give
rise to tumor recurrences,17–19 but they do, particularly in
the younger patient, represent a source of concern.
Clearly, restricting histologic evaluation to merely the
internal auditory canal (IAC) components disregards con-
sideration of the effect of various end organ changes
evidenced in the temporal bones of individuals with ves-
tibular schwannomas. Although direct invasion of 20–23 and
origin from24–26 labyrinthine structures are not rare occur-
rences, vascular, biochemical, and perhaps viscosity
changes indirectly stemming from a vestibular schwannoma
appear to be more important in peripheral dysfunction.
DeMoura and associates21,27 conducted detailed clinico-
pathologic studies of 11 vestibular schwannomas. Loss of
cochlear neurons most severe in the basal turn was the most
frequently observed finding; basal hair cell loss also was
seen but to a lesser degree. Cochlear neuronal loss out of
proportion to hair cell loss manifests with loss of speech
discrimination out of proportion to pure tone thresholds in
neural presbycusis28 and perhaps in vestibular schwannomas
as well.
Suga and Lindsay22 reviewed the temporal bone pathol-
ogy of three cases of vestibular schwannoma with a partic-
ular interest in validating the concept that impairment
of blood supply to the inner ear was the cause of the
manifested alterations. In the animal model, Perlman and
associates29 showed that temporary occlusion of the
labyrinthine artery was associated with a predominant loss
of cochlear neurons, atrophy of the spiral ligament, vari-
able hair cell loss in the organ of Corti, and little effect on
the tectorial membrane. In contrast, permanent obstruc-
tion of the labyrinthine artery30 precipitated a cascade of
events, from hair cell changes and supporting structure
degeneration to the end stages of fibrosis and ossification.
Venous obstruction (vein at the cochlear aqueduct)31 results
in scattered hemorrhages, progressive outer hair cell loss,
severe strial atrophy, mild spiral ligament atrophy, and no
tectorial membrane alterations. Since the main venous
drainage of the human inner ear is by the vein of the
cochlear aqueduct and the vein of the vestibular aqueduct,
and the arterial supply is provided by the arteries in the
IAC, notably the labyrinthine artery, Suga and Lindsay22
reasoned that vestibular schwannomas should disrupt
146 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
arterial supply to the inner ear to a greater extent than
venous drainage; moreover, the obstruction should
be chronic and partial. Using the nontumor ear as a ref-
erence, they22 attributed degeneration of nerve fibers,
ganglion cells, the stria vascularis, and the tectorial mem-
brane; fibrosis and ossification of a semicircular canal;
and relatively good preservation of sensory cells seen in
the tumor to the presence of the vestibular schwannoma.
They22 believed that their constellation of findings, partic-
ularly the good preservation of sensory cells in the pres-
ence of extensive degeneration of the nerve fibers, ganglion
cells, and stria, reflected partial vascular obstruction of the
IAC blood supply by the vestibular schwannoma.
Johnsson and colleagues32 used the surface preparation
method to study the putative vascular alterations related
to a vestibular schwannoma by comparing the normal and
tumor-associated inner ears. Although they found fewer
red blood cells in the vessels of the tumor-affected ear than
the normal ear, an observation confounded by the patient’s
death some 2 weeks after surgery for tumor removal, they
did not find any excessive capillary atrophy or devascular-
ization, as they had noted in association with presbycusis.
Thus the role of ischemia in precipitating end-organ dys-
function remains debatable.
Changes in the biochemistry of the inner ear may under-
lie some of the peripheral manifestations of the vestibular
schwannoma. Eosinophilic staining of inner fluids reflects
their increased protein content,3,21,33 which may be 5 to 15
times normal.34 Using immunoelectrophoresis, immuno-
diffusion, and disc electrophoresis, Silverstein34 and Palva
and associates35 found that the increased protein levels in
perilymph represent an accumulation of blood serum
proteins and not those from cerebrospinal fluid (CSF).
Schuknecht3 proposed that “biochemical alterations in the
inner ear fluids are responsible, in part at least, for the hear-
ing losses showing flat audiometric patterns and loudness
recruitment” (similar to metabolic presbycusis). Johnsson
and associates32 theorized that the increased protein
content of the inner ear fluids leads to an increase in their
viscosity and hence cochlear dysfunction based on altered
hydrodynamics. No concrete evidence supporting either of
these theories can be found, yet how rapidly such abnor-
malities are corrected, if ever, subsequent to tumor treatment
would seem of practical importance in the maintenance or
improvement of hearing.
Hearing loss is a frequent occurrence after tumor
removal, even in the majority of instances in which preser-
vation is attempted. Vascular disruption, spasm, and frank
injury to the cochlear nerve are most commonly impli-
cated, but the idea of a “conduction block” is perhaps
worthy of consideration as well. Sekiya and Møller36 used
the canine model to study the effect of surgical manipula-
tions (e.g., retraction), thought to be analogous to those
performed in acoustic recess tumor removal, on the
cochlear nerve. Light and electron microscopic studies
were correlated to alterations in the recorded compound
action potential (CAP). With reversible changes in the
CAP, such as latency, they found microhemorrhages
within the cochlear nerve; abrupt amplitude decrease in
the CAP was associated with near avulsion of the
Obersteiner-Redlich (OR) zone (the glial-Schwann cell
sheath junction).36 The OR zone in particular seems to be
prone to injury, even if distant from the area of compres-
sion by retraction, and Sekiya and Møller36 believe the
transition from the fragile glia of the central portion to the
collagen-reinforced Schwann sheath of the peripheral
portion of the cochlear nerve, in combination with the
significantly greater vascularity of the peripheral portion,
explains the predilection of this region for injury. Kveton
and associates37 suggest that the spontaneous improvement
in hearing experienced by four patients several months after
suboccipital/transmeatal acoustic neuroma removal may be
due to a reversible nerve conduction block phenomenon at
the OR zone.
Alternatively, Fukaya and associates38 concluded that
“occlusion of perforating arteries . . . caused lateral brain
stem infarction around the entry zone of nerves VII and
VIII,” which triggered the transient, low-frequency (retro-
cochlear) SNHL they found in 14 of nearly 1000 patients
undergoing microvascular decompression for hemifacial
spasm. They38 based their conclusion on (1) the association
of Horner’s syndrome or bulbar palsy in more than one-third
of the patients with low-frequency SNHL, (2) audiometric
findings, especially ABR and electrocochleographic (ECoG),
suggestive of brainstem pathology, and (3) surgical records
uniformly describing “extremely short perforating arteries
surrounding the entry zone of nerves VII and VIII, so
that they had to be stretched during surgery.” No patho-
logic study has been provided, but the observation
seems to have some relevance to acoustic recess surgery in
general.
NEUROFIBROMATOSIS
Cytologically, the vestibular schwannomas of neurofibro-
matosis type 2 (NF2) are indistinguishable from unilateral
schwannomas, but histopathologically there are some
differences. The schwannomas seen in NF2 generally
(1) are larger and more often multicentric; (2) are more
frequently multilobular39; (3) more often infiltrate, rather
than splay, the facial and cochlear nerves39,40,41 (Fig. 6-2);
(4) are associated with more extensive bony erosion and
enlargement of the IAC; and (5) tend to invade temporal
bone air cells and marrow spaces.1,2,42 Such characteristics
can render hearing conservation attempts more problem-
atic. In addition, as emphasized by Linthicum and
Brackmann,43 the multicentricity of the vestibular schwan-
nomas of NF2, for example, simultaneous intracochlear
or intralabyrinthine schwannomas distinct from the IAC
tumor, may foil even the most skilled surgeon’s attempts
at complete tumor removal, at least when the surgeon is
using the standard translabyrinthine approach.
Widening of the IACs, asymmetrical or symmetrical,
usually betrays the presence of vestibular schwannomas.
Rarely, however, in neurofibromatosis patients at least,
ectasia of the dural sheath of the IAC may mimic a vestibu-
lar schwannoma both in terms of symptomatology and
the finding of uni- or bilateral widening of the IACs.44–46
Pantopaque,45,46 air,44 and metrizamide44 cisternography
have been used in the past to ascertain the absence of
tumor, confirmed by several-year imaging follow-ups; now
gadolinium-enhanced magnetic resonance imaging (MRI)
is recommended for optimal evaluation.
148 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
A
B
Figure 6-5. A, This vertical section through the labyrinth shows
meningioma tissue invading the fallopian canal (arrow). B, At a higher
magnification, the meningioma can be seen abutting the facial nerve (F ).
(From Nager GT, Heroy J, Hoeplinger M: Meningiomas invading the temporal
bone with extension to the neck. Am J Otolaryngology
4:297–324, 1983.)
producing progressive hearing loss, headache, vertigo, tin-
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
Vernet’s) as well as cerebellar and brainstem involvement
can be seen.47,51
The diagnosis of meningioma must be considered when
dealing with a temporal bone, parapharyngeal space, or
jugular foramen lesion. The rarity of the primary, purely
intratympanic meningioma51 demands thorough imaging
evaluation for an intracranial component. The difficulty in
discerning normal from meningioma tissue requires wide
surgical margins47,50; for example, as cited by Maniglia,51 if
the site of dural attachment is coagulated rather than
excised, the recurrence rate of intracranial tumor after
removal is 19%. The need for long-term follow-up after
apparent excision, commensurate with the slow growth
rate of meningiomas, is evident.47 Recurrent symptomatol-
ogy alone should not serve as the indicator for follow-up
imaging; as reported by Leonetti and colleagues,52 of
A
B
Figure 6-6. A, A meningioma has densely infiltrated the petrous apex, as
seen in this vertical section (C ). B, Infiltration of the carotid canal with some
compression of the internal carotid artery (arrow). (From Nager GT, Heroy J,
Hoeplinger M: Meningiomas invading the temporal 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
the recurrence and 42% had no new physical findings.
GLOMUS TUMORS
The heritage of the chief cell of the paraganglioma and its
implications in the biologic behavior of these tumors is
reviewed elsewhere in this text; this section concentrates
on the patterns of growth and extension of jugulotympanic
and vagale tumors, which are relevant to the planning of
surgical extirpation.
Reminiscent of meningiomas, paragangliomas tend to
expand within and traverse the temporal bone by means
of preformed pathways that offer minimal resistance.53–55
The pneumatized air cell tracts of the temporal bone are the
most important route of spread; for instance, by means of
the peritubal air cells, glomus tumors can invade the petrous
apex and involve the internal carotid artery, clivus, dorsum
sella, and sphenoid sinus.53 Extension along the facial nerve
can occur in the fallopian canal.53 The eustachian tube can

A
B to occur within two “dangerous triangles”: the hypotym-
Figure 6-7. A, This vertical section through the skull base in the
region of the jugular foramen shows extensive infiltration by a meningioma.
C, Internal carotid artery; X, vagus nerve; J, jugular bulb. B, The meningioma
encroaches on the vagus nerve (X ). (From Nager GT, Heroy J, Hoeplinger M:
Meningiomas invading the temporal bone with extension to the neck. Am J
Otolaryngology 4:297–324, 1983.)
serve as a conduit beyond the temporal bone to the
nasopharynx.53 The lumens of the internal jugular vein and
sigmoid sinus are likewise avenues for tumor extension
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.
Makek and colleagues60 have published a unique study
of neural infiltration by jugulotympanic paragangliomas.
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
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
panic and the protympanic (Fig. 6-10).
The hypotympanic triangle is delimited by the inferior
petrosal sinus, the sigmoid sinus, and the internal jugular
vein. Extension from the hypotympanic triangle may occur
intraluminally in the great veins of the triangle, extralumi-
nally along the carotid sheath into the neck, or along the
cranial nerves at the base of the skull.
The protympanic triangle is determined by the eustachian
tube opening, the tensor tympani tendon, and the zygomatic
root cells. Further growth may then progress along the
Figure 6-8. Paraganglioma contacts the perineurium of the facial nerve
(stage II invasion). (From Makek M, et al: Neural infiltration of glomus
temporale tumors, Am J Otol 11[1]:1–5, 1990.)
150 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Figure 6-9. Stage IV invasion: paraganglioma tissue involves the
endoneurium of the facial nerve. (From Makek M, et al: Neural infiltration
of glomus temporale tumors, Am J Otol 11[1]:1–5, 1990.)
lumen of the eustachian tube to the nasopharynx, within
air cell tracts to the petrous apex, or along the IAC into the
middle cranial fossa.
Kinney61 found that intracranial extension most com-
monly involves the posterior cranial fossa, inferior and
medial to the IAC.
In a fashion similar to that occurring in meningiomas,
paragangliomas extend predominantly along preformed
pathways, and their complete extirpation mandates thorough
preoperative imaging evaluation and wide-field exposure.
METASTATIC TUMORS
Secondary involvement of the temporal bone by malignant
processes is a problem of increasing magnitude, relating to
improved chemotherapeutic regimens that allow for longer
survival and the development of intracranial extension, as
Figure 6-10. The protympanic and hypotympanic triangles allow for central
extension of paraganglioma. (From Spector GJ, et al: Panel discussion:
Glomus jugulare tumors of the temporal bone. Patterns of invasion in the
temporal bone. Laryngoscope 89:1628–1639, 1979.)
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
by distant and intracranial primary tumors.
Metastatic tumors most commonly gain access to the
temporal bone by hematogenous spread.64 Breast, lung,
kidney, prostate, and stomach carcinoma, in descending
order of frequency, have been reported as metastasizing to
the temporal bone.63 Deposition of tumor cells occurs pre-
dominantly in the petrous marrow (Fig. 6-11); the sluggish
flow in the sinusoidal capillaries promotes filtering of the
tumor cells from the circulation.64,65 Involvement of the
petrous apex can be found nearly uniformly.63 Metastatic
deposition within the air cell spaces of the temporal bone is
also quite common and leads to tympanic cavity and facial
nerve involvement.62 Invasion of the otic capsule is uncom-
mon, reflecting its resistance to neoplastic invasion.64
Lymphomas and leukemias infiltrate the petrous apex
almost without exception, subsequently following the sub-
mucosal plane of the mastoid air cells, the ossicles, the
middle ear muscles and tendons, the eustachian tube, the
IAC, and the subcutaneous tissues of the external auditory
canal.62,66
Regional, extracranial neoplasms, most commonly pha-
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
vertigo, and examination documented a right profound SNHL and a right
absent vestibular response. (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.)

by many of the same preformed pathways discussed previ-
ously, particularly the eustachian tube, the carotid canal,
the foramen lacerum, the foramen ovale, and the jugular
foramen.63,64 Similarly, malignant intracranial tumors may
secondarily involve the temporal bone by routes described
in the discussion of meningiomas, paragangliomas, and
vestibular schwannomas.
Leptomeningeal extension, in which the malignant
tumor cells diffusely proliferate in a lamellar manner along
the pia-arachnoid of the brain and spinal cord, may develop
both with distant primary neoplasms and primary intracra-
nial tumors, especially medulloblastomas.62 Bilateral IAC
invasion with disruption of the facial and cochleovestibular
nerves is characteristic and may lead to transgression of the
cribrose areas and membranous labyrinth.62
Symptomatic manifestations of metastatic temporal bone
disease are conspicuous by their absence; Nelson and
Hinojosa63 found that of 33 patients with metastatic tempo-
ral bone involvement, nearly 60% were asymptomatic, and
that “diffuse metastases . . . were present in all cases . . . when
the petrous apex was involved by the hematogenous route.”
It is self-evident then that metastatic temporal bone inva-
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
Schuknecht and associates64 emphasized hearing loss
as a common early manifestation of hematogenous or
directly extending metastatic tumors of the temporal bone,
with conductive hearing loss reflecting eustachian tube
dysfunction and secondary serous otitis media (Fig. 6-12);
less frequently, ossicular destruction, mucosal invasion,
and tympanic membrane infiltration precipitated the
conductive hearing loss. SNHL is a manifestation of
cochlear nerve compression or destruction, or cochlear
invasion along the IAC. Rapidly progressive uni- or bilat-
eral SNHL, especially if associated with uni- or bilateral
facial paresis, vertigo, and widespread neurologic signs, is
Figure 6-12. A chondromyxosarcoma (C ) has destroyed the right petrous
apex and has compressed and occluded both the internal carotid artery
and the eustachian tube. Clinically, the patient experienced right serous
otitis media and left hemiparesis. (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.)
Pathologic Correlates in Neurotology 151
suggestive of leptomeningeal temporal bone involvement;
lumbar puncture is particularly helpful in establishing the
diagnosis.62,67
Facial paralysis may be caused by metastatic tumor infil-
trating and destroying the facial nerve,62,64 but may also
reflect compression by tumor nodules.3
Chloromas are localized, green masses of leukemic cells,
associated particularly with acute myeloblastic leukemia.
Shanbrom and Finch68 have cited data indicating that of
those patients with chloromas, approximately half will
have temporal bone involvement. Leukemic infiltrations
in general may precipitate recurrent otitis and acute symp-
tomatology related to hemorrhage.62,68 Chloromas have
been associated with compressive effects on both the facial
and cochleovestibular nerves, tympanomastoiditis, otalgia,
hearing loss, and vertigo.
In general, the diagnosis of temporal bone metastasis
is based on clinical suspicion confirmed by appropriate
diagnostic imaging. Temporal bone biopsy may be helpful,
although the metastatic lesions are often less well differen-
tiated than the primary tumor, foiling attempts to determine
the probable site of the primary.64
AUDITORY IMPLANTS
Labyrinthitis ossificans (LO) and alterations in the cochlear
nuclei are pathologic findings with relevance to neurotol-
ogy, particularly in the consideration of cochlear implanta-
tion or auditory brainstem implant (ABI) placement.
Suga and Lindsay69 defined LO as replacement of the
fluid spaces of the inner ear by fibrous tissue and new bone.
LO may develop as a consequence of severe inflammation,
trauma, or vascular compromise of the inner ear.69–71
Specific entities associated with LO include labyrinthitis
(bacterial or viral, tympanogenic or meningogenic), far-
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
the distribution of ossification reflected the spread of
infection along the cochlear aqueduct and modiolus.70
Tympanogenic labyrinthitis tends to provoke new bone
formation only in the scala tympani near the round window
membrane, consistent with the round window membrane
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-
coccal). (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
In general, total obliteration of the cochlear fluid spaces
with new bone is rare (Fig. 6-15) and can be seen with both
meningogenic and tympanogenic labyrinthitis.70 In addi-
tion, scala tympani occlusion with new bone tends to pre-
cede ossification of the scala vestibuli, and the scala media
and vestibule are ossified only in the most severe cases.70
The predilection for ossification of the basal scala tym-
pani after labyrinthitis mandates that the cochlear implant
surgeon be prepared to perform the required cochlear
“drill out.” The excessive LO of the middle and apical turns
may explain the occasional inability to pass entirely a long
intracochlear electrode.70
Because the scala vestibuli seem to be less affected by the
ravages of LO, Steenerson and associates74 have proposed,
and have apparently successively performed, insertion of the
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
Schuknecht HF: Pathology of the Ear. Cambridge, MA, Harvard University
Press, Copyright © 1974 by the President and Fellows of Harvard College.)
Figure 6-15. Complete obliteration of the cochlea by labyrinthitis ossificans,
as seen here in an 84-year-old patient who suffered a febrile illness
(presumably meningococcal meningitis) at the age of 2 months, is unusual.
(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.)
intracochlear electrode into the scalae vestibuli of two
patients with scala tympani occlusion by LO. Alternatively,
Balkany75 has described endoscopically guided laser eradi-
cation of LO for cochlear implantation.
Extreme LO may require extensive coring out of the
cochlear modiolus, as described by Gantz and associates.76
The degree of LO has implications in the survival of the
cochlear neuronal population and their fibers, apparently
the elements stimulated by the intracochlear electrode.77
Nadol and Hsu78 have shown that, even in those cochleae
with severe occlusion by LO related to meningogenic
labyrinthitis, “significant numbers” of spiral ganglion cells
remained. More specifically, Linthicum and colleagues77
have reported that “as few as 3212 cells may produce a
useful auditory sensation.”
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
Pacchionian bodies, commonly referred to as arachnoid
granulations,82 consist of multiple arachnoid villi (see the
earlier section, Meningiomas) found in close relationship

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,
conductive hearing loss, meningitis with acute otitis media,
or intracranial extension of chronic otitis media.
The detection of bony-dural defects associated with
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
CSF flow into the mastoid may be detected either by
intrathecal metrizamide–enhanced CT scanning or MRI.83
The surgical exposure is dictated by the size of the
defect(s) and the multiplicity of defects found.83,85 Small
(<1 cm) isolated defects may be managed through a simple
mastoidectomy, but multiple or large (>1 cm) defects
generally require additional middle cranial fossa exposure.
Whatever herniated brain tissue is encountered is nonfun-
ctional and is resected.
FACIAL NERVE PATTERNS
OF DEGENERATION
Schuknecht and Shinozaki-Hori86 presented clinicopa-
thologic studies of 12 cases as illustrative of patterns of
degeneration of the facial nerve associated with disorders at
Figure 6-16. Arachnoid granulations consist of a peripheral layer of
arachnoid cells and fibrous tissue surrounding a central core (C ) of loose
arachnoid tissue. (Reprinted by permission of the publishers from
Schuknecht HF, Gulya AJ: Anatomy of the Temporal Bone with Surgical
Implications. Philadelphia, Lea & Febiger, 1986.)
Pathologic Correlates in Neurotology 153
Figure 6-17. This horizontal section shows a pacchionian body impinging
on the middle cranial fossa surface of a right temporal bone. (Reprinted by
permission of the publishers from Schuknecht HF, Gulya AJ: Anatomy
of the Temporal Bone with Surgical Implications. Philadelphia, Lea &
Febiger, 1986.)
various locations along its path from the pons through the
mastoid. Two general conclusions they made are particu-
larly germane to neurotology: (1) The facial nerve (both
motor and sensory divisions) adapts well to space-occupy-
ing lesions in the IAC; in the fallopian canal both divisions
are “highly prone” to pressure atrophy. (2) Destruction of
any segment of the motor division results in distal atrophy.
A lesion of the sensory division central to the geniculate
ganglion results in atrophy central to the lesion, while a
lesion distal to the geniculate ganglion results in distal
atrophy.
The details of four of the illustrative cases are sufficiently
relevant to neurotology to warrant expanded discussion.
An intra-axial lesion of the pons is exemplified by the
case of a 4-year-old child who presented with a progres-
sive (>2 weeks) facial paralysis and ipsilateral, profound
SNHL. An autopsy, performed 9 months later when the
patient died, disclosed a pontine astrocytoma. The motor
Figure 6-18. A pacchionian body interdigitates with the bony septa of
the posterior cranial fossa surface of the temporal bone. (Reprinted by
permission of the publishers from Schuknecht HF, Gulya AJ: Anatomy
of the Temporal Bone with Surgical Implications. Philadelphia,
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

A
B showed severe degeneration.
Figure 6-19. A, Summary diagram of the effect of an astrocytoma
(glioblastoma) of the pons on the facial, cochlear, and vestibular nerves.
B, This horizontal section through the vertical segment of the facial nerve
demonstrates pale staining consistent with degeneration of the motor
component (m). The chorda tympani nerve and sensory component are
intact. (From Schuknecht HF, Shinozaki-Hori N: Patterns of degeneration of
the facial nerve. Am J Otol 6(Suppl):47–54, 1985.)
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.)
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
In treating the patient with facial nerve symptomatology,
such as progressive paresis, the neurotologist must deter-
mine the area(s) of involvement of the facial nerve with
clinical examination supplemented by medical imaging.
Therapeutic deliberations are guided by an understanding of
the pathologic consequences of lesions at various locations.

A A
B
Figure 6-21. A, A meningioma, in this diagram, extends along the internal
auditory canal to the geniculate ganglion. B, Despite compression by the
meningioma, there is no obvious loss of neurons in the geniculate ganglion.
C, Complete degeneration of the motor component and partial degeneration
of the sensory bundle of the facial nerve occurs. (From Schuknecht HF,
Shinozaki-Hori N: Patterns of degeneration of the facial nerve. Am J Otol
6(Suppl):47–54, 1985.)
INTERNAL CAROTID ARTERY
The internal carotid artery (ICA) serves as a landmark to
the neurotologic skull base surgeon in much the same
fashion as the facial nerve guides the contemporary otolo-
gist. Just as the normal anatomic relationships of the facial
nerve, as well as their variations, are key data in surgical
undertakings, similar knowledge regarding the ICA is crit-
ical. In addition, it is important to be cognizant of the pos-
sible alterations of the ICA with age when contemplating
surgical interventions in the elderly.
The details of the anatomic relationships of the ICA
within the temporal bone and cranial cavity have been pub-
lished elsewhere.82,87 For the neurotologic surgeon, it is par-
ticularly important to be aware of the ICA as it runs medial
to the eustachian tube (Fig. 6-23) and anterolateral to the
basal turn of the cochlea (Fig. 6-24). According to Leonetti
and associates87 the mean distance of the ICA to the basal
turn of the cochlea, measured at the level of the tensor tym-
pani muscle, is 2.83 mm, with a range of 1.14 to 5.52 mm.
The congenitally ectopic ICA is theorized to derive from
an anomalous or anomalously persisting branch, fixing the
Pathologic Correlates in Neurotology 155
B
Figure 6-22. A, The metastatic nodule compresses the facial nerve in its
vertical segment. B, Both motor and sensory components of the facial nerve
(F ) show the degenerative effects of compression by the tumor nodule (T ).
(From Schuknecht HF, Shinozaki-Hori N: Patterns of degeneration of the
facial nerve. Am J Otol 6(Suppl):47–54, 1985.)
ICA at the origin of the branch and deviating the ICA
posterior and lateral to its usual course during the remain-
der of development.88 Fisch89 proposes alternatively that
the aberrant vessel in the tympanic cavity represents the
enlarged inferior tympanic and caroticotympanic arteries,
which substitute for the “original atrophic” vessel. Despite
the rarity of this anomaly, it is an element in the differen-
tial diagnosis of a jugulotympanic paraganglioma.
A marked diminution in the tissues of the carotid canal
can occur with aging; in extreme cases, the wall of the ICA
is reduced to a mere intimal layer. Clearly, in such instances,
skeletonization of the ICA would be fraught with the hazard
of ICA rupture, or the ICA may be more susceptible to
tumor invasion (Fig. 6-25).
Arteriosclerotic plaques may also involve the ICA
(Fig. 6-26), with the possibility of arterial manipulation
sending a shower of obliterative emboli. MRA (magnetic
resonance angiography) may prove invaluable in estimating
arterial obliteration by plaques; it is less invasive than stan-
dard cranial arteriography.
Aneurysmal dilatation of the ICA most commonly
develops immediately proximal to the external carotid
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,
Gulya AJ: Anatomy of the temporal bone with surgical implications.
Philadelphia, Lea & Febiger, 1986,)
injury, for example, the tympanic cavity with laceration
during tympanostomy tube insertion.90 Extraordinarily, an
intrapetrous carotid artery aneurysm can present with
facial paralysis.91
Large (Fisch types C and D) paragangliomas generally
involve the intratemporal ICA.89 No methodical study
of invasion of the ICA akin to that published detailing
facial nerve invasion by paragangliomas could be found,
yet frank invasion of the ICA is thought to be unusual
(Fig. 6-27). Perhaps the periosteum of the carotid canal
presents a protective barrier: Inadvertent disruption of the
ICA can occur with removal of invasive tumor, but more
significant in paraganglioma surgery are the caroticotym-
panic arteries, which supply the anteromedial portion of
the tumor and which can be avulsed in operative dissection
at the level of the tympanic orifice of the eustachian tube.89
The lining matrices of congenital epidermoids and der-
moid cysts generally can be peeled from the ICA.89
Figure 6-24. The basal turn of the cochlea (b) lies adjacent to the internal
carotid artery (C). (Reprinted by permission of the publishers from
Schuknecht HF, Gulya AJ: Anatomy of the Temporal Bone with Surgical
Implications. Philadelphia, Lea & Febiger, 1986.)
Figure 6-25. With age, extreme thinning of the wall of the internal carotid
artery may occur (compare with Fig. 6–23). (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.)
SERPENTINE ANEURYSMS
Massive ectasia and serpentine tortuosity of the vertebro-
basilar system is most appropriately referred to as a serpen-
tine aneurysm of the involved artery, although the term
dolichoectasia is also used.92,93 The basilar artery is most
commonly involved, but often the vertebral and internal
carotid arteries are distorted as well.93 The typical patient
is a man in his mid-60s with a history of hypertension and
arteriosclerosis. Suggestive symptoms relate to compres-
sion of the pons, medulla, lower cranial nerves, and
ventricular system, and/or embolism from mural thrombi.94
Atypically, the serpentine aneurysm may present with
vertigo, with94–96 or without97,98 SNHL and tinnitus. Central
facial nerve paralysis94 and facial numbness96 have also been
reported.
Figure 6-26. An atherosclerotic plaque (a) partially occludes the lumen of
the intratemporal internal carotid artery. (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.)
 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
Bulb vs. Jugular Bulb Diverticulum
Jugular Bulb
High Jugular Bulb Diverticulum
Lateral/Anterior Location Medial/Posterior
Yes Tympanic cavity extension No
Otoscopy Diagnostic study Radiology
Conductive Hearing loss Sensorineural
Uncommon Tinnitus Continuous or
intermittent
No Vertigo Yes
No Ménière’s symptoms Yes
Yes? Expansion Yes?
jugular diverticulum are entities of which the neurotolo-
gist should be aware in order to avert potential surgical
misadventure.
The high (enlarged) jugular bulb (Fig. 6-29) protrudes
above the level of the tympanic annulus and may attain
prodigious proportions (the so-called jugular mega-
bulb).106,107 The high jugular bulb has been reported to occur
in 3.5%108 to 7.0%109 of temporal bones studied, more
commonly occurs on the right side, and arguably has been
related to the degree of pneumatization of the peri- and
infralabyrinthine regions.110,111 The high jugular bulb may
be confused with a paraganglioma by the unwary clinician
and serves primarily as a nuisance in both translabyrinthine
and retrosigmoid tumor extirpation. The high jugular bulb
has been incriminated in subjective pulsatile tinnitus112
with mixed reports of successful symptomatic control with
surgical ligation of the internal jugular vein.106,113
The high jugular bulb may or may not have an intact
bony covering, that is, be dehiscent. Clearly, in the latter
situation, it is prone to inadvertent penetrating injury.114
An entity distinct from the high jugular bulb is the jugular
bulb diverticulum.115 According to Jahrsdoerfer, Cail, and
Cantrell115 the jugular diverticulum is a true venous anom-
aly and has some characteristic features that serve to distin-
guish it from a high jugular bulb (Table 6-2). Notably, the
jugular diverticulum may erode into the IAC or obstruct
the endolymphatic duct resulting in the “classical symptoms
of Ménière’s disease.”115
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Hearing Loss
in Neurotologic Diagnosis
Outline
Types and Mechanisms of Hearing Loss
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
and incidence of hearing loss in neurotologic disease
states. Much of the attention focuses on acoustic neuromas
(AN) (or vestibular schwannomas), since they are generally
the most common neoplasm seen in neurotology practices
and also represent a prototype for hearing loss in neuroto-
logic diagnosis.
The association of hearing loss with AN has long been
recognized. Harvey Cushing,1 in his classic 1917 mono-
graph on AN, wrote:
The chronology of symptoms in the foregoing series of cases
makes it clear that the clinical diagnosis of an acoustic tumor can
be made with reasonable assurance, only when auditory manifes-
tations definitely precede the evidence of involvement of other
structures in the cerebellopontile angle. This is characteristic of
so large a percentage of the clinical histories that the exceptions
. . . merely serve to make it more striking . . . The significance of
this does not seem to have been heretofore sufficiently empha-
sized, nor was it appreciated when the study of these cases was
first undertaken, and it must be confessed that in most of the
clinical histories, the fact was hidden in a mass of symptomatic
details, while in others it has only been brought to light by sub-
sequent inquiries directed towards this particular matter. It
would appear that patients rarely call attention to the premoni-
tory auditory symptoms, which are either forgotten or are not asso-
ciated with the subsequent and more incapacitating phenomena,
and it is equally certain that the sequences apt to be slighted by
the questioner.
The retrospective, frequent association of hearing loss
with neurotologic problems has been noted many times
throughout the succeeding 85 years; however, as noted
even in very recent AN evaluations, the time between the
onset of symptoms and first evaluation, or more impor-
tantly, between the onset of symptoms and diagnosis, has
Chapter
7
Michael A. Novak, MD
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-
picion should be maintained for any unexplained auditory
symptoms to encourage early evaluation and diagnosis of
these disorders. At present, readily available, accurate
audiologic and imaging techniques exist such that the
delay between onset of symptoms and diagnosis can be
shortened significantly if the awareness of patients and
health care providers can be heightened.
In this chapter, the types of hearing loss encountered in
neurotologic diagnosis, the pathophysiology of these
losses, and the incidence and exceptions are examined. As
mentioned earlier, the primary focus is on AN diagnosis;
other diagnostic entities will be mentioned to contrast
with the AN presentation.
Historically, since the first description of a definite AN
seen at autopsy by Charles Bell2 in 1830, the recognition of
hearing loss as a diagnostic indicator for AN has undergone
a very slow evolution. Cruveilhier3 recognized the first com-
plete clinical and pathologic description of AN, noting the
primary deafness in 1835. Stevens4 (1879) noted the first
case of a tumor of the auditory nerve that was diagnosed
prior to death based on symptoms. In 1904, Stewart and
Holmes5 described in the English literature a study of
40 cases of extracerebellar and intracerebellar tumors and
drew a distinction between the two based on symptoms. As
noted previously, Cushing’s book1 in 1917 still noted that
the hearing loss of retrocochlear lesions was often recog-
nized very late and lost in the midst of other symptoms
because the tumors were diagnosed very late in their course.
Gradual improvements in audiometry and imaging have
led to earlier diagnosis of tumors. Therefore, especially in
the last decade, the clinical picture has slowly changed.
Tumors are now being found earlier, and the degree of
hearing loss associated with AN is also changing. In 1992
163
164 SYMPTOMS OF NEUROTOLOGIC DISEASE
Tos, Thomsen, and Charabi6 examined tumors diagnosed
in the period from 1983 to 1990 and compared them with
tumors diagnosed from 1976 to 1983. In a stable popula-
tion with centralized medical care, the incidence of tumors
was 9.4 per million in the second 7-year period versus 7.8
tumors per million in the first 7 years. Fewer tumors were
more than 4 cm in diameter in the second 7-year period,
but the total number of medium-sized and large tumors
was still the same. With the widespread use of gadolinium-
enhanced magnetic resonance imaging (MRI) an increase
has occurred in diagnosis of tumors in the 1- to 10-mm
range. Associated with this earlier identification of tumors,
the index of suspicion and criteria for work-up of hearing
loss has slowly changed. Numerous authors have noted an
increase in identification of tumors in the small to medium
size range, and an associated increase in the number of
patients with symmetrical or normal hearing, or minimal
hearing loss at the time of diagnosis.
TYPES AND MECHANISMS
OF HEARING LOSS
Hearing losses are generally characterized as conductive or
sensorineural losses. Sensorineural losses can be further
subdivided into sensory or cochlear losses and neural or
retrocochlear losses. With rare exception, neurotologic
diseases cause a sensorineural type of hearing loss.
Conductive losses are rarely seen, except for glomus jugu-
lare tumors, neuromas of the facial nerve with extension
into the middle ear, rare middle ear tumors, or
cholesteatomas or cholesterol granulomas. This chapter
focuses on the nonconductive or sensorineural losses.
Sensory or cochlear losses resulting from peripheral hair
cell damage typically manifest by decreased sensitivity to
pure tones, the phenomenon of recruitment7,8 intact auditory
brainstem responses (ABR), loss of otoacoustic emissions
(OAEs), and relatively preserved speech discrimination until
widespread hair cell damage has occurred.9 Neural or retro-
cochlear losses typically show decreased speech discrimina-
tion out of proportion to the relatively unaffected pure
tones,9 auditory fatigue or tone decay,10 abnormal or absent
ABR,11 and intact OAEs.12 As widespread hair cell damage
occurs in cochlear losses, speech discrimination will deterio-
rate, but in neural losses, as increasing numbers of auditory
nerve fibers are damaged, pure tone thresholds will elevate.
Theoretically, retrocochlear lesions should produce the pic-
ture of a pure neural loss, but in reality they often appear to
be cochlear in nature or to show elements of both types of
hearing losses on objective, behavioral, or speech perception
auditory testing.13
The exact cause of hearing loss in most neurotologic
lesions is unknown; however, in tumors of the eighth nerve
and cerebellopontine angle (CPA), a number of mecha-
nisms have been theorized. Direct eighth nerve compres-
sion, stretching of the nerve, vascular compression or
occlusion of the blood supply to the eighth nerve or blood
supply to the cochlea, damage to the cochlear efferents,
biochemical changes within the inner ear, and hemorrhage
within the nerve or into the tumor all may have a place in
the etiology of hearing loss. In other neurotologic entities,
neurovascular compression of the eighth nerve near the
brainstem or direct lesions of the auditory nerve or central
pathways may also be causes.
Most ANs arise from one of the vestibular nerves at the
junction of the proximal and distal nerves (also the junc-
tion of the oligodendroglia and Schwann cells), usually
near the porus acusticus internus. They occasionally arise
more distally in the internal auditory canal (IAC) in
tumors that originate in the cochlear nerve.14 These slow-
growing lesions within the confines of the bony IAC will
cause slow compression of the cochlear nerve. The hear-
ing loss will reflect this compression of auditory nerve
fibers. The rate and amount of hearing loss will vary
depending on the rate of growth of the tumor, the plastic-
ity of the nerve, the consistency of the tumor, the location
within the IAC, and the amount of early expansion into the
CPA. The pure tone loss may be seen quite late in the
course of the tumor growth, because as Schuknecht and
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,
more than most others, explains the typical, slowly pro-
gressive hearing loss of CPA tumors. This mechanism also
partially explains the middle- and high-frequency hearing
losses usually associated with eighth nerve tumors. Sando16
demonstrated anatomically that the high-frequency audi-
tory nerve fibers from the basal turn of the cochlea are
located inferiorly and laterally all the way from the spiral
ganglion to the cochlear nuclei in the brainstem, whereas
the middle and apical fibers twist about the axis from the
spiral ganglion to the cochlear nuclei. The apical fibers
actually make approximately 13/4 turns about the long axis
before reaching the brainstem. Low-frequency apical
fibers also are more centrally located within the nerve.
These differences of position within the nerve may allow
for earlier involvement of the high-frequency basal fibers
and a variable involvement of the middle- and low-
frequency fibers from the middle and apical turns of the
cochlea. In addition to direct tumor compression of the
auditory nerve, Badie and colleagues17 proposed a theory
of increased pressure in the IAC as a cause for tumor-
related hearing loss. They measured the intracanalicular
pressure in 15 patients undergoing tumor resections.
Intracanalicular pressure directly correlated with the
amount of tumor in the IAC. There was a strong trend
toward lower IAC pressure in patients with better preop-
erative hearing, but the differences did not reach statistical
significance.
Vascular compression as a cause of the hearing loss in
AN has also been theorized. Since the anterior inferior
cerebellar artery loops into the internal auditory meatus a
variable distance, and the internal auditory artery arises
from the loop of the anterior inferior cerebellar artery
about 80% of the time,18 the blood supply to the cochlea
should be at risk with expanding lesions of the IAC. The
internal auditory artery divides into the cochlear-anterior
vestibular and vestibulocochlear arteries within the inter-
nal auditory meatus, so lesions of the internal artery should
result in vertigo or in very rapid deterioration of cochlear
hair cell function, especially in the low frequencies since
the cochlear apex blood supply is the most tenuous.13,19
These symptoms are not typically seen in AN. In fact, sel-
dom is a cochlear pure tone hearing loss seen before

decreased speech discrimination or neural type changes.
Also, acute vascular compression should cause electro-
cochleographic changes identified by a decreased cochlear
microphonic, which is not often seen.20
In an attempt to explain the different types of hearing
losses seen in AN, Lehnhardt21 suggested a theory involv-
ing both myelin and axon compression damage. He theo-
rized that early in the course of compression, the myelin
damage might be the only lesion, allowing for tone decay
and acoustic reflex decay without recruitment. Auditory
brainstem evoked responses would also be delayed. This
would be the typical picture of AN. Later on, as myelin
and axon compression both become involved, the ABR
would be delayed, still without recruitment. If the tumor
compression changes, for instance, in cessation of tumor
growth or recovery from intratumor hemorrhage, enough
axons may remain to allow for adequate nerve conduction
and remyelinization may occur. Therefore recruitment
may be positive, the ABR may be positive, but tone decay
may not occur.
Lesions of the olivocochlear system or auditory effer-
ents22 have also been implicated in early hearing losses
with auditory distortion, but little pure tone threshold
increase. Deficits of the efferent system will affect the
outer hair cells of the cochlea, allowing for difficulty with
speech understanding in noise and the subjective sensation
of distortion while having little effect on the pure tone
hearing thresholds. Outer hair cell function as evaluated
by otoacoustic emissions should be reduced or absent in
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
compression), and DPOAEs should be abnormal in losses
that have a cochlear (vascular or inner ear biochemical)
component. Telischi12 reported on 97 patients with AN
who underwent DPOAE testing. He found that from 37%
to 57% of tumors were classified as having a cochlear loss
pattern, and 41% to 59% had a retrocochlear pattern
depending on the analysis method used. He concluded
that the majority showed evidence of reduced outer hair
cell function in at least one frequency. The effects on the
OAEs did not reverse after tumor resection even when
other behavioral and objective hearing measures
improved, implying a nonreversible cochlear or efferent
pathway damage. These findings are compatible with pre-
vious studies that have demonstrated biochemical and
magnetic resonance image (MRI) changes in the ipsilateral
cochlea of some AN patients. As early as 1950, Dix and
Hallpike23 found changes in the characteristics of peri-
lymph in AN patients. Other authors24,25confirmed these
changes. Somers and coworkers26 reported on MRI studies
in AN and meningiomas, and showed increased postoper-
ative hearing preservation in ears with normal intral-
abyrinthine and lateral IAC fluid characteristics versus ears
with hypointense perilymph and fundus cerebrospinal
fluid (CSF) images. They theorized that an arterial vascu-
lar compromise in the IAC secondary to mechanical
obstruction by the tumor leads to reversible and irre-
versible intracochlear changes. Some MRI changes
returned to normal after tumor removal, but many times
OAEs do not revert to normal, again suggesting possible
Hearing Loss in Neurotologic Diagnosis 165
reversible biochemical changes but permanent hair cell
injury.
Grabel and colleagues27 suggested that the chronic
effect of high tumor volume within the infratentorial com-
partment may also play a role in AN hearing loss when
they showed a strong positive correlation between maxi-
mum tumor volume and prolonged ABR interpeak laten-
cies for waves III through V following stimulation of the
nontumor side. This suggests tumor volume-generated
distortion as an additional factor in tumors that extend
into the CPA.
Sekiya and colleagues28 demonstrated in dogs that gen-
tle traction on the eighth nerve in the CPA could lead to
hemorrhages within the nerve and secondary auditory
deficits. This mechanism may help explain the hearing loss
associated with other tumors within the CPA that cause
nerve distortion without significant compression. It may
also help explain the tinnitus and hearing loss that may
accompany neurovascular compression of the eighth nerve
in the CPA.29
Direct auditory nerve or brainstem auditory pathway
lesions30 have also been associated with neurotologic hear-
ing loss in cases of multiple sclerosis (MS).
The hearing losses associated with neurotologic entities,
and especially those of AN, most likely involve multiple
mechanisms, any or all of which may be seen in any one
lesion. The variety of mechanisms possible for the hearing
loss of neurotologic lesions also helps explain the variety of
hearing losses that may be seen.
CLINICAL DIFFERENTIATION
OF HEARING LOSS: COCHLEAR
VERSUS NONCOCHLEAR
Until the past two decades, the literature reflected efforts
to diagnose AN by the characteristics of the hearing loss it
induces. As mentioned under the discussions of the differ-
ent mechanisms of hearing loss, the loss from an AN or
other CPA lesion was considered noncochlear or retro-
cochlear. The characteristics of a cochlear loss should
reflect hair cell damage with an intact eighth nerve (i.e.,
recruitment, pure tone hearing loss with intact discrimina-
tion, evidence of hair cell damage, and the absence of audi-
tory fatigue). A number of test batteries were developed,
all with a high degree of false negativity. No one test, until
the ABR, had a sufficiently high rate of diagnostic selectiv-
ity to stand on its own or to guide further radiologic eval-
uation. Now the role of the ABR, in the MRI era, is
changing.
The phenomenon of auditory fatigue has been used to
try to differentiate cochlear versus retrocochlear losses.
The stapedial reflex decay or its absence has also been used
diagnostically for this purpose. Thomsen and coworkers31
noted positive stapedial reflex decay or an absence stape-
dial reflex in 78% of their 59-patient series in 1983.
Kanzaki and colleagues32 found absent stapedial reflex, ele-
vated threshold of the reflex, or positive decay in approxi-
mately 75% of their 132-patient series. The absence of the
reflex or positive decay did not depend on tumor size.
Moffat and coworkers33 identified only one of their 49
166 SYMPTOMS OF NEUROTOLOGIC DISEASE
CPA tumor patients as having a normal stapedial reflex
pattern.
Hirsch and Anderson10 demonstrated 73 of 75 AN
patients as having no stapedial reflexes or positive reflex
decay, and Harner and Laws34 demonstrated 49 of 61 AN
patients as having positive reflex decay or absent stapedial
reflexes. Anderson and colleagues35 examined 17 patients
with CPA tumors and hearing thresholds of less than 60
dB. Twelve of the tumors were ANs and five were not. Six
patients had normal hearing. The stapedial reflex decay
was positive in all 10 patients who attained reflex thresh-
olds.
Thomsen and coworkers31 further tried to differentiate
between AN hearing losses and that due to other causes.
They compared three groups of patients. The first group
had AN verified at surgery, the second group was evaluated
for an AN but found to be negative, and the third group
was diagnosed with Ménière’s disease. In their comparison
of the three groups, the AN patients had significantly
worse hearing at high frequencies, significantly worse
speech discrimination, significantly less recruitment, but
no significant difference in stapedial reflex decay. They did
find a significantly greater incidence of a progressive hear-
ing loss as the first symptom of the disorder. Again, gross
group distinctions were noted between AN patients and
other types of sensorineural hearing losses, but on an indi-
vidual basis, the cochlear versus noncochlear distinction is
difficult to use as a diagnostic criterion.
Beginning in the 1970s, diagnosis of neurotologic
lesions by the identification of retrocochlear hearing loss
began to take on a new picture with the advent of the ABR.
Selters and Brackmann,36 House and Brackmann,37 and
Clemis and McGee11 in the late 1970s began to demon-
strate the high rate of abnormality of the ABR in AN
patients. These authors demonstrated 92% to 98% sensi-
tivity for absent or abnormal ABR in AN patients.
Eggermont and colleagues20 suggested that the abnormal
ABR was probably from abolition of the synchronized fir-
ing of nerve fibers rather than a prolongation of the nerve
conduction velocities. This was especially true for the
high-frequency fibers, which run around the outside of the
auditory nerve, versus the middle and apical turn fibers,
which are positioned more toward the middle of the nerve
and possibly are less disturbed in the early stages of tumor
growth. The responses from the middle and apical turns
are longer in latency, due to the greater time needed for
TABLE 7-1. Tumors with Normal Auditory Responses
% Intracanalicular
Tumors with Normal
Series Year ABR
Grabel et al.27* 1991
Levine48 1991
Gordon75* 1995
Chandrasekhar73* 1995
Zappia76* 1997
Marangos40† 2001
*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.
the cochlear traveling wave to initiate the response. This
would account for the reduced synchronization of firing of
nerve fibers without necessarily a change in the hearing
itself.
Historically, the ABR has changed the evaluation of uni-
lateral or asymmetrical sensorineural hearing losses, but
the trend is toward finding more normal ABRs with the
earlier identification of very small or intracanalicular
lesions. In the past decade gadolinium-enhanced MRIs
have become more widely available, and tumors smaller
than 15 mm are more routinely identified. In tumors less
than15 mm, and especially those that are intracanalicular,
there may be insufficient neural compression to cause a
retrocochlear hearing loss as defined by an abnormal ABR.
Table 7-1 shows ABR results for several series of small
ANs. ABR continues to show a consistent asynchronous,
retrocochlear pattern in tumors >2 cm but, in intracanalic-
ular tumors, a much greater percentage will show a normal
(or cochlear) pattern.
The ABR is not specific for AN. In the series of Laird
and coworkers38 and of Granick and colleagues39 six out of
six meningiomas of the posterior fossa that had an ABR
were positive in each series. House and Brackmann37 also
demonstrated that only about 75% of patients with CPA
lesions that were not ANs had abnormal ABRS. Marangos
and coworkers40 found 23.5% of meningiomas had a
normal ABR.
The diagnostic accuracy and sensitivity of the ABR is
not matched by electrocochleography (ECoG).
Eggermont and colleagues20 evaluated the use of ECoG in
retrocochlear lesions. They found the slope of the action
potential amplitude versus intensity function similar in
range and dependent on the action potential threshold, as
it was in Ménière’s disease. Narrowband ECoG analysis
suggested the same number of viable neurons in AN
patients as in normal or recruiting cochlear losses. They
felt that for tumors with milder losses (those <60 dB)
the loss may be more cochlear in origin, possibly a slow
compression of the vascular supply with a secondary meta-
bolic dysfunction accounted for the hearing loss in AN
patients.
As mentioned previously, even though DPOAEs logi-
cally should help differentiate cochlear from retrocochlear
causes of hearing loss, in CPA lesions about half demon-
strated both patterns so DPOAEs have therefore not been
helpful as a diagnostic tool.
% Tumors % Tumors >2 cm
<15 mm with with Normal ABR
Normal ABR ABR Latency & Morphology
30
37
31 15.5
16.9
11
41.7 3.3‡
 Hearing Loss in Neurotologic Diagnosis 167

PRESENTATION OF CEREBELLOPONTINE and Selesnick and colleagues43 have demonstrated shorter

ANGLE LESIONS
In this section, the typical presentation of CPA tumors is
examined. The focus, again, is on AN, since few differ-
ences exist in the presentation of hearing loss from other
tumor types found in this area. Significant differences,
when present, are identified in this section, and hearing
losses related to other nontumor diagnostic entities are
discussed in later sections.
The typical picture or presentation of a CPA tumor, as
can be imagined from gradual compression of a slow-
growing mass, is that of a very slowly progressive sen-
sorineural hearing loss with speech discrimination much
worse than would be expected for the given degree of pure
tone hearing. As mentioned by Cushing,1 the hallmark of
AN is auditory dysfunction with hearing loss or tinnitus.
The incidence is so high that absence of these symptoms is
striking. As seen in Table 7-2, a number of authors verify
that the initial or presenting symptom is hearing loss with
or without tinnitus in about 80% of patients. Tinnitus as
the only presenting symptom is found in about 7% of
patients, and hearing loss without tinnitus is identified in
between 40% and 80%.
The picture changes when examining initial or present-
ing symptoms versus symptoms present at the time of
diagnosis for two reasons: one of which is the long delay
between onset of symptoms and diagnosis, and the other is
the proportion of patients with subjectively normal hear-
ing, but identifiable audiometric abnormalities on exami-
nation. As seen in Table 7-3, the average number of years
from onset of symptoms to diagnosis is about four. This
has changed somewhat as diagnostic methods and aware-
ness have improved; however, a long delay is still identi-
fied. Time from onset of symptoms to diagnosis is less
than 1 year in only about 20% of patients. Delays of 7 to
10 years are not uncommon. In Table 7-3, the reports by
Glasscock and coworkers41 and Hirsch and Anderson10
reflect diagnostic delays only in patients who have moder-
ate hearing losses or better. All severe and profound losses
have been excluded. This delay should decrease with the
advent of the MRI. Using MRI, Kanzaki and colleagues42
times from onset to diagnosis in intracanalicular and small
tumors than in medium and large tumors.
The signs and symptoms present at diagnosis are almost
exclusively auditory, and only rarely are other neurologic
symptoms found in the absence of auditory symptoms.
Table 7-4 demonstrates the signs and symptoms at the
time of diagnosis. The percentage of patients with hearing
loss or tinnitus (or both) at the time of diagnosis is about
95% or greater in AN patients even in patients with small
tumors; however, hearing loss or tinnitus was found in
60% of meningioma patients by Laird and coworkers38
and in 75% by Granick and colleagues.39
Unilateral tinnitus at diagnosis is identified in 56% to
85% of patients with AN. Again, in the meningioma series,
tinnitus was identified in only 34% to 50% of patients at
the time of diagnosis. The hearing loss identified is usually
moderately severe, with typical pure tone averages (PTA)
of 50 to 55 dB usually worse in the high frequencies. The
percentage of patients with a PTA worse than 80 dB was
15% to 35%. A small correlation may exist between the
degree of hearing loss and the amount of time symptoms
have been present, but such a wide variation exists that
generalization is difficult. Other auditory symptoms such
as aural fullness are occasionally identified; however, aural
fullness is rarely found in the absence of other auditory
symptoms or signs. The symptoms of hearing loss or tin-
nitus are independent of tumor size, but there is a definite
trend toward better hearing in tumors less than 1 cm.
Atypical presentations, such as normal hearing and sudden
or fluctuating hearing loss, are examined separately in a
later section.
Classically, the patient with an AN or other CPA tumor
has been described as having a high-frequency sloping
sensorineural hearing loss. Table 7-5 outlines the shape of
the audiometric configuration in several large series of
patients. The category of high tone loss is broken down in
some cases to an abrupt loss, in which hearing shows a
steep drop of at least 15 dB at frequencies greater than
2000 Hz, or a gradual high-frequency loss, in which the
hearing threshold increases less than 15 dB per octave.
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
thresholds at 2000 Hz, with increasing losses at the low
and high frequencies. As can be seen, the majority of losses
are of the high-frequency nature with abrupt high tone
losses a major proportion. If the abrupt and gradual high-
frequency losses are combined, they account for anywhere
from 32% to 68% of the configurations, with the majority
between 50% and 60%. However, large minorities of con-
figurations are flat or U-shaped. The percentages vary
from 16% to 47%, with most lying in the 20% to 30%
range. Ten to 25% of patients have severe to profound
hearing losses, with PTA greater than 80 dB at the time of
their initial audiogram. Low tone losses are very uncom-
mon. Other configurations of audiograms can be found,
but were too few to be classified into one of the character-
istic shapes. Generally, no typical shape is found for any
one type of tumor; however, Kanzaki and colleagues32 and
Dornhoffer and coworkers44 noted that 20% to 22% of
small and intracanalicular tumors had a U-shaped audio-
metric configuration.
The degree of hearing loss and speech discrimination
deficits varies widely, but historically patients have had
moderate to severe pure tone losses with poor speech dis-
crimination scores (SDS) on presentation. Table 7-6 out-
lines the findings from several large series of tumor
patients with audiometric examinations. In AN, anywhere
from 3% to 22% of patients have three frequency PTA
(500, 1000, and 2000 Hz) thresholds better than 20 to 25
dB, and 16% to 45% of patients have PTA worse than 70
dB. The figures of Kanzaki and colleagues32 include a PTA
for five frequencies from 250 to 4000 Hz. Their category
of 18% of patients in the better hearing group comprises
patients with PTA between 0 to 30 dB. This group roughly
corresponds to the other groups, because the hearing at
4000 Hz is characteristically considerably worse than that
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
8 of 15 patients, or 53%, as having a PTA of 0 to 20 dB.
Granick and coworkers39 identified 6, or 26%, of their
group with a PTA of 0 to 20 dB.
As mentioned earlier, characteristically, speech discrim-
ination for the eighth nerve tumor patients is quite poor.
Table 7-6 also lists the SDS for several large series of sub-
jects with eighth nerve lesions. The mean SDS is very
poor, with the best being from the series of meningioma
patients of Laird and colleagues.38 For an SDS greater
than 90%, the Kanzaki series32 found 13% of patients in
that category, and Harner and Laws34 found 9 of 117
patients, whereas, in the Dornhoffer series of subjects with
small tumors,44 37% had normal discrimination and the
mean speech score was 82%. Speech discrimination
greater than 80% was found in 24% of subjects in the
series by Kanzaki and colleagues,32 18% of Harner and
Law’s,34 and in 30% in the series by Selesnick and cowork-
ers.43 In the older series by Johnson,45 only 24% of patients
had a SDS better than 60%. Again, the meningioma
patients experienced less effect on their speech discrimina-
tion than the AN patients. Laird and colleagues38 found
that 40% of meningioma patients had discrimination better
than 90%, 47% had discrimination better than 80%, and
60% of their patients had discrimination better than 60%.
Historically, no correlation has been found between the
degree of hearing loss or speech discrimination deficit and
tumor size.13,46 Beginning in the MRI era, however, a trend
is developing toward better hearing thresholds and SDS in
patients with very small tumors. Selesnick and coworkers43
found that patients with tumors less than 1 cm in diameter
had average pure tone loss of 40 dB, and 50% of those
patients had a SDS of greater than 81%, and the series of
less than 2-cm tumors of Dornhoffer44 found 37% with
normal speech discrimination. In patients with medium
and large-sized tumors, the average speech reception
threshold was 47 and 58 dB, respectively, and only 25% of
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
patients with normal hearing,47–49 a poor correlation
occurs between normal hearing and tumor size, though a
definite trend exists toward better hearing in intracanalic-
ular tumors.
The very poor SDS for the tumors in general supports a
hearing loss mechanism of neural compression. Thomsen
and colleagues31 discussed the concept that discrimination
at high presentation levels is primarily an inner hair cell
function, and 95% of the fibers in the auditory nerve orig-
inate in the inner hair cells. Therefore, the neural com-
pression would inhibit inner hair cell function with the
resultant poor discrimination, especially at increasing
presentation levels.
Sudden or Fluctuating Hearing Loss
Though not common, space-occupying lesions of the CPA
and IAC can present as a sudden hearing loss or as a sud-
den exacerbation of an existing hearing loss. Table 7-7
summarizes the incidence of sudden hearing loss in a num-
ber of large series of patients with AN and other CPA
tumors. As can be seen, about 10% (4% to 26%) of patients
with AN present with a sudden hearing loss. In those man-
uscripts that specified the sudden hearing loss as a pre-
senting symptom, the incidence is 7% to 14%, with an
exacerbation of an existing loss occurring in 7% or 8%. A
number of the other series did not differentiate specifi-
cally, and in fact Selesnick and colleagues43 combined both
types of sudden loss for the incidence of 26%. The large
series by Pensak and coworkers50 described 77 patients (69
had AN and 7 had meningiomas) who complained of a
sudden hearing loss. Of the 77, 25 patients had a PTA for
the frequencies from 500 to 4000 Hz of better than 35 dB,
and of these 25 patients, 11 had an SDS of better than 88%.
Two additional patients of the 77 had an SDS better than
88%, even though their PTA fell between 35 and 60 dB.
Twelve of the 77 patients had a PTA worse than 60 dB.
They described a configuration of the audiogram as a high
tone loss in 60%, a flat loss in 19%, a U-shaped (trough)
loss in 15%, and a low tone loss in 6%. The degree of hear-
ing loss did not correlate with tumor size. Saunders and
colleagues51 also showed a very low incidence of
low-frequency losses especially compared with sudden
hearing losses not secondary to tumors. Pensak and
coworkers50 suggested the possibility of a vascular occlu-
sion with degeneration of the organ of Corti, although the
findings are too inconsistent to adequately differentiate the
vascular occlusion effect from rapid eighth nerve compres-
sion due to hemorrhage in a tumor. In the series by Ogawa
and colleagues,52 29 patients, or 22%, had a sudden hearing
loss or exacerbation of an existing loss. They felt that the
characteristics of AN with sudden hearing loss differed
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
audiogram configuration, and (5) a higher incidence of a
normal caloric response on electronystagmography. A
higher incidence of the subjective symptom of aural
fullness was also noted. Of note, of their 14 patients with
intracanalicular tumors, 5, or 36%, had a sudden hearing
loss. They questioned a vascular cause and supported a
cause from nerve compression, due to the high incidence of
midfrequency losses and the low incidence of dizziness.
Berg and colleagues53 identified 13 of 133 patients with
a sudden sensorineural hearing loss, 4 of whom recovered
some auditory function. In evaluating their series of sud-
den hearing loss patients, no clinical distinction was noted
between sudden hearing loss caused by tumors and that
caused by other disease states, other than a positive ABR
test. Saunders and coworkers51 felt that associated symptoms
of pain, facial paresthesias, or unilateral tinnitus preceding
the sudden hearing loss might suggest a tumor. Hallberg54
and Shaia and colleagues55 found a 0.6% and 0.8%, respec-
tively, incidence of AN in a large series investigating sudden
sensorineural hearing loss from any cause. Saunders and
coworkers51 studied only patients with sudden hearing losses
who had MRIs, and found an incidence of tumors of 2.7%.
Again, the distinction between hearing loss caused by
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
are aspects that mitigate against one or the other causes,
suggesting a combination of mechanisms in the majority of
these losses.
It is interesting that, even with a sudden change in hear-
ing, the delay between onset of symptoms and diagnosis is
more than 3 years on average. The series by Pensak and
colleagues50 had an average time of 39.8 months between
onset of symptoms to diagnosis, and the series by Ogawa
and coworkers56 and the one by Kanzaki and colleagues42
had an average time of 41.3 months. In some cases, the
patients had presented themselves for evaluation, but a
diagnosis of AN was not made until much later. In the
Saunders and colleagues51 series, patients who were not
diagnosed in the 6 months after onset of hearing loss often
went more than 2 years before diagnosis.
Normal Hearing
Patients with CPA tumors can present with normal hear-
ing. This fact has been recognized for some time, but has
become more significant in the current climate of early
identification and hearing preservation surgery for these
tumors. Table 7-8 represents the summation of a number
of series on patients with AN and other CPA tumors that
have presented with normal hearing. The definition of
normal hearing varies with the different series. As can be
seen, the number of patients with a PTA or speech recep-
tion threshold less than 20 or 25 dB varies from 3% to
22%; however, when patients with an SDS greater than or
equal to 90% are included, the number with normal PTA
or speech reception threshold and normal speech discrim-
ination is only 4% to 12%. The majority of series demon-
strate about a 5% to 7% incidence of truly normal hearing.
Generally, there was little correlation of normal hearing
and tumor size.
The decrease in SDS in AN patients is again seen to be
out of proportion to the pure tone findings. As seen in the
series of Mathew and colleagues,57 Selesnick and cowork-
ers,43 and Beck and colleagues,47 possibly only about one-
fourth of the patients with a normal PTA also have normal
speech discrimination. This finding is not generalized
throughout all series, but the majority of authors report a
decrease in the number of patients with normal discrimi-
nation versus the number with normal PTA.
Several series used 4000 Hz in their PTA, which seems to
be a significant differentiating factor between normal and
abnormal hearing. The hearing loss at 4000 Hz is often a
marker for unilateral losses in cases of AN, whereas a PTA,
based only on 500, 1000, and 2000 Hz, may misidentify
patients, calling them normal when they would otherwise fit
the category of a someone with a unilateral sensorineural
loss. Two series24,58 looked at hearing loss at 4000 Hz. In the
series by Beck and colleagues,47 of 21 patients with normal
hearing, the pure tone thresholds at 4000 Hz averaged
35 dB on the ear with the tumor and averaged 14 dB on the
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.
Interestingly, in the series that reported the symptom of
subjective hearing loss, most showed a very high percent-
age of patients reporting a subjective hearing loss, even
though the audiometric examination was normal.
Anywhere from 20% to 70% of the patients with normal
audiometric examinations had a subjective hearing loss,
40% to 70% had tinnitus, and 16% to 66% demonstrated
dizziness. In the series by Beck and colleagues,47 only 1
patient out of 408 was truly asymptomatic at the time of
diagnosis. Magdziarz and coworkers48 reported an inci-
dence of 2.7% with completely normal hearing (PTA <20
dB, discrimination >90%, and interaural differences <10
dB at any frequency), but again at least 40% of that group
had subjective hearing loss or tinnitus (and 70% had an
abnormal ABR). Therefore even the patient with a normal
audiometric examination frequently had objective or sub-
jective symptoms that were otologic in nature. When
adding the objective and subjective symptoms, only the
very rare patient is truly asymptomatic on presentation,
though this will probably change with the common use of
MRI for other intracranial diagnoses.
The other patient who can be considered to 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
these patients are normal, and this rate is from 1% to 8%,
with the average being about 5% to 7%.
Normal hearing on presentation is more common in
patients with noneighth nerve tumors. Hirsch and
Anderson10 reported that of their 97 patients with hearing
thresholds of 60 dB or better, 28 had hearing that was
within normal limits with respect to age and sex. They did
not specify objective audiometric criteria. In their series of
97, 22 did not have an AN. There were six meningiomas,
six gliomas or astrocytomas, four cholesteatomas, two neu-
romas not of eighth nerve origin, and several other space-
occupying lesions. In the 75 AN patients, 17, or 23%, met
their criteria for normal hearing with respect to sex and
age, whereas 50%, or 11 of the 22 non-AN patients, were
classified as normal.
There is no good correlation between tumor size and
the occurrence of normal hearing46–49 though a trend exists
toward patients with intracanalicular tumors having a
higher likelihood of normal hearing.44 Patients with nor-
mal hearing usually are younger48 and have a much shorter
length of time between onset of symptoms and diagnosis.
Thomsen and Tos59 found a positive correlation between
severity of hearing loss and the duration of symptoms. The
patients in most of the normal-hearing series have had a
shorter average time between presentation and diagnosis
than AN patients in general. This is certainly logical when
studying an entity known for producing gradually progres-
sive hearing loss, and possibly the patient presenting with
normal hearing may not represent as much a difference in
tumor type or consistency, as it does the amount of time
for the tumor effects to take place.
As a diagnostic indicator, the ABR has a high incidence
of positive findings, even in patients with normal hearing.
In the series in Table 7-8, from 70% to 94% of the patients
were identified by a positive (abnormal) ABR. The patient
with the small tumor with normal hearing, however, seems
to be the one in whom the ABR may be negative. In the
series of Selesnick and colleagues43 2 patients out of 35 had
a normal ABR, both had normal hearing, and both had
tumors less than 1 cm in diameter. Magdziarz and cowork-
ers48 found three of nine patients with normal hearing had
a normal ABR. Marangos and colleagues40 studied 50 (of
261) AN patients and 4 (of 17) meningioma patients who
had a normal ABR and found 20% of the AN group had
normal hearing (PTA) and 18% had binaurally symmetri-
cal hearing. Twenty-five percent of the patients in the
meningioma group had a normal PTA, and 50% had bin-
aural symmetry.
Again, in the consideration of mechanisms of hearing
loss in patients with CPA and IAC tumors, those with
objectively normal hearing, but subjective complaints of
hearing loss and tinnitus, and frequently an abnormal ABR
support the concept of slow nerve compression coupled
with the fact that 75% of the auditory nerve fibers can be
damaged without a change in pure tone hearing.15
Progression of Hearing Loss
Four studies31,56,60,61 have examined the progression of
hearing loss in AN patients. Nedzelski61 followed 28 eld-
erly patients with AN who chose no surgical treatment.
Eight of the 28 had serviceable hearing at the beginning of
the follow-up. The average deterioration of the PTA was
6 dB/year. The mean annual growth rate of the tumors in
the same series was 0.22 cm/year, with the median annual
growth rate of 0.1 cm/year. The range was 0.05 to 0.69
cm/year.
Thomsen and colleagues31 had 19 of 59 patients with
AN who had an audiogram 1 to 10 years prior to their
most recent audiogram. The average time was 4.2 years
between audiometric examinations. The mean deteriora-
tion of the PTA, 500 through 2000 Hz, was 9 dB/year. The
average deterioration at 1000 Hz was 9.9 dB/year, and
the average deterioration at 125 Hz was 6.1 dB/year. The
range was from 10 dB over 6 years to 60 dB in 1 year. They
found no relationship between age or tumor size in the
progress of the hearing loss.
Massick and coworkers60 followed 21 patients with a
small (<19 mm, mean diameter 7.8 mm) AN for least 2
years (mean of 3.8 years). Tumor growth by volumetric
analysis occurred in 66%, 24% showed no growth, and
10% receded. Changes in audiometric function were clas-
sified by the American Academy of Otolaryngology-Head
and Neck Surgery 1995 guidelines. They demonstrated a
significantly different mean deterioration of PTA and SDS
depending on the initial hearing. Seventy-five percent of
the patients in the best hearing group (class A) remained in
the best group throughout the study. Whereas 50% of the
group with class B hearing deteriorated to class D (non-
serviceable), and those initially with class D hearing
showed the largest drop in PTA and SDS. They demon-
strated a significant correlation between tumor volume
growth and changes in PTA and SDS, with the rate of
change dependent on the initial hearing status. There was
no difference between the groups in initial tumor location
or size. Interestingly, one patient had a regression in tumor
size and an improvement in audiometric function.
Ogawa and colleagues56 examined the progression of
hearing loss in 42 patients who could be tested for at least
6 months before surgery. They used a five-frequency PTA
from 250 to 4000 Hz and identified three separate groups:
(1) 5 of the 42, or 12%, recovered at least 11 dB during the
period, (2) 28 of the 42, or 66%, showed less than a 10 dB
change, and (3) a third group, 9 patients, or 21%, showed
deterioration greater than 10 dB during the follow-up.
The length of time from onset of symptoms to the first
visit was 49 months in the unchanged group, 28 months in
the recovery group, and 8 months in the deterioration
group. The rate of change for all patients averaged −1.1
dB/month, with a rate of +5.7 dB/month in the recovery
group, −0.3 dB/month in the unchanged group, and −8.2
dB/month in the deterioration group. The deterioration
group on average had the smallest tumor size. In fact, all
patients with tumors greater than 3 cm were in the
unchanged group. Overall, the hearing loss in 88% of the
patients was either unchanged or had deteriorated (20%
deteriorated). The average deterioration of −1.1 dB/month
for the entire group equals 13 dB/year.
The probability and rate of progression of tumor
growth and hearing loss are important considerations
when determining the timing of hearing preservation
surgery, the selection of nonsurgical treatment, or the
treatment of bilateral AN.

HEARING LOSS SECONDARY TO LESIONS
OTHER THAN ACOUSTIC NEUROMA
Two series of patients with posterior fossa meningiomas
were examined. Granick and colleagues39 and Laird and
coworkers38 examined 32 and 20 patients, respectively,
with meningiomas of the CPA.
As can be seen in Tables 7-4 and 7-6, the incidence of
tinnitus and hearing loss is somewhat lower than in AN
patients, with only 60% to 75% of patients showing one or
the other auditory symptoms at the time of diagnosis,
compared with 95% or more of patients with AN. The
patients with meningioma also showed a higher percent-
age with hearing loss less than 20 dB and discrimination
greater than 80% than did AN patients; otherwise, the
configuration of the loss and appearance audiometrically is
identical with that for patients with AN. Marangos and
colleagues40 demonstrated a higher incidence of normal
hearing, binaural symmetry, and normal ABR in patients
with meningiomas than those with AN.
In glomus jugulare tumors, the hearing loss can be
either sensorineural or conductive. As described by Alford
and Guilford62 and Brammer and coworkers63 more than
90% of patients with glomus tumors present with hearing
loss. In one series,62 25 patients were examined; 13 had
infralabyrinthine tumors and 12 had glomus tympanicum
tumors. All the patients in this series with sensorineural
hearing loss had infralabyrinthine tumors. Only one of the
patients with infralabyrinthine tumors had normal hear-
ing, but the ABR was positive in this case.
MS is also a cause of retrocochlear hearing loss. Cure
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
positive finding. Of the 14, 4 had unrecognized, clinically
probable MS that was previously unsuspected. In 9 of the
14, the demyelinating disease was the probable cause of
the auditory symptoms due to the identification of lesions
in the auditory pathways. The lesions in the auditory path-
ways in MS are usually in the brainstem, where the MRI
may be relatively insensitive because the lesions may be
microscopic or too small to be demonstrated by the imag-
ing. Bauch and coworkers58 examined 255 patients with
suspected retrocochlear hearing loss. Twenty-six of them
had surgically confirmed AN, and 6 were felt to have a
retrocochlear hearing loss secondary to MS. The ABR was
positive in four of the six MS patients. Hearing loss is not
a common presenting symptom of MS. Mustillo65 noted
that only 7% of their series of patients had hearing loss as
a presenting symptom of MS. A number of authors11,30,66,67
noted that while the hearing loss as a presenting symptom
is not common, a large percentage of patients with MS
have objective findings of auditory pathway dysfunction.
Jerger and colleagues66 found a 95% prevalence of audi-
tory abnormalities by acoustic reflex testing, speech
audiometry, or ABR testing. In 62 patients with definite
MS, the acoustic reflex was abnormal in 71%, speech
audiometry was abnormal in 55%, and the ABR was
abnormal in 52%. No typical pattern of hearing loss is
seen in MS. The loss can be unilateral or bilateral, sudden,
progressive, temporary, or permanent. The loss usually
presents itself within the first 4 years after the onset of MS
Hearing Loss in Neurotologic Diagnosis 173
and most often within the first year after the onset of neu-
rologic symptoms.68 Franklin and coworkers69 and Furman
and colleagues30 identified sudden hearing loss as a pre-
senting symptom of MS.
Another possible cause of retrocochlear hearing loss is
neurovascular compression of the eighth nerve in the CPA.
Meyerhoff and Mickey29 described two patients who had
undergone microvascular decompression of the cochlear
nerve to treat incapacitating tinnitus. They had normal
neurologic and psychological examinations, the MRI test
was normal, both had unilateral high-frequency sensori-
neural hearing losses with retrocochlear findings, and no
other cause was identified. Both patients underwent decom-
pression of the cochlear nerve, one from an offending
posterior-inferior cerebellar artery and the other from an
anterior-inferior cerebellar artery. Both obtained sympto-
matic relief, and improvement was reported in the high-
frequency sensorineural losses. These finding correlate
with those of Sekiya and colleagues,28 who demonstrated
that traction on the eighth nerve in dogs might lead to
secondary auditory deficits.
A variety of other CPA pathologies have been associated
with hearing loss. Patients with schwannomas of the facial
nerve70 in the CPA are known to present with hearing loss
that can be conductive, sensorineural, or mixed. Patients
with petrous apex cholesteatomas and cholesterol granulo-
mas typically present with either sensorineural or mixed
losses.71 Lipomas72 are rare but are also associated with
hearing loss in at least two thirds of the cases. As a general
rule, these other lesions in the CPA cause a hearing loss
that is indistinguishable from AN.
SUMMARY
The typical presentation of a CPA lesion is a slowly pro-
gressive, unilateral, sensorineural hearing loss with tinni-
tus and poor speech discrimination. However, a number of
authors have clearly demonstrated that the hearing loss of
neurotologic disorders can be of any configuration, with
any type of presentation, including that similar to a sudden
sensorineural cochlear loss. The mechanism of the hearing
loss, whether it is direct compression of the auditory
nerve, compression of the vascular supply to the cochlea,
or a combination of many factors, is not clearly under-
stood. Very likely, it is a combination, varying with the
specific site and lesion involved. The typical picture
may also be changing, as demonstrated by several
authors.6,27,42,43,48,59,73–75 More tumors are being picked up
in the less than 1-cm range, and more tumor patients are
being seen with normal or near-normal hearing than pre-
viously noted. The presentation in patients with neuroto-
logic lesions, and those with AN in particular, almost
always includes auditory symptoms. Even in the face of
objectively normal hearing, subjective complaints of hear-
ing loss or tinnitus frequently occur. The long delay
between onset of symptoms and diagnosis continues, and
as noted in the series of Selesnick and colleagues,43 the
average time from hearing loss onset to diagnosis was still
3.9 years in 1992. This delay, of course, may partially be
due to the patient not presenting for evaluation, but also
is due to physicians and audiologists not pursuing the
174 SYMPTOMS OF NEUROTOLOGIC DISEASE
evaluation of symptoms far enough. If neurotologic lesions
are to be diagnosed as early as possible, allowing for the
best treatment results, the general rule of completely
working up any unilateral sensorineural hearing loss or
tinnitus without an obvious cause is still recommended.
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 Chapter
Symptoms of Vestibular Disease
8 Outline
John F. Kveton, MD Common Symptoms
Vertigo
Imbalance
Dizziness
Syncope
COMMON SYMPTOMS
Symptoms of vestibular dysfunction are as variable as the
disorders that produce them. This variation in symptoms
for such a specific organ site as the labyrinth can be
explained by the particular pathology of the process affect-
ing the vestibular system and, as importantly, by the gen-
eral physiologic recovery process that takes place after any
insult to the system has occurred. An understanding of
these compensatory mechanisms for vestibular injury in
relation to the type of vestibular damage must be incorpo-
rated into the interview of patients presenting with
vestibular symptoms.
Certain vestibular disorders are episodic, with vestibular
dysfunction punctuated by normal function, and other
disorders produce acute, single-event injury to the vestibu-
lar system. In addition, chronic or progressive vestibular
dysfunction can also occur. Vestibular dysfunction may
be primary, with actual deterioration or damage to neural
elements, or secondary, in which metabolic or other systemic
changes produce reversible neural dysfunction. These
types of vestibular dysfunction will have characteristic symp-
toms, depending on the stage in which these disorders
present to the otologist. In any case, preliminary under-
standing of the process of vestibular compensation is the
foundation for accurate interpretation of vestibular symp-
toms to arrive at a diagnosis (Table 8-1).
Acute vestibular injury produces symptoms because the
resting tone of the vestibular system is disrupted. The loss
of tone produced by the damaged side allows for greater,
uninhibited input from the normal side, producing vertigo
TABLE 8-1. Symptoms During Stages of Vestibular Compensation
Initial Injury Early (hours/days)
Whirling vertigo Less severe vertigo
Nausea, vomiting Nausea
Prostration Severe dysequilibrium, spatial disorientation
176
Symptoms of Specific
Vestibular Disorders
The Labyrinth
Vestibular Nerve
Central Nervous System
and vegetative symptoms. Symptoms can last for hours
with prostration. For a period of hours to days the resting
tone of the intact side is reduced through central effects,
thus reducing the acute symptoms. At this point the whole
vestibular system is functioning at a lower level and is not
as sensitive to stimuli. Symptoms now are less severe,
mainly involving mild vertigo on positional changes, light-
headedness, spatial disorientation, dysequilibrium, or
unsteadiness. The duration of this stage of recovery
depends on the severity of the vestibular injury and can
last from days to months. The system compensates as
the lesion progresses; the near constant feelings of light-
headedness and spatial disorientation disappear, and dyse-
quilibrium and unsteadiness occur only with extreme
changes in head position or loss of other sensory cues that
affect balance. Symptoms become sporadic and eventually
disappear in the course of weeks to months.
For the majority of patients, this pattern of recovery is
complete, with the disappearance of all symptoms. If the
compensation process stalls or is interrupted at any stage,
the patient may continue to have symptoms according to
the stage of compensation the patient has reached. In fact,
this disruption of complete compensation from vestibular
dysfunction can be as debilitating as any recurrent, acute
process and comprises a greater number of patient visits
and treatment challenges than the acute, more easily iden-
tifiable process.
Although past emphasis of vestibular diagnosis has
focused on differentiating between peripheral and central
vestibular lesions, it is the identification of the degree of
compensation after vestibular dysfunction that is clinically
Mid (days/weeks) Late (months)
Positional vertigo Rare positional vertigo
Mild nausea Dysequilibrium
Dysequilibrium; spatial disorientation Spatial disorientation

more critical. Knowledge of the extent of compensation will
determine treatment choices as much as knowledge of the
location of the lesion. The particular symptoms of vestibu-
lar dysfunction can be reviewed in relation to these features.
Vertigo
A sensation of motion without external stimuli broadly
defines vertigo. Vertigo can be a symptom of either central
or peripheral vestibular pathology, but its absence does not
preclude the possibility of primary vestibular disease. The
character and severity, onset, duration and frequency, and
precipitating factors are all useful qualities of vertigo that
must be determined. The severity of the vertigo usually
depends on the abruptness of the process. Whirling or
turning denotes an acute unilateral process, whereas sway-
ing, rocking, staggering, weakness, or a swimming or wavy
sensation is associated with a unilateral subacute or bilat-
eral injury. Sudden onset of vertigo cannot differentiate
peripheral from central lesions, but the duration of the
vertigo can help to identify the source. Classic Ménière’s
attacks have a sudden onset and duration of 1 to several
hours. Acute toxic labyrinthitis produces a more persistent
vertigo that seems to build for 24 to 48 hours before sub-
siding. Central vestibular disorders may produce sudden
vertigo and more prolonged symptoms that last up to
several weeks. When the duration of the vertigo is similar
to peripheral disorders, central pathology can usually be
differentiated by additional central nervous system (CNS)
symptoms. Knowledge of precipitating factors can direct
diagnosis in some peripheral lesions. Changes in head or
body position suggest acute posterior canal dysfunction
when symptoms resolve during a period of weeks to
months or uncompensated unilateral peripheral disorders
when symptoms are chronic. Stress is recognized to pre-
cipitate vertigo in Ménière’s disease. A prodromal viral ill-
ness is seen in vestibular neuritis, and prior consumption
of foods, medications, or alcohol can also produce vertigo.
Imbalance
Imbalance, unsteadiness, or dysequilibrium describes a loss
of equilibrium on movement or in situations in which con-
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-
toms reflect either poor compensation after an acute vesti-
bular loss or gradual, continuous loss of vestibular function.
The symptoms worsen with fatigue or in darkness. Acoustic
neuromas or other space-occupying lesions in the posterior
fossa are the most common causes of gradual deterioration
of vestibular dysfunction.
A bilateral symmetrical loss of vestibular function builds
to a maximum intensity of dysequilibrium for days. Vertigo
at times precedes the progressive symptoms relating to sta-
tion and gait. Young healthy patients stagger in early stages
of bilateral loss, and the elderly may require a walker. The
greatest improvement in station and gait occurs within
6 weeks. Within 6 months the young patient walks with a
wide-based gait, but still feels imbalance on bending or
other rapid changes in head or body position.
Symptoms of Vestibular Disease 177
Dizziness
Any vague sensations of discomfort in the head can be
described as dizziness. Other descriptors include light-
headedness, wooziness, or disorientation. This is the most
common symptom that the patient describes on initial con-
sultation with the otologist. Spatial disorientation is the best
term to describe these symptoms as they relate to vestibu-
lar dysfunction. These symptoms must be sought out in the
history since they are difficult for the patient to describe.
Spatial disorientation is the prime indicator of poor
vestibular compensation and includes head-eye dyscoordi-
nation and postural dysfunction. Most patients with poor
vestibular compensation are visually dependent, so that
either loss of visual cues or conflicting or ambiguous sen-
sory cues enhance the symptoms (supermarket syndrome).
Head-eye dyscoordination occurs in bilateral vestibular
loss or cerebellar dysfunction. In less severe conditions
only active head movements produce dyscoordination,
whereas in severe cases with high-frequency range vestibu-
lar loss, the visual field cannot be stabilized with passive
whole-body movement (oscillopsia). Postural dysfunction
occurs in bilateral vestibular loss and demonstrates itself
as postural disorientation or abnormal postural motor
responses to movement. It is exemplified by the develop-
ment of a wide-based gait and loss of hip strategy for pos-
tural control in patients with bilateral vestibular lesions.
Syncope
Episodic loss of consciousness is a rare presentation of
vestibular dysfunction because either the function of both
cerebral hemispheres or the brainstem reticular formation
must be compromised to produce the symptom. Sudden
onset without prodromal features; focal sensory or motor
phenomena; and olfactory, gustatory, or other hallucina-
tions indicates seizure activity. Syncope as the cause for loss
of consciousness is explained on a vascular basis. Diffuse
CNS dysfunction produced by reduced cerebral blood flow
is indicated by progressive lightheadedness, faintness, or
dimming of vision. The causes for hypoperfusion are gen-
erally cardiac (Table 8-2).
More rarely, ischemia of the posterior cerebral circulation
produces syncope. In such cases vertigo may be associated
TABLE 8-2. Causes for Hypoperfusion
Valvular stenosis (aortic, pulmonic, mitral)
Mitral valve prolapse
Hypertrophic cardiomyopathy
Left atrial myxoma or thrombus
Constrictive pericarditis
Cardiac tamponade
Atrial flutter/fibrillation
Paroxysmal atrial tachycardia
Sinus bradycardia
Sinus arrest
Second- or third-degree heart block
Sick sinus syndrome
Pacemaker failure or malfunction
Ventricular tachycardia
Ventricular fibrillation
Drug toxicity
178 SYMPTOMS OF NEUROTOLOGIC DISEASE
with other symptoms such as diplopia, dysphagia, dysarthria,
occipital headaches, and other motor or sensory symptoms.
SYMPTOMS OF SPECIFIC
VESTIBULAR DISORDERS
Although not completely reliable, specific vestibular symp-
toms generally do relate to particular areas of the vestibular
apparatus. The labyrinth and vestibular nerve are consid-
ered the peripheral vestibular system, whereas the brain-
stem is the site of central vestibular pathology. Although
somewhat artificial, it is helpful to group vestibular disor-
ders according to the location of the dysfunction to arrive at
a better understanding of the symptoms associated with
each region.
The Labyrinth
Peripheral disease is the most common cause for vestibular
dysfunction. Symptoms are most severe and are associated
with vegetative symptoms. In the acute stages of the disease,
symptoms are self-limiting, with periods of normal func-
tion interspersed between symptomatic events. Symptoms
become more chronic and usually less severe when the dis-
ease causes permanent neural damage. In many cases the
symptoms of the vestibular disorders are on a continuum,
and the diagnoses must be considered on such a dynamic
disease continuum rather than a simply static condition.
Acute labyrinthitis is the most common form of episodic
vestibular dysfunction. The cause of this condition is usu-
ally viral, but can also be bacterial. A previously asympto-
matic patient experiences an acute onset of whirling
vertigo that builds over 1 hour to severe prostration with
nausea, vomiting, pallor, diaphoresis, and a complete
inability to function in the upright position. Symptoms can
last from 12 to 36 hours. The patient is bedridden for 1 to
3 days. The vertigo gradually resolves with brief, symptoms
recurring with head movement or perceived rapid move-
ments. Sudden movement or bending may produce stag-
gering or falling. Driving is difficult. Within 5 to 10 days
the patient resumes near-normal activity. Recovery is age-
dependent, with little or no residual symptoms present by
2 to 3 months.
Most cases of acute labyrinthitis of viral origin do not
demonstrate auditory symptoms. When auditory symp-
toms are associated, a more definitive diagnosis may be
possible. Deafness and vestibular loss is associated with
4% to 10% of measles infections and is mainly bilateral.
Mumps, on the other hand, is usually associated with a uni-
lateral hearing loss of varying degrees. Infectious mononu-
cleosis, although rare, should be considered in teenagers,
and cytomegalic inclusion disease can produce severe audi-
tory and vestibular dysfunction in infants. The diagnosis of
herpes zoster as the cause of acute labyrinthitis can be made
in the presence of facial paralysis and a vesicular eruption in
and around the external auditory canal. Herpes zoster is
associated with varying degrees of hearing loss as well.
Either acute or chronic bacterial infections may produce
vestibular dysfunction. Acute labyrinthitis may be caused by
penetration of bacterial toxins through the round window
membrane during acute otitis media. At times the hearing
loss associated with the infection may be sensorineural, indi-
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.
Benign paroxysmal positional vertigo (BPPV ) is a benign,
self-limiting form of vestibular dysfunction that can be
diagnosed accurately through history. Known as postural
vertigo, positional vertigo, and cupulolithiasis, this condi-
tion produces sudden attacks of brief vertigo through head
movement. Attacks can be induced by rolling in bed or
turning the head from one side to the other, but not both
sides. Extending the head to look up, turning the head, or
looking down precipitates the symptoms. The vertigo is
associated with an intense feeling of dysequilibrium, but
patients rarely lose motor control and fall. Mild nausea can
occur during or immediately after an attack. Vomiting
after the positional change is rare. Vertigo will subside
when the provocative position is maintained, but patients
do not retain this position because of the often intensely
disagreeable feeling encountered on assumption of the
provocative position. BPPV classically persists for several
weeks with complete resolution of vertigo. It is not unusual
for patients to have a recurrence of symptoms months to
years later. On rare occasions, positional vertigo persists. In
such cases a complete vestibular test battery should be per-
formed to identify a more significant vestibular pathology
as the source of the symptoms.
The accepted, although unproven, explanation for BPPV
stems from the deposition of inorganic deposits on the
cupula of the posterior semicircular canal. Schuknecht has
demonstrated basophilic deposits in the cupula of the pos-
terior canal in two patients, loosening of otoconia from the
otolithic membrane in cats after section of the anterior
vestibular artery, and the production of pure rotatory
nystagmus by stimulation of the posterior canal in isolation
to support the theory of cupulolithiasis. Loss of otoconia
from the macula through linear acceleration and impact
decelerations has been identified by several authors.
Symptoms of BPPV are recognized to occur spontaneously
or following labyrinthine concussion, otitis media, otologic
surgery, or occlusion of the anterior vestibular artery.
Endolymphatic hydrops produces vestibular dysfunction
associated with auditory symptoms of fullness, tinnitus,
and hearing loss. A change in one or several of these audi-
tory symptoms often precedes the vestibular symptoms.
Vertigo is sudden and is not precipitated by physical exer-
tion or movement. Emotional stress and fatigue can precip-
itate or enhance an attack and can extend the symptomatic
time period by either initiating repeated attacks of vertigo
or prolonging recovery from an attack. Vertigo varies in
severity and duration, although the classic attack lasts up to
several hours. Patients most commonly describe severe
whirling vertigo with nausea, vomiting, and prostration,
but symptoms may be as mild as swaying, to-and-fro eye
movements, or dysequilibrium. Vestibular symptoms can
totally disappear within hours. In severe cases or the
middle to late stages of the disease, however, patients may
experience unsteadiness or spatial disorientation for hours
to days afterward. The frequency of the vertigo attacks is
partly dependent on the stage and severity of the disease.
Patients may experience isolated attacks punctuated by
months to years of symptom-free existence. Other patients

experience attacks in series, for weeks to months, between
extended periods of remission. Decreasing intervals between
attacks or increasingly severe episodes of vertigo reflect
progression of the disease. In addition, the appearance of
chronic vestibular symptoms such as positional vertigo,
dysequilibrium, and spatial disorientation indicate that per-
manent vestibular dysfunction has occurred. Rarely, in
advanced stages of the disease, patients may experience
abrupt falling attacks (otolithic crisis of Tumarkin).
The high degree of variability of vestibular dysfunction in
endolymphatic hydrops is reflected even more by reviewing
subclasses of the disorder. Ménière’s disease is the classic
form of endolymphatic hydrops, composed of unilateral
sensorineural hearing loss, tinnitus, aural fullness, and
episodic vertigo. The severity of this condition varies greatly
from patient to patient, and symptoms within the patient
can change from episode to episode as well. Loudness
recruitment and intolerance and acoustic distortion are
common auditory symptoms, as is hearing loss. Little corre-
lation exists between the auditory and vestibular symptoms.
Hearing loss characteristically fluctuates, with primarily
low-tone sensorineural hearing loss being identified first.
Hearing loss progresses to a flat severe loss in most cases,
with total hearing loss rarely occurring. Classic auditory
(cochlear Ménière’s) or vestibular (vestibular Ménière’s)
symptoms alone constitute atypical forms of this disorder.
Other variations in auditory and vestibular symptoms of
endolymphatic hydrops have been identified. Delayed
endolymphatic hydrops can occur in patients with unilateral
congenital deafness. Vestibular symptoms usually begin
abruptly in the mid-20s. Episodic, severe, whirling vertigo
lasting minutes occurs frequently, often several times a day.
Vertigo can be aggravated by positional changes or per-
ceived visual motion. Nausea can be a predominant feature,
and vertigo and prostration are less common. Tinnitus and
aural fullness may be appreciated in the ear as well. Post-
traumatic endolymphatic hydrops can develop months
to years after traumatic injury to the labyrinth. The symp-
toms can range from a classic Ménière’s disease picture to
isolated episodes of fullness associated with vestibular symp-
toms. Some type of auditory symptom is present in this con-
dition. Vertigo is generally episodic but less severe than the
classic Ménière’s attack. Whirling vertigo, swaying, and
severe dysequilibrium are all described. The attack may be
more prolonged than the classic syndrome. Vegetative
symptoms are often less severe, with an annoying sensation
of nausea lingering in many patients. This sensation some-
times is unrelated to noticeable vestibular symptoms. Drop
attacks are slightly more frequent in post-traumatic patients
than in classic Ménière’s disease. Vestibular symptoms simi-
lar to endolymphatic hydrops have been recognized on a
limited basis in otosclerosis. Aural fullness is associated with
the acute vertigo attacks, which are less severe than classic
Ménière’s disease. Other patients with otosclerosis complain
of positional vertigo or episodic dysequilibrium.
Vestibular symptoms associated with perilymph fistula are
at times indistinguishable from those of endolymphatic
hydrops. An abrupt onset of whirling vertigo with vegeta-
tive symptoms after straining, exertion, or head trauma may
be the initial symptoms. The vertigo can last several hours,
with the usual vestibular compensation occurring if the
fistula closes. In cases of persistent perilymph fistula,
Symptoms of Vestibular Disease 179
vestibular symptoms occur in approximately 80% of
patients and can vary from recurrent, episodic vertigo to
positional vertigo, dysequilibrium, spatial disorientation,
motion intolerance, or a combination of these. The symp-
toms are generally episodic and can often be related to
exertion or straining. Dysequilibrium occurs in almost all
cases. Spatial disorientation is more common than vertigo,
which occurs in about 75% of patients. Nausea is a more
prominent feature than vomiting, which occurs in less than
half of patients. Auditory symptoms are the sole presenting
symptom of perilymph fistula in less than 10% of patients.
Hearing loss, tinnitus, aural fullness, and hyperacusis occur
alone or in combination in more than 80% of perilymph
fistula patients with vertigo.
Fistulization of the bony labyrinth produces a variety
of vestibular and auditory symptoms. Symptoms of the
superior canal dehiscence syndrome are more specific than
those of a perilymph fistula. This unusual condition must
be considered when vertigo or oscillopsia is evoked by
loud sounds or activities that change middle ear or
intracranial pressure. Patients often develop chronic dyse-
quilibrium, hyperacusis, and gaze-evoked tinnitus, but
hearing is normal. Fistulization of a semicircular canal,
usually the lateral canal, occurs in 7% to 14% of patients
with cholesteatoma. Vertigo often occurs suddenly and is
associated with hearing loss. Sudden vertigo with deafness
and a history of chronic ear disease should alert the otolo-
gist to the diagnosis of a labyrinthine fistula.
Traumatic head injury, especially if the temporal bone is
involved, can produce either immediate or delayed symp-
toms of vestibular dysfunction. Positional vertigo commonly
occurs after any head injury. Labyrinthine concussion can be
associated with any head injury and produces mild unsteadi-
ness or lightheadedness, especially on changes in head
position. An associated high-frequency sensorineural hear-
ing loss may be present. The vestibular symptoms generally
resolve during a period of several months. Cupulolithiasis
can be caused by head injury. Temporal bone fractures are
associated with more severe injury to the labyrinth. Abrupt
onset of severe vertigo with nausea and vomiting indicates
that a transverse temporal bone fracture has occurred. Total
hearing loss is also noted. Because many patients with
severe head injury are comatose, labyrinthine injury may be
identified in various stages of vestibular compensation.
Often the patient describes dysequilibrium as the first
symptom once ambulation has begun. Mild unsteadiness
may persist for 3 to 6 months, with the patient falling to
the involved side. Labyrinthine concussion in the opposite
ear may muddy the picture. Longitudinal temporal bone frac-
tures are more common and produce less severe vestibular
symptoms. Unless a perilymphatic fistula has occurred
because of ossicular chain damage (which is common),
severe vertigo is rare. Symptoms of labyrinthine concussion
are more likely, with vertigo or dysequilibrium noted on
movement or changes in head position.
Sudden, severe, incapacitating vertigo with roaring tinnitus
and total hearing loss (labyrinthine apoplexy) usually sug-
gests labyrinthine hemorrhage. Vertigo slowly resolves during
a period of 3 to 4 weeks with slow vestibular compensation.
The presentation of the symptoms can lead to a fairly close
presumption of the type of vascular injury that has occurred.
Symptoms that began in the early morning or shortly after
180 SYMPTOMS OF NEUROTOLOGIC DISEASE
arising reflect a thrombotic phenomenon, but vertigo
appearing after exertion or a hypertensive crisis suggests vas-
cular rupture. The possibility of perilymphatic fistula must
also be entertained with the exertional history. Other causes
of labyrinthine hemorrhage include leukemic infiltrates and
hemorrhage and sickle cell crisis with thrombosis.
Metabolic derangements may produce vestibular symptoms
primarily or interfere with the compensatory mechanisms
of a preexisting vestibular dysfunction. Elevated serum
lipids, diabetes mellitus, hypothyroidism, and allergy may
produce the spectrum of vestibular symptoms. Vertigo is
usually not as severe and not associated with such severe
vegetative symptoms as cases of unilateral loss of vestibular
function. Symptoms appear more constant than episodic.
Dysequilibrium and spatial disorientation are common and
can be almost continuous. Auditory symptoms are unusual
in these conditions.
The aminoglycoside class of antibiotics is well recognized
as a cause for vestibular damage. Streptomycin, gentamicin,
tobramycin, amikacin, and viomycin are primarily vestibu-
lotoxic. In general, symptoms of ototoxicity include a pro-
gressive unsteadiness followed by ataxia, anorexia, nausea,
and occasional vomiting. Acute vertigo is an unusual pres-
entation of ototoxicity. Ataxia commonly persists to a mild
degree afterward. If total ablation of vestibular function
has occurred, the patient will complain of oscillopsia.
Intravenous erythromycin or minocycyline not uncom-
monly causes mild, transient vertigo with or without hear-
ing loss. These symptoms are often reversible with cessation
of therapy.
Acute vestibular dysfunction, usually associated with
severe hearing loss or deafness, can be seen in collagen
vascular diseases, which include rheumatoid arthritis,
polyarteritis nodosa, temporal arteritis, nonsyphilitic inter-
stitial keratitis, dermatomyositis, scleroderma, disseminated
lupus erythematosus, Wegener’s granulomatosis, rheumatic
fever, and relapsing polychondritis. Sudden, severe vertigo
with roaring tinnitus and total hearing loss (labyrinthine
apoplexy) can be a result of an acute hemorrhage often
seen in Wegener’s granulomatosis. These symptoms usually
occur later in the disease along with granulomatous involve-
ment of the upper respiratory tract, maxillary swelling,
saddle nose deformity, proptosis, and palatal ulcerations.
By this stage most patients also demonstrate pulmonary
and renal involvement. The other connective tissue disor-
ders produce similar acute symptoms that often can be
improved with corticosteroid therapy. Nonsyphilitic intersti-
tial keratitis (Cogan’s syndrome) occurs in young adults and
usually begins with auditory and ocular symptoms. Sudden
onset of vertigo with nausea, vomiting, and tinnitus can
occur with rapid onset of deafness. The disease is often
bilateral and pathologically resembles endolymphatic
hydrops. Temporal arteritis occurs in the elderly and is asso-
ciated with temporal headache, scalp tenderness, and fever
in addition to inner ear symptoms. Relapsing polychondritis
produces systemic symptoms such as joint pains, cough,
fever, malaise, and fatigue in addition to intermittent
hyperemia and swelling of the auricles or nasal septum and
eye findings 2 to 3 years prior to the onset of acute vestibu-
lar symptoms.
Spirochetal disorders can produce vestibular symptoms
that resemble the range found in endolymphatic hydrops.
Both acquired and congenital syphilis predominantly demon-
strate hearing loss and often acute vestibular dysfunction.
Congenital syphilis may present symptoms that are similar
to classic Ménière’s disease. Lyme disease is a similarly com-
plex spirochetal disorder that presents with a myriad of
systemic symptoms. Patients with the disorder can present
with acute vertigo, nausea, vomiting, malaise, and fluctuat-
ing hearing loss. Such patients have symptoms similar to
those for syphilitic dysfunction with otic involvement. A
common helpful diagnostic feature in these patients is a pos-
itive Tullio’s sign. Both disorders may produce vestibular
symptoms by otic capsule or leptomeningeal involvement.
Vestibular Nerve
Certain disorders affect the vestibular nerve alone and
produce symptoms that reflect the same variety of symp-
toms as disorders that primarily involve the labyrinth.
Vestibular neuritis (vestibular neuronitis, vestibular paraly-
sis, or epidemic vertigo) produces sudden severe vertigo
with nausea and vomiting. Vertigo often begins at night
and the duration of severe vertigo is longer than a classic
Ménière’s attack. There is no hearing loss. Vertigo sub-
sides over days, and the length of time for vestibular com-
pensation is variable, with dysequilibrium subsiding within
6 months. Persistence of symptoms suggests other diag-
noses, including multiple sclerosis, acoustic neuroma, and
vascular occlusion of the posterior fossa circulation.
Vestibular symptoms are uncommon as the presenting
symptom of an acoustic neuroma, despite the fact that the
tumor originates on the vestibular nerve. This partly may
be due to the slow-growing nature of the tumor so that an
episode of vertigo years prior may be forgotten. Sudden
vertigo with nausea and vomiting, similar to vestibular neu-
ritis, is reported to occur in 5% to 19% of patients. This
presenting symptom mainly occurs in patients with small
tumors. Compensation can be complete with no residual
symptoms. Dysequilibrium or unsteadiness is a more
common symptom later in the course of acoustic neuroma.
Patients may note the symptoms on rapid motion of the head
or body only or as a constant state. Constant symptoms are
associated with increasing tumor size, with impingement
on the cerebellum and brainstem occurring in addition to
encroachment on the vestibular nerves.
Vascular compression of the eighth nerve (cochleovestibular
nerve compression syndrome) remains a controversial diag-
nosis, because it is mainly a diagnosis of exclusion. This
diagnosis is made by magnetic resonance imaging or air-
contrast computed tomographic scan identification of a ves-
sel impinging on the eighth nerve. Vestibular symptoms
have ranged from acute vertigo with vegetative symptoms
to positional vertigo to continuous motion intolerance and
dysequilibrium. Motion intolerance is the most common
feature, and this symptom worsens as the day progresses.
Patients often demonstrate mid- or high-frequency sen-
sorineural hearing loss and tinnitus. The precise pathogenic
mechanism remains in question.
Central Nervous System
Classically, the differentiation between central and periph-
eral causes of vertigo has been made by the duration of

vertigo attacks, that is, episodic or constant. Although con-
stant vertigo is definitely associated with a central cause,
many central processes produce episodic vertigo, especially
in the early stages. Careful attention to other symptoms
referable to CNS dysfunction are important in diagnosing
these disorders.
Multiple sclerosis can present with transient episodes of
vertigo, blurred vision, focal weakness, numbness, tingling,
or limb unsteadiness. Dysequilibrium is a more common
presenting symptom than acute vertigo, although severe
acute vertigo with vegetative symptoms has been known to
occur. Because the symptoms are transient early in the dis-
ease, mild vertigo or dysequilibrium may be confused with
mild vestibular neuritis or acute, mild labyrinthitis. Sudden
sensorineural hearing loss can occur, with some recovery of
auditory function occurring in many patients.
Episodic vertigo may be a symptom of temporal lobe or
complex partial seizures. The symptoms vary, but they are
stereotypical for the individual. The average length of the
seizure is 1 to 3 minutes and includes epigastric sensations
along with affective, cognitive, and sensory symptoms.
Coordinated involuntary motor activity (automatisms)
occur in the orobuccolingual region and other areas of the
head and neck in most patients.
Acute vertigo may be part of the aura associated with a
classic migraine headache. This is usually a throbbing, unilat-
eral hemicranial pain that occurs after vertigo. Visual alter-
ations (hemianopic field defects, scotomas and scintillations,
photophobia), nausea, and vomiting are common. Less
commonly, diarrhea, light-headedness, fainting, and fluid
retention can be present. Vestibular symptoms may also
occur during the headache-free interval (migraine equiva-
lent). Severe whirling vertigo may last from minutes to
hours and is often associated with nausea and vomiting. In
severe cases hearing loss and tinnitus may accompany the
vertigo. Vertigo may occur several times a year or on a more
frequent basis. Occasionally, near-constant dysequilibrium
and unsteadiness may occur. Other neurologic symptoms
such as slurred speech, leg weakness, or diplopia and a
history of migraine are important diagnostic features.
Vascular disorders are the most common cause of cen-
tral vestibular dysfunction and present with the entire
spectrum of vestibular symptoms. Vertebrobasilar ischemia, a
result of arteriosclerosis, generally occurs in the older age
group. Spontaneous, short episodes of vertigo occur and
recur frequently. Such attacks may be precipitated by head
movement. With increasing hypoxia, facial numbness or
tingling, slurred speech, and other sensory disturbances
may occur. Thrombosis of the internal auditory artery
(labyrinthine apoplexy), usually a branch of the anterior
inferior cerebellar artery, produces severe, sudden vertigo,
roaring tinnitus, and total hearing loss. Acute vertigo,
nausea, and vomiting, along with dysphagia, hoarseness,
Horner’s syndrome, limb ataxia, sensory impairment over
the face, and loss of touch and position in the limbs is evi-
dence of a lateral medullary infarct ( Wallenberg’s syndrome).
Patients note lateral pulsion to the side of the lesion.
Hearing loss is generally not associated. Residual symptoms
Symptoms of Vestibular Disease 181
are common, and their extent depends on the degree of the
infarct. Cerebellar infarction may present with similar
symptoms. Severe unsteadiness or ataxia combined with
ophthalmoplegia and confusion compose the classic triad
of Wernicke’s encephalopathy. This disorder, most common
in alcoholics, is the result of thiamine deficiency with
involvement of the brainstem and cerebellum. The
vestibular symptoms can often be reversed over weeks to
months with administration of thiamine.
Vestibular symptoms often occur after cervical injury.
Patients may experience brief episodes of vertigo, espe-
cially on positional changes, or may complain of dysequi-
librium. Labyrinthine concussion may be coincident and
therefore complicate the patient’s symptoms. In the
absence of positive findings on the vestibular test battery,
the source for the vestibular symptoms must relate to the
interaction of the neck proprioceptors with the vestibular
nuclei. This cervical vertigo is usually self-limited and usu-
ally responds to physical therapy to reduce the neck
spasms associated with the injury.
BIBLIOGRAPHY
Alpers BJ: Vertigo: Its neurological features. Trans Am Acad Ophthalmol
Otolaryngol 46:38–54, 1941.
Ballenger JJ: Diseases of the Nose, Throat, Ear, Head, and Neck.
Philadelphia, Lea & Febiger, 1977.
Black FO, et al: Surgical management of perilymph fistulas. Arch
Otolaryngol Head Neck Surg 117:641–648, 1991.
Drachman DA, Hart CW: Dizziness as a symptom of vestibular disease.
Neurology 22:323–334, 1973.
Harker LA, Rassekh C: Episodic vertigo in basilar artery migraine.
Otolaryngol Head Neck Surg 96:239–250, 1987.
Harker LA, Rassekh C: Migraine equivalent as a cause of episodic
vertigo. Laryngoscope 98:160–164, 1988.
Igarashi M: Vestibular compensation: An overview. Acta Otolaryngol
(Stockh) 406:78–82, 1984.
McCabe BF: Vestibular physiology: Its clinical application in under-
standing the dizzy patient. In Paparella M (ed.): Otolaryngology,
vol 1. Philadelphia, WB Saunders, 1980.
McNally WJ, Stuart EA: Vertigo from the standpoint of the otolaryngol-
ogist. Trans Am Acad Ophthalmol Otolaryngol 46:33–37, 1941.
Minor LB: Superior canal dehiscence syndrome. Am J Otol 21:9–19, 2000.
Paparella MM, Chasin WD: Otosclerosis and vertigo. J Laryngol Otol
80:511–519, 1966.
Paparella MM, Sugiura S: The pathology of suppurative labyrinthitis.
Ann Otol Rhinol Laryngol 76:554–586, 1967.
Schuknecht HF: Pathology of the Ear. Cambridge, MA, Harvard
University Press, 1974.
Schwaber MK: Cochleovestibular nerve compression syndrome. I.
Clinical analysis and audiovestibular test findings. Laryngoscope 102:
1020–1029, 1992.
Selesnick SH, Jackler RK: Clinical manifestations and audiologic diagno-
sis of acoustic neuromas. Otolaryngol Clin N Am 25:521–552, 1992.
Seltzer S, McCabe BF: Perilymph fistula: The Iowa experience.
Laryngoscope 94:37–49, 1986.
Sidorov JE, et al: Metabolic abnormalities and vertigo. Arch Intern Med
147:197–203, 1987.
Simon RP, Aminoff MJ, Greenberg DA: Clinical Neurology. East
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
management. These developments have also encouraged
research directed at the identification of the cause of tinni-
tus, and attempts have been made to determine the
anatomic location of the physiologic abnormalities that
cause specific types of tinnitus.
There are essentially two types of tinnitus. One type,
known as objective tinnitus, is a result of sounds that are gen-
erated in the body. The second type, subjective tinnitus, can
be heard only by the individual experiencing the tinnitus.
Objective tinnitus, which is rare, may be caused by vas-
cular anomalies that facilitate turbulent blood flow in the
region of the ear. This type of tinnitus represents a normal
perception of the sound, possibly conducted to the cochlea
by bony tissue, that results from such turbulent flow. Such
tinnitus may be pulsatile in nature, with the frequency of
the pulsations being the same as the individual’s heart rate.
Pulsatile tinnitus may occur in association with arterio-
venous malformations, glomus tumors, or aneurysms.
Objective tinnitus may also present as a clicking sound in
association with, for example, temporomandibular joint
disorders or as a result of spontaneous contractions of
middle ear muscles or palatal myoclonus.1 A patulous
182
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
the auditory system but is caused by a physical sound gen-
erated in the body and sensed in the normal way, this type
of tinnitus can usually also be heard by an observer when
proper auscultation techniques are used. We will not dis-
cuss further this particular type of tinnitus, which presum-
ably is processed by the auditory system in a way similar to
the way any other sound is processed. (For details about
objective tinnitus, see Schleuning1 and Andersen and
Meyerhoff 2).
Subjective tinnitus is characterized by an individual’s
perception of a sound in the absence of any physical sound,
and of course this sound cannot be heard by an observer.
Subjective tinnitus is more common than objective tinni-
tus and reflects an abnormality of the ear or the auditory
nervous system. Subjective tinnitus is similar to paresthe-
sia of the somatosensory system, but many forms of tinni-
tus have even greater similarities with central neuropathic
pain.3 The visual, olfactory, and gustatory sensory systems
are rarely affected by phenomena similar to tinnitus.
Most adults have occasionally experienced low-intensity
tinnitus or a more constant type of tinnitus that can easily
be masked by another sound. Tinnitus of this nature is

normally benign and it does not require any medical atten-
tion, but patients with that kind of tinnitus may benefit
from appropriate neurotologic examination to ensure that
tinnitus is not due to a treatable condition, such as a
vestibular schwannoma. However, when subjective tinni-
tus is so intense that it interferes noticeably with a person’s
daily life, it must be of concern to the neurotologist. The
pathophysiology and subjective nature of that kind of tin-
nitus has many similarities with neuropathic (central)
pain,3 including that of being a formidable challenge to the
physician. It may be associated with a history of exposure
to noise, vestibular schwannomas, or with Ménière’s dis-
ease, but often no cause can be identified.
In this chapter, the nature, pathogenesis, and patho-
physiology of different forms of subjective tinnitus are
discussed and the literature regarding the treatment of
tinnitus is reviewed.
NATURE OF SUBJECTIVE TINNITUS
Subjective tinnitus may be perceived as coming from one
ear only, from both ears with different or nearly equal
intensity, or from inside the head. (Often when tinnitus in
one ear has reached an incapacitating level, it is also per-
ceived to be in the other ear.) Tinnitus may be constant
or may vary in severity from time to time, without any
apparent cause for the variation. Conversely, variations in
intensity may be related to external events such as expo-
sure to loud sounds, ingestion of certain drugs or food, or
to changes in the patient’s stress level or physical activities.
Considerable individual differences exist in the intensity
and regularity of tinnitus, and the effects that subjective
tinnitus have on everyday life are related to these factors.
The benign tinnitus that most people occasionally experi-
ence may appear as a weak pure tone, a ringing sound, or
a soft hissing sound. Most patients with tinnitus find it dif-
ficult to describe how their tinnitus sounds. The intensity
and character of the type of tinnitus that is incapacitating
may be likened to a shrill chirping sound, similar to that
made by crickets, or to a roaring noise like that made by a
jet engine at close proximity. Severe tinnitus is often asso-
ciated with hypersensitivity to sound and an exaggerated
perception of loudness (hyperacusis). (Individuals with
Williams syndrome, infantile hypercalcemia, have a high
incidence of hyperacusis4,5). Patients with severe tinnitus
may perceive some sounds as distorted, and some of these
patients experience a sensation similar to pain from sound,
which they often describe as being more troublesome than
the tinnitus itself. In some patients, strong impulsive
sounds can cause their tinnitus to increase, and that
increase may be maintained long after the sounds that
caused the increase in the tinnitus have disappeared.
Tinnitus is often associated with affective disorders such as
depression, and some sounds can elicit fear in some indi-
viduals with pain (phonophobia).3,6
QUANTIFICATION OF TINNITUS
Several methods have been devised to quantify the intensity
and character of tinnitus. Matching and masking have
Tinnitus 183
been used to quantify the nature and loudness of tinnitus,
but the correspondence is typically poor between the
results of masking and matching studies and the degree of
annoyance the tinnitus causes in different patients. Studies
agree that masking and matching tests show very low
estimates of sound intensities even by patients who experi-
ence severe annoyance from the tinnitus.7,8 For example,
one study estimated the loudness of tinnitus by matching
the loudness of a sound presented to the ear without
tinnitus (or the lesser affected ear) and found that 75% of
the patients matched their tinnitus to sounds that were at
a 10-dB sensation level (SL) or less. In fact, in about half
of the patients tested, the loudness of the sounds to which
they matched their tinnitus was only a 5-dB SL. Vernon9
reported that only 1 of the 513 patients he tested had
tinnitus that the individual matched to a high-intensity
(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
(23.9 versus 6.6 dB, averaged in nine subjects),10 but even
these higher values seem low compared with the degree of
annoyance reportedly caused by tinnitus.
These studies thus show that masking does not have the
same effect on tinnitus as it would if the sound sensa-
tion were caused by a physical sound. This discrepancy
between the results of loudness matching and the degree
of annoyance reported by patients with has led to specula-
tion that the methods used to estimate loudness were
invalid, that loudness recruitment somehow affected the
results, or that the level of annoyance caused by tinnitus is
not directly related to its perceived loudness.9 Some inves-
tigators have interpreted these findings to indicate that
emotional factors play a role in the way patients perceive
their tinnitus.8,9,11,12 It seems more likely, however, that the
neural code generating the tinnitus is different from the
one generated by physical sounds. The neural activity that
causes the tinnitus is either generated by neurons of the
ascending auditory pathways independent of input from
the periphery of the auditory system, or it may be gener-
ated by neural structures that are not normally activated by
sounds. This latter possibility may explain why the results of
matching studies seem to underestimate the loudness of the
tinnitus and thus its severity.
Therefore a classification system based on the patients’
own estimate of the severity of the tinnitus8 seems to be
more valuable than one based on matching or masking
studies. The proposed classification defines three degrees
of severity: slight, moderate, or severe. Slight is used to
describe tinnitus that is not constant and usually bothers
the patient only in a quiet environment; moderate
describes tinnitus that is more intense and constantly
present and bothers the patient when he or she tries to
concentrate; it also disturbs sleep. Tinnitus that elicits
serious complaints from the patient, interferes greatly with
the patient’s ability to concentrate, and inhibits sleep is
classified as severe. The classification of severe is used for
incapacitating tinnitus.
The present diagnostic methods, such as various forms
of imagining techniques, cannot identify the morphologic
and functional abnormalities that cause tinnitus, thus mak-
ing differential diagnosis of tinnitus a challenge for the
physician. Although it may be helpful to determine
184 SYMPTOMS OF NEUROTOLOGIC DISEASE
whether tinnitus is pulsatile and the pulsations are syn-
chronous with the patient’s heartbeat, it is of little impor-
tance to know the nature of the sound perceived, such as
whether the tinnitus resembles a high-frequency or low-
frequency sound, because no relationship has been estab-
lished between these factors and the anatomic location of
the abnormality causing the tinnitus.
Considerable similarities occur between severe tinnitus
and pain,3,13 especially central neuropathic pain. Both
severe tinnitus and neuropathic pain occur in the absence
of objective signs, and the perception of both tinnitus and
pain vary as a result of circumstances. Both symptoms
are difficult to describe, and different individuals may
describe symptoms differently. Patients with chronic neu-
ropathic pain typically experience normal stimulation of
the skin to be painful (allodynia*), and such patients may
also have an exaggerated sensation from acute somatic pain
(hyperpathia†).
In a similar way many patients with severe tinnitus often
perceive normal sounds as stronger than normal (hypera-
cusis), and sounds that normally do not elicit any unpleas-
ant sensations may be perceived as unpleasant or even
painful. Many individuals with severe tinnitus perceive
strong sounds as being extremely unpleasant and even
painful, thus experiencing a phenomenon similar to hyper-
pathia. Individuals with neuropathic central pain often
experience increasingly painful sensations from somatic
stimulation repeated at short intervals. This phenomenon,
known as the “wind-up” phenomenon13,15,16 often occurs
together with severe pain and is described as a worsening
of pain sensations from repeated stimulation with the same
stimulus. Many individuals with severe tinnitus have anal-
ogous sensations from sounds that are repeated. Exposure
to strong sounds may cause a patient’s tinnitus to increase
for a long time after the sound has ended.
As in many patients with severe neuropathic pain, no
treatable cause can be found in many patients with severe
tinnitus. When it has been determined that the tinnitus is
not caused by a treatable illness, the objective of treatment
is to eliminate or alleviate the symptoms.
PATHOGENESIS OF SUBJECTIVE 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
available diagnostic modalities. Some conditions, however,
are well known to cause subjective tinnitus, including noise
exposure, particularly exposure to impulsive noise; many
pharmacologic agents; and some pathologic conditions,
such as vestibular schwannoma, vascular compression of
the auditory nerve, and arteriovenous malformations.
Subjective tinnitus is one of the three symptoms that
define Ménière’s disease. Otosclerosis may also be associ-
ated with tinnitus, specifically the cochlear type.
*The term allodynia is usually defined to mean the pain elicited by stim-
uli that ordinarily are innocuous.14
†
The word hyperpathia is used to describe an explosive increase in reac-
tion to pain when a painful stimulus exceeds a certain threshold, with a
continuing sensation of pain after the stimulation has ceased.14
Noise-induced tinnitus is perhaps the most common
type of tinnitus, but tinnitus is not always associated with
noise-induced hearing loss. The most severe noise-
induced tinnitus is caused by impulsive noise. Tinnitus
caused by noise is worse immediately after exposure to
noise and then gradually decreases after the end of the
exposure. Hearing loss that affects high frequencies and
occurs gradually through the process of aging (presbycusis)
is sometimes accompanied by tinnitus.
The first symptom of a vestibular schwannoma is almost
always tinnitus, and such tinnitus frequently persists after
the tumor has been removed even when the patient’s hear-
ing has been successfully preserved during tumor removal.
In fact, tinnitus may even be worse postoperatively, prob-
ably as a result of intraoperative injury to the auditory
nerve as a result of surgical manipulation.17 Surgical
manipulations of the intracranial portion of the eighth
nerve in other types of operations such as microvascular
decompression (MVD) to relieve hemifacial spasm (HFS),
trigeminal neuralgia (TGN), or disabling positional ver-
tigo (DPV) can cause tinnitus in addition to hearing loss.
Recently it has been recognized that vascular compres-
sion of the intracranial portion of the auditory portion of
the eighth cranial nerve can cause tinnitus. Tinnitus due to
this cause may be alleviated by moving the blood vessel off
the eighth nerve.18–20
Many pharmacologic agents can induce tinnitus.21 Two
of the best known of these agents are aspirin (acetylsalicy-
late) and aminoglycoside antibiotics. Other drugs that can
cause hearing loss and induce tinnitus as well are loop
diuretics (furosemide, ethacrynic acid), quinine, indo-
methacin, aminoglycoside antibiotics, and cisplatin.21,22
Carbamazepine, tetracycline, antipsychotic drugs, lithium,
tricyclic antidepressants, monoamine oxidase inhibitors,
antihistamines, beta-adrenergic receptor blockers, local
anesthetics, and steroids (to name only a few) are other
drugs that can induce tinnitus, although they have not
been associated with hearing loss. Caffeine and alcohol can
also cause tinnitus. Tinnitus caused by pharmacologic
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
Davies21). Little is known about the mechanism by which
any of these agents produce tinnitus.
PATHOPHYSIOLOGY OF SUBJECTIVE
TINNITUS
As for other diseases, we want to know (1) the anatomic
location of the abnormality that causes the symptoms (tin-
nitus, hyperacusis, and affective symptoms such as phono-
phobia and depression), and (2) the nature of the
abnormalities (morphologic or functional).
Location of the Anatomic Abnormality
that Causes Tinnitus
Because the patient with subjective tinnitus often refers to
sensation as being “in the ear,” it has generally been
assumed that the anatomic location of the physiological
abnormality causing the tinnitus is in the ear. Therefore,

tinnitus has often been associated with pathologic
processes involving the ear, and many studies of the patho-
physiology of tinnitus have focused on the ear as the
location of the physiological abnormality that causes the
symptoms. Subsequent studies have found evidence that
the anatomic location of the generation of the abnormal
neural activity that causes tinnitus is not always the ear.
Severe tinnitus is probably most often caused by func-
tional abnormalities in the auditory nervous system such as
those induced by neural plasticity. Severe tinnitus can
probably also be caused by morphologic changes in the
auditory nerve and, rarely, in the nuclei of the ascending
auditory pathways. Tinnitus is often associated with other
symptoms such as hyperacusis and phonophobia, the
anatomic location of which may be the same as or differ-
ent from the place where the neural activity engendering
the tinnitus arises.
Abnormalities that Cause Tinnitus
Some forms of tinnitus may be caused directly by abnor-
malities in the ear. Studies in animals have shown that
direct electric current passed through the cochlea can
change the spontaneous activity in single auditory nerve
fibers. Studies of tinnitus have shown that electric current
passed through the cochlea (positive current applied to
the round window) can reduce the tinnitus in some
patients,23,24 supporting the hypothesis that tinnitus is
associated with the function of the cochlea and possibly
with increased spontaneous activity in auditory nerve
fibers.
Tinnitus, at least in some patients, may also be caused by
abnormalities in the function of the auditory nerve or
more rostral structures of the ascending auditory path-
ways. Studies in animals have shown that functional
changes may occur in auditory nuclei as a result of pathol-
ogy of the auditory periphery.25,26 Such electrical anom-
alies in specific nuclei of the ascending auditory pathway
may develop over time as an expression of neural plasticity
evoked by abnormal input or lack of input from the audi-
tory periphery. These anomalies may be in the form of
reorganization of the nuclei, which may result in hyperac-
tivity. Changes in brainstem nuclei caused by abnormal
input (or absence of input) usually take time to reverse
after cessation of the abnormal input, or the changes may
in fact be irreversible. Abnormalities of central nuclei may
rarely also develop as a result of a disease process or injury
to a nucleus.
Cochlear Injuries as a Cause
of Tinnitus
Injury to the cochlea from disease processes such as
Ménière’s disease, noise exposure, or administration of
ototoxic drugs can cause verifiable morphologic changes in
the sensory epithelium in the cochlea. The fact that these
morphologic changes are related to hearing loss has led to
the assumption that the tinnitus often accompanying such
changes is caused by similar pathologic cochlear changes
as those causing the hearing loss. However, animal studies
have shown that hearing loss can also cause changes
(hyperactivity of neurons) in nuclei of the ascending
Tinnitus 185
auditory pathways.25,26 These central changes may explain
how cochlear injuries cause tinnitus.
Conflicting results have been found in studies of the
spontaneous activity of single auditory nerve fibers in ani-
mals that were treated with pharmacologic agents, such as
salicylate and aminoglycoside antibiotics, known to induce
tinnitus in humans.27,28 Some investigators27,29,30 found
that salicylate and administered acutely to experimental
animals caused an increase in the spontaneous discharge
rates of single auditory nerve fibers, and other investiga-
tors have reported decreased spontaneous activity after
administration of kanamycin, an ototoxic antibiotic that
may cause hearing loss and tinnitus.28 Other experiments
revealed reduced spontaneous activity in animals after
exposure to sounds that caused hearing loss (and presum-
ably tinnitus)31–33 and in animals that have experienced
other forms of acute injury to the cochlea.34 These con-
flicting results regarding the relationship between changes
in the spontaneous activity of auditory nerve fibers and
tinnitus indicate that tinnitus is not related directly to the
discharge rate of auditory nerve fibers. Other properties
of auditory nerve activity such as phase-locking of the
activity in many nerve fibers or the time pattern of the
discharge may be more closely related to tinnitus than
the discharge rate.35,36
In summary, there is little support for tinnitus being
caused by increased activity of auditory nerve fibers due to
injuries of the cochlea. Rather, considerable evidence
points to deprivation of input to the auditory nerve as
causing hyperactivity in more central auditory structures,
and it seems likely that such hyperactivity may be respon-
sible for some forms of tinnitus and hyperacusis. This is
similar to some forms of central neuropathic pain.3,6
Tinnitus Caused by Injuries to the
Auditory Nervous System
Injuries of various kinds to the auditory nerve are very
likely the cause of tinnitus. Tinnitus from injury of the
auditory nerve is commonly caused by vestibular schwan-
noma, which almost always has tinnitus as its first symp-
tom, indicating that tinnitus can be triggered by injury,
irritation, or compression of the intracranial portion of
the auditory nerve. This does not necessarily mean that the
neural activity producing the tinnitus is generated in the
auditory nerve, but the tinnitus can also result from func-
tional changes in more rostral portions of the auditory
nervous system, induced by abnormal or decreased neural
activity in the auditory nerve through the expression of
neural plasticity. Deprivation of input is a strong promoter
of neural plasticity, which can bring about reorganization
of neural circuits as well as hyperactivity and hypersensi-
tivity (see Møller and Rollins13).
It is also known that close contact between the auditory
nerve and a blood vessel can induce tinnitus,18,19 but stud-
ies of patients undergoing MVD to relieve incapacitating
tinnitus who had surgically verified vascular contact
(vascular compression) of their auditory nerve did not
demonstrate any noticeable abnormalities in the function
of the nerve.37 Compound action potentials (CAPs)
recorded directly from the exposed intracranial portion of
the eighth nerve were not noticeably different from those
186 SYMPTOMS OF NEUROTOLOGIC DISEASE
recorded from patients who had similar hearing loss but no
tinnitus, and who were operated on to relieve vascular
compression of other cranial nerves.37 The latencies of
peak III of the brainstem auditory evoked potentials
(BAEP, AEP, or ABR) were not statistically different in
these two groups of patients either.37 Since approximately
40% of patients who undergo MVD to treat tinnitus are
cured or their tinnitus is considerably relieved after the
procedure,37 it seems highly likely that the tinnitus in these
patients was indeed caused by the effect of vascular com-
pression of the eighth nerve. Because of the absence of
statistically significant abnormalities in responses from
the auditory nerve and the cochlear nucleus (peak III
of the BA EP), we concluded that the anatomic location of
the physiological abnormality that generated the tinnitus
in these patients must have been rostral to the structures
from which we recorded and most likely induced by reor-
ganization of neural structures through expression of neural
plasticity.6,38
Another hypothesis suggests that tinnitus may result
from a pathologic correlation between the neural activity in
individual auditory nerve fibers.35,39 Such correlations may
be caused by abnormal communication between auditory
nerve fibers or hair cells.35 When no sound is present, the
time pattern of the spontaneous neural activity in auditory
nerve fibers is assumed to be uncorrelated. Sounds elicit
neural activity that is phase-locked to the waveform of a
sound, and the neural discharges in such nerve fibers will
become correlated. Such correlation may be important for
detecting the presence of sounds.35,36 Abnormal correlation
of neural activity in many nerve fibers that is not a result of
sounds in the ear may therefore cause tinnitus.35,39
The time pattern of spontaneous activity in single audi-
tory nerve fibers in animals receiving salicylate has been
found to be abnormal.29 The fact that salicylate can induce
tinnitus in humans supports the hypothesis that tinnitus is
associated with an abnormal time pattern of spontaneous
firing of auditory nerve fibers. It is known from other
systems that nuclei may be hyperactive because of novel
stimulation or deprivation. For example, some evidence
suggests that the cause of spasm in hemifacial spasm40,41
is an example of hyperactivity resulting from abnormal
input to the facial motonucleus. The changes in the
facial motonucleus has been likened to the “kindling”
phenomenon*.40
The fact that tinnitus cannot be masked in the same way
as an external sound also supports the assumption that tin-
nitus is not usually associated with the same type of auditory
nerve activity evoked by sound. Individual variability in the
efficacy of masking (i.e., sometimes contralateral masking is
effective) and the phenomenon of residual masking support
the hypothesis that tinnitus is not associated with the type
of neural activity evoked by sounds.44
There are thus indications that abnormal correlation
between activity in many auditory nerve fibers, abnormal
time pattern of firings of those fibers, or reduced activity
*The kindling phenomenon was first described by Goddard,42
who noted that animals (rats) whose amygdala nuclei were electrically
stimulated periodically over weeks developed seizures in response to the
stimulation.43
may cause changes in the function of neurons in more
central nuclei of the ascending auditory pathways.
Tinnitus Generated by Functional
Changes in Auditory Brainstem Nuclei
Studies in animals and patients with tinnitus have indi-
cated that subjective tinnitus is unlikely to be directly
caused by neural activity in the auditory nerve. It seems
more probable that higher auditory centers are involved
and that tinnitus may be caused by a complex interplay
between the auditory periphery (ear and auditory nerve)
and more rostral structures of the ascending auditory
pathway in the brainstem.
It is likely that abnormal input or lack of input from the
ear can, over time, cause reorganization of central auditory
structures in such a way that they become hyperactive.
Animal experiments have shown that deafferentation
(cochlear removal) can produce increased metabolic activity
in auditory nuclei,45 or changes in temporal integration
in the inferior colliculus (IC),26 which is another sign of
hyperactivity. In other animal experiments strong sound
stimulation has been shown to trigger hyperactivity in the
IC and to alter temporal integration.46
If hyperactivity caused by reorganization of auditory
nuclei becomes established, it may produce abnormal
neural activity for some time after normalization of the
peripheral anomaly that caused the reorganization. This
may explain why the expected effect of MVD of the audi-
tory nerve in patients with tinnitus is often delayed.18
Intracranial recordings from patients undergoing MVD
operations for incapacitating tinnitus have shown that the
latency of peak V in the click-evoked BAEP was slightly
shorter (but statistically significant) than that obtained in
patients with matched hearing loss and no tinnitus47 who
underwent MVD operations for other cranial nerve disor-
ders such as TGN. The shorter latency of peak V may be
a sign of hyperactivity of auditory nuclei. Also other stud-
ies indicate that the IC is involved in tinnitus.48
The pathophysiology of severe of tinnitus may have
similarities with that of other disorders produced by vas-
cular compression of a cranial nerve, such as HFS and
TGN.40,41,49 Recent intraoperative studies of patients
undergoing MVD to relieve HFS have shown that the
signs of physiological abnormalities in patients with HFS
are not caused by the vascular compression of the facial
nerve itself (or rather vascular contact with the facial
nerve), but instead are a result of hyperactivity of the facial
motonucleus induced by abnormal neural activity in the
facial motonucleus from the irritation caused by the vascu-
lar contact with the nerve.40,41 There are also indications
that the pain of TGN, which can be cured with a high
degree of success (80% to 85%) by MVD of the trigemi-
nal nerve, is a result of abnormalities in the trigeminal
sensory nucleus.20,50,51
Other similarities exist between incapacitating tinnitus
and disorders such as TGN and HFS. For example,
patients with incapacitating tinnitus usually have, at most,
moderate degrees of hearing loss similar to patients with
HFS, who have little or no detectable facial weakness, and
patients with TGN, who have little loss of sensation in the

face, despite excruciating pain or involuntary muscle con-
tractions that may involve the entire face.
Vascular compression (or rather irritation) of cranial
nerves is common in asymptomatic individuals with tinni-
tus and other hyperactive disorders such as HFS, TGN,
and glossopharyngeal neuralgia (GPN) that can be cured
by MVD of cranial nerves.49,52 Therefore, vascular com-
pression of cranial nerves is not a sufficient condition for
manifestation of pathology in these disorders, but since
these disorders can be cured effectively by MVD, the vas-
cular contact must be regarded as a necessary condition.41,49
The disorder that perhaps has the greatest similarity
with some forms of severe tinnitus is central neuropathic
pain. Tonndorf was one of the first to publish a possible
analogy53 between tinnitus and pain. His proposal sug-
gested a similarity with the Melzack-Wall gating hypoth-
esis for pain.54 This hypothesis postulates that input
from A-fibers normally suppresses neural transmission in
C-fibers, which conduct pain. More recently it has been
hypothesized that some forms of tinnitus have similarities
with neuropathic pain.3,13 Such pain is assumed to be a
result of functional changes in the central nervous system
(CNS) that are caused by the expression of neural plastic-
ity. That pain may be caused by reorganization of the nerv-
ous system induced by expression of neural plasticity has
been known for a long time.55,56 These changes may be
associated with hyperactivity, hypersensitivity, and altered
temporal integration. (Temporal integration means that
the response to a stimulus is affected by previous stimula-
tion, which is mostly a property of the CNS.)
Animal experiments have shown that normally the
behavioral threshold of the response to electrical stimula-
tion of auditory nuclei decreases exponentially with the
number of impulses presented, but after impairment of
hearing the threshold became lower and the threshold
did not decrease with an increasing number of impulses,
thus altering temporal integration.25,26 These changes are
similar to those of the somatosensory system present in
patients with neuropathic pain of central origin.57 In indi-
viduals without chronic pain, the threshold of pain to elec-
trical stimulation of the skin decreases exponentially as a
function of the repetition rate of the stimulation, but in
individuals with chronic pain, the pain threshold is much
lower and nearly independent of the stimulus rate, indicat-
ing that both the threshold and temporal integration of
painful stimuli are altered in individuals with chronic
pain.57 The “wind-up” phenomenon15,16 in pain is also an
expression of abnormal temporal integration.
A change in temporal integration is just one sign of
involvement of neural plasticity that may occur in some
forms of severe tinnitus. Rerouting of information is
another change that may be induced by neural plasticity
and may be involved in chronic severe pain. How changes
in the organization of the CNS may cause different forms
of tinnitus is, however, not known in detail.
Tinnitus and Neural Pathways
Activated by Sound
Tinnitus is often associated with hyperacusis, phonopho-
bia, and emotional reactions not normally associated
Tinnitus 187
with sounds. This means that tinnitus is either caused by
activation of neural circuits that are not normally activated
by sounds or by neural circuits that are normally activated
by sounds but altered (reorganized). The subcortical clas-
sical auditory pathways have no known input from other
sensory systems, and the finding that tinnitus can be
affected by somatosensory stimulation38,58,59 and by muscle
activity60 and other forms of cross-modulation61 therefore
indicates an abnormal involvement of neural circuits not
normally activated by sound.
Some neurons of the nonclassical auditory path-
ways6,62–65 (known as the polysensory pathway65) receive
input from the somatosensory system.64,66–68 This makes
it possible to test the hypothesis that the polysensory
auditory pathway is involved in severe tinnitus. If the pol-
ysensory system is involved in tinnitus, stimulating the
median nerve electrically would be expected to alter the
perception of the tinnitus.
Studies involving electrical stimulation of the median
nerve at the wrist (that gave a strong tingling sensation
but no pain) have shown indications that the nonclassical
auditory pathways are involved in some forms of tinnitus.
Such activation of the somatosensory system affected the
tinnitus in 10 of 26 patients (6 experienced a decrease
and 4 experienced an increase in the loudness).38 The input
from the somatosensory system is excitatory in some
neurons and inhibitory in others,64 which may explain
why some individuals experienced an increase in the
perception of their tinnitus while others experienced a
decrease.
The nonclassical system receives its auditory input from
the traditional classical auditory system at the level of the
IC64 to the external nucleus and the dorsal cortex of the
IC. These nuclei project to the dorsal thalamus, which
projects to association cortices and directly to the amyg-
dala6,69 (Fig. 9-1) (see also Chapter 2). The existence of
direct connections from the thalamic auditory nuclei to
the amygdala may explain the affective components associ-
ated with some forms of tinnitus as well as the abnormal
involvement of endocrine and sympathetic systems. The
hypothesis of abnormal activation of the amygdala in some
patients with severe tinnitus has been supported by studies
using functional MRI.70
Little is known about the normal role of the nonclassi-
cal ascending auditory pathway but a recent study has
shown evidence that the nonclassical auditory system is
commonly involved in the perception of the loudness of
sounds in children but rarely in adults.13
Abnormal activation of the nonclassical pathways may
be caused by neural plasticity, resulting in functional reor-
ganization of the nervous system. The efficacy of synapses
that connect the classical pathways with the nonclassical
pathways may increase as an expression of neural plasticity
elicited by deprivation of input, as happens in the spinal
cord after severance of dorsal roots,6,71 known as “unmask-
ing of dormant synapses.” In the auditory system, this
may occur at the midbrain level as well as probably at
the pontine level of the auditory system. Deprivation
of input to the auditory system may occur as a result
of hearing loss (most patients with severe tinnitus have
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
and Other Phantom Sensations
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
some forms of tinnitus and other phantom sensations.30
Out of that work grew a method for treating patients with
tinnitus (see section on Tinnitus Retraining Method).
Interaction with Tinnitus from Other
Sensory Systems
Involvement of the nonclassical auditory system was indi-
cated by the finding that stimulation of the somatosensory
system could interact with the perception of tinnitus in some
individuals with severe tinnitus.37 Subsequent studies have
confirmed and extended these observations, and other forms
of cross-modality interaction with tinnitus have been
described.58,59,61 The relief of tinnitus by electrical stimula-
tion of the skin behind the ears72 may act through stimula-
tion of the somatosensory system (trigeminal system) rather
than the cochlea. It has been shown recently that the audi-
tory system (cochlear nucleus) receives connections from the
trigeminal sensory ganglion.66–68 That the somatosensory
system (dorsal column nuclei) provides input to the nonclas-
sical parts of the midbrain auditory nuclei64 (see Chapter 2
and Møller6) may explain the relief of tinnitus by electrical
stimulation of the somatosensory system.73,74
Several studies have shown that eye movements can
affect tinnitus in some individuals58,59,61 as can contraction
of other muscles75 in other individuals.
Tinnitus and Affective Disorders
Tinnitus is often accompanied by affective symptoms such
as depression and phonophobia. These symptoms may be
related to involvement of the nonclassical auditory path-
ways, which use the dorsal and medial portion of the tha-
lamic auditory nucleus (medial geniculate body, MGB).6
These nuclei provide direct input to the lateral nucleus of
the amygdala and thereby channel “raw” auditory infor-
mation to limbic structures6,69 (see also Chapter 2). The
amygdala nuclei connect to many parts of the CNS (see
Fig. 9-1). Involvement of the nonclassical auditory system
in some individuals with severe tinnitus37 may therefore
explain why tinnitus is often accompanied by affective dis-
orders such as depression and why sound in such individ-
uals many evoke fear (phonophobia) and hyperacusis.76
This hypothesis was supported by studies using functional
MRI that show an abnormal activation of limbic structures
in some forms of tinnitus.70
The direct route from the thalamic nucleus (dorsal and
medial geniculate body) to limbic systems (the “low
route”)69 may conduct auditory information to the amyg-
dala in a pathway that it is little controlled by the CNS
(see Fig. 9-1). The amygdala nuclei normally receive
auditory input through a much longer route (the “high

route”),69 where there are ample possibilities for process-
ing the information before it reaches the amygdala, and
the information may be modulated by input from higher
CNS centers.
That different hypotheses are considered regarding the
anatomic location of the physiologic abnormalities that
cause severe tinnitus may indicate that tinnitus has many
different causes or, alternatively, a lack of knowledge about
the disorder (or perhaps both). One fact seems evident: The
pathophysiology of tinnitus is much more complex than
previously assumed. We can only hope that these hypothe-
ses will help to suggest experimental studies and guide the
interpretation of the results of such studies so as to eventu-
ally identify the cause(s) of this (or these) disorder(s).
TREATMENT OF TINNITUS
This section discusses treatments of tinnitus, hyperacusis,
and other related disorders. Treatment is severely ham-
pered by the insufficient knowledge about the mechanisms
and the cause of tinnitus and the individual differences
between the causes of tinnitus.
Although a variety of treatments have been tried for
alleviating tinnitus and many of these are effective for
some patients, no treatment can alleviate tinnitus in all
patients. One reason is that tinnitus is not one disorder but
many with similar symptoms. Few possibilities exist for
eliminating the cause of tinnitus. Most treatments for tin-
nitus are therefore directed at reducing the symptoms.
The treatments currently in use are medical (pharmaco-
logic), masking by sound retraining, and surgical.
Masking
The annoyance caused by some forms of tinnitus can be
decreased by masking77,78 and in some patients exposure to
sound (masking) reduces the tinnitus for a longer or
shorter period after termination of the noise exposure
(residual masking).44,77 Many patients with mild to moder-
ate levels of tinnitus experience a lessening of discomfort
when hearing background sounds from a radio (or other
soft sounds such as that produced by a fish tank filter
motor). A hearing aid can often be of help to patients with
severe tinnitus, maybe because it amplifies background
sounds. However, some patients with severe tinnitus do
not seem to benefit noticeably from such masking treat-
ment, and in fact external sounds often make the tinnitus
worse in some individuals.
Tinnitus Retraining
The tinnitus retraining (TRT) program79,80 grew out of
the assumption that tinnitus is a phantom sensation.30 It is
now widely used for treatment of tinnitus and hyperacu-
sis.81,82 The method makes use of a combination of coun-
seling and exposure to moderately strong sounds.
The beneficial effect of sound exposure depends on the
sounds used; moderate sound levels seem to help some
patients.80-82 The fact that tinnitus can be relieved by expo-
sure to specific sound stimulation may be regarded as a
method similar to that used to treat central neuropathic
Tinnitus 189
pain by electrical stimulation (transdermal electric nerve
stimulation, TENS83,84).
The outcome of TRT has been difficult to evaluate and
the reported outcome of improvement of tinnitus and
hyperacusis from long-term treatment (1 year or more)
varies among investigators.81,82 The selection criterion is
no doubt an important factor in obtaining good results. It
has been claimed that counseling in itself is not new in
being beneficial to patients with tinnitus.85
Electrical Stimulation
Research has shown that direct electric current passed
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
positive current was passed through the cochlea, six of
seven patients obtained relief.24 Such stimulation is
assumed to be effective because electric current passing
through the cochlea affects the hair cells so that the spon-
taneous activity in auditory nerve fibers decreases. It is
also possible that the electric current affects the auditory
nerve directly.
Despite such positive effects from electrical stimulation
of the ear, this method has not yet become widely used in
the treatment of patients with tinnitus. The tinnitus of
deaf people can be reduced by the electrical stimulation
provided by a cochlear implant.11,87 This seems reasonable
because cochlear implants represent a way of activating
auditory nerve fibers and thereby reversing the deprivation
of input to these nerve fibers caused by the cochlear
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
help only some patients.72,88,89 In some investigations
about a third of the patients studied experience a pro-
longed relief from tinnitus after a few minutes of TENS.
Such stimulation may have its effect by stimulating the
trigeminal sensory system rather than the ear. Electrical
stimulation applied to the skin of the hand has also been
used in treatment of tinnitus.73,74
Medical Treatment
Numerous drugs have been tried to manage tinnitus.21,90
The drugs most consistently able to alleviate tinnitus are
local anesthetics, the most commonly used of which has
been lidocaine (Lignocaine, Xylocaine, Procaine). It is still
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
on peripheral nerves is assumed to be related to their
blockage of sodium channels, but these drugs also have a
considerable effect on the CNS. Lidocaine has been
widely used, for example, to stop epileptic seizures.91
Studies using recordings of auditory evoked potentials
showed that the later peaks of the BAEP are affected (pro-
longation of the interpeak latency of peaks I to V),92–94
indicating that lidocaine affects the central auditory nerv-
ous system and not the ear. These studies indicate that
lidocaine affects tinnitus due to an action on the CNS and
not on the ear.
190 SYMPTOMS OF NEUROTOLOGIC DISEASE
The consistent efficacy and sometimes dramatic effect
of IV lidocaine have motivated a search for other oral
drugs with similar and longer-lasting results. So far, the
search has had little success. Tocainide, which is similar to
lidocaine and can be administered orally,93,95 has proven
beneficial to some patients with tinnitus, but only in
dosages that were often associated with intolerable side
effects. More recently Mexiletine, another drug similar to
lidocaine, has also been tried with moderate success.96
Inspired by the success of lidocaine and recognizing
lidocaine’s anticonvulsant effect, several investigators have
tried various other anticonvulsant drugs such as carba-
mazepine and dilantin.97 Unfortunately, these drugs have
also been found unacceptable or impractical for use in
treating tinnitus.97 Because a patient with incapacitating
tinnitus would most likely have to take a medication for
the rest of his or her life, the side effects of the medication
are an important consideration.
The benzodiazepines hold some promise, especially
because some of them (diazepam, alprazolam, and clon-
azepam)98 are documented as being effective and having few
side effects in preliminary studies.98 These drugs may be
effective because they enhance the effect of γ-aminobutyric
acid (GABA) and because at least some forms of tinnitus
may be caused by a reduction of inhibition in neurons in
the ascending auditory pathway, in which GABA is the
inhibitory neural transmitter.99 Animal experiments have
shown that benzodiazepines (GABAA receptor agonists)
can reduce signs of hyperactivity and restore temporal
integration after prior exposure to loud noise in auditory
midbrain nuclei (IC).100 Other pharmacologic agents
having GABA or GABA-like effects, such as baclofen,
(a GABAB receptor agonist), would seem to be good can-
didates for managing tinnitus, a hypothesis supported by
studies in animals.100 However, clinical experience of
baclofen in tinnitus treatment has not confirmed that
hypothesis.
Antidepressants such as the tricyclic drugs (e.g., Elavil)
can sometimes be beneficial, but these drugs can also cause
tinnitus or increase the tinnitus of patients who already
have this disorder. Calcium channel blockers also have
positive effects in some patients.
Surgical Treatment
Surgical treatment of tinnitus has consisted of severing the
auditory nerve, or microvascular decompression (MVD)
or sympathectomy. Each of these treatments has had some
success.
MVD is a nondestructive surgical procedure to move a
blood vessel off the intracranial portion of the auditory
nerve.41,49,101–103 In the hands of surgeons with extensive
experience of this type of procedure, MVD of the intracra-
nial portion of the auditory nerve can provide a permanent
cure for specific selected patients.18,19,41,49,101–103 For exam-
ple, in a recent study18 in which 73 patients were operated
on with the MVD technique, tinnitus was totally relieved
or greatly improved in 40%. It is interesting to note that
the patients who underwent MVD of the auditory nerve
and obtained total relief from tinnitus also obtained relief
from their hypersensitivity to sound,18 which indicates that
the tinnitus and the hypersensitivity to sound in these
patients were most likely caused by the same or related
mechanisms. The patients who obtained total relief or
considerable improvement (40.3%) had endured their tin-
nitus for a much shorter time than those whose tinnitus
did not improve (48.6%) (2.8 years vs. 7.1 years). This is in
good agreement with the experience of MVD for TGN.104
Apfelbaum104 found that the average duration of symptoms
of TGN for those who had excellent results following
MVD was 70.9 months, whereas the average duration of
symptoms for those who had recurrences of TGN follow-
ing MVD was 109.4 months. This supports the hypothesis
that severe tinnitus may, after a time, become less respon-
sive to treatment; it may also indicate that treatment of
patients with incapacitating tinnitus should not be post-
poned unnecessarily.
More surprising was the finding that the success rate
was much higher in women than in men (54.8% vs.
29.3%), despite similar selection criteria and intraopera-
tive findings in men and women.18 Of 31 female patients
who were operated on with the MVD procedure, 54.8%
were either free from symptoms or markedly improved,
but only 29.3% of the 41 male patients obtained similar
results from the operation.18 Although the reason for the
difference is unknown, it may indicate that many factors
such as reproductive hormones may be involved.
MVD is most effective in patients with unilateral tinni-
tus. In a study of 22 patients, 11 with unilateral and 11 with
bilateral tinnitus, the outcome was favorable in 33% over-
all, but it was favorable in 63% of those 11 patients with
unilateral tinnitus, but only 2 of the 11 patients with bilat-
eral tinnitus improved (18%).105
In a recent study of 59 patients who were operated on by
MVD, more than 75% improved (30 were free of tinni-
tus).106 In another study of 18 patients, 8 were free of tin-
nitus after MVD, and improvement of the tinnitus was
achieved in 17 of 18.107 The anterior inferior cerebellar
artery (AICA) is usually found to be in contact with the
auditory nerve. Because the MVD procedure is similar for
all of these disorders, it does not seem likely that these dif-
ferences in the success of the surgical procedure are due to
the procedure itself but rather the result of the criteria for
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
in carefully selected patients, but MVD also carries a sub-
stantial risk for making the tinnitus worse, and intraoper-
ative monitoring of auditory nerve function is essential in
reducing such risks.47
There is considerable evidence that severing the audi-
tory portion of the eighth nerve can alleviate the tinnitus
in many patients with Ménière’s disease,108 but the results
are much less convincing in patients with tinnitus who do
not have Ménière’s disease. Pulec109 reported complete
relief from tinnitus in 67% of 91 patients with Ménière’s
disease. In a more recent study, Pulec reported complete
relief achieved in 101 of 151 patients with tinnitus.110
Others17,111 have obtained similar results. Relief or
improvement in tinnitus was reported in 36% of patients
with vertigo who had undergone retrolabyrinthine section
of the vestibular portion of the eighth nerve and in 31% of
patients who had undergone vestibular nerve section using
a retrosigmoid approach.112

This means that the results of auditory nerve section for
tinnitus varies among investigators. The difference in the
selection criteria used most likely contributes noticeably to
this variation. Treating tinnitus by sectioning the eighth
nerve seems to be more effective in patients whose tinni-
tus is caused by Ménière’s disease than in patients with tin-
nitus of another cause. It must be remembered that this is
a destructive treatment limited to individuals who have no
usable hearing in the ear with tinnitus, but good hearing in
the ear that will not receive treatment.
Some of the benefit of vestibular nerve section may
result from sectioning of the cochlear efferent bundle, the
fibers of which travel with the proximal portion of the
vestibular nerve and therefore may also be severed when
the vestibular nerve is cut. The efferent fibers have a sup-
pressive effect on auditory nerve fibers when stimulated
electrically, but their normal function is largely unknown
(see Chapter 2).
Sympathectomy has been used with some success in
managing tinnitus113 as well as for pain.114 One study
showed that stellate ganglion block in patients with
Ménière’s disease has a beneficial effect on tinnitus, as
much as a 56% relief rate115), whereas patients with causes
of tinnitus other than Ménière’s disease benefited less
(27% relief rate) from this procedure. Sympathectomy is
seldom done now.
A study of patients with otosclerosis who also had tinni-
tus found that 40% of the patients obtained relief follow-
ing successful stapedectomy.116 Biofeedback has been
shown helpful in treating tinnitus, as has various forms of
psychotherapy. These topics, however, are outside the
scope of this chapter, since these treatments do not seem
to affect the tinnitus as such but rather the patient’s per-
ception of it.
In summary, many treatments have been tried for tinni-
tus, none of which has been shown effective in all patients.
Some treatments have positive effects in some patients but
not in others, supporting the hypothesis that tinnitus is not
a single disorder but a group of disorders with different
pathophysiology. It has generally been difficult to evaluate
any treatment of tinnitus and the placebo effect is consid-
erable, yet another similarity with pain. Some treatments
that are effective in a limited group of patients have often
been regarded as generally ineffective and have hence
become disused, despite their effectiveness in some. The
search for treatments of tinnitus should therefore not aim
at a universal treatment but rather find diagnostic methods
that can distinguish patients with different kinds of tinni-
tus and then find specific treatments for each such group.
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 Chapter
Otalgia
10 Outline

John S. McDonald, DDS, MS, FACD
Pain Characteristics
Anatomy
Primary Otalgia
Referred Otalgia
Differential Diagnosis of Pain
Referred to the Ear
Acute Referred Otalgia
Chronic Referred Otalgia
Orofacial Pain
Temporomandibular Disorders
Atypical Facial Pain
Neurologic Disorders
Trigeminal Neuralgia
Glossopharyngeal Neuralgia
Postherpetic Neuralgia
Vagal and Superior Laryngeal
Neuralgia
Headaches
Migraine
Tension-Type Headache
Cervicogenic Headache
Cluster Headache
Chronic Paroxysmal
Hemicrania
Traction and Inflammatory
Headache
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
presents a vexing problem to the clinician. Although the
source of the pathology may be the ear or temporal bone,
in 50% or more of patients who complain of otalgia, the
pain is referred from a source other than the ear.1 As
with other complaints of pain in the head and neck, otal-
gia may be accompanied by protean symptoms, which may
be described as aching, boring, sharp, throbbing, burning,
itching, pressure-like, or the sensation of fullness. The
severity of the pain may be disproportionate to the nature
of its underlying cause; that is, an acute inflammatory
process involving the external ear may present with pain of
much greater severity than a primary neoplasm emanating
from the pharynx but referring pain to the ear.
PAIN CHARACTERISTICS
Pain is defined as an unpleasant sensory and emotional
experience associated with actual or potential tissue damage
or is described in terms of such damage.2 Pain may be char-
acterized in a variety of ways. The terms paresthesia and
dysesthesia both imply an abnormal sensation, either spon-
taneous or evoked, with dysesthesia being used to denote an
unpleasant abnormal sensation. Examples of dysesthetic
pain include allodynia or a painful response to a stimulus
that does not usually evoke pain, and hyperalgesia, which
implies an increased response to a stimulus that would
normally produce pain. Noxious stimulus or tissue damage
activates nociceptors at the termination of myelinated
A-delta and unmyelinated C-afferent nerve fibers in the
skin, muscles, joints, fasciae, and other deep somatic struc-
tures. Cutaneous receptors may be activated by mechanical,
thermal, chemical, or other algesic stimuli, and nociceptors
in the deep somatic structures may be activated by disease,
194
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
noxious stimulation or nociceptors may begin to respond to
stimuli that are normally innocuous. This process is called
peripheral sensitization and may contribute to hyperalgesia
and allodynia.
Sensory innervation to the ear and periaural region is
derived from cranial nerves V, VII, IX, and X as well as cer-
vical nerves 2 and 3. Nociceptive impulses in the distribution
of cranial nerves V, VII, IX, and X synapse with second-
order neurons in the part of the trigeminal brainstem
sensory nuclear complex known as the subnucleus caudalis or
the medullary dorsal born (MDH). Nociceptive pain impulses
from cervical nerves 2 and 3 activate neurons in the spinal
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
overlap of peripheral C2 and C3 nociceptive fibers with
the other cephalic nociceptive nerves—V, VII, IX, X, and
XII. The three types of neurons in the MDH are low-
threshold mechanoreceptors (LTM), which respond only
to nonnoxious stimuli; wide dynamic range (WDR) neurons,
which respond to both noxious and nonnoxious stimuli;
and high-threshold nociceptive-specific (NS) neurons,
which respond exclusively to noxious stimuli.
Central to the theme of referred pain to the ear is the
concept of central convergence of primary afferent neurons
at a single WDR or NS neuron in the MDH or spinal
dorsal horn. A substantial number of the WDR and NS
neurons show extensive convergence and can be excited
by peripheral afferent inputs from skin, mucosa, visceral
(laryngeal), temporomandibular joint (TMJ), jaw or
tongue muscle, tooth pulp, and neck afferents, hence the
spread and referral of pain.4 Pain referral depends not only
on the convergent afferent input patterns of nociceptive
neurons but also on the so-called neuroplasticity or central

sensitization (an increase in neuronal excitability) that may
be generated in the neurons by these inputs as a result of
injury or inflammation.5 Some of the afferent inputs to the
nociceptive neurons may be “unmasked” as a result of this
nociceptive input and become more effective in exciting
these second-order neurons with the result that pain is per-
ceived as coming from the tissue supplied by these afferents.5
Pain may also be characterized as either acute or chronic
in nature. Acute pain has been defined as a complex con-
stellation of unpleasant sensory, emotional, and mental
experiences and certain autonomic (involuntary) responses
and psychological and behavioral reactions provoked by
tissue damage.2 Chronic pain has been defined as pain that
persists a month beyond the usual course of an acute disease
or a reasonable time for an injury to heal or that is associated
with a chronic pathological process that causes continuous
pain or the pain reoccurs at intervals for months or years.5
Acute pain may result from a variety of causes including
trauma, infection, or neoplasm. Relatively speaking, acute
pain conditions are usually readily diagnosed and have
well-defined treatment parameters. As the causative condi-
tion is resolved, the resultant acute pain subsides usually
leaving no disability. This is in contrast to the chronic pain
patient who may demonstrate little or no pathology and
when pathosis is present it is frequently disproportionate
to the degree of discomfort experienced. Unlike acute
pain, chronic pain does not tend to be a protective phenom-
enon and thus serves no useful purpose. The treatment of
chronic pain tends to be less well defined and successful
with rehabilitation rather than cure being a realistic goal.
Compared to acute pain, chronic pain therapy tends to be
protracted, frequently leaving the patient with some
resultant limitation of function.
ANATOMY
From an anatomical perspective cranial nerves (CNs) V, VII,
IX, and X, cervical nerves 2 and 3 through the cervical
plexus, and the caroticotympanic nerves derived from the
carotid sympathetic plexus of the internal carotid artery pro-
vide afferent pathways for the transmission of sensory stim-
ulation of the auricle, the external auditory canal, tympanic
membrane, middle ear, and immediately adjacent areas.
The auriculotemporal branch of the mandibular or third
division of the fifth cranial nerve provides sensory inner-
vation for the tragus, anterior, and superior aspects of the
auricle and external auditory canal as well as the anterosu-
perior two-thirds of the lateral or external wall of the tym-
panic membrane. Located in the middle ear and in the
eustachian tube, respectively, the tensor tympani and tensor
palati muscles are derivatives of the mandibular or first
branchial arch and are innervated by the third division of
CN V. The masticatory muscles innervated by the third
divisions of CN V receive innervation from both motor
and sensory nerve fibers and there is no reason to assume
that sensory innervation has been lost to the tensor tympani
and tensor palati muscles merely because they have been
“borrowed” by the ear through phylogenetic development.
The majority of the sensory innervation of skeletal muscles
is derived from thinly myelinated A-delta (group III) and
unmyelinated C-afferent (group IV) fibers in muscle fascia,
Otalgia 195
between muscle fibers, in the walls of blood vessels, and
in tendons and many of these fibers act as muscle noci-
ceptors (this is more certain for the C-afferent [group IV]
units than for the A-delta [group III] fibers).6,7
Electromyographic studies of both the tensor tympani and
stapedius muscles have demonstrated contraction of both
muscles concomitantly with a number of complex move-
ments including tight closure of the eyes, jaw opening and
jaw clenching, swallowing, and speaking.8 It has been
pointed out that tonic contractions of the tensor tympani
muscle may be accompanied by otalgia, a sense of pressure
and aural fullness, and tinnitus or other transient acoustic
sensations.8 Hence the middle ear may not only be a site of
referred pain but primary otalgia may arise from chronic
contraction of the tensor tympani muscle along with, for
instance, chronic contraction of the masseter muscle in
cases of temperomandibular dysfunction worsened by brux-
ism. The question may then be: Is the middle ear pain
primary or secondary in nature?
The seventh CN supplies sensory innervation for a por-
tion of the posterior and posterosuperior auricle, an adjacent
portion of the external auditory canal and lateral aspect of
the tympanic membrane, and a small area of skin in the
postauricular area. CN VII also supplies innervation to the
stapedius muscle in the middle ear. The ninth CN provides
sensory innervation to part of the posterior portion of the
external auditory canal and meatus, an adjacent portion of
the lateral surface of the tympanic membrane, and the
majority of the mastoid air cells and the eustachian tube.1
The middle ear including the medial aspect of the tympanic
membrane receives its sensory innervation from the tym-
panic plexus, which is comprised of the tympanic branch of
the glossopharyngeal nerve (Jacobson’s nerves) and the
superior and inferior caroticotympanic branches of the
sympathetic plexus surrounding the internal carotid artery.
The auricular branch of the tenth CN (Arnold’s nerve)
innervates a portion of the posterior wall and floor of the
external auditory canal and the corresponding external
surface of the tympanic membrane.
The upper cervical nerves (C2, C3) also supply sensory
innervation to the ear or periauricular structures. The pos-
terior branch of the great auricular nerve supplies sensory
innervation to the majority of the posterior portion of the
auricle as well as a portion of the skin over the mastoid
region, which also receives some overlapping communica-
tion with the lesser occipital nerve (C2) in the mastoid
region.
Although pain may be referred to the ear by means of
any of the cranial or cervical nerves mentioned, the most
common source of referred pain to the ear is through the
fifth CN. For example, pain may be experienced in the
external ear including part of the external auditory canal
and the tympanic membrane by convergence of primary
A-delta or C-afferent nociceptive fibers from the auricu-
lotemporal branch of CN V3 with primary A-delta or
C-nociceptive afferent trigeminal nerve fibers, most com-
monly other branches of CN V3, at WDR neurons in the
medullary dorsal horn. It is also possible that pain may be
referred to the middle ear or eustachian tube by convergence
of primary afferent nociceptors from the tensor tympani
and tensor palati muscles with other primary nociceptive
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
afferent fibers from CNs V, VII, IX, and X with WDR and
possibly NS neurons in the medullary dorsal horn (trigem-
inal subnucleus caudalis) may be the means by which pain
may be referred to the ear.4 It is also thought that pain
referred to the preauricular region from C3 may be facili-
tated through overlap of C2 and C3 nociceptive fibers with
afferent nociceptive fibers from cranial nerves V, VII, IX,
and X.3
PRIMARY OTALGIA
Differential Diagnosis of Pain
Referred to the Ear
Disorders that may produce referred pain to the ear can be
either acute or chronic in their nature. For ease in differen-
tial diagnosis, disorders that present primarily as acute pain
are discussed first followed by disorders that tend to become
chronic or may present as a chronic pain condition on
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
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.

TABLE 10-2. Referred Otalgia, Typically Chronic Disorders
Orofacial Pain (Chronic)
Temporomandibular disorders (TMD, TMJ); includes myofascial facial pain
and intra-articular TMJ pain
Atypical facial pain
Neurologic Disorders
Trigeminal neuralgia
Glossopharyngeal neuralgia
Postherpetic neuralgia
Vagal and superior laryngeal neuralgia
Headaches
Migraine headache
Tension-type headache
Cervicogenic headache
Cluster headache
Chronic paroxysmal hemicrania
Traction and inflammatory headache (includes temporal arteritis)
Neoplastic Disease
Carcinoma, sarcomas (including Hodgkin’s and non-Hodgkin’s lymphomas),
and metastatic disease
Other dental factors such as unerupted or impacted teeth,
traumatic occlusion, ill-fitting dental appliances, or even
recently adjusted arch wires in a patient undergoing ortho-
dontic therapy may also be causative factors. A variety of
other painful oral inflammatory disorders may also refer to
the ear including primary or recurrent herpetic gingivos-
tomatitis, acute herpes zoster, recurrent aphthous stomatitis
(primarily the major scarring form), mucocutaneous disor-
ders such as erosive lichen planus, inflammatory lesions of
the tongue such as geographic tongue and less well under-
stood processes such as burning mouth syndrome.
Other disorders of the orofacial region that may be
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
Stensen’s duct by a stone. Some of the dural blood vessels
are innervated by fibers from CN V3 (CN V1 provides the
majority of the sensory trigeminal vascular innervation)
and because pain is the only sensation that may be evoked
by inflammatory or traction stimuli to the cerebral vascular
blood supply, then disease in this area will nonselectively
present as pain. Although temporomandibular dysfunction
of intra- or extra-articular origin may be acute in nature, this
is covered in the differential diagnosis of chronic disorders
leading to otalgia.
Disorders of the pharynx are also relatively common
causes of referred pain to the ear with inflammatory disor-
ders of the oro-, naso-, or hypopharynx, tonsillitis, periton-
sillar abscesses, and post-tonsillectomy pain being
common causes of referred otalgia. Also, Eagle’s syndrome
caused by an elongated styloid process may present as
referred pain to the ear and may classically be confused
with or mimic glossopharyngeal neuralgia, which is dis-
cussed later in this chapter.
Inflammatory disorders of the larynx and esophagus
may be referred to the ear through the vagus nerve and
include laryngitis, perichondritis, chondritis, arthritis of the
cricoarytenoid joint, hiatal hernia and inflammation, and
infection or foreign body in the esophagus. Referred otalgia
Otalgia 197
may originate from inflammatory processes in other visceral
sources such as the thyroid gland and also from angina and
aneurysms of the great vessels.
Chronic Referred Otalgia
To many practitioners chronic pain remains an enigma
from the standpoint of diagnosis and management. This is
explained to a large extent by the fact that, of necessity, the
emphasis in most training programs and hence in most prac-
tices centers on the diagnosis and management of “acute”
pain conditions, resulting in attempts to treat individuals
with chronic pain by therapies designed only for the short
term. Even those patients with more chronic conditions
such as malignancy tend to be treated with the acute pain
model.
The differential diagnosis of conditions that may produce
chronic pain in the head and neck is a broad one and includes
orofacial pain, neurologic disorders, headache, and pain
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
variety of potential pitfalls in formulating a differential
diagnosis for chronic head and neck pain. The first and
potentially most significant pitfall is that chronic pain is
usually viewed from an individual specialist’s perspective,
which is frequently less than “global” in nature and may
lead to diagnostic bias. The second is that, because the clas-
sification of these conditions is difficult, it tends to be based
more on opinion than on an understanding of pathogenesis.
This is further complicated by the fact that differential diag-
nosis always tends to be more straightforward in the litera-
ture than in the examining room where textbook distinctions
are seldom as clear as anticipated.
OROFACIAL PAIN
Temporomandibular Disorders
Acute orofacial pain conditions as a cause of otalgia are
described in an earlier section of this chapter. Chronic oro-
facial pain conditions include temporomandibular disorders
(TMD, TMJ pain), atypical facial pain (AFP) and atypical
odontalgia. Temporomandibular disorders present a com-
plex problem from a standpoint of both diagnosis and
management. The differential diagnosis of TMD includes
nonarticular conditions mimicking TMD, extra-articular
causes of jaw limitation, true pathology of the TMJs where
the disorder in question begins primarily in the joint and
remains limited to it, and finally myofascial pain dysfunction
(MPD), which is far and away the most common cause
of TMD and hence the most common cause of chronic
referred pain from the orofacial region to the ear.
At this point some explanation of the term MPD is war-
ranted. Myofascial pain dysfunction has also been termed
myofascial pain syndrome, musculoskeletal or muscle
contraction pain, myofascitis, myofibrositis and myalgia.
Myofascial pain is the most frequently encountered type of
chronic facial, head, and neck pain and according to
Laskin9 it accounts for as many as 90% of cases of TMJ
pain. It has been characterized as a regional pain syndrome
198 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
often with sudden onset and with trigger points causing
locally referred pain.10 It has been defined as pain, tender-
ness, or other referred phenomena, with the dysfunction
attributed to myofascial trigger points.11 The diagnosis of
MPD is predicated on finding a trigger point. A myofascial
trigger point is a hyperirritable spot in skeletal muscle that
is associated with a hypersensitive palpable nodule in a taut
band, which is painful on palpation and can give rise to
characteristic referred pain, referred tenderness, motor
dysfunction, and autonomic phenomena.12 Trigger points
may be latent or active. An active trigger point will pro-
duce or reproduce a clinical pain complaint while latent
trigger points, while tender to palpation and often causing
motor dysfunction with stiffness and restricted range of
motion, are pain free.13,14
Trigger points occur primarily in the deep midportion
of the muscle and are best discovered by examining a muscle
while it is relaxed, and being passively stretched by the
examiner.10 The examiner first establishes the sensation of
finger pressure by palpating a nonpainful area and then
instructs the patient to respond when the pain or tenderness
other than the pressure from finger palpation is noted.
This is done by rolling the muscle transversely under the
fingers. Usually a nodule or taut band will be felt. Many
times a verbal response by the patient is unnecessary, as he
or she may exhibit an involuntary “jump sign” when a tender
trigger point is located.
The concept of myofascial pain is discussed here not
only with regard to TMD but also in later sections in con-
junction with tension-type headache pain including cer-
vicogenic headache of myofascial origin. Women are
affected more frequently than men and although it may
appear at virtually any age, myofascial pain appears to
occur most commonly in the third, fourth, and fifth
decades of life. Historically, the etiology of TMD was
thought to be related to occlusal irregularities and dys-
functional occlusal contact.15 This misconception that
occlusion was the primary etiologic factor in temporo-
mandibular pain and dysfunction continues today to result
in diagnostic errors, unnecessary irreversible dental treat-
ments, and treatment failures. Over time, researchers and
clinicians have looked beyond occlusal dysfunction to the
musculature and the mechanics of joint function and dys-
function as the causative factors in TMD pain.
TMD patients may present with pain, muscle tender-
ness, popping or clicking of the TMJ(s), limitation and/or
deviation of jaw movement, and otologic manifestations.
They may have jaw pain, frontal, frontotemporal or occip-
ital headache pain, toothache, sinus pain, earache, pre- or
postauricular pain, sore throat, dysphagia, a sense of an
object in the throat, or periorbital pain.
Both acute and chronic orofacial pain conditions
(toothache, periodontal infection, TMD, etc.) frequently
result in referred pain to the ear. This likely occurs as a
result of the convergence of nociceptive pain impulses
from the offending structure along primary afferent nerve
fibers to WDR neurons in the medullary dorsal horn with
thinly myelinated A-delta and unmyelinated C-afferent
muscle nociceptors from the auriculotemporal branch of
CN V3 innervating the external ear and possibly primary
nociceptive afferents from the tensor tympani and tensor
palati muscles.
Atypical Facial Pain
The term atypical facial pain (AFP) is used as a moniker
for persistent chronic facial or intraoral pain that does not
fit into the diagnostic criteria for a specific orofacial pain
disorder. It is usually a poorly defined, unilateral, deep,
continuous, or nearly continuous aching, boring, or burn-
ing pain not limited to the distribution of the fifth or ninth
cranial nerves which may actually spread over the area sup-
plied by the cervical nerve roots. Although trigger zones
are absent, attacks of atypical facial pain may be set off by
mechanical stimulation including percussion or chewing.
The majority of patients are women, with the most frequent
age of occurrence being the fourth through sixth decades
of life.16 The term atypical odontalgia has been used when
the patient is convinced that their pain is emanating from
a tooth or several adjacent teeth.
Although its underlying mechanisms are unknown,
potential etiologic factors may include trauma, hormonal
factors (based largely on its strongly female prevalence),
psychological factors, and local irritation.17 The action of
these different factors may involve peripheral sensitization
following the presence of chronic irritation or inflammatory
stimuli or endodontic, surgical, or other traumatic events
that may produce ectopic activity along a peripheral nerve.
As alluded to earlier in this chapter, these peripheral
changes may result in central sensitization, which appears
to be a key mechanism in many of these idiopathic orofacial
pain conditions. Sympathetic nervous system involvement
may participate in the maintenance of the central sensiti-
zation. Loss of segmental inibition from deafferentation
following nerve injury or impairment or loss of inhibitory
interneurons may also be possible mechanisms. A neu-
ropsychiatric assessment of patients with this disorder may
show a significant number of them to have a specific psy-
chiatric diagnosis as classified by DSM-IV criteria. In one
study of 68 patients with AFP, 46 (68%) had a specific
diagnosis by DSM-IV criteria covering a wide variety of
disorders predominantly somatoform, affective, adjustment,
or personality disorders.18 While AFP may be refractory to
both medical and dental therapies, some patients may
respond to antiepileptic medications such as gabapentin,
topiramate, tiagapine, and others as well as tricyclic antide-
pressants and trazadone. Patients with AFP may experience
referred otalgia or its diffuse nature may approximate the
ear in the preauricular region.
NEUROLOGIC DISORDERS
The categorization of neuralgias of the face, head, and neck
can be both difficult and confusing. Although not usually
considered a prime suspect in the differential diagnosis of
referred otalgia, trigeminal neuralgia is included in this
section not only because it is by far the most frequently
occurring neuralgic condition in the head and neck but
also because of the close proximity of occurrence of pain to
the ear in some patients and the fact that it occasionally
will refer pain to the ear. The etiology, pathogenesis, and
management of trigeminal neuralgia has been studied far
more than any of its other head and neck counterparts;
hence the classic features of the CN neuralgias are briefly
described in the discussion of trigeminal neuralgia.

Also included in this section are glossopharyngeal neural-
gia, postherpetic neuralgia, and vagal and superior laryngeal
neuralgia. The term atypical facial neuralgia is synonymous
with AFP and is discussed in the previous section of this
chapter. Also, because the vast majority of patients with
occipital neuralgia have muscle contraction or tension-type
headaches following the distribution of the occipital nerve,
it is included in the discussion of muscle contraction
headaches under the term cervicogenic headache.
Trigeminal Neuralgia
Trigeminal neuralgia or tic douloureux is an episodic symptom
complex characterized by agonizingly intense paroxysmal
attacks of sharp, stabbing, burning, or electric shocklike
pain confined to one side of the face in the trigeminal dis-
tribution. These attacks of pain, which may last from a few
seconds to a few minutes, can be triggered by a light touch
to the face including such light stimulus as a breeze or
vibration. Trigger points are particularly common around
the mouth and nose with pain often being exacerbated by
simple acts such as taking food or fluids orally, which may
result in severe weight loss and dehydration. Whereas
light touch and vibration are the most effective triggering
stimuli, pinching or pressing the trigger area is unlikely to
provoke an attack.19 As previously mentioned, trigeminal
neuralgia may occasionally be a source of referred pain to
the ear and also may occur in close proximity to the ear.
Physical examination is essentially unremarkable, with the
absence of any detectable neurologic deficit or a subtle
sensory deficit within the distribution of the trigeminal
nerve. Although in the majority of cases no identifiable
etiology for the trigeminal neuralgia is noted, in as many
as 15% of patients there may be an underlying cause such
as the presence of a benign or malignant neoplasm in the
posterior fossa or multiple sclerosis which will present at a
later point in the disease process.20 Hence, when considering
the diagnosis of trigeminal neuralgia, a magnetic resonance
imaging (MRI) study paying particular attention to the
posterior fossa should be performed as a mass lesion in this
area may cause symptoms typical of trigeminal neuralgia in
the absence of other neurologic signs and symptoms.21
A broad range of other entities must be considered in
the differential diagnosis of trigeminal neuralgia. These
include a variety of dental causes of pulpal origin, including
dental infection or cracked teeth; periodontal pathology;
denture pain from pressure on the mental nerve; TMD,
primarily myofascial pain; atypical facial pain including
atypical odontalgia; glossopharyngeal neuralgia; postherpetic
neuralgia; cluster headache; and chronic paroxysmal hemi-
crania and temporal arteritis.
It is now believed that 80% to 90% of cases of trigeminal
neuralgia result from specific abnormalities of trigeminal
afferent neurons in the trigeminal root or ganglion resulting
in hyperexcitable afferents that give rise to paroxysmal
epsodes of pain as a result of synchronized after discharge
activity.17,22
Both medical and surgical therapies have been used to
treat trigeminal neuralgia. While trigeminal neuralgia is
an excruciatingly painful and in some cases disabling,
debilitating disorder, it should also be pointed out that in
the absence of a malignant neoplasm as its primary cause,
Otalgia 199
it is a nonfatal one and therefore the primary approach to
treatment should be medical intervention with surgery
being reserved for patients who become refractory to or
unable to tolerate available medications. Various antineu-
ralgic medications, the majority of which are anticonvul-
sants, are available for use singly or in combination and
include baclofen (antispastic category), carbamazepine,
oxcarbazepine, gabapentin, lamotrigine, topiramate, tia-
gapine, sodium valproate, clonazepam, and phenytoin. It is
recommended that in view of its greater safety, baclofen
should be the initial drug of choice in treating trigem-
inal neuralgia. In those cases where baclofen is ineffec-
tive or not tolerated, carbamazepine, oxcarbazepine, or
gabapentin is the next drug of choice. In those patients
who do not respond to therapy with either drug alone, the
combination of baclofen and carbamazepine may be effec-
tive.23 It has also been reported that baclofen and pheny-
toin may be used in those patients who cannot take
carbamazepine because baclofen and phenytoin have a
synergistic action.23 The use of lamotrigine in combina-
tion with carbamazepine or phenytoin has been reported.24
In some cases tricyclic antidepressant and nonsteroidal
anti inflammatory analgesic medications may be used in
combination with antineuralgic drugs as mentioned above.
The clinician will find that the right combination of med-
ications often becomes very individualized from patient to
patient and is often found by trial and error with the use of
multiple medications being involved. Unfortunately some
patients who have achieved good control of their symp-
toms over time may decide on their own to wean them-
selves from their medications with resultant return of their
pain. It is the author’s experience that in many cases pain
relief is not again achieved at the same combination and/or
dosage of medication as the patient was previously taking.
Nerve blockade with local anesthetic may be effective
in breaking this new cycle of pain in combination with
antineuralgic medications. In cases where adequate control
of symptoms is not achieved or where medication is
no longer effective, surgical intervention may then be
indicated.
Glossopharyngeal Neuralgia
Glossopharyngeal neuralgia is a relatively uncommon
episodic symptom complex characterized by unilateral
paroxysmal attacks of sharp, stabbing, burning, or electric
shock–like pain that may be felt in the posterior tongue,
tonsil, lateral pharyngeal wall, nasopharynx, and ear. The
trigger zone is usually located in the lateral pharyngeal
wall, tonsillar fossa, or in the area of the external ear pos-
terior to the ramus of the mandible with pain referring
outward from the trigger point. Episodes of pain may be
provoked by stimulation of the trigger zone during the act
of swallowing, yawning, or coughing. Some patients with
glossopharyngeal neuralgia may experience bradycardia,
syncope, and seizure with the attack of pain.25 As with
trigeminal neuralgia, physical examination is essentially
unremarkable, with the absence of any detectable neurologic
deficit. When considering the diagnosis of glossopharyngeal
neuralgia, care should be taken to rule out the presence
of a carcinoma or other mass lesion in the oro-, hypo-, or
nasopharynx or at the cerebellopontine angle.
200 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
A useful technique in diagnosing true glossopharyngeal
neuralgia is cocainization or blocking of the trigger point
with a local anesthetic. The pathophysiology of glossopha-
ryngeal neuralgia is thought to be the same as trigeminal
neuralgia with involvement of the ninth instead of fifth
cranial nerve. In some cases however, a specific cause for
glossopharyngeal neuralgia can be found that, in addition
to mass lesions, includes pharyngitis or tonsillitis, tonsillec-
tomy, radiation therapy to the pharynx and an elongated
styloid process. The treatment for glossopharyngeal neural-
gia is the same as that for trigeminal neuralgia except
in those cases where it is secondary to an elongated
styloid process in which case relief may be effected by
styloidectomy.
Postherpetic Neuralgia
Following a primary infection with the varicella-zoster
virus (VZV) the VZV lies dormant in trigeminal and dorsal
root ganglia and may in later life reactivate to cause herpes
zoster (shingles). It is theorized that following reactivation
the virus transmigrates in a segmental fashion along spinal
or cranial nerves, resulting in a localized painful vesicular
eruption of the skin along the distribution of the involved
nerve. Although the pain and vesicular eruption usually
resolve within 2 to 3 weeks, pain in the form of postherpetic
neuralgia may persist beyond resolution of these initial
symptoms. Although pain may be referred to the ear from
involvement of the cranial and cervical nerves and may
mimic geniculate or nervus intermedius neuralgia, it is not
uncommon for herpes zoster of the external ear to occur
with referral of pain to the face, mastoid, and occipital
regions as well as the neck.
The primary goal in the treatment of acute herpes zoster
is to palliate the patient’s pain and effect early resolution of
the acute stage of the disease and prevent the development
of postherpetic neuralgia. It is felt that in young healthy
patients with acute herpes zoster, only symptomatic treat-
ment is indicated.26 In patients more than 50 years of age,
however, treatment for prevention of postherpetic neural-
gia in addition to symptomatic relief is thought to be
essential.26 The pain of postherpetic neuralgia is described
as a persistent severe burning pain in the affected area and
is often debilitating in its nature. In cases where the acute
herpes zoster went untreated or was treated inadequately and
the symptoms of postherpetic neuralgia are noted, initial
early aggressive intervention is of the utmost importance.
Although various treatment approaches have been taken
in the management of acute herpes zoster, including the
use of antiviral medication such as valacyclovir, cortico-
steroids, analgesics, antidepressants, or topical therapy,
there is increasing evidence that an invasive approach
including the use of sympathetic nerve blocks, somatic
nerve blocks, and subcutaneous infiltration of combinations
of local anesthetic and steroid alone or in combination with
noninvasive therapies are indicated.
Nonsteroidal anti-inflammatory analgesics may be useful
in controlling the mild pain in an attack of acute herpes
zoster, with opioid therapy being reserved for severe pain
exacerbations. Tricyclic antidepressant medications such
as amitriptyline, nortriptyline, doxepin, desipramine, or
imipramine may be used for both their potential pain
relieving and sedative properties. Anxiolytic agents such as
lorazepam, alprazolam, or diazepam may also be used on a
short-term basis.26 Sympathetic nerve blocks may be per-
formed as well as subcutaneous infiltrations in the areas of
the vesicular eruption with a mixture of local anesthetic
and steroid.26
Initial therapy for postherpetic neuralgia centers on the
use of medications such as nonsteroidal anti-inflammatory
analgesics and tricyclic antidepressants alone or in combina-
tion with phenothiazines such as fluphenazine. Gabapentin
is regarded as first-line therapy. The use of other anticon-
vulsants as previously discussed for trigeminal neuralgia may
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 whose duration is of 6 months or
less, because the likelihood of achieving satisfactory pain
relief after this time is considerably diminished.
Sympathetic blockade in the form of as series of stellate gan-
glion blocks should be performed by experienced personnel
at the first sign of postherpetic neuralgia. Where persistent
severe pain is present, sustained release opioids such as
methadone and long-acting oral forms of morphine and
oxycodone and the fentanyl skin patch may be helpful.
Transcutaneous electrical nerve stimulation (TENS) may
also be a useful adjunct.
Vagal and Superior Laryngeal
Neuralgia
Vagal and superior laryngeal neuralgia is an episodic symp-
tom complex characterized by sudden severe attacks of brief
lancinating electric shock–like pain in the side of the thyroid
cartilage, pyriform sinus, and angle of the jaw; it rarely
involves the ear. Attacks are precipitated by talking, swallow-
ing, yawning, or coughing and usually occur in combination
with glossopharyngeal neuralgia.27,28 Physical examination is
essentially unremarkable with no neurologic deficit being
noted within the distribution of the vagus nerve. As with the
other cranial neuralgias, diagnosis is established by history
and by identifying a trigger zone. Laryngeal topical anesthe-
sia or blockade of the superior laryngeal nerves is said to stop
the pain and is a useful diagnostic and prognostic proce-
dure.29Also, as with the other CN neuralgias, pharmacologic
therapy is indicated for the management of this disorder
and is identical to that used for trigeminal neuralgia and
glossopharyngeal neuralgia. Surgical management may be
indicated if pharmacologic therapy is unsuccessful.
HEADACHES
Despite attempts at clarification, the classification of
headaches remains quite complex and often controversial,
generally being based on the supposed pathophysiology. In
1988 the International Headache Society (IHS) published,
on the basis of empirical findings, the first ever operational
classification of headache.20 Those forms of headache that
may present with referred pain to the ear will be discussed
in this section.

Migraine
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
migraine). Migraine headaches with and without aura differ
primarily in the presence or absence of premonitory tran-
sient focal neurologic symptoms known as the aura, the
most common of which are visual disturbances, including
the scintillating scotomata, also known as the fortification
spectrum.30 The fortification spectrum is characterized by
an area of blurred or cloudy vision, superimposed with
bright zigzag lines often of various colors and usually in
only one visual field, This phenomenon is so highly char-
acteristic that it is said to be pathognomonic of migraine
with aura.31 Somatosensory symptoms consisting of a feeling
of “pins and needles” often beginning in the fingers of one
hand and extending gradually up the arm, ultimately involv-
ing the ipsilateral side of the face particularly the nose and
mouth, may also be seen.13,30
The headache phase of migraine headache with or with-
out aura most commonly presents as unilateral pain in the
head, which may initially be dull in nature evolving into a
severe throbbing, boring pain that may spread to the con-
tralateral side. Migraine headache is frequently accompa-
nied by nausea, vomiting, diarrhea, photophobia, vertigo,
tremors, excess perspiration, and chills.30 The diagnosis of
“migraine” headache unfortunately is often used as a generic
term to indicate a variety of chronic recurring headaches,
including tension-type headache and headache for which
no satisfactory cause can be found.
Tension-Type Headache
The most common headache is the tension-type headache
(Group 2 in the IHS classification), which has also been
termed muscle contraction headache. It has been esti-
mated that of all patients who seek medical care for their
headaches, 80% suffer from tension-type headache.32
Tension-type headache may be either episodic or chronic.
The criterion for chronic tension-type headache is that a
headache must be present for at least 15 days a month dur-
ing at least 6 months. Episodic or acute muscle contraction
headache usually responds to analgesics available over the
counter.29
Tension-type headache is usually characterized as a
steady, nonpulsatile ache, which may be localized unilaterally
or bilaterally to a single region in the head or may be gener-
alized. It may occur in the frontotemporal region, occipital
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
that occurring in the temporal region unilaterally or bilater-
ally, may refer to the ear presenting as otalgia. The severity
of the headache pain will vary from soreness to gnawing or
a dull ache to a sharp, episodic, or continuous stabbing
pain. Frequently, the patient will complain of a feeling of
tightness or cramping in the neck or shoulder regions.
Tension-type headache may begin as either unilateral or
bilateral headache pain and may progress from a localized
type of headache to a generalized headache pain frequently
Otalgia 201
accompanied by photophobia, periorbital pain, lacrimation,
tinnitus, vertigo, and, as previously mentioned, otalgia.
Cervicogenic Headache
Although cervicogenic headache is a headache form that
may derive its origin from one of several structures in the
neck or back of the head including the nerves, ganglia,
nerve roots, uncovertebral joints, intervertebral joints, discs,
bone, periosteum, muscle, and ligaments, among other
structures,33 experience would indicate that arguably the
most common cause of this type of headache involves the
cervical musculature in the occipital and suboccipital
regions. As the term implies, cervicogenic headache origi-
nates in the neck with a referral pattern to the head, fre-
quently the ophthalmic division of the trigeminal nerve
presenting as retro-orbital and frontal headache pain. This
is explained by the very close proximity of the cervical
spinal and medullary dorsal horns with apparent conver-
gence of some cervical nociceptive afferent fibers in the
medullary dorsal horn.3 Through this pattern of conver-
gence, pain may also be referred to the vertex along the
midline, the periaural region, the pinna, and jaw.
Although the pathogenesis of tension-type headache
may vary from individual to individual, in the end the pri-
mary underlying cause is pain of myofascial origin. It may
be difficult to differentiate a tension-type headache that
includes occipital, parietal, or frontotemporal pain from
TMD or cervicogenic headache of myofascial origin. All of
these may present as frontotemporal, temporal, or occipi-
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-
tory of tension-type headache just as patients with tension-
type headaches will frequently mention facial pain. Another
confounding issue is the frequent bias and lack of global
perspective on the part of the examiner. The average physi-
cian may not take the time to examine the orofacial struc-
tures and musculature with the resulting diagnosis of
tension-type headache, while the average dentist frequently
may not examine beyond the orofacial region and make the
diagnosis of TMD. Musculoskeletal examination of the
patient with tension-type headache, TMD, or cervicogenic
headache of myofascial origin will demonstrate nodular or
bandlike tender muscle trigger points, which on finger pal-
pation will produce the classic active trigger points repro-
ducing the patient’s pain. The appropriate diagnosis should
be made based on the primary region from which the pain
complaint is found to emenate on clinical examination.
Cluster Headache
Cluster headache falls under Group 3 of the IHS classifi-
cation of headaches: cluster headache syndrome. The most
portentous of the primary headache disorders, it has been
known by a variety of appellations including erythro-
prosopalgia of Bing, ciliary neuralgia, migrainous neuralgia,
erythromelalgia (Horton’s headache), histaminic cephalgia
(Horton’s syndrome), lower half headache, Vidian neuralgia,
Sluder’s neuralgia, sphenopalatine neuralgia, and hemicrania
periodica neuralgiformis.34,35
202 ANATOMY, PHYSIOLOGY, AND PATHOLOGY
This type of headache is comprised of two major subtypes:
episodic cluster headache and chronic cluster headache.
Episodic cluster headache, the most common type, is said
to account for 80% of all cases. In episodic cluster headache
the patient experiences recurring clusters of headaches,
which occur regularly and usually on a daily basis, alternat-
ing with periods of refractoriness or remission. The term
chronic cluster headache is used when a remission has not
occurred for 1 year.32
Cluster headache is described as a steady, excruciating,
searing, stabbing, boring, or burning pain around the eye
and frontotemporal region that occasionally may refer to
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
may be preceded by feeling a fullness or pressure in the
area where the headache will occur. Unlike other primary
headache disorders such as migraine and tension-type
headache, which affect women more frequently than men,
cluster headache predominantly affects31 men more than
women by a ratio of up to 6:1. The differential diagnosis
of cluster headache includes migraine headache, trigeminal
neuralgia, temporal arteritis, pheochromocytoma, and
Reader’s paratrigeminal syndrome.32
Chronic Paroxysmal Hemicrania
Chronic paroxysmal hemicrania is a rare headache disorder
thought to be a variant of cluster headache. It is similar to
a cluster headache in character but differs from it in the
fact that its attacks are more frequent and of shorter duration
and it responds dramatically to indomethacin and partially
to salicylates.37,38
Traction and Inflammatory Headache
Traction and inflammatory headache is a broad category of
headache pain, which crosses several sections of the IHS
headache classification. It is caused by traction, stretching,
compression, or inflammation of pain-sensitive structures
in the skull or its components including the brain, meninges,
arteries, veins, eyes, ears, teeth, nose, and paranasal sinuses.
It denotes a nonspecific headache, which may be caused by
mass lesions, hemorrhages, or inflammatory disease and
includes inflammatory processes outside the skull such as
temporal arteritis. Because branches of the trigeminal
nerve, CN V1, and some CN V3 fibers supply the cere-
brovascular innervation, pain may be referred to the ear by
any event that produces traction on, or inflammation of,
these vessels. Innervation of this blood supply is selectively
nociceptive in its nature and hence pain is the only sensation
that may be evoked.
Temporal arteritis is included in the category of traction
and inflammatory headache and is characterized as an
intense, deep, persistent, throbbing, aching, burning pain,
which may be accompanied by hyperalgesia of the scalp
and extreme tenderness of the distended arteries. Patients
with temporal arteritis may experience pain on mastication
and may have referred pain to the teeth, ear, jaw, zygoma,
and nuchal and occipital regions. The presenting complaint
may be ocular symptoms with partial or complete loss of
vision. Temporal arteritis should be considered in any
patient with deep, intense, throbbing pain in the temple,
especially if there is accompanying loss of vision. The region
should be palpated, looking for the presence of a distended
throbbing temporal artery. The diagnosis is made by biopsy
of the affected temporal artery; however, multiple biopsies
may be necessary, as the histologic changes, essentially a
giant cell arteritis, are patchy in their distribution. The
erythrocyte sedimentation rate is almost invariably ele-
vated. Claudication of the jaw is strongly suggestive of
temporal arteritis and is characterized by pain as soon as
chewing begins, as opposed to myofascial pain in which pain
is usually noted on prolonged chewing.
NEOPLASTIC DISEASE
As should be clear from the preceding sections, disorders
included in the differential diagnosis of referred otalgia are
many and varied and, as in the case of orofacial pain includ-
ing TMD, quite common. Although many more cases of
referred ear pain secondary to toothache, sinus infection,
tonsillitis, TMD, and so on, are encountered than from
neoplastic disease, this possibility should always be consid-
ered, especially in high-risk populations such as smokers.
Even when the diagnosis seems obvious, a thorough head
and neck examination, including imaging studies as neces-
sary, should be performed to assure that the “obvious”
cause is not a “red herring.” For example, there is no rea-
son to assume that referred pain from pharyngitis will
present differently from an occult carcinoma in the
nasopharynx. All suspicious lesions should be biopsied and
there must be careful follow-up to assure that as the
assumed cause for the referred pain is resolved, the pain
itself is also resolved.
Although carcinomas are the most common cause of
neoplastic disease referred to the ear, mesenchymal malig-
nancies must also be considered. Pain may be referred to
the ear from carcinomas arising in the soft tissues of the
oral cavity, tonsillar pillars and base of tongue, nasopharynx,
soft palate, oropharyngeal wall, hypopharynx, larynx
(including epiglottis, vocal cords, and pyriform sinus),
lung, and thyroid gland.
Pain may be referred to the ear from carcinoma arising in
the maxilla or centrally within the mandible and from carci-
noma or adenocarcinoma involving the salivary glands.
Mesenchymal malignancies including rhabdomyosarcoma,
fibrosarcoma or neurofibrosarcoma (in soft tissue or bone),
osteosarcoma or chondrosarcoma, and malignant prolifera-
tive disorders from both lymphatic and extralymphatic
sites may also present as otalgia. Intracranial neoplasms
producing traction on structures innervated by the cranial
or cervical nerves as well as metastatic disease to the distri-
bution of CN V, VII, IX, X, C2, and C3 must also be
considered.
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 Chapter
Pulsatile Tinnitus
Advances in Diagnosis and Treatment
11 Outline
Aristides Sismanis, MD, FACS Pathophysiology and
Classification
Arterial Causes
Atherosclerotic Carotid
Artery Disease
Intracranial Vascular
Abnormalities
Venous Causes
Pseudotumor Cerebri
Syndrome
Idiopathic Tinnitus
Nonvascular Causes
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
subjective tinnitus, the majority of patients with PT have a
treatable underlying process. Furthermore, identifying the
cause of this symptom is imperative in order to avoid dis-
astrous consequences from associated life-threatening
intracranial pathology.
PATHOPHYSIOLOGY AND
CLASSIFICATION
Pulsating tinnitus most commonly originates from vascu-
lar structures within the cranial cavity, head, and neck
region, as well as the thoracic cavity, and is transmitted to
the cochlea by vascular and bony structures. Pulsatile tin-
nitus can arise either from increased blood flow or steno-
sis of the vascular lumen.
Vascular PT can be classified as arterial or venous
according to the vessel of origin. Differentiation between
these two types is made by applying light digital pressure
over the ipsilateral internal jugular vein (IJV). This
maneuver does not affect the intensity of arterial PT, but it
makes the venous type subside. The venous type can orig-
inate not only from primary venous pathologies, but also
indirectly from conditions causing increased intracranial
pressure (ICP) by transmission of arterial pulsations to
the dural venous sinuses.1 Pulsatile tinnitus originating
from nonvascular structures is classified as nonvascular.
Classification of PT as objective or subjective is based on
whether it is audible by both patient and examiner or by
the patient only.
204
Palatal, Stapedial, and
Tensor Tympani Muscle
Myoclonus
Evaluation
History
Examination
Audiologic and
Electrophysiologic Testing
Metabolic Work-up
Ultrasound Studies
Radiologic Evaluation
Management
Arterial Causes
Atherosclerotic Carotid Artery Disease
In the author’s experience, atherosclerotic carotid artery
disease (ACAD) has been the most common cause of PT
in patients older than 50 years of age, especially when
associated with certain risk factors such as atherosclerosis,
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
secondary to bruit(s) produced by turbulent blood flow at
stenotic segment(s) of the carotid artery. In a series of
12 patients with PT secondary to ACAD, an ipsilateral
carotid bruit was present in all of them.2 Diagnosis can
be established by duplex ultrasound studies.2 In cases of
suspected intracranial atherosclerotic vascular disease, head
magnetic resonance angiography (MRA) can be very useful.
Intracranial Vascular Abnormalities
Intracranial vascular abnormalities are uncommon causes of
tinnitus; however, misdiagnosis may have catastrophic con-
sequences for the patient. In the author’s experience, the
most common of these abnormalities presenting with PT
have been dural arteriovenous fistulae (AVFs). Aneurysms,
with the exception of dissecting aneurysms of the internal
carotid and vertebral arteries, do not present with PT.
Dural AVFs constitute approximately 15% of intracranial
arteriovenous malformations (AVMs) and usually become
symptomatic during the fifth or sixth decade of life.3,4
The transverse and sigmoid sinuses are the most common
dural sinuses involved, followed by the cavernous sinus.
In contrast to AVMs, AVFs are usually acquired and thought
 Pulsatile Tinnitus: Advances in Diagnosis and Treatment
to result from dural venous sinus thrombosis. Thrombosis
may be caused by trauma, obstructing neoplasm, surgery, or
infection, or it may occur spontaneously. As the thrombosed
segment recanalizes, ingrowth of dural arteries takes place
and artery-to-sinus anastomoses are formed.4
Patients with dural AVFs usually present with PT of the
arterial type. A loud bruit over the involved dural sinus as
well as objective PT are audible. Mortality from hemor-
rhage of a dural AVF is 10% to 20%.4 In cases with retro-
grade drainage into the cortical veins, the chance of
subarachnoid or parenchymal hemorrhage is much higher.4
The following are two representative cases.
Dissecting aneurysms are rare and more often involve the
internal carotid artery (ICA) and less often the vertebral
artery. Manifestations include PT, pain, transient ischemic
attacks, cranial neuropathies, Horner’s syndrome, and
ILLUSTRATIVE CASE HISTORIES
Case 1
Fifty-five-year-old female presented with left PT of 8 months’
duration. A bruit over the left retroauricular area as well as
objective tinnitus were audible. Figure 11-1 is a selective
Case 2
Forty-five-year-old male presented with right PT of 6 months’
duration. Six months prior to this he had sustained a
severe facial injury. A loud bruit was audible over the right
Figure 11-1. Angiography, anterior-posterior view, in case 1. Microcatheter
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).
205
subarachnoid hemorrhage.4 Sudden head rotation, especially
when accompanied by extension (i.e., the tennis “ace serve”),
is the most likely precipitating event.5 Fibromuscular dys-
plasia, various arteriopathies such as Marfan syndrome, and
osteogenesis imperfecta are predisposing factors. A patient
with ICA dissection following a severe episode of vomiting
was recently seen by the author. Pulsatile tinnitus and ipsi-
lateral retroauricular bruit were present.
Table 11-1 summarizes the arterial causes of PT.
Venous Causes
Pseudotumor Cerebri Syndrome
In the author’s experience, pseudotumor cerebri syndrome
has been the most common cause of venous PT in obese
angiogram, anterior-posterior view, of the left middle meningeal
artery demonstrating an AVF with rapid shunting between the
occipital meningeal branch and the transverse sinus.
orbit. Figure 11-2 shows a carotid angiogram, lateral view,
demonstrating an AVF between the right internal carotid artery
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
inferior (D) petrosal sinuses.
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

History
The history is of utmost importance in evaluating patients
with PT. Most patients will describe their symptom as
hearing their “own heartbeat” or a “thumping noise,”
making diagnosis of PT apparent. Occasionally, however,
patients may not volunteer the pulsatile component of
their tinnitus and this may lead to overlooking this very
important information.
Associated symptoms of hearing loss, aural fullness,
dizziness, headaches, and visual disturbances, such as visual
loss, transient visual obscurations, retrobulbar pain, and
diplopia are highly suggestive of associated pseudotumor
cerebri syndrome.1,46 Older patients with a history of
cerebrovascular accident, transient ischemic attacks,
hyperlipidemia, hypertension, diabetes mellitus, and
smoking should be suspected of having ACAD.2 Females
with associated headaches, dizzy spells, syncope, fatigue,
and lateralizing neurologic deficits should be evaluated for
fibromuscular dysplasia (FMD).13–15 The clinician should
highly suspicious of extracranial or intrapetrous carotid
artery dissection in patients with sudden onset of PT in
association with cervical or facial pain, headache, and
symptoms of cerebral ischemia.16,17
Examination
Pseudotumor cerebri syndrome should be strongly sus-
pected in young and morbidly obese females with PT.1,45
Otoscopy is essential for detecting middle ear pathology
such as a high or exposed jugular bulb, aberrant carotid
artery, glomus tumor, and Schwartze’s sign. Rhythmic
movements of the tympanic membrane can be present in
patients with tensor tympani myoclonus.
Complete head and neck examination is also very
important. A palpable thrill may be present with cervical
AVM.8 Myoclonic contractions of the soft palate can be
identified in patients with palatal myoclonus. Wide opening
of the oral cavity during examination may result in elimi-
nation of the soft palate contractions.7
Auscultation of the ear canal, periauricular region,
orbits, neck, and chest should be performed for detection
of objective PT, bruits, and heart murmurs. Particularly
special attention should be paid when auscultating the
occur in this area. Presence of a bruit in this area should be
considered an intracranial vascular abnormality until proven
otherwise. Auscultation should be performed in a very quiet
room, preferably in an audiology booth using a modified
electronic stethoscope. Auscultation with an electronic
stethoscope has been found to be more sensitive than
traditional auscultation techniques.67,68 The Litmann
electronic stethoscope model 2000 can be used for this
purpose. When objective PT is detected, its rate should be
compared with the patient’s arterial pulse. The effect of
light digital pressure over the ipsilateral IJV should be
checked. Pulsatile tinnitus of venous origin such as in
patients with pseudotumor cerebri syndrome decreases or
completely subsides with this maneuver.1,46 In patients
with an arterial type of PT this maneuver has no effect on
the intensity of the tinnitus. The effect of head rotation on
tinnitus intensity should also be evaluated since venous PT
often will decrease or completely subside when the head is
rotated toward the side of the PT. This is probably due to
compression of the IJV between the contracting sterno-
cleidomastoid muscle and the transverse process of the
atlas.1,46 A complete neurologic examination, including
cranial nerve examination, should also be performed.
Consultation with neurology or neuro-ophthalmology
should be obtained for patients suspected of pseudotumor
cerebri syndrome. Papilledema is compatible with pseudo-
tumor cerebri syndrome; its absence, however, does not
exclude this entity.47–49 Diagnosis of this condition is estab-
lished by lumbar puncture and documentation of CSF
pressure greater than 200 mm H2O.50 The characteristics
of PT in patients with pseudotumor cerebri syndrome,
ACAD, glomus tumors, and AVFs are summarized in
Table 11-6.
Audiologic and Electrophysiologic
Testing
Pure tone (air and bone conduction) and speech audiome-
try should be performed in all patients. When hearing loss
of 20 dB or more is detected, a repeat audiogram should be
obtained while the patient is applying light digital pressure
over the ipsilateral IJV. Due to elimination of the masking
effect of the tinnitus, this maneuver typically results in
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
with venous type PT such as in pseudotumor cerebri syn-
drome.1 Discrimination is typically excellent in these
patients.
Impedance audiometry should be obtained for suspected
cases of tensor tympani myoclonus.
Auditory brainstem evoked responses (ABR) should be
considered in patients with suspected pseudotumor cerebri
syndrome. Abnormalities of this test, consisting mainly of
prolonged interpeak latencies, have been detected in one
third of patients with this syndrome.52 Normalization or
improvement of these abnormalities has been noticed
in the majority of these patients following successful
management.52
Metabolic Work-up
Complete blood count and thyroid function tests should
be obtained in cases of suspected anemia and hyperthy-
roidism, respectively. Serum calcium levels and studies for
systemic lupus erythematosus should be considered when
pseudotumor cerebri syndrome is suspected. Serum lipid
profile and fasting blood sugar should be performed in
suspected cases of ACAD.
Ultrasound Studies
Duplex carotid ultrasound (including the subclavian
arteries) or echocardiogram studies (or both) should be
obtained in suspected cases of ACAD, atherosclerotic
subclavian artery disease, or valvular disease.2,31 In partic-
ular, patients with carotid bruits should have a carotid
ultrasound study prior to any radiologic evaluation
because if diagnosis of ACAD is established, the need for
any radiologic evaluation may be obviated.
Radiologic Evaluation
Radiologic evaluation should to be individualized accord-
ing to the history and physical examination findings such
as retrotympanic mass, objective PT, bruit, and
papilledema. The following represents the author’s current
radiologic evaluation algorithm:
1. For patients with normal otoscopy, screening with
high-quality MRA/magnetic resonance venography
(MRV) in conjunction with brain magnetic resonance
imaging (MRI), should be initially obtained. Small
ventricles or empty sella are findings occasionally seen
in patients with pseudotumor cerebri syndrome.31
MRI demonstration of dilated cortical veins is
suggestive of an AVM; however, neither the arterial
supply nor the nidus of an AVM may be detectable on
MRI.69 In 12 patients with angiographic diagnosis of
AVMs, 8 had dilated cortical veins on MRI.70 Dural
venous sinus thrombosis also can be diagnosed with
MRV. In patients with normal MRI/MRA/MRV
associated with objective arterial PT or a head bruit,
carotid angiography should be strongly considered to
exclude dural AVFs and fibromuscular dysplasia.23,70
2. Patients with a retrotympanic mass should have a high-
resolution, temporal bone computed tomography (CT)
as their initial evaluation.31 If glomus tympanicum,
aberrant internal carotid artery, or jugular bulb
209
abnormalities are diagnosed, no other imaging stud-
ies are needed. For patients with glomus jugulare
tumors, CT examination of the neck should also be
obtained to assess for additional chemodectomas
along the carotid arteries. Carotid angiography is
indicated only for prospective surgical cases to evalu-
ate the collateral circulation of the brain (arterial and
venous) in anticipation of possible vessel ligation or
preoperative tumor embolization.28
Figure 11-5 depicts a diagnostic algorithm for patients
with pulsatile tinnitus.
MANAGEMENT
Management should be directed toward treating any
underlying cause. Management of the most common
causes of PT are as follows:
Pulsatile tinnitus secondary to idiopathic pseudotumor
cerebri syndrome responds well to weight reduction
and medical management with acetazolamide (Diamox)
250 mg tid or furosemide (Lasix) 20 mg bid.1,49 Both of
these medications are thought to reduce CSF production.
Short courses of steroids should be considered only for
acute exacerbations of the syndrome. Lumbar–peritoneal
shunt should be considered for patients with progressive
deterioration of vision, persistent headaches, and disabling
PT.1,31,46 In morbidly obese patients, however, this
procedure is often complicated by shunt occlusion due to
increased intraabdominal pressure.71 Weight reduction
surgery has been found effective in relieving PT in mor-
bidly obese patients with associated pseudotumor cerebri
syndrome and should be considered when conservative
management has failed. Thirteen out of 16 patients who
underwent this procedure experienced complete resolution
of their PT.72 Optic nerve sheath fenestration has been
reported to be very helpful for patients with progressive
visual loss and headaches.73
Repair of a symptomatic high-dehisced jugular bulb has
been reported by using pieces of mastoid cortical bone and
septal, conchal, or tragal cartilage and surgical wax.21,74–76
Pulsatile tinnitus secondary to otosclerosis may respond to
stapedectomy.31 Tensor tympani and stapedial myoclonus
may respond to sectioning of the respective muscles via
tympanotomy.77 Botulinum toxin has also been reported
for the management of palatal myoclonus.78,79
Patients with ACAD benefit from carotid endarterec-
tomy when carotid obstruction is more than 60%.80
Angioplasty has relieved PT secondary to atherosclerotic
obstruction of the subclavian and intracranial carotid
arteries.81,82 Pulsatile tinnitus secondary to antihyperten-
sive medication such as enalapril or verapamil subsides
soon after discontinuation of these agents.31
Dural AVFs can be treated in the majority of patients with
selective embolization.83,84 Figures 11-6 and 11-7 are the
postprocedure films of the internal carotid artery/cavernous
sinus fistula (case 2) following embolization with platinum
coils. Radiosurgery or selective embolization followed by
radiosurgery are other modalities of treatment.85,86
Vascular neoplasms such as glomus jugulare tumors can
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
Stereotactic surgery may be considered for patients who
are poor surgical candidates.87
Finally, in patients with idiopathic PT, tinnitus typically
subsides with light pressure over the ipsilateral IJV making
ligation of this structure a very tempting procedure. The
results of this procedure, however, have been very incon-
sistent and poor overall. In a series of 13 patients with
essential tinnitus, 3 underwent ligation of the ipsilateral
IJV and only 1 benefited permanently. The other two
patients experienced return of their PT within a few
days.55 Furthermore, we have become aware of a signifi-
cant number of cases from different parts of the country
who underwent this procedure and developed intracranial
hypertension. Diagnosis of pseudotumor cerebri was made
in some of these cases, and in several, malpractice litiga-
tion followed. Therefore, there is rarely, if ever, an indication
for this procedure solely for the purpose of alleviating pulsatile
tinnitus.88
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60. Wiggs B, Sismanis A, Laine FJ: Pulsatile tinnitus associated with
congenital central nervous system malformations. Am J Otol
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61. Lambert PR, Cantrell RW: Objective tinnitus in association with
abnormal posterior condylar emissary vein. Am J Otolaryngol
7:204–207, 1986.
62. Forte V, Turner A, Liv P: Objective tinnitus associated with abnor-
mal emissary vein. Otolaryngology 18(5):232–235, 1989.
63. Herrmann C, Crandall PH, Fang HC: Palatal myoclonus: A new
approach to the understanding of its production. Neurology
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64. Bjork H: Objective tinnitus due to clonus of the soft palate. Acta
Otolaryngol Suppl (Stock) 116:39–45, 1954.
65. Heller MF: Vibratory tinnitus and palatal myoclonus. Acta
Otolaryngol (Stock) 55:292–298, 1962.
66. Pulec JL, Hodell SF, Anthony PF: Tinnitus: Diagnosis and manage-
ment. Ann Otol Rhinol Laryngol 87:821–833, 1978.
67. Sismanis A, Williams GH, King MD: A new electronic device for
evaluation of objective tinnitus. Otolaryngol Head Neck Surg
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68. Sismanis A, Butts FM: A practical device for detection and recording of
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69. DeMarco JK, Dillon WP, Halbalbach VV, Tsuruda JS: Dural
arteriovenous fistulas: Evaluation with MR imaging. Radiology 175:
193–199, 1990.
70. Dietz RR, Davis WD, Harnsberger HR, et al: MR imaging and
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71. Sugerman HJ, Felton WL, Salvant JB Jr, et al: Effects of surgically
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77. Badia L, Parikh A, Brookes GB: Management of middle ear
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The Neurotologic Examination
Outline
General Physical
Examination
Cranial Nerve I
Cranial Nerve II
Cranial Nerves III, IV, VI
Cranial Nerve V
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
a diagnosis initially made on clinical impression alone.
This chapter reviews the general physical examination of
neurotologic patients with special focus on the function of
their cranial nerves.
GENERAL PHYSICAL EXAMINATION
Physical clues to a patient’s pathology may be obvious
before formal examination even begins. An abnormal gait,
stance, or head tilt may indicate pathology of the vestibular
system in patients complaining of vertigo or dizziness.
Physical deformities associated with neurotologic disease
may accompany rheumatoid arthritis, congenital syphilis,
or Paget’s disease. Skin stigmata, such as those associated
with scleroderma, neurofibromatosis, or lupus, may be
associated with neurotologic symptoms. Other findings
associated with syndromic disease, such as branchio-
otorenal, Waardenburg’s, or Pendred’s, may be obvious
on meeting the patient. Sometimes, evidence of previous
injury or surgery leads the clinician to consider trauma,
metastatic disease, or iatrogenic causes of neurotologic
symptoms.
Formal examination of the neurotologic patient begins
with the external ear. Congenital conditions such as preau-
ricular pits or aural atresia suggest internal malformations,
while an aural polyp is a sign of cholesteatoma with a
sensitivity of 33% in previously unoperated ears and
71% in ears with an attic or marginal defect.1 Signs of
trauma or scars from previous surgery, including evidence
of cartilage grafts, can provide the examiner with valuable
information about the patient’s otologic history. Chronic
inflammatory conditions, such as chondrodermatitis
nodularis chronica helicis or relapsing polychondritis, may
cause a painful, reddened pinna.2 Otorrhea may represent
Chapter
12
Cochlear Timothy E. Hullar, MD
Vestibular
Lloyd B. Minor, MD, FACS
Oculomotor Examination
Cranial Nerves IX, X
Cranial Nerve XI
Cranial Nerve XII
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-
auricular edema occurs in 76% of patients with mastoidi-
tis.3 Tenderness and redness of the mastoid cortex and
stand-off of the external ear, a softening of the postauricu-
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%
of patients with coalescent mastoiditis.4 Battle’s sign, or
postauricular ecchymosis,5 has a 100% positive predictive
value for recent skull base fracture.6 An earlobe crease,
although not indicative of otologic disease, may be noted
by the neurotologist and is an indicator (with a sensitivity
of 73% and a specificity of 84%) for coronary artery
disease.7
Although handheld otoscopic examination is handy and
quick, patients referred to a neurotologist deserve the more
thorough examination only a binocular microscope and
thin-walled metal speculum allows. The microscope
increases the examiner’s sensitivity to small movements of
the tympanic membrane caused by muscular contraction,
respirations through a patulous eustachian tube, or autoin-
sufflation.8 A Siegle speculum’s angled faceplate allows pneu-
matic otoscopy under the microscope without glare; using
this technique, “perforations” diagnosed with a handheld
otoscope are sometimes shown to be monomeric tympanic
membranes. Microscopy frees both of the examiner’s hands
to manipulate the patient’s head and speculum, allowing
safe removal of foreign bodies or tightly impacted cerumen.
A video camera mounted on the microscope can feed paired
video monitors so the supine patient may follow the clini-
cian’s exam of either ear.
The otoscope allows visualization of many otologic
disease processes or their stigmata. The external canal
may show signs of infection, such as fungus associated with
otitis externa or vesicles of the Ramsay Hunt syndrome.9
Mechanical obstructions including osteoma or exostoses
215
216 NEUROTOLOGIC DIAGNOSIS
of the ear canal can predispose patients to infection.
Inflammatory processes such as Wegener’s granulomatosis
can cause otitis media and otorrhea.10 Aural tuberculosis
can cause multiple perforations of the drum with painless
otorrhea.11 Otoscopy may reveal masses, such as a high-
riding jugular bulb, cholesteatoma, glomus tumor, or aural
foreign body, and can sometimes allow visualization of a
dislodged stapes prosthesis. Hypervascularity on the
promontory due to otosclerosis causes Schwartze’s sign, a
blush behind the drum.12,8
A general otolaryngologic examination may uncover find-
ings pointing to a particular neurotologic source. This
examination includes an ocular examination, detailed in a
later section under the cranial nerves responsible for ocular
movement. A nasal exam can show a bluish nasal mucosa,
especially over the inferior turbinates, indicating allergies
contributing to eustachian tube dysfunction. Irritative
lesions of the nose, including mucosal contact points, may
cause patients to present with headache or ear pain.13
Examination of the mouth may reveal a submucous cleft
palate causing eustachian tube dysfunction, or poor denti-
tion leading to temporomandibular joint dysfunction and
referred otalgia. Cervical lymphadenopathy can represent
metastases from a nasopharyngeal carcinoma obstructing
the eustachian tube or pharyngeal malignancy, whereas a
neck abscess under the sternocleidomastoid may be a
Bezold’s abscess derived from a suppurative mastoiditis.14
Pain can be referred to the ear from pathology in the
distributions of the 5th, 7th, 9th, and 10th cranial nerves
as well as the cervical plexus. Some causes of referred otal-
gia are erupting teeth, pharyngeal malignancies, periton-
sillar abscess, pathology of the temporomandibular joint,
peritonsillar abscess, laryngitis, thyroiditis, and Eagle
syndrome, consisting of pain secondary to styloid process
irritation.15
Palpation of the scalp may find crepitus in patients with
syphilis, infantile rickets, hydrocephalus, or other causes of
bony loss,16 whereas the occiput may be tender in patients
with tumors of the posterior fossa.17 Tenderness over the
maxillary and frontal sinuses may reveal sinus disease with
a sensitivity of 48% to 50% and a specificity of 62% to
65%.18 Percussion of the head can elicit a dull “cracked-
pot” sound in children with hydrocephalus, a finding known
as Macewen’s sign.19
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
of the eustachian tube can also be determined from the
approximate length of time it takes for a patient with a
perforated drum to note the taste of antibiotic drops
placed in the ear. Pulsatile tinnitus may be due to a glomus
tumor, but noise transmitted from turbulent flow in a
diseased carotid artery or stenotic aortic valve can cause
a similar perception. Auscultation of the neck and chest
can discriminate between these causes. The most common
site of vertebral artery stenosis is at its branch from
the subclavian and is best heard in the supraclavicular
fossa.21,22 Intracranial bruits are best heard over the
globes17 although reported sensitivity for this test varies
widely.23 Palatal24 or laryngeal25 myoclonus can cause
objective tinnitus, as can myoclonus of the intrinsic mus-
cles of the middle ear.26
CRANIAL NERVE I
Olfaction in humans is derived from both cranial nerves I
and V. Noxious chemicals such as ammonia, acids, and the
penetrating odors of peppermint and menthol stimulate
intranasal branches of cranial nerve V.27 What we perceive
as taste is largely a function of cranial nerve I, although
cranial nerve VII carries fibers to chemoreceptors on the
oral tongue and soft palate and IX carries fibers to the
oropharynx.
Lesions attributable to cranial nerve I are analogous to
those of VIII in that they are either conductive or neural in
origin. Conductive losses prevent airborne molecules from
reaching the olfactory epithelium in the superior nasal
cavity. Air bypasses the nasal mucosa entirely in laryngec-
tomees and patients with nonfenestrated tracheostomies.
Patients with nasal masses or deforming nasal trauma suf-
fer olfactory loss due to mechanical obstruction. Localized
inflammation, perhaps incited by a prior upper respiratory
infection, may also block olfactory receptors, although
respiratory pathogens may be directly toxic to olfactory
neurons as well.28 Neural losses include those of the olfac-
tory epithelium itself, such as caused by chemicals or topical
medications, or central injury due to head trauma shearing
the fibers as they enter the cribriform plate or expanding
tumors. Neurodegenerative diseases such as Alzheimer’s
can also cause olfactory loss.29
A quick bedside test of olfaction is the alcohol sniff
test.30 A 70% isopropyl alcohol wipe is gradually moved
closer to the nose of a patient until he smells the odor of
the alcohol; this process is repeated five times. An average
distance less than 5 cm indicates anosmia, although this
procedure may give false-negatives due to activation of
cranial nerve V. A commercial version to test sensory
thresholds of cranial nerve I is the Smell Threshold
Test using rose scent (phenyl ethyl alcohol). This type
of test provides a more quantitative measure of thresh-
old than other odor identification tests, such as the
40-odorant scratch-and-sniff University of Pennsylvania
Smell Identification Test, known commercially as the SIT;
the 12-odor Brief Smell Identification Test (B-SIT),
also known as the Cross-Cultural Smell Identification Test;
and the 3-odor Pocket Smell Test (all from Sensonics, Inc,
Haddon Heights, NJ).31
CRANIAL NERVE II
Examination of the optic nerve includes measuring pupil-
lary reflexes, acuity, color perception, visual fields, and
funduscopy. Illuminating each eye in succession deter-
mines whether defects in the pupillary reflex are afferent
or efferent in nature. Both eyes should contract consen-
sually. Failure to constrict the illuminated eye only
indicates a defect in the efferent parasympathetic pathway
on that side. Failure to constrict either eye indicates
an optic nerve problem. With vergence, normal pupils
constrict slightly. The Argyll Robertson pupil of patients
with syphilis is small, irregular, and does not react to
light but does react to accommodation. Other conditions
affecting pupillary function include diabetes, encephalitis, sar-
coidosis, Horner’s syndrome, Lyme disease, and intracranial

mass; these patients require prompt ophthalmologic
referral.
Acuity is measured using a standard Snellen chart at 20 ft.
Dynamic visual acuity is a measure of the vestibulo-ocular
reflex and is described under the vestibular examination.
Loss of color perception is an early indicator of loss
of function of the optic nerve. Ishihara or other standard
tests can be used to measure color perception. Abnormal
findings can be seen in patients with pituitary lesions32 or
pathology of the optic nerve.
Visual fields can be tested at the bedside using confronta-
tion or in a formal visual field testing booth. To test the
visual fields using confrontation, the patient and examiner
sit closely looking at each other with the patient covering
one eye and the examiner covering his opposite eye. The
examiner then moves his outstretched hand in from the
four quadrants of the patient’s visual field until the patient
can see his gently wiggling fingers. The test is repeated
after switching eyes. Common field cuts and their causes
are shown in Figure 12-1.
Funduscopy is the specialty of the ophthalmologist and
requires dilation for anything more than a cursory examina-
tion. Elevated intracranial pressures, such as caused by
meningitis, sigmoid sinus thrombosis, or bleed, cause a loss
of venous pulsations and papilledema. Signs of papilledema
include a blurring of the margin of the optic disc, engorged
veins, and “cotton-wool” spots, each of which is caused
by increased intracranial pressure. Papilledema and optic
neuritis cause elevation of the optic disc, with the latter
usually accompanied by an early loss of vision. Cavernous
sinus thrombosis can cause venous stasis in the entire orbit
including the fundus and sclera.
Homonymous hemianopsia
Bitemporal hemianopsia
Binasal hemianopsia
Figure 12-1. Binocular field defects. Visual field defects are represented in
black, from the patient’s perspective. Homonymous hemianopsia is a conse-
quence of a postchiasmal defect. The degree of the defect (from a “pie
wedge” to half of the entire field) and the congruity of the defect between
the two sides can help determine the exact position of the defect. A total
homonymous hemianopsia, as shown here, can be caused by any postchias-
mal defect. Bitemporal hemianopsia is caused by a chiasmal lesion if the
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
chiasm. (From Wilson-Pauwels L, Akesson E, Stewart P: Cranial Nerves.
Toronto, BC Decker, 1988.)
The Neurotologic Examination 217
CRANIAL NERVES III, IV, VI
The third nerve innervates all extraocular muscles except
the abducens (from cranial nerve VI) and the superior
oblique (from cranial nerve IV). A significant palsy of any of
these nerves will cause diplopia, although central processes
such as multiple sclerosis (MS) may cause similar symptoms.
Restriction of extraocular muscle movement due to entrap-
ment, mass effect, or endocrine orbitopathy may mimic a
nerve palsy.33 These conditions can be distinguished from a
true palsy using a forced duction test, during which the
sclera of the anesthetized eye is grasped using a forceps and
passively drawn toward the side of the apparent paresis.
A true third nerve palsy leaves the eye laterally deviated
from unopposed action of the lateral rectus muscle, mydri-
atic from loss of third nerve parasympathetic input, and
with a ptosis of the upper lid from paralysis of the levator
palpebrae muscle. A unilateral complete paralysis can be
caused by elevated intracranial pressure, posterior commu-
nicating artery aneurysm, or subarachnoid hemorrhage;
more benign conditions such as diabetes may reassuringly
spare pupillary reflexes.34 Other causes of ptosis include
congenital ptosis, myasthenia gravis, aging, or Horner’s
syndrome paralyzing Müller’s muscle. Loss of function of
Müller’s muscle leaves the superior orbital crease intact,
while a ptosis due to third nerve palsy relaxes the levator
aponeurosis insertion on the eyelid and may obliterate
this fold. Other findings in a Horner’s syndrome include
ipsilateral anhidrosis and anisocoria (inequality of pupil
size, with the smaller, miotic pupil on the affected side).
Any interruption of the cervical sympathetic pathway
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-
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
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
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;
a patient can partially compensate for this by tipping the
head toward the unaffected side. This effect should not
be confused for torticollis caused by birth trauma or other
causes, including an attempt by the patient to extinguish a
positional nystagmus. The Bielschowsky head-tilt test can
help distinguish the side of a superior oblique lesion caus-
ing diplopia: By tilting the head toward the side of the
lesion, the diplopia should worsen with the unbalanced
action of the contralateral, intact superior rectus.38
218 NEUROTOLOGIC DIAGNOSIS

The abducens nerve innervates the lateral rectus muscle.
This nerve is commonly affected in cases of skull base
trauma or inflammatory conditions and in MS via inter-
ruption of the medial longitudinal fasciculus. Tumors of
the cerebellopontine angle can affect the sixth nerve, occa-
sionally bilaterally.35 Along with cranial nerves III, IV, V1,
and V2, pathology in the vicinity of the cavernous sinus can
affect function of the sixth nerve. A paralysis of lateral gaze
in an immunocompromised patient with fungal sinusitis,
for example, indicates cavernous sinus involvement and is
a contraindication to surgical intervention.39 Möbius syn-
drome includes congenital paralysis of nerves VI and VII40
although this term has also been applied to episodic cranial
nerve III palsy associated with migraine.41 Gradenigo’s
syndrome, caused by petrosal disease, comprises the symp-
toms of a draining ear, pain in the distribution of V1, and
abducens palsy. It can also cause excessive lacrimation.42,43
CRANIAL NERVE V
The fifth cranial nerve has three major branches: the oph-
thalmic (V1), maxillary (V2), and mandibular (V3) divisions
(Fig. 12-2). V1 provides sensation to the upper face, including
the cornea, bridge of nose, upper nasal mucosa, and frontal
sinus. V2 provides sensation to the midface, including the
lower nose and nasal mucosa, cheek, maxillary sinus, and
entire oral cavity except the lower lip. V3 provides sensation
to the lower teeth, lower lip, and tongue (except for taste,
supplied from cranial nerve VII via the chorda tympani).
Sensation on the face should be tested in the conven-
tional way, using a wisp of cotton for light touch, warm and
cold objects for temperature, and a pin or sharply broken
wooden stick for pain. A cotton-tipped swab touched to the
mucosa of the nose is a noxious but inoffensive stimulus
to rouse an unresponsive patient. Corneal reflexes are a
particularly important part of the neurotologic examina-
tion. If possible, the patient turns his eyes to the opposite
side to expose as much sclera as possible, protecting the
cornea and preventing the patient from observing the test.
The examiner then “walks” a fine wisp of cotton across the
sclera (which should not be reactive) toward the cornea
(which should be). A bilateral blink indicates an intact
V1 on the tested side and seventh nerve bilaterally; a con-
tralateral blink indicates loss of seventh nerve function on
the tested side, and no response indicates loss of the fifth
nerve on the tested side or loss of seventh nerve function
bilaterally.
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
and tensor tympani muscles, are controlled by the fifth
nerve via V3. Pronounced wasting of the temporalis can be
due to chronic disease or starvation or, in unilateral cases,
nerve or CNS injury. A significant weakening of the tem-
poralis or masseter will prevent the patient from closing his
mouth tightly. A reflex jaw jerk will stimulate the muscles
of mastication to close the partially opened mouth after
a sharp tap on the chin, although this response may give
little information about degree of strength. Oropharyngeal
inflammation, mass, or tumor invasion can cause spasm
of the pterygoids and trismus; a process involving the
pterygoids can be palpated transorally. A temporomandibu-
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
unilateral muscular paralysis the jaw will deviate to the
affected side.
CRANIAL NERVE VII
The facial nerve is of utmost importance to neurotologists.
Careful appreciation of its function in all branches before
treatment allows accurate monitoring of pathologic
processes and surgical results. Thorough examination of
the facial nerve includes evaluation of its intracranial and
extracranial branchings and of both its sensory and motor
fibers.
The initial branch of the facial nerve is at the geniculate
ganglion, where the greater superficial petrosal nerve
(GSPN) travels forward as the nerve turns toward the tym-
panic segment (Fig. 12-3). Preganglionic parasympathetic
fibers in the GSPN synapse in the pterygopalatine gan-
glion before innervating the nasal mucosa and lacrimal
glands. Lesions of the facial nerve can cause either a dry
eye or excessive tearing: Division of the nerve proximal to
the geniculate causes a dry eye, but distal division of the
nerve can allow exposure and irritation of the eye and exces-
sive tearing. The modified Schirmer test is a semiquantita-
tive way to measure lacrimal function. It depends on a
noxious stimulus, such as ammonia or mechanical irritation
of the nasal mucosa with a cotton swab that stimulates
cranial nerve V and stimulates tearing. Inhalation of the
substance causes reflex tearing if the GSPN is intact. The
test itself is performed after protecting or topically anes-
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
inserted in the conjunctival fornix without stimulating the
cornea. Five minutes of tear absorption onto the filter
paper are measured and compared; a distance in the tested
eye of less than 50% of the control eye indicates dysfunc-
tion.44 Patients with unilateral Bell’s palsy may have bilat-
erally reduced lacrimation, so false-negatives may result
unless a minimum total distance (summed from both eyes)
of 25 mm is reached.45
The facial nerve contributes parasympathetic fibers to
the submandibular ganglion via the chorda tympani. A loss
of parasympathetic function from a lesion of the facial
nerve may reduce salivary flow enough to cause symptoms
of xerostomia. Fibers of taste innervating the anterior two
thirds of the tongue originate in the nervus intermedius
and branch from the facial nerve in the mastoid process,
cross the inner ear as the chorda tympani, and join the
lingual nerve. In addition to lesions of the facial nerve,
MS, hypothyroidism, diabetes mellitus, liver or kidney
failure, vitamin deficiency (zinc or B3), or a history of oral
radiation treatment can alter taste. Some free endings of
the fifth cranial nerve are also present on the tongue, and
disorders of this nerve can cause altered taste sensation.
Fibers of the seventh nerve innervate taste buds on 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
normal pink velvety texture on the side of a tongue affected
by a chorda tympani injury, as denervation disrupts actin
filaments in taste pore cells.46 Chemical testing involves
placing a cotton-tip applicator soaked in salty or sugary
water or weak vinegar on the tongue. The patient must
indicate the taste by pointing rather than speaking, as
pulling the tongue into the mouth to speak permits rapid
diffusion and a false-negative result for unilateral loss. In
cases of Bell’s palsy, taste may return quicker than muscle
function.47 Electrogustometry may be a valuable addition
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
cause objective tinnitus,26 while patients with hypofunc-
tion of this muscle (following section of its tendon during
stapes surgery, for example) may complain about hypera-
cusis. An audiologist can directly test its function by elicit-
ing stapedial reflexes, a test also critical in distinguishing
otosclerosis from superior canal dehiscence.
The seventh nerve supplies sensation to the posterior
tympanic membrane and external auditory canal, lateral
concha and helix, lobule, and mastoid. Loss of sensation in
the external auditory canal may be an early indicator of
acoustic neuroma.48 Motor branches carry fibers to the
posterior auricular muscles, to the stylohyoid and posterior
belly of the digastric, and to the muscles of facial expres-
sion via the temporal, zygomatic, buccal, marginal
mandibular, and cervical branches. Weakness of the mar-
ginal mandibular nerve can be mimicked by separation of
the platysma muscle during neck dissection. Lyme disease,
syphilis, Guillain-Barré syndrome, amyotrophic lateral
sclerosis, tuberculosis, or MS may accompany weakness or
paralysis of the facial nerve.49 Crossed central fibers some-
times allow the ipsilateral forehead to function normally
after a central lesion.
The House-Brackmann scale affords a quantifiable way
to evaluate facial nerve weakness (Table 12-1).50 Paramount
on this scale is noting if the patient has a rating of 4 or
greater, indicating incomplete eye closure. Serious corneal
damage and permanent loss of vision can occur rapidly in
patients with exposed corneas, especially in those with
lesions of cranial nerve V rendering the cornea anesthetic.
Lubricant and a moisture chamber should be placed over
the eye of any patient with questionable closure, as an
intact Bell’s phenomenon cannot be relied on to protect
the cornea from desiccation during sleep. Eye patches are
not appropriate for these patients as they may not prevent
opening of the eye and may allow drying of the eye hidden
behind the patch. Any question about ability of the patient
to close the eye warrants examination of the cornea using
fluorescein and a Wood’s lamp or a slit lamp to rule out
conjunctival irritation or keratitis.
Overactive movements of the facial nerve can give diag-
nostic information. Hemifacial spasm can be caused by
arterial irritation of the facial nerve at the root entry zone51
and may be a symptom of acoustic neuroma.52
CRANIAL NERVE VIII
Cochlear
Examination of the eighth nerve is divided into cochlear
and vestibular segments (Fig. 12-4). Audiologic assessment
is an integral part of the examination of the cochlear nerve,
but bedside tests can guide initial diagnostic thinking. The
most common tuning fork tests are the Weber and Rinne
tests, both commonly performed with a 512-Hz fork. The
Weber is usually performed by placing the vibrating tun-
ing fork on the patient’s forehead; the patient will lateral-
ize the sound to the ear with a conductive loss or away
from the ear with a sensorineural loss.53 Placing the han-
dle of the fork on the upper teeth or gums increases the
patient’s awareness of the tone by 10 dB.54 Sensitivity of
this test is 58% for sensorineural loss greater than 30 dB
and 54% for conductive loss greater than 20 dB, while
specificity is 79% and 92%, respectively.55 The air-
conduction Rinne test is performed with the tines of the
fork along the interauricular axis and the bone-conduction
test on the mastoid cortex.56 To avoid overtones, the fork
must not be struck on a hard surface or too forcefully.57
A Rinne test is termed positive if the air-conduction signal
is louder than the bone-conduction signal.58 A negative
Rinne test with a 512-Hz tuning fork indicates a 25- to
30-dB hearing loss. A similar result with a 256-Hz fork
implies a gap of 15 dB, while at 1024 Hz the gap is at least
35 dB.59 There is no need to use masking during a Rinne
test.60 The sensitivity of the Rinne test at 512 Hz is 60%
to 90% and the specificity is 95% to 98%.61,62
Infrequently used tuning fork examinations include the
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
3 Moderate dysfuntion
4 Moderately severe
dysfunction
5 Severe dysfunction
6 Total paralysis
Slight weakness with possible
slight synkinesis
Obvious asymmetry; noticeable but
not severe synkinesis, contracture,
or hemifacial spasm
Obvious weakness or disfiguring
asymmetry
Barely perceptible motion
None
Normal Slight oral asymmetry; complete eye
closure with minimum effort; moderate
to good forehead function
Normal Slight oral asymmetry; complete eye
closure with effort; slight to moderate
forehead movement
Normal Asymmetrical mouth, incomplete eye
closure, no forehead movement
Asymmetrical Slight oral movement, incomplete eye
closure, no forehead movement
Asymmetrical No movement

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
canal is alternately occluded and opened. A patient with
conductive hearing loss will note no change in intensity,
while normal patients or those with sensorineural hearing
loss will find that the tone becomes louder with occlusion.
This test is not as sensitive as the Rinne test but its speci-
ficity is equivalent.63 The Schwabach test consists of placing
a vibrating tuning fork on the patient’s mastoid and remov-
ing it when he can no longer hear it. If the examiner can
still hear the fork, the patient has a sensorineural loss, but
if the patient hears the fork longer than the examiner, the
loss is conductive.64 This test depends, of course, on an
examiner with normal hearing.
Although more formally tested by an audiologist, a neu-
rotologist can also test a patient’s response to words at the
bedside. The examiner must mask the contralateral ear
and cover his mouth to prevent lip reading or stand behind
the patient while whispering letter or number triplets as
quietly as possible. If the patient fails to recognize more
than 50% of the items, the test is positive. Patients with
pathology of the auditory nerve (rather than the cochlea)
may have more difficulty with words than suggested by
their response to tuning forks or other pure tones. The
sensitivity of this test is greater than 90% and its specificity
greater than 80%.65
Vestibular
The clinical history is critical to guiding appropriate exam-
ination of the vestibular system. History-taking is notori-
ously difficult in patients complaining of disturbed
equilibrium, however, because normal sensation depends
on subconsciously integrating inputs from somatosensory
receptors, vision, and the vestibular system. Particular
attention should be paid to whether the patient has actual
The Neurotologic Examination 221
sensations of vertigo (illusory sense of rotatory, linear, or
tilting motion) or just light-headedness; direction of
perceived motion; sensitivity to head motion leading to
oscillopsia (sensation of movement of objects known to be
stationary); relationship to other otologic symptoms
such as hearing loss, fullness, and tinnitus; duration and
frequency of symptoms; exacerbating or provoking factors;
and other medical problems, including psychological disor-
ders and conditions requiring medications that may cause
symptoms of dizziness. In some patients, this history com-
bined with a thorough bedside examination is sufficient to
make a diagnosis and treatment plan, but many others
will require further testing such as calorics, rotatory chair
testing, and imaging in order to make a diagnosis.
Oculomotor Examination
The exquisite control of eye movements by the vestibular
system allows them to serve as particularly valuable meas-
ures of vestibular function. Eye movements are classified
into several categories. Fixation allows an image to be held
steady on the retina, while saccades bring an image onto the
fovea and smooth pursuit holds it there as it moves across the
field of view. Vergence moves the eyes in opposite directions
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.
The examiner must understand the physiological mecha-
nisms underlying nystagmus in order to use it as a diagnos-
tic tool. Normally, three neurologic mechanisms collaborate
to control the eye’s position in the orbit: gaze-holding, or
the ability to hold the eye at an eccentric position despite
its natural tendency to drift back to neutral position; visual
fixation, which detects drift of images across the retina and
suppresses unwanted saccades; and the vestibulo-ocular
222 NEUROTOLOGIC DIAGNOSIS
reflex (VOR), which uses vestibular input to keep the fovea
directed stably at a target despite head motion in space.66
Nystagmus is a characteristic finding in disorders of any of
these three mechanisms. It can consist of either sinusoidal
movements, termed pendular nystagmus, or alternating
slow and fast phases, called jerk nystagmus. Jerk nystagmus
is described by the direction of its fast phases, although
these are simply resetting motions separating the physio-
logically more relevant slow phases that guide the eye
smoothly across the orbit.
Failure of the gaze-holding system can cause several
types of jerk nystagmus: gaze-evoked nystagmus, cen-
tripetal nystagmus, or rebound nystagmus. The “neural
integrator” is responsible for holding the eye at an eccen-
tric position and is typically weakened following unilateral
vestibular loss. Gaze-evoked nystagmus is characterized by
slow phases caused by the drift of the eye toward its neutral
position in the orbit. Centripetal nystagmus is the reversal
of this direction. Rebound nystagmus is the short-lived
nystagmus, also opposite to the direction of gaze-evoked
nystagmus, that occurs after the eye returns from an
eccentric to a neutral position. The patient’s gaze-holding
ability is tested by maintaining eccentric horizontal, then
vertical positions of gaze (approximately 30 degrees from
center orientation). Minimal drift should normally be
encountered for periods up to 15 sec. Nystagmus due to
errors in gaze-holding is most commonly found as a side
effect of medications (including sedatives67 and anticon-
vulsants68 although it can also indicate a structural lesion in
the nucleus prepositus hypoglossi, medial vestibular
nucleus,69 or interstitial nucleus of Cajal.70 It is also seen in
familial episodic ataxia, a channelopathy responsive to
acetazolamide.71 Gaze-evoked nystagmus is a normal
finding at extremes of gaze, where it is called “end-point”
nystagmus. End-point nystagmus may be asymmetrical,
sustained, occur with less than full deviation of the eye, and
may even have a torsional component. It has a relatively
slow velocity and is not accompanied by other pathologies.
Disorders of the visual pathway can cause either jerk
or pendular nystagmus. Vertical, horizontal, or torsional
jerk nystagmus with a drifting “null” position can result
in patients with total blindness.72 Pendular nystagmus can
occur in patients with subtotal visual loss preventing rapid
feedback during normal drifting of the eye; corrective
motions are therefore delayed and ocular oscillations result.73
Pendular nystagmus may be congenital, although acquired
pendular nystagmus may be seen in demyelinating disorders,
brainstem injury, or hypoxic encephalopathy. Congenital
nystagmus, likely due to miswiring of anterior visual path-
ways, characteristically shows an increase in velocity during
each slow phase, and patients may favor an eccentric angle of
gaze where the nystagmus is minimized.66 Dynamic eye
motion is first tested by asking the patient to perform
saccades. The patient fixates on the examiner’s nose, then
shifts rapidly to a finger target held about 15 degrees away.
Velocity, accuracy, and latency are noted. Smooth pursuit is
tested by having the patient follow a target moving horizon-
tally at less than 20 degrees/sec. Corrective saccades in one
direction reflect asymmetries in horizontal tracking and are
more significant than a symmetrical decrease in smooth
tracking. VOR cancellation is tested by following a target
(e.g., the examiner’s finger) by turning the head.
The vestibular system is the third source for the signals
that produce nystagmus. Nystagmus may originate any-
where in the vestibulo-ocular pathway, including the
vestibular periphery, the eighth nerve, and the vestibular
nucleus and cerebellum. Unilateral vestibular hypofunction
causes a static imbalance in the activity of the semicircular
canal-related VOR and results in a spontaneous jerk nystag-
mus. This can be either centrally based, as in the case of
periodic alternating nystagmus, or due to a peripheral
lesion. Peripheral dysfunction tends to cause motion of the
eyes in the planes of the semicircular canals, such as with the
horizontal-torsional nystagmus typically observed acutely
following unilateral labyrinthectomy. The horizontal com-
ponent fast phases beat toward the “stronger” (intact) ear,
and the torsional component involves beating of the supe-
rior poles of the eyes toward the intact ear. The speed of the
slow phase is generally constant for peripheral vestibular
disturbances. Because nystagmus caused by peripheral
lesions is relatively suppressed with visual input, examina-
tion is best carried out using Frenzel lenses. These special
high-diopter goggles prevent patients from fixating on their
environment while allowing magnified examination of the
eyes, making them an essential tool for the neurotologist.
Vestibular imbalance may also cause a skew deviation, or
vertical misalignment of the eyes caused by an imbalance
of input along otolith-ocular pathways. Both a skew devi-
ation and an ocular motor palsy can present with diplopia,
although the misalignment due to a skew deviation is usu-
ally constant, while a fourth cranial nerve palsy’s effects
worsen with gaze downward and medially. Patients with a
skew deviation often complain of vertical or torsional
diplopia (two images tilted relative to each other). A subtle
skew can be detected as the eyes are alternately covered by
the examiner, or by covering one eye with a red lens
(Maddox rod) to dissociate the images and allow the
patient to describe the diplopia. The lower (hypotropic)
eye is usually on the side of the lesion, although lesions
higher than the vestibular nucleus (where the pathways
decussate) may cause the higher eye to be on the side of
the lesion. The head is usually tilted toward the lower eye.
A combination of defects in gaze-holding and vestibular
input contribute to several types of nystagmus. Bruns’ nys-
tagmus, found in patients with cerebellopontine angle
tumors, is a combination of gaze-evoked nystagmus with
low-frequency, large-amplitude fast phases on looking
toward the side of the lesion and jerk nystagmus with high-
frequency, small-amplitude fast phases on looking away
from the lesion.74 The gaze-holding nystagmus may repre-
sent the body’s way of canceling the jerk nystagmus caused
by vestibular imbalance.75 Nystagmus arising from a
peripheral lesion and many central lesions is more intense
(slow-phase velocity higher) when the eye is deviated in
the direction of the quick phase (Fig. 12-5).76 Known as
Alexander’s law, this effect is due to the addition of gaze-
evoked nystagmus caused by loss of the neural integrator
following a peripheral lesion and the vestibular nystagmus
caused by the static asymmetry of the lesion itself. The two
factors tend to add when looking away from the lesion and
cancel each other out when looking toward it.75
Head shaking nystagmus (HSN) evaluates the patient
for an imbalance in dynamic vestibular function. The
patient is instructed to shake the head vigorously about

Vestibular
Gaze-holding
Vestibular
Gaze-holding
Vestibular
Gaze-holding
Figure 12-5. Alexander’s law. After unilateral vestibular loss, the eye tends to
drift to center. The addition of this effect and the imbalance in vestibular
activity between the two labyrinths causes nystagmus to be more pro-
nounced when looking away from the lesion. In straight-ahead gaze (top),
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
are indicated with an arrow. When the eyes look to the direction of the slow
phase (middle), the eyes drift back towards the center, subtracting from the
vestibular slow phase. When the eyes look away from the direction of the
slow phase (bottom), the same centripetal drift of the eyes adds to the
vestibular slow phase, and the net slow phase velocity increases. (After
Carey JP, Minor LB: Mixed peripheral and central vestibular disorders.
In JA Goebel, [ed.]: Practical Management of the Dizzy Patient, Philadelphia,
Lippincott, Williams, and Wilkins, 2000, p 237.)
30 times horizontally with the chin placed about 30
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
head is turned rapidly a small arc to the right or left. Eye
movements of abnormally low amplitude will be evoked in
response to head thrusts toward a lesioned or hypoactive
labyrinth78 and will be followed by the corrective saccade
required to bring the eyes back to the intended point
of fixation.79 These saccades can be quite subtle, but the
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
detect dysfunction in the vertical canals by delivering the
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
Patients with reduced vestibular function, particularly
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.
Subjects with corrective lenses are instructed to wear their
glasses or contact lenses during this testing. A general
measure of these changes can be determined with bedside
tests, although predictive mechanisms during repetitive
oscillations of the head may augment performance during
this test and decrease its sensitivity.83
Patients often complain of dizziness on moving their head
into a certain position. Positional (sustained) and positioning
(transient) nystagmus are tested in these patients. Dix-
Hallpike positioning for identification of posterior canal
benign paroxysmal positioning vertigo (BPPV) is performed
first (Fig. 12-7).84 The patient sits upright on an examina-
tion table. For testing to detect the presence of right poste-
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
position. This position is maintained for at least 30 sec.
Figure 12-6. Head-thrust test in a case of left horizontal canal paresis.
The patient’s head is turned slightly off center (A) and then thrust rapidly
to her right (B). Note that her eyes remain fixed on the examiner during this
maneuver toward the intact side. After the identical maneuver toward the
affected side, her eyes lag momentarily (C) before refixating on the examiner
(D). This test is essentially a high-acceleration version of the familiar doll’s
eyes maneuver (After Halmagyi GM, Curthoys IS: A clinical sign of canal
paresis. Arch Neurol 45:737, 1988).
224 NEUROTOLOGIC DIAGNOSIS
Right horizontal canal excitation
Right superior canal excitation
Right posterior canal excitation
Figure 12-7. Eye movements evoked by vestibular stimulation. The effects of
individual stimulation of each of the right semicircular canals is shown. The
arrows depict the slow-phase components of the nystagmus. Excitation of
the right horizontal canal causes a horizontal nystagmus with leftward slow
phases. A vertical-torsional nystagmus is caused by excitation of the superior
or posterior canals. Note that, while turning the eyes toward the side of the
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 stimulus causes the superior canal to induce a more rotatory motion and
the posterior canal a more linear motion. This distinction can be helpful in
diagnosing BPPV and superior canal dehiscence syndrome. (After Minor LB:
Superior canal dehiscence syndrome. Am J Otol 21:9, 2000.)
The nystagmus characteristic of BPPV begins after a
latency of 2 to 10 sec, increases in amplitude over about
10 sec, and declines in velocity over the next 30 sec. Posterior
canal BPPV results in a vertical-torsional nystagmus with the
slow phase components of the nystagmus directed inferiorly
and toward the uppermost ear. Thus, the fast-phase compo-
nents of the nystagmus are superior and toward the lower
ear. Due to the orientation of pulling directions for the
oblique and vertical recti muscles, the planar characteristics
of the nystagmus change with direction of gaze (when
described with respect to an eye-fixed coordinate system):
On looking to the dependent ear it becomes more torsional;
on looking to the higher ear it becomes more vertical.
BPPV can also involve the horizontal canal. In affected
patients, a strong horizontal nystagmus builds up and
declines over the same time course as for posterior canal
BPPV. The nystagmus either beats toward the dependent
ear (geotropic) or away from the dependent ear (ageotropic)
depending on where in the canal the pathology is located.
The standard Dix-Hallpike maneuver may not elicit nys-
tagmus in cases of horizontal canal BPPV, but nystagmus
can be provoked by bringing the patient backwards into
the supine, head-hanging position and then turning the
head left ear down or right ear down. The nystagmus seen
with horizontal canal BPPV may last longer than that seen
in posterior canal BPPV.
A sustained, usually horizontal, positional nystagmus of
low velocity is a common finding in patients with central
or peripheral vestibular lesions and may also be present in
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.
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-
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
pure tones from 500 to 4000 dB at intensities of 100 to
110 dB. Hennebert’s sign is elicited with tragal compres-
sion or insufflation through a Siegle’s speculum (fistula
test). Otic syphilis, Ménière’s disease, and perilymph fistula
have also been reported to cause these signs, although
the specific features of the evoked eye movements have
not been well characterized. These signs, have recently
been documented in patients with superior semicircular
canal dehiscence syndrome,86,87 with the evoked eye move-
ments aligning with the plane of the affected superior
canal (Fig. 12-8).88
Hyperventilation may provoke symptoms in patients with
anxiety or phobic disorders but does not usually produce nys-
tagmus. Patients with demyelinating lesions of the vestibular
nerve (e.g., an acoustic neuroma or through compression by
a small blood vessel) or of central structures (e.g., caused by
MS) may show hyperventilation-induced nystagmus.89
Hyperventilation reduces PCO2, which leads to an increase
in serum and cerebrospinal fluid (CSF) pH. This relative
alkalosis increases the binding of extracellular calcium to
albumin and leads to an increase in the discharge rate and
conduction in partially demyelinated axons. Because of this
sudden jump in activity of the lesioned nerve, the direction
of nystagmus with hyperventilation reflects a relative weak-
ness on the contralesional side.
The vestibulospinal system is critical for maintaining
posture and balance and is evaluated as part of a work-up
for dizziness and imbalance. A complete examination of
(1) gait; (2) strength, reflexes, and sensation in the legs;
and (3) cerebellar function is essential for the interpreta-
tion of postural instability and dysequilibrium. Both static
and dynamic balance are tested.
Static imbalance in vestibulospinal reflexes is identified
from Romberg testing, tandem walking, stepping tests,
and evaluation of past-pointing. The Romberg test was
originally described in syphilitic patients with tabes dor-
salis90 but was later applied to cerebellar disorders by
Babinski and Duchenne.91 In the standard Romberg test,
the patient stands with eyes closed and feet together; half
of patients with sensory ataxia last only 10 sec in this posi-
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
swaying is common in normals and the degree of swaying
cannot differentiate among peripheral vestibular and cere-
bellar disorders.93 Falls during tandem walking may be
indicative of horizontal canal dysfunction. Fukuda step-
ping tests (marching in place for 30 sec with eyes closed)
can show excessive turning toward the side of a unilateral
vestibular lesion.94 An ataxic gait may also be noted during
walking tests. Ataxia is characterized by a widened base
(more than the normal 2 to 4 in. separating the feet later-
ally) and irregular or even staggering steps. Sensory ataxia
is caused by proprioceptive loss; patients tend to look at
their feet, which often slap on the ground. Patients with a
reeling, staggering gait are more likely to have a cerebellar
ataxia, which is often accompanied by other cerebellar
signs. There is poor interobserver reliability of what con-
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.
Dynamic vestibulospinal function is assessed by observing
postural stability during rapid turns or in response to
external perturbations imposed by the examiner (i.e., a gentle
shove forward, backward, or to the side). The “eyes-closed
turning test” (staggering when turning to the side of the
lesion after walking with eyes closed) has been described with
a sensitivity of 88% in patients with a perilymph fistula.96
CRANIAL NERVES IX AND X
The vagus nerve, via its auricular division (Arnold’s nerve),
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-
ryngeal nerve, as Jacobson’s nerve, carries sensation from
the entire middle ear including the eustachian tube and
mastoid cells and carries taste sensation from the posterior
one third of the tongue. Cranial nerve IX is responsible for
sensation during testing of the gag reflex. Cranial nerve
X is responsible for elevation of the palate via the levator
palati muscle.
Difficulties voicing normally or swallowing without
coughing can indicate disorders of the tenth nerve. When
appropriate, flexible laryngoscopy can help distinguish tenth
nerve disorders from other problems. A new technique has
been reported for measuring the sensory component from
the superior laryngeal nerve using an air puff from a modi-
fied laryngoscope onto the supraglottic mucosa.97 Damage
to the recurrent laryngeal nerve often results in a flaccid,
lateralized cord with a breathy voice that gradually medial-
izes to a paramedian position. Spasmodic dysphonia can
cause medialization of the vocal cord and a choking voice or
lateralization of the cord and a breathy voice, depending
which set of laryngeal muscles is most affected.98
CRANIAL NERVE XI
The spinal accessory nerve innervates the trapezius and
sternocleidomastoid muscles. The sternocleidomastoid is
tested for symmetry by feeling the muscle’s contraction
while pushing against the patient’s chin on the opposite side.
Weakness of the trapezius can be evaluated by examining
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
with spinal muscles to compensate for shoulder weakness.
Raising the arm laterally (not anteriorly) above the level of
the shoulder indicates adequate trapezius function.
CRANIAL NERVE XII
The hypoglossal nerve supplies the intrinsic muscles
of the tongue. The tongue of a patient with an acutely
denervated hypoglossal will deviate toward the affected
226 NEUROTOLOGIC DIAGNOSIS
side when thrust out of the mouth, but patients with
chronic unilateral palsy may not show this deficit. They are
unlikely to be able to lateralize their tongue to the unaf-
fected side, however. The hypoglossal nerve is particularly
susceptible to inflammation or edema of the dura from
distant processes due to its relatively narrow path through
the dura.99
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 Chapter
Neuro-Ophthalmic Manifestations
of Neurotologic Disease
13 Outline
Steven A. Newman, MD Ocular Stabilizing Systems
Vestibulo-Ocular Reflexes
Paul R. Lambert, MD
Symptoms
Decreased Visual Acuity
Diplopia
Oscillopsia
Pain
Signs
Nystagmus
Vestibular Nystagmus
Gaze Paretic Nystagmus
Congenital Nystagmus
Central Nystagmus
Downbeat Nystagmus
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
the normal function of the vestibular apparatus or its con-
nections has a direct and immediate effect on the orienta-
tion of the globes and on their ability to move. Vestibular
pathology is often brought to the attention of the clinician
by patient complaints of diplopia and blurred vision and
can be diagnosed specifically by studying ocular motility.
Although the vestibular ocular connection probably repre-
sents the phylogenetically oldest ocular motor system, its
importance has only recently been recognized. Erasmus
Darwin in 1796 first noted ocular movement induced by
body rotation.1 In 1824, Flourens2 recognized the physiol-
ogy of the semicircular canals. It has only been within the
20th century that detailed central vestibular connections
and vestibular testing have been outlined.
The role of the vestibular system in the generation of
eye movements is better understood if the five major eye
movement systems are examined teleologically. The eyes
need to move for three basic reasons. The first is to main-
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
acuity.3–6 The vestibular system is responsible for main-
taining the eye stable in space during head movements,
while the optokinetic system matches the movement of the
surrounding environment with an appropriate eye move-
ment. The second reason eyes move is based on our devel-
opment of a specialized area of maximal spatial resolution
(acuity), the fovea. The saccadic system is responsible for
228
Seesaw Nystagmus
Dissociative Nystagmus
Periodic Alternating
Nystagmus
Physiological Nystagmus
Misalignment of the Visual
Axes
Afferent System Pathology
Horner’s Syndrome
Evaluation
History
Examination
Specific Disease Processes
Conclusions
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 third reason for ocular motility is the consequence of
forward ocular migration resulting in overlapping visual
fields. Thus to maintain simultaneous foveal alignment of
both visual axes while a target moves closer or further
away, the eyes must move relative to each other. This is
accomplished by the convergence system.
A primary function of the vestibular system is to coordi-
nate eye movements with rotational and translational
movements of the head, thus maintaining clear and stable
retinal images. Visual pursuit relies on relatively slow
(approximately 75-msec) retinal processing, and therefore
cannot maintain image stability during natural head rota-
tions, which occur at frequencies of 0.5 to 5.0 cycles/sec.7,8
The semicircular canals, by contrast, can respond in less
than 16 msec to drive the eyes at exactly the head velocity,
but in the opposite direction.9,10 Compensatory eye move-
ments for linear head movement are generated by the
otolithic organs with a latency of less than 35 msec.11
OCULAR STABILIZING SYSTEMS
Because final eye movements are a combination of the
action of all the ocular motor systems, it is often possible
for one or more of the intact systems to compensate for
a compromised vestibular system. Thus, it is important
to be able to evaluate all ocular motor systems, not just
the vestibular. Ocular stability requires the integration of
 Neuro-Ophthalmic Manifestations of Neurotologic Disease
a number of visual systems with the vestibulo-ocular reflex
(VOR), including the optokinetic, smooth pursuit, and
saccadic systems. The pursuit system in particular can be
used to compensate for abnormalities or asymmetries
within the vestibular system, and it may therefore prevent
development of immediate symptomatology or obvious
pathologic findings with local vestibular damage. Attempts
to track a moving object by moving the head require addi-
tional neural mechanisms that combine pursuit and vestibu-
lar signals.12,13 Some evidence suggests that the VOR is
suppressed.14 These neural pathways are incompletely
understood, but appear to involve activation of the ocular
motor neurons by the VOR signal or its copy with an
opposite sign.15,16 It should be apparent that these stabi-
lization systems require visual input and are absent with
severely compromised vision.17–19
The ability to maintain eccentric gaze requires a gaze-
holding neural integrator mechanism.20 Aside from the
dynamic forces producing changes in ocular position,
static “elastic restoring forces” within the orbit tend to
bring the eyes back to the primary position. These may be
modeled simply as a system of soft tissue “springs” that
increase their tension as the eye is directed relatively more
eccentrically. To supply an appropriate continuous signal
that overcomes the elastic restoring forces, a “tonic”
increase must be made in the input to the extraocular mus-
cles. Obviously, this tonic force must be increased as the
eccentricity becomes greater. A neural integrator located
in the area of the nucleus propositus hypoglossi adjacent to
the medial vestibular nucleus21 automatically adjusts the
tonic signal to match the dynamic impulse needed to move
the eyes eccentrically. The pathology that affects this neu-
ral integrator results in what is referred to as a pulse-step
mismatch. Although the “pulse” produces an appropriate
saccadic (rapid) conjugate movement of the eyes to a par-
ticular eccentric position, the inadequacy of the subse-
quent “step” results in a drift of the eyes back toward the
primary position. As the elastic restoring forces increase
with increasing eccentricity, the drift back toward fixation
results in an exponentially decreasing slow velocity. This
characteristic waveform may be helpful in distinguishing
various abnormalities in ocular motility.
Vestibulo-Ocular Reflexes
The anatomy of the vestibular system is covered else-
where. Briefly, stimulation of the semicircular canal results
in a three-neuron reflex arc involving the vestibular gan-
glion, vestibular nuclei, and ocular motor nuclei. This reflex
arc and alternative interneuron projections result in eye
movements parallel to the plane of the stimulated canal.22
Theoretically, therefore, identification of a diseased semi-
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
of a specific semicircular canal.23,24
Electrical stimulation of neural fibers from the horizon-
tal semicircular canal results in horizontal conjugate devi-
ation of both eyes toward the contralateral side. This eye
movement involves both excitatory pathways (contralat-
eral abducens nucleus/lateral rectus muscle and ipsilateral
oculomotor nucleus/medial rectus muscle) and inhibitory
229
pathways (contralateral oculomotor nucleus/medial rectus
muscle and ipsilateral abducens nucleus/lateral rectus
muscle). This is coordinated through the horizontal gaze
center located within the ipsilateral sixth nerve nucleus in
the dorsal pontine tegmentum.25 Its primary input is the
contralateral medial vestibular nucleus.
The vertically oriented canals also produce a combina-
tion of excitatory and inhibitory signals. While excitatory
signals cross to the contralateral midbrain, inhibitory
information remains ipsilateral. Electrical stimulation of
neural fibers from the anterior semicircular canal causes
both upward and torsional eye movements, with the upper
pole of each eye moving toward the contralateral side. The
vertical eye movement is stronger ipsilaterally. The ipsilat-
eral superior rectus and contralateral inferior oblique mus-
cles are excited, and the ipsilateral inferior rectus and
contralateral superior oblique muscles are inhibited. This
is largely mediated by fibers crossing in the rostral medulla
to ascend in the contralateral medial longitudinal fascicu-
lus (MLF) to the contralateral third nerve nucleus where
the superior rectus and inferior oblique subnuclei are stim-
ulated. As the superior rectus subnucleus innervates the
contralateral superior rectus, both eyes rise.
Electrical stimulation of neural fibers from the posterior
semicircular canal produces conjugate deviation of the eyes
downward, with torsional eye movements directed again
contralaterally. The downward eye movement is stronger
in the contralateral eye, and eye rotation is more apparent
in the ipsilateral eye. The ipsilateral superior oblique and
contralateral inferior rectus muscles are stimulated,
whereas their antagonists, the ipsilateral inferior oblique
and contralateral superior rectus muscles, are relaxed.
Stimulatory projections from the posterior semicircular
canal also travel in the MLF to innervate the contralateral
trochlear nucleus and the inferior rectus subnucleus within
the oculomotor complex. In addition, evidence shows that
accessory pathways from the vertical canals cross at the
pontomedullary junction rising in the brachium conju-
neticum.26,27 The anterior semicircular canal pathways are
anatomically separated from those arising in the posterior
semicircular canals, which makes them asymmetrically
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
Balanced input from the left and right utricles also
affects globe position. The utricular fibers project to the
ipsilateral medial rectus and to the contralateral superior
oblique, superior rectus, inferior oblique, inferior rectus,
and lateral rectus muscles.29 Thus, stimulation of the utric-
ular nerve leads to torsion of the eyes toward the contralat-
eral side while the ipsilateral eye rises and the contralateral
eye falls.30
SYMPTOMS
Decreased Visual Acuity
Although the vestibular system may be affected in myriad
ways, the symptoms appreciated by the patient are limited.
Patients may occasionally complain of decreased visual acu-
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
patient may be aware that this visual “blurring” increases
with eccentric gaze or in one particular position. This may
represent local increase in abnormalities of visual stabiliza-
tion. This symptom is usually binocular, but it can be
monocular31 or substantially asymmetrical. In that case, the
patient may complain of unilateral decreased visual acuity.
Lack of attention to ocular motor problems may lead to a
misdirected work-up conversely. Careful attention to asym-
metrical spontaneous eye movements may provide an expla-
nation for unilateral decreased visual acuity. Thus, it is
imperative to check for an afferent pupillary defect (Marcus-
Gunn pupil) or optic atrophy, which would indicate definite
pathology within the optic nerve or visual pathways.
Diplopia
The major eye complaints related to vestibular pathology
are diplopia and oscillopsia. Diplopia arises from misalign-
ment of the two visual axes. This can be horizontal, but
vertical deviations are more commonly associated with
vestibular abnormalities. Partial involvement of the sixth
cranial nerve or of the MLF will lead to horizontal mis-
alignment. The sixth cranial nerve and its nucleus are located
just rostral to the vestibular nuclei in the area of the pon-
tomedullary junction. Tumors of the cerebellopontine
angle often compromise abducens function occasionally
bilaterally.
When lesions affect the MLF, the patient will usually
complain of horizontal diplopia on contralateral gaze. As
additional vertical inputs are carried by the MLF, more
extensive lesions, particularly with bilateral involvement,
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.
Vertical double vision occurs when relative vertical sep-
aration of the visual axes occurs. Involvement of the fourth
cranial nerve exiting the brainstem dorsally in the mid-
brain is a frequent cause. If the classical findings of a fourth
nerve palsy are not present, the most likely central cause of
vertical diplopia is a skew deviation representing asymmet-
rical involvement of the vertical prenuclear input.33,34
Vertical double vision can also occur as an isolated phe-
nomenon due to local orbital pathology such as occurs
following orbital trauma (blowout fracture) or as related to
extraocular muscle tightening seen in thyroid orbitopathy
or orbital inflammatory disease. Less commonly, neoplas-
tic processes may affect the muscles. Restrictive problems
usually can be distinguished from paretic abnormalities by
performing forced duction testing or checking intraocular
pressure in eccentric gaze. Local pathology may also be
suspected in the setting of proptosis, injection, numbness,
or globe displacement (dystopia).
Oscillopsia
Oscillopsia is one of the most suggestive complaints seen
with vestibular dysfunction.35 This is the abnormal per-
ception that a stationary object is in motion.36 It may be
distinguished from vertigo, in which the subjective sensa-
tion is of the entire world spinning. Oscillopsia rarely
occurs with abnormalities of eye movements, and in fact it
is distinctly uncommon in patients with congenital nystag-
mus.37 Primary overaction of one or more of the extraocu-
lar muscles, as in superior oblique myokymia, is another
uncommon cause of oscillopsia. In this syndrome, repeti-
tive firing of the fourth nerve results in tiny torsional and
vertical oscillations of the eye, accompanied by a unilateral
sensation of the world jumping.
Oscillopsia has its highest frequency of occurrence in
patients with bilateral peripheral vestibular pathology.28 Such
patients frequently report the inability to read signs while
walking.38 When the head is stabilized, however, the vision
is normal. Central abnormalities in VOR gain may also lead
to severe motion-induced oscillopsia. Oscillopsia may occur
at rest in the setting of acquired pendular nystagmus.39
Pain
Pain associated with neurotologic disease may also be
accompanied by ocular complaints. In Gradenigo’s syn-
drome, infection involving the petrous bone (usually fol-
lowing otitis media) results in pain due to stimulation of
the recurrent dural branches of the fifth cranial nerve.40
Diplopia develops secondary to involvement of the sixth
cranial nerve as it crosses the petrous apex in Dorello’s
canal. More commonly, however, painful double vision rep-
resents pathology affecting the skull base in the area of the
cavernous sinus.41 Here, involvement of the fifth cranial
nerve in combination with the third, fourth, and sixth nerves
produces ocular misalignment and discomfort. In the older
population, a pseudo-Gradenigo’s syndrome is not uncom-
monly related to nasopharyngeal carcinoma, which invades
that base of the skull through the foramen lacerum.
SIGNS
In neuro-ophthalmology, signs are usually separated
into those affecting the afferent visual system (those con-
nections between the eye and visual cortex responsible
for visual perception) and the efferent visual system
(those pathways responsible for ocular motility, simulta-
neous binocular alignment, and ocular stabilization).
Neurotologic pathology most frequently affects the
efferent visual system and, in particular, the vestibular
input and connections.
Nystagmus
Nystagmus is a repetitive oscillation of the eyes.42
Although some individuals may produce a nystagmus-like
picture voluntarily,43 most nystagmus is the result of asym-
metrical tonic input into either the horizontal or vertical
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
movements occur in a rhythmic fashion. Nystagmus is
most commonly binocular, although it may be asymmetri-
cal. It is also usually conjugate. That is, the two eyes are
moving in the same direction simultaneously. Disconjugate
nystagmus in which the eyes are moving in different direc-
tions, includes retraction convergence nystagmus and
seesaw nystagmus.
 Neuro-Ophthalmic Manifestations of Neurotologic Disease
Nystagmus has been classified in a number of ways.
Probably the simplest is based on direction. The repetitive
eye movements may be purely vertical, purely horizontal,
purely torsional, or some combination of the three. The
second method of classification is based on the motility pat-
tern. Nystagmus is termed pendular when the eyes move to
and fro with equal velocity and jerk when there is a fast
component in one direction and a slow drift in the other.
Although nystagmus is usually “defined” (labeled) by the
direction of the fast component, it is the slow drift that
indicates pathology in tonic input. Nystagmus can be fur-
ther characterized by the waveform of its slow component.42
Although this usually requires ocular motor recording tech-
niques, this characterization can be valuable in separating
out the presumptive pathophysiology. The slow phase may
be of constant velocity, exponentially decreasing, or expo-
nentially increasing.
Nystagmus has also been defined by degrees: In first-
degree nystagmus, the abnormal ocular movements are
present only while looking in the direction of the quick
phases. In second-degree nystagmus, abnormal ocular move-
ments occur in the primary position, and with third-degree
nystagmus, movements are present in all fields. However,
a relative area of least motility (a relative null point) may
still be present.
Vestibular Nystagmus
Nystagmus usually arises from one of two basic abnormal-
ities: vestibular pathology or pathology affecting the neu-
ral integrator. Asymmetrical input from the vestibular
nuclei or secondarily from dysfunction of the vestibular
end organ can result in ocular drift. Lesions of the periph-
eral vestibular system rarely affect just one semicircular
canal, but rather involve the entire labyrinth or vestibular
nerve on one side. The resulting imbalance in neural activ-
ity reaching the central vestibular system causes eye move-
ments that reflect the summed influence of each
semicircular canal. Nystagmus therefore often has both a
horizontal and torsional component; the vertical eye
movement from the anterior and posterior semicircular
canals negate each other. Because the tonic input is con-
tralateral in the case of the horizontal canals, pathology
affecting the vestibular system on one side will produce a
drift of the eyes toward the affected side. This is due to the
loss of tonic input into the contralateral horizontal gaze
center, whereas the ipsilateral gaze center supplied from
the opposite vestibular system is unaffected. Thus, the eyes
will drift toward the pathologic side, with quick corrective
phases away from it.
In almost all cases of vestibular pathology, loss of signal
from part of the vestibular system leads to relative drift.
One exception to that rule is benign paroxysmal positional
vertigo (BPPV). In this syndrome periodic over-reaction
from debris on the cupula is induced by change in position.
BPPV is thought to involve only the posterior semicircular
canal.44,45 The nystagmus noted when a patient is placed in
a provocative position corroborates this hypothesis.46 The
pathologic eye movement is both vertical (stronger in the eye
contralateral to the diseased posterior semicircular canal)
and torsional (stronger in the eye ipsilateral to the diseased
posterior semicircular canal). An electronystagmograph
231
does not record torsional eye movement; therefore, the
main eye movement noted will be vertical.
Gaze Paretic Nystagmus
Impairment of the neural integrator causes gaze-evoked
or gaze paretic nystagmus.21 In this circumstance, the
tonic extraocular muscle activity needed to keep the eyes
in a certain eccentric position is inadequate, thus allowing
the eyes to drift back toward fixation in an exponentially
decreasing form. Corrective saccades return the eyes to
the desired eccentric position. Multiple pathophysiologic
processes may affect the neural integrator. These include
lesions of the brainstem and cerebellum, especially the
flocculus and paraflocculus, and various drugs such as
sedatives,47 alcohol,48 and anticonvulsants.49–52
Gaze-evoked nystagmus can be symmetrical or asym-
metrical. Symmetrical gaze-evoked nystagmus has equal
amplitude with right and left lateral gaze. The most com-
mon cause of this nystagmus is ingestion of drugs such as
alcohol48 and anticonvulsants.53,54 It is also frequently
noted in patients awakening from various general anes-
thetics, and therefore must be differentiated from patho-
logical nystagmus secondary to otologic or neurotologic
surgery. Specific central nervous system (CNS) lesions
such as multiple sclerosis55 and cerebellar atrophy56 are
additional causes of symmetrical gaze-evoked nystagmus.
Asymmetrical gaze-evoked nystagmus is caused by
asymmetrical involvement of the neural integrator often
due to structural lesions of the cerebellum or brainstem.
Large cerebellopontine angle tumors42,57,58 that produce
brainstem and cerebellar compression can cause asymmet-
rical gaze-evoked nystagmus (Bruns’ nystagmus).59 Bruns’
nystagmus is characterized by a low-frequency, large-
amplitude nystagmus with ipsilateral gaze due to the leaky
neural integrator. This in turn is secondary to the com-
pression of the area of the nucleus propositus hypoglossi
by the extra-axial mass. When the patient gazes in the
opposite direction, a higher frequency, small-amplitude
nystagmus secondary to the vestibular imbalance is
induced by the compression of the ipsilateral vestibular
pathways to the contralateral horizontal gaze center.
Congenital Nystagmus
Both gaze paretic nystagmus, due to a leaky neural inte-
grator, and vestibular nystagmus, representing the most
common form of acquired nystagmus, must be distin-
guished from congenital nystagmus. Certain characteris-
tics of hereditary nystagmus, if present, can help with this
differential diagnosis. As a rule, congenital nystagmus has
an exponentially increasing slow phase (although pendular
nystagmus is possible).60,61 Although it is possible for con-
genital nystagmus to be vertical or torsional, horizontal
movement is most common. Classically, congenital nys-
tagmus remains horizontal with both up and down gaze.
Additional characteristics of congenital nystagmus include
accentuation by visual fixation62 and diminution by con-
vergence63 or by gaze in a certain direction (null region).
Congenital, vestibular, and gaze paretic nystagmus tend to
follow Alexander’s law; that is, the amplitude and possibly
even the frequency of the corrective saccadic movements
232 NEUROTOLOGIC DIAGNOSIS
increase with gaze in the direction of the quick phase.64
The cause of congenital nystagmus is unknown, but
presumably represents asymmetrical tonic input into the
horizontal gaze centers that is not compensated for by
other eye movement systems. Because most of these other
systems require visual input, it is not surprising that the
incidence of congenital nystagmus is higher in patients with
various afferent system pathologies that cause decreased
visual acuity. This undoubtedly explains in part the associ-
ation of albinism and a number of other ophthalmologic
abnormalities with congenital nystagmus.65–67
Central Nystagmus
The presence of vertical or torsional nystagmus implies a
relatively selective involvement of either the anterior or
posterior semicircular canal or of the utricle. This is possi-
ble because of the anatomic separation, seen particularly in
the area of the pontomedullary junction, as discussed earlier.
The posterior canal inputs cross dorsally in the medulla
beneath the nucleus propositus hypoglossi prior to the
ascending in the MLF. Except for the condition of BPPV,
a peripheral vestibular lesion does not affect just one ver-
tical canal. Thus vertical nystagmus almost always represents
central vestibular pathology. Isolated torsional nystagmus
also strongly suggests a central origin.68 When vertical and
torsional nystagmus are combined, a peripheral cause is
possible. Most frequently, nystagmus is not pure, but rather
combines varying degrees of torsional, horizontal, and
vertical movements.
It is usually possible on clinical examination to distinguish
nystagmus due to peripheral vestibular pathology from that
caused by central abnormalities. Peripheral vestibular nys-
tagmus is often suppressed by visual fixation and, in fact,
may only become apparent when fixation is prevented
(e.g., through the use of Frenzel lenses or recording eye
movements in the dark). The patients’ ability to use intact
smooth pursuit and visual fixation systems to negate a ten-
dency toward drift accounts for this phenomenon.
Conversely, visual fixation has little or no effect on central
nystagmus, including both downbeat and upbeat varieties.
One exception to this is the upbeat nystagmus presumably
related to nicotine seen in smokers only when fixation is
interrupted.69 Habituation may occur with time in the set-
ting of peripheral involvement, but usually does not occur
with nystagmus of central origin.
Downbeat Nystagmus
Two relatively pure isolated forms of central nystagmus are
downbeat and upbeat nystagmus. In the case of downbeat
nystagmus pathology usually interrupts the fibers crossing
in the dorsal tegmentum of the medulla. This relatively
selective involvement of information coming from the
posterior canals leads to a slow phase drift of the eyes up
and a secondary correctional movement with a fast phase
down.70 Clinically, downbeat nystagmus is usually seen
with cerebellar degeneration or pathology at the cervical
medullary junction.28,71–73 Specific causes include Arnold-
Chiari malformation,74,75 basilar invagination, and tumors
(most commonly meningiomas) at the craniocervical junc-
tion. It can also be seen in a number of other conditions
affecting the cerebellum or brainstem, including multiple
sclerosis71,76 and anticonvulsant therapy.77,78
Several interesting clinical aspects surround downbeat
nystagmus. Its intensity is consistently increased with
lateral gaze and often increased with downward gaze.79
Thus, in cases of subtle downbeat nystagmus, more dra-
matic clinical findings may be elicited by having the patient
gaze laterally and downward. Patients with downbeat nys-
tagmus also have a very high incidence of associated pursuit
deficit.76 Asymmetrical downbeat nystagmus may be seen
with more of a torsional component in one eye. This is
usually accompanied by evidence of an internuclear
ophthalmoplegia.80
Upbeat Nystagmus
Upbeat nystagmus,81–85 represents relative selective
involvement of input from the anterior canals.86
Unlike downbeat nystagmus, upbeat nystagmus does
not usually increase on lateral gaze,76 but it is enhanced by
looking upward. Selective involvement of the anterior
canal input may occur from the same anatomic separation
at the level of the pontomedullary junction, but interest-
ingly in the cat there is also additional anterior canal input
through the ventral tegmentum of the medulla.86 Selective
involvement of this area could lead to a slow drift of the
eyes down and compensatory rapid up movements. An
alternative explanation for upbeat nystagmus is based on
the selectivity of neural transmitters. In rabbits, flocculus
Purkinje cells project inhibitory stimuli to the anterior
canal projections, but not to the posterior canal projec-
tions.87 Thus, pharmacoselective involvement may provide
an explanation for this form of central vestibular dysfunc-
tion. Clinically, upbeat nystagmus is usually secondary to
infarction, tumor infiltration, or multiple sclerosis involv-
ing the midbrain, medulla, or cerebellum.82,83,85,88–90
Seesaw Nystagmus
Pathology of the otolith pathways produces a unique form
of nystagmus.91–93 In seesaw nystagmus, the ipsilateral eye
rises and intorts while the contralateral eye falls and extorts.
As mentioned earlier, it is also likely that this asymmetri-
cal otolith input is responsible for the ocular tilt reaction
and the development of a skew deviation94 usually with an
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
nystagmus and the ocular tilt syndrome may both arise
with pathology in the area of the interstitial nucleus of
Cajal,96 which is located just rostral to the third cranial
nerve nucleus within the midbrain. This area receives
input from the vertically oriented semicircular canals as
well as the otolithic organs.97 Large parasellar masses are
the most frequent cause.91,92,98 Mesencephalic skew devia-
tions usually have the pathology ipsilateral to the hyper-
tropic eye.34
Dissociative Nystagmus
Asymmetry in nystagmus may also occur when an abnor-
mality is present in the ocular motor cranial nerves or their
 Neuro-Ophthalmic Manifestations of Neurotologic Disease
internuclear connections. An example of dissociative nys-
tagmus is that seen with an internuclear ophthalmoplegia
(INO).99 Involvement of the MLF causes weakness in adduc-
tion associated with abducting nystagmus in the contralateral
eye. An INO is most frequently seen with small vessel
disease (vertebrobasilar insufficiency) in the elderly popu-
lation100 and occurs secondary to demyelinating disease101
in the young. Any pathology that affects the MLF within
the brainstem, including vascular anomalies, neoplastic, and
infectious processes, may produce a similar picture.
Periodic Alternating Nystagmus
Nystagmus may not remain fixed in pattern. Periodic
alternating nystagmus (PAN) is an acquired or congenital
horizontal nystagmus in which a slow drift occurs in
the null point from one side to the other over a cycle of
approximately 4 minutes.102 Thus the nystagmus will beat
in one direction for approximately 1.5 to 2 minutes, stop
beating, then reverse direction for the remaining 1.5 to
2 minutes. This abnormality in null point position is
thought to be secondary to pathology within the vestibulo-
cerebellum,103 including the nodulus.104–107 Discovery that
the inhibitory pathways were controlled by γ-aminobutyric
acid (GABA) lead to the theoretical use of baclofen
(a GABA agonist) in patients with PAN.108 This has often
been successful in abolishing the drifting null position,
although not in patients with congenital PAN.
Physiologic Nystagmus
Nystagmus is not always pathologic. Simple rotation,
which produces a normal vestibular slow phase in the oppo-
site direction, does induce nystagmus as the rotation con-
tinues. Similarly, a moving background target produces not
only the slow phase drift to compensate for the full-field
movement, but also the compensatory reset saccades seen
in optokinetic nystagmus. After sustained movement of the
environment, slow phase drift will continue as optokinetic-
after-nystagmus (OKAN). This has been conceptualized as
a slow discharge of the “capacitor,” which has been charged
by the moving environment. Teleologically, the presence
of OKAN is important to counteract the induced VOR in
the opposite direction that is seen when persistent rotation
is suddenly stopped.109,110
Endpoint nystagmus is a common finding in normal
patients when eye deviation from midposition is extreme
(greater than 40 degrees).111,112 The low intensity of the
nystagmus (slow phase velocity of less than 3 degrees/sec)
and the absence of other ocular abnormalities confirm its
benign nature.
Misalignment of the Visual Axes
Static misalignment of the visual axes is another form of
efferent visual system abnormality that can be present with
neurotologic disease. This may be due to pathology affect-
ing the ocular motor cranial nerves, their internuclear
connections, or the horizontal and vertical gaze centers.
The pathophysiology may be due to intrinsic brainstem
pathology or more commonly to extrinsic lesions that sec-
ondarily affect either the peripheral cranial nerves or their
233
brainstem origins. Pathology that is likely to affect both
the cranial nerves and the vestibular system includes
vascular abnormalities, neoplastic processes, and inflam-
matory lesions.
Afferent System Pathology
Although far less common than efferent system involve-
ment, the afferent visual pathways may be pathologically
involved in association with neurotologic disease. Pathol-
ogy that obstructs normal cerebrospinal fluid (CSF) out-
flow may result in increased intracranial pressure with
secondary evidence of disc edema. In this setting, trans-
mission of the elevated intracranial pressure along the
optic nerve sheath to the optic disc at the back of the eye
results in constipation of axonal transport. This is manifest
clinically as hyperemia, disc elevation, and obscuration of
the nerve fiber layer as it crosses the disc margin. Variable
hemorrhage and soft exudates may occur over the optic
nerve head surface. Clinically, the patients often complain
of headache and may have visual obscurations (transient,
characteristically brief, visual loss), particularly in associa-
tion with change in position (bending or rising rapidly).
Although visual acuity is often normal until late in the
course of this condition, variable optic nerve dysfunction
may occur.113 This can manifest itself as visual field defects,
including a combination of superior and inferior arcuate
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-
ropathy associated with increased intracranial pressure is
usually symmetrical. On occasion, however, it may affect
one eye more than the other, resulting in an afferent pupil-
lary defect. This is detected with a swinging flashlight test
and may be quantified by the use of neutral density filters.
Involvement of the optic nerve, however, will not produce
inequality in the pupil size.
Rarely, visual acuity may be affected by an autoimmune
phenomenon that attacks both the auditory system and the
cornea. In Cogan’s syndrome, an interstitial keratitis is
associated with auditory nerve involvement, resulting in
decreased visual acuity.114,115
Other forms of afferent visual system pathology include
the occurrence of visual field defects. These are probably
even less common than involvement of the optic nerves due
to papilledema, but they can happen when distal verte-
brobasilar system pathology results in compromised circu-
lation to the occipital lobe. Embolism, dissection, or simple
atherosclerosis can all affect posterior fossa circulation and
lead to various forms of homonymous hemianopsia.
Horner’s Syndrome
It is possible to see inequality in pupil size (anisocoria)
associated with neurotologic disease. This most commonly
occurs as a manifestation of Horner’s syndrome. Interrup-
tion of the sympathetic fibers, usually as they descend within
the intermediolateral column in the brainstem, results in a
smaller pupil on that side. The difference between the two
pupils is exaggerated in a low-light environment. Other
manifestations of sympathetic denervation to the orbit
include a small amount of ptosis and anhydrosis over the
234 NEUROTOLOGIC DIAGNOSIS
ipsilateral forehead. Horner’s syndrome may be confirmed
with the cocaine test. Placement of a drop of 4% to 10%
cocaine in both eyes will result in normal dilation of the
larger pupil. On the side of the smaller pupil, however,
lack of normal sympathetically released norepinephrine
leads to failure of dilation, thus exaggerating the difference
in size.
Most patients with Horner’s syndrome have pathology
affecting the carotid artery and secondarily the third-order
sympathetic neuron, which runs in the adventitia of that
artery. When associated with neurotologic pathology, how-
ever, it is most likely that the first-order neuron extending
from the hypothalamus to the cervical thoracic junction is
affected. The Paredrine test can distinguish first-order from
the more common form of third-order neuron involvement
in Horner’s syndrome. Hydroxyamphetamine 1%, when
placed in both cul-de-sacs, will cause dilation of both
pupils even in the setting of Horner’s if the third-order
neuron is intact. If, however, the pathology affects the
carotid artery and therefore the third-order neuron, no
dilation is seen. Horner’s syndrome in the setting of neuro-
tologic disease is frequently seen as part of Wallenberg’s
lateral medullary plate syndrome, as discussed later.
EVALUATION
History
As in all other areas of medicine, a detailed history can
often provide clues to a specific diagnosis. In the case of
diplopia, it is clearly important to distinguish local effects
from intracranial pathology. A prior history of thyroid dis-
ease or trauma, and certainly the occurrence of increasing
proptosis or globe displacement, suggests a local cause for
the misalignment. A progressive neoplastic or inflamma-
tory process affecting the cavernous sinus region should be
considered, especially with a prior history of facial pain or
numbness. Complaints of decreased hearing, associated with
diplopia on ipsilateral gaze, raise the question of Gradenigo’s
syndrome. In an older patient, this would require exclusion
of nasopharyngeal carcinoma.
The unusual complaint of tilt in the environment
strongly suggests involvement of the otolith pathways and
the vestibular system.116 When combined with Horner’s syn-
drome, a lateral medullary plate syndrome may be suspected.
Vertical oscillopsia involving one eye raises the possibil-
ity of superior oblique myokymia.117 Oscillopsia in general
suggests an acquired disorder of ocular motility most
commonly associated with pathology of the vestibular
pathways. When exacerbated by any head movement, severe
bilateral vestibular dysfunction may be suspected. A prior
history of aminoglycoside therapy is often elicited.38,118
Oscillopsia may also occur in association with other dis-
orders of spontaneous ocular motility. Opsoclonus repre-
sents a condition in which spontaneous conjugate irregular
movements occur in all directions without an intersaccadic
latency characteristic of nystagmus.119 This is felt to repre-
sent pathology affecting the pause cells within the brain-
stem120 and may be seen with various toxic and inflammatory
causes. In a young patient, the possibility of neuroblastoma
should be investigated,121 and in the older age group,
paraneoplastic syndrome with autoantibodies to cerebellar
tissue should be suspected.122 When confined to the hori-
zontal, rapid eye movements without intersaccadic latency
are referred to as ocular flutter. Patients with this symptom
have a pathophysiology similar to opsoclonus. In the young
adult group, demyelinating disease is a strong possibility.
If nystagmus is observed, it is most important to estab-
lish whether it is acquired or congenital. Old ophthalmic
records can be very useful. As mentioned, it would be highly
unlikely for congenital nystagmus to be associated with
vertigo or oscillopsia. On the other hand, these patients may
have problems with blurred vision, particularly when look-
ing in a certain direction. Patients can discover their own
null point, and a prior history of head posturing suggests a
problem of long duration. Details from the patient’s history
that suggest specific disease processes include exacerbation
of vertigo and blurred vision with change in posture or
head position (BPPV) or with straining, sneezing, or laugh-
ing (perilymph fistula or Arnold-Chiari malformation).
Examination
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
includes a detailed exam of both the afferent and efferent
visual systems. Although the incidence of afferent visual
pathology is far lower in neurotologic disease, it is impor-
tant to document the patient’s best corrected visual acuity,
the lack of an afferent pupillary defect, and the normality
of visual fields. Patients should always be checked wearing
their appropriate glasses or lens prescription. When it is
impossible to do a complete refraction, a pinhole acuity
test may indicate that reduction in vision is related to an
uncorrected refractive cause. In patients with complaints
of oscillopsia, visual acuity should be assessed with the
head at rest and in motion. The patient is asked to read a
Snellen chart, first with the head stationary, then with the
head randomly rotated about the visual axis by the
examiner. A drop of four lines or more in visual acuity
with motion indicates a problem with the VOR. The fundus
should be carefully checked for evidence of increased
intracranial pressure, optic atrophy, hemorrhages, exudate,
or nerve fiber bundle dropout. Vascular sheathing or
cotton wool spots may be a clue of a microvasculopathy or
a systemic vasculitis.
Any degree of head posturing should be noted; old pho-
tographs may be of help in this regard. A head turn may
indicate a long-standing problem either with restriction or
with a paretic lateral rectus muscle. Similarly, a head tilt
may indicate a congenital fourth nerve palsy, compensated
for by tilting the head away from the side of the lesion.
The efferent system remains of paramount concern.
The initial portion of the examination of the efferent
system is to ensure that the eyes are stable in primary
position. Subtle low-amplitude nystagmus may be over-
looked on direct examination, but is often brought out by
the use of Frenzel glasses that both illuminate and magnify
the globe. If these are not available, a simple means of
picking up subtle ocular instability is to examine the disc
with the direct ophthalmoscope after the patient’s eyes
 Neuro-Ophthalmic Manifestations of Neurotologic Disease
have been dilated.123 Although microsquarewave refixation
movements are always present in normals, even extremely
low amplitude nystagmus (less than 0.5 degree in excur-
sion) may be readily appreciated with the direct ophthal-
moscope. If nystagmus is present in the primary position,
it is essential to observe the direction of both the slow and
the fast phases to characterize the amplitude and velocity
and to ensure no change takes place over time. As men-
tioned earlier, it is important to distinguish among hori-
zontal, vertical, oblique, and torsional components. When
both a vertical and a horizontal component are present,
the nystagmoid movements may be either in phase, result-
ing in oblique nystagmus, or out of phase, resulting in cir-
cular or elliptical nystagmus (often occurring in the setting
of demyelinating disease124).
Several provocative stimuli should be employed to see if
nystagmus can be induced. These include positional
changes (Hallpike’s maneuvers) when BPPV is suspected,
as outlined in other chapters. When an inner ear fistula is
suspected, the Valsalva maneuver, a loud noise, or pneu-
matic otoscopy may result in change in the ocular drift.
Subtle abnormalities in the normal VOR may be detected
by rotating the patient’s head around an ocular axis in the
dark while monitoring the optic disc with a direct oph-
thalmoscope.123 If the VOR is entirely normal, the disc will
remain stationary. If the gain is greater than 1, the disc will
drift in the direction of the head rotation; if the gain is less
than 1, the drift will be in the opposite direction. Even
after adaptation, abnormalities in the peripheral vestibular
system may be detected by having patients rapidly shake
their heads horizontally and then open their eyes.125,126
Examining the patient with a direct ophthalmoscope in the
dark will indicate subtle drift of the eyes. This will occur if
asymmetrical involvement of the vestibular system is pres-
ent with the eyes drifting toward the side of the affected
peripheral vestibular system, even if habituation has led to
stability of the eyes when not stimulated.
Having established the patient’s stability in primary
position, the effect of change in gaze position should be
sought. Evidence of centripetal drift with eccentric sac-
cades suggests an abnormality in eccentric gaze position
holding, most likely related to abnormalities in the neural
integrator. This may be isolated only to the horizontal, but
usually occurs in all directions. Attention should also be
directed to the effect of eccentric gaze into all nine cardi-
nal positions on nystagmus already noted to be present.
Alexander’s law holds that in most forms of nystagmus, the
amplitude and possibly the velocity will be exacerbated
when the eye looks in the direction of the fast phase.127 If
a patient’s nystagmus changes as gaze direction is altered,
notation should be made of a possible null point where the
nystagmus is least apparent. Often a change in the tor-
sional component occurs as the patient looks either up or
down, as well as eccentrically. This may represent relative
involvement of the utricular connections. It certainly sug-
gests some variety of vestibular involvement. As men-
tioned earlier, it is common to find downbeat but not
upbeat nystagmus exacerbated by lateral gaze. Although it
is sometimes possible to judge the waveform of the slow
velocity by simple observation, particularly with Frenzel
glasses, detailed evaluation requires ocular motor record-
ing. This could be done most simply with video recording
235
and slow-motion analysis. Much better data may be obtained
through the use of electronystagmography, in which an
electro-oculogram (EOG) signal is generated by placing
electrodes on either side of the eye. This gives a largely
linear signal that corresponds to ocular position. Absolute
numbers require suitable calibration, but relatively detailed
data are possible. Simultaneously, vertical eye movements
may be studied in a similar fashion with electrodes placed
above and below the eye.
A somewhat more sophisticated approach to ocular
motor recording is the use of infrared (IR) tracking. This
requires specialized equipment, but gives an even more
detailed and linear recording of ocular motility. Unfortu-
nately, it is not good for recording vertical movements
because of problems with lid occlusion. In addition, most
systems available will not track with the lids closed and
therefore will suffer multiple interruptions with normal
blink frequency. Nonetheless, it is still a simple, noncon-
tact means of obtaining extremely accurate recordings.
Earlier systems were fixed, requiring the use of a rein-
forced head fixation device or bite bar. More recent IR
systems use detectors mounted on spectacles.
Currently, the gold standard in ocular motor recording
is that of the magnetic search coil. Placement of a fine cop-
per coil within a contact lens on the surface of the eye will
yield a signal linearly related to the position of the globe
when the patient’s head is placed within a uniform mag-
netic field. Extremely detailed recordings are thus possible
not only of horizontal and vertical movements, but also of
torsional movements, when a specially designed double
coil is used. By combining an eye coil with a coil placed on
the patient’s head, both eye and head movements as well as
eye in space movements may be studied accurately. Because
of the equipment involved, as well as the need for placing
the contact lenses directly on the eye, this testing remains
largely a research tool in certain academic centers. Fortu-
nately, this degree of precision is usually not necessary to
distinguish the various forms of nystagmus discussed.
The problem of ocular misalignment may be examined
by measuring the relative displacement of the two visual
axes with loose or bar prisms. By simply alternating fixa-
tion occlusion and adding prism until any movement of
redress is abolished, a good measurement of ocular mis-
alignment may be obtained in the primary position and in
all nine cardinal positions of gaze. When the deviation is
equal in all nine positions it is said to be comitant. Although
this usually represents long-standing or congenital strabis-
mus, paretic (ocular motor disorders), restrictive (most
frequently seen with thyroid disease or following trauma),
or even the rare causes of primary extraocular muscle over-
action may progress to increasingly comitant deviations
with time. This so-called spread of comitance probably
represents the ocular motor system’s plasticity in separately
adjusting individual gain.
With cross cover testing, any tendency for the eyes to
deviate (phoria) is measured along with the manifest
deviation (tropia). Any system that dissociates the two
eyes will also permit phorias to become manifest. The
difference between the tropia (actual deviation) and the
phoria is referred to as the fusional vergence. Fusional ampli-
tudes are much greater in the horizontal than the vertical
and also greater for convergence than for divergence.
236 NEUROTOLOGIC DIAGNOSIS
Increased vertical fusional amplitudes suggest an extremely
long-standing deviation such as that seen with a congeni-
tal fourth nerve palsy. Vergence amplitudes are affected by
generalized health. Fatigue, stress, alcohol, and various
drugs may substantially reduce the fusional vergence pos-
sible and result in the development of a tropia in the place
of a previously compensated phoria.
The simplest means of dissociating the visual axes is
with a red glass placed over one eye. The patient then
reports the separation between the red and white spots,
seen when a flashlight is directed toward the patient’s eyes.
This may produce both a horizontal and vertical compo-
nent. A Maddox rod consisting of a set of parallel small half
cylinders is more dissociative. When looking at light
through a Maddox rod a line is seen running perpendicular
to the orientation of the half cylinders. Therefore the rod
is placed horizontally if a horizontal deviation is suspected
or vertically if there is a problem with vertical separation.
In the usual situation both are done with the flashlight
briskly moved through all nine cardinal positions.
Although this can be made more quantitative by placing
prisms in front of one eye, usually the deviation is simply
estimated by the patient. By identifying the field where
maximal separation occurs, one can frequently identify the
paretic (or restricted) muscles. Although using a Maddox
rod requires more time than a red glass (needs to be done
both for horizontal and vertical separation), breaking down
the deviation into a horizontal and vertical component
actually makes analysis easier and therefore is in many
ways preferred.
Dissociation of the visual axes may be obtained with
higher technical approaches (amblyoscope, Maddox wing,
etc.), although these offer little advantage over the combi-
nation of Maddox rod and cross-cover prism testing. An
exception, the Lancaster red-green test or Hess screen,
however, does offer one additional advantage. This test
will not only identify the area of maximal deviation, but will
give a hardcopy recording so that the patient’s deviation
may be compared over time. Thus one can determine
whether the problems with ocular alignment are progress-
ing or improving.
One additional useful technique is assessment of the
area of binocular single vision. This is usually done on a
Goldmann perimeter and makes use of a size III test object.
The patient has both eyes opened and the machine is cen-
tered on the bridge of the nose. By indicating when two
objects are visible instead of one, areas of diplopia can be
identified. This is a very useful functional test because it
gives the investigator an immediate idea of the direction of
the patient’s visual gaze that will not result in double vision.
This also can be followed over time.
SPECIFIC DISEASE PROCESSES
Many neurotologic disease processes will have neurooph-
thalmic manifestations. Without attempting to duplicate
what exists in other chapters, we can briefly outline those
processes. It is most convenient to separate them into ones
that involve the end organ (semicircular canals, utricle,
saccule, and their nerves) and ones that involve the central
vestibular pathways and connections. Inflammatory,
infectious, neoplastic, compressive, traumatic, toxic, degen-
erative, vascular, and idiopathic pathologies are all possible.
The end organs are most commonly affected by ototoxins
such as aminoglycosides; idiopathic or degenerative
processes, such as Ménière’s disease and BPPV; inflamma-
tory conditions; trauma; and vascular disease. The neural
pathways are frequently affected by tumors of the cerebello-
pontine angle, including acoustic neurinomas, meningiomas,
epidermoids, and metastatic disease.128–132 Inflammation
(e.g., meningitis) may affect the eighth nerve directly. The
labyrinth or the eighth cranial nerve may be injured in the
petrous bone secondary to basilar skull fracture or shear-
ing forces.133,134 Ectatic vessels or aneurysms in the poste-
rior fossa may secondarily exert a mass effect directly on
the eighth cranial nerve.
Demyelinating disease usually affects the central
vestibular connections, but may also result in peripheral
cranial nerve involvement. Microvasculopathy and ischemic
changes are possible, particularly in the elderly vasculo-
pathic patient. They may or may not be associated with
more systemic involvement, such as polyarteritis, allergic
vasculitis, or giant-cell arteritis (a disease almost exclu-
sively of the elderly). Vascular changes may also be induced
by inadvertent embolization of the vascular supply during
interventional neuroradiologic procedures.
Prior damage of any kind to the vestibular nerve makes
it more susceptible to dysfunction associated with change
in pH and calcium concentration. This may be brought
out clinically by hyperventilation.
The central vestibular system and its cerebellar connec-
tions may similarly be affected by a myriad of pathophysi-
ologic processes. The same tumors that affect the peripheral
vestibular nerve in the cerebellopontine angle may also
compress the brainstem, resulting in central vestibular
pathology. In addition, primary intra-axial tumors, such as
gliomas, ependymomas, and medulloblastomas135 in young
patients may produce central vestibular dysfunction.136,137
Metastatic disease is uncommon. Unusual tumors, includ-
ing hemangioblastomas,138 hemangiomas,139 and germ cell
line tumors, may also present with neurotologic signs.
Arteriovenous malformation may produce a mass effect,
but also may cause local irritating phenomena or other
effects when associated with a bleed. Compromise of the
vascular supply to the lateral portion of the medulla (usu-
ally the posterior inferior cerebellar artery) produces the
so-called lateral medullary plate syndrome of Wallenberg.140
In this syndrome, torsional nystagmus141 is often com-
bined with a skew deviation94 and an associated ipsilateral
Horner’s syndrome. An almost unique complaint in these
patients is the perception of the world being tilted by 90 or
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
artery.143–145
Certain inflammatory lesions may affect both the
vestibular system and the efferent visual pathways. The
inflammatory process may be idiopathic, as with systemic
lupus erythematosus and nonspecific neuronitis,146 or it
may be related to a specific infectious agent, such as the
herpes viruses,147 HIV, various gram-positive and gram-
negative bacteria, mycobacteria, or syphilis.148,149 Inflamma-
tory lesions may be due to local contiguous spread or to
 Neuro-Ophthalmic Manifestations of Neurotologic Disease
embolic phenomena associated with subacute bacterial
endocarditis. An uncommon form of involvement, partic-
ularly in patients who are immunosuppressed, is that of the
gram-positive rod, Listeria. A peculiar syndrome referred
to as rhombencephalitis results from an abscess in the area
of the connection between the cerebellum and the lower
brainstem. These patients often present with motility dis-
turbance, diplopia, and various auditory and vestibular
complaints.
In patients who are immunosuppressed secondary to
HIV infection, parasitic infections may also occur in an
abscess form. Toxoplasmosis represents a common form of
intracranial posterior fossa pathology that may produce a
myriad of visual as well as neurotologic symptoms. A gaze
palsy is frequently the consequence of involvement of the
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,
and therefore the patient may not have diplopia and may
be unaware of other problems. The patient may note that
he or she has to turn the head more often and may describe
the problem as visual “blurring.”
Toxins, including inadvertent poisoning and routine
medications, can affect the central vestibular system.
Lithium taken as an antidepressant medication, for example,
can potentially cause downbeat nystagmus.150,151 Nicotine
can produce upbeat nystagmus,69 but this is latent unless
fixation is abolished. Alcohol may produce abnormalities
in the neural integrator as well as a direct decrease in the
vestibular gain.48
Hydrocarbon solvents have been increasingly recog-
nized as toxic to the central vestibular system.152–155
Patients complain of unsteadiness and difficulty coordinat-
ing eye movements, not of vertigo. The most common
objective abnormality is loss of VOR cancellation. It has
been hypothesized that solvents act acutely by blocking the
inhibitory neurotransmitter GABA; long-term solvent
exposure may actually cause loss of neurons.156
Anatomic abnormalities, either developmental or
degenerative, may result in pathology at the cervical
medullary junction. One of the more common causes of
central vestibular pathology is the Arnold-Chiari malfor-
mation.79,157 This may be combined with abnormalities in
the skull base, leading to basilar invagination and second-
ary external compression. Associated pursuit deficit often
occurs, indicating intra-axial pathology as well. This is
particularly true of an Arnold-Chiari malformation that
may be associated with central cord and brainstem diasta-
sis, referred to as a syrinx.158 An additional potential source
of mass effect would be an enlarged or ectatic vertebrobasi-
lar artery system. This may act as a compressive lesion or
lead to vascular compromise. Other vertebrobasilar disease
may be on the basis of atherosclerosis, embolic phenom-
ena, or dissection. Although most dissections in the poste-
rior fossa originate where the vertebral artery penetrates
the dura, dissection can specifically involve the intracranial
vertebral arteries or the basilar artery itself. The posterior
inferior cerebellar artery branching from the distil verte-
bral artery is commonly involved.
One of the more common causes of acquired vestibular
dysfunction in the young adult patient is demyelinating
237
disease.159 White matter plaques can affect any of the
vestibular pathways and connections, producing a plethora
of findings. Degenerative disease that includes cerebellar
and olivopontocerebellar degeneration160 may produce var-
ious degrees of abnormalities affecting both the vestibular
system and the efferent visual pathways.56,161,162 Paraneo-
plastic syndrome is most frequently seen with small cell
carcinoma, but has also been reported with carcinoma of
the ovaries and breast, and occasionally with gastrointesti-
nal tumors. This often produces opsoclonus or flutter, but
may also underlie downbeat nystagmus or various prob-
lems with vestibular gain.163
Metabolic depletion syndromes may also affect central
vestibular function. These include Wernicke’s encephalopa-
thy,164,165 B12 deficiency, and magnesium depletion.166
CONCLUSIONS
The vestibular system is the primary input for tonic activ-
ity to the extraocular muscles. Any abnormality within the
peripheral or central vestibular systems is likely to produce
both static and dynamic abnormalities in ocular position.
This can be manifested symptomatically as diplopia and
less commonly as oscillopsia. It may be discovered on clin-
ical testing as nystagmus, skew deviation, or other forms of
ocular misalignment. A detailed neuro-ophthalmic exami-
nation is likely to add substantial information about the
location of pathology affecting the vestibular and neuroto-
logic pathways. Although high-technology detailed eye
movement recording may be necessary for precise defini-
tion of waveforms, careful direct examination will often
supply information adequate to produce a precise localiz-
ing diagnosis and an appropriate differential. Information
obtained on clinical examination may be most helpful in
directing further testing, including the selection of imag-
ing studies and possible therapeutic intervention.
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 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
This chapter is concerned with the less common etiologies
of peripheral vertigo. Emphasis is on the understanding and
definitions of these conditions, although it will be necessary
to include some of the evaluation and treatment of these
conditions to explain these entities. Although many techno-
logic advances have occurred in the field of neurotology, the
history remains the most important part of the evaluation
of a patient complaining of dizziness. A complete history
should include a patient’s description of the character of the
dizziness, time course, precipitating factors, associated
symptoms, and predisposing factors. Following a thorough
history, a complete otoneurologic examination should be
performed. The diagnostic evaluation and management
differ markedly depending on the category of dizziness;
therefore, it is critical that the examining physician deter-
mine the type of dizziness before proceeding with exhaustive
diagnostic studies. It is crucial that the clinician be available
to reexamine the patient when the symptoms are present to
confirm the diagnosis. Only with this approach can appro-
priate therapeutic plans be instituted to treat the patient.
OTOLITH ORGAN DYSFUNCTION
Otolith-Ocular Reflexes
The otolith organs elicit eye movements provoked by static
head tilt as well as during periods of acceleration. As the
human head tilts from side to side, the otoliths provide
a compensatory ocular torsion or ocular counterrolling.
Otoliths also provide compensatory ocular torsion as the
head tilts forwards and backwards. Human ocular roll or
tilt is inefficient with a maximum torsion of about 5 to
6 degrees or a gain of about 0.1.1 Linear stimulation is the
strongest stimulation to the otolith organs. Acceleration
along the interaural axis causes a compensatory horizontal
eye movement, whereas acceleration in the occipital nasal
axis does not induce horizontal eye movements.2 The pur-
pose of the reflex is to enhance visual pursuit during linear
displacement of the head.
Most natural head movements are a combination of
linear and angular displacements. In contrast to the semi-
circular canals, the otolith organs sense change in linear
velocity, or acceleration, and sense static changes of the
head with regard to the gravitational vector. In contrast, the
semicircular canals sense angular acceleration. As the canals
mediate compensatory reflexes for head rotation, the otoliths
are responsible for otolith ocular reflex eye movements
(OOR), which compensate for linear components of head
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
senses the pull of gravity, as well as up and down and fore
and aft translations of the head. The canal and otolith ocu-
lar reflexes must work in unison to permit stable ocular fix-
ation. Only one functioning otolith set is needed to maintain
a normal OOR. In patients with bilateral vestibulopathy,
241
242 NEUROTOLOGIC DIAGNOSIS
the OOR may be absent or hypoactive patients with uni-
lateral loss have a normal OOR.3 In combined linear and
angular acceleration, the velocity of the eye adjustments is
too fast to be visually directed. The ocular system uses a
rapid, nonvisual estimate of current target location relative
to the head by combining available visual, auditory, and
proprioceptive information.4 The velocity storage feed-
back pathways in the central vestibulo-ocular reflex (VOR)
provides a key mechanism for otolith canal interactions.5,6
Otolith Anatomy
The utricle and saccule are two individual structures
contained within the vestibule. The utricle belongs to the
pars superior of the inner ear, and the saccule belongs to
the pars inferior of the inner ear. The otoliths contain
endolymph and are surrounded by perilymph. The endo-
lymph of the utricle has five paths of egress: the utricular
duct joining to the endolymphatic duct, the saccular duct
joining the utricle to the saccule, and ducts joining to each
semicircular canal. The vestibular aqueduct or the endolym-
phatic duct joins the utricle to the endolymphatic sac.7 The
saccule communicates with the endolymphatic duct by the
saccular duct and with the cochlear duct by the ductus
reuniens.
The utricle and saccular sensory neuroepithelium is the
macula. The utricular macula is 2.2 by 2.2 mm and the
saccular macula is 2.4 by 1.3 mm.7 Hair cells of the otoliths
have cilia embedded in a gelatin layer. On the surface of
Figure 14-1. Three-dimensional spatial orientation of the inner ear with its associated otolith organs. Inset shows detail of the utricle and saccule.
the gelatin layer are the calcium carbonate otoconial crystals
or otoliths. Otoconia are produced by the macular sup-
porting cells and after fracturing and becoming dislodged
from the macula are absorbed by the dark cells.8 Linear
displacement of the otoconial-gelatinous layer stimulates
the afferent nerves of the otoliths, allowing linear move-
ment detection. (See Fig. 14-1.) The maculae are at a
90-degree angle to one another. The utricle is a curved
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
and down by 25 degrees and laterally upward by about
10 degrees. A small anterior portion of the utricular macula
is curved upward. The saccular macula is oriented almost
at right angles to the utricle. Within each macula, the sen-
sory hair cells (HCs) are morphologically oriented in oppo-
site directions on either side of, and at right angles to, a
central line of demarcation named the striola. Kinocilia are
directed away from the striola in the saccule and toward
the striola in the utricle. In the striolae, the otolithic layer
of the utricle is thinnest and that of the saccule is the
thickest. Both maculae contain HC orientation vectors in
all directions. Striolae have more type I HCs and are
innervated by thicker axons, conducting at greater velocities.
The otoconia inertia causes their relative displacement in
a direction opposite to an imposed linear acceleration.
With both maculae nonplanar and both striolae curved,
the hair cell activation patterns are complex. Detailed
examination of the pathways from the otolithic maculae to
 Otolith Dysfunction and Semicircular Canal Dysfunction
the eye muscles is much more difficult than it is for the
canals because the macular nerves carry information about
all conceivable directions of movement. Gross stimulation
of the whole utricular nerve causes torsional movements of
the eyes with intorsion of the ipsilateral eye and extorsion
of the contralateral eye. The ipsilateral eye elevates and
adducts and the contralateral eye depresses and abducts.
Otolith Symptoms
Symptoms of otolithic dysfunction have not been widely
described in the otolaryngologic literature. Practitioners
may not be familiar with the symptoms of otolithic dysfun-
ction and thus cannot easily or confidently attribute symp-
toms to a diagnosis. Patients may present with symptoms
suggestive of a vestibular disorder but without the typical
signs of vestibular disease such as spontaneous nystagmus
and asymmetrical rotational and deranged caloric responses.
Patients may complain of a sensation of linear motion such
as rocking or that the ground is moving up and down.
Feelings of falling or actual falls, lateropulsion sensations, or
inability to align things horizontally or vertically are also
possible complaints.
Potential etiologies of otolith dysfunction are numerous.
(See Fig. 14-2.) Benign paroxysmal positional vertigo has
been linked to dislodged otoconia from an otolith macula
causing stimulation of the cupula of the semicircular canal,
most commonly the posterior canal. This may be related to
a post-traumatic event to the head that caused otoconia to
separate from the macula.10 Otoconia could theoretically be
released from a vascular insult to the otolith, freeing the
crystals. Also, dysfunction of the dark cells, thought to be
responsible for otoconia resorption, could lead to an excess
of freed otoconia. Symptoms can arise not only from the
free otoconia causing stimulation of the semicircular canals
but also from the resultant asymmetric loading between
right and left maculae after otoconia are dislodged.
Patients with endolymphatic hydrops or Ménière’s
disease may receive pathologic stimulation of the otoliths.11
Deformation or pressure changes in the membranous
labyrinth may result in pushing or pulling forces on the
maculae, giving the patient sensations of linear, vertical, or
243
rocking motions while symptomatic. Sudden changes in
endolymphatic fluid pressure with inappropriate otolith
stimulation have also been proposed as a source of vestibular
drop attacks, or Tumarkin crisis. Sudden otolithic stimulation
may elicit a reflex-like vestibulospinal loss of postural tone.12
Additionally, post-traumatic forms of imbalance have
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
between the right and left otoliths, resulting in asymmetric
vestibular input to the brain.13 Barotrauma or surgical
trauma has been associated with perilymphatic fistula forma-
tion and pathologic otolith stimulation.14 Rocking vertigo
and imbalance with sneezing, coughing, or straining can
be associated with leakage of perilymph fluid. This may be
secondary to stapes subluxation onto the otolith or otolith
movement with leakage of the surrounding perilymph.
Observations have also been made where the membra-
nous lining of the vestibule pulls away from the bony walls
and lies directly on the otolith organ. This vestibular atelec-
tasis may then become a mechanical link between the under-
surface of the footplate and the membrane of the otolith
organ.15 A similar mechanism has been proposed as the
etiology behind the otolith: Tullio’s phenomenon, in which
the patient may experience paroxysms of head tilt, ocular tor-
sion, and tilting of the visual surround with certain tonal
stimulation.14,16,17
Unilateral vestibular loss results in asymmetric otolith
function. In the weeks following the loss, there is a pro-
gressive recovery of the asymmetrical response, suggesting
that otolith symptoms recover after vestibular damage, just
as some static canal symptoms recover. There is likely a
process of otolithic compensation as well as one of canal
compensation.18
Testing Otolith Function
Direct testing of otolith function is difficult and currently
requires a specialized testing environment. The contribu-
tions of the otoliths to the vestibulo-ocular reflex can be
classified into several categories:19 (1) compensation for
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
of rotation is directed away from the pull of gravity (off-
vertical axis rotation), and (3) compensation for static tilt
of the head or ocular counterroll. Gresty and colleagues
were the first to use off-vertical axis rotation or eccentric
yaw rotation to assess otolith function.20 The subject is
seated in a rotational chair and leaning forward such that
the head is anterior to the vertical axis of rotation (off-axis
or eccentric rotation). These tests stimulate both the
otoliths and the horizontal canals. Translational testing is
able to test only the otolith functions and can be performed
on a linear sled, cart, or parallel swing. This testing requires
specialized equipment and currently does not lend itself
well to office testing.
With a tonic lateral head tilt, the eyes counterroll,
presumably as part of a normal attempt to align the hori-
zontal meridian of the retina with the horizon. Spon-
taneous ocular tilt reactions presumably reflect otolith,
particularly utricular, imbalance. The ocular tilt reaction
(OTR) has also been associated with both midbrain and
peripheral lesions.21–23 OTR is part of the expected com-
pensatory postural reaction to an unexpected lateral tilt of
the body. The otolith response of OTR consists of a vertical
ocular skew deviation, ocular counterroll, and head tilt. The
alternate cover test can aid the detection of skew deviation.
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
lower eye is on the side of the lesion. The otolith ocular
pathway crosses at the level of the vestibular nuclei, so that
with lesions above the decussation, the higher eye is on the
side of the lesion.24 In a peripheral lesion, the eye on the
side of the head tilted toward the ground has a downward
vertical deviation and the eye opposite the side tilted
toward the ground has an upward vertical deviation. Also,
the superior pole of the eye on the side of the head tilted
toward the ground extorts while the superior pole of the
eye opposite the side tilted toward the ground intorts. The
head usually tilts toward the side of the lesion with periph-
eral labyrinthine and lateral medullary lesions.19
Utricular function can be assessed in the office using the
subjective vertical visual (SVV) test. The SVV is a measure
of otolith and especially utricular function. Bilateral
otolith inputs provide humans with their dominant per-
ception of gravity. A patient sits with the head fixed in the
upright position and looks forward at an illuminated line
in darkness. The patient adjusts the line from various start-
ing positions to his or her SVV. This is repeated 10 times
for each eye. With acute peripheral vestibular lesions
including the utricles, there is an ipsilateral deviation of
the SVV of about 10 to 15 degrees.25,26 Patients with
otolithic dysfunction, however, are not the only patients
who have difficulty with the SVV test. Patients with acute
unilateral brainstem infarctions may also exhibit patho-
logic tilts of static SVV from the true vertical.27 The SVV
test is simple and cost effective; however, it lacks specificity
at this time—it shows positive results with both vestibular
and nonvestibular mechanisms.
Clinically, patients must be queried about vertical diplopia,
tilting of their visual surround, and sound or pressure trig-
gers to their imbalance. In such patients, examination must
include looking for head tilt, skew deviation, and elicitation
of these symptoms or signs on application of pressure or
sound to the offending ear. Signs of otolith dysfunction can
be observed as a tonic (constant) OTR and skew deviation
in the settings of perilymphatic fistula, stapes hypermobil-
ity or subluxation, acute labyrinthine loss, or posterior fossa
lesion.28 These patients may have pressure sensitivity or
Tullio’s phenomenon.29
Certain tones may provoke a tonic OTR or skew
deviation in patients with utricular imbalance known as
Tullio’s phenomenon.30 Separately, these tests may not be
specific to otolith dysfunction; however, combinations of
tests should increase overall specificity, sensitivity, and
reliability. It remains to be shown whether isolated unilateral
deficits of otolith function, that is, otolithic defects in the
presence of normal semicircular canal functions, and partial
deficits of otolith function can be detected with these tests.
It is difficult to develop a clinical test for patients suspected
of suffering from otolith dysfunction when there is an
absence of an adequate criterion reference group of patients
with proved, isolated, complete or partial, unilateral deficits
only of otolith function. Another obstacle to testing isolated
otolith function is the convergence of otolith and semicir-
cular canal inputs on secondary vestibular neurons in the
vestibular nuclei.31
SUPERIOR SEMICIRCULAR CANAL
DEHISCENCE SYNDROME
Pathology
Dehiscence of the superior semicircular canal is an entity
first described by Minor and colleagues in 1998.32 In these
patients the bony covering between the top of the superior
semicircular canal and the middle cranial fossa is missing.
(See Fig. 14-3.) This can be spontaneous or presumably
congenital. The most likely explanation of patient
symptoms of imbalance is that the superior canal dehiscence
creates a mobile third window to the inner ear. With this
third mobile window, the endolymphatic system has an
increased compliance. Pressure or sound creates a pressure
differential across the ampulla, which in turn allows the
canal ampulla to be responsive to changes in inner ear pres-
sure associated with sound stimulation. Superior canal
dehiscence is rare, arising in 0.5% of temporal bones in a
temporal bone survey or 0.7% of individuals. The condition
is often bilateral. Also, an additional 1.4% of temporal bones
have a very thin bony covering (smaller than 0.1 mm) such
that they might appear dehiscent on high-resolution CT
scan of the temporal bone.33
Symptoms
Patients with superior semicircular canal dehiscence (SCD)
may experience vertigo, tilting of their visual surround, and
nystagmus without skew deviation when pressure changes
occur in the external auditory canal, the middle ear, or the
intracranial space.34 Also, these patients may experience
imbalance and nystagmus with applications of certain tones
or sounds to the ear, or Tullio’s phenomenon.35
 Otolith Dysfunction and Semicircular Canal Dysfunction
Etiology of Symptoms
Patients may experience sensitivity to pressure or certain
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
in the plane of the affected canal. Vector analysis of the
elicited nystagmus during stimulation has mapped the source
of the nystagmus to the superior semicircular canal in
patients with SCD.35,36 The axis of evoked nystagmus in the
superior canal dehiscence syndrome aligns with the plane
of the affected superior canal, indicating that the response
originates mainly from that canal. The chinchilla has been
used as an animal model of SCD.37 Fenestration of the supe-
rior semicircular canal produced an increase in superior
canal afferents after positive pressure in the external canal
and a decrease in firing with negative pressure. Responses
could be ablated by rigidly repairing the dehiscence.
The ocular movements elicited on tests were initially
thought to be results of possible utricular stimulation.
Although appropriate stimulation of the utricle could
produce ocular torsion with horizontal eye movement, and
stimulation of the saccule could produce vertical eye move-
ment, one would expect a tonic response with otolith stim-
ulation rather than the phasic-torsional nystagmus responses
that are observed.29,35,36 The evoked eye movements in
patients with SCD syndrome arise from the superior canal,
not the utricle.
In some patients, vertigo is elicited by sound applied to
the ear. Tullio’s phenomenon is the combination of vertigo
and abnormal eye and/or head movements provoked by
sound. This vestibular response to sound was first described
by Tullio, who studied fistulized labyrinths of pigeons in
1926.38 Two possible sources of Tullio’s phenomenon have
been put forth: otolithic and semicircular canal stimula-
tion.39,40 Tullio’s phenomenon has been associated with
Ménière’s syndrome,39 congenital inner ear anomalies,41
245
Figure 14-3. A coronal view, high-
resolution, CT scan of the temporal bone
demonstrating a dehiscence of the right
superior semicircular canal.
infectious etiologies such as syphilis and chronic ear pathol-
ogy,40 trauma,42 perilymphatic fistula,43 and iatrogenic
fistulae, that is, fenestration surgery.44
Examination and Testing
A keen examiner must inquire about pressure sensitivity
symptoms as well as sensitivity to certain sounds or tones.
A patient with pressure sensitivity or Tullio’s phenomenon
warrants consideration for SCD. During testing, the
patient’s vision must be controlled to eliminate visual fixation
during the exam. This can be accomplished with Frenzel
lens testing, examination in the dark with infrared video
oculography, or scleral search coil. If the patient is allowed
visual fixation, nystagmus will likely be suppressed and
abnormalities not appreciated. Patients will present with
vertical-torsional eye movements consistent with activation
of the superior semicircular canal. A high index of sus-
picion is needed to differentiate SCD from perilymphatic
fistula (PLF). Detailed imaging and careful observation of
eye movements during exam aids in the diagnosis. High-
resolution CT scan of the temporal bone is needed to show
a superior canal dehiscence.
Treatment
For symptomatic patients, middle fossa craniotomy may
be needed to allow plugging of the canal or resurfacing of
the dehiscence. Imbalance symptoms are improved or
eliminated after surgery.45 Animal models of SCD have
shown that rigid repair of the dehiscence eliminates symp-
toms better than soft-tissue patch repair.46 If the trigger of
vertigo is sound, avoidance of the offending tone may be
all that is needed. If pressure sensitivity is the trigger, a trial
with a simple ventilation tube may be beneficial to eliminate
the pressure differential across the tympanic membrane.
246 NEUROTOLOGIC DIAGNOSIS
This, however, would not alleviate symptoms caused by
intracranial pressure fluctuations.
LABYRINTHINE HEMORRHAGE
A rare but notable condition described more recently in the
literature is vertigo associated with spontaneous hemorrhage
into the vestibule, labyrinth, and cochlea. This condition has
been described in the radiology literature in patients with a
history of sickle cell anemia. Patients can present with sud-
den onset of vertigo, sensorineural hearing loss, and patho-
logic findings on magnetic resonance imaging (MRI). High
signal intensity can be seen on T1-weighted images without
contrast in the vestibule and labyrinth. Patients present
spontaneously similarly to a sickle cell crisis. Sickling of red
blood cells causes capillary occlusion with resultant ischemia
that may lead to spontaneous bleeding.47 This may be sec-
ondary to injury to the capillary vascular bed. Labyrinthine
hemorrhage has been described in conjunction with
leukemia and thrombocytopenia,48,49 aplastic anemia,50
leukemoid reactions of malignant neoplasms, and in the set-
ting of DIC.51 As a group, these case reports have a uni-
formly poor prognosis of regaining vestibular or cochlear
function after hemorrhage. An MR screening examination
consisting of either a high-resolution T2-weighted sequence
or a contrast-enhanced T1-weighted sequence will not by
itself accurately diagnose hemorrhage. Noncontrast, thin-
section, T1-weighted MR images are the study of choice for
diagnosing intralabyrinthine hemorrhage.1,47
OTIC BAROTRAUMA
Barotrauma can be defined as tissue damage resulting from
a change in gas pressure present in a closed space. The
air-filled spaces of the middle ear and mastoid constitute a
closed volume if the eustachian tube is malfunctioning.
Using the universal gas law, PV/T = PV/T, as ambient
pressure varies, the pressure within a closed volume must
also change. When the normal communications between
the air-filled spaces and the environment are blocked,
pressure cannot equilibrate. This pressure differential
causes tissue injury. The usual mechanisms include
underwater diving, flying or air travel, blunt head trauma,
and hyperbaric oxygen therapy. A sudden change in
ambient pressure is the common denominator.
Air Travel
As a pressure reference, sea level is 1 atmosphere (ATM),
18,000 feet of altitude is 1/2 ATM. During ascent in
an aircraft, air pressure decreases at an approximate rate
of 15 mm Hg every 400 feet of altitude. During descent,
relative air pressure increases. “Pressurization” in an aircraft
is a relative term and not all aircraft are equal. A typical
airliner may be pressurized to 8.5 psi, which translates into
a “sea-level” cabin up to 16,000 feet but a 7,000-foot cabin
altitude when the aircraft is at 40,000 feet. Overall, pressur-
ization reduces but will not eliminate the risk of barotrauma.
Air usually flows passively from the middle ear on ascent;
however, on descent the eustachian tube must be actively
opened to equilibrate pressure. One usually experiences
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
(TM), 100 mm Hg to 500 mm Hg is needed.52 Goodhill’s
“implosive” and “explosive” mechanisms for ear trauma
are applicable.53 Implosive ear trauma is caused by an acute
increase in middle ear pressure or ossicular pressure forcing
the stapes footplate into the vestibule. Explosive ear trauma
is caused by either an increase in cerebrospinal fluid (CSF)
pressure or forceful Valsalva’s maneuver, resulting in an
increase in intracochlear pressure and possible rupture of
a round or oval window.
Underwater Diving
Otolaryngologic barotrauma is most common with diving.
Pain and damage usually occur during descent (middle ear
squeeze) due to the inability or failure to equalize pressure.
Symptoms include facial, tooth, or ear pain; sudden hearing
loss; vertigo; tinnitus; or fullness. Otologic findings include
petechial hemorrhages, blebs in the EAC, serous effusion,
TM retraction, conductive or sometimes a sensorineural
hearing loss, and TM rupture. As a pressure reference,
sea level is 1 ATM, 33 feet below sea level is 2 ATM, and
150 feet below sea level is 3 ATM. Farmer described a grad-
ing system for middle ear barotrauma: type I is middle ear
fullness, pain, but normal otoscopy; type II is pain, hearing
loss, TM erythema, effusion, and hemotympanum; and
type III is TM perforation.54
Hearing Loss Etiology
Hearing loss can be either conductive or sensorineural.
Conductive etiologies include serous effusions, hemotym-
panum, ossicular disruption, and tympanic membrane
perforation. Neural loss etiologies include gas embolus in the
cochlea, labyrinthine membrane tear, intracochlear hemor-
rhage, and perilymphatic fistula.55,56 Hearing prognosis from
intracochlear hemorrhage is poor due to the resultant
fibrosis. Prognosis for return of hearing is excellent if the
patient presents only with auditory symptoms.57
Treatment Options
To prevent or avoid barotrauma, several conservative and
preventive measures can be performed. These may include
no flying within 24 hours of diving, staying awake on
airplane descent, yawning, swallowing, and maintaining
good control of allergies. Pressure relief measures are also
available. Self-politzerization involves pinching the nose,
closing the mouth, and gently exhaling to force air back
into the middle ear or sinuses. The Toynbee maneuver
involves pinching the nose, closing the mouth, and swal-
lowing to increase nasopharynx pressure. Last, the Frenzel
maneuver involves contracting the muscles of the floor of
the mouth and nasopharynx with the mouth closed.
Medications can also provide benefit to the patient.
Oxymetazoline HCl and pseudoephedrine taken 1 to 2 days
before a flight might provide some degree of deconges-
tion and vasoconstriction. A myringotomy with or with-
out a tube is indicated in refractory conditions as long as
 Otolith Dysfunction and Semicircular Canal Dysfunction
a nasopharyngeal mass is ruled out. A middle ear explo-
ration may be needed if severe cochleovestibular symptoms
are present.
Decompression Sickness
Decompression sickness (DCS) occurs when the surrounding
atmospheric pressure decreases too rapidly. As the atmos-
pheric pressure decreases, the nitrogen-carrying capacity of
the blood decreases. If the atmospheric pressure decreases
too rapidly, the excess nitrogen coming out of solution
from the blood will not be able to be excreted by the lungs
quickly enough. DCS arises when nitrogen bubbles form in
the blood. The body tries to rid nitrogen faster than the
lungs can exchange it with the environment. Type I DCS
includes musculoskeletal pain and cramping, cutaneous
modeling, skin discoloration, and joint pain. Type II DCS
includes severe, emergent symptoms.58 Neurologic signs
include deafness, vertigo, loss of vision, paraplegia, and in
some cases cardiopulmonary shock. Factors potentiating
DCS include unpressurized altitudes above 25,000 feet,
long duration at altitude, a rapid ascent (either flying or
diving), and flying within 24 hours of diving.
To reduce the risk of DCS, one can ascend from a
dive slowly with decompression stops and use pressu-
rized aircraft when flying. “Prebreathing” pure oxygen for
30 minutes before a deep dive or high-altitude flight makes
a nitrogen diffusion gradient so as to reduce the overall
volume of nitrogen in tissues. Mixing helium with oxygen
instead of nitrogen for deep dives reduces the risk of
nitrogen bubbles forming in the bloodstream.
Type I DCS treatment includes 100% oxygen and obser-
vation with the expectation that symptoms will resolve in
a matter of hours. Type II DCS treatment necessitates a
hyperbaric oxygen chamber with recompression to 3 ATM
greater than when the symptoms started. Transport to the
hyperbaric oxygen (HBO) facility should be at no greater
than 800 to 1000 feet above ground level or in a pressurized
transport.59
LABYRINTHITIS
Viral
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,
influenza, and chickenpox. Viral labyrinthitis may also occur
in the absence of systemic viral disease.
The initial symptoms are severe vertigo exacerbated
by head movement. When associated with systemic viral
infection, patients often develop a sensorineural hearing
loss. The hearing loss may be transient but is more often
permanent. Early examination usually reveals an irritative
nystagmus toward the affected ear. The vestibular symptoms
usually improve in 48 to 72 hours but may take weeks to
resolve. Lingering episodes of dysequilibrium or unsteadi-
ness may follow the acute episode for a variable time depend-
ing on the patient’s physical activity level and other factors
that affect compensation.
Histopathologic study of the temporal bones of such
patients has shown the principal changes to consist of atrophy
247
of the organ of Corti, tectorial membrane, and stria vascu-
laris. These findings are similar to the histopathologic
studies of patients with mumps and measles.
Serous
Serous labyrinthitis is a sterile inflammatory condition of
the inner ear, induced by chemical or toxic irritation of the
membranous labyrinth. This may occur from acute or
chronic otitis, or from trauma or surgery. Patients typically
develop mild to moderate vertigo with nystagmus directed
toward the affected ear. Mild to moderate, temporary or
permanent, sensorineural hearing loss is common especially
in the high-frequency range nearest to the oval window and
presumed proximity to toxins in the middle ear.
Suppurative
Suppurative labyrinthitis occurs when pyogenic bacteria
enter the inner ear. This may occur in acute or chronic
otitis media with or without cholesteatoma, meningitis, or
rarely, in systemic bacterial infections. Iatrogenic fistula
during middle ear surgery may also result in suppurative
labyrinthitis. Patients are often violently ill with fever,
severe vertigo, and profound hearing loss. The route of
meningitic spread is via the cochlear aqueduct to the scala
tympani and is usually bilateral. Ossification of the cochlea
may ensue within weeks to months after recovery of menin-
gitis, necessitating prompt consideration of and cochlear
implantation if warranted. Nystagmus is directed away
from the affected ear and the patient falls and past points to
the affected side. In suspected cases of fistula, caloric investi-
gation is contraindicated because it may spread the infection
by intralabyrinthine fluid.60 The combined vestibular and
auditory loss is usually permanent. Fortunately, suppurative
labyrinthitis is rare in the antibiotic era.
Treatment of the vestibular symptoms in all forms of
labyrinthitis involves use of vestibular suppressant medi-
cations for the acute attack and vestibular rehabilitation to
enhance compensation as soon as practical after the acute
stage has passed. If no contraindications exist, high-dose
steroids may be given for a viral labyrinthitis. Parenteral
antibiotics will likely be needed for patients with a suppu-
rative labyrinthitis.
PERILYMPH FISTULA
A perilymphatic fistula (PLF) is an abnormal connection
between the inner and middle ear due to a defect in the
labyrinthine bone or in the round or oval windows. Such fis-
tulas cause sudden or fluctuating sensory hearing loss and
dizziness. There are various causes of perilymphatic fistula
including both acquired and, more rarely, congenital causes.
Acquired PLF may arise secondary to erosive cholesteatoma,
syphilitic gummas, benign or malignant neoplasm, or
traumatic and iatrogenic etiologies. Congenital PLF may
be present with or without cranial anomalies. The exis-
tence of other causes that do not involve the labyrinthine
bone but involve one of its windows is not well accepted by
all surgeons. The reason for this is that there is no clear
method of determining the diagnosis preoperatively, and
248 NEUROTOLOGIC DIAGNOSIS
even surgical exploration often depends on subjective inter-
pretation of the findings.
Pathogenesis
The arguments of Goodhill53 regarding the “implosive and
explosive” etiology of perilymph fistula and those of
Simmons61 regarding an alternate lesion causing the same
symptoms have received the most attention, and both have
supporting experimental findings. Goodhill theorized that
sudden or severe changes in middle ear pressure, via the
eustachian tube, could direct force internally toward
the inner ear, causing rupture of the oval window or round
window seals (implosive route). Autoinsufflation of the
eustachian tubes may cause fistula by this mechanism. Blunt
head trauma including whiplash and even low-velocity head
trauma can result in PLF.62 Acoustic trauma or external
atmospheric pressure, which causes relatively large displace-
ment of the tympanic membrane, may also cause fistula by
this mechanism, according to Goodhill. Similarly, force
could be directed externally toward the inner ear by
increased CSF pressure, via the cochlear aqueduct or inter-
nal auditory canal (explosive route). Physical exertion such
as lifting weights, coughing, and sneezing could cause fis-
tula this way. In humans, we know that a patent cochlear
aqueduct can exist and that the largest volume displacement
of perilymph occurs at relatively low-pressure changes.63
Furthermore, round window ruptures have been docu-
mented after barotraumatic events such as scuba diving.64,65
Just prior to Goodhill’s presentation on the theory of
labyrinthine window rupture, Simmons had presented an
alternative theory for sudden sensorineural hearing loss. His
theory suggested the CSF pressure changes are transmitted
to the labyrinth, which result in intracochlear membrane
breaks, and the subsequent mixing of endolymph and peri-
lymph causes the symptoms.61 This theory was based on ear-
lier experimental evidence in cats showing intralabyrinthine
membrane rupture and deafness.64
Symptoms
The classic symptoms of perilymph fistulas are sudden
severe sensorineural hearing loss, vertigo, and tinnitus.
Several of the early reports emphasized sudden sensory
hearing loss as the presenting symptom of perilymph fistula,
particularly seen related with a history of physical exertion.
Further experience has shown that many patients actually
complain of fluctuating hearing loss.64,65 As such, the symp-
toms of perilymph fistula can often be identical to those of
Ménière’s disease. The severity of the hearing loss bears no
relationship to the extent of the perilymph leakage, nor does
it help predict the likelihood of finding a perilymph fistula.
In some, PLF symptoms may arise immediately or within
days after head trauma; however, Ménière’s type symptoms
may take months to years to develop. Patients with fistula
can present with vertigo, positional dizziness, or dysequilib-
rium. Findings of nystagmus have shown no definite pattern
and have not been predictive for fistula.
Diagnosis and Testing
The fistula test is the most widely used clinical test for this
condition. Patients with PLF often become vertiginous
after pressurization of the external ear canal on the side of
the fistula. Observing this phenomenon, the fistula test was
first described by Lucae in 1881.66 It consists of registration
of ocular deviation or nystagmus following pressurization
of the external ear canal. There are three types of ocular
response to the fistula test thought to indicate abnormality
and the potential presence of fistula. The fistula sign is a
nystagmus that continues for 10 to 15 seconds following
application of positive or negative pressure.67,68 Hennebert’s
sign is a slow conjugate horizontal ocular deviation at the
onset of pressurization and a movement in the opposite
direction at the end of stimulation.66,67,69 The ocular tilt
reaction, described more recently, is a combined vertical
and torsional movement of the eye, of rapid onset and
resolution, provoked by pressure.14,70
The fistula test is used to select patients for exploratory
tympanotomy in an attempt to detect and repair a PLF.
However, inconsistent criteria are often used to interpret
the fistula test. The fistula test as conventionally performed
is insensitive for the diagnosis of PLF.71 In normal subjects,
the change in nystagmus between prepressure and post-
pressure tests ranged from −1.3 to 0.9 degrees per second.
In patients, change in nystagmus greater than the 95th
percentile limits of normal was not a reliable indication of
PLF.71 The test may be falsely positive in patients with
Ménière’s disease and caloric testing is nonspecific. Patients
with fistula present with a wide variety of hearing loss
patterns, and in fact no audiometric parameter has been
found to be predictive of a perilymph fistula.
Accurately diagnosing a fistula remains difficult and
disputed. Each surgeon must establish reasonable guidelines
before considering surgical exploration of patients with
dizziness. A diagnosis may be considered when a clear his-
tory of a traumatic event or other predisposing cause is doc-
umented. Furthermore, the presence of vestibular symptoms
alone, with no hearing loss or tinnitus, makes the diagnosis
less tenable. There is no clear evidence for the existence of
spontaneous (idiopathic) perilymph fistula. In the experience
of most practitioners, perilymph fistula remains a relatively
uncommon cause of dizziness and hearing loss.72
Management
Initial care of a patient with perilymph fistula involves
conservative measures. Bed rest, head elevation at all
times, avoidance of physical straining and blowing of the
nose, and controlled sedation is advised for 10 days.
Persistent otologic symptoms after this period, particularly
with a history of recent trauma, warrant an exploratory
tympanotomy for definitive diagnosis and repair of a fistula.
Under local anesthesia with sedation, the surgeon can
carefully expose and observe the round and oval windows.
Placement of the patient in the Trendelenburg position,
application of external pressure on the jugular vein, and the
Valsalva maneuver will help reveal a fistula. Because laby-
rinthine defects are not always associated with perilymph
leakage, repair at the windows is undertaken whether or not
a fistula is clearly seen. Small pieces of autogenous perichon-
drium can be packed over the round window membrane and
around the annular ligament and stapes footplate after the
respective niche is scarified with a fine pick or knife. Hearing
improvement after fistula repair is infrequently seen (about
 Otolith Dysfunction and Semicircular Canal Dysfunction
25% of patients) but improvement in vertigo occurs in a
majority of patients (60% to 80%).
Congenital Perilymph Fistula
Congenital perilymph fistulas are unlike acquired perilymph
fistulas in the character of the leakage and in etiology.
Suspect a congenital perilymphatic fistula when progressive
sensorineural or mixed hearing loss, with or without
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
have had recurrent episodes of meningitis because commu-
nications between the intracranial space and the middle ear
provide an easy pathway for the spread of infection. The
most common finding has been leakage from the oval
window area. Anatomic anomalies of the ossicles, windows,
or labyrinth are often noted.
POST-TRAUMATIC VERTIGO
Eighth Nerve Trauma
Blunt head trauma can cause shearing force on intracranial
structures due to sudden head acceleration forces. A collision
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
be observed in the region of the vestibular nuclei.75,76 These
patients may have a persistent form of imbalance that
compensates poorly. This compensation is poor due to only
partial damage to the end organ as well as damage to the
vestibular nuclei. For compensation to be effective, one needs
a normally functioning vestibular nucleus on the side of the
acute loss.77 Symptoms may persist because of an incomplete
unilateral loss as well as a dysfunctioning vestibular nucleus.
Testing may show an acute hemorrhage on MRI.
Electronystagmography (ENG) may show a unilateral
caloric hypofunction. Rotary chair testing may demonstrate
an asymmetry of gain during low-frequency sinusoidal
harmonic acceleration testing and an increased phase lag
at low frequencies. With time, the asymmetry of gain may
disappear, but the increased phase lag would remain
indefinitely.78,79 Treatment may include intensive vestibular
physical therapy to maximize compensation. If conservative
measures fail, consideration can be given to chemical or
surgical labyrinthectomy or vestibular nerve section to
eliminate a partially functioning vestibular system.
Labyrinthine Concussion
Following blunt head trauma, the semicircular canals
can be injured even if there is no obvious temporal bone
fracture. The complete pathophysiologic mechanisms of
trauma are not yet fully understood. Mechanisms for laby-
rinthine concussion have been proposed. Sudden accelera-
tion forces can cause shearing trauma to the vestibular end
organs and disruption of the sensory epithelium.80 Laby-
rinthine hemorrhage may result in fibrous tissue deposition,
scarring, and new bone growth.81,82 The delicate vasculature
to the vestibular end organs can be disrupted by shearing
forces, and small clot formation results.83
249
Treatment resides in determining a peripheral source of
the vertigo. If the vertigo persists following rehabilitation,
the patient may obtain relief from a chemical or surgical
labyrinthectomy or a vestibular nerve section. Before any
destructive means are taken, the diagnosis must be certain,
central etiologies must be ruled out, and the patient should
be capable of postoperative rehabilitation to speed com-
pensation. Ideally, the patient’s vision and proprioceptive
senses are intact.
Post-Traumatic BPPV
The sudden blunt force from head trauma can result in
direct shearing force to the utricle. The otoconia from the
otolith organ can be sheared off their gelatinous matrix into
the endolymph. The patient not only will have the BPPV-
like symptoms and positive Dix-Hallpike test, but also may
have resultant otolith dysfunction. This otolith dysfunc-
tion may persist several weeks until new otoconia are
formed and the otolith organ ad can restore the structure
and function to the utricle or saccule. The examiner
should be aware of this possible dual diagnosis and be keen
during the history and examination to detect multiple
complaints and findings that do not necessarily “fit” the
classic diagnosis of BPPV.
Post-Traumatic Endolymphatic
Hydrops
Post-traumatic endolymphatic hydrops is an entity that
presents with aural fullness, tinnitus, fluctuating sensori-
neural hearing, and episodes of vertigo. This presentation
is very similar to that of classic Ménière’s disease. Hydrops
can arise even without evidence of temporal bone fracture.
Intralabyrinthine hemorrhage can theoretically cause
scarring of the vestibular aqueduct and delayed symptoms
that may arise months to years following the traumatic
event.84–86 Treatment options are similar to those for
Ménière’s disease, as described elsewhere in this text. The
practitioner should also be aware of the possible risk of CNS
etiology due to the trauma as well as possible bilaterality.
These factors may reduce the efficacy of treatment when
compared with success rates with conventional treatment of
Ménière’s disease. Also, since symptoms may be similar and
traumatic in etiology, traumatic perilymphatic fistula may
be possible and should be considered in a patient with
temporal bone fracture, pressure sensitivity, or penetrating
mechanism.
LUETIC VESTIBULOPATHIES
Otologic syphilis can arise from either a congenital or an
acquired infection, and symptoms may occur either early or
late in the infection. It is a multisystem, multistage disease
caused by infection with the spirochete, Treponema pallidum.
Infection can be present with long periods of latency and late
progression. Otosyphilis should be considered in any patient
with unexplained vestibular symptoms. Vestibular symptoms
may be the sole presentation of the infection.87 Awareness of
this disease is especially relevant because of the increased
250 NEUROTOLOGIC DIAGNOSIS
incidence of syphilitic infections in recent years. This rise
has been directly correlated to the spread of the human
immunodeficiency virus (HIV).88
Congenital syphilis has two stages. The early stage results
from transplacental infection from the mother. Thirty-eight
to 64% of patients may be asymptomatic. Those affected
may have profound hearing loss and multisystem disease.89
Late-stage congenital syphilis is disease presenting after
2 years of age. Children usually present with hearing loss
with vestibular symptoms, whereas adults may present
with episodes of vertigo, tinnitus, and fluctuating hearing
loss. Most late-stage, congenital syphilitic patients have
other physical findings including interstitial keratitis,
Hutchinson’s teeth, saber shins, frontal bossing, and
Clutton’s joints (painless hydrarthrosis).90
Acquired syphilis can be divided into various stages.
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
complaints. Vestibular symptoms are usually minimal.
A latent period then follows for a variable length of time,
often years. Forty percent to 70% of patients do not
progress beyond this phase. The remaining patients progress
to tertiary syphilis. These are partitioned approximately
equally between gummatous syphilis (benign late syphilis),
cardiovascular syphilis, and neurosyphilis.91
Vestibular symptoms vary depending on the stage of
active syphilis. In the early stage (less than 2 years after
exposure) of both the congenital and the acquired forms,
vestibular symptoms are rare.90,92 With late stages of syphilis,
the audiovestibular symptoms are variable. Symptoms may
be indistinguishable from those of Ménière’s disease.93 The
patient may also demonstrate vertigo or imbalance when
exposed to certain sounds or tones (Tullio’s phenomenon).
The patients may demonstrate vestibular symptoms with
atmospheric pressure change suggestive of a perilymphatic
fistula. There may be no other “classic” syphilis findings
on exam. Unsteadiness or vertigo as the initial symptom has
been found in 20% to 100% of all congenital and 30% to
50% of all acquired forms of otosyphilis.93,94
Apart from episodes of vertigo, the patient may have
fluctuating sensorineural hearing loss, relatively poor speech
discrimination, tinnitus, and bilateral, somewhat symmetric
decreased caloric responses. The signs easily mimic
Ménière’s disease, perilymphatic fistula, or autoimmune
hearing loss. Other diseases that must be kept in the
differential diagnosis are multiple sclerosis, migraine variant,
Cogan’s syndrome, Vogt-Koyanogi Harada syndrome,
cerebellopontine angle masses, and vasculitic diseases.
Syphilitic infection of the otic capsule starts as a mononu-
clear leukocyte infiltration and progresses to an obliterative
endarteritis and osteitis of all three layers of the otic capsule.
This results in narrowing of the endolymphatic duct and sac
with resultant hydrops. Additionally, a gummatous deposit
can form a perilymph fistula.
Physical exam may produce a positive Hennebert’s sign
or Tullio’s phenomenon. Slit-lamp exam of the cornea may
reveal an interstitial keratitis in 90% of late-stage syphilis.93
ENG findings often show either unilateral or bilateral
reduced vestibular response.94 Along with the appropriate
cochleovestibular symptoms, the diagnosis of otosyphilis
rests on a positive serum fluorescent treponemal antibody
absorption test (FTA-ABS). This test may be false-positive
in autoimmune diseases and hepatic cirrhosis.
Surgical treatment in the form of endolymphatic sac
surgery has been found by most to be unsuccessful in
alleviating symptoms.95 Failure is presumed to result from
obstruction in the vestibular aqueduct proximal to the site
of surgery. Linthicum and Abd El-Rahman have shown
microgammas obstructing the endolymphatic duct.96
Medical treatment includes benzathine penicillin 2.4 million
units intramuscularly once weekly for 3 weeks. Prednisone
may be considered in the face of rapidly declining otologic
function. Doxycycline 200 mg twice daily for 30 days can be
used for penicillin-allergic patients. If neurosyphilis is
confirmed by lumbar puncture, penicillin desensitization
may have to be considered because it remains the only
proved therapy for neurosyphilis.97
OTOTOXICITY
Ototoxicity is “the tendency of certain therapeutic agents
and other chemical substances to cause functional
impairment and cellular degeneration of the tissues of the
inner ear, and especially of the end organs and neurons of
the cochlear and vestibular divisions of the eighth cranial
nerve.”98 This entity has been recognized since the late
1800s when quinine and acetylsalicylic acid produced
dizziness, tinnitus, and hearing loss. Streptomycin in the
1940s had great therapeutic potential as an antibiotic to
treat tuberculosis, but the delayed ototoxic effects
devastated patients and the earlier form was discontinued.
Since then, other drugs have been found to have ototoxic
effects, such as newer antibiotics, antineoplastic agents,
and diuretics. Many reports concerning ototoxic agents
must be reviewed quite carefully since the compromised
patient who develops ototoxicity may have previously
received other potentially ototoxic agents or actually may
be receiving synchronously ototoxic agents or potentiating
medications. Also, one must carefully review the condition
of the patient at the time the medication is used to see if
that patient may be in an oliguric state or receiving
chemotherapy or radiation therapy.
Patients who receive ototoxic drugs are often bedridden
and suffer from multiple symptoms of systemic illness, so
additional symptoms of auditory and vestibular dys-
function may be easily overlooked. Vestibular symptoms
are particularly difficult to identify in this setting. Only
after the patient begins to recover will the devastating
effects of vestibular loss become apparent. By this time, the
damage is irreversible. The examining physician must be
keenly aware of the potential auditory and vestibular
toxicity of any drug that is used if ototoxicity is to be
prevented. Currently, there is no standard of practice as to
the appropriate auditory or vestibular monitoring test to
obtain or guidelines as to the frequency of any monitoring
technique.
Aminoglycosides
All aminoglycoside antibiotics can produce both auditory
and vestibular damage. Streptomycin and gentamicin are
relatively specific for the vestibular system and kanamycin,
 Otolith Dysfunction and Semicircular Canal Dysfunction
tobramycin, and amikacin produce more damage to the
auditory system.99,100 Aminoglycosides have bactericidal
activity that results from inhibition of protein synthesis
at the level of the ribosome. This class of antibiotic is
used to treat serious aerobic gram-negative infections. The
aminoglycosides do not undergo any significant degradation
in the body and are excreted unaltered into the urinary tract
by glomerular filtration. The concentration of aminogly-
coside in the perilymph rises slowly, reaching its peak
2 to 5 hours after injection, at a level 3% to 5% of peak
serum level. The half-life of aminoglycoside in perilymph
has been reported to be from 3 to 5 hours, which permits
significant accumulation of aminoglycosides.101,102 Patients
with renal impairment cannot excrete the drug, so the
aminoglycoside accumulates in the blood and inner ear
tissues. Aminoglycosides have been shown to cause ototox-
icity by several means. Outer hair cells, spiral ganglion
cells, dark cells, and stria vascularis structures can all be
damaged by aminoglycosides.103 Toxicity is seen at the
level of the cochlear hair cell calcium channels, transduction
channels at the stereocilia tips, and N-type and P/Q-type
channels in the neurons in addition to uptake mechanisms
and cellular actions.104
The earliest effect of the vestibulotoxic compounds such
as streptomycin and gentamicin is a selective destruction
of type I hair cells in the crista. Later, type II hair cells are
destroyed, but the supporting cells remain unaffected.
With the cochleotoxic agents such as kanamycin and
amikacin, selective destruction of the outer hair cells in the
basal turn of the cochlea occurs first, followed by total hair
cell loss throughout the cochlea as the dose and duration
of treatment are increased. Even after treatment is
terminated, some of the aminoglycosides (dihydrostrepto-
mycin, gentamicin, and tobramycin, in particular) have
been shown to produce continued damage to the sensory
structures of the organ of Corti.
Experimentally, certain growth factors such as neu-
rotrophin-3 can at least partially protect against aminoglyco-
side-induced ototoxicity. However, systemic application has
been limited due to the significant amount of cell cycle medi-
ation of nonotic cell lines.105 Brain-derived neurotrophic fac-
tor (BDNF) has also shown protective properties for the hair
cells against aminoglycosides in experimental models.106
Also, studies of the NMDA excitotoxic pathway have
demonstrated that antagonizing the NMDA system allows
cytoprotection of vestibular hair cells and only partial loss of
apical sensory hair cells in experimental studies.107 Recently,
Sha and Schacht108 found that salicylates protect against
gentamycin-induced ototoxicity, putatively by serving as both
antioxidants and iron-chelating agents. Salicylates decreased
threshold shifts and basal outer hair cell loss in the guinea pig
model. Genetics of aminoglycoside ototoxicity appear to
have a random or multifactorial inheritance pattern related
to the ribosomal RNA gene of mitochondrial DNA.109
Loop Diuretics
The two main ototoxic loop diuretics, furosemide and
ethacrynic acid, act by inhibiting active resorption of
chloride in the loop of Henle of the proximal renal tubule,
thereby preventing the renal resorption of sodium that
passively follows chloride.110 The mechanism of their
251
ototoxic effect is not completely known, although these
drugs clearly influence ion pumps in the kidney and in the
cochlear duct. The ototoxic effects of the loop diuretics
appear to be confined mostly to the cochlea, although
histopathologic changes in the vestibular end organ have
been documented.111 About 6% of patients who receive
furosemide develop a temporary hearing loss that is nearly
always reversible. Several characteristic features of loop
diuretic ototoxicity are readily apparent because most
patients affected have concomitant renal disease and most
receive furosemide intravenously. Other case reports involve
the co-administration of an ototoxic drug such as an amino-
glycoside, or in fact the drug was given to an oliguric patient.
Histologically, the major changes that have been
observed in animal temporal bones involved the stria
vascularis: intercellular edema, capillary narrowing, and
degeneration of the intermediate cell layer. Degeneration
of the outer hair cells, primarily of the basal turn, have also
been observed, but are less common. Changes in the
vestibular labyrinth have also been observed, with degener-
ation of both type I and type II hair cells in the ampullae
and maculae.112
Clinical experience with ethacrynic acid and furosemide
indicates that they may produce transient or permanent
hearing loss following either oral or intravenous admini-
stration. There are certainly risk factors in their administra-
tion that have been identified. One must consider the rate of
intravenous infusion, the dosage, and other potentiating
medication that the patient may be receiving. The renal
status is particularly important for the oliguric patient who
may receive a relatively high dose intravascularly since it is
not cleared effectively.
Salicylates
Patients receiving high-dose salicylate therapy frequently
complain of hearing loss, tinnitus, loss of balance, and
occasionally of vertigo. Sensorineural hearing loss involves
all frequencies and is associated with recruitment, which
suggests a cochlear rather than a nervous system etiology.
The tinnitus is high pitched and frequently precedes the
onset of the hearing loss. Both hearing loss and tinnitus
invariably occur when the plasma salicylate level approaches
0.35 mg/ml. Caloric testing often reveals bilateral depressed
responses consistent with bilateral vestibular end organ
damage.113 All symptoms and signs are rapidly reversible
after the cessation of salicylate ingestion (usually within
24 hours). As with the aminoglycosides, salicylates are highly
concentrated in the perilymph.
Cisplatin
Cisplatin is commonly associated with both auditory and
vestibular toxicity. It is an extremely effective drug in the
treatment of patients with nonseminomatous germ cell
tumors, ovarian carcinoma, and squamous cell carcinomas
of the head and neck, cervix, and genitourinary tract.
Cisplatin is administered intravenously. It appears to
undergo basically renal excretion without metabolism in the
body. The drug is frequently administered with the patient
well hydrated, with mannitol being administered to protect
against nephrotoxicity.
252 NEUROTOLOGIC DIAGNOSIS
Cisplatin effects its activity in at least two mechanisms.
The first involves the blockade of ion transduction channels
within the membranes of outer hair cells, producing hair cell
hyperpolarization and auditory threshold elevations.114 The
other mechanism of cisplatin ototoxicity involves the forma-
tion of reactive oxygen species in the cochlea. Free radicals
deplete intracellular glutathione levels and alter antioxidant
enzyme activity. Lipid peroxidation increases, resulting in
hair cell, supporting cell, stria vascularis, and auditory nerve
cell apoptosis.115 Ototoxicity induced by cisplatin has been
directly related to damage within the organ of Corti. The
cochlear hair cells visualized by scanning electron microscopy
showed actual degeneration. The outer hair cells are more
involved than the inner hair cells, as well as the basilar turns
being more involved than the apical turns. Although the
vestibular effects were markedly less than cochlear effects fol-
lowing the chemotherapy, reports have demonstrated exten-
sive degeneration changes of the vestibular receptor organs.
Cristae showed dramatic hair cell loss (type I involvement is
greater than type II). Advanced neuroepithelial degeneration
was also seen in the otolith organs, where there was almost
total loss of otoconia as well as hair cell loss. There has also
been some direct neural effects and decreased myelinization.
A cytoprotective effect has been found with D-methionine
in the rat model. Reduction in outer hair cell loss and
reduction in auditory brainstem response (ABR) threshold
shifts is evident. D-methionine may function as both a
metal binder and an antioxidant.116 Feghali and colleagues
have demonstrated protective effects of L-N-acetylcysteine
on auditory neurons and hair cells from the toxic effects of
cisplatin in vitro.117 In vivo studies have not yet been per-
formed, and applications to prevent vestibulotoxicity have
yet to be assessed.
Clinically, hearing tests are performed with conventional
frequencies from 250 to 8000 Hz and demonstrate that
the first sign of hearing loss usually appears within 3 to
4 days of cisplatin administration. Recent studies using
ultrahigh-frequency measurements indicated that substan-
tial shifts in hearing thresholds occur initially and in some
cases are restricted to frequencies above the conventional
range of 8000 Hz.
Wide variations in individual ototoxic susceptibility
to cisplatin have been reported. Ototoxicity appears to
be directly related to several factors: the method of admin-
istration (bolus versus slow infusion), the dose per
treatment, and total accumulated dose. Patients older than
40 years of age, patients with previous hearing or vestib-
ular conditions, patients with previous renal conditions,
or patients in whom other ototoxic agents are used appear
to be at a higher risk for the development of cisplatin
ototoxicity.
Diagnosis
The clinician must be constantly alert for the early detection
of symptoms or signs of ototoxicity. This is particularly
important in critically ill patients, bed-confined patients, or
any patient who has renal impairment, particularly renal
failure. Clinical bedside evaluation of these individuals
becomes very important because of their limited access to
a soundproof audiologic testing center or vestibular testing
center. Some high-frequency hearing testing equipment is
available that may be useful in certain bedside situations.
A large-scale prospective study simultaneously comparing
the efficacy of conventional audiometry, high-frequency
audiometry, and otoacoustic emissions in detecting
ototoxicity does not yet exist.118
Assessing vestibulotoxic effects of potentially ototoxic
medications is important. Identifying vestibular hypofunction
early in its course prior to development of end-stage
oscillopsia is the goal in ototoxic vestibular testing. Bedside
vestibular testing incorporates head thrust testing and
assessment of dynamic visual acuity. When fixation is inhib-
ited, spontaneous nystagmus and positional nystagmus can
be identified with the use of Frenzel glasses. One must
remember to test these at-risk patients if possible so as to
have a baseline for comparison. In our experience, bedside
caloric evaluation is useful only in the severely vestibular
ablated patient. Ambulatory patients may be assessed with
quantitative caloric and rotation testing as part of the
ENG examination. High-frequency rotational chair testing
is ideal for identifying early vestibular ototoxic effects and
is the testing method of choice in patients suspected of
having a bilateral vestibular loss or those patients who have
minimal remaining vestibular function. Rotational chair
testing stimulates the VOR at higher frequencies (usually
2 Hz or less, some can test up to 10 Hz) than does caloric
testing (0.025 Hz). Cost and availability of this testing
equipment may be an issue in vestibular labs.
Head autorotation testing, which relies on voluntary head
movements by the patient, tests the VOR at 2 to 6 Hz. Head
velocity is recorded using a velocity sensor attached to a
special helmet. Cost is usually low and the unit is portable.
Autorotation testing has not yet gained wide clinical appeal
secondary to issues of test-retest reliability and need for
standardization of tests.119 Also, self-generated predictable
head movement paradigms, such as head autorotation
testing, are less accurate than passive (examiner-initiated)
head thrust testing. The patient controlling his or her own
head movements can preprogram expected eye movement
strategies and thus artificially augment an otherwise defi-
cient VOR and compensate for a planned or anticipated
head movement. Tests using passive high-acceleration head
thrusts delivered unpredictably in time and direction should
be more sensitive for discerning VOR hypofunction than
tests using active and predictable stimuli.120
Management
The key to the management of ototoxicity is prevention.
Kidney function should be measured before beginning a
potentially ototoxic drug. Drug levels are not necessarily
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
been established. When the earliest detection of ototox-
icity is detected, adjustments in the dosage schedule often
can reduce the degree or likelihood of symptom progres-
sion. Sometimes drugs with fewer ototoxic effects may be
substituted.
Management of patients with permanent bilateral vestibu-
lar ablation should be directed at retraining the nervous
system to use other sensory signals to replace the lost vestibu-
lar signals. Younger patients will have a greater propensity
 Otolith Dysfunction and Semicircular Canal Dysfunction
to recover substantial vestibular activity over a period of
years, but elderly patients are rarely able to compensate fully.
In a retrospective study, 51% of patients were found to
improve after vestibular rehabilitation therapy, 34% showed
little or no change, and 15% were lost to follow-up. Patients
without improvement are those with chronic disorders and
medical comorbidities. Lower gains (<0.2) and lowered time
constants (<2 sec) on rotatory chair testing were also seen in
the patients that did not improve.121 Vestibular rehabilitation
progress can be measured through platform posturography
and evaluating improvements in both gain and time constant
during rotatory chair testing.
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 Chapter
Dynamic Posturography
15 Outline
Courtney D. Hall, PhD Introduction
Historical Perspective
Susan J. Herdman, PhD
Methodology
Sensory Organization Test
Limits of Stability Test
Motor Control/Adaptation Tests
Reliability and Validity of
Dynamic Posturography
Application to Patient
Management
Risk for Falls in Older Adults
Vestibular Deficits
Central Balance Deficits
Nonphysiological Component
of Balance
INTRODUCTION
Postural control involves the dynamic interplay between
multiple body systems, including the sensory, central
nervous, and musculoskeletal systems. In order to meet
the demands of a constantly changing environment
(1) body position and movement must be detected via
information gathered from the visual, somatosensory, and
vestibular systems; (2) the central nervous system must
integrate this sensory information and select an appropri-
ate response; and (3) the response must be executed by the
musculoskeletal system with adequate force and within a
task-appropriate time. Failure in any one of these systems
can result in an impaired ability to control posture. By
incorporating dynamic posturography into the balance
assessment, clinicians and researchers can quantify each
aspect of postural control and identify specific system
impairments or functional limitations. Appropriate inter-
ventions to improve balance can then be initiated. Research
demonstrates that interventions targeted to improve spe-
cific deficits are successful in improving postural control
and in reducing risk for falls.1
Historical Perspective
The measurement of postural sway during static stance has
been used for over 100 years in the clinical assessment of
patients with neurologic disorders. The Romberg test was
originally used to distinguish between cerebellar and
somatosensory deficits. Although the Romberg test is now
a standard part of the assessment of patients with balance
256
Treatment
Considerations and
Limitations
Sensory Organization Test
Conditions 1 and 2
Age
Diagnosis
Motor Control/Adaptation
Tests: Automatic Postural
Responses
Center of Gravity Alignment
Subject Characteristics
Initial Center of Gravity
Alignment
Summary
problems, its utility is limited. It is not sensitive to subtle
problems of postural instability, can be normal in the pres-
ence of relatively severe postural deficits, and cannot be
used to distinguish among deficits from different causes.
The use of computerized force plates in clinical assessment
has extended our ability to identify subtleties of postural
sway in patients and better define patients’ problems.
Dynamic posturography can quantify multiple aspects of
postural control including quiet stance, the use of sensory
cues, voluntary weight shifting, and automatic postural
reactions. Recent advances include the assessment of daily
activities including sit-to-stand, turns, and gait. At this
time, there are little data on the use of dynamic posturog-
raphy to assess these latter activities, so discussion of these
assessments will not be included in this chapter. While
dynamic posturography itself does not allow the clinician to
identify the cause of dysfunction, some of the force plat-
form measures yield information that aids in diagnosis. For
the most part, however, dynamic posturography test results
are used to improve patient treatment by identifying func-
tional deficits and establishing and monitoring treatment.
METHODOLOGY
A dynamic posturograph, or a computerized dynamic pos-
turograph, as it is often called, is a device with a force
platform and a computerized system that controls it.2
Critical elements of dynamic posturography include the
ability of the force platform to move abruptly in a transla-
tional or rotational (pitch) direction, as well as the ability

to synchronize movements of the force platform and a
visual surround with an individual’s movements. Finally,
dynamic posturography must include the collection and
analysis of the force data.
The most common method of measuring the vertical
and horizontal forces applied to the force platform uses
transducers located under a separate force plate for each
foot. The sums of the vertical and horizontal forces for
each foot are calculated and combined to locate the center
of (foot) pressure. The patient’s height and force data are
used to estimate the vertical location of the center of grav-
ity (COG) of the body. The force plate system does not
directly measure COG because this requires information
about the position of each body segment in space. Rather
COG is estimated based on theoretical assumptions about
the location of COG relative to height, ankle position, and
center of pressure.3 COG angle of sway is also estimated.
Data from dynamic posturography can be expressed as
peak-to-peak anterior–posterior or medial–lateral sway,
sway path length and time, sway frequency and velocity,
direction of sway, and reaction time.
Sensory Organization Test
The dynamic posturography test that assesses use of sen-
sory information is known as the sensory organization test
(SOT). Postural sway is measured under conditions in
which visual and somatosensory feedback is altered
(Table 15-1). In the most commonly available apparatus
(NeuroCom International, Inc., Clackamas, OR), the
change in sway angle is used to move either a visual surround
or the support surface in synchrony with the individual’s
sway.4 Movement of the visual surround in parallel with
the individual alters visual cues normally used for postural
stability. For example, in quiet stance we normally have a
small amount of anterior and posterior (AP) sway. This
sway results in changes in retinal disparity and image size,
which are visual cues used to determine whether you or
the world is moving.5 If the visual world around you (visual
surround) is moved in parallel with your sway, these visual
feedback cues are inaccurate and cannot be used effectively
to maintain postural stability. Similarly, when the support
surface is moved in parallel with sway there is little change
in ankle angle. This alteration in somatosensory feedback
renders it a less effective signal in the maintenance of
upright posture. The ability of the visual and somatosen-
sory surrounds to be moved in parallel with AP sway is
imperfect, however. At frequencies of sway greater than
0.3 Hz, the mechanism cannot perfectly match sway, so
TABLE 15-1.
Sensory
Organization Test
Conditions Sensory Cues
Condition 1 (C1) Eyes open, visual surround and platform stable
Condition 2 (C2) Eyes closed, visual surround and platform stable
Condition 3 (C3) Eyes open, moving visual surround, platform stable
Condition 4 (C4) Eyes open, visual surround stable, platform moving
Condition 5 (C5) Eyes closed, visual surround stable, platform moving
Condition 6 (C6) Eyes open, visual surround and platform moving
Dynamic Posturography 257
visual and somatosensory cues are altered rather than min-
imized or absent. Other systems (e.g., Balance System,
Biodex Medical Systems, Shirley, NY; Balance Quest,
Micromedical Technologies, Chatham, IL; the modified
clinical test of sensory interaction in balance [M-CTSIB]
test, NeuroCom International, Inc.) alter somatosensory
feedback by having the individual stand on dense foam or
an unstable surface, rather than by sway-referencing the
support surface. In addition, vision is not sway-referenced;
rather, it is removed by closing the eyes. These tests are
modifications of the SOT and comprise four other condi-
tions (eyes open/closed and firm/compliant surface) that
can be assessed.
The SOT is organized into a series of six conditions
of increasing difficulty. The first three conditions are
performed on a firm surface with eyes open, eyes closed,
and finally with vision sway-referenced. The final three
conditions are performed with the support surface sway-
referenced with eyes open, eyes closed, and with vision
sway-referenced (see Table 15-1). Results of the SOT
are calculated based on maximum peak-to-peak AP sway
expressed as an equilibrium score ranging from 0 to 100,
with 0 indicating loss of balance and 100 indicating
perfect stability (Figure 15-1).
Data also include sway path and COG alignment at the
start of each trial. Performance on the different conditions
is used to determine relative use of different sensory cues
and is depicted in bar graph form. Determination of motor
strategy used (ankle or hip) is inferred from the relative
amount of shear force during each trial. The ankle strat-
egy, in which the body primarily rotates about the ankle
joint, is defined by the predominance of vertical forces.
The hip strategy, in which movement occurs about the hip,
is defined by the predominance of horizontal (or shear)
forces.
Limits of Stability Test
The test of voluntary sway is known as the limits of stabil-
ity (LOS) test. LOS measures the maximum COG sway
angle an individual is willing or able to shift the COG.
During the test, the individual views a screen that displays
the COG location and a series of visual targets. The
patient is required to shift his or her weight to move the
COG cursor toward a visual target, without moving the feet.
The support surface does not move during this test. The
individual is instructed to move directly to the target as
quickly as possible. The targets are positioned at eight
places around a circle at either 75% or 100% of limits
Cues Available for Stability
Normal visual, somatosensory, and vestibular cues
No visual cues, normal somatosensory and vestibular cues
Normal somatosensory and vestibular cues, altered visual feedback
Normal visual and vestibular cues, altered somatosensory feedback
Normal vestibular cues, no visual cues, altered somatosensory feedback
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
posturography. However, postural sway does correlate
with the Berg balance scale, which is an accepted test of
functional balance.14
The final aspect of validity is construct validity, which
implies predictive capabilities. Because balance impairment
is a major risk factor for falls, if dynamic posturography is
to have construct validity, it should be able to predict falls.
The results regarding the ability of posturography to identify
older individuals as either fallers or nonfallers have been
mixed.4,15,16 Although a single measure of postural stabil-
ity—sway velocity—did not successfully differentiate older
fallers from nonfallers,4 the use of composite scores (from
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
condition 1 (eyes open, firm surface) of the M-CTSIB—did
differentiate between these groups.15,16
APPLICATION TO PATIENT MANAGEMENT
Risk for Falls in Older Adults
The increased incidence of falling in older adults is well
documented. Nearly one third of adults older than age 65
experience a fall in a given year, and this incidence increases
to 50% by the age of 80.17 Of those who do fall, 10% to
15% experience a fall-related injury. Given the conse-
quences of falls, it is important to identify individuals at risk
before they fall in order to provide appropriate interven-
tion. Several studies have found the use of dynamic postur-
ography valuable in identifying older individuals who are at
risk for falling. In a study comparing performance-based
tests and posturography-based tests, the LOS maximum
excursion composite score was the most accurate at pre-
dicting fallers, whereas the performance-based tests such as
Tinetti’s performance-oriented mobility assessment and
the timed up and go were most accurate at identifying
nonfallers.15 The combination of reaction time and move-
ment velocity composite scores from LOS and sway velocity
during condition 1 (eyes open, firm surface) of the M-
CTSIB was found to have an overall accuracy of 73% in
differentiating fallers from nonfallers.15 In a comparison
among the functional reach, SOT (composite score), and
LOS (anterior score only),16 only the SOT (composite
score) differentiated between older fallers and nonfallers.
Thus, dynamic posturography appears to be useful in
identifying older adults at risk for falls, but only if composite
scores or multiple measures are used.
Vestibular Deficits
Dynamic posturography, by itself, is not an appro-
priate tool for the identification of vestibular deficits.
Posturography and rotary chair test results agree in only
25% of all patients.18,19 The difference in test results may
be ascribed to several factors. First, dynamic posturogra-
phy measures the output of the vestibulospinal and other
balance systems acting in concert. In contrast, caloric and
rotary chair tests assess only one system, the vestibulo-
ocular system.20 Thus, during posturography testing,
vestibular deficits may be masked by other functioning
balance systems. Second, the caloric, rotary chair, and
posturography tests assess the function of different
components of the vestibular apparatus (horizontal canals
versus vertical canals plus otoliths, respectively). This
might result in different test results in some vestibular
disorders, such as vestibular neuronitis, where the deficit
can be limited to only the distribution of the inferior
vestibular nerve. Finally, balance, as measured by dynamic
posturography, may recover fully,21 whereas caloric and
rotary chair test results continue to be abnormal in the
majority of patients. In terms of identifying individuals
with vestibular deficits, dynamic posturography has sensi-
tivity and specificity of approximately 50% compared with
other tests of vestibular function including caloric and
rotary chair testing.22 When used as an adjunct to caloric
and rotary chair tests, posturography testing increases the
likelihood of identifying a vestibular problem.19,23
Although the SOT dynamic posturography should not
be used as a diagnostic tool, the results of studies on
patients with different problems show performance pat-
terns that are useful as guides to expectations for certain
diagnoses (Table 15-3). The overlap in findings across diag-
noses can be clearly seen; therefore, difficulty on tests 5 and
6 cannot be interpreted as indicating a vestibular deficit.
Although it is well documented that patients with severe
bilateral vestibular loss are unable to maintain their balance
under conditions in which both visual and somatosensory
cues are altered,24–27 the results of the SOT are not specific
for vestibular loss. Patients with other balance problems, as
diverse as Huntington’s disease and fear of falling, may lose
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
test performance. Several common patterns in test per-
formance have been identified and ascribed to difficulties
in using different sensory cues (Table 15-4) rather than
diagnoses. It is important to remember that although this
test provides us with reliable data, test performance can be
strongly influenced by subjective factors, including patient
effort, fear, and cognition.

TABLE 15-3.
Diagnosis Posturography Performance Pattern

Peripheral vestibular deficits24,25,30
Severe bilateral vestibular loss24,25,39
Incomplete bilateral vestibular deficit
Acute unilateral vestibular deficit31
Compensated unilateral vestibular deficit40,42
Benign paroxysmal positional vertigo46–48
Central deficits30
Abnormal sensory organization tests; Rare motor test abnormality (<2%)
Loss of balance C5, C6 with increased sway C3, C4; Correlation of sensory organization
tests with severity of deficit (VOR Tc)
Increased number of falls C3, C5, C6 but not necessarily on all trials
Increased sway or loss of balance especially on C5, C6;
Can be normal within few days postonset
Normal sensory organization tests but evidence on decrement in performance several
months out
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
>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-

Although dynamic posturography is less sensitive for
identifying peripheral vestibular dysfunction than ENG, it
can provide significant information for certain central
disorders.22,23 Although the amplitude of peak-to-peak AP
sway seen during conditions 1 and 2 of the SOT does not
discriminate among different balance disorders, direction
of sway and sway frequency sometimes can be useful
diagnostically.29 Normal subjects present with omnidirec-
tional sway of small amplitude (Figure 15-5). Eye closure
(no vision) results in a small increase in sway amplitude. In
contrast, patients with lesions of the vestibulocerebellum
directional sway with a tendency for more lateral sway.29
Patients with atrophy of the anterior lobe of the cerebel-
lum display prominent AP sway with markedly increased
amplitude of sway with eyes closed.29
Research paradigms use Fourier analysis of sway to
identify the dominant sway frequency when a subject is
standing quietly. Although this analysis is not used exten-
sively in clinical studies, it is available and promises to
contribute significantly to the ability of posturography to
aid in diagnosis. Studies reveal a dominant frequency of
sway (2.5 to 3.5 Hz) in subjects with atrophy of the ante-
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
the earlier stages of degeneration and may disappear in
patients with chronic degeneration of the anterior lobe.
Assessment of automatic postural responses is also useful
in identifying patients with central lesions affecting stabil-
ity.30 In patients with nonvestibular central balance prob-
lem, either the latency or symmetry of the reactive torque
is abnormal in 80% of patients. In contrast, the automatic
postural responses are rarely abnormal in patients with
peripheral vestibular deficits.24,30,31
Delays in the onset of the short-, middle- and long-
latency responses give site of lesion information (see
Table 15-2).8,32,33 The short-latency response is affected by
peripheral neuropathy. The middle-latency response is
delayed in patients with spinal cord disease such as multi-
ple sclerosis or syringomyelia. The long-latency response
can be delayed with lesions in the peripheral nerve or
anywhere in the long tracts of the central nervous system.
The short- and middle-latency responses appear to be
independent of cerebellar influences, but the cerebellum
may modulate the long-latency response.9
Nonphysiological Component of Balance
Poor performance on the SOT does not necessarily indi-
cate a specific physiological problem. One of the difficul-
ties in medicine is identifying those patients with
psychological or functional components to their postural
instability. These functional components can include fear
of falling as well as anxiety, somatoform disorders, and true
malingering. For example, older individuals who report
fear of falling exhibit increased sway velocity during the
M-CTSIB compared with those who were not fearful.4
Nonphysiologic balance problems (e.g., occurs in conver-
sion disorder or malingering) can be characterized by
several components of the patient’s performance on the
SOT and the motor tests (Table 15-5).34–37 Cevette and
colleagues35 found that patients with symptoms unrelated
to organic findings had erratic performance within each
condition (i.e., greater intertrial variability) and relatively
better performance on the more difficult conditions than on
the easier conditions of the SOT (Fig. 15-6). Additionally,
they described a discrepancy between the patients’ abnor-
mal performances on dynamic posturography and their
ability to walk. Goebel and colleagues34 identified two addi-
tional criteria from the MCTs—exaggerated responses to
small perturbations and inconsistent responses to small and
large perturbations—that had a high specificity for identify-
ing persons who were deliberately feigning instability. By
combining criteria from the SOT and MCT, the false-
positive rate (i.e., identifying a problem where there is no
organic cause) was reduced to zero.34 The criteria used to
identify nonphysiological sway was validated in a recent
study, which found that only 8% of patients without sec-
ondary gain exhibited exaggerated patterns, but 76% of
those with secondary gain had exaggerated patterns.36
One concern about the use of computerized posturogra-
phy in identifying malingerers is that individuals may learn
to successfully manipulate their results. That is, people
deliberately malingering may learn how to produce results
that mimic real disorders rather than producing results
that are clearly identifiable as nonphysiological patterns.
Fortunately, Morgan and colleagues38 showed that an indi-
vidual’s ability manipulate the results does not improve
when they have additional information regarding dynamic
posturography.
Treatment
Dynamic posturography is useful in establishing treatment
and in monitoring patient recovery, especially as part of the
rehabilitation process. For example, patients may use differ-
ent sensory cues to maintain postural stability. Figure 15-7
illustrates the results of the sensory organization test in
three patients with bilateral vestibular loss secondary to
aminoglycoside ototoxicity. None of the patients can
maintain balance when both visual and somatosensory
cues are altered (conditions 5 and 6), which is consistent
with the findings of numerous studies on patients with
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
as long as either visual cues (conditions 1 and 4) or
somatosensory feedback (conditions 2 and 3) is present. In
contrast, other patients rely on somatosensory cues for
stability and therefore lose their balance when somatosen-
sory feedback is altered (Fig. 15-7B). Similarly, patients
may rely on visual cues (Fig. 15-7C). Identifying reliance
on a particular sensory cue can then be used to establish
specific exercises for the patient.
Studies have reported the rapid spontaneous recovery of
postural stability in patients with acute and chronic unilat-
eral vestibular deficits.31,40,41 Cass and colleagues42 followed
patients for up to 20 months following vestibular nerve
section. They found that all patients had normal sensory
organization tests by one month after surgery. Surprisingly,
21% of the patients showed a decrease in stability 3 to
20 months after surgery, suggesting that reevaluation and
possible reinstitution of vestibular exercises would be
appropriate in these patients.
Computerized dynamic posturography results also have
been used in numerous studies to monitor the effective-
ness of vestibular rehabilitation of patients with vestibular
disorders.31,43–45 Improved postural stability has been doc-
umented in patients with acute and chronic vestibular
deficits compared with control groups21,31,44 and in patients
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
C Sensory test condition
Figure 15-7. Performance of three patients with bilateral vestibular loss
secondary to aminoglycoside ototoxicity on the sensory organization test
demonstrates the variability in test performance that can occur even within
the same diagnostic groups. A, One subject loses his balance only when
both visual and somatosensory cues are altered (conditions 5 and 6). The
other two subjects have additional difficulty when B, somatosensory feed-
back is altered (condition 4) or C, when visual feedback is altered (conditions
2 and 3). Equilibrium scores (higher number indicates more stable) for three
trials of each condition are shown. Loss of balance is indicated by “stop.”
posturography has been used to document that a super-
vised program of customized vestibular exercises results in
a greater improvement in stability than unsupervised
generic exercises.45 In fact, subjects with peripheral
vestibular dysfunction who underwent individualized
vestibular rehabilitation improved performance on the
SOT to within normal limits, while subjects in the control
group did not change their SOT scores.21 In individuals
with bilateral vestibular loss (BVL), improvements have
been noted in functional limitations, as well as measures of
disability and balance confidence although no significant
changes were reported for the SOT.49 These findings indi-
cate that although patients with BVL improve following
therapy, they continue to demonstrate significant physical
impairments.49 There is also some evidence that dynamic
period after onset and continue to have a small but signif-
icant increase in AP sway even in the chronic stage.25
Age
Equilibrium scores results obtained during testing must be
interpreted based on the age of the subject (Figure 15-8).
Across all ages, AP sway increases (lower equilibrium
scores) for conditions in which somatosensory feedback is
altered (conditions 4, 5 and 6).8,53,54 Additionally, perform-
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
difficult test conditions. The effect of altering both visual
and somatosensory cues is greatest in subjects older than
70 years.8,53 Presumably, when both visual and somatosen-
sory cues are altered, the subject must rely on vestibular
cues in order to maintain balance (see Table 15-1).
Increased difficulty maintaining balance on tests 5 and 6 in
older subjects, therefore, may reflect age-related changes
in the vestibular system or the increased difficulty of those
tests.55,56 Wolfson and colleagues8 suggest that the poorer
performance of older persons on tests in which visual and
somatosensory feedback is altered is due to either biome-
chanical factors or to changes in central processing of
sensory information. Regardless, test results of patients
who are older must be made taking the normal age-related
test scores into consideration.

EQUILIBRIUM SCORES BY AGE
100
80
Equilibrium score
60
40
20
0 conditions 5 and 6 (C5 and C6) in which both visual and
C1 C2 C3 C4
Sensory test conditions
20–29 30–59 60–69
Diagnosis
Presently, the results of the sensory organization tests are
not considered to be useful in the diagnosis of specific dis-
orders. This is because the results are variable even within
specific diagnostic groups. Furthermore, considerable
overlap occurs in results among different diagnostic
groups and even between normal and abnormal subjects in
the older population.8 The sensitivity of the sensory
organization test in identifying vestibular disorders has
been reported as between 45% and 95%, depending on
the clinical criteria used to identify vestibular dysfunc-
tion.22,30,57 Goebel and Paige19 concluded that posturogra-
phy testing did not distinguish between patients who did
or did not experience vertigo.
Attempts have been made to improve the sensitivity of
dynamic posturography as a diagnostic tool by assessing
postural stability with the subject’s head in different posi-
tions. The rationale is that head position will affect
vestibular input if a unilateral vestibular deficit is present.
Neither head extension nor lateral tilt has improved
the sensitivity of dynamic posturography.58,59 Other work
has examined the effect of horizontal head movement
during the SOT. The results suggest that the addition of
the head movements increases the difficulty of condition 5
of the SOT and therefore the sensitivity of posturography
testing in identifying compensated peripheral vestibular
lesions (Shepard, personal communication). It is also
possible that the sensitivity of dynamic posturography may
be increased if a measure other than peak-to-peak AP sway
were used; for example, measures such as sway velocity
may be more sensitive.60
Motor Control/Adaptation Tests:
Automatic Postural Responses
Abnormalities in force development and the latency to
onset of force development of the automatic responses can
be due to pain, leg length differences, limitation in ankle
range of motion, and weakness as well as neurologic prob-
lems. Subject age has only a minimal effect on responses to
translational perturbations.6
Dynamic Posturography 267
Figure 15-8. Anterior/posterior sway, as reflected by the
equilibrium score, is shown for each of the different
conditions of the sensory organization test for subjects of
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
conditions become more difficult. Note that there is little
variation in stability in people age 20 to 69 years across
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
somatosensory feedback are altered concurrently.
C5 C6
70–85
Center of Gravity Alignment
The ability or inability to maintain balance may also be
affected by COG alignment prior to the toes-up or toes-
down perturbation. Shifts in static alignment posteriorly
would be likely to result in loss of balance with toes-up
perturbations, whereas shifts anteriorly would result in
loss of balance with toes-down perturbations. Although
loss of balance when the support surface is rotated toes-up
may indicate retropulsion, it should be remembered that
patients afraid of falling backward may shift their center of
mass forward and therefore may lose their balance during
toes-down perturbations.
Subject Characteristics
Age, gender, and height all affect the long-latency
responses measured using surface electrode EMG.
Increasing age of the subject results in increased latency to
onset and duration of the short-latency response and in
increased integrated amplitude and duration of the long-
latency responses.61 Although Lawson and colleagues61
found subject height was correlated significantly with time
to onset, it accounted for a relatively small amount of the
variance of the latencies (3% to 21%).
Initial Center of Gravity Alignment
It is clinically important to recognize that these latencies can
be altered if the subject leans either forward or backward.
Leaning forward, for example, increases the length of the
gastrocnemius/soleus muscle group prior to the stretch
produced by the support surface movement. The added
stretch imposed by rotating the support surface toes-up
elicits a short-latency response with a shorter time to onset.
Similarly, the latencies do not seem to be affected by head
position or vision.9 Other than by leaning forward or back-
ward, it is not possible to voluntarily modify the time to
onset of the automatic postural responses.62 Measurement
of reactive torque can be used as a screening test. When it
yields abnormal results, a combination of measurement of
reactive force and EMG activity can be used to determine
268 NEUROTOLOGIC DIAGNOSIS
whether abnormalities in the automatic postural responses
are due to biomechanical or neurologic factors.
SUMMARY
The use of force platforms has provided more detailed
objective data in the assessment of postural control than that
available through clinical examination alone. Current tech-
nology enables us to measure a patient’s ability to use differ-
ent sensory cues for balance, to voluntarily weight shift, and
to react to external perturbations. Some of these tests can
assist in diagnosis, such as measures of sway frequency
during quiet stance and EMG recordings of lower extrem-
ity muscle activity during automatic postural responses. Of
particular interest is the ability of dynamic posturography to
identify individuals who are at risk for falling; an ability
that can lead to the initiation of appropriate intervention to
prevent falls. In addition, posturography is effective in iden-
tifying performance abnormalities that suggest nonphysio-
logic balance problems. Dynamic posturography is a useful
tool for establishing and monitoring treatment. Newly
developed testing protocols should enable us to quantify
postural stability during functional activities such as moving
from sitting to stand or during ambulation.
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Chi Quan and computerized balance training on postural stability in
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Cooperative Studies on Intervention Techniques. Phys Ther
77:371–381, 1997.
53. Camicioli R, Panzer VP, Kaye J: Balance in the healthy elderly:
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54. Cohen H, et al: Changes in sensory organization test scores with
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55. Baloh RW, Jacobson KM, Socotch TM: The effect of aging on
visuo-vestibulo-ocular responses. Exp Brain Res 95:509–516, 1993.
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57. Hamid MA, Hughes GB, Kinney SE: Specificity and sensitivity
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Exp Brain Res 56:126–134, 1984.
 Chapter
Vestibular Evoked Myogenic
Potentials
16 Outline
Steven D. Rauch, MD Introduction
Discovery of Vestibular
Evoked Myogenic Potentials
Basic Physiology of
Vestibular Evoked Myogenic
Potentials
INTRODUCTION
Brief (0.1 msec) loud (>90 dB sound pressure level, SPL)
monaural clicks or tone bursts produce a large (60 to
300 μV ) short-latency (8 msec) inhibitory potential in the
tonically contracted ipsilateral sternocleidomastoid
muscle, known as vestibular evoked myogenic potentials
(VEMP). Considerable robust evidence supports the
contention that VEMP is a vestibulocolic reflex whose
afferent limb arises from acoustically responsive neurons
in the saccule, with signals conducted centrally via the
inferior vestibular nerve. Thus the VEMP can be used as a
test of otolith organ and peripheral vestibular function.
Since it depends on both sound transmission through the
middle ear and structural integrity of the saccule, it also
has merit in diagnosis of superior semicircular canal dehis-
cence syndrome and in Ménière’s syndrome (cochleosac-
cular hydrops).
DISCOVERY OF VESTIBULAR EVOKED
MYOGENIC POTENTIALS
Thirty-five years ago, when the science of averaged evoked
response measurement was in its infancy, Bickford, Cody,
and others first characterized the range of evoked
responses in human subjects.1–5 The postauricular response
was determined to be an acoustically evoked contraction,
or “sonomotor” response, of the postauricular muscle.
The integrity of the cochlea and cranial nerve VII were
required for this response to be present. In contrast, the
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
neurectomy. Though initially thought to arise from cortex,
the averaged inion response was eventually demonstrated
to originate from extracranial musculature.2 Furthermore,
the inion response was preserved in patients with semicir-
cular canal ablation due to streptomycin toxicity and in
270
Measuring Vestibular Evoked
Myogenic Potentials
Clinical Applications of
Vestibular Evoked Myogenic
Potentials
Future Directions
patients with benign paroxysmal positional vertigo, but
absent in patients with advanced Ménière’s disease and
Ménière’s patients having undergone a Cody tack proce-
dure.6 Based on these observations, Townsend and Cody
proposed that the averaged inion response to acoustic
stimulation was mediated by the saccule.6
BASIC PHYSIOLOGY OF VESTIBULAR
EVOKED MYOGENIC POTENTIALS
Speculation about the origin of VEMP has been supported
by animal research. McCue and Guinan identified acousti-
cally responsive fibers in the cat vestibular nerve.7,8 Single-
unit recordings from the inferior vestibular nerve in these
animals revealed fibers with irregular background activity
that phase-lock to low-frequency (800 Hz) tone bursts of
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
1.0 msec. Fibers fell into two classes: with the shortest
latency either to compression (“push” fibers) or rarefaction
(“pull” fibers) clicks. The observation of preferred
response phases approximately 180 degrees apart was
interpreted to mean that fibers innervate hair cells having
opposite morphologic polarity, an arrangement found in
the saccule. Biocytin fiber labeling and tracing confirmed
bipolar cell bodies in the inferior vestibular ganglion with
peripheral processes innervating saccular epithelium and
central processes going to vestibular nuclei and a region
ventromedial to the cochlear nucleus.
MEASURING VESTIBULAR EVOKED
MYOGENIC POTENTIALS
Short broadband clicks or tone bursts of 0.1-msec duration
delivered via headphones can be used as stimuli for VEMP
testing. The response is recorded electromyographically

(EMG) using surface electrodes over the ipsilateral stern-
ocleidomastoid muscle. The positive electrode is posi-
tioned over the upper third of the muscle, and the negative
electrode is positioned over the muscle tendon just above
the clavicle. Patients are seated upright and instructed to
turn their head forcefully away from the test ear (i.e., try to
push their chin over the contralateral shoulder). This tenses
the ipsilateral sternocleidomastoid muscle, a necessity for
measuring the inhibitory VEMP response. Ongoing EMG
activity is visually monitored on an oscilloscope to ensure
uniform muscle tension during testing, and patients are
instructed to relax their neck muscles between runs. The
EMG recording is bandpass filtered and averaged as in
evoked response audiometry. The resultant response con-
sists of a biphasic wave with an initial positive peak (P1) at
12–13 msec latency and a subsequent negative peak (N1) at
22–23 msec latency (Fig. 16-1).
A number of investigators have sought to characterize
the normal VEMP response.9–16 These studies have shown
that the VEMP is more consistently detectable and has a
lower threshold for click than tone burst stimuli. The
click-evoked VEMP has a normal threshold of 85 to 90 dB
SPL. With tone bursts, there is a “tuning curve” showing
greatest sensitivity (i.e., lowest threshold) for frequencies
of 500 to 1000 Hz. Systematic variation of stimulus rate
shows decreasing VEMP P1 latency with increasing rate.
Above the 5-Hz stimulus rate, VEMP peak-to-peak ampli-
tude decreases with increasing rate. Above the threshold,
VEMP amplitude increases with stimulus level. Amplitude
of the VEMP response is proportional to the mean level of
tonic muscle activation of the sternocleidomastoid during
recording.
40
P1
20
Amplitude (μV p-p)
0 been confirmed in several studies.26–32 De Waele and
:20
N1
:40
0 10 20 30
Latency (ms)
Figure 16-1. Normal VEMP response. A typical VEMP response, evoked
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
peak-to-peak amplitude, P1 latency, and N1 latency.
Vestibular Evoked Myogenic Potentials 271
CLINICAL APPLICATIONS OF VESTIBULAR
EVOKED MYOGENIC POTENTIALS
Clinical utility of VEMP testing has been demonstrated in
three areas: assessment of vestibular nerve function, diag-
nosis of superior semicircular canal dehiscence syndrome,
and evaluation of Ménière’s syndrome. Colebatch and
Halmagyi first noted that the VEMP response was extin-
guished following ipsilateral vestibular neurectomy and
speculated that the response may provide useful informa-
tion in assessment of patients with hearing and balance
disorders.17 Murofushi and colleagues studied VEMP and
its relation to vestibular neuritis and benign paroxysmal
positional vertigo (BPPV).18 They found the VEMP absent
in 16 of 47 vestibular neuritis patients, none of whom went
on to develop BPPV. In 10 of 47 patients with vestibular
neuritis, BPPV did develop and all 10 had intact VEMP.
These findings indicate that absent VEMP in acute vesti-
bular neuritis is indicative of inferior vestibular nerve
involvement. Such patients lose innervation of the saccule
and posterior semicircular canal and therefore lose the
VEMP reflex and cannot develop BPPV. Acute vestibular
neuritis patients with intact VEMP have involvement of
their superior vestibular nerve. A significant proportion of
them go on to degeneration of the utricle, with subsequent
shedding of otoconia and symptomatic BPPV. In another
study, Murofushi and colleagues showed that the VEMP is
abnormal in 80% of acoustic neuroma patients, even in the
presence of normal calorics.19 As might be predicted, the
test is particularly sensitive for inferior vestibular nerve
involvement.19–21
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,
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
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
altered motion mechanics of the distended saccule might
create an altered VEMP in Ménière’s patients. This has
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
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-
nificantly enhances its sensitivity or specificity remains to
be seen.
FUTURE DIRECTIONS
Notwithstanding existing demonstrations that the click-
evoked and tone burst-evoked VEMP are altered in
272 NEUROTOLOGIC DIAGNOSIS
peripheral vestibulopathies, such as vestibular neuritis,
superior canal dehiscence syndrome, and Ménière’s
syndrome, much work remains to be done to understand,
characterize, and use the VEMP clinically. Specifically, the
effects of stimulus rate and intensity on click-evoked
response, the frequency-specific thresholds (“tuning
curve”) of the tone burst-evoked response, and the modu-
lating effect of gravitational input to the saccule during
testing have not been adequately defined for different
disorders. The specific nature of these alterations will have
implications for biophysical models of the saccule.
Correlation of VEMP results with other vestibular func-
tion tests, and especially with other otolith organ tests,
such as subjective visual vertical (SVV) or off-vertical axis
rotation (OVAR), has not been systematically studied.
Results of such investigations are likely to improve our
understanding of the physiology of the otolithic vestibular
organs as well as provide the refinements of the VEMP
test protocol that improve its diagnostic sensitivity and
specificity.
REFERENCES
1. Bickford RG, Jacobson JL, Cody DTR: Opportunities and pitfalls
in the processing of neuroelectric data: Observations on averaged
potentials recorded from the scalp in man. In Fifth IBM Medical
Symposium, 1963.
2. Bickford RG, Jacobson JL, Cody DTR: Nature of average evoked
potentials to sound and other stimuli in man. Ann NY Acad Sci
112:204, 1964.
3. Cody DTR, Jacobson JL, Walker JC, Bickford RG: Average evoked
myogenic and cortical potentials to sound in man. Ann Otol Rhinol
Laryngol 73:763, 1964.
4. Jacobson JL, Cody DTR, Lambert EH, Bickford RG: Physiologic
properties of the post-auricular response (sonomotor) in man
[abstr]. Physiology 7:167, 1964.
5. Kiang NYS: An auditory physiologist’s view of Ménière’s syndrome.
In Second International Symposium on Ménière’s Disease.
Cambridge, MA, Kugler & Ghedini Publications, 1988.
6. Townsend GL, Cody DTR: The averaged inion response evoked by
acoustic stimulation: Its relation to the saccule. Ann Otol Rhinol
Laryngol 80:121, 1971.
7. McCue MP, Guinan JJ Jr: Influence of efferent stimulation on
acoustically responsive vestibular afferents in the cat. J Neurosci
14:6071, 1994.
8. McCue MP, Guinan JJ Jr: Acoustically responsive fibers in the
vestibular nerve of the cat. J Neurosci 14:6058, 1994.
9. Colebatch JG, Halmagyi GM, Skuse NF: Myogenic potentials
generated by a click-evoked vestibulocollic reflex. J Neurol
Neurosurg Psychiatry 57:190, 1994.
10. Bath AP, Harris N, Yardley MP: The vestibulo-collic reflex. Clin
Otolaryngol 23:462, 1998.
11. Wu CH, Young YH, Murofushi T: Tone burst-evoked myogenic
potentials in human neck flexor and extensor. Acta Otolaryngol
119:741, 1999.
12. Wu CH, Murofushi T: The effect of click repetition rate on vestibu-
lar evoked myogenic potential. Acta Otolaryngol 119:29, 1999.
13. Welgampola MS, Colebatch JG: Characteristics of tone burst-
evoked myogenic potentials in the sternocleidomastoid muscles.
Otol Neurotol 22:796, 2001.
14. Ochi K, Ohashi T, Nishino H: Variance of vestibular-evoked
myogenic potentials. Laryngoscope 111:522, 2001.
15. Cheng PW, Murofushi T: The effects of plateau time on vestibular-
evoked myogenic potentials triggered by tone bursts. Acta
Otolaryngol 121:935, 2001.
16. Cheng PW, Murofushi T: The effect of rise/fall time on vestibular-
evoked myogenic potential triggered by short tone bursts. Acta
Otolaryngol 121:696, 2001.
17. Colebatch JG, Halmagyi GM: Vestibular evoked potentials in human
neck muscles before and after unilateral vestibular deafferentation.
Neurology 42:1635, 1992.
18. Murofushi T, Halmagyi GM, Yavor RA, Colebatch JG: Absent
vestibular evoked myogenic potentials in vestibular neurolabyrinthi-
tis. An indicator of inferior vestibular nerve involvement? Arch
Otolaryngol Head Neck Surg 122:845, 1996.
19. Murofushi T, Matsuzaki M, Mizuno M: Vestibular evoked myogenic
potentials in patients with acoustic neuromas. Arch Otolaryngol
Head Neck Surg 124:509, 1998.
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.
21. Chen CW, Young YH, Wu CH: Vestibular neuritis: Three-
dimensional videonystagmography and vestibular evoked myogenic
potential results. Acta Otolaryngol 120:845, 2000.
22. Streubel SO, Cremer PD, Carey JP, et al: Vestibular-evoked
myogenic potentials in the diagnosis of superior canal dehiscence
syndrome. Acta Otolaryngol Suppl 545:41, 2001.
23. Brantberg K, Bergenius J, Tribukait A: Vestibular-evoked myogenic
potentials in patients with dehiscence of the superior semicircular
canal. Acta Otolaryngol 119:633, 1999.
24. Ostrowski VB, Byskosh A, Hain TC: Tullio phenomenon with
dehiscence of the superior semicircular canal. Otol Neurotol 22:61,
2001.
25. Rauch SD, Merchant SN, Thedinger BA: Ménière’s syndrome and
endolymphatic hydrops. Double-blind temporal bone study. Ann
Otol Rhinol Laryngol 98:873, 1989.
26. de Waele C, Huy PT, Diard JP, et al: Saccular dysfunction in
Ménière’s disease. Am J Otol 20:223, 1999.
27. Heide G, Freitag S, Wollenberg I, et al: Click evoked myogenic
potentials in the differential diagnosis of acute vertigo. J Neurol
Neurosurg Psychiatry 66:787, 1999.
28. Akin FW, Murnane OD: Vestibular evoked myogenic potentials:
Preliminary report. J Am Acad Audiol 12:445, 2001.
29. Colebatch JG: Vestibular evoked potentials. Curr Opin Neurol
14:21, 2001.
30. Murofushi T, Shimizu K, Takegoshi H, Cheng PW: Diagnostic
value of prolonged latencies in the vestibular evoked myogenic
Potential. Arch Otolaryngol Head Neck Surg 127:1069, 2001.
31. Murofushi T, Matsuzaki M, Takegoshi H: Glycerol affects vestibu-
lar evoked myogenic potentials in Ménière’s disease. Auris Nasus
Larynx 28:205, 2001.
32. Shojaku H, Takemori S, Kobayashi K, Watanabe Y: Clinical useful-
ness of glycerol vestibular-evoked myogenic potentials: Preliminary
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33. Seo T, Yoshida K, Shibano A, Sakagami M: A possible case of
saccular endolymphatic hydrops. ORL J Otorhinolaryngol Relat
Spec 61:215, 1999.

Central Auditory Processing Disorders
Assessment and Remediation
Outline
Introduction
Definition of Auditory
Processing
Prevalence of Auditory
Processing Disorders
Historical Perspective
Behavioral Tests of Auditory
Processing
Manner of Presentation
Monaural Measures
Binaural Measures
Dichotic Measures
Anatomical Level Tested
Electrophysiologic Tests
Auditory Brainstem Response
Auditory Middle-Latency
Response
The P300
Mismatch Negativity
Other Late Auditory Evoked
Responses
Factors Affecting Auditory
Processing Test Results
Subject’s Age
Peripheral Hearing Loss
INTRODUCTION
For many years clinicians have recognized, according to
pure tone thresholds and other standard audiometric
tests, a population of patients whose ability to hear in
everyday situations is poorer than expected. These patients
may have hearing that is within normal limits to pure tones
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
comprehension of auditory information. In many cases, a
disorder of auditory processing has been identified. This
chapter was written for the neurotologist with two pur-
poses in mind: to provide an understanding of the basics of
auditory processing testing and remediation and to discuss
the latest developments and issues in this ever-growing
field.
A note about terminology is in order. Until recently,
auditory processing disorders were referred to as central
Chapter
17
Intelligence, Cognition, and Wileen Chang, MS
Language
Robert W. Keith, PhD
Medications
Auditory Processing Testing
Children
Adults
Screening for Auditory
Processing Disorders
A Multidisciplinary Approach
Goals
Test Battery Components
Test Interpretation
Remediation of Auditory
Processing Disorders
Auditory Processing Abilities
in the Elderly
Auditory Processing Testing
in Hearing Aid Applications
Future Directions
Functional Magnetic
Resonance Imaging
Brain Mapping and Scalp
Topography
Summary
auditory processing disorders, auditory perceptual disorders, and
auditory language-learning disorders.1 The most recent
change of terminology from central auditory processing dis-
orders (CAPD) to auditory processing disorders (APD) was
made to avoid the implication of the exact site of lesion
and to emphasize the interaction of peripheral and central
disorders and processes.2
DEFINITION OF AUDITORY PROCESSING
According to the American Speech-Language-Hearing
Association (ASHA) Task Force on Central Auditory
Processing, central auditory processes [auditory process-
ing] are “auditory system mechanisms and processes
responsible for the following behavioral phenomena:
Sound localization and lateralization
Auditory discrimination
Auditory pattern recognition
273
274 NEUROLOGIC DIAGNOSIS
Temporal aspects of audition, including temporal resolu-
tion, temporal masking, temporal integration, and tem-
poral ordering
Auditory performance decrements with competing
acoustic signals
Auditory performance decrements with degraded acoustic
signals
These mechanisms and processes are to apply to nonver-
bal as well as verbal signals and to affect many areas of
function, including speech and language.”3 A central audi-
tory processing disorder [auditory processing disorder] “is
an observed deficiency in one or more of the above-listed
behaviors.”3
To further define these terms, sound localization refers to
a person’s ability to find the direction of a sound source.
Sound lateralization refers to a person’s ability to determine
where inside the head a sound appears to be (e.g., on the
right side of the head, left side, or in the center). Auditory
discrimination refers to one’s ability to determine if two
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
between two tones for them to be perceived as two distinct
tones [gap detection]). Temporal masking refers to forward
and backward masking. In this phenomenon, noise that is
presented slightly before or after a stimulus can partially
mask or cover part of the stimulus. Temporal integration is
the increase in sound intensity required to hear a sound of
shorter duration. So, for example, a tone of 200 millisec-
onds will have a 10-dB lower threshold than a tone that
lasts only 20 milliseconds. Finally, temporal ordering
involves the ability to recognize the sequence of acoustic
stimuli as they occur in time.
PREVALENCE OF AUDITORY
PROCESSING DISORDERS
Prevalence of APD varies; there is no “gold standard” for
measuring the prevalence of APD. Many children who
have learning disabilities (prevalence of 4% to 5%) also have
APD.4,5 Chermak and Musiek6 estimate that APD occurs
in 2% to 3% of all children, with a 2:1 male-to-female ratio.
The literature presents the prevalence of auditory process-
ing disorders in adults across a broad range, depending on
the investigator and criterion used. The prevalence in
adults ranges from 0% to 75% (1% to 23% in Cooper &
Gates,7 19% in Gang,8 58% in Kricos et al,9 60% in
Rodriguiez et al,10 74% in Arnst,11 74% in Shirinian and
Arnst,12 and 75% in Stach et al13).
HISTORICAL PERSPECTIVE
Early research of central auditory testing was conducted in
the 1950s in Milan, Italy, by a group of otolaryngologists
that included Bocca, Calearo, Antonelli, and Teatini.14
Those early investigators recognized that routine audiomet-
ric tests do not identify lesions affecting the central hearing
pathways. Special techniques, called sensitized speech tests,
were needed to identify those lesions. Sensitized speech
measures use speech stimuli (syllables, words, or sentences)
that are distorted in some way to reduce the intelligibility
of the message. The basic principle of sensitized speech
testing is that the distorted message can be understood by
persons with normal hearing and a normal central auditory
system. When an auditory processing disorder is present,
however, speech intelligibility will be poor. The construct
of sensitized speech testing is extremely powerful and is
the basis of all behavioral speech tests of central auditory
function.
The purpose of central auditory testing—initially to
identify lesions of the brainstem and cortex—has changed
as a result of developments in radiology with techniques
such as magnetic resonance imaging. Currently, auditory
processing testing in children focuses on identifying prob-
lem areas that affect academic performance. In adults the
focus is on determining how APD affects communication
and vocational achievement. In both populations, then, the
focus is on what Bergman and colleagues15 refer to as the
“functional disorders of communication” or “functional
auditory performance deficits.”3
BEHAVIORAL TESTS OF
AUDITORY PROCESSING
The premise of behavioral testing of auditory processing
lies in the concept of using sensitized speech measures to
reduce extrinsic redundancy. Speech contains multiple
acoustic and linguistic cues, not all of which are necessary
to understand the incoming message. For example, in the
sentence “the cats are drinking milk,” it is not necessary to
hear the s at the end of “cats” to know that more than one
cat is being discussed; the verb are signals the plural form.
Speech carries a multitude of other redundant linguistic
cues, such as tense and intonation.
In addition, the speech signal typically contains a greater
amplitude and a wider range of frequencies than is neces-
sary for understanding. For instance, most people can eas-
ily understand quiet speech even though the frequency and
amplitude spectrum is very different from normal conver-
sational speech. In addition, most persons can understand
speech on the telephone, which has a limited frequency
range compared to normal face-to-face communication. The
frequency range on a telephone is 300 to 3000 Hz, whereas
face-to-face communication has a range of 250 to 6000 Hz.
The structure of the central auditory nervous system
(CANS) itself creates intrinsic redundancy. The CANS is
well documented as a complicated neural network of
ipsilateral and contralateral connections that originate
and terminate at multiple points. Auditory information is
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
can often perform normally in ideal, quiet listening situa-
tions. The system with a lesion in the CANS can compen-
sate, given the extrinsic redundancy that exists in this
situation. However, if a damaged system with decreased
intrinsic redundancy is placed in an environment that has
decreased extrinsic redundancy (e.g., hearing in background
noise), the system is unable to compensate. The information
needed to understand the speech signal cannot reach the
auditory cortex and the person cannot understand the
incoming speech. Most behavioral tests of central auditory
 Central Auditory Processing Disorders: Assessment and Remediation
processing decrease the extrinsic redundancy of the incom-
ing signal to “tax” the central auditory nervous system.
Despite the vast number of them, behavioral auditory
processing tests can be classified by two methods: the
manner of stimulus presentation16 or the anatomic level
being tested. In the first method of categorization, called
the manner of presentation, the tests are distinguished by
how the stimuli are presented: monaural, binaural, and
dichotic. In monaural tests, a single stimulus or multiple
stimuli are presented to one ear. In binaural tests, stimuli
are presented to both ears. The third category, dichotic
testing, is a special kind of binaural test. During dichotic
testing, two different signals with equal onset and offset
times are presented to the two ears simultaneously. This
form of testing is separated out from other binaural tests
because of its importance in APD assessment.
Manner of Presentation
Behavioral AP tests are broadly classified as monaural,
binaural, or dichotic according to the manner in which they
are presented and the way in which the signal is configured.
Monaural Measures
Filtered Speech or Frequency-Altered Speech
In this form of sensitized speech measure, the patient is
asked to repeat single-syllable words. These words, how-
ever, are low-pass filtered to reduce the amount of high-
frequency information. Low-pass filtering is commonly
done using cut-off frequencies of 500, 750, or 1000 Hz
at either 18 dB or 32 dB per octave. Two current, norm-
referenced tests for filtered speech are the Filtered Words
subtest of the SCAN–C Test for Auditory Processing
Disorders in Children–Revised17 and the same subtest in
the SCAN–A Test for Auditory Processing Disorders in
Adolescents and Adults.18
Time-Compressed Speech
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,
and Rintleman19 found that persons with normal auditory
perception understand speech with time compression rates
up to 50% but have difficulty with time compression of
60% or greater. An example of this test is the Time
Compressed Sentence Test (TCST),20 which presents sen-
tence material at 40% and 60% time compression. This
test is norm-referenced for children from 6 to 12 years old.
Background Noise
Three terms—speech recognition in noise, auditory figure
ground, and speech in competition—describe the same basic
task. The subject is asked to repeat words or sentences
spoken when background noise is present. The competing
signal can be linguistic, ranging from a single speaker to a
multiple-speaker speech babble, or it can be nonspeech,
such as white noise or speech noise. The level of the
speech in relation to the competing signal is often
described in terms of a signal-to-noise ratio. Thus, a
speech signal that is 10 dB higher in intensity than the
competing noise is described as a 10-dB signal-to-noise
275
ratio or “10dB S/N ratio.” Signal-to-noise ratios can be
positive or negative, depending on whether the speech or
noise is higher in intensity. Examples of this form of test
include the Auditory Figure Ground subtests of the
SCAN–C17 and SCAN–A,18 the Speech Perception in Noise
(SPIN) test,21 and the QuickSIN test.22 A notable instrument
that has withstood the test of time is the Synthetic Sentence
Identification–Ipsilateral Competing Message (SSI-ICM)
test, developed by Jerger, Speaks, and Trammel.23
Frequency and Duration Pattern Recognition
The frequency patterns test (FPT) includes two frequen-
cies presented in six patterns of high and low. The patient
is asked to identify the tone pattern (e.g., high-high-low,
low-high-low). The duration patterns test (DPT) presents
one frequency in six patterns of two durations (e.g.,
350 msec and 500 msec). The patient identifies the pattern
of the signal (e.g., short-long-short, long-long-short). The
FPT and the DPT are nonlinguistic (nonlanguage) tasks;
however, the response can be either linguistic (the patient
labels the stimulus pattern) or nonlinguistic (the patient
manipulates blocks to represent the stimulus pattern).
Recent research states that abnormalities in DPTs may
indicate the presence of a cortical lesion.24
Temporal Processing Disorders/Gap Detection Tests
Temporal processing disorders can be identified using gap
detection tests. In this method, two tones are presented
with a variable time interval between the tones. The
patient reports whether one or two tones were heard. The
gap detection threshold is the shortest time gap in which
the patient perceived two tones. Patients with a normal
auditory system can identify time intervals as brief as
2 milliseconds between tones, with a normal average gap
detection threshold of approximately 10 milliseconds.
When gap detection thresholds exceed 20 milliseconds,
the individual is likely to have difficulty discriminating
speech sounds, and a temporal processing disorder is said
to exist. A current test of gap detection is the Random Gap
Detection Test (RGDT).25
Binaural Measures
Masking Level Differences
Masking level differences (MLDs) are tested to determine
the presence of brainstem abnormalities based on a phe-
nomenon called binaural release from masking. This
process is tied to the auditory system’s ability to detect
timing differences between ears. Detecting timing cues
is actually the detection of phase differences between ears
and is used in the localization of sounds, especially low-
frequency ones.
The concept of binaural release from masking is as
follows. Tones can be presented between ears which are in
phase and out of phase with one another. In-phase tones
are presented first. A masking noise is introduced to just
cover the tone. If the tones are changed to be out of phase,
the tone becomes audible again and is “released from
masking.” Binaural release from masking is a result of brain-
stem processing at the level of the superior olivary com-
plex.26 In addition, speech can be used instead of tones as
the target stimulus.
276 NEUROLOGIC DIAGNOSIS
In the MLD test, the MLD is the difference in intensity
needed for the tone to be just audible over the masking
noise between the in-phase and out-of-phase conditions.
For a 500-Hz tone, the MLD should be greater than 7 dB
with an average of approximately 12 dB.26 Wilson and col-
leagues27 found MLDs of approximately 13 dB for a 500-
Hz tone in normal young adult listeners. MLDs lower
than normal are consistent with lower brainstem dysfunc-
tion. A number of studies indicate that abnormal MLDs
are consistent with disorders of the brainstem.28–32 The
largest MLD effects are seen in the lower frequencies (300
to 600 Hz).33 The introduction of a prerecorded MLD test
on compact disc by Wilson and colleagues27 simplifies the
procedure and makes it feasible for more clinics to
perform this test.
Localization
Localization is the ability to identify the source of
sounds in the surrounding environment. Poor localiza-
tion ability is associated with auditory brainstem disor-
ders26,34,35 and cortical disorders.26,35,36 Although tests
that use localization are common when investigating
hearing in infants behaviorally (visual reinforcement
audiometry), testing of localization for purposes of central
auditory disorders is not practiced in most centers. A
promising strategy has been recently described by
Koehnke and Besin’s 3-D (three-dimensional) auditory
test of localization, in which virtual reality techniques and
digital signal processing are used to assess localization
under headphones.37
Dichotic Measures
Dichotic testing is an extremely sensitive measure of audi-
tory maturation and auditory nervous system function and
dysfunction. During dichotic testing, different speech sig-
nals with equal onset and offset times are presented simul-
taneously to both ears. A number of speech stimuli are
used, including nonsense syllables, numbers (referred to as
“digits”), monosyllabic words, compound words or spon-
dees, sentences, and nonsense sentences. Test instructions
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”).
Dichotic tests of young subjects find a strong right ear
advantage (REA), that is, better scores in the right ear than
the left. The REA results from the direct relationship
between the right ear and the dominant left language
hemisphere. As children approach 12 to 14 years, the REA
disappears, which is a sign of auditory maturation. In
normal adults, a slight REA is often observed. However,
individuals with lesions of the auditory regions of the
central nervous system (CNS) or those with APD show
various response patterns including:
Deficits in left ear performance
Poor overall performance
Enhanced right ear advantage
Switch from right ear advantage on a “directed right” con-
dition to a left ear advantage on “directed left” listening
condition
Abnormal dichotic test results are associated especially
with lesions of the corpus callosum or auditory cortex.26
Dichotic measures include the following:
Dichotic Consonant-Vowel (CV) test
Dichotic Digits38
Staggered Spondaic Word (SSW) test39
Competing Sentence Test40
Dichotic Sentence Identification (DSI) test41
Competing Words and Competing Sentences subtests of
the SCAN–C Test for Auditory Processing Disorders
in Children–Revised17 and SCAN–A Test for Auditory
Processing Disorders in Adolescents and Adults18
Anatomic Level Tested
Auditory processing tests can also be categorized accord-
ing to the presumed anatomic level being assessed (see
Table 17-1). The bottleneck principle, discussed in the
“Test Interpretation” section, should be considered as well.
ELECTROPHYSIOLOGIC TESTS
The role of electrophysiologic testing has great promise in
the auditory processing test battery. A large body of liter-
ature has emerged in the past decade in this arena. Elec-
trophysiologic tests discussed for use in APD assessment
include the auditory brainstem response (ABR), the mid-
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
out auditory neuropathy. This phenomenon is character-
ized by normal otoacoustic emissions, absent or abnormal
ABR, and absent acoustic reflexes. The implication of
these findings is that persons with auditory neuropathy
have normal cochlear outer hair cell function with abnor-
mal neural synchrony of cranial nerve VIII or abnormal
cochlear inner hair cell function.42 The remediation efforts
for auditory neuropathy are significantly different from
those for APD, and they include possible cochlear implan-
tation. Nevertheless, the requirement that all children
TABLE 17-1. Auditory Processing Tests
Anatomic Level Type of Test
Brainstem Masking level differences, lower brainstem
lesions
Binaural fusion of low- and high-pass filtered
speech
Rapidly alternating speech
Localization
Lateralization
Cerebral cortex Dichotic tests
Low-pass filtered word tests
Auditory figure ground, speech recognition
in noise
Time-compressed speech
Difficult monaural tasks
Impaired localization
Reduced temporal processing
Nondominant hemisphere Frequency and duration pattern recognition
 Central Auditory Processing Disorders: Assessment and Remediation
undergo electrophysiologic tests as part of an APD assess-
ment remains controversial.2,43,44
Electrophysiologic testing does have significant limita-
tions and considerations. First, although these are physio-
logic responses, they are not truly objective because they
need to be interpreted by an examiner. In addition, sub-
jects must often cooperate during testing. This may mean
that subjects need to rest quietly during the test or need to
pay close attention to a task. Middle-latency and cortical
evoked potentials especially are affected by sleep states and
attention.
Auditory Brainstem Response
The best known of the auditory evoked potentials, the
ABR is a series of neurologic responses that are assumed to
reflect the sequence of activity of the auditory nerve and
nerve tracts and nuclei of the ascending auditory path-
way.45 These compound action potentials result from an
acoustic stimulus of a fast rise time (a click) and occur
within the first 10 milliseconds following the stimulus.
Because the ABR reflects pontine-mesencephalic trans-
mission of neural activity, it is a measure of central audi-
tory processing at the brainstem level. Early investigators
reported abnormalities in the ABR in children with audi-
tory processing and language-learning disorders.46–49 Stein
and Kraus report various studies showing ABR abnormal-
ities in patients with confirmed hydrocephalus, autism,
and Down syndrome.50 Lynn and colleagues report ABR
abnormalities in patients with olivopontocerebellar degen-
eration.51 Keith and Jacobson report ABR abnormalities
commonly observed in patients with multiple sclerosis.52
A newer application of the ABR in auditory processing
is maximum-length sequences. (See Jirsa53 for further
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.
Auditory Middle-Latency Response
The middle-latency components of the auditory evoked
response occur after the ABR and within the first 100
milliseconds following the presentation of an effective
auditory stimulus.6 There are two major positive and neg-
ative peaks in the response, typically labeled Na, Pa, Nb,
and Pb.54 The MLR is believed to have multiple genera-
tors, including the temporal lobe or thalamocortical proj-
ects, the reticular formation, thalamus, and inferior
colliculus, as well as contributions outside of the central
auditory nervous system.55 It is affected by the depth of
sleep, which may explain the variability found in the MLR
of children. It is best obtained when awake.55 In regards to
age effects, MLRs in infant and young children have dif-
ferent morphologies and latencies from those in adults.
Kraus and colleagues reported that detectability of the
MLR increased significantly as a function of age.
Detection of MLR Na components increased from 75% to
90% as subjects’ age increased from 0 to 20 years. The
detection of the Pa component increased from 40% to
90% during the same time frame.56
Jerger and colleagues published a case report of an
11-year-old boy with a classic history of auditory processing
277
disorder.57 The MLR obtained on that child was abnormal
with no repeatable patterns in the responses from either
ear. Fifer and Sierra found a correspondence with abnormal
performance on the SSW test and the MLR in a 7-year-old
with auditory processing disorder.58 Jerger and colleagues,
Fifer and Sierra, and Ozdamar and Kraus all postulated that
the MLR has potential for identifying and understanding
central auditory processing disorders.57–59 This evoked
response’s degree of success in the assessment of auditory
processing disorders is yet to be established.
The P300
The P300 is a cognitive evoked potential that evaluates
attention and information processing. One of the late
auditory evoked responses, it is also known as P36. It con-
sists of one large peak that occurs approximately 300 mil-
liseconds after an effective stimulus,54 hence the name P300.
To elicit the P300, an “oddball paradigm” is employed.
A series of stimuli are presented to the patient, with an
occasional different stimulus, or “oddball,” presented about
20% of the time. The patient’s task is often to attend to the
oddball stimuli, often by counting them. The attention to
the oddball stimuli causes the P300 to appear. The P300 is
greatly influenced by the subject’s attention, alerting, arousal,
and psychological state with small or delayed amplitude
responses occurring when there is some abnormality of
cognitive processing.60 As such it has been used to study
attention deficit and auditory processing disorders in
children. For example, Jirsa and Clontz found reduced
amplitude of the P300 in a group of children with auditory
processing disorders.61 Jirsa also found that the P300
decreased in latency and increased in amplitude after
structured treatment in an APD group of children.62
Mismatch Negativity
The mismatch negativity is a late, endogenous evoked
potential that occurs after 100 milliseconds and after the
P2 late cortical response. Kraus and colleagues studied the
MMN in detail.63 They report that the MMN is associated
with neurophysiologic processing during discrimination of
acoustic stimuli. They note that it is especially appealing
because it is not influenced by attention and does not require
a behavioral response from the subject, even though it is
elicited with an oddball paradigm, as with the P300. It also
is free of the confounding effects of language develop-
ment, cognitive ability, and behavioral development. They
also indicate that the MMN is stable throughout the school
years (ages 6-15 years) and provide MMN normative data
for speech syllable stimuli. It is interesting to note that
they found changes in the MMN that occurred with some
speech stimuli but that were not distinguished in conscious
behavioral discrimination tasks. They suggest that the
MMN may be related to preconscious discrimination ability.
Some data indicate that the MMN in normal, healthy
subjects may not be quite as robust as described. For
example, Kurtzberg and colleagues, Dalebout and Stach,
and Cunningham all found MMN to be absent in 25% to
35% of normal children and adults.64–66 Other work
with the MMN and auditory processing has been done by
Liasis and colleagues, Naatanen, Kraus and colleagues,
278 NEUROLOGIC DIAGNOSIS
Jansson-Verkasalo, Purdy and colleagues, Hugdahl and
colleagues, Bertoli and colleagues, and Schulte-Korne and
colleagues.67–74 Therefore, while MMN continues to be a
promising research tool for groups of subjects, its use in
the assessment of individual subjects should be approached
with caution.
Other Late Auditory Evoked Responses
Research is being conducted to investigate other late audi-
tory evoked responses in the assessment of APDs. These
responses occur after 80 to 100 milliseconds. Besides the
MMN and P300, other responses are the N1, P2, and N2.
Research related to APD populations include the work of
Jirsa and Clontz, who found that the N1 and P2 had
increased latencies in a group of children with APD.61
Tonnquist-Uhlen found significant differences in N2 and
P2 latencies in language-impaired children.75 Purdy and
colleagues found different P1 and P3 responses in learning-
disabled children.71 Ponton and colleagues suggest that
late potentials can provide information about the
maturation of the CANS.76 Hayes and colleagues also
measured differences in P1 and N2 in children with learn-
ing problems, after a computer remediation program was
used.77 This also corresponded with a change in behavioral
performance measures.
FACTORS AFFECTING AUDITORY
PROCESSING TEST RESULTS
Subject’s Age
The age of the subject vastly affects the performance on
auditory processing tests. The effects of age are based on
changes resulting from neural maturation, changes in the
auditory nervous system in aging, and language level.
When referring a patient for APD assessment, the cor-
rected age based on language ability, and not just the
chronological age, should be considered. Electrophysio-
logic tests also are affected by age.
Peripheral Hearing Loss
Peripheral hearing loss, both conductive and sen-
sorineural, is a significant factor in testing and interpreta-
tion of auditory processing. Patients with peripheral
hearing loss cannot be tested reliably with most of the cen-
tral auditory measures that incorporate speech signals
because of cochlear distortion and asymmetrical hearing
loss. For example, the dichotic consonant-vowel (CV) test,
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
or adapted for testing subjects with peripheral hearing
loss. According to Stach,26 these tests include:
Dichotic Sentence Identification (DSI) test, which can be used
with PTA of 50 dB or lower41
Synthetic Sentence Identification (SSI) test, which has norma-
tive data based on degree of hearing loss78
Dichotic digits test, interpretation of which can be adjusted
based on hearing loss present38
Staggered Spondaic Word (SSW ) test, which has corrections
for hearing sensitivity loss39,79
Competing sentences, MLR, and P300 are less likely
to be affected by peripheral hearing loss.3 In addition, a
wide range of nonlinguistic tests that use tones can be
considered when attempting to identify an auditory
processing disorder in this population; they include
Random Gap Detection, Median Plane Localization, dif-
ferential thresholds for frequency and intensity, and tone
decay tests.
Intelligence, Cognition, and Language
The effect of intelligence and cognitive ability is well
documented. Subjects’ performance will generally be
commensurate with their mental age and should be
interpreted appropriately. Language ability is an important
factor as well because many auditory processing measures
are language based. For instance, vocabulary knowledge is
essential for the recognition of words with reduced extrin-
sic redundancy.
In addition, native language and language dialect can
have an impact on test results. It has been demonstrated
that normal adult subjects who are not native speakers of
English typically have difficulty performing sensitized
speech tasks, even years after being immersed in the
English language.80,81 Native English speakers from other
English-speaking countries also have difficulty taking
American-accented speech tests of auditory processing.
Marriage found that normally performing children in
Great Britain fell at the 16th percentile of performance on
SCAN–C because they were unable to interpret some of
the American-accented test items.82
Medications
The effect of medications on auditory processing tests
is beginning to emerge in the field. Keith and Engineer
found that children with attention deficit disorder (ADD)
who were taking methylphenidate (Ritalin) had signif-
icantly improved auditory processing performance.83
Tillery and colleagues found auditory attention improved
with Ritalin in children with both APD and attention
deficit hyperactivity disorder (ADHD), but auditory pro-
cessing abilities were unchanged.84 The effect of selective
serotonin reuptake inhibitors (SSRIs) such as fluvoxamine
and fluoxetine on auditory processing abilities needs
investigation, as shown by the case study presented by
Gopal and colleagues.85 Chermak reviews this subject
briefly.86
AUDITORY PROCESSING TESTING
Children
Children younger than 5 years old are difficult to test with
these special measures, and there are few normative tests
available. After the age of 6 years, children can be tested
with relative ease using standardized tests. Nonverbal per-
sons or persons with limited intelligence are not candi-
dates for testing. For further information, consult the
 Central Auditory Processing Disorders: Assessment and Remediation
guidelines for referring children for APD assessment
published by a group of Houston audiologists.87
The focus of testing children’s auditory processing is to
investigate a possible factor for poorer school perform-
ance, language delays, reading problems, learning difficul-
ties, and behavior difficulties. The majority of children
referred for testing do not have specific identifiable brain
lesions and many have completely normal neurologic
examinations. The purpose of APD testing of children is
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.
Children with auditory processing disorders often mis-
understand what is said, give inconsistent responses to
auditory stimuli, and frequently request that information
be repeated. These children have poor auditory attention,
have difficulty listening in the presence of background noise,
and are easily distracted. They have difficulty with phonics
and speech sound discrimination and have poor auditory
memory. Their speech and language skills, both receptive
and expressive, may be poor. These problems occur with-
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
different theories about this relationship. In the normal
child, auditory processing abilities develop in a parallel or
a reciprocal relationship with language abilities. Children
with auditory processing disorders are a subset of children
with receptive and/or expressive language disorders.
In addition, issues of attention need to be considered.
APD can coexist with attention deficit hyperactivity disor-
der or attention deficit disorder. The relationships among
all these disorders is not yet completely understood.88
Nevertheless, APD can be distinct clinically from ADHD.89
Adults
Auditory processing disorders in adults often manifest
themselves in everyday communication, either socially or
vocationally. Like children with APD, adults with APD have
more than normal difficulty in challenging listening situa-
tions. They often report difficulty hearing in noisy environ-
ments, when speaking with an individual with a foreign
accent, or with someone who speaks very fast. APD in this
population may be related to acquired etiologies; it has been
documented with Parkinson’s disease, chronic alcoholism,
Alzheimer’s disease, stroke and head trauma, tumors, multi-
ple sclerosis, and chemical exposure. APD also may be iden-
tified in previously undiagnosed learning-disabled adults.90–94
As mentioned earlier, APD testing of adults can be use-
ful in identifying lesions of the central auditory nervous
system, although this is not the typical purpose today.
APD testing can be used to track the recovery of auditory
processing skills95 and provide information on the impact
of APD on everyday function.
Screening for Auditory Processing
Disorders
Mostly, children are screened for APD. According to the
2000 Bruton Conference on APD, this can be done by
observation of the child using questionnaires and/or
279
formal screening tests.2 Examples of questionnaires include
the Children’s Auditory Performance Scale (CHAPS) and
the Screening Instrument for Targeting Educational Risk
(SIFTER).96,97 An example of a formal screening test is the
Selective Auditory Attention Test (SAAT).98 A word of
caution: Auditory processing tests designed for screening
should not be used to diagnose auditory processing disor-
ders, as has been done in the past.2 This results in an
overdiagnosis of auditory processing disorders.
A Multidisciplinary Approach
The test battery used in auditory processing assessment
needs to be part of a multidisciplinary approach. Essential
members of this team are the audiologist and speech-
language pathologist. For assessment of children, teachers
and parents are also essential members of the team. This
team approach is recommended in two consensus state-
ments by specialists in central auditory processing.2,3
Other specialists, such as psychologists, also may be
involved.
Goals
The ASHA Task Force reveals that “the purpose of the
central auditory assessment is to determine the presence of
a central auditory processing disorder and to describe its
parameters.”3 Concerning children specifically, there is con-
troversy as to whether the assessment should focus on delin-
eating a deficit specific to the auditory realm, differentiating
APD from other disorders such as language and learning
problems, or determining management strategies.2,43
Test Battery Components
The components of the APD test battery vary, based on
the model of auditory processing. The tests chosen are
especially important for assessment of children’s hearing
because they are still learning the basic components of lan-
guage. Audiologists tend to approach APD testing with a
bottom-up approach, believing that language problems
stem from deficit(s) in basic auditory processes. Speech-
language pathologists tend to approach auditory process-
ing with a top-down approach, believing that the auditory
processing difficulty is due to problems with higher-level
influences, such as language, cognition, information pro-
cessing, and attention.
Not surprisingly, then, the essential auditory processing
test battery is highly variable among audiologists. The
American-Speech-Language-Hearing Association Task
Force on Central Auditory Processing consensus statement
provides a workable guideline. For both adult and pediatric
populations, the test battery can include the following3:
I. Case history
II. Nonstandard but systematic observation of
auditory behavior
III. Audiologic test procedures
A. Behavioral techniques
1. Measures of peripheral function
a. Pure tone thresholds
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
involved. Scores are often reduced bilaterally when the
lesion crosses the midline or through secondary effects
of pressure, even from remote lesions.111 In difficult mon-
aural tasks, with lower brainstem lesions, the performance
is poorer usually ipsilateral to the lesion. With higher
brainstem lesions, performance can be poorer ipsilateral
and contralateral to the lesion.26
One recent trend in APD assessment is the development
of the concept of a central auditory processing disorder
divided into subtypes of deficits. For example, Bellis and
Ferre delineate auditory processing disorders into three
primary subprofiles and two secondary subtypes. The
three primary subtypes are Auditory Decoding Deficit,
Prosodic Deficit, and Integration Deficit. The two sec-
ondary subtypes are Associative Deficit and Output
Organization.55
As a second example, the subtypes of auditory processing
deficits have been described by Masters, Stecker, and Katz
in the Buffalo Model.100 This model uses four clusters of
test results and behavioral characteristics, speech-language
test results, and academic factors. The four clusters are
Decoding, Tolerance-Fading Memory, Integration, and
Organization. Although these models of auditory process-
ing have been popularized, there is no evidence to
substantiate claims that the remediation proposed to be
associated with each model has an effective outcome.
REMEDIATION OF AUDITORY
PROCESSING DISORDERS
Different management strategies of auditory processing
disorders exist. Regardless of the management approach, it
is important that the management approach be multidisci-
plinary. It also should be individualized based on the areas
of weakness or deficit identified in the auditory processing
assessment.
Additionally, it is important to be specific in the man-
agement approach; some professionals still believe that
intervention strategies are not specific enough to warrant
auditory processing testing.112 An example of the possible
downfalls of a nonindividualized approach is the use of FM
assistive listening devices for school-age children. FM sys-
tems are not necessarily the best recommendation in all cases. It
is possible that this reduction of background noise may not
allow the auditory skills to develop in those environments
with some individuals.55
Strategies for remediation of APD fall into three major
categories:
1. Management of the environment, which includes strate-
gies such as preferential seating, FM systems, sound
field systems, teaching suggestions (comprehension
checks, use of visual aids, etc.), classroom acoustics,
and communication strategies.
2. Remediation techniques designed to improve the per-
son’s auditory processing skills. This includes training
in auditory closure, speech in noise, dichotic listening,
localization, prosody, and temporal patterning. It also
includes computer-assisted therapy with such soft-
ware programs as Fast ForWord (Scientific Learning
Corp.) and Earobics (Cognitive Concepts).
281
3. Compensatory strategies designed to teach the individual
how to overcome residual dysfunction and maximize
use of auditory information. These focus on improv-
ing learning and listening skills. They include teach-
ing the person to be an active listener, increasing
motivation, attribution training, whole body listening
techniques, and metacognitive strategies.55
Remediation of APD in children needs to take full
advantage of the neural plasticity of the central auditory
nervous system.113,114 Neural maturation must also be
taken into account. The treatment plan for adults may
focus more on management of the environment and
compensatory strategies and less on direct remediation
training techniques. This makes sense because of the
decreased neural plasticity in adulthood.
For more thorough and comprehensive sources of man-
agement approaches and issues, consult Bellis,55 Masters,
Stecker, and Katz,100 and Chermak.115 In addition, Musiek
describes three useful and practical management approaches
that can be used as part of a comprehensive APD manage-
ment program.116
Of course, the existence of a strategy does not mean it is
an effective strategy. In the area of auditory processing, a
great amount of research is needed to determine treatment
effectiveness and outcome measures. Hayes and colleagues
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
performance improve in measures of auditory processing,
but changes in cortical potentials were also measured.
Other studies that report improved auditory abilities and
language function after formal training were conducted
by Merzenich and colleagues, Tallal and colleagues, and
Habib and colleagues.117–119
AUDITORY PROCESSING ABILITIES
IN THE ELDERLY
In the 1990s special interest was focused on auditory pro-
cessing abilities and the elderly population. The familiar
concept of phonemic regression and central presbycusis was
revisited. Recall that phonemic regression describes the
phenomenon in which an elderly adult’s ability to under-
stand words, often measured by word recognition scores,
is disproportionately poorer than would be expected based
on pure tone thresholds. This, indeed, was simply refer-
ring to an auditory processing disorder becoming evident
with aging. It is often forgotten that Gaeth found the
prevalence rate of phonemic regression in 1000 elderly
individuals to be only 2.7%.120 Research suggests that
auditory processing disorders in the normal elderly may
not be the rule, but the exception, which is consistent with
Gaeth’s early findings.
A number of studies challenge the common assumption
that auditory processing decreases with age in most or all
individuals. Hearing loss is often a confounding variable.
Humes and Christopherson found that the threshold ele-
vation in sensorineural hearing loss was the primary factor
affecting the speech identification performance of elderly
subjects, and not just age alone.121 To read other studies
282 NEUROLOGIC DIAGNOSIS
that challenge the common assumption that auditory
processing declines with aging, consult Surr,122 Grady123
Holmes, Kricos, and Kessler,124 Jerger and colleagues,125
Humes and colleagues,126 and Harris and Reitz.127
Thompson discusses several alternative hypotheses to
explain phonemic regression.128 They include experimen-
tal artifacts that include failure to account for the fact that
elderly persons are less willing to guess, prolonged reac-
tion time in this population, insufficient stimulus presenta-
tion level, and the effects of decreased hearing sensitivity.
In addition, she suggests that cognitive factors such as
changes in attention, declining memory, need for more
practice, and social expectations (defined as the expectation
that the elderly person’s hearing is poorer than a normal
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
processing disorders in the elderly may not be a global
phenomenon, characteristic of all elderly.
On the other hand, there still exists a strong argument
that auditory processing does decrease during the aging
process. Histologic and morphologic evidence still seem to
support this concept; age-related changes in the cochlea,
the auditory nerve, and the central auditory pathways at
both the brainstem and temporal lobe levels have been
described.129,130 Declined performance on behavioral audi-
tory processing measures also are presented in the litera-
ture. Jerger and colleagues used a number of auditory
processing disorder tests on 130 elderly subjects. They
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
Neils and colleagues,131 Von Wedel,132 Baran,133 and
Willott134 also provide evidence that suggests that auditory
processing changes do occur with aging.
AUDITORY PROCESSING TESTING
IN HEARING AID APPLICATIONS
Interestingly, auditory processing tests to help determine
hearing aid success has been discussed more recently.
Givens, Arnold, and Hume found statistically significant
correlations between certain auditory processing tests and
hearing aid satisfaction. They suggest that a full battery
with auditory processing tests may be helpful.135 Studies by
Chmiel and Jerger and by Stach and colleagues further
investigate this application.136,137
Auditory processing tests may also be helpful in deter-
mining when to recommend binaural versus monaural
hearing aids. This is related to a phenomenon called bilat-
eral interference. Some people with APD find that their
ability to perform binaurally is actually poorer than the
best monaural performance. This has been seen in some
elderly individuals and in a multiple sclerosis patient.138,139
An interesting case study of an elderly patient who per-
formed better with monaural hearing aid use was pub-
lished by Chmiel and colleagues.140
Another interesting concept applicable to hearing aid use
is acquired suprathreshold asymmetry. Evidence is suggesting
that when an individual develops an asymmetry caused by
a peripheral hearing loss, the auditory processing in the
poorer ear is disproportionately affected compared with
the other ear. Using concepts of auditory neural plasticity,
then, it would be recommended to aid the poorer ear
as soon as possible to preserve auditory processing in that
ear. It should be noted that the concept of acquired
suprathreshold asymmetry is still controversial and is not
supported in all studies conducted.26
Last, late-onset auditory deprivation should also be consid-
ered in hearing aid use. This can occur in monaural hearing
aid fittings with bilateral, symmetric hearing loss. In some
individuals, the unaided ear decreases in word recognition
ability, whereas the aided ear does not. However, the plastic-
ity of the auditory system becomes apparent as this negative
effect is reversible if the other ear is aided soon enough.26
FUTURE DIRECTIONS
Further research is needed to collect and refine norms for
many behavioral APD tests. More information needs to be
gathered on electrophysiologic tests, such as MMN, MLR,
and P300. Outcome measures and efficacy measures are
needed to assess different remediation and treatment meth-
ods. There is a need for a “gold standard” definition of audi-
tory processing, providing the basis for studies of sensitivity
and specificity for different auditory processing tests. This
will pave the way for improved models of assessment and
management. In addition, the use of functional MRI and
brain mapping and scalp topography show promise.
FUNCTIONAL MAGNETIC
RESONANCE IMAGING
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-
zation of brain activity resulting from increases in regional
cerebral blood flow associated with processing of sensory
information. Through fMRI, auditory neuroscience will
be able to investigate aspects of auditory nervous system
organization, attention, memory, and other factors in
ways that were unimaginable several years ago. Cacace,
Tasciyan, and Cousins summarize that this new research
frontier provides insights into fundamental properties of
human sensory, motor, and cognitive functions in both
normal and pathologic states. They state that the appeal of
this technique is “based on its noninvasive nature, tempo-
ral and spatial resolution, suitability for studying humans,
and its potential for wide-range future availability.”141 See
the article by Cacace and colleagues for an excellent tutorial
on this subject.141 Other researchers looking at fMRI and
auditory processing are Suzuki and colleagues,142 Poldrack
and colleagues,143 Seifritz and colleagues,144 Sevostianov and
colleagues,145 Novitski and colleagues,146 Engelien and
colleagues,147 and Hall and colleagues.148
Brain Mapping and Scalp Topography
Scalp topography of auditory evoked potentials with color
imaging techniques provide a scheme for easy visualization
of the voltage distribution of evoked potentials at key
 Central Auditory Processing Disorders: Assessment and Remediation
latencies. These has also been called event-related potentials
and event-related potential (ERP) topography. Color
imaging of the scalp topography of the middle-latency
response was first described by Kraus and McGee.149
These authors examined MLR scalp topography in 40
normal-hearing subjects. Jerger and colleagues used this
technique in an interesting case study with two twins, only
one of which exhibited symptoms of APD.150 Although
results of behavioral auditory processing tests were compa-
rable for the two twins, the ERP topographies were quite
different. The ERP results were consistent with a deficit in
the efficiency of interhemispheric transfer of auditory
information in the twin who exhibited APD symptoms.
In this way, ERP topography was used to differentiate
among possible diagnoses. Pros and cons of brain mapping
are discussed by Cranford and Hymel.151 This technique
provides interesting avenues of studying auditory process-
ing disorders in subjects of all ages and is the subject of
other researchers, among them Estes and colleagues152 and
Tonnquist-Uhlen.153
SUMMARY
Auditory processing disorders, formerly referred to as cen-
tral auditory processing disorders, are complex phenom-
ena that can be assessed systematically with a number of
different behavioral tests. Although the minimal test bat-
tery is controversial, there are many guidelines provided
by a multitude of authors. Electrophysiologic techniques
are deemed essential in the APD assessment by some and
nonessential by others. These tests include ABR, MLR,
P300, MMN, and other late auditory evoked potentials.
Either way, it is clear that electrophysiologic techniques
are an area of promise that requires more research.
The essentials of auditory processing assessment and
remediation encompass many factors, including age, hear-
ing loss, language, and intelligence. The role of auditory
processing testing in children is focused on improving
language and academic abilities. In adults, the emphasis is
on “functional disorders of communication” in social and
vocational situations. The occurrence of auditory pro-
cessing that occurs with aging is a debatable topic. The use
of auditory processing testing in hearing aid assessment
is also an area of promise. Future techniques for use in
this intriguing field of auditory processing may include
functional MRI and brain mapping.
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Objective Measures
of Auditory Function
Outline
Introduction
Otoacoustic Emissions
Electrocochleography
Auditory Brainstem Response
Detection of Hearing Loss
Using the Auditory Brainstem
Response
Estimating Amplification
Benefit: Electrophysiologic
Procedures
INTRODUCTION
Beginning with the 1939 discovery of human auditory
evoked potentials by Pauline Davis1 there has been
remarkable progress in the clinical application and effec-
tiveness of electrophysiologic and other objective measures
of auditory function. These developments have been
prompted in part by distinct technological changes since
the advent of the first electronic response averager, devised
by G. D. Dawson in 1952. It consisted of a revolving
commutator charging condensers, resulting in a total of
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
such as the first human scalp–recorded auditory brainstem
response (ABR) by Jewett, Romano, and Williston.2
Over the years, clinical auditory neurophysiology has
contributed to both diagnostic and surgical monitoring
applications. Electrophysiologic measures are now used
for both diagnosis and enhancement and support of
sophisticated microsurgical interventions in the temporal
bone, subtemporal skull base, and posterior fossa. In the
diagnostic arena, it is possible to evaluate the function and
the integrity of the auditory pathway from end-organ
receptor to cerebral cortex. Evoked otoacoustic emissions
provide information regarding the status of cochlear outer
hair cells. Electrophysiologic measures provide us with
information about functional characteristics of outer hair
cells via the cochlear microphonic as well as the status of
the cochlea in presumed Ménière’s disease using electro-
cochleography. Also, the cochlear nerve and brainstem
auditory pathway for neurodiagnostic or hearing threshold
applications is assessed via the auditory brainstem
Chapter
18
Acoustic Neuroma Diagnosis Paul R. Kileny, PhD
with the Auditory Brainstem
Response Bruce M. Edwards, AuD
Measurement Criteria for
Diagnostic Auditory
Brainstem Response
Case Studies
Middle Latency Responses
Auditory Potentials in
Cochlear Implant Surgery
response; other electrophysiologic applications involve the
subcortical and cortical auditory regions. Methods for the
electrophysiologic assessment of auditory system activation
by electrical stimulation including cochlear implants have
been developed and refined, allowing one to record
preoperative and postimplant electrically evoked auditory
brainstem or middle latency potentials. All of these may be
accomplished by noninvasive or minimally invasive stimu-
lation and recording techniques. This chapter reviews
principles and practices of auditory neurodiagnostic tests
in current clinical use.
OTOACOUSTIC EMISSIONS
Otoacoustic emissions (OAEs) are sounds produced
actively by the human ear as part of the normal hearing
process and were first described by Kemp.3 The active
nonlinear mechanism of outer hair cell (OHC) motility
amplifies the motion of the cochlear partition 100- to
1000-fold and, as a byproduct, produces various forms of
OAEs.4 Because OAEs are acoustic byproducts of the
inner ear, they are often referred to as “cochlear echoes.”
There are two primary types of OAE: spontaneous
OAEs (SOAEs) are present even in the absence of an
exogenous stimulation of the ear; evoked OAEs (EOAEs)
occur in response to the presentation of an acoustic stimulus
to the ear.5 Evoked OAEs may be further divided into the
categories of transiently evoked OAEs (TEOAEs), which
are elicited by an acoustic transient such as a click or tone
burst, stimulus frequency OAEs (SFOAEs), which are
elicited by a single continuous pure tone, and distortion
product OAEs (DPOAEs), which are generated by two
287
288 NEUROTOLOGIC DIAGNOSIS
continuous pure tones separated by a specific frequency
difference.5 Evoked OAEs can be detected in most ears
with normal hearing and are reduced or absent in ears
affected by cochlear disorders.5
The test procedure for obtaining OAEs requires little
subject preparation and relatively brief examination periods,
and it is performed in a relatively straightforward manner.
During testing, a probe that contains both a miniature
loudspeaker and a microphone is sealed into the ear canal.
The loudspeaker delivers the stimulus to the ear canal
while the microphone samples the output (emission) for
approximately 20 ms following stimulus presentation. The
signal from the microphone is then amplified and averaged
in order to enhance the signal-to-noise ratio.
Signals used to generate TEOAEs consist of clicks or
tone bursts. Transient OAEs in response to click stimuli
consist of a delayed, nonlinear, frequency-filtered echo of
the stimulus.3 Healthy ears typically demonstrate several
regions of strong response for TEOAEs between 0.4 and
6 kHz and between 0.5 and 8 kHz for DPOAEs.5–7 The
latency of TEOAEs is typically 5 to 20 ms in humans and
tends to decrease as frequency increases, supporting a
cochlear origin of TEOAEs.5
Signals used to generate DPOAEs consist of two stimulus
tones, separated in frequency, presented at 55 to 85 dB
SPL. Nonlinear cochlear processes are responsible for the
emission of responses at frequencies that are not present in
the two-tone input. The output requires averaging to
measure DPOAEs at specific frequencies. The most
prominent DPOAE occurs at the cubic difference frequency
described by the expression “2F1-F2,” in which F1 repre-
sents the lower frequency stimulus and F2 the higher
frequency primary tone.5,8,9 Distortion product OAEs are
low in amplitude, usually about 60 dB lower than the levels
of the eliciting primary tones.
Otoacoustic emissions have shown promise as occupa-
tional audiologic test tools not only because they can be
obtained and measured in a relatively straightforward
manner, but also because they have considerable potential
for assessing the role of OHC dysfunction in hearing
impairment.5,7 OAEs specifically test the micromechanical
activity of OHCs, that is, the auditory receptors most
sensitive to the damaging influence of noise.5 Additionally,
OAE measures demonstrate excellent intrasubject test/
retest reliability,5,10,11 as well as stability over several years
for any one ear.3,12
An additional advantage is that OAEs test discrete
frequency-specific regions of the cochlea, thereby
enabling one to clearly denote differences between areas of
normal and abnormal function and also to accurately track
dynamic changes in outer hair cell–based disease such as
noise-induced hearing loss. Factors known to cause sen-
sorineural hearing loss may reduce or abolish OAEs.
Studies have shown that acoustic overstimulation that
results in a temporary threshold shift reduces OAEs.5,13
Several variables affect the presence and magnitude of
OAEs including middle and outer ear disorders, environ-
mental and biologic noise levels, the number of averaged
sweeps, and primary tone characteristics (in DPOAE).
Because both the forward and reverse transmission of
acoustic energy are necessary for the documentation of an
OAE, external and middle ear conditions such as increased
mass resulting from middle ear effusion or increased stiffness
caused by eustachian tube dysfunction may adversely affect
an OAE. Thus, even in cases in which cochlear function is
normal, attenuation resulting from mass or stiffness effects
could render OAEs unmeasurable. Significant for neonatal
hearing loss detection, Doyle and colleagues have shown14
that the obstruction of the external ear canal by debris/
vernix was significantly related to more hearing screening
referrals using OAEs. The majority of the infants in the
study, however, did pass an ABR hearing screening. The
discrepancy between results of hearing screening by
DPOAE and ABR was further demonstrated by Barker
and colleagues15 who screened a population of 569 new-
borns using ABR and DPOAEs. All infants passed the ABR
hearing screening. Since no universally accepted standards
exist for a DPOAE hearing screening pass, several pass cri-
teria based on response replication and/or presence of a
DPOAE at 2000 Hz were applied post hoc. With the most
stringent pass criteria for DPOAE, only 64.4% of ears
passed, whereas with the least stringent criteria, 88.9%
passed. This represents a discrepancy in the pass rate
between ABR and DPOAE of 11% to 35% when the ABR
is considered the gold standard. None of the infants
enrolled in this study carried risk factors for hearing loss,
and long-term follow-up did not identify any delayed-
onset hearing loss. Koivunen and colleagues16 investigated
the effects of the physical properties such as the weight and
fluid viscosity of middle ear effusion on emissions and tym-
panogram configuration. These authors demonstrated that
7% of ears with normal tympanogram findings and 46% of
ears with abnormal tympanograms yielded reduced or
absent emissions. A significant correlation was found
among the mean weight of the effusion, the reproducibility
of emissions, and the tympanogram configuration. Fifty-
seven percent of ears with mucoid effusion and 26% with
nonmucoid effusion had no emissions recorded. Koivunen
and colleagues asserted that the effects of middle ear func-
tion on the ability to record an otoacoustic emission are
not related specifically to tympanogram configuration.
Figure 18-1 shows side-by-side recordings of distortion-
product (“A”) transient-evoked (“B”) otoacoustic emis-
sions from the same ear of a normal hearing young female.
These two modes of eliciting an OAE provide analogous
information but require stimulus paradigms that result in
different displays. For the TEOAE, the emission is pre-
sented in the frequency domain with added information
regarding magnitudes at discrete frequencies and repro-
ducibility. For the DPOAE, the emission is presented in an
audiogram form (hence, “DP-gram”) that plots emission
intensity as a function of the F2 frequency. In general, the
distortion product method results in a better frequency
resolution for higher frequencies. Clinical applications for
otoacoustic emissions may be divided into two areas:
estimation of auditory thresholds and site of lesion differ-
ential diagnosis. In terms of auditory threshold estimation,
otoacoustic emissions cannot be used to determine
specific thresholds, only to infer threshold ranges.
Generally, when otoacoustic emissions are present, one
can infer the presence of auditory thresholds no poorer
than approximately 30 to 35 dB HL (hearing level);
analyzing individual band reproducibility and signal-to-
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
synchronously activating the auditory pathway for this
patient. She received a cochlear implant at age 2. Using the
cochlear implant, detection threshold levels in the 35 to
40 dB HL range were established (Fig. 18-6), which com-
pared favorably with her preimplant audiometric studies.
ELECTROCOCHLEOGRAPHY
The term electrocochleography refers to the recording of
acoustically evoked neuroelectric events generated by the
cochlea and the auditory nerve. Early cochlear-produced
potentials and auditory nerve action potentials constitute
the electrocochleographic response.
Electrocochleographic measurements may be obtained
using several recording techniques. The original method
of electrocochleographic recording involves placing a
transtympanic needle electrode on the promontory.
dB
60 L1
L2
DP
40 NF
Although this type of recording results in a very large ampli-
tude response, it is an invasive method not well accepted by
a substantial proportion of patients. Noninvasive methods
are available (i.e., a gold foil “Tiptrode,” or Coats’ “Leaf”
electrode) but may be less efficient in providing an inter-
pretable response or may be uncomfortable for the patient.
Another noninvasive recording device uses a soft
hydrogel-tipped electrode placed against the lateral
tympanic membrane surface under direct visual control
(“TM-ECHochGtrode,” manufactured by BioLogic
Systems Corp.). This electrode can provide consistent, satis-
factory resolution of the cochlear microphonic, summating
potential, and action potential. Although response ampli-
tudes obtained with the hydrogel device are reduced when
compared to those obtained with a transtympanic needle
electrode, the noninvasive, comfortable nature of this
recording paradigm obviates the need for a physician’s
involvement in electrode placement without sacrificing
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
transducer tip, and in our experience it is tolerated well by
patients as young as 10 and 12 years of age.

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).

CI Detection Skills
0
Hearing level in dB (ANSI-96)
10
20
30
C C
40 C C C CM
50
60
70
80
90
100
110
250 500 1K 2K 4K 8K
Frequency in Hz
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).
Electrocochleography consists of the following
components:
1. The cochlear microphonic (CM), an alternating
current (AC) potential that closely resembles the wave-
form of the acoustic stimulus and reflects changes in
the resistance of the outer hair cells during stimulation.
To obtain a cochlear microphonic, click or tonal stim-
uli must be delivered in a constant polarity fashion.
2. The summating potential (SP), a direct current (DC)
potential that follows the stimulus envelope, appearing
as a baseline shift of the recorded cochlear micro-
phonic. It arises from DC intracellular potentials
generated by hair cells. To resolve the SP better, stim-
uli must be delivered in an alternating polarity fashion;
otherwise, individually obtained condensation and rar-
efaction responses are summed to cancel out the
cochlear microphonic.
3. The eighth nerve action potential (AP) is the equivalent
to wave I of the ABR, reflecting the summed activity
of synchronously firing cochlear nerve fibers.
We recommend the following recording technique: prior
to placement of the tympanic membrane surface electrode,
self-adhering surface electrodes are placed in the midline of
the forehead just below the hairline, and on each mastoid.
This allows one to simultaneously record an electro-
cochleogram (ECoG) from the ear with the tympanic
membrane (TM) electrode as well as an ABR wave V from
the contralateral side. Clicks of alternating or constant
polarity and tone burst stimuli are presented at an intensity
of 85 dB nHL or greater if the patient has a substantial
hearing loss. One or two kilohertz (kHz) tone bursts have a
5-millisecond rise time and a 10-millisecond plateau.
Figure 18-7 shows a click-evoked ECoG with well-defined
SP and AP components (top trace), a contralaterally recorded
ABR with the wave V marked, and a tone burst ECoG
consisting of a cochlear microphonic with no discernible SP.
Electrocochleography is used most as a neurotologic
diagnostic aid in identifying cochlear hydropic conditions
associated with Ménière’s disease and other cochleopathies.
It is thought that the presence of hydrops alters the
Objective Measures of Auditory Function 291
AP amp
ECoG
Base SP amp
ABR v
ECoG/ABR recording
Sensitivity and Sweep Time/Division
ECoG: 1.24 uV 1.0 msec
ABR : 1.24 uV 1.0 msec
CM : 0.31 uV 1.0 msec
Figure 18-7. Two-channel recording consisting of electrocochleographic
and auditory brainstem responses (top two traces); the lowermost tracing is
the cochlear microphonic response to a tone burst stimulus with no dis-
cernible summating potential.
mechanical characteristics of the basilar membrane and
contributes to the increased amplitude of the SP considered
to be diagnostic of endolymphatic hydrops.19
In order to reduce interpatient variability, the ratio
between the amplitude of the SP and the AP (SP/AP ratio)
is employed instead of measuring the absolute amplitude
of the SP.20 Owing to the increase of the SP amplitude
associated with endolymphatic hydrops, patients are
expected to exhibit larger SP/AP ratios. In a study of subjects
with normal hearing for age,21 SP/AP amplitude ratios
recorded extratympanically ranged from 0.04 to 0.59. Other
studies have found similar values of the ratio in normal-
hearing patients. Using transtympanic recordings, Gibson
and colleagues22 calculated SP/AP ratios that ranged from
10% to 63%. However, the sensitivity of this measurement
appears limited because an overlap exists between SP/AP
ratios of patients with (nonhydropic) cochlear hearing loss
and patients with classic symptoms of endolymphatic
hydrops. Coats and colleagues23 found that 44% of
Ménière’s ears tested fell under the 95% upper limits of
normal ears. This translates into a sensitivity of only 56%,
reflecting the fluctuant nature of hydropic conditions.
Increased amplitude of the SP/AP ratio is not limited to
hydropic conditions. Marangos and colleagues24 reported
increased SP/AP amplitude ratios in patients with CP
angle tumors. Therefore, caution should be exercised to
avoid the missed diagnosis of CP angle tumors that may be
associated with increased SP amplitude. A normal SP/AP
amplitude ratio does not rule out endolymphatic hydrops
and an increased ratio should be considered a supportive,
but a nonpathognomonic finding of hydrops.
The following clinical criteria for electrocochleography
are used in our clinic: SP/AP ratio exceeding a value of
0.40 with click stimuli; summating potential amplitude for
tone burst stimulation of 2 microvolts or more. The N1
(or AP) component condensation-versus-rarefaction click
latency difference has not been used systematically in
our clinic.25 If it is used, a difference greater than
0.38 milliseconds (condensation latency is greater than
rarefaction latency) is considered abnormal. The electro-
cochleography criteria are based on the following clinical
assumptions: In the presence of hydrops, a distended scala
292 NEUROTOLOGIC DIAGNOSIS
media results in an increase of the negative SP amplitude
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.
The increase in the amplitude of the negative SP alone or
in combination with a decrease in AP amplitude is the
underlying cause for the increased SP/AP amplitude ratio
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.
A 42-year-old woman came to our clinic with a 5-year
history of episodic vertigo, progressive right ear hearing
loss that fluctuated, and right-sided tinnitus and aural
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-
went an electrocochleographic evaluation. Both clicks and
1000-Hz tone bursts were used as stimuli. As illustrated in
Figure 18-9, she presented with a normal SP/AP ratio of
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-
phy was characterized by a prominent SP with amplitude
of approximately 2 microvolts in her right ear (top trace)
as opposed to a barely measurable SP with the same stim-
ulus in the left ear (lower trace). The increased SP ratio on
the right side as well as the large amplitude SP obtained
with tone burst stimulation helped confirm a diagnosis of
Ménière’s disease in her right, symptomatic ear. Notably,
the caloric test results obtained during the patient’s
vestibular evaluation showed a reduced caloric response in
the right ear compared to the left but in absolute terms still
within normal limits. Consequently, the interpretation was
“paretic lesion in the right ear or an irritative lesion in the
left ear.” The presence of abnormal electrocochleography
in conjunction with right ear symptoms helped determine
the laterality of the disease.
0 figure illustrates a normalization of the SP/AP ratio
10
dB (ANSI S 3.6, 1996)
20
30
40
50
60
70
80
90
SRT %
RE 30 92
LE 05 100
250 500 1,000 2,000 4,000 8,000
Frequency in hertz (Hz)
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
left ear and a moderate lower frequency hearing loss in the right ear; speech
audiometrics are compatible with the pure tone information.
AP amp
SP amp
LE: 0.3
Base
AP amp
SP amp
RE: 0.6
Base
ECoG: SP/AP<Rt. side
Figure 18-9. Electrocochleographic responses from a 42-year-old woman
with unilateral hearing loss (see Fig. 18-8). The summating potential (SP) to
action potential (AP) amplitude ratio is beyond the normal limit of 0.4 when
measured from the right ear.
Electrocochleography may also be used as an objective
indicator of treatment efficacy. This is illustrated by the
following case involving a 55-year-old patient with a several-
year history of left-sided Ménière’s disease. Over the years,
he had been treated conservatively with low-sodium diet
and diuretics; however, he continued to have spontaneous
vertiginous episodes and fluctuating low-frequency hearing
loss. He was seen in our clinic, where he received a pressure
equalization tube placed in the left tympanic membrane in
preparation for treatment with the Meniett device
(Medtronic Xomed). This device is recommended to alle-
viate symptoms of Ménière’s disease and it delivers brief
pressure pulses through a tympanometry-like ear tip placed
into the ear canal. For some patients this type of treatment,
which is recommended 3 times a day for 5 minutes, results
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
from a value of 0.7 to a value of 0.34. It is of note that the
RE
SP
LE
1.2 uV
2 msec
ECoG: CM on large SP, RE
Figure 18-10. Tone burst-evoked electrocochleography reveals a prominent
summating potential from right ear responses (top trace); combined with an
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
Base
Pre: 0.7
AP amp
SP amp
Base
Post: 0.34
ECoG: pre- v. post-treatment
Figure 18-11. Electrocochleography results from a patient treated with
a Meniett device (Medtronic Xomed) for Ménière’s disease. Note the
increased amplitude of the action potential (AP) in the post-treatment
condition. A delay in the absolute latencies of responses in the lower trace is
due to a pressure equalization tube in the left tympanic membrane.
amplitude of the AP is increased in the post-treatment
waveform. The post-treatment latency is slightly delayed
with respect to the treatment latency owing to the pres-
ence of the PE tube.
AUDITORY BRAINSTEM RESPONSE
The ABR is the averaged surface-recorded activity from
multiple-source neural generators in the peripheral and
lower central auditory nervous system and represents the
synchronous discharge activity of onset-sensitive single
units from first- through sixth-order neurons (Fig. 18-12).
The high-intensity ABR is characterized by five or more
waves, the positive peaks of which are conventionally
labeled with Roman numerals.2,27 Studies by Moller and
through V to the auditory pathway between the cochlear
nerve and the nucleus of the lateral lemniscus in the mid-
brain. Waves I and II are generated by activity at the distal
and proximal cochlear nerves, respectively. The presence
of two action potentials originating from activity within
the same cranial nerve is attributed to a transition in nerve
fiber covering from the central neuroglial cells to the
peripheral Schwann cell endoneurium at the segment of
the auditory nerve nearest the porus acusticus. Near-field
recordings enhance both waveform peaks, as seen in
electrocochleography.
Activity in the cochlear nucleus and in the superior olivary
complex is represented by ABR waveform peaks III and IV,
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
temporally with the post-wave V negativity recorded on
the scalp. Waveform peaks IV through VI are highly complex
and probably reflect multiple neural generator activity.
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
are brief rectangular pulses of constant or alternated polarity,
while tonal stimuli may be characterized as sinusoidal
signals with brief rise, fall, and plateau durations. To be
effective in evoking a response, the intensity level of the
acoustic stimuli must lie within a patient’s dynamic range.
Therefore, patients with severe to profound hearing
losses are less likely to have an ABR. In order to ensure
that the highest-quality ABRs are recorded, stimulating
and recording parameters are carefully adjusted for the
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
Stimulus type* Click, 1-kHz tone burst
Stimulus rate† 21.1/sec
Stimulus rise, fall time‡ Click: NA; tone: 2-0-2
Number of sweeps 2000–3000
Intensity (or range) 75–95 dB nHL
Stimulus delivery§ Insert earphone
Bandpass settings (Hz) 100–3000
Amplification × 100 k
Analysis duration 15 msec
*Alternating polarity used for neurodiagnostic testing to reduce spread of stimulus
artifact into recording; single polarity clicks useful to visualize cochlear microphonic in
auditory neuropathy/auditory dys-synchrony.
†
Rate, number of averages increased in studies of the effects of demyelinating disease.
‡
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
the like.
assessments should be conducted before neurodiagnostic
ABR testing.
The ABR is a far-field representation of responses along
the auditory pathway. The term far-field indicates that
recording electrodes do not directly contact anatomic gen-
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
site(s) and recording site. Second, other sources of electrical
noise may obscure the ABR. Such “competing” electrical
signals may have electroencephalographic, electrocardiac,
or electromyographic sources, or they may originate from
electrical devices in or proximal to the test location or
from an essential medical monitoring device such as a
pulse oximeter. Unless properly controlled and canceled,
the competing electrical potentials can easily diminishing
ABR waveform quality.
Optimizing the electrode sites via thorough cleansing
and gentle abrasion techniques is crucial. So, too, properly
selected recording parameters enhance the ABR recording.
For example, the ABR consists of energy in a specific band.
Bandwidth filters set to record responses in the approximate
frequency range 20 to 3000 Hz provide a high-quality
recording that includes all waveform peaks (Fig. 18-13). In
the figure, note that relatively smaller changes are evident
after opening bandpass settings beyond 20 to 1000 Hz,
attesting to the dependence of the ABR on energy at or
below 1000 Hz.
Several technological tools exist that allow an examiner to
extract electrophysiologic target responses from competing
noise. These include the following:
1. Differential amplification, which functions by reject-
ing voltages with equal or common amplitude and
phase at positive and negative inputs, referenced to
ground; then, the remaining difference in voltage at
those two inputs is amplified. This process is known
as common mode rejection.
2. The ratio of common mode noise rejected, specified
in decibels; larger decibel ratings indicate better
Hearing Estimation
Click; 0.5 to 2-kHz
tone burst 20–250 Hz
31.1/sec
Click: NA; tone: 2-0-2
1200–4000
05–95 dB nHL
Insert, supra-aural,
bone-conduction
transducers 20–1000 Hz
20/30–3000 Hz
× 100 k
20–25 msec
v
III
I
20–3000 Hz
0.31 uV
1.5 msec
Figure 18-13. ABR waveforms reflect alterations in bandpass filter settings.
Note the slow-wave component of the ABR in the uppermost ABR tracings,
upon which wave peaks ride; second, observe improved clarity of waveform
peaks once the high-frequency cutoff reaches or exceeds 1000 Hz, confirm-
ing ABR dependence on relatively low-frequency energy.
amplifier gain.29 The capacity for common mode signal
rejection depends largely on preparation, that is, the
physical layout of the test area in relation to devices
that generate electrical fields, the shielding of the
measurement channel(s), and the quality of compo-
nents such as leads used to record responses.
3. Signal averaging, which is important for measurement
of low-amplitude, repetitive responses time-locked
with a precise trigger source (synchronized response
summing); the amplitude of unsynchronized noise
diminishes with successive averaging, decreasing by
the square root of the number of sweeps resulting in
a signal-to-noise ratio above unity. Larger response
amplitudes are obtained with greater stimulus intensity
and generally require fewer averages. Approximately
1500 to 2500 samples typically produce adequate
signal-to-noise ratios. Figure 18-14 demonstrates the
improvement in ABR waveform morphology that can
be expected when additional sweeps are included in
the averaging process.
Investigators have used four-channel recordings to more
accurately identify individual components of the ABR in
patients who have intracranial injuries30 or acoustic nerve
tumors.31 In the latter report, the investigators used
Tiptrode ear canal reference electrodes and reported that of
the four recording choices, the ipsilateral record afforded
the best neurodiagnostic information. Presumably, this
reflected the somewhat “nearer-field” recording of ABR
responses, adding to the amplitude of individual com-
ponents and leading to improved signal-to-noise ratios.
A four-channel ABR was obtained at 80 dB nHL from a nor-
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
v v
I III (70) (55)
v v
(20) (45)
v v
(10)
(05)
0.31 uV
2.0 msec
Auditory brainstem responses
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.
The latencies of the responses to tonal stimuli are prolonged relative to the
click ABR responses, and tonal amplitudes are reduced as well.
the technique has higher sensitivity and associated costs,
requires a more sophisticated and experienced operator,
and limits screening statements to higher-frequency hearing.
“Refer” results mandate rescreening with ABR or otoa-
coustic emissions. Based on the outcome, diagnostic evoked
potential testing may be needed.
Click-evoked ABR threshold testing continues to be a
common procedure, despite the significant limitations asso-
ciated with use of transient stimuli.35 Investigators continue
to search for protocols that produce threshold results that
simulate the “speech-frequency band,” that is, 0.5 to 2 kHz
of the audiogram. Retrospectively, click threshold results
have been found to correlate best with high-frequency
thresholds near 2000 Hz.36–38 These findings are partially
attributable to changes in the frequency and amplitude
characteristics of broadband, rapid-onset stimuli that are
delivered to the diminutive, pliable infant ear canal via
an insert transducer through 26 centimeters of flexible,
polyethylene tubing.
Gorga and colleagues39 compared click-evoked ABR
threshold and latency characteristics to pure tone audio-
metric findings in normal-hearing (N = 22) and sen-
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
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
during hearing screening and in subsequent hearing
threshold estimation, tonal stimuli are used with ever
greater regularity. This is due to the recognition of certain
inherent limitations associated with the use of click stimuli
as well as the desire to more closely approximate the behav-
ioral audiogram for precise amplification fitting. Lower-
frequency hearing estimates via the click ABR are less
predictable.41 So-called ramped tonal stimuli have longer
temporal characteristics (on and off times as well as plateau
duration) and reflect the activity of fewer neural fibers.42
(35)
The morphology of the tonal ABR waveform is dissimilar
to click-evoked responses, reflecting fewer contributing
(25) neural elements and a more apical orientation in its gener-
ation along the basilar membrane. Absolute latencies of
tonal ABRs are prolonged and amplitudes may be reduced
(see Fig. 18-16). Extended averaging will result in improved
morphologic characteristics such as improved signal-to-
noise ratios and more distinct waveform peaks while pro-
viding averaged results that are better suited to threshold
determination.
As alluded to earlier, the impetus to establish universal
hearing screening and provide appropriate, comprehensive
habilitation propels the desire to record frequency-specific
ABRs. Appropriately programmed amplification will be fit
to newly identified hearing impaired infants. There are
numerous methodologies for tonal ABR evaluation and
Hyde43 summarized many of them. For example, a spectrally
constrained transient stimulus with a nominal center fre-
quency is delivered to the test ear; masking may be used in
the contralateral ear. It is useful to know how much side
band energy is present above and below the center fre-
quency. Nonlinear gating functions (e.g., Blackman, cosine
square) help to attenuate side band energy characterized
by approximately 30 dB of attenuation within one octave
from the nominal center frequency (Fig. 18-17). However,
differences in results obtained using various gating strategies
may be less than expected. Purdy and Abbas44 reported
2-kHz and 4-kHz tone burst ABR thresholds exceeded
behaviorally elicited thresholds by 10 to 13 dB using either
linear or Blackman gating. This investigation emphasized
the importance of setting appropriate filter bandwidths
when using tone burst stimuli; that is, appropriate low-
frequency weighting must be a recording parameter choice
when using tone burst stimuli with a center frequency
below 1000 Hz.
2.031 kHz
31.25 Hz 3.156 kHz 6.281 kHz
Figure 18-17. Spectral waveform of a Blackman-gated tone burst with a
center frequency equal to 2031 Hz used in ABR frequency-specific estimates
of hearing sensitivity. Sideband energy peaks were −28 dB relative to peak
energy at 2031 Hz.

The efficiency with which tonal ABR thresholds predict
behavioral audiometric thresholds continues to be scruti-
nized. Stapells45 performed a meta-analysis of the literature
concerning air conducted tone-evoked ABR testing in
children and adults. Thirty-two investigations were
reviewed, representing the results from 1203 subjects
including 388 subjects with sensorineural hearing loss. He
reported that tonal ABR thresholds in normal listeners
ranged from 10 to 20 dB nHL. In the group of hearing-
impaired subjects, tonal thresholds were 5 to 15 dB higher
than behavioral thresholds in adults and were ± 10 dB than
behavioral thresholds in infants. The use of the tone-
evoked ABR was strongly encouraged. In a retrospective
study that compared behavioral pure tone and electro-
physiologic thresholds, Edwards and colleagues46 reported
that a combination of click, 0.5 kHz, and 1.0 kHz frequency
tone burst thresholds, when averaged and given one of
four data set assignments reflecting average thresholds
from normal to severe, compared favorably to similarly
ranked behavioral assignments. They reported that despite
a 100% incidence of recurring otitis media, a combination
of air- and bone-conducted ABR testing produced results
with good predictive value for identifying both type and
magnitude of hearing loss. Notably, the data were skewed
toward moderate and greater degrees of hearing loss,
reflecting the common hearing status of multiply involved
children with CHARGE syndrome.
Several salient points must be considered when comparing
electrophysiologic and behavioral test results. They
include the following:
1. Significant differences in calibration methodologies
for electrophysiologic and audiometric tonal stimuli
2. Discrepancies between ABR stimulus intensity as
“set” on test equipment versus the actual output
measured in the ear canal (particularly in younger
patients with small volume ear canals), which can lead
to underestimation of actual ABR stimulus intensity
3. The possibility of fluctuating or progressive hearing
loss, as in patients with large vestibular aqueduct
syndrome or those with a genetic predisposition for
progressive hearing loss
4. Spectral differences between electrophysiologic
stimuli, particularly brief, broadband clicks, and audio-
metric thresholds38
ESTIMATING AMPLIFICATION BENEFIT:
ELECTROPHYSIOLOGIC PROCEDURES
The early provision of appropriately fitted amplification is
a worthy goal toward which hearing professionals strive.
Unfortunately, until newborns and infant children achieve
developmental levels that allow one to obtain reliable and
valid behavioral test results, “appropriately fitted amplifi-
cation” is an objective reached via a combination of care
provider observation and subjective scaling measures.
Prescriptive fitting measures based on electrophysiologic
data are helpful for managing multiple amplification char-
acteristics but do not functionally describe the effect of the
intervention on hearing sensitivity. Thus, efforts continue
Objective Measures of Auditory Function 297
that aim to develop an objective clinical technique to
gauge aided benefit better in very young patients.
Many investigations have analyzed the use of the ABR as
an objective measure of amplification benefit for infants
vis-à-vis the absolute latency of ABR wave V referenced to
normal listeners.47 Although transient clicks have been
shown to have a role, tonal stimulus artifacts contaminate
evoked responses,48 and an inability to describe changes in
evoking stimuli by amplification has presented challenges.
Further, the failure of click-evoked ABR to adequately
define lower-frequency gain49 and demonstrate the utility
of compression circuits in hearing aids50,51 has curbed
investigational interest.
Despite these hurdles, objective techniques continue to
be examined to determine their role in assessing aided
benefit. For example, Purdy and Kelly52 reported that the
cortical auditory evoked potential (CAEP)53 might be
effective during hearing aid assessments by using speech
stimuli. Until approximately 7 years of age, a large, late P1
response dominates the CAEP and may help to demonstrate
the benefits of amplification in youngsters reported by
Rapin and Graziani54 and Gravel and colleagues.55 With
inherently higher face validity than tonal stimuli, longer
duration speech stimuli (cumulative durations of 30 to 75 ms,
onset duration longer than 10 ms) might also better assess
the utility of compression circuitry, broadening the scope
of hearing aid assessment56 and may help to moderate several
of the technical difficulties mentioned earlier such as stim-
ulus ringing and an inability to demonstrate input-output
characteristics of an amplification device.
Auditory steady-state responses (ASSRs) are elicited by
amplitude-modulated tones that are common in infants
and unaffected by sleep.57 Multiple tones can be presented
simultaneously to each ear for threshold testing, while
amplitude-modulated tones transduced through free-field
speakers resist distortion, making them ideal stimuli for
assessing aided hearing. Picton and colleagues58 sought out
aided threshold responses using ASSRs in a group of 35
older children with hearing impairment. One goal of the
study was to compare ASSRs and behavioral thresholds in
developmentally advanced children in order to be able to
estimate the predictive ability of ASSR results for very young
children and others who would not be able to offer behav-
ioral responses. The investigators discovered that
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
of aided, cooperative children. Picton’s group suggested
that responses to such amplitude and frequency-
modulated stimuli might better evaluate aided speech
perception processes while determining both audibility
and discrimination ability.57
ACOUSTIC NEUROMA DIAGNOSIS WITH
THE AUDITORY BRAINSTEM RESPONSE
Mass lesions of the retrocochlear pathway are thought to
produce ABR abnormalities through pressure on, displace-
ment of, or attenuation of the auditory nerve or auditory
brainstem. Depending on its volume and location, a mass
298 NEUROTOLOGIC DIAGNOSIS
in proximity to retrocochlear auditory structures may atten-
uate, delay, or abolish certain ABR waveform components.
This model for ABR interpretation may be applicable in
cases where tumor involvement with the auditory pathway
is discrete and when preexisting hearing thresholds are
normal. However, these principles frequently may not
apply because of preexisting pathology leading to extensive
interplay between brainstem components in processing
auditory stimuli.59,60 Therefore, use of the ABR for diagnos-
tic purposes mandates consideration of other supporting
audiologic information.
A good example is provided by the absence of an ABR in
an ear with a severe hearing loss. If an inadequate stimulus
level is used to generate electrophysiologic responses, test
results may be misinterpreted inappropriately and elevate
one’s index of suspicion for an eighth nerve or brainstem
lesion. Clearly, the ABR should be evaluated with suitable
attention paid to the patient’s hearing levels at the time of
the test. Accordingly, cochlear dysfunction can often be
compensated to enhance the accuracy in the ABR-directed
assessment of the auditory pathway.
Differential diagnosis based on the ABR involves a
strategy that considers several characteristics of evoked
waveforms. This “hierarchy of analysis” assesses the overall
configuration of the response and its composing waves in
the context of the hearing status.
The first step in the analysis is to determine the presence
or absence of an ABR evoked by an appropriate stimulus.
For instance, in the presence of severe to profound hearing
impairment at frequencies exceeding 500 Hz, morpholog-
ically defined responses to 75 dB nHL clicks are not
anticipated.
The second level of ABR analysis verifies the presence of
all major composite peaks and their replicability. If the
recorded waveforms are of sufficient technical quality, the
following characteristics apply:
1. Wave V should stand out as the most robust of the
ABR components in normal-hearing subjects and the
most resilient component in patients with cochlear
pathology, with threshold preserved at or near behav-
ioral threshold levels.
2. Wave I is less robust and its morphology fails to
resolve at stimulus levels below 40 dB SL. An absent
or poorly resolved wave I (with waves III and V pres-
ent) with moderate to severe sensorineural hearing
loss carries little implication for retrocochlear function;
however, the absence of waves III or V, or both, with
a robust and well-defined wave I is highly sugges-
tive of auditory brainstem impairment. Absence of
components beyond wave I can occur in cases
of acoustic neuroma with or without significant
hearing loss.
The third level of ABR interpretation measures the
latencies of waveform peaks and intervals between peaks,
provided the morphology of the response permits. I–III
and III–V interpeak latencies are measured and compared
with normative data. Normative data are plotted as a fre-
quency distribution that incorporates standard deviation
intervals. I–III and III–V latencies are classified as normal
if the values fall within the 95% confidence interval for
mean latencies.
When wave I is not attainable, the absolute latencies of
wave V should be determined bilaterally, and interaural
differences (ILD-V) calculated. Hearing impairment,
whether conductive, cochlear, or retrocochlear, prolongs
wave V latency.
In the presence of a hearing loss, ILD-V is interpreted
with consideration given to the magnitude of the hearing
loss at 4 kHz. Appropriate adjustment of wave V latency
diminished the false-positive rate from 24% in the uncor-
rected condition, to 8% of a group of 266 patients with
unilateral sensorineural hearing loss. In a group of 94 con-
firmed cases of acoustic neuroma, the same correction for
hearing loss at 4 kHz produced a false-negative rate of 2.3%
(3 patients).61 Rosenhamer and colleagues62 recommend an
adjustment of 0.1 ms/10 dB increment in hearing threshold
above 30 dB at 4 kHz.
The audiometric configuration has been shown to influ-
ence the I–V interpeak latency. Keith and Greville59 found
increased I–V interpeak latencies in patients with notched
high-frequency hearing loss in the absence of CP angle
lesions. This probably reflects the greater role assumed by
high-frequency generators in producing wave I relative to
those responsible for wave V. The I–III interpeak latency
is influenced to a lesser extent by cochlear hearing loss.
Moreover, the most reliable ABR manifestation of an
acoustic tumor appears to be an increase in the I–III
interpeak latency on the affected side.63,64 This interval is
therefore recommended for neurotologic diagnostic appli-
cations whenever these peaks are available.
When the lack of definition of the ABR obtained with
clicks prevents measurement of interpeak latencies, narrow-
band tonal stimuli may take advantage of lower thresholds
at specific frequencies. To use lower thresholds at 1000 Hz
in evoking the ABR, 1000-Hz tone pips can supplement
the click-evoked ABR. Suggested parameters for 1000-Hz
tone pips include gating with a nonlinear function
(Blackman) using a 1-ms rise-fall time and a very brief
plateau (100 ms).
In selected cases, Telian and Kileny65 found the use of
1000-Hz tone pips helpful in circumventing the effects of
elevated thresholds in the 2000 to 4000 Hz range on the
click-evoked ABR. Of 17 patients with surgically confirmed
acoustic neuromas, 15 of which presented with sloping
high-frequency SHL, reliable evidence of retrocochlear
involvement could be made from the click-evoked ABR in
only 5 cases based on abnormal interpeak latencies and
ILD-V. In two patients, wave V was the only replicable and
identifiable component for both clicks and 1000-Hz tone
pips, and the diagnosis of retrocochlear involvement.
Some of these were cases where click responses were
absent and the diagnosis was based on the significant pro-
longation of wave V latency for tone pips. In other cases,
despite the fact that the ILD-V for clicks normalized after
correcting for hearing loss at 4000 Hz as recommended by
Selters and Brackmann,61 the ILD-V for tone pips was
significantly prolonged in spite of symmetric hearing
sensitivity at 1000 Hz.
Recently, the auditory brainstem response has come
under scrutiny for the detection of small acoustic neuromas;
that is, sensitivity has been reported to range from 63% to
93%. A recent study66 reported on 25 patients with surgi-
cally proven small acoustic neuromas measuring 1 cm or less.

The ABR was abnormal in 92% of patients in this series. Our
data shows that when using optimal technique including the
combination of click- and tone-evoked ABR, the ABR sensi-
tivity for small acoustic neuromas can be increased to a clin-
ically acceptable 90+%. Like other diagnostic tests, the ABR
is only as good as the operator and the interpreter. This is
also true for imaging studies with a theoretical sensitivity
approximating 100%; however, poor imaging quality or
interpretation error can alter this high sensitivity.
A novel approach to diagnosing small acoustic neuromas
with the ABR was developed by Don and colleagues.67
These investigators coined the concept of the “stacked
derived-band ABR.” The diagnostic criterion here is the
amplitude of a reconstructed auditory brainstem response
from the sum of click-evoked ABRs obtained with different
ipsilateral high-pass filtered noise. By embedding clicks in
high-pass filter noise with different cut-off frequencies,
ABRs are generated that represent different, specific fre-
quency regions along the basilar membrane. Responses
within this set have different latencies dictated by place of
stimulation along basal and more apical basilar membrane.
Those obtained from the more apical regions have a
longer latency than those obtained from the basal region.
Averaged responses are realigned and summed to obtain a
reconstructed grand average. Don and colleagues found
that the amplitude of the reconstructed ABR was sensitive
to the presence of small acoustic neuromas; that is, it was
reduced when compared to normal ears with no acoustic
neuroma or to the contralateral ear of a patient with a uni-
lateral acoustic neuroma. These investigators surmise that
summing the ABRs obtained from different regions along
the basilar membrane provides the total neural-synchronous
response to stimulation. Amplitude reduction most likely
reflects the reduction in the number of stimulable neural
elements in an ear with an acoustic neuroma. This technique
is not in widespread use, although the software is available
on at least one commercial-evoked potential instrument.
Measurement Criteria for Diagnostic
Auditory Brainstem Response
The diagnostic sensitivity and specificity of absolute and
interpeak latency measures depends on how normal limits
are specified. For example, “normal” defined by wave latency
+/− one standard deviation of the mean (derived from a pop-
ulation of normal subjects) will produce few missed cases
(high sensitivity) and a larger number of “false-positive”
findings (low selectivity).
Thomsen and colleagues68 analyzed the effects of the
criteria choice on diagnostic outcome. ILD-V values in
27 patients with surgically confirmed acoustic neuromas
were compared with ILD-V values in 70 patients with
Ménière’s disease. A criterion of ILD-V more than 1.0 ms
for ABR positivity produced no false-positives and a 15%
false-negative rate (i.e., confirmed tumor cases classified as
nontumor). When ILD-V criteria were restricted to 0.5 ms,
there was an increase in the false-positive rate to 11% and
a reduction of the false-negative rate to 4% (only one
tumor case classified as nontumor). Further restriction of
the ILD-V criterion to 0.3 ms left the false-negative rate
at 4% but raised the false-positive rate to 23%, clearly an
effect that can make the ABR test results misleading.
Objective Measures of Auditory Function 299
Mangham69 investigated the performance of ABR with
and without sinusoidal harmonic acceleration testing. The
study included 74 patients with acoustic tumors and
78 controls. ABR testing outperformed harmonic acceler-
ation alone or in combination with the ABR and proved
to be more cost-effective than a protocol that included
both ABR and sinusoidal harmonic acceleration. When
the Selters and Brackmann61 criterion for ABR positivity
(ILD = V > 0.2 msec) were applied, the sensitivity of the
ABR testing alone was 94% and its specificity was 79%. In
a hypothetical case with a posterior probability for an
acoustic tumor of 0.01, an ILD-V of 0.2 msec increases
the probability of an acoustic neuroma to 0.047. The
probability of a tumor increases monotonically until the
ILD-V reaches a value of 0.7 ms, the point at which
there is little increase in the posterior probability for a
tumor.
Based on data collected in normal subjects and confirmed
cases of acoustic neuroma in the Audiology Clinic at the
University of Michigan Medical Center, criteria for a
positive test result are as follows:
I–III > 2.3 msec; III–V > 2.1 msec;
I–V > 4.4 msec; ILD-V > 0.4 msec;
ILD-V (1-kHz tone burst) > 0.60 msec.
For several years, the authors have evaluated the neuro-
diagnostic applications of tonal or frequency-specific ABR.
Previously, we investigated the feasibility of using 1-kHz
tonal ABR in normal-hearing subjects and in patients with
high-frequency hearing loss beyond 1 kHz.
A comparison of wave V latencies between these two
groups indicated an absence of statistically significant
differences for 1-kHz stimuli, indicating the utility of this
stimulus for neurodiagnostic applications. The mean
latency for the normal group was 6.35 ms compared with
6.45 for those with high-frequency hearing loss. That is,
the latency of 1 kHz was not affected by the presence of
high-frequency hearing loss. The mean latency for clicks
was 5.6 ms for normals and 5.9 ms for high-frequency
losses, which was statistically significant.
We then compared wave V latencies to 1-kHz tonal
stimuli between two audiometrically matched groups, one
with cochlear hearing loss and the other with confirmed
acoustic neuromas. As expected, patients with acoustic
neuromas had significantly prolonged wave V latencies
when compared with their audiometrically matched
cochlear hearing loss counterparts. Patients with cochlear
losses had a mean latency of 6.7 ms, while the acoustic
neuroma patients had a mean latency of 7.6 ms, representing
a statistically significant difference.65
Gorga and colleagues70 also reported reliability in
ABRs to tone bursts covering a wide range of frequencies
and levels in normal subjects. They found the flexibility
offered by tonal stimuli to be helpful in evaluating subjects
with various configurations of hearing loss. Fowler
and Mikami71 in a retrospective analysis of patients
with asymmetrical cochlear losses reported a high
correlation between ears for wave V latency evoked with
1-kHz tone bursts. She further suggested that 1-kHz
tone bursts can supplement interpretation of click-
evoked ABR in patients with significant high-frequency
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.

+ III v Neural Response Telemetry
II
LE
RE
.50 uV
2 msec
− Time (msec)
EABR @ 600 uA
Figure 18-23. Transtympanic electrocochleography from a 3-year-old boy
undergoing cochlear implant workup. Note the absence of a response from
the right ear (IAC absent on CT).
contamination by movement and myogenic artifacts. The
alternatives are the measurement of electric auditory
potentials (EAPs) recorded via telemetry procedures,
hence the term neural response telemetry, or NRT. These
measurements use the two-way telemetry (currently com-
mercially available for only Cochlear Corporation/Nucleus
implants and Advanced Bionics implants). This can be
accomplished by using one pair of electrodes to deliver the
stimulus and a nearby pair to record the response that is
returned via back-telemetry. The response recorded by elec-
trodes designated as recording electrodes of the implants
array are transmitted back transcutaneously to the speech
processor interface. With certain additional manipulations,
these responses are averaged much like an evoked potential,
displayed on the computer screen, stored, or printed for the
record. This technique does not require surface recording
of electrodes as is the case for standard evoked potential
recording. Because this technique does not employ surface
recording electrodes, these responses are immune to move-
ment and myogenic artifacts so it allows a patient to engage
in some activity during the measurement, which makes
this technique very useful with young patients during initial
programming. Figure 18-24 illustrates a series of EAPs
obtained via neural response telemetry with the Nucleus
24R in a 7-year-old patient with some cognitive delay. He
was difficult to program, although based on these
responses, the map could be established. This illustration
shows responses obtained on electrode 4 with a threshold
of approximately 186 clinical units. A threshold of 155
units was estimated for this electrode with a C level of 204,
based on the assumption that these values fall somewhere
between the actual comfort (C) level and the threshold
(T) level. As shown by Brown and colleagues,79 EAP
threshold at times coincides with actual comfort levels and
at other times falls between threshold and comfort levels.
The responses never exceed actual psychophysical C levels;
therefore, it is safe to use EAP threshold in estimating
mapping characteristics. Hay-McCutcheon and colleagues81
investigated differences between EAPs and EABRs in
adult recipients of the Nucleus CI 24R cochlear implant.
Objective Measures of Auditory Function 303
4 180
4 183
4 186
4 189
4 192
4 195
4 195
127 uV
0.0 0.5 1.0 1.5 2.0
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
youngster. A threshold of 186 clinical units was established for electrode 4.
They found no significant differences between EAP and
EABR threshold levels; therefore, these two techniques
may be used interchangeably in adult populations. It is still
preferable, however, to use the EAP in children who may
necessitate sedation to obtain an EABR.
ACKNOWLEDGMENTS
We would like to acknowledge the contributions of John
K. Niparko, MD, and Karin E. Young, MA, who helped
write the first version of this chapter in 1994. Also, we
would like to recognize and thank Mrs. Janice LaPointe,
secretary to the senior author, who helped prepare the
manuscript.
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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

In the version of this chapter included in the previous
edition of this book, we identified emerging clinical issues
and fundamental questions in the study and evaluation of
the auditory system concerned with (1) identifying the
anatomic sites where various aspects of auditory process-
ing occur in the brain, (2) the temporal nature of the
processing, (3) whether such processing can be measured
objectively, and (4) how such measurements change with
various kinds of pathology. Answers to these issues and
questions are critical prerequisites in understanding the
origin and extent of hearing disorders, which in turn may
be helpful in assessing and guiding rehabilitation
processes.
306
evoked electrical and magnetic potentials recorded at the
surface of the head by means of topographic mapping
(“brain-mapping”) and spatiotemporal source modeling
(STSM) techniques. Although our major emphases in the
previous edition were electromagnetic approaches, we also
touched on functional imaging with positron emission
tomography (PET) and the then newly emerging attempts
to image functionally with magnetic resonance imaging
(fMRI). Since the publication of this chapter over 10 years
ago, significant advances have taken place in all of these
technologies. Much more research has focused on the
potential clinical applications of these techniques. In par-
ticular, the research and application of fMRI has experi-
enced tremendous growth. Numerous published studies

have attempted to identify and characterize neural activity
in cortical areas of the brain while processing simple and
complex (e.g., speech) auditory stimuli. In this chapter, we
now expand our review of the fMRI work in addition to
updating the information on other brain imaging tech-
niques. Again, for each of the various methods we present
a brief description of the technical aspects, the kinds of
information obtained, their advantages and disadvantages,
and the current and future clinical applications in evaluat-
ing the auditory system. The technical complexities
and vast literature on the development and application
of these methods preclude a comprehensive review of either
the technical aspects or application results. Our intention
in this revised chapter, despite its brevity, is that this review
will provide an effective overview of the basic principles
of these techniques, their current and potential value,
and the limitations of the clinical evaluation of auditory
function.
We emphasize at the outset that the techniques
described in this chapter are physiologically based and are
concerned with characterizing the distribution, location,
and temporal variations in amplitude of electric, magnetic,
and metabolic activity from auditory-evoked sources of
neural activity in the cortex. Ten years ago, clinical appli-
cation of these techniques for assessing auditory function
was limited, but we suggested that with continued devel-
opment and evolution, these techniques would prove to be
very valuable in the assessment of cortically mediated
auditory function. During these last 10 years or so, ample
evidence has emerged to support this suggestion.
FUNCTIONAL IMAGING OF
NEUROELECTRICAL AND
NEUROMAGNETIC SCALP ACTIVITY
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
activity. Such a simple review should help the reader
understand these imaging techniques. Also, our focus will
be on the middle and late auditory evoked potential activ-
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
important principles. The point of departure for us is that
from the scalp surface, we can record electrical potentials
Functional Imaging of Auditory Cortical Activity 307
and magnetic fields associated with neural activation
following auditory-sensory stimulation. However, it is
important to acknowledge that some neural activity pro-
duces local current paths that are contained close to the
generator and may not generate the far-field electric and
magnetic fields that extend to and are recordable from
the scalp.
It is generally accepted that the far-field scalp-recorded
brain activity primarily represents excitatory postsynaptic
potentials (EPSPs) produced by pyramidal cells that are
uniformly organized perpendicular to the cortical surface.
It is likely that this far-field activity represents the
synchronous EPSPs of tens of thousands to millions of
cortical pyramidal cells. This far-field activity produces
intrinsically related electric and magnetic fields at the
scalp. A simplistic view of this relationship is to consider
activation of a small segment of neural tissue, as schemat-
ically shown in Figure 19-1. This activation can be repre-
sented in a short length of current flow. The direction of
this small current flow is shown by the arrow and, in this
example, is oriented tangential to the surface of the head.
This is often described as an equivalent current dipole.
Current flows out of the head of the arrow (+ pole) and
flows into the tail of the arrow (−pole), producing both an
electric and magnetic field. The electric field (Fig. 19-1A)
is perpendicular to the magnetic field (Fig. 19-1B).
Temporal variations in the current flow result in temporal
variations in both the electric and magnetic fields. The
advantage of brain-generated electrical potentials and
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,
both electrical and magnetic responses should, in general,
provide similar information because they are intrinsically
related phenomena resulting from current flow due to
ionic movement in the underlying tissue.
Electric Fields
In the past, most auditory evoked response studies
measured the voltage (electrical potential) between two
electrodes on the scalp. One electrode was usually placed
A B
Figure 19-1. Current dipoles and resulting electric (A) and magnetic (B)
fields.
308 NEUROTOLOGIC DIAGNOSIS
at the vertex and the other (reference) at some other
location such as the mastoid or earlobe. Because the
magnitude of stimulus evoked, time-locked neural activity
is very small (orders of magnitude smaller) relative to the
background electrical activity, response averaging tech-
niques are required to average the nonstimulus-locked
component of the electroencephalograph (EEG). The
resultant averaged responses, or voltage waveforms, are
assumed to represent electrical activity from neural struc-
tures at the brainstem, thalamic, or cortical levels depend-
ing on the recording parameters of sampling rate, filtering,
and amplification. The data of interest have been the
latency and amplitude of component peaks in these aver-
aged waveforms. The most important limitation associated
with averaged evoked scalp-recorded electrical potentials
is that the waveform from any given location on the scalp
represents compounded electrical activity evoked by the
stimulus. Given the possibility that more than one area of
the brain contributes to the activity, it is not possible to
separate the contributions from differential recordings
between a single pair of electrodes. That is, the evoked
response waveform from a differentially recorded pair of
electrodes is basically the linear summation of all volume-
conducted electrical activity originating from different
structures and areas of the brain.
Furthermore, the waveform recorded depends not only
on the pattern of activity of the sources, but also on the
location, distance, and orientation of these sources relative
to the recording electrodes. It is possible that peak activity
observed at the surface for a given electrode pair occurs at
a time when none of the contributing sources shows peak
activity. The frequently used method of simply measuring
the latencies and amplitudes of peaks and valleys as direct
evidence of the time and magnitude of specific neural
events is often inappropriate. Such simple recordings
cannot provide unambiguous information about the local
origin of brain activity, nor the true temporal nature of the
underlying activity pattern(s). Nevertheless, we can still
record and use these measures for diagnostic purposes as
long as we do not assume they represent the true activity
patterns of the underlying sources.
Magnetic Fields
The recording of the magnetic fields associated with
cortical currents requires special technical considerations
as well as a magnetically shielded environment to avoid
artifact contamination from extraneous sources. Several
studies5–11 have described recording methodologies for
these minute magnetic fields using magnetic sensors and
SQUID (superconducting quantum interference device)
magnetometers. Just as variations in voltage can be plotted
over time, so can the corresponding variations in magnetic
flux. Thus, magnetic recordings show “peaks” and
“troughs” of magnetic flux amplitude over time.
Some of the issues noted earlier for electrical evoked
potentials also apply for evoked magnetic fields except for
the issue of a reference; magnetic recordings are refer-
ence-free. Unlike electric fields, magnetic fields recorded
at the surface are nearly undistorted by the skull and other
tissue. Compared with the EEG, which is volume-
conducted through fluids, tissue, and bone to the scalp,
smearing and spreading of the magnetoencephalograph
(MEG) is extremely limited. Furthermore, the sensitivity
of MEG drops off approximately twice as fast as a function
of the angle (θ) of the sensor to the source as the sensitiv-
ity of EEG. Consequently, sources of pure tangential
orientation are much more accurately localized by MEG
than EEG.12 However, sources of current in the brain that
are radially (perpendicularly) oriented to the surface are
not detectable magnetically. Moreover, because of the
more rapid drop in sensitivity, magnetic fields from
deep brain structures are typically too weak to be detected
at the scalp surface. Thus, studies that make use of
magnetic recordings are predominately focused only on
surface cortical activity. However, MEG resolution con-
tinues to improve with the advent of technology that
decreases the distance between the detector and the head
and by improvements in signal-to-noise ratios.12 Other
than extremely deep or radially oriented sources, a
magnetic counterpart to any EEG activity can always be
measured.
Both MEG and EEG have advantages and disadvan-
tages. Some debate still persists about which is best for a
given application. Since MEG more accurately locates
sources oriented tangentially and EEG is more accurate
for radial sources, the techniques can be complimentary.12
Williamson and colleagues13 and Hari11 provide clear
succinct reviews of the different advantages of electrical
and magnetic recordings and stress that a combination of
both kinds of recordings will provide the best and most
complete information about underlying neural activity.
Aside from the theoretical issues, practical considerations
may be just as important in determining which technique
is more suitable for a specific clinical application. For
example, MEG recordings require that a patient’s head
remains essentially stationary (in the same position
beneath a set of sensors imbedded in a helmet) for the
duration of a recording. Because EEG electrodes are fixed
to scalp with a water-soluble conductive gel or paste, some
movement is possible. Consequently, for young children,
or for individuals with uncontrollable tremor (e.g., those
with Parkinson’s disease), EEG-based recording may be
more practical. Conversely, the setup and acquisition time
to obtain good-quality (high signal-to-noise ratio) record-
ings can be much shorter for MEG data. Additionally, the
equipment and maintenance costs for multichannel mag-
netic field recordings (i.e., SQUID devices) are far greater
(orders of magnitude) than that for electrical recordings
(i.e., EEG systems). Thus, controversy remains about
whether MEG provides sufficient additional information
and advantages to justify the cost.
The Need for Multichannel Recordings
Single-channel recordings provide limited information
about how the compounded or net electrical or magnetic
activity at a single location on the scalp varies over time.
This is usually appropriate and sufficient when the need
for information regarding the location(s), activity, or the
distribution of the sources is unnecessary for the analyses
and if the requisite information can be observed in that
single-channel recording. However, as Lehmann4 points
out, the electrical potential at any point on the scalp is an

ambiguous value since it is only defined in relation to the
electrical potential at another point. In the following sections
we discuss the principles and techniques of multichannel
recordings and advantages for functional imaging.
Electrical Multichannel Recordings
In order to assess the loci of sources that contribute to the
surface evoked electrical activity, recordings from multiple
locations on the scalp are required. Figure 19-2 (top) shows
typical location of 32 electrodes according to the standard
10–20 system14 and the associated potential waveforms
recorded from those locations. Today, sophisticated
systems permitting the recording, display, and analyses
of 256 channels (electrodes) of electrical potential data
Functional Imaging of Auditory Cortical Activity 309
are not uncommon. In general, the more channels and,
therefore, the closer the spacing between electrodes, the
better the resolution in characterizing the distribution
and in computing the estimated loci of underlying sources
at the brain surface. The upper limit of the number of
electrodes to use remains a practical and theoretical issue.
Typically, evoked responses from sources deep in the
brain (e.g., the brainstem) are recorded with very few
channels because that activity tends to be widely distrib-
uted at the surface of the head. Although it has been shown
that auditory brainstem responses (ABRs) can also be
analyzed with spatial information,15,16 multichannel
recordings to describe the spatial distribution of the
electrical activity are applied mainly to potentials gener-
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
for describing the scalp surface potential distribution, the
recording at each location must be made, by definition of
a voltage potential, with reference to some other locus on
the scalp or body. The issue of the reference electrode is an
important one that can affect interpretation.17 A typical
reference is the mastoid of one ear. Many studies have
been conducted with the two electrodes on the mastoids or
earlobes linked together for a reference in an effort to
minimize certain electrical artifacts of nonneural origin.
However, linking electrodes creates an inherent problem
in that it modifies the electrical potential distribution over
the whole scalp by imposing the same potential on both
ears. In essence, linking electrodes, although not affecting
the generators, may distort the recorded electric fields by
providing an electric “short” between these two loca-
tions.17 Furthermore, the undistorted field cannot be
recovered. Whether such distortions are significant for
typical recording conditions is controversial, but it is best
to avoid this problem by not recording the activity using
linked mastoid or earlobe electrodes. A recommended
approach now adopted by many laboratories is to compute
reference-free data by using an average reference, which is
simply the average of potentials recorded at each electrode
at all times subtracted from each individual electrode.17,18
Typically, we are interested in examining changes in the
evoked responses across the scalp, which are easier to
detect when activity common to all scalp locations (in
essence, a constant, which may be very large relative to the
remaining activity) is removed from the data.
Magnetic Multichannel Recordings
Similar to electrical recordings, the assessment of the loci
of sources that contribute to the surface-recorded evoked
magnetic activity also requires recordings from multiple
locations on the scalp. Although in the early 1980s only
single-channel magnetometers were available, SQUIDs
containing more than 120 channels are now the standard.
The main reason for the increase in channels is the same
as for electrical studies: to improve the resolution for
isolating the loci of the source of activity.
Brain Maps
In brain mapping, the emphasis is no longer on analysis
of waveforms recorded at selected scalp sites but rather
on analysis of the spatial potential distribution over the
scalp at selected times. Thus, spatial analysis by means
of multichannel recordings is necessary because it trans-
forms the potential differences between electrodes into
reference-independent values, which can provide descrip-
tions of activity across the scalp.
In early work, Vaughan and Ritter19 and a number of
laboratories analyzed data from multichannel electrical
recordings. They demonstrated the use of methods and
mathematical algorithms for converting activity from mul-
tiple electrode sites into a topographic map, the so-called
brain map, that approximates an almost continuous plot of
evoked potential amplitudes or current source densities
(CSDs) across the scalp.20–22 These topographic maps,
enhanced by color or gray-scale representation of the
distribution of surface activity, became a popular tool
for studying electrical brain activity during the 1980s.
(For general reviews, see Lehmann et al.,18 Picton et al.,23
and other studies.24–26)
Now these color or gray-scale representations of the
distribution of surface activity are giving way to the use of
equipotential maps1 to avoid bias by the selection of the
color scale and also to emphasize the shape of the voltage
or CSD distribution rather than the peak areas.
Technical Aspects
The principles for constructing a map are similar for
electrical or magnetic activity. The example we discuss is
for electrical activity, that is, voltage maps. At any given
instant, that is, latency, the voltage at each of the record-
ing sites can be presented visually by colors or pseudo gray
scales.20,27 For example, we can specify that the voltage
range of ±100 μV can be presented by the two major
colors, red and blue. The darkest shade of red represents
the maximum positive value of +100 μV. The less positive
the voltage value, the lighter the shade of red. Zero and
nearly zero values will be white. When the voltage
becomes negative, the value is represented by shades of
blue. The more negative the value, the darker the blue.
Similarly, when color use is inappropriate, a computed
pseudo gray-scale map of the activity can be used, with the
dithered gray pattern representing negative and black
representing positive potentials. Since the recorded activ-
ity is only at the specified electrode locations, a map of the
whole surface of the head requires much interpolation.
There are various schemes of interpolation. Thus, if the
value at one location was 40 μV and 60 μV at an adjacent
electrode, then the area between these electrodes would
show, depending on the kind of interpolation, a gradient
of increasing darkness of the red or gray colors, that
represents the increasing positivity from +40 to +60 μV.
Obviously, the more electrodes and closer spacing, the
more accurate the interpolation.
In the earlier edition of this chapter, we provided a
detailed example of the use of the gray-scale method that
will not be repeated here. Instead, we now briefly review
equipotential voltage or CSD maps because they provide
better information about the distribution of electrical or
magnetic activity.
Figure 19-2 (bottom, left) shows the grand mean wave-
forms evoked by a brief click-train recorded from various
locations on the scalp and an equipotential map of the
activity. In this figure, the equipotential maps are shown
for latencies of 100 msec at the maximum of the N1 com-
ponent. For the 100-msec N1 component map, there is a
clearly asymmetrical representation of the activity with a
strong negative/positive reversal over the right scalp, con-
tralateral to the stimulus left ear. These results are consis-
tent with those reported by Borg and colleagues,28 who
found that on isovoltage maps, the focus of the N1 audi-
tory potential is slightly contralateral to the stimulated ear
for most subjects.
In Figure 19-2 (bottom, center), the distribution at a later
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

compound activity of all cortical segments on one side and
in the vicinity of the right side of the cortical fold. Even
the oblique activity can be represented by the radial and
tangential dipoles.
Early Dipole Source Localization Methods:
Single- and Moving Dipole Models
Early dipole localization methods tried to account for the
instantaneous spatial distribution of the scalp potential,
magnetic field, or CSD at a fixed time (see Wood39 for a
good review). These methods involve the use of a physical
model of signal propagation in the head to compute the
expected surface topography usually associated with a
current dipole source having arbitrary parameters. For
electrical potentials, six parameters are usually required to
specify a source (three for position, two for orientation, and
one for strength). For magnetic recordings, five parameters
are required to specify the source (three for location, one
for strength, and only one for orientation since MEG is
sensitive to only tangentially oriented sources). The posi-
tion, orientation, and intensity of the source are iteratively
adjusted to reproduce maximally the target topography.43
Usually, interpretation is restricted to latencies at which a
single equivalent dipole source accounts well for the data.
These early methods restricted analysis to a single equiva-
lent dipole because the number of independent parameters
underlying a single instantaneous scalp map is only less or
equal to the number of recording channels. The use of a
single source keeps the number of parameters small relative
to the number of data values, which is an essential prereq-
uisite for reliable estimates in the presence of recording
noise.43 Hence, for a given instant, not much more than a
single equivalent dipole, which already has six coordinates,
can be extracted with confidence.44
Instantaneous single equivalent dipole solutions have
some problems. When a part of the brain becomes
activated while a previous part is still active, instantaneous
single-dipole solutions often describe virtual sources
remote from both actual sources. In other words, the loca-
tion of this equivalent dipole does not necessarily coincide
with the loci of the activated brain structures if multiple
sources instead of a single source underlie the actual scalp
map39,43; rather the solution may represent the “center of
gravity” for the distributed activity at that instant. For
cortically mediated neural activity, it is quite likely that
more than one distinct source contributes to the scalp
activity at any given instant. Certainly for the auditory
system, it is well documented that bilateral cortical activity
exists even to monaural stimulation. Consequently, a
single-dipole or moving dipole model of such activity will
frequently generate a source located along the midline of
the head, which clearly represents a physiologically
implausible solution. In such cases, single-dipole or mov-
ing dipole models are poor representations based on their
physiologic plausibility.43 This does not rule out the value
of single- or moving dipole solutions under all conditions.
For example, if a single-dipole model is used to describe a
generator with an established single underlying source
over the period of its activation, the clustering of the
single-dipole sources can provide information about (1) the
validity of the single generator model or (2) the quality of
Functional Imaging of Auditory Cortical Activity 313
the data based on the density of the clustering of the indi-
vidual dipole fits (or both). Thus, a cluster with a large
spatial extent that changes systematically as function of
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
specified time interval may provide an indication of the
reliability of the source location based on the spatial extent
(or volume) of the cluster of single dipoles.
Spatiotemporal Source Modeling:
Technical Aspects
The dipole solution cannot provide an unambiguous
statement about sources because there is no unique
solution to the inverse problem, and each potential distri-
bution may be generated by many simultaneously
activated processes.18 However, Scherg15 and Scherg and
von Cramon16 created a different viewpoint and asked
whether a combined spatiotemporal approach would not
greatly enhance the validity of dipole source analyses.
They demonstrated that with the use of a precise defini-
tion of the equivalent of a model dipole in conjunction
with reasonable spatial constraints (hemispheric symmetry
etc.), the source problem can be reduced so that a unique
solution likely exists for a certain hypothesis.2 The princi-
ples of this approach are (1) use available information from
anatomy and physiology to construct an electrical model
of the head, (2) put forward different hypotheses of the
origin of an evoked potential by placing equivalent model
sources within all structures known or assumed to respond
to a certain stimulus, and (3) attempt to explain the
complete evoked potential data set over space and time by
such a model. The solution can then be tested and com-
pared with competitive hypotheses.2 Thus, spatiotemporal
dipole modeling is fundamentally a hypothesis-driven
technique for examining the origins of cortical activity.
Spatiotemporal source modeling as developed by
Scherg15 and Scherg and von Cramon16,45 is an approach
to brain source localization that accounts for the whole
sequence of scalp topographies by a few equivalent dipole
sources having fixed positions and orientations but a
varying strength over time. STSM solutions provide the
locations, the orientations, and the strengths of activity
over time of equivalent dipoles that could explain the
measured spatiotemporal data. Although equivalent
dipoles can now be computed in several ways, Figure 19-4
summarizes the STSM approach developed by Scherg.15
Although the figures are schematically shown in two
dimensions, the process must be visualized in three dimen-
sions. Recall that the activity recorded from any given
electrode site on the surface of the head is the sum of all
the active sources. This is illustrated in Figure 19-4A
for four sources (two pairs of bilateral sources). The
amount of contribution from any source to that electrode
site depends on the conductivity of the medium, the dis-
tance, the orientation, and the strength of the activity. The
activity recorded at each of the four electrode sites relative
to the reference at the top of the head (Cz) is the sum of
these four equivalent dipole sources. The bipolar voltage
waveform recordings shown in Figure 19-4B are simply
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
four equivalent dipole sources that are active in the brain
have a simple time-varying source waveform. Thus, the
sum at each electrode is different as shown by the surface
waveforms because the relative contribution from each
source is different owing to these parameters of the dipole
activity. Note that even though the source activity is
relatively simple, the summed activity as shown by the
bipolar derivation can be more complex because of three-
dimensional summation of the source activity.

Each electrode site has an associated equation for the
summed voltage activity. For a given distance and orienta-
tion, and a head model for which size and conductivities of
the various compartments (brain, CSF, skull, and skin) are
known or assumed, the source activities are computed by
an iterative procedure, by means of matrix algebra. These
computations produce a modeled set of waveforms corre-
sponding to the actual location of electrodes on the scalp.
These modeled waveforms are then compared with the
recorded data in a statistical least-squares procedure. The
iterative procedure is completed when the best fit, which
is the smallest residual variance for a given solution, is
achieved. In essence, the procedure attempts to construct
a set of dipoles whose location, orientation, and strength
over time will add at the surface of the modeled head and
come close to matching the data recorded from the subject.
The following is an example of this process:
Figure 19-5 shows the scalp waveforms (top, left), dipole
source location (top, right), and source waveforms (bottom,
left) for the auditory evoked potential data previously
shown in Figure 19-2. This solution was obtained with an
approximated three-shell head model. Computationally,
the few sources are fitted simultaneously to all data across
space and over time. This fitting over both space and time
has the effect of increasing the reliability of the model-
ing.43 A best fit solution is shown for a bilateral set of
regional dipoles, which are a set of three dipoles having a
common location but orthogonal orientations. Therefore,
the total number of dipoles for a pair of bilateral regional
dipoles is six. The computed source waveforms for each of
the six dipoles is shown for the best fit solution (Fig. 19-5,
bottom, left. It can be seen that all three pairs of dipoles in
each set of regional dipoles show significant activity. The
tangential dipoles contain the typically observed N1–P2
complex, indicating a predominate site of origin on the
superior surface of the temporal lobe. The second pair of
dipole sources shows activity consistent with the T com-
plex. The T complex represents a set of peaks and troughs
that are generated along with the larger N1–P2 complex.
The dipoles associated with this activity have a radial ori-
entation, indicating a site of generation predominately on
the lateral surface of the temporal lobe, likely reflecting
activation of secondary, parabelt areas of auditory cortex.
The third set of dipole waveforms contains two major
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-
nal to the tangential orientation of the
N1–P2 peaks. The origin of the regional dipoles localized
to the area of superior temporal cortex of the head model,
which is consistent with the expectation of auditory
processing. The statistical best fit approach indicates that
more than 95% of the variance in the original scalp
recordings is accounted for by the modeled waveforms
over the response time epoch.
Many complex issues are involved in the modeling
process, including the assumptions of the nature of the
head model. Initially, most analyses relied on simple spher-
ical, multishell head models because more realistic models
were too computationally intensive. However, with the
widespread availability of high-speed computing in personal
computers, use of more realistic boundary element and
Functional Imaging of Auditory Cortical Activity 315
finite element models are becoming more widespread.
Application of these models may be particularly appropri-
ate for assessing the auditory system. Although a spherical
shell model conforms reasonably well to the geometry of
occipital cortex, it is much less appropriate for temporal
cortex. Both boundary and finite element models conform
to the natural shape of volume conductor compartments
(skull, CSF, and brain). Consequently, these volume con-
ductors serve to minimize the localization errors inherent
in applying a volume conductor model that does not
conform to the shape of the brain. Details of dipole
modeling based on these volume conductors are beyond
the discussion of this chapter. However, note that, as is
true with scalp voltage mapping, the dipole analysis can be
improved by generating more realistic head models
obtained from individual anatomic MRI data (e.g., Teale
et al. and Fuchs et al.),46–48 as seen in Figure 19-5 (middle
and bottom right.
With current available commercial software, the local-
ization accuracy of the STSM approach for electrical
potentials approaches about 1 cm, but is highly dependent
on the signal-to-noise ratio in the data. More accurate
localization with the use of dipole modeling is possible
with magnetic fields,49 but with the limitation that radially
oriented activity cannot be characterized. However, con-
siderable continuing work seeks to improve accuracy
and speed of dipole localization estimations through the
use of sophisticated algorithms.46,50–55 For example, by
generating precalculated matrices, Fuchs and cowork-
ers47,48 have provided the capacity to use more realistic
boundary and finite element models in near real-time
operations. These improvements are necessary if evoked
electrical potentials and magnetic fields are used to esti-
mate sources of neural activity. Modeling electric or mag-
netic fields produces comparable results.56 The focus is
now more on the determination of the temporal properties
of the neural activity and only their general potential loca-
tions rather than accurate specific loci. Instead, accurate
localization and temporal characterization of the neural
activity can be obtained by combining dipole modeling
or current density reconstruction with other metabolic
(PET or single-photon emission-computed tomography,
SPECT) or hemodynamic (fMRI) techniques discussed later
in this chapter.
Advantages and Disadvantages
of Spatiotemporal Source Modeling
In summary, Achim and colleagues43 noted the following
advantages of the STSM approach:
1. Compared with two-dimensional surface color or
gray-scale maps, localizing the origin of distributed
brain activity is more adequately resolved by fitting
a number of sources simultaneously from a number
of consecutive scalp topographies. Much of the
power of STSM arises from its capitalization on both
spatial and temporal information. The temporal
aspect is the important distinction from earlier dipole
localization models.
2. For phasic neuroelectric activity, STSM is typically
more plausible physiologically than the alternative
316 NEUROTOLOGIC DIAGNOSIS
interpretation of a moving dipole, which models time-
varying topographies as the displacement of a unique
focus of activity whose position, orientation, and inten-
sity vary across time and often successfully accounts
only for a fraction of the observed topographies.
3. STSM is more parsimonious than the moving single-
source model, requiring fewer parameters to account
for a complete spatiotemporal data matrix.
4. It has been shown that large localization errors can
occur with source analysis techniques for a given
time, depending on the type of head model.57 These
errors are reduced by performing the fitting over
many time points instead of one, as is the case with
STSM. Nonetheless, the complexities of source
analyses require careful interpretation.
The major disadvantages of this technique are its com-
plexities and the need to use models and assumptions that
are imperfect. Furthermore, for electrical activity, with
current commercially available software, localization
accuracy is limited to about 1 cm depending on the head
model and various other assumptions. Current research
demonstrates several ways to improve the technique when
used alone. Nonetheless, even with the currently com-
mercially available software, one can, through cautious
and careful application, use these techniques to provide
information about auditory processing not available
otherwise.
Clinical Applications of Dipole
Source Analyses
Although the STSM or dipole source localization tech-
niques have proved useful in clinical studies aimed at local-
izing epileptic spike activity58–63 and cerebral tumors,64
clinical application of STSM alone has yet to become rou-
tine in the assessment of auditory problems.
Clinical application of dipole source-modeling tech-
niques to problems related to hearing require studies of
processing in normal auditory systems. During the previ-
ous decade, numerous studies have focused on such
processing laying the groundwork for comparisons related
to clinical issues. In their early work, Scherg and von
Cramon37 showed that the STSM analysis may have clinical
value in patients with cortical lesions affecting the auditory
system. They demonstrated varying types of abnormalities
in the dipole source waveforms associated with lesions of
primary auditory cortex, acoustic radiations, and auditory
association cortex.
We attempted to use the source localization technique
with cochlear implant patients, particularly younger chil-
dren, to determine (1) the extent that responses (behav-
ioral and physiologic) are auditory only and (2) if the
different channels of stimulation activate different neural
subpopulations in the periphery.65 Because electric current
stimulation can potentially activate any nearby neural
pathway, often other neural structures (vestibular and sen-
sorimotor) may be stimulated. Such nonauditory evoked
potentials have been observed.66 Our preliminary findings
suggest that this technique may be very useful in identify-
ing auditory and somatosensory contributions to evoked
electrical activity from implant stimulation.
Even more valuable is the possibility that we may be
able to determine if different channels of cochlear implant
stimulation are reflected tonotopically in auditory cortex
as revealed by the loci of the best fitting regional diploes.
Evoked magnetic fields produced by acoustic stimulation
have demonstrated tonotopic organization of auditory
cortex.67–69 An example of using STSM in evaluating
cochlear implant patients from our work65 is shown in
Figure 19-6. At the time of these recordings, the subject
was an 8-year-old child implanted with the 22-channel
Nucleus Cochlear Corp. cochlear implant. The stimuli
consisted of short bursts of biphasic current pulses spaced
2 msec apart and presented at a burst rate of one per
second. Electrode pairs were activated at three locations in
the cochlea: near the basal end of the array (electrodes 2
and 6), adjacent to this basal location (electrodes 6 and 10),
and at the apical end of the array (electrodes 18 and 22). The
locus of the regional dipole source solution for electrical
stimulation of each of the three cochlear regions is shown
in Figure 19-6. For all three stimulus conditions, the locus
of the regional dipole best fit solutions was consistent with
activation of auditory cortex. Furthermore, as seen in the
sagittal view of the model, the loci for the three different
areas of cochlear stimulation were organized such that the
most basal stimulation was posterior and the most apical
stimulation was most anterior along the supratemporal
plane of auditory cortex. This organization is consistent
with a tonotopic arrangement of going from high frequency
to low frequency found in the magnetic studies with
acoustic stimulation.
The shift in the loci is significant and consistent with
magnetic studies.67–69 For this individual, we are confident
that the shifts are not accounted for by simple variability of
the solutions. However, it is important to point out that,
although differences in source location as a function of site
of stimulation within the cochlea have been obtained in
many implanted adults, the patterns do not consistently
match previously observed tonotopic maps. This inconsis-
tency might reflect variability unrelated to the site of stim-
ulation. Alternatively, these variable patterns of spatial
representation may reflect reorganizational differences
between individuals with varying causes of deafness. Much
work remains to determine whether this approach is viable
means for assessing multichannel cochlear implant stimu-
lation to ascertain the degree of separation and overlap in
activating different neural channels.
Most of the studies to date have been demonstrations
of the feasibility of the technique and its application to var-
ious types of evoked potential activity related to auditory
processing such as the mismatch negativity (MMN) poten-
tial70 and P300.71 Other studies focused on the localization
of evoked potentials related to processing various sounds
including speech.72–74 Because the accuracy of source local-
ization using dipole modeling alone is limited, much of the
current research is now focused on using a combination
of dipole and other imaging techniques. As discussed later,
combining dipole source analyses with metabolic or fMRI
techniques may provide a powerful approach for studying
the function of brain structures related to hearing. The
dipole source analyses estimates the neural activity with
good temporal resolution, and the other imaging tech-
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

Background and General Principles
Positron emission tomography (PET) is an imaging tech-
nique that delineates the magnitude of metabolic activity
in the brain. PET is used to measure blood flow, oxygen
and glucose metabolism, amino acid metabolism, tissue
acid–base balance, membrane transport, and receptor–
ligand interactions in the human body.75 The measure-
ment of metabolism is indirect since PET devices detect
concentrations of positron-emitting isotopes that have
been injected into the bloodstream. These isotopes or
radionuclides become concentrated in areas of the body
where metabolic demand is high. The nucleus of the
radionuclide contains an excess positive charge, which
diminishes in one of two ways. Negatively charged elec-
trons orbiting the nucleus may be captured or the nucleus
may emit a positron. A positron emitted from the nucleus
quickly combines with an electron in a process known as
annihilation. During annihilation, the masses of the elec-
tron and positron convert to electromagnetic radiation in
the form of two gamma rays of equal intensity that are
emitted 180 degrees to each other.76 Positron emission is
registered by the PET imaging system only when annihi-
lation photons traveling in opposite directions activate
coincidence detectors simultaneously.77 By adjusting the
location of the coincidence detectors, concentration patterns
for photon emission can be generated for the whole body
or for a specific organ of interest such as the brain.
Advantages and Disadvantages
of Positron Emission Tomography
PET images can provide extensive information on func-
tional neurochemical activity in the brain. Radionuclides
such as proton-rich isotopes of carbon, nitrogen, or oxygen
are used as tracers in PET studies of blood flow or oxygen
11
C-SCH23390 may be used to assess function in
dopaminergic systems. Other tracers may be used to target
specifically function of monoamine oxidase, benzodiazepine,
or opiate receptors.75,77
PET studies generate three-dimensional representations
with an effective resolution of better than 2 cm, so compar-
isons of metabolic activity between adjacent cortical regions
are possible.75,78 However, analysis of functional organization
within a region is limited because most subcortical and cor-
tical structures such as auditory cortex have dimensions equal
to or less than 2 cm. Attempts to resolve detail of less than
2 cm produce a partial volume effect in which gray and white
matter of the brain are blended in the PET image. Errors in
PET data introduced by the partial volume effect can be
minimized through correcting PET79 or by performing
baseline PET studies for comparison.75 Baseline studies are
also important for establishing local background metabolic
rates, which vary from one part of the brain to another in
both nonhuman species and in humans.75,80
Although the spatial resolution of PET limits the study
of functional organization within auditory cortex, the
temporal resolution of PET studies also places limits on
stimulation paradigms. For example, transitional changes
on the order of 20 to 200 msec in a speech segments are
sufficient to allow discrimination between phonemes.
However, changes in cortical regional blood flow and
metabolism follow a much longer time course. According
to Mazziotta and Phelps,75 30 to 40 minutes may be
required for metabolic activity to achieve a stimulus-
dependent steady-state necessary for PET imaging with
deoxyglucose. Thus, it is likely that cortical activation
patterns represented in PET data not only reflect local
activation of sensory cortices but also activations associ-
ated with manipulations of task demands and expectations
that may vary from one experimental condition to another.
PET activations can be obtained with 15O-labeled
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.

sufficient flow information during stimulation. However,
even 60-second epochs are too long to examine local
neural responses to the microstructure of speech.
One additional limitation for PET imaging results from
the use of radioactive tracers. Although these tracers clear the
body quite rapidly, the number of times an individual may be
safely exposed to these elements is limited. Consequently,
repeated PET imaging of a single individual over a short
interval (weeks) is not possible. Moreover, the use of radioac-
tive isotopes necessary for PET studies essentially precludes
the use of this to assess central auditory function in children.
Clinical Applications
PET studies may not be useful for examining rapid changes
in neural activity in response to transient acoustic stimula-
tion, but global studies of auditory function and brain
organization are possible with PET. Early PET or SPECT
studies have been conducted with a variety of acoustic stim-
uli, including noise, tones, words, stories, and music.81–91
An early study of auditory function using PET performed
by Reivich and coworkers81 reported that monaurally
presented stories produced a 20% to 25% increase in local
cerebral metabolism throughout the right temporal lobe
regardless of the ear of stimulation. Other studies have
found lateralized patterns of activation dependent on the
manner of presentation or the content of the presented
material. Results of Greenberg and colleagues85 showed that
the local cerebral metabolism rate for glucose was 7%
higher in the temporal lobe on the side contralateral to the
stimulated ear. Mazziotta and coworkers88 used PET to
study cerebral activation patterns to verbal and nonverbal
acoustic stimulation. Although verbal discourse increased
metabolism in left hemisphere structures including the thal-
amus and frontal cortex, the pattern of metabolic asymme-
try for nonverbal stimuli was dependent on the processing
strategy used by the subject. Metabolic activity was greater
in the left than in the right hemisphere for musically trained
individuals or individuals who used visual imagery to
process the nonverbal stimuli. In contrast, metabolic activ-
ity was greater in the right than the left temporal lobe in
subjects who did not use visual imagery or who lacked an
extensive musical background. During the past decade
numerous additional studies have been aimed at localizing
brain areas devoted to these various aspects of auditory
function and to the processing of speech stimuli.92–97
Cochlear Implant Stimulation
PET has also been used to assess cortical neural activation
produced by electrically stimulating nerve fibers with a
cochlear implant array. In an early PET study, Ito and
colleagues78 studied preimplantation and postimplantation
cortical activity in a 38-year-old man who had suffered
from profound hearing loss at age 11/2 years following
treatment with streptomycin. PET images obtained as a
baseline before implantation showed broadly distributed
areas of low metabolic activity in the left middle-frontal,
posterotemporal, and parietal cortices. The parietal and
temporal lobe, as well as Heschl’s gyrus in the right hemi-
sphere, showed little metabolic activity, although activity
levels were somewhat higher in the right than in the left
Functional Imaging of Auditory Cortical Activity 319
hemisphere. Three months after implant surgery, the areas
of low metabolic activity and the asymmetry between left
and right hemisphere metabolic activity were no longer
apparent. PET images obtained while the patient listened
to recorded speech showed increased levels of metabolic
activity in the left parietal cortex. According to Ito and
colleagues,78 the increased metabolism found in auditory
cortex extended to auditory association cortex, perhaps
indicating that the neural activity evoked by the implant
had been perceived as speech. Although this conclusion
may be somewhat premature, PET imaging provided evi-
dence of changes in local patterns of cortical metabolism
following implantation and demonstrated that regions of
the brain normally associated with auditory function were
activated by implant stimulation.
Many additional PET or SPECT studies during the pre-
vious decade have examined the distribution of activated
brain areas to stimulation with a cochlear implant. For the
most part, the basic findings are similar and demonstrate
that electrical stimulation of the auditory pathway results in
activation of areas seen with normal acoustic stimulation or
consistent with behavioral responses to the stimuli98–105 as
well as for evaluating the effectiveness of the implant106–113
or for assessing neuroplasticity resulting from deafness or
use of the cochlear implant.114–120
The exploration of central auditory function in normal-
hearing children will likely remain limited due to the neces-
sity of using radioactive isotopes. However for deaf children
and adults, the use of PET or SPECT imaging is more justi-
fiable if such data can add significantly to preoperative deci-
sions regarding the appropriateness of cochlear implantation
as a therapeutic treatment. Recent data reported by Roland
and coworkers112 examined SPECT activations to auditory
stimulation before and after cochlear implantation in three
adults with pure-tone average audiograms of 90 dB or greater
bilaterally. Results of the study showed that despite having
relatively similar hearing losses across subjects, significant
differences in patterns of cortical activation were observed
between ears. Such results might provide important insights
about which side should be implanted. For adults and
postlingually deafened individuals, behavioral testing can
often provide sufficient information for such decisions.
However, for young children or prelinguistically deafened
individuals, PET studies of cortical activation patterns pro-
vide a preoperative method of assessing objectively which ear
would provide the best postoperative activation of cortex.
PET imaging might also be used to determine the extent
of damage and preserved auditory function following trau-
matic or ischemic brain injury.75 PET data may be useful for
delineating deficits associated with damage to primary audi-
tory receiving areas from those associated with damage to
higher-order speech reception areas in temporoparietal cor-
tex. PET studies might also provide insight on the origins of
so-called central auditory processing disorders.121 Atypical
cortical metabolism patterns might exist in those individuals
affected by central auditory processing disorders.
Tinnitus Studies with Positron
Emission Tomography
Several studies have explored PET imaging as a technique
for objective detection and identification of origin (i.e.,
320 NEUROTOLOGIC DIAGNOSIS
peripheral or central) for tinnitus. PET studies may provide
general information regarding activity and its locus.
Whether the source of the tinnitus lies in the auditory
periphery or in central structures of the auditory pathway,
auditory cortex might show evidence of chronic activation
by a change in metabolic activity. For example, it has been
suggested that tinnitus associated with unilateral activation
of cortex is an indication of a central origin since a periph-
eral origin should have bilateral representation.122 Studies
comparing cortical metabolic patterns from patients with
tinnitus and those without have been performed. The results
of Arnold and colleagues123 and Wang and coworkers124
using 18F-deoxyglucose (FDG)-PET studies on patients
with disabling chronic tinnitus showed increased metabolic
activity mostly in the left primary auditory cortex compared
with nontinnitus subjects. PET studies have evaluated those
patients whose tinnitus can be altered in loudness by orofa-
cial movements125 or by eye movements.126 Studies during
habitual tinnitus and when the tinnitus has been suppressed
in the same patient have also been studied.128–130 In addition,
individuals whose tinnitus is triggered by consuming certain
foods or drinks such as caffeine might be appropriate for
repeated studies comparing PET images obtained before
and after ingesting the tinnitus-inducing foods or beverages.
Many of these studies also suggest that other brain areas may
be involved in the response to emotional responses to the
adverse percept of tinnitus (e.g., Mirz et al.).131
Johnsrude and colleagues132 recently published a review
of the use of PET for functionally imaging the auditory
system. However, its poor temporal resolution, its need for
radioisotopes, its invasiveness, and its high cost have
limited its clinical utility. For many applications, it may be
replaced in the future by fMRI. Although, PET may still
have the major role in imaging cortical activity to electri-
cal stimulation when prostheses with metal, such as the
cochlear implant, are used.
FUNCTIONAL IMAGING WITH MAGNETIC
RESONANCE IMAGING
Background and General Principles
A technical description of MRI is not presented here. The
reader is referred to the brief review by Andrew.133 In
essence, MRI involves imaging in a slice of the head, the
distribution of protons that have been selectively excited
(i.e., in resonance) by applying a magnetic field gradient.
In its most basic application, MRI does not use ionizing
radiation and is noninvasive. However, contrast improve-
ment can be achieved by intravenous injection of a para-
magnetic solution such as gadolinium diethylenetriamine
pentaacetic acid (Gd-DTPA). Most MRIs are maps of the
proton nuclear magnetic resonance (NMR) signals from
water and fat in the tissues but images of blood flow and
diffusion can also be obtained.133 Currently, the spatial
resolution of MRI, below 1 mm, is far superior to that of
other neuroimaging techniques.
The early application of MRI provided mainly anatomic
imaging technique devoid of dynamic functional informa-
tion. However, during the past 15 years, a variant of MRI
was developed to provide functional maps of the human
brain with better temporal and spatial resolution than
PET techniques. The new functional imaging MRI (fMRI)
method relies on changes in the blood supply to the brain
that accompany sensory stimulation or changes in cogni-
tive state. An excellent review of the early work with this
technique is provided by Tank and colleagues.134 Following
this early work, numerous fMRI studies have been con-
ducted of many aspects of auditory function, which we will
briefly review later. Other recent reviews of studies that
use fMRI to investigate the auditory system can be found
in Huckins and coworkers,135 Cacace and colleagues,136
Seifritz and coworkers, and Bernal and Altman.137,138
Currently, three basic methods are used to image func-
tionally with MRI. Two of the three methods are noninva-
sive approaches, and the third uses exogenous vascular
contrast agents.
Blood Oxygenation Level–Dependent
Contrast Imaging
Blood oxygenation level–dependent (BOLD) contrast
imaging is based on the magnetic properties of hemoglo-
bin. For example, because deoxyhemoglobin (hemoglobin
without a bound oxygen molecule) is paramagnetic, a blood
vessel containing deoxyhemoglobin placed in a magnetic
field will alter the field in its vicinity. The greater the
amount of deoxyhemoglobin, the greater the local distortion
of the magnetic field surrounding the blood vessel. This
distortion surrounding the blood vessel can, in turn, affect
the magnetic resonance images of nearby water protons.
Thus, the changes in the hemoglobin that are present in
low concentrations are difficult to monitor directly by
MRI. However, these changes affect the signal character-
istics of water molecules that are easier to measure since
water molecules are 100,000-fold higher in concentration.
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
blood flow and oxygen utilization.
Blood Perfusion Imaging Using Vascular
Contrast Agents
For the commonly used magnetic field strength in clinical
MRI systems, the signal changes observed by the BOLD
contrast technique are only a few percent. One can obtain
significantly larger changes in signal intensity, ranging from
50% to 100%, by intravenous injection of an exogenous
paramagnetic contrast agent. These perfusion-based maps
have excellent spatial resolution. Furthermore, maps can be
calibrated to provide quantitative changes in cerebral blood
flow and cerebral blood volume. Belliveau and cowork-
ers,140,141 using Gd-DTPA, first reported perfusion-based
maps with a focus on cerebral blood volume changes accom-
panying stimulation of the visual system.
Blood Perfusion Imaging Using Inversion
Recovery Methods
Kwong and coworkers142 demonstrated that the perfusion
of blood in brain areas can be measured noninvasively with
a method called inversion recovery (IR). This method

depletes the concentration of MRI-visible water protons in
a brain region and measures water protons that enter the
region through blood flow, providing a direct measure-
ment of flow without the use of exogenous contrast agents.
Improvement in resolution can also be achieved by
increasing the strength of the magnet. In the past, typical
clinical systems had a magnet strength of 1.5 T (teslas);
now it is much more common to find systems with magnet
strengths of 3 to 4 T, with the occasional research lab having
more high-powered magnets of 7 T.
The use of fMRI to study auditory neural function is
based on the fact that changes in neural activity are accom-
panied by changes in energy metabolism. Tank and
colleagues134 discuss several lines of evidence that support
the notion that increased metabolic rate is correlated in
many mammalian species, including humans, with an
increase in blood flow that can be controlled locally.143–146
In addition to the variety of methods that have evolved
for acquiring fMRI, two major stimulus presentation/
experimental design paradigms have been adopted for use
in most fMRI experiments: the so-called box or block
designs and event-related, or sparse stimulation, designs.
A number of excellent reviews have been written describ-
ing the benefits and drawbacks of these techniques. Briefly,
boxcar designs are experimental sequences in which stim-
ulation is simultaneous with (occurs at the same time as)
the imaging sequence. Event-related, or sparse, designs
are those in which a series of stimuli are presented during
a period prior to the onset of the MR scanning sequence.
The justification for this approach is that for BOLD stud-
ies, a buildup time of approximately 4 seconds is needed
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-
factual acoustic stimulation produced by the scanning
sequence. It is now well established for many auditory
processes that psychophysical data obtained in the pres-
ence of high levels of background masking noise do not
always match those for stimuli presented in quiet. For
example, Shtyrov and coworkers147 demonstrated that for
speech-evoked MEG responses, the degree of lateralized
cortical activity evoked by the presentation of a deviant
stimulus (MMN) changes dramatically between no-noise
and background noise conditions. Thus, with no back-
ground noise, speech-evoked MMN dipole activity was
strongly lateralized to the left hemisphere. However, in
the presence of background white noise, the magnitude
of the left hemisphere response decreased, while activity in
the right hemisphere increased. These results, combined
with psychophysical studies of the effects of background
noise on auditory perceptual processes, would suggest that
the event-related or sparse experimental paradigm would
be preferable for fMRI studies of central auditory
processes. A brief review of the advantages and disadvan-
tages of these two techniques as described by Horwitz and
colleagues148 is outlined in the following sections.
Advantages and Disadvantages of Boxcar Designs
As one advantage, boxcar design experiments are typically
able to measure higher levels of cortical activation, result-
ing in greater statistical power. This in turn leads to faster
fMRI acquisition times. Because the interstimulus interval
Functional Imaging of Auditory Cortical Activity 321
is shorter than the hemodynamic response function for
each stimulus item, data collected with boxcar designs are
interpreted as a brain state- (task-induced) dependent
measure. The disadvantage of boxcar designs is that the
acoustic noise of the imaging sequence is concurrent with
the fMRI stimulation, which may significantly affect the
arousal and attention. In addition, the acoustic noise of
the imaging sequence will act as a mask for experiments
using auditory stimulation.
Advantages and Disadvantages
of Event-Related Designs
In an event-related paradigm, stimulus presentation is
asynchronous with fMRI acquisition sequences. One
disadvantage of event-related design experiments is their
somewhat lower level of cortical activation (compared with
boxcar designs), thus resulting in lower statistical power.
Lower levels of cortical activation lead to longer fMRI
acquisition times. One advantage of event-related or
sparse designs is that responses to single stimulus type can
be characterized by averaging activation across multiple
stimulus presentations.The data are more easily inter-
pretable relative to specific types of stimulus events. As
such, the fMRI data recorded during event-related
sequences are much more comparable to evoked (or event-
related) potentials. Another major advantage of event-related
paradigms is that since stimulus presentation precedes
each scanning sequence, the arousal and attentional effects
produced by the high noise levels of the imaging sequence
are not superimposed on cortical activations produced by
the stimulus events.
Auditory Studies Using Functional Magnetic
Resonance Imaging
Cortical Areas Involved in Basic Processing
of Auditory Stimuli
Functional imaging techniques have been trying to answer
the fundamental question of where in the cortex certain
types of auditory processing take place. The assumption is
that with simple acoustic stimuli such as tones, one acti-
vated area must be primary auditory cortex. Examples are
studies trying to identify areas involved in basic processing
for simple tones to verify tonotopic organization at cortical
levels or effects of parametric changes in the stimuli.149–162
Although a number of these studies suggest that tonotopic
organization can be seen, the fMRI studies of Talavage and
colleagues154 and Schonwiesner and coworkers163 suggest
that multiple frequency-dependent activation sites exist
and that it is difficult to demonstrate a single primary
tonotopic organization. Another basic processing issue is
where and how the brain is activated in response to simple
monaural and binaural stimuli.164–168
Cortical Development, Maturation, and Plasticity
In the study of activation and processing of simple auditory
input, understanding the time course of the development
and maturation of such processing is very valuable. Such
knowledge is vital to understanding not only pathology but
also the plasticity of a compromised auditory system. It has
been demonstrated that fMRI studies can be carried out in
322 NEUROTOLOGIC DIAGNOSIS
children169 as well as in infants and neonates170 and could
provide insight to cortical development and maturation
when compared with studies in adults. Understanding
development and maturation of cortical processes helps us
to understand changes due to deafness and the related
issues of reorganization and brain plasticity. For example,
Tschopp and colleagues171 and Bilecen and coworkers172
used fMRI to study activation of auditory cortical areas in
unilaterally deaf patients, and Suzuki and colleagues173
showed that cortical patterns change very quickly in
patients who suffered sudden hearing losses. Studies in
totally deaf patients who subsequently received cochlear
implants may provide clues about brain plasticity and how
it may be affected by deprivation and the reintroduction of
auditory stimulation.
Cross-modal Activation in Primary Auditory Cortex
One of the more controversial issues related to deafness
and plasticity is whether reorganization subsequent to
deafness is such that stimulation in the visual modality
produces activation in primary auditory cortex (PAC).
Although ample fMRI evidence demonstrates that visual
stimulation associated with communication (e.g., lip reading)
can activate auditory cortical areas,174–178 as well as evidence
that activity increases in auditory areas of the temporal
lobe of deaf subjects performing visual tasks or stimulated
visually,176,179–181 it is unclear that such visual stimuli
activate the PAC. Some claim activation of PAC with
visual stimuli alone.176,180,181 Others claim from their fMRI
analyses that activation occurs in nonprimary auditory
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-
modal reorganization of primary auditory cortex. In other
words, primary auditory cortex remains specific to audi-
tory stimuli. A problem that leads to this controversy is the
identification of primary auditory cortex from the MR
scans. Such identification can be difficult. More cytoarchi-
tectonic studies are needed to develop an accurate
anatomic reference system.183,184
Cochlear Implant Assessment
Assessing cortical plasticity may lead to an understanding
of performance differences with a cochlear implant.
Although a number of PET studies of cochlear implant
patients have been done, little has been done with fMRI
because of the metal content in implants (discussed later).
Truy107 and Giraud and colleagues119 reviewed the use of var-
ious neurofunctional imaging techniques including fMRI to
study cochlear implant patients and cortical plasticity and
noted their advantages and disadvantages.
Speech and Language Studies
During the previous 10 years numerous fMRI studies have
tried to determine the cortical areas involved in speech
perception and discrimination as well as areas important
for language processing. A review of these studies is not
possible here. We simply provide a few examples of the
kinds of studies that are being conducted. Studies of
speech processing under dichotic and diotic conditions185
suggested differences in areas activated that may be due to
attention factors. A number of studies investigated the
effect of attention186,187 and involuntary attention switch-
ing188,189 in the processing of sounds. Other issues related
to the processing of speech and language are differences in
activation between words and nonwords or speech and
nonspeech,190–193 listening comprehension,194–196 semantic
processing,196 sex differences in laterality of language com-
prehension,196,198 identifying where speech parameters are
processed in the brain,199,200 and specific sensitivity to
vocal sounds.201 Because of the complexities involved in
speech and language processes, interpretations of the
activations observed in fMRI studies are often difficult and
do not always parallel findings with direct cortical stimula-
tion.202 The popularity of language studies and fMRI was
recently emphasized by a special journal issue devoted to
“Functional Brain Imaging of Language” (Human Brain
Mapping, vol. 18, 2003).
Tinnitus
We already discussed attempts to detect the presence of
tinnitus with the PET imaging methods. Functional MRI
has been similarly used to identify objectively the presence
of certain kinds of tinnitus and the locations in the
auditory system that might be involved. Thus far, only
certain forms of tinnitus have been amenable to study
with fMRI.203–206 Studying with fMRI the neural activity
associated with the presence or onset of tinnitus is
particularly difficult because of the high noise levels
produced by the scanner. Attempts to overcome this inher-
ent disadvantage of fMRI are discussed in the following
section.
Advantages and Disadvantages
of Functional Magnetic Resonance
Imaging
The obvious advantage of those fMRI techniques that
image without exogenous contrast agents is their noninva-
siveness. Unlike PET and SPECT, MRI has no known
toxicity issues and many repetitions of experiments on
individual subjects are possible.
However, perfusion-based fMRI imaging techniques
that use intravenous injections of paramagnetic solutions
to improve the contrast suffer the same drawbacks of
invasiveness and toxicity that limit the number of scans
on a single patient. Also, only a single map is produced
by imaging during the transit of a contrast agent, and
the time course of the hemodynamic changes cannot be
measured.
A major disadvantage for auditory studies is that fairly
high levels of noise are generated by MRI units, which
makes it difficult to conduct auditory studies.188,207 A
detailed specification of the spectral characteristics of
the noise from the scanner can be found in Ravicz and
colleagues.207 Several studies have addressed the noise
issue. McJury and Shellock208 discuss in their review (1) the
various types of acoustic noise produced during the oper-
ation of MRI systems, (2) the characteristics of the acoustic
noise, and (3) information regarding noise control tech-
niques. As described previously, it may be preferable for
fMRI-based studies of central auditory processing to use
those experimental designs that rely on the physiologic

delays between the onset or the end of stimulation, and the
corresponding hemodynamic response can be used to min-
imize the MRI noise in acoustic stimulation studies.137,209–214
Alternatively, developing effective methods to attenuate
or cancel the noise generated by the MRI systems215 or use
of a loudness-matching formula to reduce the effects
of scanner noise on the activation measures should be
considered.211
Another major disadvantage for auditory investigations
is that the use of MRI with cochlear implants is con-
traindicated because of the possible torquing that can
result when applying a magnetic field to metal containing
ferrous material.216 However, Lazeyras and colleagues217
claim that fMRI scans can be safely obtained in patients
with a cochlear implant with methodologic changes and
careful techniques. Alwatban and coworkers218 and Schmidt
and colleagues219 demonstrated methods for electrically
stimulating the auditory system in deaf subjects and also
studying them with fMRI in order to assess the patient’s
suitability for a cochlear implant.
Clinical Applications and Combining
Imaging Techniques
Because each of the imaging techniques has advantages
and disadvantages, which technique is appropriate depends
on the type of patient and the information desired. It is
obvious that if it were possible to gather information from
more than one technique, better information could be
obtained than from any single technique alone. The prob-
lem is that these imaging techniques are expensive and
require facilities that are not always widely available.
Nonetheless, the value of information that a combination
of techniques can provide for clinical application is great,
and we believe such combination studies will be more
common as issues of cost and availability are resolved. The
main advantage of fMRI and PET studies is their ability to
localize sources of presumed activity with fairly good
accuracy. However, their main disadvantage is that they
provide poor temporal information, especially PET
images. Localization of neural activity with dipole source
analyses of electrical and magnetic surface recordings is
less precise, but these methods provide good temporal
information. Combining these methods yields both local-
ization and temporal information. Some combinations rely
on surface electrical potentials or magnetic fields to
provide temporal aspects of the neural activity and on PET
scans220–222 or fMRI166,223,224 scans to provide information
of the neuroanatomic loci. For example, some studies
combine PET scans with source localization of electrical
potentials225 or with source localization of magnetic
fields.226 Other studies have combined fMRI with MEG
source localization.227 These studies also allow compar-
isons between the electric or magnetic dipole source local-
ization techniques and the more precise localization
techniques that use metabolic (PET) or hemodynamic
(fMRI) changes. Studies that must rely only on dipole
source localization of electrical or magnetic activity find it
helpful to superimpose the calculated dipoles on static
MRI images of the patient’s head.228
Although basic issues of the methodologies are still being
investigated, methods for improving the measures230–232
Functional Imaging of Auditory Cortical Activity 323
and clinical application of functional imaging techniques
related to auditory evaluation are now emerging. Although
a review of clinical application is not possible, we can exam-
ine some of the assumptions about the potential value of
these imaging techniques. Many of the possible clinical
uses for auditory evaluation can be seen from the various
topics we have just reviewed. In addition, it has been shown
that functional imaging with MRI can be useful in mapping
epileptic foci and studying patients with psychiatric and
neurologic disorders.121,233 We briefly mentioned that
many of these metabolic and blood flow neuroimaging
studies have directed their attention to determining the
anatomic location of important language areas and map-
ping areas involved in higher cognitive processing.
SUMMARY
Functional imaging of electrical, magnetic, and metabolic
activity of the brain in response to sensory stimulation is
a rapidly evolving area of investigation. Each of the
techniques can provide different views of brain activity,
and each has its own advantages and disadvantages. In
general the neuroimaging methodologies can be catego-
rized into those that have high temporal resolution (EEG
and MEG) and those that have high spatial resolution
(PET, SPECT, and fMRI). For investigations of central
auditory processing, particularly those involved with
speech, some advantage might be gained by acquiring the
high temporal resolution of EEG and high spatial resolution
of fMRI simultaneously. This technologically challenging
approach will likely become a focus of much development
and investigation over the next few years. Although the
clinical value and applications of these techniques have not
been clearly defined, the demonstration of their enormous
potential for helping us understand the nature and location
of sensory deficits is emerging. Realization of this poten-
tial will take some time, but the information provided by
functional imaging techniques should be valuable in
diagnosis and treatment of auditory-impaired patients.
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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.

Imaging of the Labyrinth
Outline
Magnetic Resonance
Imaging Techniques for the
Labyrinth
Labyrinthine Lesions
Congenital Malformations of
the Inner Ear
Labyrinthine Hemorrhage
Labyrinthitis
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
technique is obviously still important and in fact relied on
by most centers for imaging many temporal bone diseases,
the advent of magnetic resonance (MR) contrast agents
has clearly expanded the role of MR imaging (MRI) in this
region.1 Recent technical innovations in fast imaging and
high-resolution techniques have finally made MRI appro-
priate for many of these conditions, and in some cases
uniquely so. This chapter discusses the role of MRI in the
evaluation of the labyrinthine pathology.2
MAGNETIC RESONANCE IMAGING
TECHNIQUES FOR THE LABYRINTH
The labyrinth is always imaged together with the internal
auditory canal (IAC) and cerebellopontine angle. MRI of
the labyrinth should include high-resolution pre- and post-
contrast T1-weighted images in the axial plane and post-
contrast T1-weighted images in the coronal projection.
Conventional spin-echo 3-mm-thick T1-weighted images
(14–16 field of view, 192 × 256 matrix, and four excitations
on a 1.5-T imager) provide good images of the labyrinth.
Nevertheless, today more and more thinner 2-mm spin-
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
vestibule, semicircular canals, and, in many cases, the endo-
lymphatic sac in even more detail. Even the nerves and
vessels inside the IAC and cerebellopontine angle become
visible on the 1-mm-thick images. Precontrast T1-weighted
images are necessary to differentiate enhancement from
Chapter
20
Perilymphatic Fistula Alexander S. Mark, MD
Labyrinthine Neoplasms
Labyrinthine Schwannomas
Other Tumors Involving the
Labyrinth
Postoperative Changes
Endolymphatic Hydrops
Conclusion
spontaneous hyperintensities inside the labyrinth, which
can be caused by fat (lipoma), blood (trauma, cholesterol
granuloma, vascular malformation), tumor (schwannomas),
or a high protein concentration of the intralabyrinthine
fluid (in case of acoustic schwannomas). In the coronal
plane, fat-suppressed, T1-weighted spin-echo images
should be used to eliminate the high signal intensity of
the bone marrow, often present in the walls and especially
in the roof of the IAC. These images can also be used to
exclude a lipoma or to differentiate lesions from the fat
used to close the surgical access route.
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,
0.5 to 0.7 mm, and must provide high contrast between
the cerebrospinal fluid, intralabyrinthine fluid, nerves, and
bone. This sequence is mainly used to check the three
branches of the vestibulocochlear nerve and the facial nerve
in the IAC and to verify possible loss of intralabyrinthine
fluid due to the presence of fibrosis or a tumor.5 Three-
dimensional reconstructions, multiplanar reconstructions,
and virtual images6 of the fluid-containing membranous
labyrinth can be obtained with these images,7 which are
used more and more frequently prior to cochlear implanta-
tion.8 However, one must bear in mind these sequences are
prone to magnetic susceptibility artifacts.9
LABYRINTHINE LESIONS
In the past, the labyrinth was almost exclusively imaged with
HRCT. CT still has its value for the evaluation of congeni-
tal SNHL although modern MR sequences can depict most
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-
riovenous malformation, Fig. 20-3), cholesterol granuloma,
or carcinoma of the endolymphatic sac21 (Fig. 20-4), or
secondary to trauma with or without an associated fracture.
Viral labyrinthitis may also be hemorrhagic22 (Fig. 20-5).
Labyrinthine hemorrhage cannot be demonstrated by CT.
However, it can be suspected when a fracture of the tem-
poral bone23 is identified passing through the labyrinth.24
MRI is uniquely suited to the demonstration of
labyrinthine hemorrhage. Precontrast studies demonstrate
high signal intensity in the labyrinth consistent with sub-
acute hemorrhage.25 Theoretically, acute hemorrhage
should be diagnosed on T2-weighted images as a very low
intensity signal, but we have not encountered such cases in
our experience. Realistically, most patients will be studied
at the subacute stage.
If the bleeding was severe enough, the mixture of intra-
labyrinthine fluid and blood will eventually become a clot or
show soft tissue/fibrotic characteristics. This can be recog-
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
Figure 20-5. Acute hemorrhagic viral labyrinthitis. Thirty-year-old woman
with acute SNHL on the right and vertigo during the course of a viral illness.
Axial unenhanced T1-weighted image reveals high signal intensity in the right
cochlea and vestibule consistent with subacute hemorrhage. (Courtesy of
Dr. D Schellinger, Washington, DC)
a region where the high signal intensity of the intra-
labyrinthine fluid is replaced by low-signal-intensity material.
When a fracture is present, the loss of the high-signal-
intensity intralabyrinthine fluid can also be caused by
leaking of the fluid into the middle ear cavity. The empty
space inside the labyrinth is then very quickly obliterated
by clot and fibrous tissue formation. A less well-known
cause of labyrinthine hemorrhage and subsequent obliter-
ation of the intralabyrinthine fluid spaces is surgery. Stapes
surgery can result in intralabyrinthine bleeding. The
drilling performed during middle or posterior fossa
approach to treat acoustic schwannoma can also result in
subtle intralabyrinthine bleeding (concussion) and can
eventually cause complete obliteration of the intra-
labyrinthine fluid spaces.
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.
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
and results very quickly in fibrous obliteration of the intra-
labyrinthine fluid spaces. In these patients high signal
intensity can be seen in the labyrinth on the unenhanced
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
quickly, even during the first 2 weeks following the infec-
tion, and can eventually lead to complete labyrinthitis
ossificans. Calcified obliteration cannot be distinguished
on MRI; only CT can identify the calcified areas.
However, fibrous obliteration will remain unnoticed on
CT. Therefore, MRI and CT are complementary in the
study of patients with labyrinthitis. The detection of
calcifications or fibrous obliteration inside the membra-
nous labyrinth is, of course, essential in the preoperative
assessment of cochlear implant candidates. As mentioned
earlier, only a combined CT-MRI evaluation provides the
surgeon with all the necessary information. Moreover,
unlike CT, MRI is often capable of showing whether a
single scala is still open and can be used for cochlear
implantation.
 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

Figure 20-9. Bacterial labyrinthitis. Middle-aged man with right middle
ear infection, acute hearing loss, and facial nerve paralysis. Coronal
gadolinium-enhanced, axial T1-weighted image demonstrates enhancement
of the right cochlea and vestibule (arrow) consistent with extension of the
infection to the labyrinth.
Bacterial labyrinthitis can result either from extension
to the labyrinth of a middle ear infection (otogenic suppu-
rative labyrinthitis), in which case the infection usually
penetrates the labyrinth through the oval window, or after
meningitis, in which case it is usually bilateral (meningo-
coccal bacterial labyrinthitis). Otogenic suppurative
labyrinthitis is characterized pathologically in the acute
phase by a polymorphonuclear infiltrate in the perilym-
phatic space followed by a fine fibrillar precipitate and
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.
Primary autoimmune labyrinthitis is a relatively new cause
of SNHL.39 The diagnosis is based on a positive lympho-
cyte transformation test to inner ear preparation and a
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.
Cogan’s syndrome is an autoimmune disease characterized
by interstitial keratitis and hearing loss in Venereal Disease
Research Laboratory (VDRL)-negative patients. The dis-
ease responds to steroids. Enhancement of the cochlea and
vestibule as well as obliteration of the membranous labyrinth
has recently been reported in autoimmune labyrinthitis and
in patients with Cogan’s syndrome41 (Fig. 20-11). Relapsing
polychondritis is an autoimmune disease characterized by
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
hearing loss and vertigo. We have recently demonstrated
labyrinthine enhancement in this entity (Fig. 20-12). Finally,
intralabyrinthine enhancement can also be seen in cases of
tuberculosis and sarcoidosis, and can even occur after
gamma-knife treatment in the vicinity of the labyrinth.
CONTRAST ENHANCEMENT
OF THE LABYRINTH
Study of the functional correlation between labyrinthine
enhancement and objective and subjective cochlear and
vestibular symptoms reveals that the enhancement is a
highly specific finding of labyrinthine pathology.42 Indeed,
all patients with enhancement of the cochlea or vestibule
have cochlear or vestibular findings, both subjectively and
objectively. Furthermore, these symptoms and signs are
severe when the standard dose of contrast medium
(0.1 mmol/kg) was used. We have recently used a triple-dose
contrast medium in the setting of only moderate SNHL.
This study demonstrated marked enhancement of the
cochlea and vestibule. Our anecdotal observation suggests
that the use of higher doses may increase the sensitivity
for such abnormalities. Thus, similar to enhancement in
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
enhancement may parallel resolution of the patient’s
symptoms42 (Fig. 20-14), or, if the inflammatory process
has resulted in permanent damage to the labyrinthine
membrane, the enhancement may resolve but the patient’s
symptoms persist indefinitely. Enhancement may also
recur if the inflammatory process is reactivated, even in
patients who have been deaf for years.
In a subset of patients with SNHL, we have demon-
strated segmental enhancement of different turns of the
cochlea.44 In certain patients the level of enhancement
correlates with the frequency range of the hearing loss; that
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
of the apical turn results in low-frequency hearing loss
(Fig. 20-16). This correlation is not always present because
certain patients with isolated enhancement of the basal
turn will have complete hearing loss over all frequencies.
The remarkable degree of correlation between high-
resolution-enhanced MRI and clinical examination in
many cases should prompt further investigations using
MRI in this highly specialized anatomic region.
PERILYMPHATIC FISTULA
Perilymphatic fistula45 is a controversial condition defined
as an abnormal communication between perilymph of the
inner ear and the middle ear typically involving injury to
the membranes of the oval window, round window, or
both.46 This condition is one of the many causes of sudden
hearing loss and vertigo. It is a difficult condition to diag-
nose even at surgery because the leakage of perilymph may
be intermittent and such small amounts of fluid are
involved that its direct observation may be difficult. The
condition is associated with either direct trauma to the ear
or barotrauma. Experimental studies in guinea pigs have
shown that barotrauma can induce ruptures of the round
window and oval window membranes and intralabyrinthine
hemorrhage, which predominates in the basal turn of
the cochlea,47 where the round window opens. We have
seen three patients with perilymphatic fistulae suspected
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.)

A B
enhancement was present (Fig. 20-17). As suggested in the
experimental studies, the enhancement predominated in the
basal turn of the cochlea but was also seen in the vestibule
in some patients. Some of these patients improved following
surgical patching of the oval window.
LABYRINTHINE NEOPLASMS
Labyrinthine Schwannomas
Labyrinthine schwannomas48 are the most common benign
neoplasms of the labyrinth.49 They are histologically identical
to their counterparts in the IAC. Isolated intralabyrinthine
schwannomas are reported to be more common in the
cochlea (Fig. 20-18) (based on the European experience), but
in our experience they are more common in the vestibule.50
In patients with neurofibromatosis they are more frequent
in the vestibular system. Schwannomas in the vestibule
originate in the fibers of the vestibular nerves. Branches of
these nerves reach the ampullae of the semicircular canals
(superior vestibular nerve reaches the superior and lateral
semicircular canal, the inferior vestibular nerve reaches the
posterior semicircular canal), and therefore larger schwanno-
mas will eventually grow into these ampullae. Labyrinthine
schwannomas can present with SNHL or vertigo (or both)
Imaging of the Labyrinth 339
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.)
and be clinically indistinguishable from Ménière’s disease.51
In fact, in the past these lesions were mostly diagnosed dur-
ing destructive labyrinthectomy for intractable “Ménière’s
disease.” In the past, the diagnosis on CT could be made
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-
strates a markedly enhancing mass in the cochlea (Fig. 20-
19) or vestibule (Fig. 20-20).
The major differential diagnosis of labyrinthine schwan-
noma is labyrinthitis. Schwannomas usually enhance much
more intensely, the enhancement persists over many
months, and the lesions may expand, contrary to labyrinthi-
tis, where the enhancement resolves over several months
with or without resolution of the patient’s symptoms.
In patients with labyrinthine schwannomas, the high-
signal-intensity intralabyrinthine fluid is replaced by the
hypointense tumor on the submillimetric T2-weighted
spin-echo or gradient-echo images. On these very detailed
images it is sometimes even possible to depict in which
scala the schwannoma is located. On the contrary, the
fluid retains its high signal intensity in the early stages
of labyrinthitis. T2-weighted images are important, espe-
cially since two nonenhancing intralabyrinthine schwanno-
mas have been recently reported.53 Schwannomas also
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
images. This is another sign that can be used to differenti-
ate intralabyrinthine schwannomas from labyrinthitis.
Moreover, in patients with intralabyrinthine schwannomas
most frequently only one compartment (cochlea or
vestibule/ semicircular canals) is involved, whereas in
labyrinthitis both compartments are more frequently
involved.
Patients with labyrinthine schwannomas have stable or
progressively worsening symptoms. Vestibular schwannomas
may be associated with intracanalicular and cerebellopon-
tine angle schwannomas in patients with neurofibromatosis
(Fig. 20-21).
Other Tumors Involving the
Labyrinth
Malignant neoplasms of the cochlea are exceptional.
Squamous cell carcinoma or adenoid cystic carcinoma in
the adult or rhabdomyosarcoma of the temporal bone in
the child may extend into the labyrinth. Metastasis may
extend perineurally along the cochlear nerve and penetrate
the cochlea (Figs. 20-22 and 20-23).
Endolymphatic sac tumors (ELSTs) are rare, low-grade
malignant neoplasms of the temporal bone, which may
be hemorrhagic54 and invade the vestibule and cochlea.
Isolated reports suggest a possible association between
ELSTs, which are extremely rare in the general popula-
tion, and von Hippel-Lindau disease (VHL). In a recent
large series, MRI revealed evidence of 15 ELSTs in 13
(11%) of 121 patients with VHL, but in none of the 253
patients without evidence of VHL.55
Middle ear cholesteatomas in the later stages may also
invade the inner ear (Fig. 20-24), but the patient’s history
and the CT findings are usually obvious.
Other lesions growing or invading the membranous
labyrinth include lipomas, histiocytosis X,56 cholesterol
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.

Figure 20-17. Perilymphatic fistula. Thirty-year-old man with sudden SNHL
after lifting heavy weights at the gym. Coronal, postcontrast, T1-weighted
image demonstrates enhancement of the cochlea (arrow). The patient’s
symptoms improved following surgical patching of the oval window.
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-
ing with extension of middle ear infection into the
vestibule. Postoperative enhancement of the labyrinth
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

C from perioperative extension of hemorrhage from the
Figure 20-20. Right vestibular schwannoma in a patient with a 1-year history
of vertigo and hearing loss. A, Axial and, B, coronal T1-weighted images
show globular enhancement of the right vestibule (arrow). The long-standing
history and the focal enhancement suggest schwannoma rather than
labyrinthitis. C, Pathologic specimen from another patient demonstrates an
intravestibular schwannoma. (Courtesy of Dr. H Schuknecht, Boston, MA.)
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”
IAC into the cochlea or vestibule. This finding, rather
than direct injury to the cochlear nerve at the time of
surgery, may explain some of the surgical failures in these
cases.
Membranous labyrinth fibrosis may also occur when
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.)

Figure 20-24. Cholesteatoma fistulizing into the labyrinth. Coronal,
postcontrast, T1-weighted image demonstrates a nonenhancing mass in the
middle ear with a peripheral rim of enhancement. Notice enhancement of the
labyrinth.
geniculate ganglion of the facial nerve can also result in
subsequent complete obliteration of the intralabyrinthine
fluid spaces. This can also explain occasional poor postsur-
gical results in some patients.
ENDOLYMPHATIC HYDROPS
Endolymphatic hydrops57 is defined pathologically as
dilatation of the endolymphatic spaces. Extensive experi-
mental evidence suggests that endolymphatic hydrops is
the result of a functional failure of the endolymphatic sac to
resorb the endolymph,58 resulting in dilatation of the
endolymphatic spaces with or without rupture of Reissner’s
membrane and communication of the endolymph and the
perilymph.
Schuknecht and Gulya59 classified endolymphatic hydrops
in congenital, acquired, and idiopathic forms. Any congenital
malformation can result ultimately in endolymphatic
hydrops. Among the best known is the large vestibular aque-
duct syndrome, in which a markedly dilated endolymphatic
sac and vestibular aqueduct are associated with other inner
ear malformations and congenital SNHL and vertigo. Any of
the inflammatory or traumatic lesions mentioned earlier may
have labyrinthine hydrops as the end result.
Among the idiopathic forms of labyrinthine hydrops,
Ménière’s disease is the best known. This condition is
clinically characterized by fluctuating SNHL with or
without vertigo and tinnitus. It is most often unilateral
and, when bilateral, it is usually asynchronous. Ample labo-
ratory evidence suggest that Ménière’s disease is caused by a
functional failure of the endolymphatic sac to resorb the
endolymph. Electromicroscopy study of biopsies of the
endolymphatic sac60,61 in patients with Ménière’s have
revealed a wide spectrum of findings from a near normal
sac to an inflammatory reaction to fibrosis and complete
atrophy and obliteration of the endolymphatic sac. This
spectrum of histologic findings explains the great
heterogeneity of the clinical findings in these patients from
mild forms with occasional episodes of vertigo to severe
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
We recently encountered a series of patients with symp-
toms compatible with Ménière’s disease in whom MRI
demonstrated enhancement of the endolymphatic sac68
(Fig. 20-25). Similar to enhancement of the cochlea and
vestibule, enhancement of the endolymphatic sac is consis-
tent with an inflammatory process in this location,69 such
as a viral infection,70 and may correlate with the acute
stage of the disease. It is possible that in later stages the
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-
high-field MRI (above 2T) is a hopeful new development
that should allow direct diagnosis of endolymphatic
hydrops in the future.71
Otosclerosis is a condition of unknown origin in which
the normal endochondral bone is replaced by foci of
spongy, vascular, irregular new bone that is less dense.72
These spongy decalcified foci in the later stages become
less vascular and more solid. The condition is bilateral in
most patients and often symmetrical. There is a 2-to-1
female predominance, and the disease usually appears in
the second or third decade of life. Otosclerosis is classified
into two major clinical categories. The fenestral type of
otosclerosis involves the lateral wall of the labyrinth,
including the promontory, facial nerve canal, and both
the oval and round window niche. The involvement of
the oval window results in fixation of the footplate of the
stapes and conductive hearing loss. Retrofenestral otoscle-
rosis occurs when the process of demineralization involves
the otic capsule itself. These changes in the bone may
affect the spiral ligament at the surface of the membranous
labyrinth and result in SNHL; thus, a patient with otoscle-
rosis may have a combined conductive and sensorineural
hearing loss depending on the relative distribution and
severity of the disease. CT is the imaging modality of
choice for diagnosing otosclerosis.73 Depending on the
location of the foci of demineralization along the cochlea,
specific frequency ranges may be affected more than oth-
ers.74 The lesions visualized on CT can sometimes be seen
as enhancing lesions on MRI35 (Fig. 20-26). This finding
probably reflects the leakage of gadolinium in the highly
vascular spongiotic bone during the early stages of the
disease. In the later stages of the disease, when the spongi-
otic bone is replaced by dense bone, the enhancement
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.)

Paget’s disease and osteopetrosis are best evaluated with
CT, and MRI has little to add.
However, in patients with fibrous dysplasia, MRI may
be helpful.75 Enlarged dense bone with a “ground glass”
appearance is seen in fibrous dysplasia, and the bony
changes can narrow the IAC or can encase the aqueducts
or membranous labyrinth. The bone abnormalities in
fibrous dysplasia vary considerably,76 but high signal inten-
sity on T2-weighted spin-echo images and precontrast
T1-weighted images and strong enhancement on the post-
contrast images (isointense or hyperintense compared with
fat) indicate active or progressive fibrous dysplasia.
CONCLUSION
The availability of intravenous contrast agents sensitive to
the disruption of the blood-brain and blood-labyrinth bar-
riers coupled with high-resolution imaging have
significantly expanded the potential role of MRI in the
evaluation of the membranous labyrinth. Although many of
the findings described in this chapter are still of uncertain
significance in terms of patient management, the potential
for insight into the natural history and pathophysiology of
many of these poorly understood disease processes is clear.
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22. Mark AS: Vestibulocochlear system. Neuroimag Clin North Am
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23. Swartz JD, Swartz NG, Korsvik H, et al: Computerized tomo-
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28. Nomura Y, Hiraide F: Sudden deafness: A histopathological study.
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30. Westmore GA, Pickard BH, Stern H: Isolation of mumps virus from
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32. Lindsay JR, Hemenway W: Inner ear pathology due to measles. Ann
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33. Liao BS, Byl FM, Adour KK: Audiometric comparison of Lassa
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35. Mark AS, Seltzer S, Harnsberger HR: MRI of sensory neural
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36. Schachern PA, Paparella MM, Hybertson R, et al: Bacterial
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39. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol
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40. Schuknecht HF: Disorders of the immune system. In Schuknecht
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41. Casselman JW, Mojoor MHJM, Albers FW: MR of the inner ear in
patients with Cogan syndrome. AJNR 15:131–136, 1994.
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ment on GD-MRI inpatients with sudden hearing loss and vertigo:
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43. Seltzer S, 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.
44. 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
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45. Althaus SR: Perilymph fistulas. Laryngoscope 91:538–556, 1981.
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48. Babin RW, Harker LA: Intralabyrinthine acoustic neurinomas.
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50. Fitzgerald DC, Grundfast KM, Hecht DA, Mark AS:
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52. Mafee MF, Lachenauer CS, Kumar A, et al: CT and MR imaging of
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54. Mukherji SK, Albernaz VS, Lo WW, et al: Papillary endolymphatic
sac tumors: CT, MR imaging, and angiographic findings in 20
patients. Radiology 202(3):801–808, 1997.
55. Manski TJ, Heffner DK, Glenn GM, et al: Endolymphatic sac
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56. Claros P, Claros A Jr, Claros A, Gilea I: Labyrinth involvement in
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58. Lundquist PG: Aspects on endolymphatic sac morphology and
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59. Schuknecht HF, Gulya AJ: Endolymphatic hydrops-an overview and
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61. Arenberg IK, Marovitz WF, Shambaugh GE Jr: The role of the
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67. Tanioka H, Kaga H, Zusho H, et al: MR of the endolymphatic duct
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gadolinium magnetic resonance imaging of the inner ear: Preliminary
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71. Koizuka I, Seo R, Kubo T, et al: High-resolution MRI of the human
cochlea. Acta Otolaryngol Suppl 520 Pt 2:256–257, 1995.
72. Wiet RJ, Rasian W, Shambugh GE: Otosclerosis 1981 to 1985, our
four year review and current perspective. Am J Otol 7:221–228, 1986.
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in the diagnosis of cochlear otosclerosis. Otolaryngol Head Neck
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74. Swartz JD, Mandell DW, Berman SE, et al: Cochlear otosclerosis
(otospongiosis): CT analysis with audiometric correlation.
Radiology 155:147–150, 1985.
75. Moreau S, Bourdon N, Goullet de Rugy M, et al: Temporal fibrous
dysplasia with labyrinthine involvement. Apropos of a case and
review of the literature. Ann Otolaryngol Chir Cervicofac
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76. Casselman JW, De Jonge I, Neyt L, et al: MRI in craniofacial
fibrous dysplasia. Neuroradiology 35:234–237, 1993.

Imaging of the Cerebellopontine Angle
Outline
Technical Considerations
Classifications and Incidence
of Cerebellopontine Angle
Tumors
Vestibular Schwannoma
Meningioma and Simulants
Epidermoid and Other Cysts
TECHNICAL CONSIDERATIONS
Modern imaging techniques for the cerebellopontine
angle (CPA) and internal auditory canal (IAC) consist
principally of magnetic resonance imaging (MRI) and
computed tomography (CT). Angiography is occasionally
employed when evaluating vascular lesions.1
Because of its superior soft tissue contrast, multiplanar
capability, and lack of ionizing radiation, MRI holds a
substantial advantage over CT in imaging the CPA.2
Furthermore, with paramagnetic contrast enhancement,
MRI has become the unquestioned method of choice for
visualization of small acoustic tumors.3 The frequent
untoward reactions to intravenous (IV) iodinated contrast
material for CT are obviated. Furthermore, recently
developed heavily T2-weighted, submillimeter thin-
section, spin-echo or gradient-echo images exquisitely
outline cisternal nerves and vessels better than gas CT-
cisternography, and the otic labyrinth as well as or better
than high-resolution CT.4–7 This chapter therefore focuses
primarily on MRI.
CT remains useful in special situations, for example,
when MRI is not available, when patients are too claustro-
phobic or too large to be accommodated in the scanner,
when visualization of calcium or bone changes is impor-
tant,8 or when acute hemorrhage is in question.9,10
Although a detailed discussion of the technical aspects
of MRI is beyond the scope of this chapter, a general
understanding of the capabilities and limitation of the
technique will greatly assist the clinician in effectively
using MRI for investigation of the CPA or the IAC.
Although not all CPA symptoms are caused by tumors,
the principal concern raised is usually the presence or
absence of a tumor. Because most of the tumors in the
CPA are intradural extra-axial (outside the brain) and
partly outlined by cerebrospinal fluid (CSF) and because
T2-weighted images (T2WI) superbly outline nerves and
Chapter
21
Nonvestibular Posterior William W. M. Lo, MD
Fossa Schwannomas
Michael M. Hovsepian, MD
Vascular Lesions
Extradural Lesions
Intra-axial Tumors
Intracanalicular Lesions
Conclusion
brain tissue against CSF, noncontrast, heavily T2-weighted,
submillimeter thin-section images have been recom-
mended for low-cost screening for acoustic tumors.11 Such
images may be obtained by fast spin-echo (FSE) or by
gradient-echo technique (constructive interference steady
state, or CISS). Normal structures as demonstrated by CISS
images are illustrated in Figure 21-1.4–7 However, gadolin-
ium chelates as paramagnetic contrast agents administered
intravenously, markedly enhance the signal intensity of
most tumors, as well as inflammatory lesions on T1WI,
and aid in characterization and differential diagnosis of
lesions. Thus, contrast-enhanced T1WI is nearly always
used for detection or evaluation of CPA and IAC tumors,
in a comprehensive study.3,12–15 Normal T1WI are illus-
trated in Figure 21-2.16,17
Although T2WI add little to the detection of extra-axial
tumors, they are useful in assisting characterization of
tumors (e.g., in meningioma, lipoma, peritumoral cysts,
peritumoral edema, hemorrhage, etc.). They are also more
sensitive than T1WI for detection of intra-axial lesions
(inside the brain) that can produce acoustic symptoms,
such as occur in multiple sclerosis, infarct, and edema, as
well as in hemosiderin deposition in superficial siderosis.18
Thus, a comprehensive study of the CPA would typi-
cally include T1WI in thin sections through the posterior
fossa and IAC before and after the administration of
gadolinium chelates, and T2WI in thicker sections to
survey the brain.
Under some circumstances, modified or additional
techniques may be employed. For example, in neurofibro-
matosis 2 (NF2),19,20 in which multiple intracranial schwan-
nomas and meningiomas, and spinal schwannomas,
meningiomas, and ependymomas are often present, post-
contrast T1-weighted surveys that include the entire head
and spine may be desirable.19,21–22 When vascular lesions
such as aneurysm, arteriovenous malformation (AVM), or
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
When confirmation of lipoma or fat, including operatively
placed fat, is desired, a fat suppression technique may be
invoked.24
Obviously, the desire for completeness and quality must
be balanced against the constraints of time, cost, through-
put, and patient tolerance. For practical purposes, a
comprehensive study probably should not exceed half an
hour per patient. A noncontrast, heavily T2-weighted,
thin-section survey specifically used for screening for
acoustic tumors may be accomplished in less than 15 minutes
at considerably lower cost. Such a study, however, carries
the disadvantage of not being able to differentiate lipomas
or melanotic melanoma,25 which are hyperintense on
preconstrast T1WI, from schwannomas, which are
isointense or mildly hypointense on precontrast images.
Furthermore, multiple sclerosis (Fig. 21-4) or superficial
siderosis (Fig. 21-5) may be completely missed, should
either be present. A fat-suppressed postcontrast sequence
is generally necessary for evaluation of postoperative
recurrence.3 A precontrast T1-weighted sequence is nec-
essary for evaluation of paragangliomas, which may
become nearly isointense with bone marrow on postcon-
trast images (Fig. 21-6). Thus, each institution or facility
must devise protocols best suited to its own needs or
practice and adapt to new technical developments that
emerge. Our current protocol is offered as an example in
Table 21-1.
Although one study showed that 5-mm sections com-
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
practicable for imaging of the IAC whenever permitted
by the capability of their equipment, most commonly
2- to 3-mm sections,3,27 because intracanalicular tumors
are often only a few millimeters in diameter and may
be suboptimally visualized or even obscured by partial
volume effect in thicker sections. The interslice gap also
differs, from varying degrees of overlap up to perhaps
20% gaps. A minimum qualitative standard, which perhaps
should be insisted on, is that the facioacoustic nerves
through their cisternal and canalicular portions be
recognizable bilaterally, either on T1WI or T2WI (see
Figs. 21-1 and 21-2). An unfocused study of the brain
with 5-mm or thicker sections is inadequate for imaging
the IAC.
Images in a second orthogonal plane should be
obtained when a tumor is encountered20 to demonstrate
the relationship of tumor to the tentorium and the jugular
fossa, and when volumetric measurements are desired.
Gadolinium contrast agent should be routinely used in
comprehensive studies because it markedly improves
visualization of small tumors, permits identification of
residual or recurrent tumor, and adds precision to the
delineation of tumor in the IAC (Fig. 21-7).3 There are
only a few contraindications to its use, and side effects
rarely occur. Furthermore, gadolinium chelate enhance-
ment confirms labyrinthitis28 and reveals nondestructive
intralabyrinthine schwannomas.29,30
Numerous studies have been performed to identify the
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
Comprehensive Study of Cerebellopontine Angle/Internal
Auditory Canal
Axial survey of brain: T2WI, 5.5-mm thickness
Axial posterior fossa detail: T1WI precontrast, 2.0-mm thickness
Axial submillimeter posterior fossa detail: CISS, 0.8-mm thickness
Axial survey of brain: DWI, 5.0-mm thickness
Axial posterior fossa detail: T1WI post-Gd FS 2.0-mm thickness
Coronal posterior fossa detail: T1WI post-Gd FS, 2.0-mm thickness
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
thickness
CISS, constructive interference steady state; DWI, diffusion-weighted images; FS, fat-
suppressed; Gd, gadolinium chelate; NF2, neurofibromatosis 2; T1WI, T1-weighted images;
T2WI, T2-weighted images.
determined any significant hazards.31,32 More directly
related to otologic interest is acoustic noise produced by
the activation and deactivation of the gradient magnetic
filed.33,34 Reversible hearing loss may be induced by such
noises.35 Disposable ear plugs or other noise reduction
devices should be routinely used.31
Certain prosthetic implants and metallic materials are
associated with potential hazards. Examples are cardiac
pacemakers, ferromagnetic cerebrovascular aneurysm
clips, and intraocular ferromagnetic foreign bodies.31
High-field MRI is strictly contraindicated for patients
with cochlear implants,31,36 although low-field scanners
may be safe. Stapes prostheses are safe for MRI with the
exception of the Richards-McGee platinum-stainless steel
piston manufactured in a relatively small quantity and only
for a brief period after mid-1987, using C17NI4 stainless
steel instead of the more common 316L stainless steel.37
Eyelid springs used for patients with facial nerve palsy
have shown deflection in vitro but no significant ill effects
in vivo.
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.)
CLASSIFICATIONS AND INCIDENCE OF
CEREBELLOPONTINE ANGLE TUMORS
Approximately 10% of intracranial tumors originate in the
CPA.38 Most of them arise from the cranial nerve sheath,
the meninges, the blood vessels, and the congenital rests
located in the extra-axial compartment. Some arise from
the petrous bone or the jugular foramen and are extradural
in origin but intrude into the CPA. A few are exophytic
growths of intra-axial lesions arising from the brain.
Lesions in the CPA are extremely diverse. Provided in
Table 21-2 for reference are the lesion types and numbers
from three major series.39–41 The Brackmann series repre-
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
lesions. The three series also agree that the distant second,
third, and fourth most common tumors by narrow margins
are meningioma, congenital intradural epidermoid tumor
or cyst, and nonacoustic posterior fossa schwannomas,
respectively. These four common tumor types account for
about 75% to 98% of all CPA mass lesions.
Beyond the four most common tumors, the types of
mass lesions in the CPA are extremely diverse and numer-
ous (see Table 21-2). The Revilla series of 205 CPA lesions
includes 1 primary melanoma, 1 paraganglioma, and 13
cerebellar and petrous bone tumors infiltrating the CPA.40
The Brackmann series of 1354 CPA tumors includes
7 arachnoid cysts, 4 hemangiomas, 1 hemangioblastoma,
2 astrocytomas, 2 medulloblastomas, 3 metastatic
tumors, 2 dermoids, 2 lipomas, 1 malignant teratoma, and
1 chondrosarcoma.39 The series of 455 CPA lesions of
Valavanis41 includes among primary tumors, 1 melanoma
and 3 hemangiomas; among secondary tumors, 47 para-
gangliomas, 1 ceruminoma, 2 chondrosarcoma, 8 chor-
doma, and 6 extensions of cerebellar and petrous bone
 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
grow to fill the canal (see Fig. 21-7). At times, intra-
canalicular VSs may be lobulated or globular and focally
erode the canal.
Schwannomas are typically isointense or mildly
hypointense to brain on T1WI, enhance markedly on
gadolinium, and are between brain and CSF in intensity
on T2WI (see Figs. 21-7 through 21-12). As a group, they
enhance far more than any other benign extra-axial tumor,
but sufficient overlap occurs among tumors of different
types so that the degree of enhancement alone cannot
always be relied on to differentiate the type of tumor.47
The enhancement may or may not be homogeneous
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
presence of Antoni type B tissue (see Figs. 21-8 and
21-10).1,38,48,49 Initially, nonenhancing microcystic compo-
nents on a short sequence may attain enhancement in time
as equilibration of contrast material in extracellular space
takes place.1
Schwannomas may also be accompanied by one or more
overlying arachnoid cysts (Fig. 21-13), and at times be
dominated by one.50 Calcification is rarely present in
schwannomas.41,49,51–54
Rarely, intratumoral hemorrhage may cause focal hyper-
intensity or hypointensity depending on the age of the
hemorrhage.55–58 Even more rarely, subarachnoid hemor-
rhage may be the presenting symptom of a large VS.59,60
However, acute subarachnoid hemorrhage may not be
apparent on MRI even when obvious on CT.10 CT is
therefore indicated when the signs and symptoms suggest
subarachnoid hemorrhage.14
A dural “tail” often observed in meningiomas (Figs. 21-12,
21-14, and 21-15), on rare occasions may be seen associ-
ated with a VS (see Fig. 21-11).61
Funnel-shaped enlargement of the IAC is common in
VSs and rarely seen in other lesions (see Figs. 21-8 and
21-11).41,54 The incidence of hydrocephalus roughly corre-
lates with tumor size. One report noted hydrocephalus in
17 of 44 patients in whom a tumor of 3 cm or larger was
present.62 Rarely, a large VS compressing the brain may
cause peritumoral edema.41
CT and MRI have been extremely useful in studying the
natural history of VS. Many such studies have been pub-
lished.63–73 Their methodologies may vary, but the results
appear to concur that most tumors are stable or slowly
growing (of the order of 2 mm or less a year) but some
grow as much as 1 cm or more a year. These results appear
to correlate with those revealed by monoclonal antibody
studies.74 To establish the growth rate of a tumor, an initial
follow-up study in perhaps 6 months may be done. If the
tumor is found to be stable or very slow growing, subse-
quent follow-up studies then may be repeated at 1- to
2-year intervals.
In postoperative studies for residual or recurrent tumor,
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
tumor.75 Fat suppression technique should be used.24 After
hearing-conservation techniques have been performed to
remove small VSs, enhancement of varying degrees at the
operative site is usually present.76 Serial follow-up studies
are necessary to establish the presence or absence of
tumors.77
After stereotactic radiosurgery, one series shows VSs
often shrank (22%) but more commonly remained stable
in size (73%) and rarely continued to grow (4%).78 The
corresponding numbers for untreated tumors were 3%,
59%, and 38%, respectively.78 The majority (79%) of
tumors after radiosurgery showed loss of central enhance-
ment, which sometimes returned (Fig. 21-16). Some 5 to
15 months after treatment, 9% developed hyperintensity
on T2WI in the adjacent pons and the cerebellar peduncle
with associated contrast enhancement on T1WI sugges-
tive of breakdown in the blood-brain barrier. Some of
these changes resolved after months and were not neces-
sarily associated with neurologic symptoms. Similarly,
contrast enhancement was observed in the trigeminal
nerve in some of the patients. Up to 10% of the patients
developed hydrocephalus months after radiosurgery and
required ventriculoperiotoneal shunts.78–80 Some tumors
continued to grow and required reradiation or eventually
surgical resection.79
The distinction of neurofibromatosis 1 (NF1) (von
Recklinghausen’s disease) from NF2 (bilateral acoustic
neurofibromatosis), established by the National Institute
of Health (NIH) Consensus Development Conference as
separate disorders, represents a significant advance in the
understanding and management of these disorders.19
Although both disorders are autosomal-dominant and may
be inherited or acquired by mutation, they are associated
with defects in different chromosomes.81,82 Because both
disorders may have central nervous system (CNS) involve-
ment, the terms peripheral and central neurofibromatosis
should be discarded.83 It is important to be aware of their
differences so that the MRI examination may be appropri-
ately tailored to the disorders.83,84
The diagnostic criteria for NF1 may be found in
Chapter 46. The criteria for NF2 include (1) bilateral
eighth nerve masses seen with appropriate imaging
techniques, such as CT or MRI (see Fig. 21-12) or (2) a
first-degree relative with NF2 and either a unilateral
eighth nerve mass or two of the following: neurofibroma,
meningioma, glioma, schwannoma, or juvenile posterior
subcapsular lenticular opacity.19
Besides bilateral VSs, NF2 patients are at risk for
schwannomas of other cranial and spinal nerves, and
intracranial and spinal meningiomas, often multiple (see
Fig. 21-12).21,83 Members of some kindreds also develop
ependymomas.22 Choroid plexus calcification is com-
mon.85 NF2 patients, however, are not at risk for optic
gliomas, focal cerebral hamartomas, and many other
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

MENINGIOMA AND SIMULANTS
In the CPA, meningioma is a distant second to VS in inci-
dence.39,40,86 It is most often the lesion difficult to differ-
entiate from VS.41,52,86,87 (See Chapter 47.)
Meningiomas in the CPA most commonly arise from
the posterior petrous surface (Fig. 21-17). Like VSs they
are extra-axial, but unlike VSs they are usually eccentric
to the porus (see Fig. 21-14). Also unlike VSs, menin-
giomas frequently herniate into the middle cranial fossa,
(see Figs. 21-14 and 21-17).41 They may grow into the
middle fossa through the tentorium or the temporal bone
(see Figs. 21-15 and 21-17).41,87
Most characteristically, meningiomas are sessile and
hemispherical in configuration, with their broad base
against the petrous bone (see Fig. 21-14). They show
obtuse bone tumor angles (see Fig. 21-14) in contrast
to VSs, which are typically spherical or ovoid and show
acute bone tumor angles (see Figs. 21-8 through 21-13 and
21-16).41 Less commonly, meningiomas are flat or plaque-
like (en plaque) (see Fig. 21-15), and rarely pedunculated
and nearly rounded.38 The en plaque meningiomas are
notably prone to cause deep infiltration of the petrous
bone (see Fig. 21-15).38 The surface of meningiomas is
usually smooth or slightly lobulated.
On MRI, like VSs, meningiomas are isointense or slightly
hypointense on T1WI but, unlike VSs, they vary from
hyperintense to hypointense on T2WI (see Fig. 21-14).8
(Hypointensity on T2WI may be due to calcification,
fibrous tissue, melanotic elements, hemosiderin, fat, etc.)58
Gentry and colleagues8 found that when the intensity of
the CPA mass was equal to or less than that of gray matter
on T2WI, meninigioma was the most likely diagnosis.
The variability in signal intensity of meningiomas on
T2WI appears to reflect the histopathologic diversity of
meningiomas. Tumors significantly hypointense to brain
cortex tend to be composed primarily of fibroblastic or
transitional elements, whereas those significantly hyperin-
tense tend to be composed primarily of syncytial
(meningothelial) or highly vascular elements.38,88,89
Generally, however, accurate prediction of histology by
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 21-17. Diagrammatic representation of locations of 19 meningiomas
producing CPA symptoms (left and right sides combined). (From House JW
and O’Connor AF [eds.]: Handbook of Neurotological Diagnosis, New York,
1987, Marcel Dekker, Inc, p 290, by courtesy of Marcel Dekker, Inc.)
Imaging of the Cerebellopontine Angle 361
Meningiomas often calcify on CT (25%).41,94 On MRI,
calcification appears hypointense on both T1 and T2WI
(see Fig. 21-14), although hyperintense calcification has
also been reported.95 MRI is less sensitive to calcification
than CT and may not detect faint calcifications.
Underlying hyperostosis is infrequently seen but strongly
diagnostic when present (see Figs. 21-14 and 21-15).41 The
IAC is rarely if ever enlarged.
Cystic foci may be present in the tumor but appear
much less commonly in meningiomas that in VSs.52
Peritumoral edema is more commonly associated with
meningiomas than with VSs. Meningeal blood supply in
the form of an arborizing signal void is highly characteris-
tic if present. Marginal vessels and surrounding CSF cleft
may be seen but are nonspecific.96
Dural thickening surrounding meningiomas, best seen
with gadolinium enhancement (see Figs. 21-12, 21-14, and
21-15)97 has been variously termed meningeal sign, dural
tail, and flare sign.98–100 Initially found to correspond to
tumoral extension within or around the dura,97,99 the dural
thickening in many subsequent cases has been found to
contain only connective tissue, hypervascularity, and no
tumor.101 Hence, to establish the histopathology in a peri-
tumoral meningeal thickening, biopsy is necessary. In most
cases, the thickening represents reactive rather than neo-
plastic changes.102
Dural thickening has been found in 52% to 72% of the
meningiomas on postcontrast MRI.98–100 It has also been
found, although much less frequently, in nonmenin-
giomas, including oligodendroglioma, schwannoma (see
Fig. 21-11),61,100 glioblastoma, metastases, and other
tumors (see Figs. 21-6, 21-18, 21-19, and, later in this
chapter, Fig. 21-35).102 Thus, peritumoral dural thickening
is strongly suggestive but not diagnostic of meningioma.
Aoki and coworkers98 found dural thickening and
enhancement extending into the IAC in two of four CPA
meningiomas that simulated the stem of a VS.
Several rare neoplastic and inflammatory diseases
involving the meninges may simulate meningiomas on
CT or MRI. Among the neoplasms are loculated lep-
tomeningeal metastasis (meningeal carcinomatosis)
Figure 21-18. Loculated and diffuse meningeal metastases from carcinoma
of the prostate. Gd-T1WI, Loculated metastases are present in both IACs
(arrows) and diffuse metastasis (long thin arrows) similar to dural “tail.”
Differential diagnosis: meningeal lymphoma, melanoma, sarcoidosis,
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-
phoma,42,106 and primary malignant melanoma.41,107,108
Among the inflammatory diseases are meningeal sarcoido-
sis,44,109 tuberculosis, syphilis, and idiopathic hypertrophic
cranial pachymeningitis (see Fig. 21-19).43 All of the pre-
ceding conditions may appear as diffuse dural thickening
simulating en plaque meningiomas or localized dural-based
masses simulating sessile meningiomas. However, they are
not expected to have underlying hyperostosis, intratu-
moral calcification, or discernible arborizing meningeal
arterial feeders.
EPIDERMOID AND OTHER CYSTS
Congenital intradural epidermoid tumors or cysts are the
third most common mass lesion in the CPA (Figs. 21-21
and 21-22).39,41
They may be anterolateral or posterolatral to the brain-
stem. They tend to expand where the physical resistance is
low, often extending into the prepontine and suprasellar
cisterns and “dumbbell” into the contralateral cistern or
the middle cranial fossa. Their shapes are thus quite vari-
able. They tend to burrow into the surface crevices of the
brain and possess a fine surface irregularity reminiscent of
that of cauliflower.110 The petrous apex may be eroded.41,111
On CT they are well known to be isodense with CSF.8
But, rarely they may be hyperdense (see Fig. 21-22).112–114
On MRI they are slightly hyperintense to CSF on T1WI
and isointense on T2WI in the vast majority of
cases.8,110,115,116 But, rarely, they show reversed signal inten-
sities and are hyperintense on T1WI and hypointense on
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
than displace the cisternal arteries.116 Small punctate calci-
fications are infrequently seen in the periphery.119
Epidermoid cysts are nonenhancing (see Fig. 21-12).119
Association of an enhancing component should arouse the
suspicion of a squamous carcinoma arising from an epider-
moid cyst.120,121
A number of other cysts may simulate epidermoid cysts
in the CPA. They are all nonenhancing extra-axial masses
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
MRI)—hypointense on T1WI and hyperintense on
T2WI. Lipoma is also considered at this time because it is
nonenhancing, although its x-ray attenuation and MR sig-
nal intensities of fat are distinctive from those of most
cysts.122,123
Arachnoid cysts in the CPA are usually large masses and,
like epidermoid cysts, hypointense on T1WI and hyperin-
tense on T2WI (Fig. 21-23).124,125 (See Chapter 55,
Neurotologic Aspects of Posterior Fossa Arachnoid
Cysts.) But unlike epidermoid cysts, their surfaces are
smooth and their contents homogeneous. They displace
rather than surround the arteries in the cistern. An attempt
to differentiate the two lesions on the basis of imaging is
worthwhile, since the symptoms of arachnoid cysts may be
controlled by diuretics alone.126 Diffusion-weighted and
fluid-attenuated MR sequences may help in differentiating
the two lesions when routine spine-echo studies are incon-
clusive.127
Cysticercosis should be considered in endemic areas.
Cisternal cysticercal cysts are also of CSF attenuation and
intensity, but are usually smaller than arachnoid cysts and
often detected only by the presence of focal cisternal
widening (Fig. 21-24).128 Unlike parenchymal and ventric-
ular cysticercal cysts, which are separate from one another,
cisternal cysts are racemose, a few centimeters in diame-
ters, and lack a scolex.128 The majority are detectable only
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.)
on T1WI, but T2WI demonstrate the surrounding
parenchymal reaction to greater advantage.129 Coexistent
parenchymal, ventricular, or additional cisternal cysts,
when present, strongly support the diagnosis.
Very rare congenital cysts that may be encountered in
the CPA include epithelial cysts,130–133 neurenteric cysts,134
and craniopharyngioma.17,135 Although their CT and MR
images have been illustrated, generalization of their find-
ings is difficult on the basis of the very few cases reported.
Some of them show CT attenuation and MR intensities
atypical of uncomplicated cysts.132,134,135
In contrast to most CPA tumors and cysts, lipomas are
hyperintense on T1WI and hypointense on T2WI and
parallel the signal intensity of orbital and subcutaneous fat
(Fig. 21-25).122,136–140 They show no contrast enhance-
ment, and their hyperintensities on T1WI are diminished
by fat suppression sequences.24 Without pregadolinium
images for comparison, their inherent hyperintensity on
T1WI will not be recognized when only postgadolinium
T1WI are obtained; nor will their characteristic short T2
values be appreciated without adequate T2WI. Because
conservative management for lipomas may be advis-
able,122,136,137,139,141–143 diagnosis on the basis of imaging
findings is of considerable importance. Besides the charac-
teristic MRI intensities, the negative Hounsfield values of
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
FOSSA SCHWANNOMAS
Schwannomas arising from PF cranial nerves other than
the vestibular are rare.38,44 They resemble VSs in appear-
ance but differ from them in location.41,144 Not infre-
quently, facial and intracranial jugular foramen
schwannomas are associated with symptoms relating pri-
marily to the eighth nerve. Careful assessment of their
relationship to the cranial foramina is important so that
the correct diagnosis can be made and inappropriate use of
the translabyrinthine approach avoided.145
Among the PF schwannomas, trigeminal schwannoma
is a distant second to VS in frequency of occurrence.144
Trigeminal schwannomas may arise intradurally from
the nerve root in the CPA and the Meckel cave or extradu-
rally from the gasserian ganglion in the middle cranial
fossa (Fig. 21-26).146–149 They often dumbbell into the
posterior and middle fossae through the porus trigemi-
nus.86,147–149 The foramen ovale or foramen rotundum
(or both) may be enlarged. They tend to be larger than
the average VS,149 and more often contain cystic
components.41,150
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.
Facial schwannomas are, in most cases, indistinguish-
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
or the IAC, they tend to show vestibulocochlear symptoms
and may be indistinguishable from VSs clinically as
well,151–153 unless a cisternal facial schwannoma lies clearly
anterior to the course of the acoustic nerve.
Schwannomas of the glossopharyngeal, vagus, and
spinal accessory nerves (jugular foramen schwannomas)
may be predominantly intracranial (type A), predomi-
nantly in the skull base (type B), or predominantly
extracranial (type C).154 Type A tumors tend to present
with eighth nerve and cerebellar signs and symptoms, and
type B and C tumors tend to present with palsies of the
ninth, tenth, or eleventh cranial nerves.154–157 Thus type A
tumors mainly need to be differentiated from VS and type
B tumors from paraganglioma (glomus jugulare tumor),
meningioma, and other tumors that may involve the jugu-
lar foramen (Fig. 21-28). (See also Chapter 61.) On CT
the jugular foramen enlarged by a schwannoma shows a
smooth rounded margin.1 On MRI, the prominent ser-
pentine arborizing signal voids common in large paragan-
gliomas are seldom present,158 and on angiography the
 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
than meningiomas.154,155,159 (See also Chapters 22 and 61.)
When the pars nervosa of the jugular canal is selectively
expanded, a glossopharyngeal schwannoma can be recog-
nized. When the entire jugular foramen is diffusely and
enlarged, however, differentiation among the jugular fora-
men schwannomas is not possible by imaging.1
Rarely a hypoglossal schwannoma may also appear as a
mass in the CPA. Its identity can be traced if the hypoglos-
sal canal is smoothly and selectively enlarged.160–162 When
the bone erosion incorporates the adjacent jugular fora-
men, identification of precise origin of the tumor is then
no longer possible.160
VASCULAR LESIONS
Vascular lesions in the CPA are rare, but a number of them
may clinically mimic neoplasms and should be considered
in the differential diagnosis on imaging.163
VBD, or elongation and dilatation of the vertebrobasi-
lar arteries, is probably the vascular lesion most commonly
associated with compressive symptoms of the PF cranial
nerves (Figs. 21-3 and 21-29).164 The basilar artery may
be considered ectatic if its diameter is more than 4.5 mm
(see Fig. 21-29) and elongated if it deviates beyond the
lateral margin of the clivus (see Fig. 21-3) or the dorsum
sellae or if it bifurcates above the plane of the suprasellar
cistern.165
Patients with VBD may or may not be symptomatic.166
The incidence of cranial nerve compressive symptoms, how-
ever, appears to correlate with the degree of tortuosity.167
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
dilated and tortuous artery is likely to have multiple com-
pressive or ischemic neurologic deficits or hydrocephalus
(see Fig. 21-29).164
In most cases the actual compression of a cranial nerve is
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
or vestibulocochlear, or the posterior inferior cerebellar
artery (PICA) on the glossopharyngeal. Hence, vascular
cross-compression by a branch of the vertebrobasilar
artery may occur without the vertebrobasilar itself neces-
sarily being substantially dilated or tortuous. In fact, the
offending vessel may at times be a vein instead of an artery.168
Furthermore, vessel-nerve contact or even vascular grooving
of the nerve does not necessarily mean disease.169
Positive identification of the offending vessel by imag-
ing is difficult. Angiographic localization, which visualizes
the vessel but not the nerve, is indirect and invasive.170,171
CT with IV contrast shows the vertebrobasilar arteries
and the brainstem but not adequately the branches of
the vertebrobasilar or the cranial nerves in question.172
MRI offers improved resolution of the structures, but expe-
rience with MRI in this application is as yet limited.173–175
With future improvements MR angiography may become
a useful adjunct (see Fig. 21-3).23
For preoperative diagnosis of neurovascular cross-
compression, some centers use CT or MRI only to exclude
other causes of symptoms,168,176 whereas others use, in
addition, gas-CT cisternography for positive identification
of the offending vessel before surgical microvascular
decompression (Fig. 21-30).9,177 The point of contact may
be in the cistern, the porus, or the canal and not necessar-
ily limited to the canal as described in some reports.169,177
Concerns about postprocedural morbidity,178 even with
25-gauge rather than the “standard” 22-gauge spinal nee-
dles,179 have discouraged continued use of the gas-CT cis-
ternogram in favor of the MR cisternogram with fast spin
echo or CISS (see Fig. 21-1).4,5,11
Aneurysms of the vertebrobasilar system comprise about
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
are detailed in Chapter 22, Imaging of the Lateral Skull
Base. Here they are briefly discussed only as a reminder that
they may intrude into the CPA.1 Bone lesions in the petrous
apex include cystic lesions such as cholesterol granuloma
(cholesterol cyst) (Fig. 21-34), congenital intrapetrous
epidermoid cyst, and petrous apex mucocele193; solid tumors
such as chordoma, chondroma, chondrosarcoma (Fig. 21-35),
giant cell tumor, myeloma, metastases, xanthoma,194 and so
on; and intrapetrous carotid aneurysm. Papillary endolym-
phatic sac tumors, which may also protrude into the
CPA, are discussed in Chapter 23, Imaging of the Facial
Nerve. The more aggressive of the extradural tumors may
at times transgress the dura and form an intradural mass
(see Fig. 21-35). The same may be said for paragangliomas
from the jugular foramen (see Fig. 21-6). The associated
bone changes of an apparently intradural mass may reveal its
true origin.
Intra-axial tumors arise from the brain and a detailed dis-
cussion is beyond the scope of this chapter. Some of them
produce exophytic masses in the CPA and must be consid-
ered in the differential diagnosis.
Intra-axial PF tumors arise from the brainstem, the
cerebellum, or the fourth ventricle. Tumors of the brain-
stem are mainly astrocytomas that occur in children or
young adults (Fig. 21-36).195–197 Exophytic growths are
common. Tumors in the cerebellum may arise from the
vermis or the hemispheres. The vermian tumors are prin-
cipally medulloblastomas in childhood, now classified as
primitive neuroectodermal tumors (PNETs).196,198,199 The
hemispheric tumors include astrocytomas,196 usually of the
pilocystic variety in young adults, hemangioblastomas in
middle-aged individuals,200 and metastases.196 Any of the
three may be cystic or solid.96 Lymphoma of the brain is
seen with increasing frequency in recent years, particularly
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,
tumors from the fourth ventricle are particularly prone to
do so.202 They are ependymomas (Fig. 21-38)203,204 and
choroids plexus papillomas (Fig. 21-39).205–208 Both of
these tumors often contain granular calcifications.
Although extra-axial tumors are more common in the
CPA in adults and older teens,209 exophytic intra-axial
tumors are more common in childhood.199
Nonneoplastic brain lesions such as multiple sclerosis
(see Fig. 21-4)210–211 and infarct (Fig. 21-40)210,212 also
enter into the differential diagnosis, as do AVMs,213 cav-
ernous angiomas,214,215 developmental venous anomaly
(venous angiomas), and capillary telangiectasia.214
INTRACANICULAR LESIONS
Intracanalicular lesions of the IAC carry a slightly different
differential diagnosis from lesions of the CPA (Table 21-4).
In the IAC as in the CPA, tumors other than VSs are
uncommon, but because therapeutic implications for some
of the lesions are significantly different from those of VSs,
each of the lesions should be carefully considered and if
possible preoperatively identified. In general, few intra-
canalicular schwannomas, either vestibulocochlear or
facial, are associated with signs of facial nerve involvement.
Presence of such signs in a patient with an intracanalicular
tumor should be a clinicoradiologic clue that arouses
suspicion of a nonschwannomatous tumor.216
1. Vestibular schwannomas again constitute about 90%
of the tumors.48,179,216
2. Facial schwannomas are rare and usually indistin-
guishable from VSs preoperatively.1,152,153
3. Meningiomas have been said to cause facial palsy
more often than VSs but rarely have they been fully
documented.217,218 They may be accompanied by
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
to VSs in incidences in the IAC.219–222 They tend to
cause a greater degree of nerve deficits and are more
commonly accompanied by facial nerve symptoms
than VSs of comparable size.216,221,223–225 Some of
them contain intratumoral bone spicules discernible
on high-resolution CT with bone algorithm
(Fig. 21-41)226,227; some may be associated with honey-
comb changes of the adjacent bone (see Fig. 21-41).221
On MRI, some are isointense or hyperintense to CSF
on T2WI and a few are moderately hyperintense on
T1WI, but often they are indistinguishable from
schwannomas, especially when precontrast T1WI and
adequate T2WI are lacking (Fig. 21-42).220,222
5. Intracanalicular metastases may be suspected from a
short duration of symptoms, facial weakness, a known
history of malignancy, and a rapid growth rate on
serial studies.1,228,229 Not infrequently they are bilat-
eral (Figs. 21-18 and 21-43).
other ectopic mature mesenchymal tissues, such as
smooth muscle, in varying proportions, with fat
usually predominating. Fat shows distinctive MR
signal intensities, being markedly hyperintense
on T1WI and moderately hypointense on T2WI
(Fig. 21-44)142,230 and can be confirmed by precon-
trast fat-suppressed T1WI.24,139
7. Melanotic melanomas are also hyperintense on
T1WI and hypointense on T2WI, but amelanotic
melanomas do not follow such a pattern (see Figs.
21-20 and 21-43).58,108,231
8. Lymphoma in the IAC may involve the lep-
tomeninges.232
9. Glioma of the acoustic nerve is an extreme rarity.233
10. Osteomas of the IAC are also rare and are better
demonstrated on CT than on MRI (Fig. 21-45).
Osteomas containing purely cortical bone are
hypointense on all sequences; those containing fatty
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
Hamartoma of the acoustic nerve has also been
reported.216,234 Other nonneoplastic IAC lesions include
(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
inflammation and adhesion (Fig. 21-46),237,238 and (4) neuri-
tis of the facial or acoustic nerves (Fig. 21-47).239–243 One
report described four cases of vestibulocochlear neuritis with
hearing loss, positive auditory brainstem response, and MRI
finding of focal nerve enhancement indistinguishable from
small intracanalicular VSs.244 A period of observation was
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.)
thus advised for very small lesions to verify persistence of
symptoms or tumor growth.244,245
CONCLUSION
The variety of tumors and other lesions that may arise in
the CPA and the IAC are indeed enormous. However, the
common extra-axial types, which are well over 90% of
the lesions, are quite consistent in their appearance on
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.)

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.)
other cysts, nonvestibular PF schwannomas, and vascular
lesions. Most of the extradural and the intra-axial lesions
are also recognizable under systematic analysis. With
attention to technical detail, careful analysis of findings, a
systematic approach to differential diagnosis, and close
clinicoradiologic correlation, a correct radiologic diagno-
sis is possible, even for many of the rare lesions.
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 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
roughly with the medial temporal bone. In this context,
the other regions are the anterior skull base and the central
skull base. The anterior skull base is predominantly the
floor of the anterior cranial fossa and subjacent nasal cavity,
upper ethmoid sinuses, and orbits. Central skull base refers
to the region close to the sphenoid bone and includes the
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.
This chapter emphasizes the petrous apex and medial
temporal bone but also includes some description of the
pathology in contiguous regions more appropriately
assigned to the central skull base. Lesions of the middle ear
and external auditory canal are briefly discussed. The
proximity of the cavernous sinus and clivus to the temporal
bone makes them appropriate for inclusion in a discussion
of the lateral skull base. The differential diagnoses of lesions
in these areas are closely related and pathology can certainly
cross from one part of the skull base to the next.
A large number of diagnostic possibilities must be con-
sidered when a lesion is detected in the temporal bone or
lateral skull base. The diagnosis can be limited considerably
depending on the precise location or apparent site of the
lesion’s origin. A tumor arising in one location may have a
diagnosis completely different from that of a lesion arising
in another location only millimeters away.
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
(EAC). The internal auditory canal would represent a fifth
major area but this is discussed in a separate chapter along
with the cerebellopontine angle cistern. The seventh nerve
has a tortuous course through the entire temporal bone
and must be considered in the differential diagnosis in
many regions.
TECHNICAL CONSIDERATIONS
Computed tomography (CT) and magnetic resonance
imaging (MRI) are used in evaluation of the skull base.
Individual radiologists have certain preferences in some
regions, but one modality may be clearly superior in certain
situations.
High-resolution CT scanning is usually preferred as the
initial imaging study for the evaluation of most temporal
bone disease other than that in the internal auditory canal.
CT offers the greatest structural definition of current
imaging modalities with the advantage of demonstrating
thin bony septations and fine bony anatomy to localize and
characterize disease.
Air, thin plates of cortical bone, septations in the mas-
toids, and the otic capsule all have a similar appearance on
MRI. All appear black or as a signal void and little structure
is appreciated. MRI, however, has the ability to distinguish
383
384 NEURORADIOLOGY
subtle differences in soft tissues. In some cases, the signal
characteristics can strongly suggest a certain diagnosis. A
gadolinium-enhanced MRI is also considered the most
sensitive study for the evaluation of possible internal audi-
tory canal pathology, particularly for acoustic neuromas
(vestibular schwannomas).
Computed Tomography
High-resolution axial thin section CT is usually performed
to visualize the extent of bone involvement in lateral skull
base lesions. Care should be taken to ensure that any exten-
sion above or below the skull base is included in the scanned
area. To ensure maximal bone detail, bone algorithms should
be performed on the data.
Reformatted coronal images can be generated from the
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
erosions in a plane other than the axial were to be detected.
The recent introduction of multidetector CT scanners
has further improved image quality by improving spacial
resolution. The images are obtained with very thin sections
(as thin as 0.5 mm) allowing for less partial volume artifact.
The cross-sectional data can be postprocessed or reformat-
ted into multiple planes, most commonly axial and coronal.
Occasionally, additional planes such at various obliquities
are helpful in assessing certain pathologies and complex
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.
Currently, at our institution, we do not do direct coronal
scanning.
The middle ear, mastoid, and external auditory canal are
often evaluated without intravenous contrast. In evaluation
of the petrous apex and the carotid/jugular area, contrast
is often helpful and is routinely used. Bolus injection is
important for evaluating lesions involving the jugular
fossa, particularly differentiating an occluded jugular vein
from tumor. With multidetector machines, CT angiograms
(CTA) and CT venograms (CTV ) can be useful in detecting
arterial and venous pathologies such as aneurysms and
venous sinus thrombosis.
Magnetic Resonance Imaging
On MRI scans through the skull base, spin echo images are
still the usual images used. For small lesions, the thinnest
cuts possible should be performed. Unenhanced T1-
weighted images are best for demonstrating the fat planes
beneath the skull base. Postcontrast images are essential
for evaluating intracranial extension and certain pathologies.
Routine T2-weighted images do not provide anatomic
detail but are often helpful in narrowing the differential
diagnosis. Very high resolution T2-weighted images are used
as pseudocisternograms and give excellent detail regarding
the anatomy of the IAC.
Fat suppression on the enhanced images may be helpful
in evaluating lesions that extend beyond the petrous bone
into the extracranial tissues. Caution is necessary, however,
when evaluating near air-containing structures, such as
nasopharynx and sphenoid sinus. The suppression of fat
signal may fail, mimicking an enhancing lesion.1 Other
artifacts may obscure important anatomy.
Other current MRI techniques such as magnetic reso-
nance angiography (MRA) and magnetic resonance spec-
troscopy (MRS) may also aid in the diagnosis. MRA should
be performed if vascular lesions such as aneurysm or
anatomical vascular variations are questioned. MRS may
help further characterize a malignant lesion.
Diffusion-weighted images (DWI) do not give good
anatomic detail but may give information regarding
molecular motion or Brownian movement within a lesion.
Lesions with similar imaging characteristics on routine MRI
sequences can sometimes be distinguished. For instance,
epidermoids are bright on diffusion-weighted images while
a cerebrospinal fluid (CSF)-containing structure tends to
be dark.
PATHOLOGY
To aid differential diagnosis, the lateral skull base is divided
in four regions: petrous apex, jugular/carotid area, middle
ear, and external canal. Although there is some overlap, the
lesions that arise in each of these regions are fairly distinct so
the regions are discussed separately in the following sections.
Although regional divisions are important, some lesions
such as metastasis, multiple myeloma, and soft tissue sar-
comas may involve any portion of the petrous bone.
PETROUS APEX
The petrous bone is a simple block of bone covered by dura
and frequently penetrated by air cells from the middle ear or
mastoid. The bone is separated from the greater wing of the
sphenoid by the petrosphenoidal fissure and from the clivus
by the petroclival or petro-occipital synchondrosis. Lesions
in the petrous apex typically are related to the bone, the dura,
or the air cell system with its associated modified respiratory
epithelium. Many lesions involve the apex secondarily.
Cholesterol Cysts or Granulomas
The petrous apex cholesterol cyst, or granuloma, consists
of variable amount of granulation tissue and fluid in what
is considered an expanded air cell of a pneumatized petrous
apex. The cholesterol cyst is most likely the end point of a
continuum of pathology beginning with a simple obstructive
effusion and ending with an expanded air cell that contains
fibrosis, granulation tissue, fluid, and blood breakdown
products. The narrow drainage path of an apex air cell may
be compromised by a minor infection or simple mucosal
edema related to pressure changes in the middle ear. Fluid
may accumulate, giving an effusion. At some time in the
evolution of the lesion small hemorrhages may occur from
the wall (Fig. 22-1). The blood breakdown products are
poorly absorbed from the closed cavity and contribute to
the characteristic findings on CT and particularly MRI.
On CT scans, the cholesterol cyst is an expansile lesion at
the petrous apex. The bone is smoothly remodeled similar to
a mucocele (Fig. 22-1A). Indeed, the findings of an apex cho-
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
procedure and do not attempt to resect the walls of the mass.9
Mucoceles
True simple mucoceles of apical petrous cells are rare but
have been described. Such lesions have low T1 and bright
T2 signal with peripheral enhancement of the lining
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
sinuses have variable signals depending on their protein
content, so theoretically they might be very bright on
T1-weighted images and difficult to distinguish from

A A
B image shows asymmetry of the signal at the petrous apex. On the right, the
Figure 22-3. Epidermoid. A, Axial T1-weighted MRI demonstrates an
expansile low signal right petrous apex lesion (arrow). B, The lesion
(arrowhead) has high signal on T2-weighted image.
cholesterol granulomas. Mucoceles, like epidermoids and
cholesterol cysts, do not enhance centrally and therefore
are distinguished from more solid tumors, which do have
central enhancement. Chordomas, chondrosarcomas,
metastasis, plasmacytomas, and pituitary adenomas
enhance to some degree throughout their mass.
Pseudolesions of the
Petrous Apex
Several pseudolesions can be confused with cholesterol
granuloma or epidermoid. For example, if there is
nonpneumatized medullary bone at one petrous apex
Imaging of the Lateral Skull Base 387
B
Figure 22-4. Normal fat of the petrous apex. A, Noncontrast T1-weighted
petrous apex is pneumatized. On the left, medullary fat at the petrous apex
has high signal (white arrow). B, CT scan at approximately the same level.
Compare the pneumatized right petrous apex with the medullary bone in the
left petrous apex (black arrow).
and pneumatization of the contralateral side, T1-weighted
MRI images show a high signal in the nonpneumatized
bone. The high signal represents medullary fat (Fig. 22-4A).
The air in the pneumatized bone gives a signal void typical
of air. T2-weighted images reveal the normal drop-off
in signal from the medullary fat and exclude cholesterol
granuloma. On fast spin echo images, this fading of the
fat signal is less dramatic. In such cases, fat suppression
sequences with T1 images can be used to eliminate the
signal from fat and clarify the situation. CT can also
differentiate these two entities.
Fluid or mucus in apical air cells is more challenging.
Mucus, depending on its protein concentration, has highly
388 NEURORADIOLOGY

variable signal characteristics that could mimic cholesterol

Figure 22-5. Fluid in apical air cells. CT scan demonstrates opacification of
the right petrous apex (arrow). Note the preservation of the septae, excluding
cholesterol granuloma and mucocele from the differential.
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
from an epidermoid. Coronal and sagittal T2-weighted
imaging are often useful planes for demonstrating the
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
Petrous apicitis is a destructive infection involving the
petrous apex. Facial pain, sixth nerve palsy, and ipsilateral
ear drainage is a clinical triad described by Gradenigo in
patients with petrous apicitis (Fig. 22-7). CT will show air
cell opacification (Fig. 22-7B) and sometimes bone break-
down. The dura may enhance (Fig. 22-7A) and epidural
abscess can develop as the infection progresses. MRI will
show the enhancement of the apex extending to the dura
and toward the gasserian ganglion in Meckel’s cave.
Aneurysms
Aneurysms of the petrous segment of the carotid artery are
rare.11 Because of their location they may grow quite large
before compressing vital structures and producing symp-
toms. When these aneurysms erode into the middle ear
cavity, they are particularly dangerous. The turbulent flow
within the aneurysms produces a variable MRI signal that
can be very confusing (Fig. 22-8A), particularly if flow-
sensitive MRI is not performed. In other cases, much of
the aneurysm can be filled with thrombus. CTA and MRA
are currently the most sensitive imaging modalities for
assessing aneurysms.
Clinically, aneurysms can mimic a middle ear mass such
as a glomus tumor. In these cases, CT is helpful because it
can show the remodeling or erosion of the wall of the
petrous carotid canal (Fig. 22-8B). This thin wall of bone
is invisible on most MR images because dense cortical
bone has the same signal as the adjacent air in the
tympanic cavity. (See also the section on Aberrant Carotid
Arteries.)
Chordomas and Chondrosarcomas
Chordomas and chondrosarcomas share many imaging
features and are therefore considered together. These
lesions arise medial to the apex but can extend into the
temporal bone as they enlarge. Chordomas are more often
midline and arise from notochordal remnants in the
basiocciput and basisphenoid (Fig. 22-9). Conversely, chon-
drosarcomas usually arise from cartilage in cranial base
synchondroses. Most chondrosarcomas in the lateral skull
base region arise off midline at the petroclival synchon-
drosis (Figs. 22-10 and 22-11). They may also arise from
the smaller synchondroses in the spheno-occipital separa-
tion, nasal septum, paranasal sinuses, and the more anterior
skull base.12–14
Both tumors are bright on T2-weighted images. This is
important because several mimics lack this intense T2 signal.
For example, metastasis, multiple myeloma, and invasive
prolactinoma may all mimic the CT and T1-weighted
MRI appearance of a chordoma. However, on T2-weighted
images, these lesions generally do not have a bright
T2 signal (Fig. 22-12D).15 The distinction is important
because chordoma and chondrosarcoma may be managed
by a major skull base resection and radiation, whereas the
other lesions can be managed by biopsy and radiation or
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).

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
one study, 7 of 26 (27%) chordomas and 7 of 16 (44%)
chondrosarcomas contained calcifications. Many times
the mineralization or bone and calcium in a chordoma rep-
resent remnants of bone largely destroyed by the tumor
(Fig. 22-9C). Large fragments may exist. Chondrosarcoma
calcifications are variable and may be large and clumped
(see Figs. 22-10D and 22-11A) and are often easily visualized
on MRI as a region of very low signal on all imaging
sequences (Fig. 22-11B). Some chondrosarcomas, however,
show no obvious mineralization. Both chordomas and
chondrosarcomas enhance moderately to intensely after
contrast (Fig. 22-10B and C). The enhancement is often
easier to appreciate on MRI.
The position of the lesion is a major determinant in
differentiating chordoma from chondrosarcoma. Chordoma
is almost exclusively a midline lesion; chondrosarcomas,
although they occur occasionally in the midline, are more
commonly located off midline in the area of the synchondrosis
separating the central skull base from the petrous apex.
Other Lesions
Fibrous Dysplasia
Fibrous dysplasia can present a serious diagnostic challenge
with MRI. Elements in the dysplastic bone are metabolically
active and enhance after contrast. On enhanced MRI
scans, fibrous dysplasia may look like an enhancing skull base
neoplasm (Fig. 22-13A–C). Most often it is hypointense on
T2-weighted images because of the bone matrix within it;
Imaging of the Lateral Skull Base 393
however, occasionally parts of the fibrous dysplasia have a
high T2 signal (Fig. 22-13D).17
Computerized tomography can be definitive if it reveals
the dense “ground glass” characteristic of this lesion (Fig. 22-
13E–F ). However, fibrous dysplasia and other benign
fibroosseous lesions are extremely variable in appearance
radiologically (Fig. 22-14) and may be difficult to exclude
from a list of differential diagnoses. This is particularly
true in lesions where the fibrous elements dominate.
Benign Vascular Tumors
Benign vascular tumors, or ossifying hemangiomas, can
arise in the petrous apex near the geniculate ganglion. The
lesions often have indistinct margins and may have intratu-
moral bone spicules, which can be seen on high-resolution
CT (Fig. 22-15). The intratumoral bone has led to the
term ossifying hemangioma. Although the bulk of the tumor
lies outside the facial nerve canal, expansion of the canal is
common. Occasionally, the lesions are well circumscribed
and lack internal bone spicules. These well-demarcated
hemangiomas are hard to differentiate from a facial nerve
sheath tumor. In most cases, however, the internal spicules
and ill-defined bony margins suggest the correct diagno-
sis.18 Meningiomas can have a similar appearance.
Meningiomas
Intracranial or dural processes may involve the petrous
apex by remodeling or invading through the dural covering.
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
or superior surface of the bone. The margins usually taper
to the surface of the bone at an obtuse angle. The tumor
can cause remodeling of the bone, hyperostosis, or enhance-
ment of the marrow cavity (Fig. 22-16). This may be best
appreciated with fat-suppressed postcontrast images. The
most common scenario is to have a meningioma growing
along the petrous apex without apparent bone change.
Occasionally, cavernous sinus tumors spread into the
petrous bone along the carotid canal.
Endolymphatic Sac Tumors
Tumors thought to arise from the endolymphatic sac give the
appearance of a locally destructive lesion in the bone just
posterior to the labyrinth along the medial aspect of the
posterior semicircular canal.19,20 This location is very charac-
teristic and corresponds to the position of the endolymphatic
sac and vestibular aqueduct. The papillary cystadenomatous
lesion frequently contains hemorrhagic foci as well as cystic
areas. The cysts appear as bright areas on T2-weighted
images and the hemorrhagic areas can have a bright signal on
T1-weighted images and dark areas on T1- and T2-weighted
images, reflecting the appearance of various blood breakdown
products in the tumors. The lesions are usually more cystic
and more focally invasive than meningiomas that can also
occur in this area. These lesions can occur in patients with
von Hippel-Lindau disease in whom they can be bilateral.
Fifth Nerve Sheath Tumor and Cavernous
Sinus Hemangiomas
Trigeminal nerve sheath tumors (trigeminal neuromas) may
smoothly remodel the petrous apex. They are differentiated
from meningiomas because they almost never calcify, rarely
have enhancing dural tails, and are usually higher in signal
and less homogeneous on T2-weighted images (Fig. 22-17).
Meningiomas may have moderate signal intensity on
T2-weighted images, but they are seldom as bright as
neuromas.21,22 Hemangiomas involving the cavernous sinus
are rare, but when they are large they can erode the petrous
apex. These lesions are indistinguishable from meningiomas
by CT and on angiography they can show “puddling” of
contrast, which can be confused with meningioma. MRI
makes the distinction because hemangiomas are extremely
bright on T2-weighted images.23 Differentiation of a cav-
ernous sinus hemangioma from a nerve sheath tumor may
be more difficult.
Direct Extension from Nasopharyngeal
and Infratemporal Lesions
Malignancy arising in the nasopharynx or infratemporal
fossa can grow into the lateral skull base. Although any
location can be involved, the petroclival synchondrosis and
contiguous foramen lacerum are particularly prone to inva-
sion especially from nasopharynx carcinomas (Figs. 22-18
and 22-19). The petroclival and petrosphenoidal fissures
are close to the fossa of Rosenmüller, where these neo-
plasms tend to arise. Extension beyond the fissures brings
the tumor to the cavernous sinus.
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
sinus. MRI visualizes the actual tumor within the bone and
is considered by most to be more precise in showing cav-
ernous sinus invasion (see Fig. 22-19) and more sensitive in
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
The petrous apex is a bone with a medullary space and so
metastasis to the apex can occur. Metastasis results in a
destructive mass. The center part enhances to some extent
and gives a solid appearance rather than the “cystic”
nonenhancing appearance of the epidermoid or the choles-
terol cyst. In an adult, an enhancing destructive mass of the
apex suggests a metastasis or meningioma.
Plasmacytomas can arise in any bone, including the
petrous apex. The lesions tend to be fairly homogenous on
CT. They are relatively dark on T2-weighted images on
overlaps with that of metastasis. Because they enhance, they
are not confused with cholesterol cyst or epidermoid.
Langerhans’ cell histiocytosis can involve the mastoid
region and middle ear but can also involve the petrous
apex. The lesion is frequently described as “punched out”
with a sharp margin and without sclerosis but occasionally
the margin can be more sclerotic. On MRI, the lesion is
seen as a solid mass often with loss of the cortex. The sig-
nal is usually described as high on T2-weighted sequences
but this is variable. The lesion enhances on either CT
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
Superior semicircular canal dehiscence is covered in the
chapter on the labyrinth but is mentioned briefly here
because it does involve the bone over the labyrinth. Several
recent reports relate symptoms of sound (Tullio’s phenome-
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
oval and round windows are the only two movable openings
in the system. As the acoustic energy is transmitted via the
ossicles to the oval window, the footplate of the stapes
vibrates slightly. Fluid is not compressible and so a compen-
satory motion must occur somewhere in the system if there is
to be movement of the fluid or propagation of the vibration.
There is subtle motion of the perilymph of the cochlea as the
round window membrane moves outward in response to the
inward movement of the footplate. Normally, there is no sig-
nificant movement of the fluids in the semicircular canal.
Each is a closed system with no external opening. If there is
a dehiscence of the bony canal, however, subtle movement
can occur and this compresses the endolymph. Motion
within the endolymph is interpreted as dizziness. Most such
“third windows” are related to fistulas into the labyrinth
resulting from cholesteatoma and surgical interventions.
An important cause that is potentially treatable is dehis-
cence of the superior semicircular canal roof (Fig. 22-20).
The etiology of the dehiscence is not exactly known. These
patients can undergo surgical packing of the dehiscent area,
which often provides symptomatic relief.24,25
Coronal CT images demonstrate a defect in the superior
curve of the superior semicircular canal.24 The reformatting
capabilities of multidetector give excellent images in any
plane. A 45-degree oblique (Stenver’s plane) image passing
perpendicular to the arc of the superior semicircular canal
often show the dehiscence best.
JUGULAR AND CAROTID REGION
The jugular foramen and vertical portion of the carotid
artery canal are grouped together because differential
diagnoses of lesions affecting these areas overlap.
The carotid canal is anterior to the jugular fossa. Both
the artery and the vein are separated from the middle ear
by very thin but very important cortical plates of bone.
Anatomically, the jugular fossa is divided into the
smaller medial pars nervosa and the larger lateral pars vas-
cularis (Fig. 22-21B). Cranial nerves IX, X, and XI pass
along the medial part of the jugular fossa. The more lateral
pars vascularis contains the jugular vein.
The size of the pars vascularis may vary greatly according
to the variable size of the jugular vein. The bony wall
separating the jugular bulb from the middle ear is very thin
or may even be absent in the case of dehiscent jugular fossa
(Fig. 22-21A). The vascular part of the jugular fossa is
smoothly marginated (see Fig. 22-21B). Evaluation of
these bony walls is best achieved with CT.
The MRI appearance of the jugular fossa varies con-
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
nerve immediately inferior to the skull base (Fig. 22-25).
This tumor is called a glomus vagale. The glomus vagale
can enlarge to involve the skull base or extend into the
posterior fossa. Such tumor extension tends to follow the
pars nervosa (medial jugular foramen). The lateral wall of
the jugular fossa is usually intact.
Paragangliomas can be multiple, so once one lesion is
found the imaging study is usually extended to the level of
the bifurcation of the carotid to search for carotid body
tumors as well as glomus vagale tumors.27
Paragangliomas are easily detected on MRI. They
enhance intensely, reflecting high vascularity. In larger
lesions, there are flow voids that indicate large tumor vessels
detected on standard spin echo or flow-sensitive MRI
(see Figs. 22-24D and 22-25D) giving a “salt-and-pepper”
appearance to the lesion. Flow voids in a lesion in this
area suggest a paraganglioma. Occasionally, large vessels
in a meningioma or vascular metastasis (from thyroid or
renal cancers) create confusion with paraganglioma. On
CT, tumor vessels usually cannot be resolved from adja-
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

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
the cochlear promontory (glomus tympanicum).
Although almost all paragangliomas are detectable on
MRI, CT is usually used for the initial evaluation because
of the importance of lateral plate of the jugular foramen
in separating a glomus tympanicum from a glomus jugu-
lare. That landmark is poorly seen with MRI and so its
integrity is difficult to assess. Once the diagnosis of glo-
mus jugulare is made, however, MRI can provide valuable
information regarding potential intracranial extension
and the patency of the jugular vein and sigmoid sinus.
MRI visualizes tumor growing into the vein and sinus
as well.
Imaging of the Lateral Skull Base 405
Nerve Sheath Tumors
Nerve sheath tumors also occur in the jugular fossa. As
schwannomas of cranial nerve IX, X, or XI enlarge, they
erode or expand the medial part of the jugular foramen.
The lateral plate of the pars vascularis is usually spared
(Fig. 22-26A and B). The margin of the expanded foramen
is usually smooth, unlike the more irregular margin of a
paraganglioma.
MRI features that suggest a nerve sheath tumor include
high T2 signal, involvement of the medial jugular foramen,
smoothly marginated bone remodeling, and cystic change
(Fig. 22-26C and D).28,29 In some cases the cystic change in
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
voids and have fairly abrupt margins with surrounding
meninges.
Aberrant Carotid Arteries
Normally, the vertical portion of the petrous carotid artery
is covered by a thin plate or wall of bone separating it from
the tympanic cavity.31 Absence of this plate of bone indicates
an anomalous vessel. As with the plate of the jugular fora-
men, CT is the method of choice for visualizing the thin
plate of bone separating the artery from the tympanic cavity
(Fig. 22-27A and B). The anomalous artery itself is a soft
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).
If there is a persistent stapedial artery associated with
the aberrant carotid, the tympanic segment of the facial
nerve canal may be enlarged. The stapedial artery courses
through this part of the facial nerve canal to enter the cranial
cavity and form the middle meningeal artery. The foramen
spinosum is absent in this instance.

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
imaging study of the temporal bone but particularly when
a red mass is seen behind the tympanic membrane. CT can
differentiate an aberrant carotid artery from a glomus tym-
panicum or jugulare. The differential depends on demon-
stration of the presence or absence of the lateral plates of
the jugular and carotid canals.
Other Lesions Involving the Jugular
and Carotid Area
Meningiomas are rare in the jugular fossa. They probably
arise from arachnoid cap cells that are in the sheaths that
surround the cranial nerves as they exit the skull.32,33
Although they may be difficult to differentiate from more
common paragangliomas, calcification, hyperostosis, and
enhancing dural rims (dural tail) may suggest the correct
diagnosis. The destruction or demineralization may be less
obvious than in paraganglioma.
Chondrosarcomas and chordomas are seldom confused
with lesions of the jugular fossa because they are centered
more medially. However, it is very important to evaluate
the involvement of the jugular fossa in these lesions. This
is particularly true in large lesions, which can involve the
jugular fossa bilaterally. The lower cranial nerves are at
risk during the surgical approach to these lesions.
The hypoglossal canal is located just inferior and medial
to the jugular fossa and is frequently involved with processes
that occur there. It is well demonstrated in both the axial
and coronal plane and by CT or MRI. Enhancement within
the hypoglossal canal is frequently seen as a normal finding
and should not be confused with pathology. Abnormality
can be established only if there is an obvious mass, erosion,
Imaging of the Lateral Skull Base 407
or enlargement of the canal (Fig. 22-28) or enhancement of
the medullary cavity surrounding the canal.
Involvement of the hypoglossal nerve is clinically indi-
cated by unilateral atrophy of the intrinsic and extrinsic
muscles of the tongue. The imaging correlate of atrophy is
fatty infiltration of one-half of the tongue, which is visible
on CT or MR (Fig. 22-29C). During acute muscle atrophy,
there may be enhancement of the muscle before fatty
replacement is apparent. Similar findings are observed with
atrophy of the muscles of mastication when the trigeminal
nerve is involved with tumor.
MIDDLE EAR AND MASTOID
Inflammatory Middle Ear Disease
The majority of middle ear disorders are inflammatory and
related to eustachian tube dysfunction. CT is preferred to
MRI in most cases because of its superior demonstration
of the ossicles, bony labyrinth, tegmen tympani, facial
nerve canal, and the septations within the mastoid air cells;
structures often affected by middle ear pathology.
Acute and chronic otitis media may result in opacification
of the middle ear. Fluid, mucosal thickening, and granulation
tissue are usually indistinguishable on CT. These inflam-
matory responses are also difficult to differentiate on MRI;
all tend to be intermediate in signal on T1-weighted
images and bright on T2-weighted images. Gadolinium
may enhance mucosal thickening or granulation tissue but
obstructed fluid will not be enhanced.
Cholesteatomas tend to occur in the upper tympanic
membrane and grow into Prussak’s space and the upper
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
and usually the mastoid air cell system is poorly developed.
If a cholesteatoma is suspected, CT is the study of
choice. Erosion of the scutum and tegmen tympani are
best demonstrated by coronal CT (Fig. 22-30B). Erosion
of the horizontal semicircular canal is best assessed in the
axial CT because the entire lateral margin can be seen in a
single image slice (Fig. 22-31). Reading subtle erosions of
the horizontal semicircular canal in the vertical plane can
be difficult because an oblique slice through the anterior
curve of the canal can suggest a false defect. The facial
nerve canal can also be eroded.
Primary epidermoid tumors (congenital or primary
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
to result from the growth of a congenital rest of squamous
epithelium. They are not related to chronic ear infections
and the mastoid air cells may be well pneumatized.
Intracranial complications of mastoiditis and
cholesteatomas require careful imaging. Epidural, subdural,
and brain abscesses are best evaluated with MRI. Small
extra-axial collections and meningeal enhancement may be
obscured by artifact from the adjacent bone on CT scans.
Septic thrombophlebitis may occlude the sigmoid sinus.
Venous sinus thrombosis may be demonstrated by either
MRI or CT. The CT demonstration of clot requires bolus
injection of contrast (Figs. 22-22 and 22-32). The intralu-
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
complicated; flow artifacts on standard spin echo
sequences often give a false-positive impression of clot
within the sinus and jugular bulb.
Herniation of brain or meninges through a defect in
the tegmen can present as a conductive hearing loss and
a mass in the middle ear or mastoid. Such a defect may
represent a congenital dehiscence. A cholesteatoma may
erode or thin the tegmen and once the cholesteatoma
has been removed a herniation can occur through the
weakened area.
CT can suggest a defect in the tegmen and is better than
MRI at demonstrating the thin cortical plate of bone
(see Figs. 22-30 and 22-33B and C ). However, since the
bone is very thin, a partial volume effect may average the
bone with contiguous soft tissue and suggest a defect
where there is none. Small defects can also be missed.
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
CT has its limitations.
MRI can be very helpful in these situations. Even
though the thin cortical bone of the tegmen is not seen,
the status of the inferior surface of the brain is well defined.
The coronal image can indicate if the brain is clearly
separated from the area in question or, alternatively,
protrudes down into the defect (Fig. 22-33F).
Tumors of the Middle Ear
Tumors that involve the middle ear are uncommon.
Paragangliomas (glomus tympanicum) arise at the
cochlear promontory and have already been discussed.
These tumors must be differentiated from aberrant carotid
artery and glomus jugulare tumors, any of which can present
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
keratosis obturans, EAC cholesteatomas demonstrate focal
erosions along the canal (Fig. 22-35).37
Exostosis and Osteoma
Two benign lesions associated with bony overgrowth are
exostosis and osteoma. Exostoses (Fig. 22-36) are much
more common and are often bilateral. They are considered
to be induced by cold water swimming. They arise in the
most medial aspect of the osseus canal adjacent to the
tympanic membrane. They are broad based and very
dense. Osteomas (Fig. 22-37) tend to be unilateral, arise
more laterally, and are rounder or more focal.
Malignant Lesions of
the External Canal
Malignant lesions of the external canal are diagnosed by
biopsy, but imaging is used to determine if the lesion is
resectable. Squamous cell carcinoma is most common but
basal cell carcinomas, minor salivary gland tumors (for
example, adenoid cystic carcinoma), and spread from
malignant parotid tumors also occur. Erosion of the bony
external canal is best demonstrated by CT (Fig. 22-38).
B
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).
Tumors of the external canal may spread along paths of
least resistance—medially into the middle ear or laterally
into the cartilaginous portion of the external canal. From
here they can spread inferiorly beneath the skull base or
anteriorly into the parotid gland.
Such soft tissue extension can be demonstrated with CT
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
if thin sections are used. In general, CT can be used as the
first examination because of its demonstration of bone ero-
sion. If extension beneath the skull base is inadequately
demonstrated, MRI should be performed.
When the tumor extends across the middle ear, the bony
labyrinth and the lateral plates of the carotid canal and
jugular fossa again become important landmarks if a surgical
resection is planned.
Occasionally, severe radiation osteonecrosis produces bone
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).
Figure 22-36. EAC exostosis. Axial CT bone algorithm demonstrates bony
overgrowth into both external auditory canals causing narrowing (arrowheads).
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
preferentially extends inferiorly at the junction of the bony
and cartilaginous canals to involve the soft tissues beneath

B enhancement of the mucosa of the middle ear cavity (white arrow). There is
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
lesion also extends through the tympanic membrane into the middle ear.
Note the handle of the malleus and the incus (arrowhead).
the external auditory canal. From here the disease can
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
nerves of the jugular foramen and cranial nerve XII.
Extreme cases of MEO spread across the midline and
eventually involve the bone of the petrous apex and clivus.
Newer antibiotics have significantly diminished the
morbidity and mortality of this disease.
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
also more modest enhancement of the tumor (black arrow).
Differentiation of MEO from a malignant neoplasm of the
external canal is usually not possible based on imaging. The
distinction is made on clinical grounds. MEO is almost
exclusively a disease of diabetic patients. Biopsy will be neg-
ative for neoplasm and pseudomonas can be cultured.
SUMMARY
Imaging is used to detect and to stage lesions of the lateral
skull base. Although opinions vary greatly, in most cases
high-resolution CT (particularly multislice CT) is preferred
because of the ability to visualize the fine bony anatomy,
418 NEURORADIOLOGY
Figure 22-40. Focal radiation necrosis of the skull base. Axial CT bone
algorithm shows destruction of the posterior wall of the right external
auditory canal (straight arrow). There is marked sclerosis of the squamosal
portion of the occipital bone adjacent to the mastoid (curved arrow). The
cystic changes in the mandibular condyles (arrowheads) are of uncertain
etiology.
which is very important in evaluating the region of the
temporal bone.
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Imaging of the Facial Nerve
Outline
Technique
Congenital Anomalies
Normal Variants
Congenital Ear Deformities
Tumors
Schwannomas
Vascular Tumors
Epidermoid Cysts
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-
ing (MRI). It has gone from the era of plain films, followed
by conventional polytomography,1,2 popularized in the
1960s, through cisternographic tomography,3 performed
primarily through the mid-1970s, to the present standards
of HRCT and MRI.4–9 The advantages of CT over the
techniques in use previously are (1) high-contrast resolu-
tion; (2) simultaneous display of densities of air, soft tissue,
and bone; (3) ease of examination; and (4) half of the
radiation dose of polytomography. The advantages of MRI
include (1) easy multiplanar projection without patient
repositioning, (2) superior soft tissue resolution, and (3) lack
of exposure to ionizing radiation. Facial nerve imaging is
today accomplished by using MRI with gadolinium dieth-
ylenetriamine pentaacetic acid (DTPA) enhancement and
HRCT, either jointly or alone.
The facial nerve has a complex, multiplanar course, both
intracranially and extracranially (Figs. 23-1, 23-2, and
23-3).10–12 The intracranial portion extends from the
brainstem to the internal auditory canal (IAC), for a length
of 23 to 24 mm, and includes the premeatal segment,
which lies in the cerebellopontine angle (CPA). The
intratemporal portion is subdivided into three segments.
A length of 5 to 12 mm (average = 10 mm) passes through
the IAC and then passes anteriorly and slightly inferiorly
in its labyrinthine segment for 3 to 5 mm to reach the
geniculate fossa. The nerve has its first surgical genu at the
geniculate ganglion, where it turns at an acute angle of
approximately 75 degrees to run posteriorly and slightly
laterally and from which emerges anteromedially the
greater superficial petrosal nerve. The tympanic portion of
the facial canal is straight, 10 to 12 mm in length, and, in
65% of cases, covered by a thin bony lamella over its exter-
nal wall. The mastoid, or second surgical, genu occurring
Chapter
23
Carcinomas Sujana S. Chandrasekhar, MD
Rare Tumors
Antonio De la Cruz, MD
Trauma
Inflammatory Disease William W. M. Lo, MD
Intrinsic Inflammation Fred F. Telischi, MD
Extrinsic Inflammation
Hemifacial Spasm
Summary
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
of the facial nerve canal descends 13 mm to the stylomas-
toid foramen. The extratemporal facial nerve, as it
emerges from the stylomastoid foramen, runs anteriorly in
the substance of the parotid gland and divides into two
primary branches: the temporofacial, or superior, division
and the cervicofacial, or inferior, division. These two
divisions in turn elaborate main branches and break up
into a plexus to supply the facial muscles.
Accurate clinical history and physical examination
are necessary when choosing the imaging modality that
will best evaluate facial nerve lesions. Different sites of
neural injury must be imaged differently. MRI and HRCT
often yield complementary information and at times both
are required for optimal demonstration of facial nerve
pathology.
MRI is the method of choice when (1) the site of
involvement is clinically unlocalized because it is the only
imaging modality that demonstrates the facial nerve
comprehensively from the pons to the parotid gland; (2) the
site of lesion is clinically localized to either the intracranial
or the extratemporal portion of the nerve because it pro-
vides excellent soft tissue contrast; or (3) the onset of
symptoms is acute because, with gadolinium enhancement,
MRI is capable of showing changes of inflammation not
seen on CT.13–15
Thin-section HRCT that makes use of a bone or edge-
enhanced algorithm renders exquisite bony detail. It is the
preferred initial imaging modality when a lesion is clini-
cally localized in the middle ear or mastoid and is the
method of choice in cases of temporal bone trauma.16–18
CT with a standard soft tissue algorithm with and without
an intravenous iodinated contrast medium may be used to
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
intrathecal gas injection this modality does not exclude
small IAC tumors.3 This is used only as a secondary option
when MRI is not available or when the patient cannot be
imaged on the MR scanner, for example, if the patient is
too claustrophobic or too large.
TECHNIQUE
The technical considerations for MRI of the facial nerve
are nearly identical to those for MRI of the CPA and the
IAC. These considerations are fully discussed in detail in
Chapter 21, Imaging the Cerebellopontine Angle, and are
not repeated here. When necessary, similar techniques are
extended to cover the course of the extratemporal facial
nerve through the parotid gland see (Fig. 23-3F).
For detection and demonstration of facial nerve lesions,
a well-focused MRI is indispensable because many of these
are only a few millimeters in size. The technique employs
imaging in transverse and coronal planes, with contiguous
or overlapping thin sections of 3 mm each in thickness,
covering the pons to the parotid gland, before and after
intravenous injection of a paramagnetic contrast agent.
Sagittal or oblique sagittal images can be helpful in
displaying lesions in the facial nerve canal (FNC) (see
Fig. 23-3E) and do not require patient repositioning.9,14,19,20
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
presence of a perineural vascular plexus in the FNC and
may be asymmetrical in normal individuals. Compared
with the findings in Bell’s palsy or Ramsay Hunt
syndrome, the enhancement in normal subjects is less
intense and does not extend into the premeatal segment of
the nerve in the IAC (see Figs. 23-3A, B).
HRCT for facial nerve evaluation is done in contiguous
thin sections, no thicker than 2 mm, with a bone or edge-
enhanced algorithm for maximal spatial resolution.4,22
Transverse sections of the temporal bone are obtained at
either a 0- or 30-degree plane with respect to the infra-
orbital-meatal line. Scanning in either plane avoids direct
radiation to the ocular lenses. The 30-degree plane is
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
thereby avoids sectioning of this segment in a cross-
sectional or “salami” fashion.23 Additional images may be
obtained in a modified coronal plane (by tilting the gantry)
with the patient either supine or prone. With multirow-
detector CT, which is now commonly available, coronal
and sagittal images can now be reformatted from axially
acquired data with ease and with little loss of resolution.
CONGENITAL ANOMALIES
Normal Variants
The labyrinthine FNC may originate from the midportion
rather than the fundus of the IAC.24 The geniculate fossae
may vary in size, although there is generally symmetry
between the right and left sides.17 The most common
variations in the course of the FNC involve the distal
portion of the nerve.25–28 A “drooping,” or protruding,
tympanic segment that overlies the oval window and
compromises surgical access may be seen on HRCT and
should be recognized (Fig. 23-4A).29 The bony wall of the
FNC may be developmentally dehiscent in 35% to 55% of
the population, most commonly in the midtympanic
segment over the oval window niche.26–28,30,31 The most
common tympanic segment aberrations that may be
encountered in surgery are: a course over the oval window;
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
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
Imaging in the coronal plane is most helpful in excluding
an aberrant tympanic segment.6
The anterior portion of the tympanic FNC may be
enlarged by a persistent stapedial artery in its course from
the tympanic cavity to the middle cranial fossa to termi-
nate as the middle meningeal artery.32,33 Most individuals
with this finding have few or no symptoms, and such a
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
when the artery itself is too small to be visible on CT, in
the absence of the ipsilateral foramen spinosum (Fig. 23-5).32
HRCT is diagnostic. MR angiography may be used for
confirmation; conventional angiography is not indicated in
these cases. The marrow of the styloid process may mimic
the mastoid segment of the facial nerve (see Fig. 23-4B) on
HRCT; a distinction between the two structures can be
made by following the course of the facial nerve on serial
images.

A facial nerve only secondarily, facial nerve schwannomas
B involved. Because they involve the nerve by compression
C to make (see Fig. 23-7), although histologically they
Figure 23-4. Congenital variant: protruding tympanic segment–coronal
HRCT, left ear. A, Tympanic segment of facial nerve (arrowhead) covers the
oval window. B, Mastoid segment of facial nerve (arrow) should not be
confused with the marrow of the styloid process (arrowhead). Both
anomalies are associated with external auditory canal atresias. C, Lateral
subcutaneous exit of the mastoid segment of the facial nerve, a rare but
highly treacherous anomaly of the facial nerve canal.
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
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
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
appear quite different.40 Certain imaging “clues” may aid
in differentiating these lesions. Anterosuperior erosion of
the IAC or erosion of the labyrinthine FNC on HRCT has
been suggested as a diagnostic clue, but it is not reliable.41
Eccentric placement of the tumor in the IAC may help in
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

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.
(Reproduced with permission from Latack JT, et al: Facial nerve neuromas.
Radiologic evaluation. Radiology 149:731–739, 1983.)
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,
as discussed previously.
Differential diagnosis for geniculate ganglion lesions
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

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
briskly with gadolinium–DPTA on postcontrast T1WI. C, On T2WI, the mass
is mildly hyperintense to brain.
cysts, and meningiomas. Distinguishing among these
lesions can be done with MRI and HRCT, based on the
sharpness of their borders and on enhancement character-
istics. On HRCT, the borders of hemangiomas are not
sharp (Figs. 23-13 and 23-14), the borders of schwanno-
mas are moderately sharp (see Fig. 23-12B), and the
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-
Vascular Tumors
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
collagen. The two lesions may coexist in a single mass.
The most common site of occurrence is the geniculate
ganglion, followed by the IAC and then the mastoid genu.
They are usually less than 1 cm in diameter. The nerve is
involved by invasion and these tumors cause hemifacial
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:
conductive hearing loss. A, Axial HRCT. Arrowhead points to small soft
tissue mass between cochlear promontory and ossicles. B, Coronal T1WI
MRI. Arrowhead to small component of tumor corresponds to soft tissue in
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
than would be expected based solely on size.43 Early detec-
tion may allow complete removal with preservation of
facial nerve function, avoiding facial nerve resection and
grafting.44
Intratumoral bone spicules may be seen (see Fig. 23-13).
This bone formation is a reaction to the hemangioma
itself.45 Labyrinthine and geniculate ganglion lesions show
subtle CT findings that include irregular and indistinct
bone margins and reticular or “honeycomb” bone (see
Fig. 23-14). Geniculate ganglion vascular tumors seen
with MRI demonstrate nonhomogeneous intensities,
which are the MRI correlate of the “honeycomb” seen on
CT (see Fig. 23-15). They are difficult to distinguish from
schwannomas when they occur at the mastoid genu. Their
enhancement with contrast is not helpful on CT because
density changes in such small lesions interspersed among
bone are difficult to discern. HRCT with gas cisternog-
raphy is usually required for lesions of the IAC, but MRI
with gadolinium-DTPA enhancement demonstrates these
lesions well and is preferred over CT (see Fig. 23-16).
Figure 23-10. Tympanic FNS, left. A, Axial HRCT. Arrowhead points to soft
tissue mass in middle ear, medial to the ossicles, lying along the tympanic
FNC. B, Axial T1WI, postcontrast MR. Arrowhead shows enhancing mass
along tympanic FN.
Many of these tumors are similar to schwannomas in
signal intensity on T1WI and T2WI, but some are
most hyperintense than typical schwannomas on T2WI
(Fig. 23-17).46,47
Epidermoid Cysts
Petrous apex epidermoid cysts attain considerable size
before involving the facial and acoustic nerves in the CPA
or IAC. More common facial nerve involvement is seen
with congenital epidermoid cysts of the supralabyrinthine
region of the temporal bone.48 From this point of origin
they readily erode the proximal FNC and can either reach
around the superior semicircular canal and extend medi-
ally superior to the IAC or laterally into the epitympanum,
or they can erode the cochlea or superior semicircular
canal, which causes fistulization. CT demonstrates an
expansile lesion-eroding bone, with sharp bone margins.
Calcifications may be seen. T1WI MRI demonstrates low
to intermediate signal, and T2WI shows high signal inten-
sity (Figs. 23-18 and 23-19).

A are used in imaging this tumor.
B not involved, catheter or MR venography is helpful.
Figure 23-11. FNS–sagittal T1WI MRI. Note multifocal lesions from the
geniculate ganglion to the stylomastoid foramen (arrowheads). Compare
this to the normal sagittal view seen in Figure 23-3E. A, Precontrast.
B, Postcontrast.
Acquired epidermoid cysts of the temporal bone may
also cause facial nerve symptomatology. Radiologically,
they are similar to congenital epidermoid cysts except that
they originate from the middle ear and mastoid and may
extend around the bony labyrinth to the petrous apex. A
common location of FN involvement is in the geniculate
ganglion region. Changes of chronic inflammation are
seen in the middle ear and mastoid (Fig. 23-20).
Cholesterol Cysts
Cholesterol granulomas form from obstruction of
drainage of petrous apical air cells, followed by repetitive
cycles of hemorrhage. They may cause irritation and initi-
ate a foreign body reaction from their cholesterol crystals.
They grow silently in the petrous apex until they exert
pressure on cranial nerve V, VI, VII, VIII, IX, X, XI, or
XII. These lesions are best imaged by combining HRCT
and MRI. CT shows a sharply marginated, expansile
lesion, without calcifications. MRI demonstrates high
signal intensity on both T1WI and T2WI.
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
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
Jugulotympanic paragangliomas may grow to affect the
facial nerve secondarily, which is demonstrated on imaging
of the tumor.
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.
Papillary adenomatous tumors of endolymphatic sac origin
(ELST) are rare, locally invasive, and often extend into the
medial mastoid to cause facial palsy (Fig. 23-22).60 Bilateral
ELSTs have been found in patients with von Hippel-
Lindau disease.61 Of metastatic lesions to the temporal
bone, 34% present with facial nerve palsy.62 The primary
tumors are usually in the prostate, breast, or kidney. CT
demonstrates bony destruction with tumor encroachment
on the FNC; MR with gadolinium-DTPA is useful in
equivocal cases.63
Langerhans’ cell histiocytosis causing facial palsy has
been reported in 15 cases.39 The pathophysiology is
histiocytic infiltration of the temporal bone leading to
compression of the nerve within the eroded fallopian
canal. CT shows an expansile soft tissue mass with bony
labyrinthine and ossicular erosion. Embryonal rhabdomy-
osarcoma, an early childhood malignancy, involves the tem-
poral bone in 7% of cases. Of 12 cases reported by Wiatrak
and Pensak,64 6 had seventh cranial nerve paralysis as a
presenting manifestation, and all of these 6 patients had
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
and destruction of the FNC with infiltration of the facial
nerve, extension to the IAC, and from there on to the
leptomeninges. The imaging modality of choice in these
cases is HRCT because it assesses bony destruction and
can evaluate response to therapy. Middle ear salivary gland
choristomas, which are tumors composed of normal cells
not normally found at the site of occurrence, usually affect
the tympanic segment of the facial nerve and the ossicles.65
TRAUMA
Specific thin-section HRCT is necessary in the radiologic
evaluation of temporal bone trauma, because approxi-
mately 60% of temporal bone fractures are not apparent
on routine head CT examinations.66 It is preferable to
obtain both axial and coronal sections; however, if the
status of the patient’s cervical spine precludes positioning
for direct coronal images, coronal reconstructions from
direct axial images can suffice.6 Accurate preoperative
localization with HRCT is vital because the surgical
approach to decompression varies with the exact site of
facial nerve injury.67 Gadolinium-enhanced MRI has been
advocated for identifying focal enhancement as a method
for localizing traumatic injury to the facial nerve.68
Classically, temporal bone fractures have been divided
into two types: longitudinal (70% to 90%) and transverse
(10% to 30%), defined by the orientation of the fracture
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
fracture line is oriented along the long axis of the tempo-
ral bone and, in palsy cases transgresses the nerve in the
perigeniculate region (Figs. 23-23A, B). Facial paralysis
occurs in 50% of transverse fractures, and is more fre-
quently of immediate onset and complete. The facial nerve
is usually involved in the labyrinthine or tympanic seg-
ment (Fig. 23-24). More recent literature indicates that a
large percentage of temporal bone fractures are “mixed,”
in that the fracture line is both along and across the long
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
large series have looked at fractures as either otic capsule
“sparing” or “involving,” with capsule-involving fractures
having a higher incidence of facial palsy.70
INFLAMMATORY DISEASE
Intrinsic Inflammation
Bell’s palsy, or idiopathic isolated peripheral facial palsy,
represents 50% to 85% of all cases of facial nerve palsy.71
The majority of cases have a typical clinical presentation
and do not require imaging; however, in 15% there is an
atypical presentation or a prolonged course.72,73 In these
cases, gadolinium-enhanced MRI is useful and can help the
clinician avoid missing a CPA/IAC tumor. The presumed
accumulation of gadolinium in areas of inflammation and
disruption of vessel integrity has provided the basis for
evaluation by means of this modality.14 A number of stud-
ies have demonstrated significant enhancement of the facial
nerve in these individuals.74–77 The pathologic enhance-
ment seen on gadolinium-enhanced MRI is much more
intense than seen in normal subjects, usually involves the
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
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
acute and chronic cases, and there is no prognostic signifi-
cance attributable to the presence or the degree of facial
nerve enhancement in patients with viral inflammatory
facial paralysis.79 Enhancement with enlargement of the
nerve suggests tumor rather than inflammation.
Herpes zoster oticus, or Ramsay Hunt syndrome, man-
ifests as auricular vesicles, ear pain, and facial paralysis.
Abnormal gadolinium enhancement of the facial nerve is
seen, similar to that seen in Bell’s palsy. If the inflammation
spreads to involve the eighth nerve and membranous
labyrinth, variable enhancement of these structures is also
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
that is transmitted by a deer tick (Ixodes dammini). Ten
percent of all patients with Lyme disease and 50% of those
patients with central nervous system infection will have
unilateral or bilateral facial nerve palsies.82 Enhancement
of the facial nerve on MRI is seen and is identical to that
seen with herpes zoster oticus and Bell’s palsy.
Extrinsic Inflammation
Acute otitis media, chronic otomastoiditis, and cho-
lesteatoma have been associated with facial paralysis.
Cholesteatoma is present in more than half of the cases of
chronic otitis media and facial palsy.83 Imaging is indicated
in patients with facial palsy and chronic otomastoiditis or
cholesteatoma and is directed toward preoperative surgical
planning. HRCT is the imaging modality of choice
because it can clearly identify areas of the fallopian canal
violated by surrounding inflammatory soft tissue.84 Other
temporal bone infections secondarily causing facial nerve
palsy include mucormycosis, tuberculosis, and syphilis.85–87
Malignant (necrotizing) otitis externa, a skull base
osteomyelitis, can be complicated by facial palsy through
spread of infection via the fissures of Santorini in the
external auditory canal, which involves the nerve at the
B
Figure 23-22. Papillary adenomatous tumor of the endolymphatic sac,
left ear, axial projections. A, HRCT. The tumor is destroying bone in the
retrolabyrinthine region with extension to the medial mastoid (arrowheads)
at the area of the mastoid facial nerve genu. B, T1WI MRI. This tumor
(arrowheads) is heterogeneous, containing hypointense, isointense and in
particular, hyperintense foci, precontrast.
stylomastoid foramen.88 Nuclear medicine evaluation with
technetium scanning to detect the extent of skull base
osteomyelitis and gallium scanning for early detection of
recurrence are invaluable in this disease. Facial nerve
imaging per se is not indicated in these cases; however, CT
and MRI are helpful in assessing the extent of disease
because they can demonstrate evidence of inflammatory
and soft tissue changes around the stylomastoid foramen
and mastoid segments of the facial nerve.89
HEMIFACIAL SPASM
Hemifacial spasm (Fig. 23-26) is a hyperactive facial nerve
dysfunction characterized by painless paroxysmal spasms
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
limb of the lateral semicircular canal (arrowhead), transecting the underlying
tympanic segment of the facial nerve.
Figure 23-26. Hemifacial spasm. This heavily T2-weighted CISS image
illustrates the neurovascular cross-compression that can be seen in
hemifacial spasm.
434 NEURORADIOLOGY
result of compression of the facial nerve at its root exit
zone from the brainstem by vascular loops or aneurysms
of the posterior or anterior inferior cerebellar artery, the
vertebral artery, or the internal auditory artery. Both
dynamic HRCT with contrast and MRI have been used to
demonstrate the vascular aberrance. Angiography for diag-
nosis was reserved for equivocal cases in which CT failed
to demonstrate the pathology; however, the use of conven-
tional angiography has declined with the advent of MRI
and MR angiography.90–93
SUMMARY
Effective use of imaging for evaluation of facial nerve
disorders requires knowledge of the multiplanar anatomic
course of the nerve and an understanding of the clinical
disease. Properly oriented, thin-section multiplanar
imaging is necessary to evaluate the different facial nerve
segments and their disorders. The predicted site and type
of onset of facial nerve pathology determine the type of
initial imaging modality used. Lesions suspected of involv-
ing the intracranial portion of the facial nerve are best
seen with MRI with gadolinium-DTPA enhancement.
These include brainstem, CPA, and IAC tumors, as well
as intracranial vascular aberrancies. When involvement of
the intratemporal portion of the facial nerve is suspected,
as with cholesteatoma, chronic otitis media, congenital
temporal bone abnormality, carcinoma, or trauma, HRCT
is the imaging modality of choice. In Bell’s palsy, Ramsay
Hunt syndrome, and Lyme disease, facial nerve inflamma-
tion is identified most readily on MRI, if indicated. For
lesions of the extratemporal facial nerve, soft tissue
resolution is best obtained with MRI. Acute palsies are
best imaged with MRI. Most importantly, detailed
communication between the clinician and the radiologist
will result in the optimal combination of imaging
techniques for maximal patient benefit.
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 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

Radiologic evaluation of patients who present with
symptoms or signs suggesting neurotologic disease usually
commences with performance of plain-film radiography,
computed tomography (CT), or magnetic resonance
imaging (MRI). In selected circumstances, this evaluation
can be enhanced by performing angiography to visualize
the circulation of the head, neck, and brain optimally.
Moreover, endovascular therapy (therapeutic angiography,
embolization) has emerged as an accepted and valuable
therapeutic option in treating many vascular conditions of
the skull base and brain. The role of angiography and
endovascular therapy in the evaluation and treatment of
pathologic conditions producing pulsatile tinnitus, otalgia,
otorrhagia, hearing loss, vertigo, and lower cranial nerve
palsies, including angiographic techniques and indications
for diagnostic and therapeutic angiography, will be
presented in this chapter.
TECHNIQUES
Arteriography
It is important to review the pertinent history, both from
the referring physician and from the patient, to document
the necessity of the angiogram and to elicit any history of
allergies. Review of all prior radiographic studies including
CT or MRI scans is important to delineate the diagnostic
goals of the angiogram. Assessment of peripheral pulses
and a neurologic examination are necessary to properly
436
from the patient including an explanation of the indica-
tions for the angiogram, the procedure itself, and risks.
The majority of cerebral angiograms are performed via
a transfemoral artery approach.1 The patient is placed in
the supine position on the fluoroscopy table, a peripheral
intravenous (IV) line is established, and mild IV sedation
may be administered. The skin over the femoral artery
is prepped and draped in a sterile fashion, and 1% lido-
caine is administered as a local anesthetic. A hollow punc-
ture needle is placed into the common femoral artery,
through which a soft-tipped guidewire is directed retro-
grade into the aorta. The puncture needle is removed, and
the angiographic catheter is advanced over the guidewire
into the aorta. The catheter and guidewire combination
may be advanced cephalad under fluoroscopic guidance
to select one of the great vessels arising from the aortic
arch, thus gaining access to the circulation of the neck
and head.
Once in position, iodinated contrast is injected through
the catheter while radiographic films are exposed, either
directly (“cut film” technique) or by computerized digital
subtraction. Injection of multiple arteries in multiple
projections is often necessary. Finally, the catheter is
removed, and direct pressure is placed over the femoral
puncture site for 15 minutes. The patient is instructed to
remain supine with the leg used for the puncture straight
for 6 hours, under observation.
Alternatively, access to the arterial circulation may be
achieved via axillary or brachial artery approach, using
similar techniques. Rarely, direct puncture of the common
carotid artery is performed.2

Embolization
Devascularization of a tumor, arteriovenous malformation
(AVM), or arteriovenous fistula (AVF) requires placement
of embolic material into the affected artery (embolization)
while maintaining patency of the normal surrounding
vessels. Diagnostic angiography is performed and assessed
initially, and an embolization plan is determined. A longer,
softer, more slender embolization catheter (usually 2–3
French) is placed coaxially through the diagnostic guiding
catheter and navigated to the site for embolization.
Systemic anticoagulation is used if the catheter enters the
intracranial circulation to prevent thrombus formation
along the catheters and to avoid the risk of distal emboliza-
tion to normal arteries. Once in position, superselective
arteriography is performed to search for normal arteries
that must be preserved. A provocative injection of Amytal
Sodium (amobarbital sodium), a short-acting barbiturate,
may also be used to detect supply to the central nervous
system and retina. A positive test consists of production
a reversible neurologic deficit. Two percent cardiac
lidocaine is used to detect supply to cranial nerves. A
negative test does not guarantee safety of embolization. If
embolization is deemed safe, selection of the embolic
agent is made based on the nature of the pathology, size
of the vessels to be treated, and potential risks. Embolic
agents include particulate material (polyvinyl alcohol
[PVA], Gelfoam particles, and acrylic microspheres),
detachable silicone or latex balloons, liquid adhesives
(N-butyl cyanoacrylate), platinum or coils, custom-cut silk
suture, and ethanol. Embolization of cerebral aneurysms
requires placement of platinum coils directly into the
aneurysm with the goal of preserving flow in the parent
artery. The patient is monitored carefully for neurologic
changes during the embolization. Control angiography is
performed after embolization to document the adequacy
of the procedure.
Major Artery Occlusion
Large or fusiform aneurysms, arterial dissections causing
thrombus formation, and malignant skull base or neck
tumors3 may require permanent occlusion of the internal
carotid or vertebral artery as definitive therapy or as a
presurgical adjunct. Prior to permanent occlusion, a test
occlusion of the artery in question is necessary to
determine whether the collateral supply to the brain is
adequate to avoid ischemia or infarction. A common site
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
nondetachable balloon can be positioned in the proximal
internal carotid.4 Under constant neurologic surveillance,
the balloon is inflated to occlude the artery, and arterial
back-pressures can be measured through the catheter
lumen distal to the inflated balloon. The test occlusion
is performed for 30 minutes. Neurologic tolerance of the
test occlusion without new deficit and adequate pressure
measurements are essential for predicting tolerance of
a permanent occlusion. Some authors advocate the addi-
tion of cerebral blood flow evaluation using stable xenon
CT5,6 or technetium hexamethylpropyleneamine oxime
Diagnostic and Therapeutic Angiography 437
(99mTc-HMPAO) perfusion imaging,7–9 or provocative test
occlusion by artificially lowering systemic blood pressure
during test occlusion,10 but the role of these tests is not
fully defined. In Higashida’s series of cavernous internal
carotid aneurysms treated by detachable balloon occlu-
sion,4 10% of patients developed new neurologic deficits
despite tolerance of the test occlusion, although the major-
ity of these deficits were transient and were treated
successfully by volume expansion or antiplatelet therapy.
Test occlusion of the smaller-caliber distal carotid circula-
tion or vertebral artery may also be achieved using a
nondetachable balloon catheter system; however, this pre-
cludes use of the double-lumen catheter measurement of
distal pressures.
Permanent occlusion is performed by simultaneously
placing detachable balloons into the internal carotid in
tandem, in order to ensure against deflation of one bal-
loon. Platinum coils can also be used, but are often used in
combination with a balloon, because coil use alone may
allow thrombus formation while some antegrade flow
persists, risking distal embolization and stroke. Vigorous
IV fluid administration for volume expansion and strict
limitation of activity, usually for a period of 3 days, to allow
adequate cerebral perfusion is important to limit the
possibility of delayed ischemia or infarction. These
balloons are filled with radiopaque contrast material, so
they can be visualized on serial plain skull radiographs,
thus ensuring continued adequate positioning and guard-
ing against deflation or distal migration.
Intraoperative Angiography
The neuroradiologist is asked to perform diagnostic cere-
bral angiography in the operating theater to assist in
surgical procedures with increasing frequency.11 Neurosur-
geons in particular rely on excellent quality angiographic
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.
This portable technique has application to skull base
surgery as well, in evaluating aneurysms, AVMs, dural
AVFs, and patency of major arteries. The technique is
similar to conventional angiography, using a transfemoral
arterial approach. It is helpful to place a femoral arterial
introducer sheath at the beginning of the operation,
which can be slowly perfused with saline during surgery.
This sheath can be accessed for angiography at any
desired time.
Venography
Evaluation of skull base tumors or conditions that cause
pulsatile tinnitus may require performance of a cerebral or
jugular venogram. This is also the access route of choice
for endovascular treatment of some dural AVFs. This can
be performed safely via puncture of a femoral vein, with
navigation of the catheter through the vena cava to the
internal jugular vein. Vigilance must be maintained to
avoid cardiac arrhythmia production by stimulation of the
right atrial or ventricular wall during catheterization, an
uncommon complication. The catheter can be placed at
any location in the venous system and a venogram
438 NEURORADIOLOGY
obtained. Smaller catheters are required for intracranial
use to limit the risk of venous sinus perforation. Pressure
measurements can also be performed to evaluate the
hemodynamics at the site of a lesion, such as a meningioma
invading the transverse sinus.12,13 With patient cooperation,
provocative measures using Valsalva’s maneuver, lateral
head turning, or flexion and extension may assist in re-
creating or temporarily obliterating subjective pulsatile tin-
nitus, and venography can be performed in those positions.
DISEASE PROCESSES
Vascular
Aneurysms
An aneurysm is an abnormal focal arterial dilitation.13
Aneurysms can be classified in a number of ways.
Morphologically, aneurysms can be termed saccular,
fusiform, dissecting, or giant. Pathologic differentiation is
made between true aneurysms, which are composed of
normal arterial tissue layers with a defect in the media,14
and false aneurysms, or pseudoaneurysms, which are
bounded only by adjacent bone, soft tissue, or even clot
formed as a result of previous aneurysm rupture or vascular
injury. Etiologically, aneurysms are classified as congenital,
traumatic, atherosclerotic, mycotic, or dissecting.13 These
categorizations overlap: for example, congenital aneurysms
are true aneurysms, whereas traumatic or mycotic
aneurysms are pseudoaneurysms.
The majority of aneurysms are located intracranially.
Common sites for congenital (or “berry”) aneurysms are in
the regions of the anterior communicating artery, middle
cerebral artery trifurcation, supraclinoid ICA, basilar
artery, and at the origin of the posterior inferior cerebellar
artery (PICA). A small percentage may arise in locations
that can produce otologic symptoms, including lower cra-
nial nerve palsies, otorrhagia, localized pain, and dizziness.
This is especially true of traumatic pseudoaneurysms,
which commonly occur at the skull base.
The prevalence of congenital aneurysms is estimated
from autopsy studies at 2%;13 this estimate varies consider-
ably among these studies. Many of these individuals are
never symptomatic. Unfortunately, there is no effective,
noninvasive screening measure for detecting aneurysms. As
a result, the most common presentation is subarachnoid
hemorrhage (SAH), which can produce catastrophic symp-
toms ranging from severe headache and nuchal rigidity
to coma and death. Secondary complications include
aneurysm rerupture, most likely to occur within the 30 days
following the initial hemorrhage,15,16 and vasospasm, which
arises in 20% to 30% of aneurysmal SAH cases. Unruptured
aneurysms can present with local mass effect, headache or
pain, and ischemic neurologic events resulting from throm-
boemboli arising within a partially thrombosed aneurysm.
A distinction must be made between aneurysms arising in a
subarachnoid location and those arising extracranially (e.g.,
petrous or cavernous portion of ICA), as the latter are at
considerably reduced risk of SAH. Associated conditions
include polycystic kidney disease, coarctation of the aorta,
fibromuscular hyperplasia, and AVMs.13 Congenital
aneurysms are multiple in 20% of cases.
Traumatic pseudoaneurysms occur as a result of pene-
trating injuries (knife or missile wounds) or fractures of
the skull base. The cervical portions of the carotid arteries
are free, but become fixed as they enter the petrous bone,
creating candidate sites for deceleration, hyperextension,
or rotational injury. These pseudoaneurysms are associ-
ated with epistaxis,17,18 active hemorrhage per os, cranial
nerve palsies from mechanical compression, otorrhagia
(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
of thrombosis of an AVF or may rupture in a delayed fashion
to form a fistula.
CT scanning has a 90% sensitivity for detecting
aneurysmal SAH within 24 hours, but is much less sensitive
in identifying the aneurysm. Larger aneurysms can be seen
as focal, contrast-enhancing areas adjacent to the parent
vessel. They may exhibit mural calcification, circumferen-
tial layers of internal thrombus that may not enhance, or
adjacent mass effect. Giant aneurysms may erode the
petrous or sphenoid bones, creating a smooth contour.
MRI may demonstrate the aneurysm as a focal area of flow-
related signal void in the expected zones around the circle
of Willis. Inhomogeneity of signal within the aneurysm
may represent turbulent flow or partial thrombosis. MRI
detects calcification in the aneurysm wall poorly.
Angiography is the most effective method for identify-
ing cerebral aneurysms. A thorough angiographic study is
essential and includes examination of both internal carotid
and vertebral arteries. Identification of aneurysms arising
from the PICA origins may be accomplished by contrast
injection of one vertebral artery, as long as reflux down the
contralateral vertebral artery demonstrates its PICA ori-
gin. Common carotid compression during injection of the
contralateral ICA may be necessary to opacify the anterior
communicating artery, the most common site for congen-
ital aneurysms and for aneurysms overlooked on initial
angiography.
Formerly, the treatment of choice for congenital
intracranial aneurysms was craniotomy and surgical clip-
ping. This may be precluded in giant or heavily calcified
aneurysms, those with a wide or absent neck, in those
occurring in locations difficult to access surgically, or in
patients with severe underlying medical conditions.20–22
This is especially true of aneurysms located in the petrous
or cavernous segments of the ICA, sites more likely to
produce otologic symptoms.4,23,24 Endovascular therapy
for aneurysms was introduced by Serbinenko in 1974,25
and the first large series were reported in the early
1980s26,27 using latex balloons. Higashida and colleagues
subsequently reported the endovascular treatment of 215
aneurysms using a detachable silicone balloon as the
embolic agent,22 as well as treatment of cavernous carotid4
and vertebrobasilar28 aneurysms. Fibered pushable coils
were used in the late 1980s and early 1990s,29 but
were supplanted by the detachable platinum microcoil.
These were developed and introduced in 199230,31 and
remain the current endovascular embolic agent of choice
for aneurysm therapy with parent artery preservation.
These detachable coils use a monopolar current to permit
atraumatic coil detachment within the aneurysm. The goal
of endovascular therapy is to exclude the aneurysm from

the circulation while preserving flow in its parent artery32
by placing the embolic device within the aneurysm. This
is precluded in fusiform or wide-necked aneurysms,
which permit migration of the embolic device into the parent
arterial lumen. In such cases, permanent occlusion of the
parent artery, if tolerated by the patient as predicted by test
occlusion, can provide effective aneurysm thrombosis.4,33,34
The most widely used embolization device for treat-
ment of fusiform aneurysms of the extracranial carotid
artery has been the detachable balloon.35 Carotid test
occlusion is followed by permanent occlusion using two
balloons in tandem. The balloon is loaded onto a micro-
catheter and is directed from the femoral artery into the
affected vessel. It is then inflated and detached within the
artery. Halbach and coworkers have used these techniques
to treat six aneurysms of the petrous portion of the ICA23
(Fig. 24-1), a location in which direct operative exposure
is difficult. Presenting symptoms included hearing loss,
vertigo, pulsatile tinnitus, trigeminal neuralgia, and head-
ache. All aneurysms were cured, documented angiograph-
ically. Only one minor complication (amaurosis fugax)
arose in this series. Despite the uncommon occurrence of
petrous aneurysms,36–39 they may present emergently with
otorrhagia spontaneously19 or after biopsy.40 Few petrous
aneurysms have been reported in the literature, 27% of
which present with hemorrhagic rupture, equally divided
between otorrhagia and epistaxis.23 Larger aneurysms
arising from the vertebrobasilar system can also produce
cranial nerve deficits secondary to mass effect and can be
treated in similar fashion.28
Trauma is the most frequent cause of aneurysms involv-
ing the cervical and petrous segments of the ICA, external
carotid artery, and extracranial vertebral artery41 (Fig. 24-2).
These are technically pseudoaneuryms and are treated by
a different protocol. In the acute setting, the walls of these
pseudoaneurysms are formed of fresh thrombus of insuffi-
cient strength to contain a balloon or other embolic
devices. Direct embolization of the pseudoaneurysm is
contraindicated, and parent vessel occlusion is required to
prevent life-threatening epistaxis or massive pseudoan-
eurysm formation. Exception to this rule can be made
when the aneurysm is sufficiently surrounded by bony
structures (e.g., foramen transversarium of the cervical
spine) to hold these embolic materials in position. In the
chronic setting, the fibrosis of the pseudoaneurysm wall
has taken place, which may allow direct embolization with
parent artery preservation.
The risks of endovascular aneurysm therapy have been
well-documented and include aneurysm rupture during
embolization, thromboembolic phenomenon, stroke due
to intolerance of major vessel occlusion, and transient cra-
nial nerve deficits from mass effect. The risk of the pro-
posed embolization procedure must be tailored to the risk
of the underlying condition to the patient.
Arteriovenous Malformations
An AVM is an abnormal network of arteriovenous connec-
tions without the normal intervening capillary bed. It can
be found throughout the body and is a common vascular
malformation in the central nervous system.42 It is discov-
ered with one-seventh the frequency of intracranial
Diagnostic and Therapeutic Angiography 439
aneurysms.43 This congenital condition can be seen at any
age, but symptoms arise most commonly in the third
decade.44 Intraparenchymal hemorrhage represents the most
catastrophic form of presentation, may be accompanied by
intraventricular or subarachnoid hemorrhage, and carries
a 10% mortality rate and 30% morbidity rate. The risk
of hemorrhage is estimated at 1% to 3% per year, but each
hemorrhage augments this risk.44,45 Other common
presenting symptoms are seizures and headaches. AVMs
located in the occipital lobe have a particular association
with migraine headaches. Progressive neurologic deterio-
ration, seen in a minority of patients in the absence of
hemorrhage, is thought to result from either venous
hypertension or “steal” of blood supply to the AVM from
normal brain tissue.
Rarely, posterior fossa AVMs can present with neuroto-
logic symptoms, including vertigo, diminished hearing,
trigeminal neuralgia, and hemifacial spasmic46 (Fig. 24-3).
Pulsatile tinnitus is distinctly unusual. These symptoms
are often related to the venous drainage pattern of the
AVM rather than to the location of the AVM nidus itself.
As a result of long-standing high flow and elevated pres-
sure, AVM draining veins may become enlarged, tortuous,
restricted, or thrombosed and may impinge on cranial
nerves as they exit the brainstem.
CT scanning will delineate the AVM as a serpiginous
tangle of contrast-enhancing tubular structures, represent-
ing the AVM nidus. Routine spin-echo MRI sequences will
show a similar pattern, with signal dropout, or “flow void”
within the AVM due to fast-flowing blood. Newer flow-
sensitive MRI sequences will demonstrate the AVM as
high signal, confirming the presence of flow within the
lesion. Enlarged feeding arteries and draining veins enter
and exit this nidus. The relationship of the AVM to adja-
cent normal structures is more easily identified on MRI
because of improved differentiation of soft tissue struc-
tures and lack of artifacts in the posterior fossa normally
seen on CT. Acute hemorrhage is better evaluated with
CT, and subacute/chronic hemorrhage on MRI.
Angiography remains essential to confirm the diagnosis,
search for risk factors for hemorrhage, and plan therapy.
Feeding arteries are often multiple and enlarged due to
increased flow,47 and each must be demonstrated angio-
graphically. Primary supply is derived from pial arteries
(e.g., anterior, middle, or posterior cerebral artery
branches), but dural branches may be recruited secondar-
ily and are thought to have the capacity to produce
headache by affecting the highly innervated dura. The
angioarchitecture of the nidus is seen only on angiography,
and aneurysms arising from feeding arteries or within
the nidus can be delineated. Irregular, restricted patterns
of venous drainage may represent increased risk of
hemorrhage, by increasing pressure within the AVM
nidus.
The treatment of choice is complete surgical resection.
This cannot always be achieved with acceptable morbidity
rates, and surgeons have devised pretherapeutic grading
systems to evaluate such risks.48 Alternatively, stereotactic
radiosurgery can provide effective therapy for smaller AVMs
with unacceptable surgical risk. In either case, embolization
undertaken as prior adjunctive therapy can improve the
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

by improved visibility and reduced operative blood loss
and operating room time,50 and the radiotherapist by
diminished flow in a smaller target.51 Occasionally,
embolization alone is curative or provides palliation in
large AVMs that produce neurologic deficits related to
cerebral steal phenomenon or effects of abnormal venous
drainage.46
The first AVM embolization was performed by direct
catheterization of the common carotid artery and deposi-
tion of embolic spheres that flowed preferentially to the
AVM.52 Presently, the embolization procedure uses a
No. 2 French microcatheter, which can be superselectively
navigated into an AVM feeding artery. These micro-
catheters are of two general types: steerable or flow-
directed. A general anesthetic is used most often to
eliminate patient motion during the delicate embolization,
but in some circumstances the patient may be treated
under IV sedation alone, allowing the possibility of selec-
tive tolerance testing using Amytal Sodium. Embolic
materials in common use include particulate emboli
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.
(PVA particles),53 liquid adhesives54,55(N-butyl cyanoacry-
late), ethanol, and acrylic spheres. In AVMs with large
fistulous connections, embolic platinum coils,56 silk suture
segments, or even detachable balloons57 can be deposited
at the fistula site.
Complications of endovascular AVM therapy include
AVM rupture, perforation of a feeding artery,58 and stroke
from inadvertent embolization of normal arteries. Improved
catheter technology and advances in angiographic imaging
capabilities can reduce these risks, but do not substitute for
the skill and judgment of the experienced interventional
neuroradiologist.
Dural Arteriovenous Fistulas
A dural arteriovenous fistula (DAVF) is an acquired artery-
to-vein shunt in the dura mater without an intervening
malformation or nidus. This usually occurs along one of
the dural venous sinuses draining the brain. It differs from
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).

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.
cause (acquired rather than congenital),59 morphology
(lack of AVM nidus), and arterial supply (dural rather than
pial). The majority of these lesions arise spontaneously,
although there are associations with trauma60 and a history
of venous sinus thrombosis, infection, and hormonal
changes.41 The specific genesis of the condition is unclear,
although it is speculated that small arteriovenous connec-
tions arise in the wall of a thrombosed dural sinus, which
progress to form the DAVF. Alternatively, venous sinus
thrombosis is a known sequela of DAVFs,61 raising the
question of which pathologic state, thrombosis or arteri-
ovenous shunting, precedes the other. Djindjian62 classi-
fied DAVFs according to pattern of venous drainage and
presented the first large series of patients treated with
embolization therapy.
DAVFs occur in certain locations with some frequency,
including the transverse sigmoid sinus, cavernous sinus
(also termed indirect carotid cavernous fistulas),63,64 tento-
rium, ethmoidal groove,65 vein of Galen area,66,67 superior
sagittal sinus, marginal sinus (foramen magnum), and pet-
rosal sinuses.68 Symptoms depend heavily on location and
routes of venous drainage,69 with the exception of pulsatile
tinnitus,70–72 which is seen in the majority of DAVFs, espe-
cially if the venous drainage from the fistula involves a
petrosal sinus. A bruit is classically auscultated by the physi-
cian and characterized as loud, harsh, and of variable high
pitch. A small subpopulation of infants73 and children gen-
erally exhibit more arteriovenous shunting than their adult
counterparts and may also experience high-output conges-
tive heart failure, cortical atrophy, and a poorer prognosis.41
The major characteristic of a DAVF that directs its
therapy is the pattern of venous drainage.62 This also has
a direct bearing on symptomatology. A DAVF may drain
exclusively into the affected venous sinus in an antegrade
Diagnostic and Therapeutic Angiography 443
Continued
direction. This drainage route may become inadequate if
the arterialized inflow overwhelms the drainage capabili-
ties of the sinus or if venous stenosis or restriction devel-
ops. In this instance, venous outflow may be reversed and
drain to the contralateral transverse sinus, or retrogade
into cortical/parenchymal veins. This type of aberrant
venous drainage places the patient at significant risk for
cerebral hemorrhage or infarction, which may be the ini-
tial symptom, especially if stenoses or varices develop in
these cortical veins (Figs. 24-4 and 24-5). The character of
the pulsatile tinnitus may change, becoming softer or even
disappearing. Such a phenomenon may herald the devel-
opment of cortical venous drainage as the dominant sinus
undergoes thrombosis.41 As experience with this phenom-
enon has accrued, indications for urgent therapy have been
identified,74,75 including hemorrhage, cortical venous
drainage, visual loss, and raised intraocular pressure.
DAVFs involving the cavernous sinus variably produce
pulsatile tinnitus, proptosis, chemosis, orbital pain, oph-
thalmoplegia (cranial nerves III, IV, VI), decreased visual
acuity (cranial nerve II), and raised intraocular pressure.
Most patients present to an ophthalmologist, but if the
superior ophthalmic vein is occluded, the patient may
experience only pulsatile tinnitus without ophthalmologic
symptoms. DAVFs involving the transverse, sigmoid, and
petrosal sinuses can present more insidiously. Patients
with these types of DAVFs typically experience pulsatile
tinnitus without a vascular tympanic mass on otoscopy76,77
and sometimes headache, otalgia, or lower cranial nerve
deficits (Fig. 24-6), but lack of more specific symp-
toms often hinders the diagnosis. In Halbach’s series of
28 patients with transverse or sigmoid sinus DAVFs, 18
presented with pulsatile tinnitus and another 8 with
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
of Galen often present catastrophically with hemorrhage
because development of cortical venous drainage fre-
quently precedes development of other symptoms.
Cross-sectional imaging can assist in the diagnosis
of a DAVF, but CT and MRI should not be used as a screen-
ing measure because of their relative lack of sensitivity.
DAVFs without veno-occlusive disease may demonstrate
an entirely normal magnetic resonance appearance.79
Patients who have developed veno-occlusive changes
show dilated vessels representing cortical venous drainage,
without a focal parenchymal AVM nidus, differentiating
DAVFs from AVMs. Major sinus thrombosis may also
be evident. Complications of veno-occlusive disease,
such as hemorrhage or infarction, are well demonstrated
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

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).
Subselective angiography is necessary for diagnosis and
should be performed even when CT or MRI is normal
when a DAVF is suspected clinically. This will allow con-
firmation of the exact location of the DAVF, visualization
of all feeding arteries, assessment of the venous drainage
including sinus occlusion and cortical venous outflow, and
examination of patency of important dural-pial artery
anastomoses. Because dural arteries provide arterial input
and can originate from many sources, the angiogram
should specifically include injection of the internal carotid
(meningohypophyseal and inferolateral trunks), external
carotid, vertebral (posterior meningeal and muscular
branches), ascending pharyngeal, occipital, and middle
meningeal arteries.41 Supply may be bilateral: depending
on expected shunt location, the appropriate contralateral
arteries must be examined (i.e., both vertebral arteries in a
torcular DAVF; both middle meningeal arteries in a supe-
rior sagittal sinus DAVF.)
In considering therapeutic options, it is useful to
remember that DAVFs are dynamic lesions. A DAVF may
be considered a benign disease in the absence of veno-
occlusive disease, visual loss, or elevated intraocular pres-
sure. Under such conditions, conservative therapy is
indicated. A small percentage of DAVFs undergo sponta-
neous regression without therapy or following diagnostic
angiography.
Assisted thrombosis of such benign fistulas can also be
achieved using carotid–jugular compression therapy, espe-
cially in cavernous sinus DAVFs.80 The patient uses the
contralateral fingertips to manually compress the common
carotid artery and internal jugular vein simultaneously for
Diagnostic and Therapeutic Angiography 447
Continued
a period not to exceed 30 seconds, up to three times per
hour. This results in static blood flow at the fistula site due
to the combination of reduced inflow and outflow. This
maneuver is contraindicated with atherosclerotic carotid
bifurcation disease, cortical venous drainage, high-flow fis-
tulas, DAVF-associated visual loss or elevated intraocular
pressure, or in children.
Just as DAVFs may regress spontaneously, progression
can produce veno-occlusive changes and cortical venous
drainage resulting in cerebral hemorrhage or infarction,
underscoring the dynamic nature of this process. Endo-
vascular therapy has become the treatment of choice in
DAVFs to prevent such sequelae. Transarterial approaches
allow navigation of microcatheters through feeding arter-
ies as close to the fistula site as possible. The goal of
embolization is to obliterate the fistula site, since proximal
feeding artery occlusion will not cause thrombosis of the
DAVF, but will encourage collateral supply to the fistula
and will preclude future use of the embolized artery as a
potential route for embolization. Embolic material that
traverses the shunt and produces only venous occlusion
causes redirection of venous outflow and possible aggrava-
tion of cortical venous flow without reducing arterialized
inflow. Liquid adhesive agents (N-butyl cyanoacrylate) are
ideal when there is minimal risk of embolizing normal
dural arteries because they allow less chance of recanaliza-
tion. However, particulate agents (PVA particles) are tech-
nically easier to use and may be selected when increased
risk of normal artery embolization is present, despite the
greater possibility of recanalization. Preembolization
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
assist the choice of embolic agent. Often, a series of staged
embolizations will permit access to certain feeding arteries
that were initially too small to permit catheter passage for
embolization, by allowing them to enlarge. The severity of
veno-occlusive changes will direct whether conservative or
aggressive management is pursued.
Despite the best efforts at transarterial embolization,
some DAVFs may remain patent. Others may have no
adequate arterial access because of prior embolization or
surgical ligation of feeding arteries. Transarterial
embolization may be hazardous in still others because of
crucial territory supply from adjacent arteries. In these
instances, transvenous catheterization and embolization
may provide safe occlusion at the fistula site. Embolization
of veins away from the fistula site will only raise venous
pressure and aggravate symptoms. Cavernous sinus
DAVFs lend themselves particularly well to this tech-
nique.63 From a transfemoral venipuncture, a microcatheter
system is navigated through the internal jugular vein and
inferior petrosal sinus (IPS) to the cavernous sinus.
Embolic materials in frequent use include platinum coils56
and silk suture. Frequently, the IPS will permit catheter
passage even if it fails to opacify on preembolization
angiography. Other transvenous routes to the cavernous
sinus include external jugular to angular to superior
ophthalmic vein, and from the contralateral cavernous
sinus across the sellar veins. Transverse sigmoid sinus
DAVFs have also been treated successfully using the trans-
venous approach.78,81 Embolization of the diseased sinus
itself is achieved by placement of a series of platinum or
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.

antegrade flow, without cortical venous reflux, should not
be considered for this technique, as this type of DAVF is
low-risk and other sinus drainage routes may be inade-
quate for normal venous drainage, if the affected sinus is
closed.
Surgical obliteration of the DAVF may be necessary
when neither transarterial nor transvenous embolization
can be performed. This is particularly true in ethmoidal
DAVFs65 occurring along the floor of the anterior cranial
fossa, which present with frontal lobe hemorrhage or
subarachnoid hemorrhage. Other DAVFs are termed
“complex”82,83 because they require a combination of
endovascular and surgical techniques for cure. This com-
bined approach is reserved for DAVFs likely to produce
hemorrhage or neurologic deficits from veno-occlusive
disease and has been effective in transverse/sigmoid and
deep venous DAVFs.
After embolization, certain clinical sequelae are
expected. They include transient headache, disappearance
of pulsatile tinnitus, and transient ophthalmoplegia in cav-
ernous sinus DAVFs. True endovascular complications are
uncommon and include stroke or cranial nerve deficits
from inadvertent embolization of crucial normal arteries
or occlusion of normal venous drainage patterns, hemor-
rhage from occlusion of normal veins or perforation of
subarachnoid veins or dural sinuses, and visual loss from
iatrogenic restriction of the superior ophthalmic vein
without closure of the DAVF. Due to the great number
of skull base collateral pathways, complexity of vascular
anatomy, and variety of technical materials available, such
surgical complications can be limited only by training and
experience.
Extracranial Arteriovenous Fistulas
Acquired arteriovenous fistulas involving direct major
artery-to-vein shunts may also occur in expected locations in
and around the skull base, not involving dura. Characteristic
types include direct carotid–cavernous, vertebral, and scalp
arteriovenous fistulas. Most of these fistulas result from
direct traumatic injury to the affected artery and subse-
quent fistula formation with an adjacent vein. Although
symptoms differ with location, the classical presentation
includes pulsatile tinnitus and an objective bruit.
Direct Carotid–Cavernous Fistulas
Direct carotid–cavernous fistulas (CCFs) represent
acquired communications between the cavernous portion
of the ICA and its surrounding cavernous venous sinus.
A tear in the ICA causes arterialized inflow into the cav-
ernous sinus, which must direct this high pressure to other
draining veins. This entity differs from the cavernous sinus
dural AVF (indirect carotid–cavernous fistula) in that the
latter is composed of numerous small shunts in the wall of
the cavernous sinus from small dural internal or external
carotid branches, although similar symptoms may result.
Common venous drainage pathways from the cavernous
sinus include inferior and superior petrosal sinuses, supe-
rior and inferior ophthalmic veins, pterygoid venous
plexus, sphenoparietal sinus (to cerebral veins), and con-
tralateral cavernous sinus across the sella. Several of these
venous routes must drain in a retrograde direction to
Diagnostic and Therapeutic Angiography 451
decompress the cavernous sinus. Trauma is by far the most
common cause. Because the cavernous segment of the ICA
is fixed by dura at the skull base, it is susceptible to injury
from skull base fracture.84 Nontraumatic CCFs result from
ruptured cavernous carotid aneurysms or may occur spon-
taneously in association with fibromuscular dysplasia,
Ehlers-Danlos syndrome,85 or neurofibromatosis.41
As with DAVFs, symptoms depend on routes of venous
drainage, but pulsatile tinnitus is present in the overwhelm-
ing majority of patients. One can often auscultate a bruit
over the temporal bone, mastoid region, or eye. Retrograde
drainage through an enlarged superior ophthalmic vein may
produce proptosis, chemosis, orbital pain, ophthalmoplegia,
trigeminal pain or numbness, visual loss, and raised intraoc-
ular pressure to variable degrees depending on patency of
other venous outflow pathways. Retrograde drainage
through the sphenoparietal sinus to cortical veins places the
patient at risk for intracerebral or subarachnoid hemorrhage
or infarction. The contralateral eye may become involved
if venous drainage crosses the sella to pressurize the con-
tralateral cavernous sinus. Drainage along the petrous bone
(inferior and superior petrosal sinuses) most often produces
pulsatile tinnitus.
The diagnosis of CCF is made clinically and confirmed
angiographically, but cross-sectional imaging may assist the
evaluation of these patients. CT is best suited to demon-
strate skull base fractures, especially using bone reconstruc-
tion algorithms. CT or MRI may reveal dilatation of the
cavernous sinus, proptosis, enlargement of the superior
ophthalmic vein, cortical venous drainage, or infarction or
hemorrhage in the brain.
Angiography is necessary to delineate the CCF and its
venous drainage pathways. The angiographer must be
vigilant in identifying trauma-related injuries to other
arteries, such as dissection, pseudoaneurysm formation, or
a second fistula. Depending on the clinical scenario, both
internal and external carotid arteries should be studied
angiographically. Specific angiographic maneuvers use
manual compression of the ipsilateral common carotid
artery while injecting the vertebral artery (Huber’s maneu-
ver)86 or ipsilateral ICA (Mehringer’s maneuver)87 to aid in
identifying the exact site of the fistula in the cavernous
carotid. High flow necessitates a fast filming rate.
Surgical therapies have been supplanted by transarterial
balloon embolization, the treatment of choice.88–90 From a
transfemoral approach, a detachable balloon is directed
through the ICA to the fistula site. Fistula flow allows
entry of the balloon through the defect in the ICA into the
cavernous sinus, where it is inflated and detached to close
the CCF and preserve patency in the ICA91 (Fig. 24-7).
This procedure has achieved closure of the CCF in almost
all cases, with a residual ICA patency rate of 90%.84 A
pseudoaneurysm may develop at the site of injury after
embolization, which rarely requires additional therapy due
to production of cranial nerve palsies (III, IV, V1, or VI).
Embolic or ischemic complications are unusual, but can be
caused by premature detachment and distal migration of a
deflated balloon or intolerance of carotid occlusion. Care
must be taken to avoid occlusion of the ICA proximal to
the fistula site, as this will increase retrograde arterial steal
to the fistula from the supraclinoid ICA and preclude
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
Vertebral fistulas represent acquired abnormal arteriove-
nous shunting from the extracranial vertebral artery to
adjacent veins. Penetrating trauma, especially knife and
gunshot wounds, is the most common cause by far.
Clinical symptoms and signs include pulsatile tinnitus
(especially with more distal lesions), expanding hematoma,
neck pain, progressive vertebrobasilar ischemia from arte-
rial steal, and various cerebral and spinal cord neurologic
deficits associated with venous hypertension, mechanical
compression, or subarachnoid hemorrhage.
Angiography will define the exact site of the fistula and
route of venous drainage. Arterial steal can be confirmed, if
present, by injection of the contralateral vertebral artery
and observation for retrograde opacification of the affected
vertebral artery from the vertebrobasilar junction to the fis-
tula site. Complete transection of the vertebral artery with
retraction of the severed stumps is difficult to assess prior
to treatment, as retrograde arterial steal distally in the
affected vertebral artery may not allow its opacification
from ipsilateral proximal vertebral artery injection.
As with CCFs, transarterial balloon embolization has
become the primary therapy.91–94 One or more detachable
balloons can be navigated through the vertebral artery tear
into the receiving vein and inflated to close the fistula
(Fig. 24-8). The angiographer must avoid producing a
normal perfusion pressure breakthrough (NPPB) phe-
nomenon as a result of the treatment. Abrupt restoration
of cerebral blood flow immediately after closure of a high-
flow vertebral fistula of long duration with arterial steal
can overwhelm the ability of the cerebral vasculature to
compensate, as it may have lost its autoregulatory capacity.
This could theoretically result in intracerebral hemor-
rhage or malignant cerebral edema.95 Gradual occlusion of
the fistula using staged procedures will limit such cata-
strophic complications.

A B
C raphy (CTA) have improved spatial resolution and have
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,
anteroposterior angiographic view, shows a high-flow vertebral fistula
with multiple draining veins. Antegrade flow in the left vertebral artery
(curved open arrows) is seen proximal to the fistula site. A shrapnel
fragment (black arrow) is shown for orientation. B, Right vertebral artery
injection, anteroposterior angiographic view, shows antegrade flow in the
right vertebral artery (black curved arrow) with angiographic steal seen as
retrograde flow in the distal left vertebral artery (open curved arrow) to
the fistula site (large black arrow). The shrapnel fragment is again shown
(smallblack arrow). C, Postembolization left vertebral artery injection,
high-magnification anteroposterior angiographic view, shows antegrade flow
in the artery (long arrow) without residual arteriovenous shunting. A single
balloon was detached across the fistula site, now demarcated by a small
residual pseudoaneurysm (large arrow) adjacent to the shrapnel fragment
(small arrow).
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
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-
allowed better estimation of the degree of stenosis caused by
a given lesion, conventional angiography remains the
standard for evaluation of atherosclerotic carotid and verte-
bral arterial occlusive disease. Antiplatelet medications and
endarterectomy remain treatment staples, although transar-
terial balloon angioplasty99–102 and carotid stenting103–106
have emerged as alternative treatments for clinically and
hemodynamically significant atherosclerotic lesions. These
endovascular treatments are especially helpful in more distal
surgically inaccessible locations, in patients who have under-
gone prior neck irradiation, and in recurrent stenoses.
Fibromuscular Dysplasia
Fibromuscular dysplasia (FMD), also called fibromuscular
hyperplasia or fibromuscular disease, is an idiopathic
454 NEURORADIOLOGY
stenotic condition of large arteries97 most often seen in
middle-aged women. Stenosis develops from overgrowth
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
disease sites. Symptomatic FMD most often presents
as cerebrovascular insufficiency, but pulsatile tinnitus has
been reported.107,108 Patients with FMD are prone to arte-
rial dissection, AVFs,109 and aneurysm formation. Indeed,
we have encountered a middle-aged woman, previously
treated with carotid occlusion for a cavernous segment
ICA aneurysm, who later presented with pulsatile tinnitus
attributed to FMD in the contralateral cervical ICA
(Fig. 24-9).
Angiography is necessary for the diagnosis and classi-
cally demonstrates a long-segment “string-of-beads”
appearance, with variable stenoses. Endarterectomy or
surgical revascularization has been the mainstay of therapy
in symptomatic FMD, but successful reports of balloon
angioplasty100,110 and stent placement in selected cases
Figure 24-9. FMD in a 58-year-old woman with pulsatile tinnitus. Left
common carotid artery injection, anteroposterior angiographic view, shows
alternating areas of dilitation and stenosis (“string-of-beads” appearance) in
the cervical segment of the internal carotid artery (arrows) indicative of FMD.
No other cause for pulsatile tinnitus was found.
encourage further investigation and may provide a prom-
ising primary therapy.
Normal Variants
Aberrant Petrous Internal Carotid Artery
An aberrant petrous ICA is a rare anatomic variant
wherein the petrous portion of the ICA can take an anom-
alous course through the middle ear cavity and may pres-
ent with pulsatile tinnitus or conductive hearing loss as a
retrotympanic mass, simulating a glomus tympanicum
tumor.111–114 During embryogenesis, the dorsal and ventral
aortas are connected by a series of four arches. Further
modification occurs both by anastomosis and by arterial
regression. Abnormal development of the third aortic arch
can result in agenesis of the cervical segment of the ICA.
Collateral supply is derived from a primitive ascending
pharyngeal artery that courses through the tympanic cav-
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
the jugular foramen allowing protrusion of the jugular
bulb into the middle ear cavity.76,117 Smooth, regular ero-
sion of the jugular foramen permits differentiation of this
condition from glomus tumor.112 As with an aberrant

A petrous ICA, radiographic evaluation prior to surgery will
B frequency at higher altitudes.
Figure 24-10. Aberrant pertous internal carotid artery. Longstanding pulsatile
tinnitus. A, Transaxial CT scan shows a rounded soft tissue mass representing
the internal carotid artery in the medial aspect of the left middle ear cavity
(arrows) continuous with its slender petrous segment anteromedially. B, Left
common carotid artery injection, anteroposterior angiographic view, shows
the unusual lateral course (arrow) and sharp angulation of the aberrant ICA
within the middle ear cavity. (Case courtesy of William P. Dillon, M.D.)
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.)
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
Five percent of glomus tumors can secrete vasoactive
hormones. Patients with episodic hypertension, diaphore-
sis, headache, flushing, anxiety, or palpitations may harbor
glomus tumors that produce catecholamines or serotonin.
Hypertensive crises may be sporadic or precipitated by
massage, surgical manipulation, or angiography.125 Analysis
456 NEURORADIOLOGY
of these functional tumors may yield elevated serum,
urine, or tumor values of catecholamines, norepinephrine,
or homovanillic acid. Patients considered for angiography
or embolization should undergo screening for urine
vanillylmandelic acid (VMA) or 5-hydroxyindoleacetic acid
(5-HIAA), breakdown products of the vasoactive substances.
Prophylactic alpha blockade (phentolamine, phenoxy-
benzamine) should precede angiography in patients with
evidence of elevated catecholamines. Antihypertensive
agents (nitroprusside,126 labetalol) should be readily avail-
able during the procedure. Additionally, posttherapy
hypotension can develop due to baseline circulatory
volume constriction coupled with a precipitous drop in
circulating catecholamines.
Presenting clinical symptoms depend on tumor loca-
tion.127 Glomus jugulare tumors present with the jugular
foramen syndrome consisting of palsies of cranial nerves
IX–XI (difficulty speaking or swallowing, hoarseness,
trapezius and sternocleidomastoid weakness). Retro-
auricular pain may be noted, but subtle pulsatile tinnitus
may be overlooked initially. With tumor growth, tongue
deviation (involvement of cranial nerve XII), jugular bulb
occlusion by the tumor mass, or vertigo and hearing loss
may ensue. Very large tumors may produce cerebellar
compression or raised intracranial pressure. Glomus tym-
panicum tumors classically present with unilateral pulsatile
tinnitus, which may be accompanied by conductive hear-
ing loss or peripheral facial nerve palsy (occurring acutely
in 30% of cases128). Situated on the cochlear promontory,
the tumor may appear as a purple-red mass behind the
tympanic membrane on otoscopy and produce otorrhagia.
Medial invasion to the inner ear can produce vertigo and
sensorineural deafness. Posterior invasion can produce
lower cranial nerve deficits, as with a primary glomus
jugulare tumor. Finally, these tumors may be multifocal or
multicompartmental and can be seen clinically, pathologi-
cally, and angiographically.129
Initial diagnostic radiologic evaluation should consist of
CT or MRI. The benefit of CT lies in its ability to evalu-
ate bone erosion with optimal resolution.76,77,130 Glomus
jugulare tumors erode the jugular foramen initially,
whereas glomus tympanicum tumors appear as a tuft of
enhancing tissue eroding the cochlear promontory.112 A
characteristic feature of glomus tumors is the pattern of
simultaneous local extension along canals and vessels.131
MRI offers the ease of multiplanar imaging and can evalu-
ate differences among soft tissue structures well, but is less
effective evaluating subtle bony changes.
Diagnostic angiography remains an effective method of
evaluating glomus tumors preoperatively and assessing
arterial supply and ability to carry out preoperative
embolization, degree of vascularity, encasement of major
arteries, degree of arteriovenous shunting, presence of
major venous sinus occlusion by tumor, multicompart-
mentalization or multifocality of tumor, confirmation of
the expected diagnosis, and exclusion of other vascular
skull base processes mimicking glomus tumors. Classical
angiographic features include enlargement of feeding
arteries, intense tumor stain, and arteriovenous shunting.
These tumors may be supplied by a single enlarged artery
or by multiple feeders, depending on tumor size and
number of compartments, which can be separate from one
another.129 When evaluating a glomus tumor, angiography
must include injection of ascending pharyngeal, occipital,
posterior auricular, middle meningeal, and internal maxil-
lary branches of the external carotid artery. Internal carotid
and vertebral arteries also give rise to dural branches that
can supply the tumor. Tumors invading intradurally may
parasitize pial supply including anterior and posterior
inferior cerebellar arteries.41 Occasionally, angiography
will reveal an unsuspected additional glomus tumor. The
ascending pharyngeal artery (particularly its inferior
tympanic branch132) nearly always supplies jugulotympanic
glomus tumors, as it gives off branches that supply normal
structures in these locations. As such, it is postulated that
bilateral ascending pharyngeal artery injections can
effectively diagnose all jugulotympanic glomus tumors.41
The stylomastoid artery, which normally supplies the
descending portion of the facial nerve, can arise from
the occipital, posterior meningeal, or posterior division of
the middle meningeal arteries and can supply glomus tumors
extending posterolaterally. Tumors extending superiorly
will involve the middle meningeal artery.
Embolization is performed as a preoperative adjunct to
limit surgical blood loss (Figs. 24-12 and 24-13). Its effi-
cacy has been demonstrated by many authors.41,133,134
Supraselective catheterization of a feeding artery is fol-
lowed by high-resolution arteriography. Functional testing
of cranial nerves with 2% cardiac lidocaine (10–20 mg)
may be helpful. PVA particles 300 μm or larger can satu-
rate the tumor bed and generally avoid cranial nerve
deficits. Vigilance will allow detection of anastomoses with
intracranial arteries, such as connections between the
occipital artery or odontoid branch of ascending pharyn-
geal artery with the vertebral artery. Particular care is
necessary to preserve the neuromeningeal branch of the
ascending pharyngeal artery (cranial nerves IX–XI) and
the stylomastoid artery (facial nerve). Embolization of pial
supply is difficult to achieve safely.41
Among the limited complications arising from the large
number of embolization procedures performed to treat
glomus tumors are transient facial nerve palsy, extravasa-
tion of contrast related to high-pressure injection of the
embolic agent, and palsies involving cranial nerves IX–XI.
These last are related particularly to liquid adhesive
embolization of the neuromeningeal branch of the ascend-
ing pharyngeal artery.41
Meningiomas
Meningiomas are common benign extraaxial tumors of the
meninges covering the brain.135 These tumors are thought
to have arisen from cells that form arachnoid villi, which
serve to reabsorb cerebrospinal fluid from the cerebral cis-
terns into the venous sinuses. As such these tumors are
found in locations where the arachnoid villi are most plen-
tiful, along the dura lining the venous sinuses of the brain
and skull base.
Specific presenting symptoms depend on tumor loca-
tion and size. Common locations include parasagittal and
lateral cerebral convexity (most common sites), sphenoid
wing, petrous ridge, cerebellopontine angle (CPA), teno-
rium, foramen magnum, orbit, cavernous sinus, or rarely
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
jugular foramen, internal auditory canal, geniculate gan-
glion area, and along the lesser and greater superficial
petrosal nerves,136 meningiomas arising from these cells
may present with neurotologic symptoms, including
conductive hearing loss (temporal bone, middle ear), sen-
sorineural hearing loss and vestibular symptoms (internal
auditory canal, simulating an acoustic neuroma), tinnitus,
and facial nerve palsy (CPA), or hoarseness, cough, dys-
phagia, difficulty speaking and handling secretions, and
trapezius weakness (jugular foramen).137
A number of histologic subtypes have been described,138
including syncytial, transitional, fibroblastic, angioblastic,
and malignant varieties, depending on the predominant
cell type.139 There is a correlation between incidence of
meningioma and a history of prior irradiation, with a
latent period of 5 to 25 years.140
CT and MRI have supplanted plain skull radiography in
the initial diagnostic evaluation of meningiomas. CT scan-
ning will show a well-circumscribed extraaxial mass rela-
tively isodense or hyperdense compared with normal brain
tissue on noncontrast images; these enhance brightly with
458 NEURORADIOLOGY
administration of IV contrast.131 MRI scanning with admin-
istration of gadolinium–DTPA allows more facile tumor
evaluation in multiple planes, which is especially helpful
for evaluating the dural attachment of the tumor and
patency of dural sinuses.
Meningiomas are typically vascular tumors, as would be
expected of tumors arising from the vascular dura.
Additionally, meningiomas receive their blood supply pri-
marily from dural arteries, especially from external carotid
branches.141 Depending on tumor location, arterial supply is
derived predominately from middle meningeal, accessory
meningeal, ascending pharyngeal, or occipital transmastoid
perforating branches of the external carotid artery and may
be bilateral, especially in a midline tumor. Superselective
catheterization of these branches is important for excluding
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.
each as a supply source because a global common carotid or
even external carotid injection may visualize these arteries
inadequately. Dural arteries from the internal carotid
(meningohypophyseal trunk, inferolateral trunk, ethmoidal
branches of ophthalmic artery) and vertebral (posterior
meningeal) arteries may also supply the tumor. As a menin-
gioma grows, it parasitizes pial branches, which supply small
twiglike branches to the periphery of the tumor. Another
characteristic feature of meningiomas is the angiographic
staining pattern: uniform radial arrangement of tiny tumor
vessels in a well-defined round tumor. Opacification begins
in the arterial phase, augments, and persists into the venous
phase without washout (Fig. 24-14).
Cerebral venography has a limited role in the evaluation
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
studies, can be made. This assessment is important for the
surgeon because the tumor and occluded adjacent sinus
can be resected without danger of venous infarction,
whereas a patent sinus should be preserved. This is espe-
cially true of the dominant (usually the right) transverse
sinus and posterior two-thirds of the superior sagittal
sinus. Delineation of the exact site of sinus tumor invasion
by venography is superior to that of arteriography. Finally,
venous pressure gradients across a sinus partially obstructed
by a meningioma can be measured,12 and sinus test occlu-
sion performed to assess tolerance of surgical resection of
the tumor and adjacent sinus.
The goal of therapy for meningiomas is complete erad-
ication of the tumor. This is best achieved by complete
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
preoperative embolization in meningiomas with feeding
arteries easily accessible to the surgeon.142 However, pre-
operative devascularization of the microvascular tumor
bed by embolization143,144 provides the following advan-
tages: diminution of surgical blood loss and operative time,
improvement of visibility for the surgeon, allowing the
surgeon to amputate a portion of the tumor devascularized
by embolization, and control of arterial flow in surgically
inaccessible tumor feeders (especially at the skull base).
Advances in technology, including improved spatial
resolution of digital subtraction “road-mapping” angio-
graphic systems and development of softer steerable or
flow-directed microcatheters, have provided the angiogra-
pher with safer supraselective access to tumor vascularity.
However, experience with endovascular techniques is nec-
essary to avoid the many pitfalls associated with these
procedures. Prior to embolization, the patient is given cor-
ticosteroids to reduce the immediate risk of tumor
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-
ticles (measuring 50 to 200 μm), Gelfoam powder, or small
acrylic spheres will penetrate well into the tumor bed, but
risk permeating normal branches of similar size that are
too small to resolve well on angiography, particularly at
the base of the skull where the dense petrous bone will
hinder optimal radiography. Large particles may result in
proximal occlusion of the artery without adequate tumor
penetration. Therefore, an intermediate size particle (250
to 500 μm) may achieve the desired result with less risk
to small normal branches. Liquid adhesive agents (e.g.,
N-butyl cyanoacrylate) need not be used in this setting,
as their permanence is unnecessary and they will easily
permeate small normal branches below the resolution
capacity of current angiographic systems. Vigilance must
be maintained to avoid reflux of embolic material into nor-
mal proximal branches by overly vigorous embolization.
Pial meningioma supply is generally not embolized preop-
eratively, as pial branches provide only a small percentage
of tumor vascularity, and the risk of embolization is greater
than that of dural artery embolization. A postembolization
control angiogram is performed to document adequate
results.
Despite the many potential pitfalls of meningioma
embolization, the complication rate is very small in expe-
rienced hands.41,142,145,146 Berenstein reports 3 permanent
(monocular blindness, stroke) and 5 transient (facial nerve)
neurologic deficits in 185 patients.41 Two cases of sub-
arachnoid hemorrhage have been encountered.41,145
Trismus, resulting from internal maxillary artery branch
occlusion, was more prevalent prior to the introduction of
microcatheters.142
Schwannomas
Schwannomas, 90% of which occur in the CPA, are benign
extraaxial tumors arising from the cranial nerve sheaths,
which are formed of Schwann cells.112,139 Usually solitary,
multiple schwannomas are characteristic of neurofibro-
matosis, and bilateral acoustic schwannomas are the hall-
mark of the central form of neurofibromatosis, or NF2.147,148
Sensory cranial nerves are overwhelmingly involved.
These tumors are generally seen in middle-aged individu-
als and have a predilection for females. Association with
head and neck irradiation during childhood has been pos-
tulated.149
The so-called acoustic schwannoma is by far the most
common site of tumor origin. Ninety percent of these
tumors arise in the superior division of the intracanalicular
vestibular nerve. The trigeminal nerve is the next most fre-
quent site of origin.112 Schwannomas in other locations are
most often manifestations of neurofibromatosis. The facial
nerve, although infrequently a tumor site, is the most com-
monly affected motor nerve.139
Generally, schwannomas are firm, encapsulated tumors
that may contain cysts. As the tumor grows, it may become
lobulated, increase in vascularity,150 or develop arachnoid
adhesions that may result in arachnoid cysts.151
Clinical presentation depends on the size and site of ori-
gin of the tumor. Acoustic schwannomas initially present
with tinnitus and progressive, high-frequency neurosensory
hearing loss due to cochlear nerve compression. Although
most acoustic schwannomas arise in the vestibular nerve
sheath, vertigo, disequilibrium, and dizziness are less com-
mon. Similarly, the facial nerve, which shares the internal
auditory canal with its cochlear and vestibular eighth nerve
counterparts, is affected infrequently,151,152 possibly
because motor fibers are less sensitive to local effects of
compression than sensory fibers. Tumor enlargement into
the CPA and posterior fossa can compress the cerebellum
producing ataxia, compress the brainstem or exiting cra-
nial nerves (most commonly the trigeminal nerve), or
result in obstructive hydrocephalus or raised intracranial
pressure.110 Schwannomas arising in the trigeminal nerve
sheath present with facial paresthesias and hypesthesia, but
may become quite large in the absence of such symp-
toms.120 Schwannomas of cranial nerves IX to XI can pro-
duce the jugular foramen syndrome (difficulty speaking and
swallowing, hoarseness, and trapezius and sternocleidomas-
toid paralysis) due to the intimate anatomic arrangement of
these three cranial nerves.
CT scanning demonstrates an extraaxial, well-circum-
scribed tumor eroding the involved canal and may enhance
variably with IV contrast administration. More recently,
MRI has supplanted CT in the primary evaluation of
schwannomas, especially acoustic schwannomas, because
of superior intrinsic soft tissue contrast differences, lack
of artifacts produced on CT by density differences at
air-bone or soft tissue-bone interfaces, and ease of multi-
planar image acquisition. Small intracanalicular acoustic
schwannomas can be detected easily on MRI and are
best evaluated on gadolinium–DTPA-enhanced short TR
(repetition-time) images obtained in both transaxial and
coronal planes.
Several angiographic features of schwannomas assist in
differentiating them from meningiomas, which have a sim-
ilar angiographic appearance. Schwannomas have been
described as hypervascular in up to 68% of cases,41 espe-
cially in larger tumors or in the rare childhood case,153 but
feeding arteries are generally of normal or minimally
enlarged caliber, and tumor stain, when present, is less
dense than that of a meningioma.154,155 No arteriovenous
shunting occurs, but a network of capsular veins may
encircle the tumor. The most suggestive angiographic
finding is the presence of multiple small puddles of con-
trast that persist into the venous phase.156 Arterial supply
can be predicted from tumor location and may arise from
external carotid branches or from the anterior (AICA) or
posterior (PICA) inferior cerebellar arteries in cases of
acoustic schwannomas.155
Preoperative embolization has been shown to be effica-
cious in treating vascular schwannomas153,156 by reducing
tumor blood supply and easing surgical resection, as with
meningiomas. Embolization techniques are also similar. Use
of intermediate-sized PVA particles (300 μm) in selected
branches of the external carotid artery can effect adequate
tumor devascularization while safely avoiding cranial nerve
deficits, especially if undertaken after provocative lidocaine
testing. Pial artery embolization should be reserved for very
large vascular schwannomas, as the risk of producing neuro-
logic deficit from embolization of the PICA (Wallenberg’s
syndrome) or AICA (vertigo, diminished hearing) is

considerably greater than with external carotid branch
embolization. Although no large body of experience with
embolization of schwannomas has been compiled, smaller
series suggest minimal risk in experienced hands.156
Miscellaneous Tumors
Malignant Skull Base Tumors
Endovascular therapy can provide palliation or adjunctive
therapy for surgery in vascular primary or secondary
malignant skull base tumors. Angiography will assess the
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
chance of significant hemorrhage. In palliative cases, such
embolization can reduce the frequency of spontaneous
bleeding and diminish pain.41 Properly sized particulate
emboli are most suitable because they provide the greatest
permeation of the vascular tumor bed with the least risk of
side effects. Additionally, ICA test occlusion with meas-
urement of arterial pressures distal to the occlusion bal-
loon will enable the skull base surgeon to determine
whether the patient can tolerate carotid occlusion should
this become necessary during surgery. If permanent
carotid occlusion is deemed mandatory for safe and suc-
cessful skull base tumor resection, this can be carried out
in the angiography suite following test occlusion.3 One
must adhere to the policy of vigorous volume expansion
and strict limitation of activity following carotid occlusion
to avoid hemispheric ischemia. The anesthesiology team
should be apprised of the need to avoid episodes of
hypotension during the subsequent operation for the same
reason.
Hemangioblastomas
Posterior fossa hemangioblastomas are highly vascular
intraaxial tumors primarily supplied by pial arteries, but
may demonstrate dural arterial supply and meningeal inva-
sion especially in large or recurrent tumors.157 Such
tumors can produce lower cranial nerve palsies. Surgical
resection can be aided by preoperative embolization to
produce tumor necrosis and reduce blood flow. Risk of
embolization is greater than with many other types of
tumor because of the apparent fragility of tumor arterioles,
which can lead to parenchymal or subarachnoid hemor-
rhage during embolization.
Juvenile Angiofibromas
Juvenile angiofibromas (JAFs) are benign vascular tumors
arising in the pterygopalatine fossa in pubescent males, usu-
ally presenting with epistaxis and nasal obstruction.158 Large
JAFs with posterior extension may come to the attention of
the neurotologist because of secondary hearing loss.159
Transarterial particulate embolization, usually involving the
ascending pharyngeal and internal maxillary arteries has
become the standard of care in preoperative devasculariza-
tion.160 Because a high degree of correlation exists between
the angiographic tumor blush and actual tumor boundary,
this feature can be used to determine tumor extent before
therapy and to assess efficacy of embolization.41
Diagnostic and Therapeutic Angiography 465
CONCLUSION
Diagnostic angiography plays an essential role in the eval-
uation of vascular abnormalities and tumors presenting to
the skull base surgeon. Additionally, embolization of these
abnormalities has become an accepted form of therapy,
broadening the treatment options for both the surgeon
and the patient. Further technical developments and
experience will permit an expanded role of endovascular
therapy by well-trained individuals who have mastered
endovascular techniques and who are aware of their capa-
bilities and limitations.
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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

Introduction
Auditory neuropathy (AN) is a term used to describe patients
with a hearing disorder characterized by (1) a bilateral pure
tone sensorineural hearing loss (SNHL); (2) absent or
severely abnormal auditory brainstem responses (ABR)
beginning at wave I, suggesting impairment of function of
afferent neural transmission; (3) preserved otoacoustic
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
has only been recently described, the condition is not
new.6–8 AN was difficult to recognize in the past because
tests to distinguish disorders of the cochlear receptors from
those of the auditory nerve were not routinely performed.
Incidence
Data regarding the incidence of AN in children is
gradually accumulating due to widespread institution of
infant hearing screening programs. There are no data for
adults. In a study from Australia the incidence of AN
presenting in infancy was found to be 0.23% of the general
population. Of the 5199 infants who underwent screening,
109 had an abnormal ABR (2.09%). Of these, 12 had
present OAEs or CMs, consistent with the diagnosis of
the general population appears small, one in nine infants
found to have a permanent hearing deficit met the criteria
for AN.3 Park and Lee found that 6% of patients with
bilateral severe to profound hearing loss had present oto-
acoustic emissions.9 Among patients with AN, there
appears to be no gender preference.10 The identification of
AN in older children and adults is complicated by the fact
that the OAEs are sometimes lost and therefore the disor-
der cannot be distinguished from other types of SNHL.
Etiology
The causes of AN are currently being investigated and
appear to be diverse. In approximately 50% of patients
AN has no defined cause. Genetic factors have been iden-
tified and appear to account for the disorder in ≈40% of
patients with AN. Other associated causes, including
toxic-metabolic, infectious, and immunologic factors that
account for ≈10% of patients.10 In infants AN has been
associated with neonatal hyperbilirubinemia,11,12 hypoxia,
congenital infection, and prematurity.3,13 It may occur as
part of a generalized metabolic, toxic, or inflammatory
neuropathy, as seen with diabetes,14 uremia,15 or exposures
to cisplatin, which appears to selectively damage inner hair
cells.16 AN has been diagnosed in patients with Friedreich’s
ataxia,17 in patients with a hereditary motor and sensory
neuropathy (HMSN)18–20 and Charcot-Marie-Tooth
471
472 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
TABLE 25-1. Main Features of Auditory Neuropathy
Clinical Findings
Difficulty understanding speech, particularly in background noise
Normal physical exam, except for hearing loss
Audiometric Findings
Bilateral pure tone sensorineural hearing loss
Preserved otoacoustic emissions and cochlear microphonic
Absent or severely abnormal ABR
Impaired word recognition score out of proportion to degree of hearing loss
Imaging Findings
Normal CT and MRI
ABR, auditory brainstem response; CT, computed tomography; MRI, magnetic
resonance imaging.
disease,21 or as an isolated and sporadic event.22 A genetic
mutation of the PMP22 gene in Charcot-Marie-Tooth
disease,23 as well as a mutation mapped to 8q24 in some
Bulgarian and Italian Gypsy families with AN have been
identified.19
Pathophysiology
The site of the pathology causing the findings of absent
ABRs and preserved OAEs and CMs in AN has yet to be
discovered. It has been suggested that the disorder may
occur at the level of the inner hair cells, the synapse
between the inner hair cells and the eighth nerve, the gan-
glion neurons, the nerve fibers, or any combination of
these.4 Along the auditory nerve, the site of pathology may
be the myelin sheath or the neuron (axon and dendrite).10
Other authors have hypothesized that the normal synchro-
nous activity of the auditory nerve is disrupted, which may
be secondary to a demyelinating process, leading to tem-
poral and speech-processing deficits, without necessarily
affecting the amplification function of the inner ear.4,24,25
An increase in body temperature has been associated with
marked worsening of hearing in some patients with AN.26
Starr noted that heat sensitivity is common among patients
with multiple sclerosis and that this worsening in hearing
in patients with AN may represent a conduction block sec-
ondary to a myelin disorder.10 Chinchillas with carbo-
platin-induced lesions of the inner hair cells (IHCs) and
type I neurons demonstrated similar characteristics to
patients with AN.27 Temporal bone findings in patients
with Friedreich’s ataxia revealed a pronounced loss of
nerve fibers and spiral ganglion cells, increasing from base
to apex, with preservation of the outer hair cells.28
Hyperbilirubinemia has been implicated but because this
is a common occurrence after birth it is difficult to know if
there is a causal relationship.
Clinical Presentation
AN has been diagnosed in all ages from newborns to
adults. A study of 67 patients with AN by Starr and
colleagues found that children under the age of 10 years
account for the majority of the population with AN
(≈75%), whereas adolescents and adults account for the
minority (≈25%). They suggest that the reason for the
discrepancy may be secondary to the more widespread use
of OAEs and ABRs in the evaluation of hearing loss in
infants and children than in adults. Furthermore, ≈20% of
the children with AN currently being followed have been
found to lose their OAEs over time. AN in adult patients
who have subsequently lost their OAEs would therefore
be underdiagnosed.10
Infants with AN usually present when abnormal ABRs
and preserved OAEs are found during routine infant
screening. In older children and adults, the clinical pres-
entation is typically that of a gradual hearing loss. These
patients report extreme difficulty understanding speech,
especially when using the telephone or in noisy environ-
ments. Many are dependent on lip reading. Some patients
report fluctuations in hearing over time. It is not uncommon
for them to be accused of malingering or for their hearing
disorder to be mistaken for a behavioral problem. It can be
confusing for older children and young adults and the sur-
rounding friends and family because the hearing can be
quite satisfactory in quite environments but very poor in
other settings.
Audiometric Findings
Hearing loss ranges from mild to profound, and there is no
characteristic audiometric pattern. Patients with AN often
have difficulty providing consistent responses during
testing and demonstrate test-retest variability. Starr and
colleagues reported that 31% have a hearing loss of 35 dB
or less, 39% have between a 35- and 70-dB loss, and
30% have a greater than 70-dB loss. Thresholds remain
constant over time in ≈40% of patients, fluctuate in 30%,
and worsen in ≈15%.10 Impaired word discrimination is
disproportionate to pure tone loss. The audiogram reveals
a flat configuration in 41%, an upsloping pattern consis-
tent with a low-frequency loss in 29%, an irregular “saw
tooth” pattern in 9%, a U-shaped pattern in 5%, tent-
shaped loss in 5%, and a downsloping pattern in 11%
(Fig. 25-1).10
ABRs are either absent or severely abnormal in all cases
(Fig. 25-2). A few patients with preserved components
(wave V with or without wave III) have been identified
when the stimulus rate was slowed.10 In these cases, wave
V was of prolonged latency and decreased amplitude, and
wave III was of abnormal morphology. The differences in
ABRs suggest that the loss of neural synchrony is variable
among patients with AN secondary to different causal and
physiologic factors.10 Stapedial reflexes are absent in all
but a few patients with AN. Normal distortion product
and transient evoked otoacoustic emissions (DPOAE,
TEOAEs) or CMs are present at initial examination.
Increased amplitude of CMs has been observed in patients
with AN who are younger than 10 years compared with
normal subjects.1,19 In one study increased amplitude of
CMs was observed in 50% of patients.10 The significance
of this finding is currently unknown. There have also been
reports of loss of OAEs on future testing with preservation
of CMs,2,11 with a 20% incidence reported in a recent
study.10 The reason for this finding is also currently
unknown, but may represent a primary disorder of the
outer hair cells (OHCs) or damage to the OHCs from
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-
laryngologist, geneticist, ophthalmologist, and pediatrician.
Evaluation by a pediatric neurologist has not been a routine
part of our evaluation because of the rarity of a peripheral
neuropathy at a young age but is considered on an individual
basis. Because these children may develop other neu-
ropathies later in life, a neurology appointment at some
point seems reasonable. Laboratory work typically consists
of an ECG, thyroid function test, urinalysis, glucose, and an
MRI or computed tomography (CT) scan of the head.
Genetic screening for abnormalities in the Connexin-26 gene
is encouraged and performed in most cases. Our evaluation
procedure continues to evolve, and with advances in genetic
screening over the next several years we will continue to alter
our routine to minimize the number of tests obtained.
Audiology Evaluation
Accurate audiometric testing is critical to making the diag-
nosis, and the knowledge and abilities of an experienced
audiologist are invaluable. In addition to standard audio-
metric tests and age-appropriate speech perception tests,
otoacoustic emissions are obtained and followed over time.
Evoked potentials always include an ABR in which we
record phase-reversing clicks or tone bursts in order to
identify the cochlear microphonic. Middle (MLR) and late
(LLR) latency responses may also be recorded. For adults,
the Hearing In Noise sentence Testing (HINT) is quite
beneficial in delineating the difficulty that patients have in
different listening situations.
Lastly, although most patients are asymptomatic with
regard to vestibular function, abnormalities of vestibular
caloric stimulation have been identified. Therefore, it may
be appropriate for patients to undergo vestibular testing to
identify baseline function.
Treatment Options
Treatment options for children with AN include intensive
speech and language therapy, hearing aids, or cochlear
implantation. From the time that AN was first reported in
the literature, clinicians have questioned whether it was
wise to consider amplification with hearing aids or
cochlear implants,3,11,17,18,22 There was concern that ampli-
fication would cause further injury to the cochlea and that
cochlear implants would not work because the hearing loss
was due to a problem with the nerve. In an effort to not
injure the outer hair cells, hearing aids were often fitted
using a low-gain and wide-dynamic-range compression
strategy. The hearing aids were usually tolerated, but
because the gain was low they seldom provided any bene-
fit. The trend now is to fit the hearing aids to the behav-
ioral audiogram according to accepted rules and assess
auditory skill development. Most children will tolerate the
aids but many will not demonstrate adequate progress in
acquisition of speech and language skills. For those who do
show progress, amplification is the treatment of choice.
Adults with mild or moderate losses often reject hearing
aids, stating that “the sound is louder but I still can’t under-
stand the words.” It is likely that the children who fail to
progress with hearing aids are having the same problem.
Despite some early reports of poor outcomes, cochlear
implantation has now been shown to be a viable option for
patients with AN.31,32 A recent review at our institution of
10 children with AN compared with a matched group with
hearing loss from other causes showed no difference in
performance after cochlear implantation (unpublished
data). Evoked intraoperative and postoperative potentials
(EABR) and electrical compound action potentials
(ECAP) demonstrate the ability of the cochlear implant to
restore neural synchrony. We have had similar favorable
results in adults.
Future Directions
The following factors vary among patients with AN: cause,
age of onset, presence or absence of a peripheral neuropa-
thy, degree of hearing loss, differences in physiological
measures of auditory function (ABRs, OAEs/CMs), and
differences in treatment outcomes. As more is learned
about AN, it will become more evident whether this is
truly a single disorder or many different ones that share a
few common features. Routine use of nerve conduction
studies in patients with AN will help to identify the rate of
a peripheral nerve disorder in this population. Genetic
studies may identify a common link in hereditary cases of
AN. Long-term outcomes of AN patients with cochlear
implants will shed light on the effectiveness of this treatment.
Our understanding of AN is evolving, with many ques-
tions still to be answered.
SARCOIDOSIS
Introduction
Sarcoidosis is a chronic systemic granulomatous disease of
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-
monary, ocular, dermatologic, and lymphatic systems, the
central nervous system (CNS) may also be affected.33 CNS
symptoms include hearing loss or vertigo (or both). Other
otolaryngologic manifestations of sarcoidosis include
involvement of the salivary gland (uveoparotid fever), the
larynx (most often supraglottic), nasal cavity and nasophar-
ynx (mucous membrane lesions, septal perforation), and
neck (cervical adenopathy).34,35
Incidence
The overall incidence of sarcoidosis is 40 per 100,000.36
Neurosarcoidosis occurs is approximately 5% to 10% of
cases.37,38 The cranial nerve (CN) most commonly affected
is the facial nerve, presenting with unilateral or bilateral
facial paralysis with a good prognosis for spontaneous
recovery.37,39–41 Lesions of the optic, trigeminal, and
vestibulocochlear nerves are fairly common. Symptoms
include optic neuritis/atrophy (CN II) and unilateral
sensory loss of the face (CN V).41,42 Sarcoidosis of the
eighth nerve presenting with hearing loss or vertigo is
often associated with other cranial neuropathies. Isolated
eighth nerve involvement is rare.35 Whereas the overall
incidence of hearing loss among cases of sarcoidosis is
≈0.5%,43 in cases of neurosarcoidosis it occurs in 10% to
20% of cases.36 Cranial nerves less commonly involved
 Auditory Neuropathy, Sarcoidosis, Siderosis, and Idiopathic Pachymeningitis
may cause symptoms of dysphagia and hoarseness (IX, X),
anosmia (I), and disturbances of ocular movements
(III, IV, VI).42
Etiology
Despite advances in the understanding of sarcoidosis, a
specific cause has not been identified. Human leukocyte
antigen (HLA) studies show a higher prevalence of the
disease among first-generation relatives of patients with
sarcoidosis, suggesting a genetic factor.44 The current the-
ory suggests that a combination of environmental factors
and a genetically susceptible individual is most likely
responsible for the induction of the disease.36
Histopathology
The typical histopathologic features of sarcoidosis include
noncaseating granulomas consisting of epithelioid cells
surrounded by mature lymphocytes (Fig. 25-3). Other cells
that are often present include giant cells, both Langerhans’
and foreign body types. The inflammatory process is associ-
ated with an increase in activated T cells and macrophages,
initiating an immune response with the release of inter-
feron-γ, interleukin-2, other cytokines, and proinflamma-
tory factors.36 The diagnosis of tuberculosis is excluded by
the absence of central caseation and acid-fast bacilli.45
Pathophysiology
Autopsy findings of the temporal bone in a patient with
sarcoidosis and neurosensory deafness revealed a striking
perivascular lymphocytic infiltration of the eighth nerve,
resulting in myelin and axonal degeneration. Within the
inner ear, degeneration was evident in the cochlear and
labyrinthine neuroepithelium and stria vascularis.45 It has
been hypothesized that the neurosensory deafness and
vestibular dysfunction in sarcoidosis begins as a reversible
neuropathy. With the persistence of the inflammatory
response, fibrotic changes occur, resulting in irreversible
tissue damage.36,46
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
475
In neurosarcoidosis, a predilection for the basal lep-
tomeninges is evident and often presents as granulomatous
meningitis affecting the hypothalamus, third ventricle,
pituitary, and cranial nerves. Less commonly, neurosar-
coidosis presents as a mass lesion. Sarcoid granulomas
occurring at the cerebellopontine angle (CPA) have been
reported.35,46–53 In one of these cases, the CPA lesion was
the only clinical finding, and the sarcoid granuloma was
mistaken for a meningioma and treated surgically.47
Clinical Presentation
The clinical presentation of hearing loss with sarcoidosis
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
Isolated cases of hearing loss have been reported as the
presenting symptom of sarcoidosis.35,47,55 The hearing loss
may be fluctuating55,56 or of sudden onset.35,53,54,57 Other
symptoms include tinnitus, vertigo, or disequilibrium with
a positive Romberg test and hypoactive calorics.53,54
Depending on the site of the lesion(s), the hearing loss
may be unilateral or bilateral. Typically the hearing loss is
sensorineural, although cases of a conductive loss have
been reported secondary to nasopharyngeal granulomas
obstructing the eustachian tube.52 Systemic symptoms
include fever, malaise, weight loss, and night sweats. The
age of presentation of neurosarcoidosis is typically young
adulthood between ages 30 and 44 years,37,39–41,58 although
there have been reports in children.59
The differential diagnosis of hearing loss in the setting of
neurosarcoidosis includes syphilis, multiple sclerosis,
Cogan’s syndrome, Vogt-Kyoanagi-Harada disease, endo-
lymphatic hydrops, other granulomatous diseases including
tuberculosis and Lyme disease, CPA tumors, and AIDS.42,56
Evaluation
In patients presenting with a unilateral or asymmetric
fluctuating or sudden-onset hearing loss, the diagnosis of
sarcoidosis should be included in the differential diagnosis.
476 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
Initial work-up includes a thorough history with a detailed
review of systems, inquiring about fatigue, weight loss,
changes in vision, and so on. Physical examination should
include a general exam, including assessment of the
skin, as well as complete otolaryngologic and neurologic
evaluations. Facial nerve function should be documented.
Due to the high incidence of associated ocular findings,
most often uveitis, patients who are suspected of having
sarcoidosis should undergo ophthalmologic evaluation.
Audiology
Audiometric testing includes pure tone audiometry, word
recognition, stapedial reflexes (usually absent), tympanom-
etry, and ABR (often absent or abnormal). If patients have
associated vestibular symptoms, electronystagmography
should be performed.
Diagnostic Tests
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-
ulomas. Plain film chest radiograph is performed to search
for hilar adenopathy and pulmonary infiltrates, which are
present in ≈90% of patients at some time during the course
of their disease.38 Biopsy specimens may be obtained from
any involved tissue in the body. If pulmonary involvement is
evident, the diagnosis may be obtained by transbronchial or
mediastinoscopic biopsy or bronchoalveolar lavage (BAL).36
Fine-needle aspiration can give an accurate diagnosis when
taken from involved lymph nodes or salivary glands.60 If no
specific lesions are identified, a random lip biopsy of minor
salivary glands may confirm the diagnosis in 40% to 50% of
patients with hilar adenopathy.61
Serologic testing, although nonspecific, should be
obtained to support the diagnosis of sarcoidosis. Tests
include CBC (leukopenia, anemia, thrombocytopenia),
electrolytes (elevated blood urea nitrogen [BUN] and cre-
atinine), serum calcium (hypercalcemia), liver function
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
sarcoidosis and thought to be specific for this disease, but
increased levels are also seen in patients with leprosy,
Gaucher’s disease, liver disease, diabetes mellitus, hyper-
thyroidism, systemic infection, and malignancy.61,62
Purified protein derivative (PPD) and appropriate skin
tests should be performed to rule out anergy, which occurs
in ≈25% of patients.
Cerebrospinal Fluid Findings
Cerebrospinal fluid (CSF) findings in neurosarcoidosis
are nonspecific. However, up to 80% of patients with
neurosarcoidosis show some CSF abnormalities.37 Abnor-
malities include mononuclear pleocytosis, increased protein,
elevated CSF pressure and low glucose levels. Increased CSF
ACE occurs in ≈50% of patients with neurosarcoidosis.
Levels tend to fall with treatment and correlate with the
activity of the disease42; however, Ferriby and coworkers
found no correlation between blood or CSF ACE and
TABLE 25-2. Laboratory Findings Supportive of the
Diagnosis of Sarcoidosis
ACE ↑
WBCs ↓
Hemoglobin ↓
Platelets ↓
BUN and creatinine ↑
Serum calcium ↑
Liver function tests ↑
ESR ↑
ACE, angiotensin I-converting enzyme ; BUN, blood urea nitrogen; ESR, erythrocyte
sedimentation rate; WBCs, white blood cells.
clinical outcome.63 Increased immunoglobulin G (IgG)
index and oligoclonal bands have been reported, suggesting
that intrathecal immunoglobulin synthesis is increased.39,41
Elevated CD4:CD8 ratios of CSF lymphocytes have
been reported,64 as have elevations in lysozyme and
β-2-microglobulin.42
Imaging
MRI with gadolinium is the imaging study of choice. The
granulomatous lesions will enhance on T1 images with
gadolinium. MRIs performed without contrast may miss
the diagnosis of sarcoidosis.49 Lesions are usually well
defined, slightly hyperdense, and homogenously enhanc-
ing.42 Some lesions are quite large (Fig. 25-4), whereas
others may be very subtle. MRI is also helpful for moni-
toring the response of CNS lesions to treatment.51 A lack
of vascularity of sarcoid granulomas is seen on angiogra-
phy.47 CT scanning is typically less sensitive but may reveal
a large mass as shown in Figure 25-4.
Gallium-67 scanning can identify sites of inflammation
and may be useful in identifying asymptomatic lesions that
can be accessed for directed biopsy. Although the test can
be positive in any inflammatory or neoplastic lesions, the
identification of pulmonary lesions is relatively specific for
sarcoidosis.65
Treatment
Systemic steroids are the cornerstone of treatment for sar-
coidosis and neurosarcoidosis. Typically larger doses of
steroids are used with neurosarcoidosis, that is, 60 to 80 mg
methylprednisolone daily.42 Dosages should be tapered
carefully. In patients in whom corticosteroids may be con-
traindicated, other agents including methotrexate, aza-
thioprine, cyclosporine, chloroquine, hydroxychloroquine,
radiation, and other immunosuppressive drugs have been
used.66 In cases of acute hydrocephalus, expanding mass
lesions, and progressively worsening neurologic deficit
secondary to increased intracranial pressure unresponsive
to medical treatment, surgical intervention is recom-
mended for decompression.38,42
Outcomes
The hearing loss often improves with the initiation
of steroids. However, it may also be relapsing or chroni-
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-
sis without neurologic involvement. Patients with cranial
neuropathies and aseptic meningitis tend to do better, with
a greater than 90% recovery or improvement compared
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-
sarcoidosis is between 5% and 15%.40,41,64
SUPERFICIAL SIDEROSIS OF THE
CENTRAL NERVOUS SYSTEM
Introduction
Superficial siderosis of the CNS is a rare, but potentially
fatal, cause of SNHL.67 The disorder is caused by deposi-
tion of hemosiderin in the CNS secondary to recurrent or
persistent bleeding into the subarachnoid space.68–70 In the
past the diagnosis was officially made only at autopsy,67
whereas today the diagnosis is almost always made with
MRI. The cardinal clinical features of superficial siderosis
are progressive SNHL and cerebellar ataxia.68
Incidence
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
world literature.68 With the advent of MRI, the diagnosis
can be made more readily and even detect presymptomatic
cases. In one series, MRI findings consistent with the diag-
nosis of superficial siderosis were found in 0.15% of 8843
consecutive MR studies. Eighty-five percent of these
patients reported no symptoms.71 Superficial siderosis can
occur in any age group, with age of onset ranging between
14 and 77 years. Males are typically more commonly
affected than females (3:1).68
478 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
Etiology
The cause of superficial siderosis of the CNS is persistent
or recurrent bleeding into the subarachnoid space, leading
to a deposition of hemosiderin in the CNS. In a review
series of 63 patients, the bleeding site was identified in
54% of cases, whereas in 46% of patients the source of
bleeding remained unknown.68 In the cases in which the
site of bleeding was identified, the source was found to be
due to dural pathology (CSF cavity lesion or cervical root
lesion) in 47% of patients; a vascular tumor (ependymoma,
oligodendroglioma, and astrocytoma) in 35%; and a vas-
cular abnormality (arteriovenous malformation or
aneurysm) in 18% of patients.68 Systemic iron overloaded
conditions, such as hemachromatosis, do not typically lead
to iron excess in the CNS due to the blood-brain barrier
for iron.72
Pathophysiology
In superficial siderosis of the CNS, hemosiderin deposi-
tion is primarily seen in areas bathed by circulating CSF,
including the cerebellum, brainstem, and eighth nerve.
Chronic exposure of blood to the CSF leads to the break-
down of hemoglobin into ferritin and hemosiderin, which
accumulates in the microglia.73 Immunohistochemical
staining has shown that selective siderosis of the cerebel-
lum and eighth nerve is due to the biosynthesis of ferritin
in the microglia of these tissues.74 It has been postulated
that ferritin synthesis is neuroprotective by binding the
iron released into the CSF by the red cells and that tissue
damage occurs only after this reserve has been exhausted.75
A characteristic finding of superficial siderosis involving
the cranial nerves is preferential staining to the proximal
(glial) segments versus the distal (Schwann cell) seg-
ments.74 The eighth nerve, unlike the adjacent facial nerve,
retains its glial sheath up to the internal auditory canal
(IAC). This long glial segment makes the eighth nerve
particularly susceptible, resulting in a greater chance of
hemosiderin deposition and chance of axonal damage. In
addition, the location of the eighth nerve in the pontine
cistern exposes the nerve not only to a large pool of CSF,
but also a greater flow of CSF.68 Cranial nerve I is also
affected for similar reasons, and it is speculated that anos-
mia is underreported in association with siderosis.68
Pathology
Gross pathology of superficial siderosis reveals character-
istic light-brown staining of diffusely thickened and
fibrotic leptomeninges.76 The eighth nerve, and to a lesser
extent, cranial nerves I and II, are typically darkly pig-
mented secondary to a dense accumulation of hemosiderin
often associated with demyelination and atrophy.74
Hemosiderin deposition in the tissues, revealed by staining
with Prussian blue, is associated with demyelination, neu-
ronal loss, reactive gliosis, and the appearance of intra-
cellular rounded eosinophilic ovoid bodies.77,78 Ovoid
bodies represent degenerated axonal swellings caused by
heme-iron complexes, which catalyze lipid peroxidase
reactions, resulting in a local oxidative effect and neuroax-
onal dystrophy.79
Clinical Presentation
Prior to the onset of symptoms there is reported to be a
presymptomatic phase, in which superficial siderosis is
present, but not sufficient to cause symptoms. This phase
ranges from 4 months to 30 years, with a mean of 15 years.68
Clinically superficial siderosis of the CNS presents as a
distinct syndrome characterized by progressive SNHL
(95%), cerebellar ataxia (88%), and pyramidal signs (76%).
The pyramidal signs range from mild symptoms, such as
hyperreflexia, to severe symptoms of paraparesis and quadri-
paresis. Other symptoms include dementia (24%), bladder
disturbance (24%), anosmia (17%), anisocoria (10%), and
sensory signs (13%) (Table 25-3).68
The most common feature of superficial siderosis is
bilateral progressive SNHL, with the high frequencies
being more severely affected.68 The hearing loss may be
asymmetric and is typically retrocochlear, supported by
absence of stapedial reflexes and abnormal brainstem
evoked potentials.68 Takasaki and coworkers suggest that
there may also be damage to the cochlea due to the eleva-
tion of the detective threshold of CM and no response on
DPOAE in one patient.80 It is possible that damage to the
organ of Corti could occur by way of a patent cochlear
aqueduct.81 One case of a sudden bilateral profound hear-
ing loss occurring at the time of a subarachnoid hemor-
rhage has been reported.82
Vestibular function has been evaluated and reported in
only a few patients with superficial siderosis. In all of the
patients evaluated, the vestibulo-ocular reflex is absent or
diminished.77,83 Symptoms of vertigo and unsteadiness
reported by patients probably have a combination of
vestibular and cerebellar components.
History and Physical Exam
Patients presenting with SNHL with or without ataxia
should undergo a complete history and physical exam,
including a neurologic evaluation. Questions related
to history of head trauma recently or in the past,
headaches, change in sense of smell or vision, and
symptoms of imbalance should be included. During the
otolaryngologic exam, the patient’s sense of smell should
be tested.
Audiology
Audiometric testing includes pure tone audiometry, word
recognition, and stapedial reflexes. Further testing may
include ABRs or OAEs (or both). Vestibular testing
should be considered if patients report imbalance or
vertigo.
TABLE 25-3. Key Clinical Features of Superficial Siderosis
Progressive sensorineural hearing loss (95%)
Cerebellar ataxia (88%)
Pyramidal signs (hyperreflexia, paraparesis, quadriparesis) (76%)
Dementia (24%)
Bladder disturbance (24%)
Anosmia (17%)
Anisocoria (10%)
 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
T1-weighted images: Appear normal
T2-weighted images: Marginal hypointensity of brainstem, cerebrum,
cerebellum
is currently unknown whether the disease continues to
progress after the bleeding has been stopped. In most
cases, the disease is ultimately fatal, although it may
progress slowly over several decades. The mean survival of
reported cases is 11 years.68
480 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
IDIOPATHIC HYPERTROPHIC
PACHYMENINGITIS
Introduction
First described by Naffziger and Stern in 1949, idiopathic
hypertrophic pachymeningitis (IHCP) is a rare fibrosing
inflammatory process characterized by marked thickening
of the dura.86 The site of dural involvement can be subdi-
vided into intracranial, spinal, and craniospinal, with the
intracranial form being rarer than the spinal form. The
most common intracranial symptoms are headache, cranial
nerve palsies, and ataxia. Presenting symptoms may
include hearing loss and tinnitus or vertigo. IHCP is
a diagnosis of exclusion, since other clinical entities can
produce thickening of the meninges. The diagnosis is
made with biopsy and supported with characteristic MRI
findings.
Incidence and Etiology
The incidence and cause of IHCP are currently unknown.
Early reports of pachymeningitis were typically attributed
to syphilis or tuberculosis. Today, however, most reported
cases are idiopathic.87 The age at presentation in reported
cases ranges from 20 to 78 years, with a mean age of
51 years. The incidence is equal in males and females.87,88
The three main known causes of IHCP are sarcoidosis,
tuberculosis, and syphilis.89–91 Other infectious causes
include fungi and viruses, including human T-cell lym-
phoma virus-1 (HTLV-1).92 Autoimmune causes include
rheumatoid arthritis, Wegener’s granulomatosis, polyar-
teritis nodosa, and multifocal fibrosclerosis.91 Neoplastic
processes include lymphoma, plasmacytoma, meningioma,
and metastatic prostate cancer.89 IHCP has also been asso-
ciated with spontaneous intracranial hypotension93 and
dialysis.90 Spontaneous intracranial hypotension (SIH) is a
rare syndrome associated with low intracranial pressure
Pathology
Intense
inflammation
(less than 60 mm H2O) that occurs without an inciting
event, such as trauma or lumbar puncture. The clinical
course of SIH, unlike IHCP, is typically benign.93
Histopathology
Gross pathology of IHCP reveals an immensely thickened
and fibrotic dura. Histologic features are characterized by
a chronic nonspecific inflammatory infiltrate of lympho-
cytes, plasma cells, and histiocytes (Fig. 25-6).89,91
Granulomas may or may not be present.88 Chronic infec-
tious and neoplastic processes are absent. It has been
theorized that the symptoms of headache and cranial
neuropathies are secondary to nerve encasement and
ischemia due to the chronic inflammation and fibrosis of
the dura.88-90 Fibrosis may also cause occlusion of the venous
sinuses.94
Clinical Presentation
The clinical presentation of IHCP is extremely variable
and depends on the site of involvement of the dura. The
most common symptoms are a subacute or chronic local-
ized headache and single or multiple cranial neuropathies.
A review of 33 cases in the literature by Parney revealed
that the most commonly affected cranial nerve is the
eighth followed by the second cranial nerve.87 Symptoms
include asymmetrical SNHL, tinnitus, and vertigo. The
hearing loss may be sudden in onset.95 Symptoms also
include ataxia. In a review of their series, Hatano and
colleagues divided IHCP into two main sites of involve-
ment: (1) cavernous sinus to superior orbital fissure
involvement, affecting cranial nerves III, IV, V, and VI,
and (2) falcotentorial to posterior fossa dural involvement,
involving cranial nerves V, VII, VIII, IX, and X.89 IHCP
has also been associated with the Tolosa-Hunt syndrome
(painful ophthalmoplegia), optic neuropathy, and diabetes
insipidus.89
Giant cell
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
Infectious Tuberculosis, syphilis, fungal, HTLV-1
Autoimmune Rheumatoid arthritis, Wegener’s granulomatosis,
polyarteritis nodosa, multifocal fibrosclerosis
Neoplastic Lymphoma, plasmacytoma, meningioma, metastatic
prostate cancer
Other Sarcoidosis, spontaneous intracranial hypotension,
dialysis
HTLV-1, human T-cell lymphoma virus type I.
In cases with a positive PPD, but negative histologic exam
and cultures for tuberculosis (TB), a trial of anti-TB med-
ications may be warranted.87
Outcomes
Although the number of reported cases of IHCP has
recently increased with the advent of MRI, there is still
much to learn with regard to cause, incidence, treatment,
482 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
and long-term outcomes. Reported cases of IHCP reveal a
chronic clinical course. Patients may improve initially, but
many relapse and become steroid-dependent. Often the
disease progresses despite treatment.93,98 Otolaryngo-
logists should be aware that IHCP may present early as an
asymmetrical SNHL alone or with associated symptoms
and that screening procedures, such as fast spin-echo T2-
weighted MRI, may miss the diagnosis.
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 Chapter
Vestibular Neuritis
26 Outline
Joel A. Goebel, MD, FACS Introduction
Historical Background
Gerard Gianoli, BSE, MD
Pathophysiology
Clinical Features
INTRODUCTION
Vestibular neuritis (VN) is a clinical diagnosis made in
cases presenting with severe vertigo, nausea, and vomiting
in the absence of significant hearing loss or central nervous
system signs. Throughout the years, numerous names have
been used for this clinical picture, including epidemic ver-
tigo, neurolabyrinthitis epidemica, acute labyrinthitis,
vestibular paralysis, and vestibular neuronitis. As the name
implies, VN is thought to be caused by an inflammatory
condition of the vestibular nerve, although the exact cause
of the inflammation remains speculative. Even though the
clinical picture can be variable, certain key features in the
patient history and, to a lesser extent, the examination and
laboratory findings makes this diagnosis possible.
In the following sections, we will explore the historical
background of VN and the evolution of thought regarding
its pathophysiology and then discuss the main features of
the history, examination and laboratory findings. We will
then present current therapeutic options based on recent
evidence regarding anatomic considerations and probable
viral causes. Emphasis is placed on controversial issues
such as the exact nature of viral involvement, single versus
recurrent attacks, and the cause of selective superior versus
inferior vestibular nerve involvement.
HISTORICAL BACKGROUND
The first case of what might today be called VN was
reported in the literature in 1909 by Ruttin.1 In 1952, Dix
and Hallpike reported 100 cases with either single or mul-
tiple attacks of vertigo without hearing loss and com-
mented that canal paresis with caloric irrigation was
unilateral in 47% and bilateral in 53% of the cases. They
mentioned that all symptoms ceased within a few years
after diagnosis.2 Harrison (1962) studied 67 patients and
noted recurrent attacks up to seven years later in 29
patients.3 Lumio and Aho (1965) followed 27 patients for
at least 6 months and noted that all patients showed
complete recovery or only mild unsteadiness.4 Boffi (1965)
484
Diagnosis
Treatment
Prognosis
Future Directions
studied 85 cases and postulated a relationship between VN
and paroxysmal positional nystagmus.5
In 1956, a landmark article appeared by Lindsay and
Hemenway describing seven cases of acute vertigo without
hearing loss and the accompanying histopathologic
findings.6 In all seven cases, severe positional vertigo
developed after the initial prolonged attack and varying
degrees of superior vestibular nerve, lateral and superior
canal ampulla, and utricle damage was found with sparing
of the inferior vestibular nerve and posterior canal
ampulla. Although they postulated vascular occlusion of
the anterior vestibular artery as the probable cause in
one case, no direct evidence of occlusion was noted and a
viral cause was included in their differential diagnosis.
Schuknecht (1962) studied these cases and four additional
patients and postulated that the positional vertigo was
caused by loosened otoconia from the damaged utricle
stimulating the intact posterior canal ampulla.7 From
these two papers, it was suspected that, regardless of
cause, V N was a selective degenerative process that spared
the inferior vestibular nerve, posterior canal ampulla, and
saccule.
In 1981, Schuknecht and Kitamura described temporal
bone findings in patients with VN.8 In certain cases, selec-
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
evidence of arteriolar thrombus or intralabyrinthine hem-
orrhage was seen. They concluded that VN preferentially
damaged the superior vestibular nerve and corresponding
end-organs without offering a plausible explanation for
this selectivity. Furthermore, a viral cause was suspected in
this disorder, but no definitive direct evidence was noted
on histopathologic examination.
The presence of a latent viral infection in VN had been
suspected for many years before recent electron micro-
scopic techniques and polymerase chain reaction (PCR)
amplification became available. As noted earlier, Schuknecht
and Kitamura felt that the lack of vascular injury in their
specimens and a similarity in labyrinthine and neural
injury in three of their cases to a case of herpes zoster

Total atrophy
of ampullary
nerve fibers Atrophy of crista
Normal ampullary
Normal crista nerve fibers
Figure 26-1. Photomicrographs through sections of the superior vestibular
nerve and lateral semicircular canal ampulla in a patient with right vestibular
neuronitis. A, Right ear shows severe atrophic changes in both the nerve and
crista ampullaris. B, Left ear demonstrates normal nerve and end-organ
architecture. (Reprinted with permission from Schuknecht HF, Kitamura K.
Vestibular neuronitis. Ann Otol Rhinol Laryngol 78(Suppl):1–19, 1981.)
oticus described by Zajtchuk and colleagues was suggestive
for a viral cause.9 Friedman and House described an abun-
dance of lipofuscin inclusion bodies in Scarpa’s ganglion
cells in a case of clinical VN and felt that this may repre-
sent a “wear and tear” phenomenon following a viral infec-
tion.10 In similar fashion, Baloh and coworkers described
Scarpa’s ganglion cell loss in a patient with clinical vestibu-
lar neuritis and felt the changes were consistent with viral
infection even though electron microscopy or immuno-
histochemistry failed to demonstrate evidence of viral
particles.11 However, Furata and colleagues reported 6 of
10 temporal bones of patients with VN had herpes simplex
virus (HSV) particles identified by PCR.12 Arbusow and
coworkers studied evidence of HSV-1 infection in both
Scarpa’a ganglion and the geniculate ganglion and found
widespread distribution of the viral elements throughout
both ganglia. According to their study, serologic evidence
of primary exposure by HSV-1 can be found in more
than 80% of the adult population and has been identi-
fied in Scarpa’s ganglion in 60% of temporal bone speci-
mens by PCR.13 Historically, the evidence seems to
support a viral etiology for VN although by the strictest
definition a cause and effect relationship has not been
established.
As noted in the histopathologic studies of VN, a
predilection for superior vestibular nerve or related end-
organ structures is fascinating. Even the early observations
of Schuknecht and Kitamura that benign positional ver-
tigo frequently occurs following VN suggests that poste-
rior semicircular canal function is intact on the involved
side. Indeed, Fetter and colleagues used multiple-axis rota-
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
and anterior canal function on the same side were vari-
ably reduced.14 In some instances, however, either all
canal function or, rarely, only posterior canal function
is affected. In most cases, however, it appears that VN
Vestibular Neuritis 485
affects the superior vestibular nerve and related labyrin-
thine receptors.
PATHOPHYSIOLOGY
Since the diagnosis of vestibular neuritis is clinical rather
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
most likely viral due to the pattern of hair cell loss and
fibrosis and the lack of any arterial or venous occlu-
sion seen on temporal bone microscopic examination.
Subsequent reports have supported the presence of viral
particles in Scarpa’s ganglion in temporal bones of patients
with and without a clinical history of VN but have failed
to definitively prove that these viral particles are the
cause of the clinical picture rather than a coincidental
bystander. There is, however, enough compelling immuno-
histochemical evidence in support of viral ganglionitis
(especially HSV-1) as the cause of VN to make it the
leading hypothesis.
Two puzzling observations about VN require further
investigation—that is, (1) why the superior vestibular nerve
and its end-organs are more often affected than the inferior
vestibular nerve, posterior canal, and saccule and (2) why
the amount of histologic injury varies widely from case to
case. One theory states that VN is caused by a selective
viral ganglionitis that only affects superior vestibular nerve
cells.15 However, because no anatomic barrier exists within
the ganglion to prevent viral spread between cells, this
explanation seems unrealistic Arbusow and coworkers pro-
posed a dual innervation of the posterior canal ampullae via
separate bony channels to explain sparing of posterior canal
function. Recently, Goebel and colleagues and Gianoli and
coworkers proposed anatomic differences in the length,
trabeculation, and arteriolar channels between the superior
and inferior vestibular nerve bony paths to explain selective
superior nerve and end-organ injury.16 Both studies con-
firmed a longer, narrower, more trabeculated bony path for
the superior vestibular nerve compared with either the
inferior vestibular or singular nerves in normal temporal
bones (Fig. 26-2). They hypothesized that VN causes neu-
ral edema and subsequent entrapment and possible
ischemia of the superior more than inferior nerve and end-
organ structures. This theory also accounts for milder cases
with more complete recovery of function (no permanent
ischemic changes) and more severe cases with loss of
canal and otolith function. It must be noted, however, that
no study to date has documented definitive evidence of
vascular compromise.
CLINICAL FEATURES
Typically, vestibular neuritis begins with an abrupt onset of
vertigo accompanied by nausea and vomiting. In some
instances, the onset of the attack is less dramatic with an
486 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
A to a combination of the extent of end-organ damage and
B
Figure 26-2. Photomicrographs of sections through the labyrinth and
internal auditory canal in a normal temporal bone specimen. A, Superior
vestibular nerve and canal. A denotes lateral semicircular canal crista,
B superior vestibular nerve, C arteriole of superior vestibular nerve, 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
the canal, C the arteriole within the canal, and D posterior canal ampulla.
Note the shorter course and looser trabeculation compared with part A.
(Reprinted with permission from Goebel J, O’Mara W, Gianoli G. Anatomic
considerations in vestibular neuritis. Otol Neurotol 22:512–518, 2001.)
antecedent period of vague dizziness and nausea. Many
times the initial episode awakens the patient at night or is
first noticed when they get out of bed. The vertigo may
wax and wane but is present in all head positions. Most
patients feel better lying flat and still, although some pre-
fer to sit upright during the episodes. In all cases, head
movement exacerbates the vertigo and nausea. Sometimes
there is a history of upper respiratory infection or even
influenza preceding the attack, but this is not a predictable
historical finding. What is remarkable, however, is the
absence of auditory or central nervous system signs and
symptoms. In a minority of cases, unilateral tinnitus may
be present and audiometry may document a high-fre-
quency hearing loss. There is no loss of consciousness,
memory loss, or motor or sensory deficits that might be
seen in brainstem ischemia or infarction. The time course
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
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.
DIAGNOSIS
The diagnosis of VN is made by a typical history and
exclusion of other causes of sudden loss of unilateral
vestibular input. At times, the diagnosis of VN is difficult
because many other recurrent vestibular pathologies can
mimic VN at their onset. For example, the initial episode
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,
however, these entities can usually be identified by the
natural course and progression of the disease. In general,
VN is typically a single severe episode of vertigo without
involvement of the auditory system, whereas the other
entities tend to be recurrent vestibulopathies and may have
auditory involvement at some point as the disease pro-
gresses. However, some cases of VN involve recurrent
bouts of vertigo and can only be distinguished from other
causes by the lack of hearing loss or any central nervous
system signs or symptoms after a thorough investigation.
The typical history of VN includes the abrupt onset of
severe rotary vertigo associated with nausea, vomiting, and
diaphoresis. There are typically no auditory symptoms to
localize the lesion. There may be a history of a prior cold
or upper respiratory infection in the days or weeks prior
to the onset of the acute vertigo. During the attack, the

patient prefers to sit or lie perfectly still to minimize nausea.
There should be no neurologic symptoms, such as blurred
or double vision, dysarthria, dysphagia, or alterations in con-
sciousness. Vomiting is common and may be severe enough
to require hospitalization and intravenous fluids. Very often
the patient will be convinced that he is having a stroke or a
heart attack, precipitating a visit to the emergency room.
The length of the initial vertigo spell is usually a few hours
with a lingering disequilibrium for days to weeks. During
the recovery phase, the patient usually notes symptoms
brought on mainly by quick head movements, particularly to
the affected side. The patient may feel off balance for several
months after the incident and in some cases may have symp-
toms persist for years. Additionally, it is not uncommon for
patients to develop BPPV after a bout of VN.
Physical examination during the acute phase of VN will
demonstrate a brisk horizontal-rotary nystagmus with the
fast phase beating to the uninvolved side, implying
involvement of semicircular canals in both the horizontal
and vertical planes. Removal of fixation by using Frenzel
lenses intensifies the nystagmus. An otherwise normal
neurologic exam and the ability to stand unassisted with-
out lateropulsion is important in distinguishing VN from
an acute cerebellar hemorrhage or infarct. Imaging studies
are usually normal, but high-resolution MRI with gadolin-
ium may show enhancement of the eighth cranial nerve.
Oculographic studies are usually not indicated during the
initial episode but may demonstrate either unilateral or
bilateral caloric reduction and a lingering nystagmus with-
out fixation. If the extent of vestibular injury is substantial,
the patient may exhibit refixation saccades on unilateral
head thrust toward the affected ear even months to years
following the initial episode.
In most cases, the patient with VN experiences a single
episode of vertigo lasting up to a day and recovers com-
pletely over a few weeks. Some cases with documented
severe vestibular loss may experience poor compensation
and lingering dysequilibrium. Finally, in a few cases of
suspected VN the vertigo attacks recur although usually
in diminishing intensity.
The key features of VN and common vestibular disor-
ders in the differential diagnosis are listed in Table 26-1.
TREATMENT
Medical management of VN can be divided into acute treat-
ment, chronic treatment, and treatment of concomitant
TABLE 26-1. Comparison of Vestibular Neuritis with Other Common Labyrinthine Disorders
Vestibular Neuritis Labyrinthitis
Onset Abrupt Abrupt
Duration Hours Hours
Intensity Severe Severe
Hearing loss None Severe
Recurrence Possible None
Treatment Suppressants Suppressants
Steroids Steroids
BPPV, benign paroxysmal positioning vertigo; CRP, Canalith Repositioning Procedure; RT, Radiation Therapy.
Vestibular Neuritis 487
BPPV. The conventional treatment of acute-onset VN is
supportive care—antiemetics, hydration, and judicious use
of vestibular-suppressant medications. In mild cases,
meclizine 25 mg PO tid is sufficient, whereas severe cases
may benefit more from diazepam either orally or par-
enterally to suppress vertigo and nausea. Inpatient admis-
sion may be justified in some cases due to the severity of
vomiting and dehydration. Although vestibular suppres-
sants may benefit the patient during the acute phase
of the disease, long-term use of these medications may
actually delay central compensation by masking ongoing
symptoms. Consequently, tapering of vestibular suppres-
sants should be done as soon as possible after the onset of
VN—usually within a week. There is also some evidence
that early use of corticosteroids in VN may reduce the
intensity and duration of the vertigo and may actually
improve overall recovery of function.17 Finally, since VN
is felt to be viral in origin, there is a theoretical basis for
using antiviral agents early in the disease process although
no studies have confirmed their efficacy.
Chronic treatment of VN should start soon after the
diagnosis is made. Vestibular rehabilitation therapy with or
without assistance of a therapist should begin once the
patient has been stabilized to help speed central compensa-
tion. Exercises that reinforce the vestibulo-ocular reflex and
ambulation should be encouraged. Vestibular-suppressant
medications should be tapered to prevent symptom masking
during central compensation. Most patients will note signif-
icant improvement in their symptoms within the first sev-
eral weeks. However, some symptoms may persist for many
months and in some severe cases indefinitely. Persistent
symptoms may include disequilibrium with fast head
movement, particularly when turning to the affected side.
As noted earlier, the appearance of BPPV following the
initial episode of VN is not uncommon. Treatment of
concomitant BPPV is probably best delayed until the
patient has resolved the most severe symptoms of VN.
Canalith repositioning with the Epley or Semont maneu-
vers usually suffice as treatment. Treatment of concomi-
tant BPPV is mandatory to enhance the patient’s chances
for full central compensation.
Once satisfactory central compensation has occurred,
some patients may exhibit “decompensation.” Typically
when patients are fatigued or under physical or emotional
stress they may exhibit an exacerbation of movement-
induced disequilibrium. This will resolve when the fatigue
or physical/emotional stress has resolved. Vestibular exer-
cises may mitigate these symptoms. Vestibular suppressants
Ménière’s Disease BPPV Acoustic Neuroma
Variable Abrupt Slow
Minutes Seconds Days
Variable Variable Mild
Variable None Variable
Yes Yes Possible
Suppressants CRP Surgery
Diet, diuretic Observation
Gamma RT
488 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
usually do not help and may exacerbate these symptoms.
A Dix-Hallpike exam should be performed during these
episodes to ensure these symptoms are not secondary
to BPPV.
PROGNOSIS
In most cases, VN is a benign self-limited process with an
excellent prognosis once the patient recovers from the ini-
tial attack. Recovery of balance is generally complete, and
alteration of lifestyle is not necessary. In some cases, how-
ever, lingering disequilibrium is disturbing and requires
ongoing exercise therapy and modification of daily activi-
ties. If BPPV develops, it may be recurrent, and reposition-
ing maneuvers may be needed from time to time. Finally,
in a few instances, recurrent vertigo attacks develop and
require suppressant therapy.
FUTURE DIRECTIONS
As the cause and pathophysiology of VN becomes more
clearly known, interventional therapy will be aimed at
reducing the ultimate amount of injury to the vestibular
nerve and end-organ. Clinical trials are necessary to deter-
mine the utility of corticosteroid and antiviral therapy
early in the course of the disease. Specific virus identifica-
tion in Scarpa’s ganglion and end-organ tissues in cases of
VN will enhance our understanding of whether direct cel-
lular injury or indirect neural and end-organ damage sec-
ondary to edema and ischemia is the mechanism of injury.
REFERENCES
1. Ruttin B: Zur Differentialdiagnose der Labyrinth-u.
Hornervekrankungen. Z Ohrenheilkd 57:327–331, 1909.
2. Dix M, Hallpike C: The pathology, symptomatology and diagnosis
of certain disorders of the vestibular system. Ann Otol 61:987–1016,
1952.
3. Harrison M: Epidemic vertigo-vestibular neuronitis: A clinical
study. Brain 85:613–620, 1962.
4. Lumio J, Aho J: Vestibular neuronitis. Ann Otol Rhinol Laryngol
74:264–270. 1965.
5. Boffi A: Positional nystagmus and vertigo in vestibular neuronitis.
Laryngoscope 75:484–490, 1965.
6. Lindsay JR, Hemenway WG: Postural vertigo due to unilateral
partial vestibular loss. Ann Otol 65:692–708, 1956.
7. Schuknecht HF: Positional vertigo: Clinical and experimental
observations. Trans Am Acad Opthalmol Otolaryngol 66:319–331,
1962.
8. Schuknecht HF, Kitamura K: Vestibular neuronitis. Ann Otol
Rhinol Laryngol 78(Suppl):1–19, 1981.
9. Zajtchuk JT, Matz GJ, Lindsay JR: Temporal bone pathology in
herpes oticus. Ann Otol Rhinol Laryngol 81:331–339, 1972.
10. Friedmann I, House W: Vestibular neuronitis—Electron microscopy
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,
1996.
12. Furata Y, Takasu T, Fukada S, et al: Latent herpes simplex virus
type I in human vestibular ganglia. Acta Otolaryngol (Stockh) 519
(Suppl):93–96, 1995.
13. Arbusow V, Schulz P, Strupp M, et al: Distribution of herpes simplex
virus type I in human geniculate ganglia; Implications for vestibular
neuritis. Ann Neurol 46:416–419, 1999.
14. Fetter M, Dichgans J: Vestibular neuritis spares the inferior division
of the vestibular nerve. Brain 119:755–763, 1996.
15. Gacek R, Gacek M: The three faces of vestibular ganglionitis. Ann
Otol Rhinol Laryngol 111:103–114, 2002.
16. Goebel J, O’Mara W, Gianoli G: Anatomic considerations in
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:
1059–106, 2001.

Otologic and Neurotologic
Sequelae of Meningitis
Outline
Introduction
Epidemiology
Microbiology
Pathophysiology and
Histopathology
Signs and Symptoms
INTRODUCTION
Meningitis is a major cause of sensorineural hearing loss in
both the pediatric and adult populations. Despite recent
advancements in its prevention, diagnosis, and treatment,
it is still associated with significant neurologic morbidi-
ties and mortality. Meningitis remains a major cause of
sensorineural hearing loss.1–3 The effect of meningitis on
hearing is primarily a direct effect of infection in the inner
ear, but compromise of any structures along the auditory
pathway of the central nervous system may also play a role.
The importance of understanding the disease process is
critical to the neurotologist since cochlear implantation has
assumed a prominent role in the treatment of postmeningitic
sensorineural hearing loss.4
Although the incidence of bacterial meningitis has
significantly decreased since the implementation of conju-
gate Haemophilus influenzae type b vaccine, other forms of
bacterial meningitis are still prevalent and are associated
with high rates of deafness. Rates of hearing loss have been
reported in up to 40% of children with meningitis.2,5,6
Also, as the number of immunocompromised individuals
continues to increase, deafness associated with viral and
fungal meningitis are increasing in prevalence.
The influence of meningitis on speech and language are
amplified in prelingually deafened children. A major prob-
lem associated with postmeningitic hearing loss is the diffi-
culty of identifying the condition in a young child. Optimum
diagnosis and treatment of meningitis continues to change
with medical advancements. Once meningitis is diagnosed,
the choice of antibiotics becomes a critical decision for
the physician and family. In addition, the adjunctive use
of steroids continues to be hotly debated. Identification of
hearing loss can lead to earlier intervention, such as hearing
aid selection and cochlear implantation. Since the degree of
cochlear pathology at the time of surgery has surgical and
prognostic implications for patients who receive cochlear
implants, early coordination with a cochlear implant team is
essential if there is a profound bilateral hearing loss.
Chapter
27
Other Neurologic Alexis H. Jackman, MD
Abnormalities
David R. Edelstein, MD
Testing
Treatment
Conclusion
EPIDEMIOLOGY
The development and widespread use of H. influenzae type b
vaccine has greatly altered epidemiologic patterns
of meningitis. Consequently, the epidemiology of post-
meningitic hearing loss reflects this change, yet its impact
remains. Wolff and Brown noted in a 1987 study that
9% of children enrolled in special education programs
suffered from hearing loss–associated meningitis.3
Presently, meningitis-associated hearing loss is a common
indication for cochlear implantation.7
Several types of meningitis exist and the probability of
developing a sensorineural hearing loss can often be pre-
dicted based the etiology of the disease. Hearing loss is
most often attributed to the bacterial form of the disease.
Furthermore, the probability of developing a sensorineural
hearing loss has been shown to differ among bacterial
organisms, Streptococcus pneumoniae having the highest
reported incidence of hearing loss.8 Although fungal menin-
gitis rarely occurs, it has been reported to have as high as
43% chance of causing significant hearing loss; whereas,
viral meningitis, the most common form of meningitis, is
associated with a low rate of hearing loss.9–11
The reported incidence of hearing loss associated with
bacterial meningitis has varied over the past 40 years. A
major retrospective study in 1978 by Nadol reported that
6% of the 547 participants exhibited hearing loss after
meningitis.11 Whereas, Rosenhall and Kankkunen in 1981
reported 30% of the 270 participants developed hearing
loss after meningitis.12 A recent meta-analysis of 45 studies
with a total of 4920 cases of pediatric meningitis reported
hearing loss in 11% of patients, with a severe to profound
sensorineural hearing loss of 5%.13 Other studies have
reported the percentage of significant hearing loss due
to meningitis to be as low as 6% and as high as 40%
(Table 27-1). This variation in incidence has been attributed
to several factors such as biases in the data collection, sample
size, geographic location, and screening for effects of
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
survivors. Despite advances in treatment, there is still a sig-
nificant incidence of mortality. A study from Bowman Gray
showed the death rate to be 12% in patients with acute
meningitis and 31% in a smaller group with chronic
meningitis.14 In 1995, the case fatality rate for bacterial
meningitis in the United States ranged from 6% for
H. influenzae to 21% for S. pneumoniae (Table 27-2).15 In
contrast, a recent Canadian study of acute bacterial menin-
gitis in adults in 2000 reported a mortality rate of 18%. In
this study, the highest meningitis-related mortality was
seen with Listeria monocytogenes of 40% followed by a rate
24% with S. pneumoniae.16 There is a strong possibility that
this subgroup would have experienced a high incidence of
hearing loss and other neurologic sequelae if these patients
had survived.
Another reason for possible underreporting of meningitis-
related hearing loss is unidentified unilateral hearing loss.
The incidence of unilateral and bilateral meningitis has also
varied in several studies. Henneford and Lindsay reported
a 5% incidence of bilateral hearing loss versus Nadol’s
reporting a 77% incidence of bilateral hearing loss.11,17
This loss often remains undetected unless the affected ear
or the contralateral ear undergoes additional otologic insult
that necessitates hearing testing.
The effect of the patient’s age on the incidence of
meningitis-associated hearing loss is also debated. Twenty-
one percent of children older than 2.5 years exhibited a
sensorineural hearing loss compared with only 5% of chil-
dren younger than 2.5 years.11 Similarly, Vernon reported a
high incidence of multiple neurologic sequelae in addition
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.

who contracted meningitis.2 However, Ozdamar, Kraus,
and Stein found a lack of statistical significance to age or
prematurity on the probability of developing a hearing loss
after meningitis.18
There is some question as to the correlation of sex with
the incidence of hearing loss. Keane and colleagues, for
example, reported a male preponderance of 1.4 to 1 in the
younger than 1 age group.19 Similarly, in Vernon’s classic
study boys outnumber the girls 82 to 32.2 Feigin and
colleagues also reported a male-to-female ratio of 62% to
38%.20 In contrast, however, Nadol, Ozdamar, and others
have not confirmed this sex distribution, nor has any other
researcher proposed a convincing explanation for such a
sex-related pattern of hearing loss.11,21
MICROBIOLOGY
Meningitis may be caused by many bacterial and fungal
organisms as well as by several viral strains. Historically,
meningitis was a disease of infancy and childhood and
was most commonly due to bacterial organisms such as
H. influenzae and S. pneumoniae. Other well-known causes
of bacterial meningitis include Neisseria meningitidis,
L. monocytogenes, Staphylococcus aureus, and group B strep-
tococcus. The relative importance of different pathogens
among various age groups continues to be seen in popula-
tion studies, but the predominance of various organisms
within these groups has changed in the recent past.
Twenty years ago, H. influenzae type b (HiB) meningitis
developed in 1 in 200 children younger than 5 years and
accounted for 70% of bacterial meningitis in this age
group.22 In December 1987, HiB conjugate vaccines were
licensed for routine use. Its widespread use in preschool-
age children has lead to dramatic declines in diseases
caused by HiB, reportedly up to 94%, and the hope for
eradication of the disease due to HiB now seems an attain-
able goal.23 Consequently, infants and children, the group
HiB most affected, are no longer the age groups most
commonly associated with meningitis and meningitis-
related hearing loss.
In a multistate surveillance study of bacterial meningitis
in 1995, the median age of patients with bacterial menin-
gitis had risen from 15 months in 1986 to 25 years, and
S. pneumoniae replaced H. influenzae as the most common
pathogen. The most prevalent pathogen in neonatal menin-
gitis remained Streptococcus agalactiae (group B streptococ-
cus). However, in infants 1 to 23 months old, S. pneumoniae
and N. meningitidis have replaced H. influenzae as the
predominant organism in this age group, accounting for
45% and 31% of cases, respectively. N. meningitidis has also
replaced H. influenzae as the most common pathogen in the
2 to 18 years age group and N. meningitidis was reported
to cause of 59% cases in this age group. In the over 19 age
group, S. pneumoniae was the most common bacteria
(62% of cases).15 It is also important to consider less com-
mon causes of meningitis, which may have a regional or
seasonal occurrence such as Lyme neuroborreliosis.24
Neuroborreliosis presenting as encephalitis or meningitis
is more common in the European form of this disease.
The incidence of L. monocytogenes is increasing in inci-
dence with up to 12.5% of adult cases caused by this
Otologic and Neurotologic Sequelae of Meningitis 491
organism, making it now the fourth most common cause
of meningitis in adults.25 Its prevalence among patients
who have deficits in cell-related immunity, such as in
patients with human immune deficiency syndrome or hema-
tologic abnormalities, has been noted.26,27 As the number of
immunocompromised individuals increases, more cases of
viral and fungal meningitis and meningitis-related hearing
loss are being reported. Postviral meningitis–associated
hearing loss, although not as common as bacterial-associated
hearing loss, does occur. The neurotropic nature of viruses
such as herpes simplex and human immunodeficiency virus
(HIV) are well known and their presence in the cochlea
and the eighth cranial nerve has been demonstrated.28
PATHOPHYSIOLOGY AND
HISTOPATHOLOGY
The most prevalent etiology of hearing loss associated
with meningitis results from an inflammatory labyrinthitis
initiated by an infectious pathogen via the cochlear aqueduct.
The inflammatory infiltrate is then replaced by fibrous
tissue and cellular debris, and subsequently, neoossification
within the cochlea occurs. The end result, termed cochlear
ossificans or labyrinthitis ossificans, is the pathological hall-
mark of meningitis-related sensorineural hearing loss.
Several authors have reported on histopathologic
changes in the temporal bone after meningitis. Schuknecht
presented seven cases of pneumococcal meningitis that
caused a variety of pathologic findings including widespread
inflammation of the pneumatized spaces of the temporal
bone, large pacchionian bodies in the posterior cranial
fossa extending into the mastoid, and a suppurative
labyrinthitis with pus in the cochlear aqueduct and
vestibule.29 Igarashi described destruction of the stria vas-
cularis and massive hemorrhage in the cochlear duct. He
postulated that primary bacterial endolymphatic involve-
ment could occur not only in suppurative labyrinthitis but
also in the serous form via destruction of local vessels. He
highlighted the presence of large amounts of inflammatory
cells along all the nerves of the internal auditory canal.
Inflammation was noted in the spiral ganglion cells, the
loose perivascular tissue, the modiolus, and directly in the
endolymphatic space via Reissner’s membrane or the base-
ment membrane.30,31
Keithley and Harris demonstrated the sequential cellular
changes in the cochlea in response to a viral pathogen in
animal models. Lymphocytes, macrophages, and polymor-
phonuclear cells and other inflammatory cells entered the
cochlea and caused variable degrees of structural damage,
although hair cells were identified. Later changes in the
cochlea included fibrotic tissue, blood vessels, and ectopic
bone, which was shown to persist even after the viral
particles were cleared.32 Similar cellular changes have been
seen in response to bacterial meningitis in an animal
model using S. pneumoniae. Evidence for bacterial spread
via the cochlear aqueduct in meningitis was also demon-
strated as the most intense inflammatory response and
greatest amount of ossification occurred in the scala tym-
pani of the basal turn of the cochlea, where the cochlear
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.)

Figure 27-3. A larger view of the anterior basal turn showing pus in the two
scalae. (From Gary N, Powers N, Todd JK: Clinical identification and
comparative prognosis of high-risk patients with H. influenzae meningitis.
Am J Dis Child 143:307, 1989.)
intracranial complications as meningitis, brain abscess,
otic hydrocephalus, lateral sinus thrombosis, and subdural
abscess. The common symptoms of meningitis include
stiff neck, abnormal vision (blurring and diplopia), tremor,
ataxia, and seizures. Common signs that should be investi-
gated include papilledema, dysmetria, hemianopsia,
abnormal eye movements, abnormal Romberg and gait,
and other neurologic abnormalities.43
In a paper from the Children’s Hospital of Denver, a
system called the Herson-Todd scoring method was
devised to predict hearing loss in certain high-risk patients
with meningitis due to H. influenzae (see Table 27-3). The
criteria included coma, hypothermia, seizures, shock, age,
cerebrospinal fluid (CSF) white blood cell count, hemo-
globin CSF glucose, and symptoms lasting more than
3 days. Outcome parameters included cognitive, motor,
clinical, speech, hearing, and visual factors.44,45 All of these
factors should be documented in the patient’s record.
The most common type of hearing loss following
meningitis is a sensorineural loss, although a conductive
component may be present initially due to concurrent
Figure 27-4. High-power view of the organ of Corti demonstrating its
disintegration as well as some changes in the stria vascularis.
Otologic and Neurotologic Sequelae of Meningitis 493
Figure 27-5. Pus in the internal auditory canal. There are some fibrotic
changes and inflammatory cells in the scala media.
middle ear disease. Ozdamar, Kraus, and Stein found that
64% of patients with meningitis had normal or borderline
hearing, 16% had a conductive loss, and 22% had a sen-
sorineural hearing loss.18 Predictably, conductive hearing
loss was largely related to the presence of otitis media.
A correlation analysis revealed the presence of a sen-
sorineural hearing loss to be statistically related to both the
pathogen involved and a hospitalization longer than 14 days.
Similarly, Borkowski and colleagues reported on a group
of 94 children with meningitis in which 44% had normal
hearing, 18% had a sensorineural hearing loss, 17% had a
conductive hearing loss, 11% had mixed losses, 9% had
retrocochlear pathology, and 1% were identified as other
or unknown.46
Fluctuating and delayed hearing loss have both been
described by Rosenhall and Kankkunen.12 In a series of
327 patients followed for 3 years, Trolle found no cases of
fluctuating hearing.47 However, in a series of 236 patients
followed for 6 months, Guiscafre and colleagues found
28 patients with fluctuations in their sensorineural hearing
loss.41 Vienny and colleagues also found in their series that
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
vestibuli. The inflammatory cells are scattered among the ganglion cells and
in the adjacent tissue.
494 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
Figure 27-7. This auditory nerve has been invaded by many purulent cells.
changes, and only 10% had early and persistent hearing
loss.48 Similar findings have been recorded by several
other authors.18 Rosenhall and Kankkunen reported cases
of delayed hearing loss after a normal hearing interval
between 6 and 12 months.12
Several configurations of hearing loss have been
reported. In Brookhauser’s series, 53% of the children
with meningitis had a sensorineural hearing loss, of which
83% had a bilateral profound hearing loss, 14% had a
moderate hearing loss, and 3% had a mild hearing loss. In
the better hearing ear, there was fairly even distribution of
sharply sloping flat, through-shaped, and rising hearing.49
In Vernon’s classic work on prematurity and deafness, he
compared the various causes of deafness and found meningi-
tis to result in the largest average level of hearing loss (93 dB)
compared with such other causes as genetics (88 dB), prema-
turity (83 dB), rubella (82 dB), and kernicterus (76 dB).2
OTHER NEUROLOGIC ABNORMALITIES
Before the introduction of antibiotics, up to 60% of the
children with meningitis developed either brain damage or
some other form of serious neurologic dysfunction.1 Since
the 1950s, the incidence of neurologic sequelae after
meningitis has ranged from 10% to 30%.50 The major
neurologic sequelae include retardation, seizures, and
TABLE 27-3. Scoring System for Prediction of Morbidity
in H. Influenzae Meningitis
Factor at Admission
Severe coma
Hypothermia
Seizures
Shock
Age <12 months
CSF white blood cell count <1000 × 10/L
Hemoglobin <110 g/L
CSF glucose <1.1 mmol/L
Symptoms persisting >3 days
From Gary N, Powers N, Todd JK: Clinical identification and comparative prognosis of
high-risk patients with H. influenzae meningitis. Am J Dis Child 143:307, 1989.
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
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
meningitis with rates of up to 31%. Seizures included both
generalized and focal and several patients experienced
prolonged episodes of status epilepticus.53
Ataxia and other symptoms of vestibular dysfunction
have also been described as a both short- and long-term
sequelae of meningitis. Farmer in 1945 reported on unilat-
eral and bilateral vestibular involvement in children with
meningococcal meningitis.54 Schwartz reported several
children who had ataxia before treatment and two who
developed ataxia without other vestibular abnormalities.55
The ataxia was most likely cerebellar. Some of these patients
could have also developed ataxia due to use of streptomycin.
In one series, eight children with postmeningitic ataxia were
reported. Of the seven children who were tested, electronys-
tagmography was abnormal in three, and all of the children
had a gradual improvement in their ataxia.56 Lindberg and
colleagues reported that 12% of the 82 children in their
study developed temporary ataxia.57
Several other cranial neuropathies have been reported.
Dodge and Swartz best described the many focal signs of
cerebral dysfunction. Among the 147 cases in their study
were 3 cases of dysphagia, 8 cases of disconjugate gaze,
3 cases of visual defects, 10 episodes of hemiparesis, and
6 cases of paraplegia. Many of these complications may be
due to multiple factors including heightened intracranial
pressure, generalized cerebral swelling, and purulent
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
reported to affect between 15% and 71% of meningitis
patients. The percentage of deafness associated with other
Points major neurologic problems was reported by Vernon to be as
high as 28%. These associated problems included cerebral
3 palsy, aphasia, mental retardation, and emotional distur-
2 bances. The prevalence of multiple disturbances was as
2
1
high as 38%. He reported that children younger than 1 year
1 were most susceptible to these sequelae and that 35% of
1 postmeningitic deaf children had an IQ level lower than 90.2
1 Sell and colleagues in 1971 attempted to study two groups
0.5 of children: one with meningitis and a second matched pair
0.5
or a near-age sibling. They found that based on several test
methods, the postmeningitic child had a greater chance of
having a low IQ and other psychological sequelae.58

TESTING
Patients with meningitis usually undergo many tests during
their hospital stay. The normal workup includes a physical
examination, lumbar puncture, multiple blood tests, and a
basic neurologic and infectious disease review. In a recent
study of adult bacterial meningitis in 100 patients, Huessein
and colleagues found almost all patients (97%) presented
with fever higher than 37.7°C, 87% of patients had nuchal
rigidity, and 51% had a decreased level of consciousness.16
Radiographs and magnetic resonance imaging (MRI) may
help to identify the source of infection and possible
intracranial complications. However, computed tomography
(CT) scans do not yield additional information useful in
prognosticating the outcome of the disease.59
Hearing tests should be performed as soon as the patient
has been stabilized. Unfortunately, audiograms are often
delayed to end of the hospitalization because of the needs
of these sick children in the intensive care unit. Follow-up
audiograms are just as important as the initial studies. Tests
should be performed promptly if there is a questionable
hearing loss. After hospital discharge, hearing tests should
be repeated every 3 to 6 months until hearing has stabilized
because both delayed deterioration and recovery of hearing
are possible.12
One challenge of otologists is assessing the neonatal or
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
localize the side of loss and can miss significant fluctuations
in hearing. In 1971, Jewett and Williston suggested the use
of ABR testing as a major advance in testing young children
or patients with serious neurologic damage who would not
comply with the usual audiometric protocols.60 Thresholds
in the higher frequencies are similar in the traditional click-
specific ABR. In these tests, wave 1 may be used to monitor
the integrity of the auditory nerve with the remaining
waves monitoring the brainstem auditory pathway. Absolute
latencies, interwave latencies, and latency shifts can be
used to identify cochlear pathology, hypoxic encephalopathy,
intracranial hemorrhages, demyelination, and other brain-
stem abnormalities.61,62
Several authors have used ABR tests to monitor hearing
loss in their patients with meningitis. In 1981, Finitzo-
Hieber, Simhardi, and Hieber demonstrated the importance
of using ABR by identifying 14% more children suffering
from unilateral hearing loss following meningitis than
would have been identified by standard audiometric tech-
niques.6 Similarly, by using ABR, Ozdamar, Kraus, and
Stein were able to identify hearing abnormalities in 37%
of children included in the 1983 study. Of this group, 15%
had conductive hearing loss and 22% had sensorineural
hearing loss (10% had brainstem neuropathology).18 In
1984, Vienny and colleagues studied 51 children prospec-
tively with ABR; 69% had normal recordings, 22%
showed transient abnormalities, and 9% had persistent
auditory pathology.48 MacDonald and Feinstein in 1984
found a 62% agreement between standard conditioned
orienting response testing (COR) and ABR. They con-
cluded that ABR was more effective than COR for testing
infants younger than 6 months, children with significant
handicaps, and patients with unilateral hearing loss. They
Otologic and Neurotologic Sequelae of Meningitis 495
recommended that ABR tests be performed either when
the child is recovering or at least 1 week following the
beginning of the antibiotic therapy.62
One limitation of traditional click-stimulus ABR is an
inability to identify hearing loss in the low- or middle-range
frequencies. In 1988, Brookhauser, Auslander, and Meskan
highlighted this conflict. They noted that postmeningitic
hearing loss could have a “wide array of audiometric con-
figurations,” not all of which could be easily outlined by
ABR.49 Frequency-specific ABR and pure tone audiograms
become critical in these patients. They also emphasized
the importance of the audiologist’s impressions regarding
the test reliability in determining the type of test and repeti-
tion of testing necessary per patient. Newer techniques
using otoacoustic emission testing may also be helpful with
the young or uncooperative child or infant.
If the patient has been identified as a potential cochlear
implant candidate, additional radiographic testing is usually
requested. Although high-resolution computed tomography
(HRCT) is traditionally used in cochlear implantation, a
high-resolution fast spin-echo T2-weighted MRI scan of
the temporal bone has been shown to be advantageous in
postmeningitic patients for its ability to detect cochlear
fibrosis, which can be undetected by HRCT.63 Therefore,
a temporal bone MRI is often part of the preoperative
workup in postmeningitic patients.
TREATMENT
Children with meningitis may present with either a mild
febrile illness with neck stiffness or a profound illness with
seizures, coma, and disseminated intravascular coagulation.
Both groups need aggressive treatment and intensive care
monitoring after the diagnosis is made. Since the introduc-
tion of antibiotics, the principal debate regarding the treat-
ment of meningitis has concerned the choice of antibiotics
and the possible use of steroids in diminishing complications.
Fluid management and frequent neurologic evaluations are
also essential.
The first priority in the treatment of meningitis is the
initiation of antimicrobial therapy, which usually begins
with empiric therapy until Gram stain and culture results
are available. Decisions regarding empiric therapy are
based on probable types of organisms and their known
patterns of antibacterial resistance as well as on factors that
affect the bactericidal activity of an antibiotic in the
cerebrospinal fluid. Optimal antibiotic therapy requires
that the drug have a bactericidal effect in the cerebrospinal
fluid because specific antibody and complement factors are
frequently absent in this immunologically deficient site.
Major factors that influence bactericidal activity in the
CSF include degree of CNS penetration, concentration in
the CNS, and the antibiotic’s intrinsic activity. The advan-
tages of third-generation cephalosporins include their
increased antibacterial activity, increased CSF penetration,
and expanded spectrum against β-lactamase organisms and
gram-negative enteric bacilli as well as a reduced toxicity
compared with chloramphenicol and aminoglycosides.
The age of the patient as well the health status and
immunization records of the patient will direct the clinician
toward the most likely organisms. For example, for a
496 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
nonimmunized 3-year-old child, antibiotic coverage
should be obtained for H. influenzae, N. meningitidis, and
S. pneumoniae. In the case of a 50-year-old patient receiving
cytotoxic chemotherapy for leukemia, treatment should
include coverage for Listeria and gram-negative organisms
as well as for S. pneumoniae.
After identification of the probable causative organism,
knowledge of current patterns of antimicrobial resistance is
critical. A worldwide increase in antimicrobial resistance
strains of S. pneumoniae has been documented. Resistance
of S. pneumoniae is mediated by alterations in penicillin-
binding proteins involved in the synthesis of bacterial cell
walls.64 In a 10-month surveillance study of S. pneumoniae
in Atlanta, Georgia, in 1994, 25% of patients with invasive
pneumococcal infection were resistant to penicillin and
9% of those were also resistant to cefotaxime.65 Presently,
S. pneumoniae remains sensitive to vancomycin, which is
the recommended therapy with presumed antibiotic resist-
ance S. pneumoniae. If H. influenzae is suspected, the high
prevalence of β-lactamase-resistant strains require empiric
treatment with a third-generation cephalosporin such as
cefotaxime. Fortunately, most strains of N. meningitidis are
sensitive to ampicillin, although isolates with penicillin-
binding proteins have been identified in the United States,
Europe, and South Africa.66–68 In these cases, a second- or
third-generation cephalosporin can be used.
The interval between the first signs of meningitis and
the beginning of antibiotic therapy may affect the clinical
and audiologic outcomes. Nadol reported that for children
who suffered no hearing loss, the average time to treatment
was 32 hours compared with 47 hours for those who sus-
tained a hearing loss.11 Others have confirmed his result,
including Vienny and colleagues, who found that most
hearing loss associated with meningitis occurs early in the
course of the disease.48,69 A recent study compared the
audiologic outcomes of cefuroxime and ceftriaxone in
order to elucidate if the time to CSF sterilization had any
effects on hearing. The group, which received ceftriaxone,
which is known to more rapidly sterilize CSF, was found to
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
determine the time when meningitis begins.69 Although
early antibiotic intervention is a priority in the treatment
of any infection, the literature on the relationship of the
timing of treatment of meningitis with long-term results
remains controversial.
Adjuncts to antibiotic treatment of meningitis have been
a focus of widespread study and speculation. In Dodge and
Swartz’s landmark work in 1963, they suggested the use of
high-dose corticosteroids to decrease the high CSF pressure
associated with meningitis.53 Other actions of steroids in
meningitis include decreasing brain edema, decreasing
prostaglandin concentrations, and inhibiting arachidonic
acid formation. It may also reduce the concentration of
lactate and protein and increase glucose in the CSF.
Several case reports of glucocorticoid therapy were pre-
sented with good results. In 1969, two independent studies
by DeLemos and Haggerty and Belsey, Hoffpauir, and
Smith failed to show beneficial effects of steroids on the
outcome of meningitis.71,72 In this study the incidence of
long-term neurologic effects was high among the patients
who received steroids. Unfortunately, hearing was not
monitored as an outcome parameter. Eden and Cummings
in 1978 and Berlow and colleagues in 1980 reported the
possibility of reversing the hearing loss of patients with
meningitis if they are treated with steroids.73,74 The best
study of this subject was undertaken by Leben and colleagues
in 1988 when two double-blind placebo-controlled trials
in children with bacterial meningitis were performed. In
one study cefuroxime was used and in the second ceftriaxone
was used and both were combined with either a placebo or
steroid. Lebel and colleagues found that the patients who
were treated with steroids had less moderate or severe
bilateral hearing loss than the placebo group. Fifteen percent
of the patients in the placebo group had bilateral sen-
sorineural hearing loss compared with only 3% of the
recipients of dexamethosone.59 Gary, Powers, and Todd in
1989 reported that children with high Henson-Todd
scores who were given steroids had a better outcome than
those who did not receive steroids.14
Once culture and sensitivity results are available, thera-
peutic treatment can be tailored to these results, but it is
also essential to try to identify the underlying cause of the
meningitis. The otolaryngologist should not lose sight of
his or her role in identifying middle ear effusions or other
possible otologic causes. In many patients, particularly
children, the underlying cause may be an upper respiratory
infection or a middle ear infection. Rapid drainage and cul-
turing of these sources will help both to relieve the inciting
infection and to identify the pertinent organisms and their
sensitivities. Patients with mastoiditis should undergo a
complete mastoidectomy once antibiotics have been started
and the patient is considered stable. In some individuals,
HRCT scanning of the temporal bone may detect a congen-
ital cochlear abnormality or a traumatic break in the bony
barriers between the cerebrospinal space and the environ-
ment. Unfortunately, the otologic cause of meningitis often
goes unrecognized. Gower and McGuirt found, for example,
that only 22% of patients with a CNS complication of ear
disease had a complete otologic evaluation.75
CONCLUSION
Meningitis remains a serious cause of hearing loss and
other neurologic disorders. Advances in the antibiotic
development over the last 40 years have diminished the
incidence of the disease and lessened the chance of death.
Over the last 15 years, the greatest advance in reducing the
prevalence of meningitis has come from the new vaccines.
Nevertheless, the incidence of temporary and permanent
hearing loss remains high in these patients, and cochlear
implantation remains the treatment of choice for many
patients with severe to profound hearing loss.
Otologists often observe meningitis as a result of otitis
media. Early recognition of signs of meningismus and
prompt intervention with antibiotics and steroids may
alleviate or lessen long-term neurologic sequelae. Every
patient should have a full otolaryngologic and audiologic
evaluation in addition to medical and neurologic workups.
Close follow-up collaboration among the otologist,
implant team, and medical teams provides the best care and
outcome in patients with meningitis-related hearing loss.

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1. Kresky B, Buchbinder S, Greenberg IM: The incidence of
neurological residua in children after recovery from bacterial
meningitis. Arch Pediatr 79:63, 1962.
2. Vernon M: Meningitis and deafness: The problem, its physical,
audiological, psychological, and educational manifestations in deaf
children. Laryngoscope 77:1856, 1967.
3. Wolff AB, Brown SC: Demographics of meningitis-induced hearing
impairment: Implications for immunization of children against
Hemophilus influenzae type b. Am Ann Deaf 132:26, 1987.
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5. Baldwin RL, Sweitzer RS, Friend DB: Meningitis and sensorineural
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6. Finitzo-Hieber T, Simhardi R, Hieber JP: Abnormalities of the
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7. Telian SA, Zimmerman-Phillips S, Kilney PR: Successful revision of
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8. Eisenberg LS, Luxford WM, Becker TS, House WF: Electrical
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9. Adair CV, Gauld RL, Smadel JE: Aseptic meningitis, a disease of
diverse etiology: Clinical and etiologic studies of 854 cases. Ann Int
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10. Adams RD, Kublik CS, Bonner FJ: The clinical and pathological
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12. Rosenhall U, Kankkunen A: Hearing alterations following meningitis:
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18. Ozdamar O, Kraus N, Stein L: Auditory brainstem responses in
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23. Adams WG, Deaver KA, Cochi SL, et al: Decline of childhood
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24. Christen HJ: Lyme neuroborreliosis in children. Ann Med 28:235,
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25. Schwartz B, Robinson ZK, Wegner JD, et al: Bacterial meningitis in
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30. Igarashi M, Schuknecht HF: Pneumococcic otitis media, meningitis,
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35. Leichenberg H, Abelson SM: Deafness associated with meningo-
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36. Paparella MM, Sugiura S: The pathology of suppurative labyrinthitis.
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37. Suzuki, C, Sando I, Fagan JJ, et al: Histopathological features of
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38. Ohlms LA, et al: Recurrent meningitis and Mondini dysplasia. Arch
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40. Yuan-ch’eng T, Juei-hua L, Yin-hsiang H: Meningitis and deafness:
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41. Guiscafre H, et al: Reversible hearing loss after meningitis:
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42. Silkes ED, Chabot J: Progressive hearing loss following Haemophilus
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44. Gantz B, McCabe B, Tyler R: Use of cochlear implants in obstructed
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46. Borkowski WJ, et al: Cerebrospinal fluid parameters and auditory
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47. Trolle E: Defective hearing after meningococcal meningitis. Acta
Otolaryngol 38:384, 1950.
48. Vienny H, et al: Early diagnosis and evolution of deafness in childhood
bacterial meningitis: A study using brainstem auditory evoked
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49. Brookhauser PE, Auslander MC, Meskan ME: The pattern and
stability of postmeningitic deafness. Laryngoscope 98:940, 1988.
50. Hutchison PA, Kovacs MC: The sequelae of acute purulent menin-
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51. Crook WG, Clanton R, Hodes HL: Hemophilus influenzae meningitis.
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52. Smith ES: Purulent meningitis in infants and children: A review of
409 cases. J Pediatr 45:425, 1954.
53. Dodge PR, Swartz MN: Bacterial meningitis: A review of selected
aspects II. Special neurologic problems, postmeningitis complica-
tions and clinicopathological correlations. N Engl J Med 272:954,
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54. Farmer TW: Neurologic complications during meningococcic menin-
gitis treated with sulfonamide drugs. Arch Int Med 76:201, 1945.
55. Schwartz JF: Ataxia in bacterial meningitis. Neurology 22:1071, 1972.
56. Kaplan SL, et al: Ataxia and deafness in children due to bacterial
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57. Lindenberg J, et al: Long-term outcome of hemophilus influenzae
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498 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
58. Sell SHW, et al: Psychological sequelae to bacterial meningitis: Two
controlled studies. Pediatrics 49:212, 1972.
59. Lebel MH, et al: Dexamethasone therapy for bacterial meningitis
results of double-blind, placebo-controlled trials. N Engl J Med
319:964, 1988.
60. Jewett DL, Williston JS: Auditory-evoked far fields averaged from
scalp of humans. Brain 94:681, 1971.
61. Jerger J: Prediction of sensorineural hearing level from the brain
stem evoked response. Arch Otolaryngol 104:456, 1978.
62. MacDonald JT, Feinstein S: Hearing loss following Hemophilus
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audiometry. Arch Neurol 41:1058, 1984.
63. Arriaga MA, Carrier D: MRI and clinical decisions in cochlear
implantation. Am J Otol 17:547, 1996.
64. Coffey TJ, Daniels M, McDougal LK, et al: Genetic analysis of
clinical isolates of Streptococcus pneumoniae with high-level resistance to
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65. Hofmann J, Cetron MS, Farley MM, et al: The prevalence of drug-
resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 333:481,
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66. Van Esso D, Fontanals D, Uriz S, et al: Neisseria meningitides strains
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67. Seaz-Nieto JA, Lujan R, Berron S, et al: Epidemiology and molecular
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68. Woods CR, Smith AL, Wasilauskas BL, et al: Invasive disease
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sequelae of cute bacterial meningitis. N Engl J Med 311:869, 1984.
70. Schaad UB, Suter S, Gianella-Borradori A, et al: A comparison of
ceftriaxone and cefuroxime for the treatment of bacterial meningitis
in children. N Engl J Med 322:141, 1990.
71. Belsey MA, Hoffpauir CW, Smith MHD: Dexamethasone in the
treatment of acute bacterial meningitis: The effect of study design
on the interpretation of results. Pediatrics 44:503, 1969.
72. DeLemos RA, Haggerty RJ: Corticosteroids as an adjunct to treat-
ment in bacterial meningitis: A controlled clinical trial. Pediatrics
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73. Eden AR, Cummings FR: Sudden bilateral hearing loss and meningi-
tis in adults. J Otolaryngol 7:304, 1978.
74. Berlow SJ, et al: Bacterial meningitis and sensorineural hearing loss:
A prospective investigation. Laryngoscope 90:1445, 1980.
75. Gower D, McGuirt WF: Intracranial complications of acute and
chronic infectious ear disease: A problem still with us. Laryngoscope
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76. Sproles ET, et al: Meningitis due to Hemophilus influenzae: Long-
term sequelae. J Pediatr 75:782, 1969.
77. Jones FE, Hanson DR: H. influenzae meningitis treated with ampi-
cillin or chloramphenicol, and subsequent hearing loss. Develop
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78. Nylen O, Rosenhall U: Hemophilus influenzae meningitis and hearing.
Int J Pediatr Oto 1:97, 1979.
79. Kotagal S, et al: Auditory evoked potentials in bacterial meningitis.
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80. Feldman WE, et al: Relation of concentrations of Haemophilus
influenzae type b in cerebrospinal fluid to late sequelae of patients
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81. Munoz O, et al: Hearing loss after Hemophilus influenzae meningitis:
Follow-up study with auditory brainstem potentials. Ann Otol
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82. Kaplan SL, et al: Onset of hearing loss in children with bacterial
meningitis. Pediatrics 73:575, 1984.
83. Lin TY, et al: Seven days of ceftriaxone therapy is as effective
as ten days’ treatment for bacterial meningitis. JAMA 253:3559,
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84. Edwards MS, Baker CJ: Complications and sequelae of meningo-
coccal infections in children. J Pediatr 99:540, 1981.
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hood: A 13-year review. NZ Med J 107:758, 1988.
87. Smyth V, et al: Audiological management in the recovery phase of
bacterial meningitis. Int J Pediatr 75:782, 1969.
88. Lebel MH, McCracken GH: Delayed cerebrospinal fluid sterilization
and adverse outcome of bacterial meningitis in infants and children.
Pediatrics 83:16, 1989.
89. Pomeroy SL, Homes SJ, Dodge PR, Feigin RD: Seizures and other
neurologic sequelae of bacterial meningitis in children. N Engl J
Med 323:1651, 1990.
90. Habib RB, et al: Hearing impairment in meningococcal meningitis.
Scand J Infect Dis 11:121, 1979.
91. Snedeker JD, Kaplan SL, Dodge PR, et al: Subdural effusion and its
relationship with neurologic sequelae of bacterial meningitis in
infancy: A prospective study. Pediatrics 86(2):163, 1990.
92. Taylor HG, Mills EL, Ciampi A, et al: The sequelae of haemophilus
influenzae meningitis in school-age children. N Engl J Med 323(24):
1657, 1990.

Demyelinating Diseases
Outline
Introduction
Epidemiology
Pathology and
Pathophysiology of Multiple
Sclerosis
Clinical Features
Internuclear
Ophthalmoplegia
Vestibular Manifestations
of Multiple Sclerosis
Auditory Manifestations
of Multiple Sclerosis
Acoustic Reflex
INTRODUCTION
This review will focus on multiple sclerosis (MS), the most
common demyelinating disorder and the one most often
encountered by the otolarygologist, neurotologist, and audi-
ologist (Table 28-1). MS is a disorder whose demyelinating
effects on the central nervous system (CNS) are dissemi-
nated in space and time in 85% to 90% of patients on pre-
sentation. Because the brainstem is commonly affected,
otologists and neurotologists are often called on to assist
in various ways in the diagnosis and management of MS.
MS may be suspected on the basis of findings from
routine evaluation of dizziness, hearing loss, or cranial
nerve symptoms. A patient may be referred to help deter-
mine whether early or mild brainstem findings on exami-
nation or testing support the diagnosis of MS in
combination with other findings. A question may arise
whether a new symptom in a patient with an established
diagnosis of MS is due to the disease or to an unrelated,
peripheral cause. Otologists and neurotologists may be
asked to treat dysequilibrium, facial palsy, hemifacial
spasm, or another symptom, and to provide rehabilitation
of hearing loss.
EPIDEMIOLOGY
The female to male preponderance of definite MS is 1.5 to
2:1.1,2 The onset is typically from ages 20 to 40. Onset
before puberty is rare. The prevalence of familial MS is
approximately 17%, though much less in first-degree rela-
tives. It is more common to have an affected sibling than
Chapter
28
Auditory Evoked Responses Edwin M. Monsell, MD, PhD
Facial Weakness
Speech Disorders in Multiple
Sclerosis
Visual Evoked Potentials
Other Ophthalmologic
Manifestations
Other Cranial Nerves
Radiologic Imaging of
Multiple Sclerosis
Formal Diagnosis
Management
a parent or child. MS is primarily a disease of persons of
northern European racial background. It is seen least often
in Asians and native African blacks and with intermediate
frequency in African Americans.1,3
The prevalence increases geographically as latitude
increases. In the United States, the 37th parallel seems
to be a divider between a zone of higher prevalence
(50 to 150/100,000) to the north and a zone of lower
prevalence (10/100,000) to the south.3 (In the United
States the 37th parallel is approximately described by a line
connecting the cities of San Francisco, St. Louis, and
Washington, D.C.)
There seems to be an increase in relative risk for those
who moved north, but the magnitude of this increase
appears less than the corresponding decrease found in
those who moved south. The greatest reduction in risk
occurs among those who moved south before the age of
9 years. Some reduction occurs among those who moved
south between the ages of 15 and 19 years (Table 28-2).3,4
PATHOLOGY AND PATHOPHYSIOLOGY
OF MULTIPLE SCLEROSIS
The literature on the pathogenesis of MS is voluminous,
contradictory, and controversial. Theories of genetic, viral,
autoimmune, and multifactorial causation have been pro-
posed.5 Interruption of the blood-brain barrier has been
invoked as an important early event in the causal sequence,
as has inflammation.6
Because of its high lipid content, normal myelin is
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
and Fig. 28-2).20–22 Acute vertigo is an initial complaint in
only 3% to 7% of MS cases.16,22 Dysequilibrium is proba-
bly due to abnormalities in cerebellar, spinal cord, somato-
sensory, and motor control mechanisms as well as vestibular
function.
Completely normal electronystagmography has been
reported in no more than 12% of cases.23,24 The most com-
mon findings are abnormal visually induced eye movements
(saccade test, smooth pursuit test, optokinetic nystagmus
test), positional nystagmus, and hyperactive caloric
responses.17,20

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
prevalent in approximately 4% of MS patients late in
their disease.27 Monocular nystagmus should suggest the
diagnosis of MS.
Abnormal saccade latency, velocity, and accuracy have
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
pure peripheral vestibular disorders. When the smooth
pursuit mechanism is not functioning, tracking is saccadic.
Saccadic tracking may occur from the effects of sedative
medication, inadequate alerting during testing, fatigue,
age, or poor visual acuity.
Rotational testing of the vestibulo-ocular reflex and
dynamic posturography have been used only infrequently
in MS. There is evidence that posturography may be more
sensitive than electronystagmography in detecting extra-
vestibular abnormalities in posture control mechanisms
and may serve as a useful guide for balance therapy, though
further study is necessary.31,32
AUDITORY MANIFESTATIONS OF
MULTIPLE SCLEROSIS
Hearing loss and tinnitus are not common complaints in MS
(see Table 28-5). There is no evidence that the prevalence of
hearing loss is different from the rate in the general popu-
lation.33 It has been reported that MS can cause sudden
sensorineural hearing loss, though apparently does so
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
brainstem responses38 or normal evoked otoacoustic emis-
sions may identify a central cause of the loss.39
Reports of insidious, chronic sensorineural hearing loss
in MS vary widely, and not many studies were controlled
for age or sex. One report indicated that 59% of MS
patients had hearing loss compared with 27% in a control
group, though this high an incidence has not been con-
firmed in other studies.40 No consistent pattern of pure
Demyelinating Diseases 503
Figure 28-3. T2-weighted axial MRI scan from a 31-year-old man presenting
with sudden sensorineural hearing loss. There were no other clinical findings
corroborating the diagnosis of MS, but the CSF demonstrated an elevated
IgG index and oligoclonal bands. The arrow indicates an MS plaque in the
low pons anterior to the fourth ventricle on the side opposite the sudden
hearing loss. Used with the permission of the author.
tone slope in acute or chronic hearing loss associated with
MS has emerged.20,21
Standard clinical speech audiometry (speech reception
threshold and word recognition) reveals few abnormalities
in MS.17,20,40 Poor speech discrimination scores relative to
pure tone thresholds may be consistent with a CNS lesion
(or acoustic neuroma); however, reported rates in MS are
typically low, 3% to 7%.20
Although results of traditional audiometric tests are usu-
ally normal in MS, tests requiring response to a sustained
stimulus, discrimination of speech in noise, and binaural
masking tests are commonly abnormal.20 Abnormal word
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
small shifts in tone frequency, but retain the ability to
detect small differences in intensity.42 Additional audio-
metric measures that have been found to be abnormal in
MS include the synthetic sentence identification test, some
of the dichotic speech tests (staggered spondaic word test,
dichotic sentence identification test, dichotic digits test),
the rapid alternating speech perception test, and low-pass
filtered speech.33
ACOUSTIC REFLEX
In the normal acoustic reflex, the stapedius muscle
contracts bilaterally when a loud tone is presented to the
ear. The afferent limb of the reflex involves the auditory
nerve and the ventral cochlear nucleus, which in turn
stimulates the medial superior olivary nucleus bilaterally.
The efferent limb reaches the facial motor nuclei bilat-
erally; these send motor twigs to the stapedius muscles
504 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
bilaterally. Ipsilateral stimulation is more effective than
contralateral, and binaural stimulation is more effective
than monaural.
Several measurements of the acoustic reflex may be
made. In standard clinical testing, the reflex thresholds are
recorded through an impedance bridge or otoadmittance
meter. Adaptation, or “decay” of the acoustic reflex is
defined as the loss of half or more of the reflex amplitude
within the first 5 seconds of a 10-second stimulation
period at 10 dB above the reflex threshold. Adaptation is
normal at high frequencies, but abnormal at 500 or 1000 Hz.
Positive acoustic reflex decay occurs in retrocochlear dis-
orders such as acoustic neuroma.
Between 13% and 69% of MS patients have been
reported to display abnormal results for acoustic reflex
thresholds elicited by pure tone stimuli.43–45 Bilaterally
absent acoustic reflexes have been noted in 20% of MS
cases.46 In one review of 40 MS patients, elevated or absent
reflex thresholds were found in all subjects with hearing
loss.47 Reflex amplitude and, to a lesser extent, latency meas-
ures were more sensitive markers for MS (75%) than thresh-
old measures (23%) in 122 subjects with MS48; however,
measures of acoustic reflex rise time and latency of onset are
apparently not sensitive enough to detect otherwise asymp-
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
not become established for routine clinical use in MS.
AUDITORY EVOKED RESPONSES
The detection of subclinical disease in the brainstem by
evoked potential testing can be valuable in the diagnosis
of MS. The auditory brainstem response (ABR) is elicited
by the application of acoustic click stimuli to the ear
and recorded as far-field responses from the scalp within
the first 10 to 15 msec of the stimulus onset.50 It is
now assumed that the generators of waves I and II reflect
cochlear and auditory nerve activity and that waves III to
VI arise from several sites within the central auditory
pathways.51 The asynchronous firing of impulses through
the auditory brainstem in MS would be expected to result
in abnormal ABR.
The ABR has been found to be abnormal in up to 83%
of cases of MS.52,53 Clinically manifest and even clinically
silent MS plaques may yield alterations in ABR waves I to
V, such as prolonged interwave latencies, higher amplitude
of earlier than later waves in the response, absent waves,
and poor replicability.17,52–54 Nevertheless, the ABR has not
been accepted as a means of demonstrating “dissemination in
space” under new diagnostic criteria (see Table 28-9).13
Latency values may show a bimodal distribution, with
modes associated with either normal latency or markedly
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
brainstem may be normal if there is no lesion, but even a
small lesion can cause a marked impairment of conduc-
tion.53 Latency increases may be more indicative of MS
than changes in wave amplitude.55 It is unclear whether
increases in stimulus rate can enhance latency changes in
MS patients.54,56 Some effects of stimulus rate may depend
on the polarity of the click stimulus.57
The middle latency response (MLR) occurs approxi-
mately 30 msec after the onset of the stimulus, and the late
vertex response (LVR) consists of two peaks occurring nor-
mally at 90 and 180 msec, respectively, after the stimulus.
Abnormal MLRs and LVRs have been reported in brain-
stem lesions, central auditory processing disorder, devel-
opmental dysphasia, acoustic neuroma, and some central
disorders.58–60 These late potentials are less likely to be
abnormal in MS than is the ABR, though there is evidence
that the addition of the MLR, but not the LVR, to the
ABR can increase the diagnostic yield in MS.61 Direct
comparisons of multimodality evoked potentials have
found that visual evoked responses (VERs) are more
sensitive (66%) for definite MS, followed by somatosen-
sory evoked responses (23%), followed by ABR (18%).62,63
Multimodality testing is more sensitive than any modality
alone, over 85%. The diagnostic yield of evoked potentials
drops when they are needed most, that is, in probable and
possible MS.64 Due to the many clinical and technical vari-
ables, evoked potential testing has not become established
in clinical settings to follow the progress of MS or its
response to treatment.
FACIAL WEAKNESS
Facial weakness is infrequently a presenting symptom of
MS.15,65 Given that MS is a central nervous system disease,
it may be assumed that facial motor pathology in MS is
due to upper or lower motor neuron disease within the
CNS. The location of the lesion is usually the brainstem.65
Approximately 15% of individuals with MS eventually
develop some degree of facial weakness (see Table 28-5).
The most common manifestation is mild paresis in the
lower division of the face. The appearance of facial weak-
ness in a patient with established MS should not be
assumed to be due to the MS, because of the high general
incidence of idiopathic facial palsy (Bell’s palsy) and other
causes of facial paralysis. For example, in the author’s expe-
rience, bilateral acoustic neuromas were found by MRI in
a patient with established MS who developed unilateral
facial weakness.
Hemifacial spasm has also been reported in MS and is
associated with the presence of a plaque involving the ipsi-
lateral facial nucleus.66 Facial myokymia, which may occur
in any or all divisions of the facial nerve, consists of flick-
ering and undulation of the facial muscles. It is caused by
rhythmic discharge in individual muscle fascicles and sin-
gle motor units rather than entire muscle groups. Facial
myokymia is more often associated with MS than is hemi-
facial spasm.66,67 The two entities may be distinguished by
electromyography and may coexist rarely.66
SPEECH DISORDERS IN MULTIPLE
SCLEROSIS
Dysarthria, one of the symptoms comprising Charcot’s
triad (dysarthria, intention tremor, and nystagmus), may be
caused by paresis or incoordination of speech musculature.68

The triad is classic in MS, but rarely occurs early in the
disease.9 Dysarthria should be distinguished from disorders
of higher centers, such as apraxia of speech and aphasia.69
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
various speech deviations included impaired loudness con-
trol and harshness (77%), defective articulation (46%),
impaired emphasis (39%), impaired pitch control (37%),
hypernasality (24%), inappropriate pitch level (24%), and
breathiness (22%). These defects are presumed to be due
to the effects of MS plaques on the lower cranial nerve
nuclei and motor control pathways. Lesions of the
supranuclear corticobulbar tracts are associated with
pseudobulbar palsy.70
VISUAL EVOKED POTENTIALS
This sensory evoked potential modality can detect both
clinically apparent and subclinical damage to the optic
nerve, tract, and radiations.71,72 Abnormal visual evoked
potential (VEP) findings have been reported in 57% to
100% of MS patients.71–73 The number of clinically silent
lesions disclosed by VEP is considerable, ranging from 8%
to 24% of MS cases.72,73 Thus, VEPs are more sensitive
indicators of MS than is the ABR and remain abnormal in
more than 90% of cases.
OTHER OPHTHALMOLOGIC
MANIFESTATIONS
Visual disturbances have been reported in 55% to 77% of
MS patients.74,75 Optic neuritis, often presenting as a cen-
tral scotoma, is the most common visual manifestation of
MS. Scotomata may evolve over hours to days into a visual
defect of any size, including complete blindness. Usually
the scotomata resolve over a few weeks or months with a
minimal residual visual deficit, though effects are perma-
nent in some cases.
Optic neuritis affects red and green color perception and
occurs to varying degrees in 31% to 55% of MS cases.72,74,75
Swelling of the optic disc may occur if a demyelinating
lesion is located anteriorly. Other ophthalmologic manifes-
tations of MS include: anisocoria, Horner’s syndrome, ocu-
lomotor defects, and abnormalities of visual psychophysical
tests.
OTHER CRANIAL NERVES
Loss of taste and dysgeusia have been reported in 8% to
17% of MS cases.76,77 Changes in smell, which are more
difficult to assess, have been reported in up to 68%.78
Facial numbness is an initial complaint in 2% to 3% of
individuals with MS.15,76 Hyperpathia may precede
hypoesthesia. Isolated persistent facial numbness is
unlikely to be due to MS. Trigeminal neuralgia is rare in
MS, occurring in only 1% to 2% of patients.15,16 Among
patients with trigeminal neuralgia the incidence of MS is
approximately 3%.79 It is rare to observe paralysis of the
Demyelinating Diseases 505
motor division of the trigeminal nerve in MS; however,
when it occurs in a young person, it may be the first symp-
tom of MS.
RADIOLOGIC IMAGING OF MULTIPLE
SCLEROSIS
T2-weighted MRI is currently the most sensitive imaging
modality for the detection of MS plaques in the brainstem,
whereas fluid-attenuated inversion recovery (FLAIR)
sequences are more sensitive for lesions in the cerebral
hemispheres. The sensitivity and specificity of MRI in MS
vary in different series with stage of disease, technique, and
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
CNS being studied by MRI. Sensitivity and specificity
may be enhanced with the addition of T1-weighted
sequences.80 Gadolinium contrast material can cross the
broken blood-brain barrier of active MS lesions, resulting
in enhancement within the plaque.80–82
Sensitivity and specificity are less in subtentorial regions
than in supratentorial regions, particularly when clinically
probable and possible MS are considered. In one study
MRI was 60% sensitive in infratentorial regions in clini-
cally definite MS and 33% in clinically probable MS,
whereas the corresponding results for supratentorial
regions were 97% and 82%, respectively.80
The most common associations of lesions with high
signal intensity on T2-weighted MRI are with normal aging
and with white matter ischemic lesions.82 The prevalence
of nonspecific incidental white matter changes is as high as
20% among healthy individuals, higher among hyperten-
sives, and from 30% to 100% in demented persons.80
Lesions that enhance on T2-weighted sequences may also
be found in neurosarcoidosis, Lyme disease, granulomatous
angiitis of the CNS, connective tissue disorders, subcortical
atherosclerotic encephalopathy, vasculitides, acute dissemi-
nated encephalomyelitis, subacute sclerosing panencephali-
tis, autoimmune disease, central pontine myelinolysis,
vitamin B12 deficiency, tumors and tumor-like lesions, and
other demyelinating and dysmyelinating diseases.82,83 Many
of the bright lesions in these disorders can be distinguished
from lesions due to MS. Superatentorial MS lesions are
characteristically wider in the transverse diameter than the
coronal diameter due to the orientation of fiber tracts.
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
MS in the context of clinical findings and abnormal CSF
studies. This specificity is further enhanced if lesions are
periventricular.80–82 Lesions in infratentorial regions or the
corpus callosum are worrisome.
The extent of MS lesions seen on MRI does not corre-
spond well to the duration or clinical severity of MS. The
majority of lesions identified on MRI are not associated
with symptoms. Meaningful comparisons between the
sensitivity of MRI and other laboratory investigations are
difficult to make because of the number of variables
involved, though with current technology MRI appears to
be more sensitive than evoked potential testing.84–86
506 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
TABLE 28-6. Differential Diagnosis of Multiple Sclerosis
I. Diseases causing multiple lesions
A. SLE
B. Primary Sjögren’s syndrome
C. Polyarteritis nodosa
D. AIDS
E. Acute disseminated encephalomyelitis
F. Lyme disease
G. Cerebrovascular disease
II. Systematised diseases
A. Hereditary spinocerebellar ataxia
B. Subacute combined degeneration of the spinal cord
C. Leukodystrophy
III. Single lesions of the CNS with a relapsing/remitting course
A. Intracranial meningioma during pregnancy
B. Glioma of brainstem
C. Extramedullary tumors in region of foramen magnum
D. Primary cerebral lymphoma
E. Arteriovenous malformations involving brainstem
F. Tumors involving spinal cord
IV. Single lesions with a progressive course
A. Cervical spondylotic myelopathy
B. The chiari malformation
V. Monosymptomatic presentation: Note: 45% of MS patients
A. Visual failure, i.e., optic neuritis
B. Diplopia, i.e., internuclear ophthalmoplegia
C. Vertigo: Note: as an initial symptom of MS, this is indistinguishable
from an episode of vestibular neuronitis; however, the course is
generally shorter with MS.
D. Sensory symptoms
VI. Nonorganic Symptoms
AIDS, acquired immunodeficiency syndrome; CNS, central nervous system;
MS, multiple sclerosis; SLE, systemic lupus erythematosus.
From Matthews WB, Compston A, Allen IV, Matyn CN: McAlpine’s Multiple Sclerosis,
2nd ed. New York, Churchill Livingstone, 1991.
FORMAL DIAGNOSIS
MS remains a clinical diagnosis and has an extensive dif-
ferential diagnosis (Table 28-6).76,87 Although the diag-
nosis of MS may be clear on presentation, in mild or
uncertain cases, years may be required to establish it. The
variable natural history of MS has made necessary the
development of diagnostic criteria for clinical and research
purposes consistent with the dynamics of the disease
(Tables 28-7 through 28-9). Bladder hypertonia, bowel or
sexual dysfunction, and the hot bath test can be used to
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).
CSF immunologic studies are abnormal in up to 90% of
cases. No single CSF study is confirmatory of MS. These
studies are of less clinical value than evoked potentials or
imaging.87 In one study at least one component of a test
battery consisting of visual evoked potentials, somatosen-
sory evoked potentials, and CSF studies was positive in
100% of definite, 95% of probable, and 80% of possible
MS cases.1
MANAGEMENT
The rate of publication on the medical treatment of MS
has tripled since the first edition of this book.89
Corticosteroids are often used to treat acute relapses.
TABLE 28-7. Rose Criteria for the Clinical Diagnosis
of Multiple Sclerosis, 1976
I. Clinically definite multiple sclerosis
A. Relapsing and remitting course with at least two bouts separated by
no less than one month; or
B. Slow or stepwise progressive course extending over at least
6 months.
C. Documented neurologic signs attributable to more than one site of
predominantly white matter central nervous system pathology.
D. Onset of symptoms usually between ages of 10 and 50.
E. No better neurologic explanation.
II. Probable multiple sclerosis
A. History of relapsing and remitting symptoms but without
documentation of signs and presenting with only one neurologic
sign commonly asscociated with multiple sclerosis, or
B. A documented single bout of symptoms with signs of mulifocal white
matter disease with good recovery and followed by variable
symptoms and signs.
C. No better neurologic explanation.
III. Possible multiple sclerosis
A. History of relapsing and remitting symptoms without documentation
of signs, or
B. Objective neurologic signs insufficient to establish more than one site
of central nervous system white matter pathology.
C. No better neurologic explanation.
From Rose AS, Ellison GW, Myers LW, Tourtellotte WW: Criteria for the clinical diagnosis
of multiple sclerosis. Neurology 26:20–22, 1976.
Two immunomodulators are well established in the treat-
ment of MS, glatiramer acetate,90 and interferon beta-1.91
In clinical trials most other agents were not demonstrated
to be effective, or toxicity was unacceptable.
The diagnosis of MS and overall management should be
the responsibility of a trained and experienced physician,
who will usually be a neurologist. Otolarygologists and
neurotologists have important supporting roles in patient
evaluation and treatment. The management of balance
disorders may require vestibular testing, counseling, and
rehabilitation. Hearing evaluation and rehabilitation,
including the use of amplification, may be appropriate.
Reasonable physical activities such as walking to help
maintain balance function are recommended along with
precautions to avoid falls. Muscle strengthening may
improve gait and balance function, but weak muscles
can be strained by overuse. Stretching exercises are often
TABLE 28-8. Clinically Definite MS—Schumacher Criteria,
1965
1. Neurologic examination reveals objective abnormalities of CNS function.
2. Examination or history indicates involvement of two or more parts of CNS.
3. CNS disease predominantly reflects white matter involvement.
4. Involvement of CNS follows one or two patterns.
a. Two or more episodes, each lasting at least 24 hours and a month or
more apart
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
process.
CNS, central nervous system; MS, multiple sclerosis.
From Schumacher GA, Beebe G, Kibler RE, et al: Problems of experimental trials of ther-
apy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of
therapy in multiple sclerosis. Ann N Y Acad Sci 12:552–568, 1965.

TABLE 28-9. Diagnostic Criteria, International Panel, McDonald, 2001
Clinical Presentation
Two or more attacks; objective clinical
evidence of two or more lesions
Two or more attacks; objective
clinical evidence of one lesion
One attack; objective clinical evidence
of two or more lesions
One attack; objective clinical evidence
of one lesion (monosymptomatic
presentation; clinically isolated
syndrome)
Insidious neurologic progression
suggestive of MS
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
diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol
50:121–127, 2001.
helpful in states of hypertonia, but should be properly
supervised. Appropriate counseling and involvement in
support groups for the patient and family are important
(National Multiple Sclerosis Society, 733 Third Avenue,
New York, NY 10017, http://www.nmss.org.)
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 Chapter
Migraine
29 Outline
Lee A. Harker, MD Introduction
Etiology and Pathogenesis
Migraine and Neuro-otologic
Disorders
Benign Paroxysmal Positional
Vertigo
Benign Recurrent Vertigo
Ménière’s Disease
Familial Episodic Ataxia
Transient Ischemic Attacks
Stroke
Neurotologic Symptoms
Vertigo
INTRODUCTION
Migraine affects 28 million Americans, approximately
18% of women and 6% of men. After puberty the preva-
lence is much higher in women than men, is highest
between ages 30 and 45 years in both sexes, and varies
inversely with household income (Figure 29-1).1,2 It occurs
in two principal forms: migraine without aura and
migraine with aura. Although most patients with migraine
have no symptoms related to an aura, slightly more than
30% experience aura on some occasions.3 Migraine
headaches are a major cause of work absenteeism and
decreased work productivity. But despite its pervasiveness
and its associated disability, migraine is underrecognized
and undertreated. It is estimated that almost 4 million
individuals who meet the diagnostic criteria for migraine4,5
(Table 29-1) are diagnosed with sinus or tension-type
headache but not with migraine.6
Of significance to otolaryngologists, vertigo and abnor-
mal sensitivity to motion are frequently associated with
migraine, and they also can be severe enough to cause
absence from work and disability. These facts are grossly
underappreciated by general physicians evaluating and
treating patients with migraine, and by otolaryngologists
evaluating and treating patients with vestibular symptoms.
This chapter discusses migraine from the perspective of
the otolaryngologist and reviews the etiology and patho-
genesis of migraine, discusses the relationship of migraine
to other neurotologic disorders, reviews the neurotologic
symptoms associated with migraine and the types of
migraine that evoke those symptoms, and discusses current
management.
510
Motion Sickness
Auditory Symptoms
Migraine Types Associated
with Neurotologic Symptoms
Migraine with Aura
Basilar Migraine
Migraine Aura without
Headache
Management
Management of Headaches
Management of Vestibular
Symptoms
Summary
ETIOLOGY AND PATHOGENESIS
Migraine is not caused by a primary vascular event as had
been previously thought.4 It is best understood as a
primary disorder of the brain, a form of neurovascular
headache in which neural events result in the dilation of
blood vessels, which, in turn, results in pain and further
nerve activation. In all probability, the basic biologic prob-
lem is dysfunction of an ion channel in the aminergic
brainstem or diencephalic nuclei that normally modulates
sensory input and exerts neural influences on cranial
vessels.4
The migraine aura reflects a neural dysfunction, spread-
ing depression, that is followed by vasoconstriction and
oligemia. Spreading depression is actually a wave of
neuronal excitation that travels over the cerebral cortex at
a rate of approximately 3 mm/min that is followed by a
prolonged depression of cortical neuronal activity.7,8 In
patients with typical scintillating scotoma, this process
begins at the center of the visual cortex, propagates to the
periphery within 10 to 15 minutes and returns to normal
within another 10 to 15 minutes. This wave of cortical
spreading depression is responsible for the neurologic
symptoms of the aura. It is followed by a period of hypo-
volemia representing a 20% to 30% reduction in cortical
blood flow that persists for 2 to 6 hours. During this time
period the patient suffers from headache but has no focal
neurologic deficits.
The mechanisms underlying the pathogenesis of pain in
migraine are not fully understood, but key factors include
the cranial blood vessels, the trigeminal innervation of
blood vessels, and reflex connections of the trigeminal

Figure 29-1. Correlation of low income and high incidence of migraines.
(From Stewart WF, Lipton RB, Celentrano DD, et al: Prevalence of migraine
headache in the United States: Relation to age, income, race, and other
sociodemographic factors. JAMA 267:64–69, 1992.)
system with the cranial parasympathetic outflow.4 The
brain itself is essentially insensate, but pain can be gener-
ated by large cranial vessels, proximal intracranial vessels,
or by the dura matter. The ophthalmic division of the
trigeminal nerve innervates the vessels, and branches of
the second cervical nerve roots innervate the structures of
the posterior fossa. Stimulation of the trigeminal system
causes release of vasoactive neuropeptides including
calcitonin gene-related peptide. Levels of this peptide are
consistently elevated during migraine headaches with or
without aura and are reduced when sumatriptan success-
fully ameliorates migraine headaches.
Voltage-gated calcium channels mediate the entry of
calcium into the cell. The opening and closing of these
channels are controlled by changes in voltage across the
cell membrane. The gradient between intracellular and
extracellular calcium controls neurotransmitter release,
neuronal excitation, and many other neuronal functions.9
Mutations in one such gene have been identified in
TABLE 29-1. Modified Diagnostic Criteria for Migraine
Migraine is defined as episodic attacks of headache lasting 4 to 72 hours
With two of the following symptoms:
Unilateral pain
Throbbing
Aggravation on movement
Pain of moderate or severe intensity
And one of the following symptoms:
Nausea or vomiting
Photophobia or phonophobia
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
216 patients no cause was identified.
The incidence of migraine was three times greater in the
large group of patients with no identifiable trigger than in
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
in the eighth decade, but when BPPV and migraine coex-
isted, the age of onset of BPPV was distributed rather
evenly over multiple decades. Nearly half of the patients
with onset of BPPV before age 50 had migraine, whereas
only 15% of the patients with onset after age 50 had
migraine.
Baloh postulated that vasospasm of the labyrinthine
arteries could be responsible for BPPV in migraine patients,
because vasospasm is a well-documented phenomenon
with migraine, and BPPV is a well-documented sequela
to ischemic changes of the inner ear. The ischemia is
postulated to cause the otoconia responsible for the BPPV
symptoms to be released from the macular membrane.
Benign Recurrent Vertigo
Recurring spells of vertigo unassociated with any auditory
or neurologic symptoms are a very common reason
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
long as 3 or 4 days and coined the term benign recurrent
vertigo.12 Most were women, and their episodes were more
common before or at the beginning of their menstrual
periods and often awakened them in the morning. They
were asymptomatic between spells. Many had a personal
or strong family history of migraine.
Basser had previously described recurrent vertigo in a
group of young children and called the condition benign
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
children acted perfectly normal again after their cessation.
The condition would frequently begin before age 4, recur
for a few years, and spontaneously remit, although some-
times it persisted into adulthood.
Patients with histories and symptoms similar to these
often receive different diagnoses in different locations and
clinics. Leliever and Barber13 described a group of patients
with recurrent isolated vertigo without auditory or clinical
neurologic abnormalities lasting 5 minutes to 24 hours and
named the condition recurrent vestibulopathy. The mean
age of onset of symptoms was 37 years, significantly
younger than that for a comparable, larger group of
patients with unilateral Ménière’s disease seen during the
same period. Migraine was said to be present in 3% of the
Ménière’s group and 7% of the recurrent vestibulopathy
group. Both figures are well below current prevalence
numbers for migraine in the general population, and the
study predated the development of the IHS criteria. Over
a mean follow-up period of 3.5 years, the diagnosis was
changed to unilateral Ménière’s disease in only 10% of this
group of patients.
Vestibular Ménière’s disease is another diagnosis given to
patients who experience recurrent vertigo that lasts for a
few minutes to a few hours, but who have no associated
auditory or neurologic symptoms. Although the American
Academy of Otolaryngology—Head and Neck Surgery
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
Baloh and his colleagues have studied patients diag-
nosed with benign recurrent vertigo (BRV) who had
vertiginous episodes that lasted minutes to hours, or
occasionally a few days and whose attacks were commonly
triggered by emotional stress, sleep deprivation, and the
beginning of menstrual periods.12 There was a female
preponderance of more than 2 to 1, and most patients with
BRV also had migraine headaches even though the
headaches often occurred independent of the episodic
vertigo. They studied 24 patients with BRV who also
reported a history of similar vertiginous spells in some
family members. All patients underwent extensive evalua-
tion to rule out other causes of vertigo, and none had
hearing loss or other auditory features of Ménière’s
disease. All were interviewed regarding a personal and
family history of vertigo and migraine, and completed the
standardized questionnaire, which was also sent to all
relatives who agreed to participate. The IHS criteria for
the diagnosis of migraine were used. Response rates were
quite good; in addition to the 24 probands, 111 first-
degree relatives (parents, siblings, children), 110 other
relatives (uncles, aunts, and cousins), and 43 unrelated
spouses participated in the study.
Twenty of the 24 probands were female, and 20 met the
IHS diagnostic criteria for migraine. Nearly 40% of all of
the relatives who completed the questionnaire reported
spontaneous recurrent attacks of vertigo. By contrast, only
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
high prevalence of benign recurrent vertigo and migraine
in these groups suggests autosomal-dominant transmission
of a migraine vertigo syndrome with decreased penetrance
in humans.12
The important clinical point of the study is that patients
who present with disabling recurrent vertigo without
neurologic or auditory signs and symptoms also are likely
to have migraine, and the disabling vestibular symptoms
can often be ameliorated or eliminated by prophylactic
migraine medications (see Management section).
Ménière’s Disease
Ménière’s disease is difficult to clinically distinguish from
migraine. Both conditions lack a definitive diagnostic test
and rely instead on clinical diagnostic criteria, those of the
American Academy of Otolaryngology—Head and Neck
Surgery and the IHS. But patients with Ménière’s disease
also have auditory symptoms and signs, and there are no
neurologic symptoms and signs associated with the spells.
Because the pathophysiology of Ménière’s disease is
restricted to the cochlea, it cannot be responsible for any
associated positive or negative visual phenomena or
proprioceptive symptoms, so their presence during spells
of vertigo rules out the diagnosis of Ménière’s disease.
Similarly, although it is possible for central nervous system
pathophysiology to result in fluctuating sensorineural
hearing loss and other auditory symptoms, it is exceed-
ingly uncommon.
Familial Episodic Ataxia
The familial episodic ataxias are rare dominantly inherited
diseases characterized by dramatic episodes of ataxia.15
Both sexes are equally affected. Episodic ataxia type 1 (EA-1)
patients are usually children who exhibit brief episodes of
ataxia triggered by exercise, startle, or emotional upset that
have a duration of seconds to a few minutes. Aura-like
symptoms are common, including a feeling of weakness or
falling, dizziness, and blurring of vision. The ataxia
involves the trunk and extremities and speech is slurred. In
between episodes of ataxia, muscle rippling (myokymia) is
frequently clinically evident in the periorbital region and
the fingers or can be detected with electromyography. The
ataxia episodes associated with EA-1 frequently diminish
as the child becomes older and may completely disappear
later in life.
Patient with episodic ataxia type 2 (EA-2) have ataxia
episodes that last for hours, and one-third of the patients
exhibit spontaneous vertical nystagmus, particularly down-
beat nystagmus, between spells. The episodes vary from
pure ataxia to a combinations of symptoms that usually
includes vertigo, nausea, and vomiting. As with EA-1,
episodes are triggered by exercise and emotional stress and
often they are dramatically relieved by acetazolamide.
About half of the patients with EA-2 also have migraine
headaches, and there is a genetic association between the
two disorders. Mutations at the same locus on chromo-
some 19p have been demonstrated for both diseases.16
Transient Ischemic Attacks
Differentiating migraine with aura from transient ischemic
attacks (TIAs) is clinically very important and sometimes

difficult especially if there have only been one or two
sensory episodes. Repeated identical self-limited attacks
occurring over weeks to months suggests migrainous aura,
but there may be other clues evident along the way.
Symptoms of the aura usually develop gradually and
consecutively over a 5- to 20-minute period and then
subside, whereas TIA symptoms usually develop more
rapidly and frequently simultaneously. Blumenthal17 stresses
that the visual symptoms of TIA are usually negative phe-
nomena presenting as a black or blank visual loss such as
amaurosis fugax or hemianopic scotoma. In contrast, the
visual sensations in migraine aura usually include positive
phenomenon such as scintillations or fortification spectra
as well as negative phenomena such as scotomata.
Stroke
Without question, individuals with migraine are at higher
risk for ischemic stroke than those without migraine.18
The association is highest in those who have migraine with
aura, but the risk probably extends to those who have
migraine without aura and to children with migraine. This
risk is increased in those under age 40 years, and by the use
of oral contraceptive agents and smoking. Patients with
migraine should not smoke. Women with migraine should
not use combined oral contraceptive pills, including those
with low estrogen, even if no other risk factors for stroke
exist.18
Vertigo can also be a manifestation of cerebrovascular
disease, and since the circulation to the inner ear arises
from the vertebrobasilar system, either central or periph-
eral vascular insufficiency can be responsible. Infarctions
of the vestibulocerebellar pathways in the most dorsolat-
eral portion of the rostral medulla and bilateral cerebellar
infarctions in the distribution of the posterior inferior
cerebellar artery have been described in patients who
exhibited only gait ataxia and acute vertigo without other
symptoms suggestive of Wallenberg’s syndrome.15
Otolaryngologists must be aware that isolated vertigo can
be a manifestation of posterior fossa infarction and should
suspect it in elderly patients and those with cerebrovas-
cular risk factors.
NEUROTOLOGIC SYMPTOMS
Vertigo
At least 25% of all patients with migraine experience
vertigo.19,20 The episodes can constitute all or part of a
migraine aura, can occur spontaneously and seem to be
unrelated to any migraine headaches, or can develop in
response to motion of the individual or the individual’s
surrounding environment.
In some patients 10- to 15-minute episodes of vertigo
precede a migraine headache as a prodrome and are
sometimes or always sequentially associated with other
symptoms of the aura, most commonly scintillations or
numbness and tingling. However, the vertiginous spells do
not always precede the headaches as a prodrome. In Kayan
and Hood’s 53 patients with both symptoms, vertigo
immediately preceded the headache in only 15%, whereas
Migraine 513
it occurred sometime during the headache in 47% and in
the headache-free interval in 36%.20
Spontaneous vertigo attacks in patients with migraine
can last as little as 5 minutes or as long as 3 to 6 days but
commonly last from 30 minutes to 2 hours. The spells of
each patient usually have a similar duration. Generally, the
spells are severe and evoke pallor, diaphoresis, nausea, and
commonly vomiting. Cutrer and Baloh21 propose two
different mechanisms for the production of dizziness with
migraine. They believe that vertiginous episodes lasting
minutes to 2 hours that are temporally associated with
headaches are due to the spreading wave of depression
or transient vasospasm (or both), as are the other aura
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
central vestibular structures and cause an increased base-
line firing rate of primary afferent neurons and increased
sensitivity to motion.
Motion Sickness
Several authors have noted a close relationship between
migraine and motion sickness. In a classic study of 9000
Swedish schoolchildren, Bille22 matched children with
clearly established migraine to a similar group without
migraine. Severe motion sickness was present in 49% of
the children with migraine and only 10% of the control
group. Barabas, Matthews, and Ferrari studied motion
sickness in 60 children with migraine and three similarly
sized control groups.23 They defined motion sickness as
three or more episodes in which an otherwise normal
appearing child vomited during or immediately after an
automobile ride. Forty-five percent of the children with
migraine had motion sickness compared with 5% to 7% of
the three control groups. In adults, Baloh19 reported two-
thirds of migraine patients to be motion-sensitive. Kayan
and Hood reported the association in more than 50% of
their 200 unselected migraine adults,20 and Kuritzky noted
motion sickness to be more prevalent in patients who had
migraine with aura than in those without aura.24
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
their life. They limit their head motion to an absolute
minimum, plan their day’s activities to minimize move-
ment, and rest several times during the day, remaining
motionless for a half hour or so until symptoms abate.
If they cannot avoid continuous motion, the queasiness
proceeds to nausea and imbalance, vertigo, emesis, and a
migraine headache.
Auditory Symptoms
Hearing loss and tinnitus are much less common than
vestibular symptoms in migraine. However, in the small
subset of patients with basilar migraine, a fluctuating
low-frequency sensorineural hearing loss identical to that
seen in Ménière’s disease is found in more than half of
affected individuals.25 Phonophobia (and photophobia) is
extremely common and helps differentiate migraine from
nonmigraine headache.
514 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
MIGRAINE TYPES ASSOCIATED
WITH NEUROTOLOGIC SYMPTOMS
Migraine with Aura
In the IHS classification, aura denotes the occurrence of
any or all of the neurologic manifestations experienced as
a result of migraine whenever they occur and does not
represent the time period in relation to the headache in
which these symptoms occur.5 The IHS describes migraine
with aura as an:
idiopathic recurring disorder manifesting with attacks of neuro-
logical symptoms unequivocally localizable to cerebral cortex or
brain stem, usually gradually developed over 5-20 minutes and
usually lasting less than 60 minutes. Headache, nausea, or photo-
phobia usually follow neurological aura symptoms directly or
after a free interval of less than an hour. The headache usually
lasts 4-72 hours, but may be completely absent.5
Visual symptoms are by far the most common compo-
nent of the migraine aura, and the most common visual
phenomena are (1) scotomata, or blind spots, (2) teichop-
sia or fortification spectra (a zigzag pattern in the visual
field resembling a fort), and (3) flashing of lights (photopsia)
or colored lights. Bartleson3 has provided a clear concise
summary and states that the visual symptoms:
… usually affect both eyes simultaneously but can affect one eye
alone. The patient may experience negative phenomena only and
describe hemianopia and quadrantanopia, complete blindness,
tunnel vision, asymmetric field deficits, monocular blindness,
altitudinal defects, or one or more scotoma. More frequently,
positive phenomena occur and consist of stars, sparks, unformed
flashes of light (photopsia), simple and complex geometric
patterns, or jagged zigzags of light (teichopsia or fortification
spectra). These visual hallucinations are usually white but can be
any color. They are typically present with the eyes open or
closed. The slowly evolving images have a shimmering, flickering
quality. The positive and negative visual phenomena are fre-
quently combined and the term scintillating scotoma is used. The
patient may report wavy lines like heat off pavement or as though
looking through rain covered glass …
The most common sequence is the slow onset of bilat-
eral central scotomata or luminous phenomena that move
slowly in an arc to the periphery of one visual field. The
leading edge is a zigzag of light followed by moving
geometric patterns, which in turn leave behind expanding
homonymous scotomata. (Author’s note—compare this
description with the discussion of pathophysiology.)
Paresthesias present as a numbness, tingling, or both,
and affect the face, upper or lower extremities, or occa-
sionally the trunk. According to Fisher26 “a reliable sign of
migrainous paresthesias is the ‘march’ of numbness as it
gradually spreads over the face or fingers and hand and
migrates from face to limb or vice versa or crosses to the
face and hand on the opposite side.” These paresthesias
are not the result of hyperventilation but rather reflect
the effects of spreading depression (see Etiology and
Pathogenesis section).
Vertigo can also constitute part of the migraine aura, but
the frequency with which this occurs is unknown. Five to
fifteen minutes of vertigo are followed by a typical migraine
headache. The vestibular aura may precede only some and
not all of a patient’s headaches, and visual scintillations or
numbness and tingling may be part of the aura as well.
Basilar Migraine
Bickerstaff27 described a subset of migraine in which the
aura symptoms reflected ischemia in the distribution of the
basilar artery. The majority of Bickerstaff’s patients were
adolescent girls in whom the migraine attacks often
occurred premenstrually. The clinical picture also can
include stupor, loss of consciousness, neurotologic symp-
toms, and extreme postictal fatigue. To establish the
diagnosis of basilar migraine, the episodes must contain
two or more of the following symptoms5:
• Visual symptoms in both temporal and nasal fields of
both eyes
• Dysarthria
• Vertigo
• Tinnitus
• Decreased hearing
• Diplopia
• Ataxia
• Bilateral paresthesia
• Bilateral pareses
• Decreased level of consciousness
These symptoms reflects dysfunction of the involved
neural structures, including the brainstem, cerebellum,
cranial nerve nuclei, and occipital lobe cortex.
Migraine Aura without Headache
This category of migraine is confusing to many physicians
and patients alike. Often, neither group even considers
migraine as a possible cause for vertigo when the headache
and the vertigo occur at different times or when the
vertigo is much more distressing to the patient than the
headaches.
Whitty28 reported a series of patients who experienced
symptoms typically seen during a migraine aura, but who
had no headaches with their symptoms. Some of the
patients had the same aura symptoms earlier in life associ-
ated with migraine headaches, and some developed typical
migraine headaches later in life in association with their
aura. Other patients experienced the aura symptoms alone
on some occasions and together with a typical migraine
headache on other occasions. Others have described
similar patients and used the terms migraine equivalent
or migraine accompaniments.26 The key to the diagnosis is
the history of repeated episodes in which neurotologic
symptoms coexist with symptoms typical of a migraine
aura. A past history of migraine, motion sickness, premen-
strual clustering of attacks, headaches associated with
some of the attacks, or a family history of migraine are
frequently present in these patients.
MANAGEMENT
Management of the neurotologic symptoms of migraine
is made difficult by at least three problems. First, as

mentioned above, migraine is underdiagnosed and the
neurotologists may not suspect it as the cause of the
patient’s symptoms. Second, much of the general migraine
literature ignores any reference to neurotologic symptoms
associated with migraine, and concentrates on the
headaches or the other neurologic symptoms of the aura.
Third, there is almost no clinical research evaluating treat-
ment of the neurotologic symptoms associated with
migraine.
Management of Headaches
It is necessary to first review management of the headache.
Strategies typically include (1) lifestyle changes and
the identification and avoidance of specific triggers,
(2) treatment of the acute headache, and (3) prophylactic
therapy.
In many patients with migraine, the brain does not seem
to tolerate the peaks and troughs of life very well. Regular
sleep, regular meals, exercise, and avoidance of peaks of
stress and troughs of relaxation can help reduce the occur-
rence of episodes.4 In some patients, barometric pressure
changes or excessive exposure to motion (especially in
children) regularly initiate migraine headaches. Many
women recognize that their migraine attacks are more
predictable and more severe around menstruation, under-
scoring the influences of hormonal changes. Although it
sometimes requires a personal headache and diet diary,
many patients are able to report a spectrum of migraine
triggers that that can initiate their attacks. For some
patients, certain forms of alcohol, such as red wine, beer,
or champagne are common inciters; in other individuals
headaches are stimulated by caffeine, cured meats,
monosodium glutamate, aspartame, strong cheeses,
yogurt, or pickled foods. Finally, external sensory stimuli
such as cigar smoke, certain bath oils, perfumes, or visual
sensory stimuli from bright lights or repeated striped
or geometric patterns can provoke attacks.17 In all these
situations, careful attention to the investigation, identifica-
tion, and subsequent elimination of the offending stimuli
can dramatically reduce the frequency of migraine
headaches.
Since the introduction of sumatriptan in 1992, the trip-
tans have become the mainstay of symptomatic or abortive
treatment for moderate to severe migraine headaches.
Today at least five triptans are available for prescription
and, although oral, nasal, intramuscular, and suppository
forms of administration are available, 80% of the prescrip-
tions are for oral use. The cost, efficacy, and side effects
differences are reviewed elsewhere,4,29 but all the triptans
are very effective in ameliorating the pain of a migraine
headache. However, they are not able to terminate an
attack, and the headache recurs in 25% to 40% of patients
with long-lasting migraine attacks. Nearly 25% of all
patients do not respond to any of the triptans. Another
problem is that with frequent migraines, repeated use of
the triptans decreases the time interval between migraine
attacks, and drug-induced headaches result. Furthermore,
all triptans exhibit vasoconstrictive action and are
contraindicated in patients with ischemic heart disease,
uncontrolled hypertension, cerebrovascular disease, and in
pregnancy. There are other management strategies for the
Migraine 515
treatment of acute migraine headaches, but these are
beyond the scope of this chapter.4
Migraine prophylaxis is recommended for patients who
experience three or more attacks per month, whose attacks
are incapacitating and impair normal activities, who can-
not tolerate or are not helped by abortive therapy, who
cannot psychologically cope with attacks, and who have
certain other special situations.30 Drugs commonly used
for migraine prophylaxis include beta-blocking agents,
calcium channel-blocking agents, antidepressants, anti-
convulsants, and others.
The benefit of prophylactic treatment by beta blockers
was detected incidentally in migraine patients being
treated for hypertension or angina pectoris. Propranolol is
the most effective of these. Meta-analysis of 53 studies
including 2403 patients treated with 160 mg of propra-
nolol versus a reference substance or placebo yielded a
44% reduction in migraine activity when daily headache
recordings were used to assess outcome, and 65% reduc-
tion in migraine activity when clinical ratings of improve-
ment in global patient reports were used.29 The dropout
rate due to side effects was 5.3%. Although calcium chan-
nel blockers such as verapamil and nimodipine are touted
by some, others regard them as only marginally effective
or ineffective.29
The antidepressant amitriptyline is an effective
migraine prophylactic agent, even in children. Side effects
usually necessitate initiating treatment with a subthera-
peutic dose and gradually increasing the dosage over a
period of several weeks until an effective therapeutic level
is achieved.
The carbonic anhydrase inhibitor acetazolamide was
originally developed as an antiepilepsy drug. In addition
to its diuretic effects, it slightly acidifies blood and tissue
including the brain. It produces dramatic benefit in
patients with familial EA-2 and familial hemiplegic
migraine who exhibit mutations in the same calcium
channel gene necessary for both central and peripheral
neurotransmission. That gene is expressed throughout
the brain but is particularly prominent in the cerebel-
lum and is also heavily expressed in the neuromuscular
junction where it tightly couples with neurotransmitter
release.16
Several controlled clinical studies have documented the
prophylactic effectiveness of valproic acid in preventing
migraine headaches, but adverse effects resulted in suspen-
sion of treatment in up to 20% of patients in different
studies. Rarely hepatitis, pancreatitis, and significant
platelet effects occur, and the drug has significant risk of
teratogenicity.30 There is no evidence that valproic acid
mitigates vestibular symptoms accompanying migraine.
Another interesting approach to migraine prophylaxis
is the use of botulinum toxin (Botox) injections into the
neck or scalp. The mechanism by which botulinum toxin
works to prevent migraine headaches is unknown, but it
is probably unrelated to Botox’s known effect on muscle
relaxation. Although not yet approved for use in migraine,
several case studies and trials have demonstrated safety and
efficacy, and the effects after pericranial injections can last
3 or more months.31,32 No data indicate whether Botox
injections eliminate or improve vestibular symptoms
associated with migraine.
516 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
Management of Vestibular
Symptoms
Vestibular symptoms associated with migraine can be
managed symptomatically, can be treated prophylactically,
or can be managed with vestibular rehabilitation therapy.
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
their head when the physician or nurse enters the room
and will react unfavorably if the examining chair is turned
quickly. In such individuals, mild vestibular suppression
(e.g., with diazepam 2 mg every 4 to 6 hours as needed) is
often quite helpful if prophylactic measures are ineffective
(see later discussion).
Management of the acute severe vestibular episode
associated with migraine is supportive. If oral agents can be
used, that is, if there is no emesis, low dosages of benzodi-
azepine drugs such as diazepam are helpful. The adminis-
tration of antiemetic agents such as metoclopramide
(Reglan) that increase gastric motility can facilitate the
absorption of the primary drug and thus help ameliorate
the attack. Promethazine (25 or 50 mg orally or by sup-
pository) has both antivertiginous and antiemetic proper-
ties and is also recommended.
When the associated vestibular symptoms are incapaci-
tating, prophylaxis is appropriate. No controlled clinical
trials have documented beneficial effects of drugs, but
in the author’s experience propranolol often dramatically
eliminates spontaneous spells of vertigo in these patients
and greatly ameliorates the abnormal sensitivity to motion
they experience. The effective dose is usually 80 to 120 mg
a day in two divided doses. Monitoring resting pulse for
bradycardia is essential, and fatigue and reduced energy
are sometimes observed. The drug is contraindicated in
patients with asthma. Beneficial effects may not be appar-
ent for the first 2 to 3 weeks of therapy.
Several patients taking acetazolamide 250 mg bid have
had similar, sometimes dramatic improvements in sponta-
neous vertigo and motion sensitivity associated with
migraine. Baloh believes the drugs beneficial effect results
from its altering the pH within the cerebellum, thus
stabilizing the mutated calcium channel.16 All patients
taking acetazolamide notice that carbonated beverages
taste terrible, and up to 20% experience episodic acral or
facial paresthesias lasting up to 30 minutes. The paresthe-
sias become shorter in duration and less frequent over a
few months. Long-term therapy increases the risk of renal
calculi, but this risk can be reduced by drinking citrus
juices. Because of cross-reactivity, the drug should not be
given to patients allergic to sulfa preparations.
The antiepileptic drug lamotrigine has not been used to
treat vestibular symptoms in migraine, but perhaps it
should be studied. Although it has been shown to be inef-
fective in preventing migraine headaches, it is very effec-
tive in treating the aura associated with migraine.30 It
blocks voltage-sensitive sodium channels, leading to inhi-
bition of the neuronal release of glutamate and aspartate,
which are essential to spreading depression.
Vestibular rehabilitation therapy has been recom-
mended for use in migraine patients. However, since
most migraineurs with disabling symptoms suffer from
abnormal sensitivity to motion, it seems counterintuitive
to recommend as therapy an exercise program based on
repetitive motion. One is reminded of the early therapeu-
tic efforts at treating BPPV with exercises designed to
bring on the symptoms.
SUMMARY
Migraine is common and often is disabling, both because
of headaches and because of associated vertigo and motion
sensitivity. It is related to benign paroxysmal positional
vertigo, benign recurrent vertigo (sometimes diagnosed as
recurrent vestibulopathy, vestibular Ménière’s disease, or
benign paroxysmal vertigo), and familial episodic ataxia.
Understanding of the etiology and pathophysiology is
improving, but there is a disturbing lack of awareness of
the association of vestibular symptoms in patients with
migraine by most nonotolaryngologists treating migraine
patients, and no research studies have evaluated drug
effectiveness in treating vestibular symptoms associated
with migraine. However, empiric evidence suggests that
effective treatment is available, and the great majority of
patients with severe or disabling vestibular symptoms can
be very effectively treated without surgery.
REFERENCES
1. Lipton RB, Diamond S, Reed M, et al: Migraine diagnosis and
treatment: Results from the American Migraine Study II. Headache
41:638–645, 2001.
2. Stewart WF, Lipton RB, Celentrano DD, et al: Prevalence of
migraine headache in the United States: Relation to age, income,
race, and other sociodemographic factors. JAMA 267:64–69, 1992.
3. Bartleson JD: Transient and persistent neurological manifestations
of migraine. Stroke 15:383, 1984.
4. Goadsby PJ, Lipton RB, Ferrari MD: Migraine—Current under-
standing and treatment. N Engl J Med 346(4):257–270, 2002.
5. Headache Classification Committee of the International Headache
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cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):1–96, 1988.
6. Diamond ML: The role of concomitant headache types and non-
headache co-morbidities in the underdiagnosis of migraine. Neurol
58(Suppl 6):S3–S10, 2002.
7. Lauritzen M: Cortical spreading depression in migraine.
Cephalalgia 21:757–760, 2001.
8. Spierings ELH: Mechanisms of migraine and action of antimigraine
medications. Headache 85(4):943–958, 2001.
9. Edvinsson L: Aspects on the pathophysiology of migraine and
cluster headache. Pharmacol Toxicol 89:65–73, 2001.
10. Ophoff RA, Terwindt MN, Vergouve R, et al: Familial hemiplegic
migraine and episodic ataxia type 2 are caused by mutation in the
Ca2+ channel gene CACNL1A4. Cell 87:543–552, 1996.
11. Ishiyama A, Jacobsen KM, Baloh RW: Migraine and benign
positional vertigo. Ann Otol Rhin Laryngol 109:377–380, 2000.
12. Oh AK, Lee H, Jen JC, et al: Familial benign recurrent vertigo. Am
J Med Genetics 100:287–291, 2001.
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91:1–6, 1981.
14. Pearson BW, Brackmann DE: Committee on Hearing and
Equilibrium Guidelines for Reporting Treatment Results in
Ménière’s Disease. Otolaryngol Head Neck Surg 93:579–581, 1985.

15. Baloh RW: Episodic vertigo: Central nervous system causes. Curr
Opin Neurol 155:17–21, 2002.
16. Baloh RW, Jen JC: Genetics of familial episodic vertigo and ataxia.
Ann NY Acad Sci 956:338–345, 2002.
17. Blumenthal HJ, Rapoport AM: The clinical spectrum of migraine.
Headache 85(4):897–909, 2001.
18. Tietjen GE: The relationship of migraine and stroke.
Neuroepidemiology 19:13–19, 2000.
19. Baloh RW: Neurotology of migraine. Headache 37(10):615–621,
1997.
20. Kayan A, Hood JD: Neuro-otological manifestations of migraine.
Brain 107:1123–1142, 1984.
21. Cutrer FM, Baloh RW: Migraine-associated dizziness. Headache
31:300–304, 1992.
22. Bille BS: Migraine in school children. Acta Paediatr Scand 51(Suppl
135): 1–151, 1962.
23. Barabas G, Matthews WS, Ferrari M: Childhood migraine and
motion sickness. Pediatrics 72:188, 1983.
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24. Kuritzky A, Zergler DK, Hassanein R: Vertigo, motion sickness and
migraine. Headache 21:227, 1981.
25. Olsson JE: Neurotologic findings in basilar migraine. Laryngoscope
101:1–41, 1991.
26. Fisher CM: Late-life migraine accompaniments as a cause of unex-
plained transient ischemic attacks. J Can Sci Neurol 7(1):9–17, 1980.
27. Bickerstaff ER: Basilar artery migraine. Lancet 1:15–17, 1961.
28. Whitty CWM: Migraine without headache. Lancet 2:283–285,
1967.
30. Diener HC, Limmroth V: Advances in pharmacological treatment
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30. Krymchantowski AV, Bigal ME, Moreira PF: New and emerging
prophylactic agents for migraine. CNS Drugs 16 (9):611–634, 2002.
31. Gobel H, Heinze A, Heinze-Kuhn K, et al: Evidence-based medi-
cine: Botulinum toxin A in migraine and tension-type headache.
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32. Silberstein SD: Review of botulinum toxin type A and its clinical sig-
nificance in migraine headache. Exp Opin 2(10):1649–1654, 2001.
 Chapter
Seizure Disorders
30 Outline
Nancy M. Young, MD Diagnosis and Evaluation
Management of Seizures
John Grant, MD
Management of Status
Epilepticus
Neurotogenic Manifestations
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-
ence at least one seizure and that 4% of persons who live
until age 80 will have a chronic seizure disorder.1 Second,
seizure activity can produce symptoms of vestibular and
auditory disease that need to be recognized as central and
not peripheral. Third, surgeons who diagnose and operate
on lesions in the cranial vault need to understand the
significance and treatment of seizures.
Pain is a symptom of peripheral nerve irritation.
Analogously, a seizure is a symptom of irritation of the
brain. A seizure occurs secondary to excessive neuronal
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
electroencephalographic (EEG) findings (Table 30-1).
Seizures are either partial or generalized depending on
whether clinical or EEG data demonstrate the area of
onset as limited to a part of the brain in one hemisphere or
beginning simultaneously in both hemispheres. Therefore,
the onset of partial seizures is by definition focal. They are
further subclassified depending on whether consciousness
is impaired. If partial seizures occur without impairment of
consciousness, they are classified by whether symptoms
are sensorimotor, autonomic, or psychic. In contrast, the
onset of generalized seizures involves both hemispheres
and lapses of consciousness always occur. Generalized
seizures can be nonconvulsive or convulsive. Absences are
nonconvulsive generalized seizures. Petit mal epilepsy
consists of typical brief absences. In contrast, convulsive
generalized seizures are characterized by major motor
events. For example, tonic-clonic generalized seizures (pre-
viously referred to as grand mal) begin with extension of the
extremities followed by synchronous jerking movements.
Single seizures can occur and recur as a normal response
of brain tissue to physiologic stress. These seizures are
often referred to as reactive. They can be caused by sleep
deprivation, alcohol or sedative withdrawal, and reversible
518
Vestibular Seizures
Vestibular Vertigo in Children
Vestibulogenic Seizures
Audiogenic Seizures
Summary
or irreversible toximetabolic processes, which include
hyponatremia, hypocalcemia, hepatic encephalopathy, and
hypoxia.
Epilepsy refers to a chronic condition in which there are
recurrent seizures of cerebral origin. This term implies
that a chronic underlying neurologic problem is present.
Classification of epilepsy (Table 30-2) depends on age of
onset, whether the seizures are partial or generalized, and
whether the etiology is idiopathic or acquired. Some
authors reserve the term epilepsy for patients who have
idiopathic recurrent seizures. Seizure disorder is a more
general term for chronic recurrent seizure, regardless of
etiology.
DIAGNOSIS AND EVALUATION
Seizures need to be considered in the diagnosis of any
patient with a history of a lapse or alteration of conscious-
ness, memory, sensation, or movement. A blackout is a
common presentation of seizures and many other disorders.
The differential diagnosis of blackout includes a number
of disorders including syncopal episodes secondary to car-
diac function or poor cerebral circulation, head trauma or
concussion, transient ischemic attacks (TIAs), and verte-
brobasilar migraine. Patients being initially evaluated for
loss of consciousness of unknown etiology often undergo
testing to determine whether cardiac syncope versus an
epileptic seizure has occurred. Unusual and subtle presen-
tations of recurrent seizures can include a history of “day-
dreaming” episodes, frequent automobile accidents, bed
wetting, or aphasic or dysphasic episodes. Of special impor-
tance to the neurologist is the fact that vertigo can occur
secondary to seizure activity.
A careful history is critical to the diagnosis of seizure
disorders. Descriptions of any prodrome, aura (initial signs
and symptoms), and the ictus (the event itself ), and postictal
events are critical. An aura consists of abnormal sensation
of motion, thought, or movement. It signifies a partial

TABLE 30-1. International Classification
of Epileptic Seizures
I. Partial (focal, local) seizures
A. Simple partial seizures
1. With motor signs
2. With somatosensory or special sensory symptoms
3. With autonomic symptoms or signs
4. With psychic symptoms
B. Complex partial seizures
1. Simple partial onset followed by impairment of consciousness
2. With impairment of consciousness at onset
C. Partial seizures evolving to secondarily generalized seizures
1. Simple partial seizures evolving to generalized seizures
2. Complex partial seizures evolving to generalized seizures
3. Simple partial seizures evolving to complex partial seizures
II. Generalized seizures (convulsive or nonconvulsive)
A. Absence seizures
1. Typical absences
2. Atypical absences
B. Myoclonic seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures
F. Atonic seizures (astatic seizures)
III. Unclassified epileptic seizures
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.
seizure even if a generalized seizure follows as a result of
spread of discharge from the initial focus. A patient is able
to describe the seizure and the events that follow only if
a purely sensorimotor partial seizure has occurred. It is
much more common, however, that seizures involve alter-
ations of consciousness or memory that necessitate the
account of a reliable witness. Generalized tonic-clonic
seizures should not be remembered by the patient unless
they are due to malingering or hysteria.2
The physical examination may provide information
regarding possible seizure etiology. Patients with neuro-
cutaneous syndromes such as tuberosclerosis or Sturge-
Weber syndrome may have characteristic skin findings in
addition to cerebral lesions. Papilledema and other signs
of increased intracranial pressure are important as well
as evidence of meningeal signs. Any sensory or motor
asymmetry may point to the site of the structural lesion.
Seizure occurs as an initial symptom in 15% of brain
tumor patients.3 However, their occurrence depends
greatly on tumor location. Tumors in or near the sensori-
motor cortex are more likely to cause seizure. The presen-
tation of tumors of the cerebellopontine angle (CPA) is not
associated with seizure. In House’s initial series of 500
patients with acoustic tumors, seizure was not a reported
symptom.4 In terms of surgical management of CPA
tumors, chronic seizures can occur in patients who
have undergone procedures that include a transtentorial
approach in order to expose the temporal lobe widely.5,6
Cabral, King, and Scott7 reported that 22% of 45
patients with large tumors who underwent a combined
translabyrinthine and transtentorial approach developed
chronic seizures and required treatment with antiepileptic
drugs. In contrast, the occurrence of chronic seizures has
Seizure Disorders 519
not been reported as a consequence of acoustic tumor
removal via the translabyrinthine, middle fossa, or posterior
fossa approaches, all of which involve less manipulation of
the temporal lobe. So although the potential for a seizure
disorder to develop is always present during surgery adjacent
to or within the brain, it is more likely to occur when
manipulation is traumatic or protracted.
In any patient with new onset of a seizure disorder or
recurrence of previously controlled seizures, a thorough
examination must be done to look for an underlying etiology
and potentially treatable cause. The most important aspect
of investigation is obtaining a detailed history in order to
determine whether the episode was, indeed, consistent
with a seizure and whether there have been recurrent
episodes. In children with a family history of seizures, it
may not be necessary to perform additional studies.8 The
most common causes of seizures are age related. In child-
hood, typical causes include perinatal asphyxia or trauma,
congenital malformations, and toximetabolic disorders. In
adolescents, trauma and neoplasms predominate. In older
adults, stroke, tumor, and degenerative diseases are most
frequently the underlying problem.
Many drugs are known to precipitate seizures. They
include many common agents, some of which are often
prescribed by otolaryngologists. Examples include antihis-
tamines, sympathomimetics, and prednisone (in the setting
of hypocalcemia). General and local anesthetics, narcotic
analgesics, and iodinated contrast agents (such as metriza-
mide) are also agents reported to cause seizures.9
Laboratory tests to be considered include studies of
hepatorenal function, glucose, calcium, magnesium, and
electrolytes, complete blood count (CBC) with platelets,
erythrocyte sedimentation rate (ESR), and serologic and
immunologic studies. The occurrence of seizures second-
ary to hyponatremia must be kept in mind in any patient
undergoing a surgical procedure. Hyponatremia in head-
injured patients is not uncommon, especially in children,
and usually presents as a seizure.10 Some patients secrete
inappropriate levels of antidiuretic hormone (ADH) dur-
ing the postoperative period, which can lead to intractable
seizures.11 Selected patients may need to undergo a lumbar
puncture so that cerebrospinal fluid (CSF) can be sent
for protein, glucose, culture, and serology for syphilis.
Neuroimaging studies are often essential to the workup
of seizure disorders. Magnetic resonance imaging (MRI)
and, in some cases, functional MRI have replaced com-
puted tomography as the neuroimaging modality of
choice.
EEG is one of the few diagnostic tests that is sensitive to
abnormalities of brain function as opposed to structure.
The use of EEG is important to confirm the clinical
diagnosis of seizure and to assist in classification. Most
EEG laboratories use procedures to provoke seizure activ-
ity in order to increase diagnostic yield. These procedures
can include hyperventilation, photic stimulation, sleep
deprivation, and use of pharmacologic agents. It is impor-
tant to realize that a normal interictal EEG does not
exclude a seizure disorder. Nor does an abnormal EEG
necessarily confirm the diagnosis of seizure disorder.
When there is doubt about the diagnosis, 24-hour video
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
It is of utmost importance that any patient who has a
seizure disorder be fully evaluated for the presence of a
treatable underlying cause. It must be remembered that
seizure is simply a symptom of brain dysfunction and not a
disease entity in itself. The diagnosis of “idiopathic
epilepsy” is a diagnosis of exclusion analogous to the diag-
nosis of Bell’s palsy in patients with facial nerve paralysis.
If an underlying disease is found, then in some cases
treatment with an antiepileptic drug (AED) may not be
required. Patients with an idiopathic seizure disorder or
one due to a known lesion that cannot be corrected need
to have their seizures medically controlled. There are
many AEDs, all of which nonspecifically increase the
brain’s seizure threshold. Often this effect is accomplished
by influences on ionic mechanisms critical to membrane
excitability. The choice of AED depends on the classification
of the seizure disorder and the number of possible side
effects. In general, the drug of choice for partial and gen-
eralized convulsive seizures is carbamazepine (Tegretol)
and the drug of choice for absence of seizures is ethosux-
imide (Zarontin). These two AEDs have good efficacy and
low incidence of unacceptable side effects. If these agents
are unsuccessful, then alternative single agents should be
used. Adding drugs (polytherapy) can be tried in refractory
patients but is not highly successful.1 Because many newer
agents are available in only oral form, Dilantin and pheno-
barbital are still useful anticonvulsants in the surgical pop-
ulation. Intravenous phosphenytoin is a safer formulation
of Dilantin and is usually preferred. The most common
reason for failure of monotherapy is failure to achieve
appropriate drug levels.12
Common side effects of AEDs include sedation, behav-
ioral changes, tremor, vertigo, diplopia, nystagmus, and
ataxia.13 Thus, it is important to realize that a patient with a
522 NEURORADIOLOGY
sensation, which can occur before and between episodes of
generalized seizures.17
Vestibular seizures are defined as seizures that are simple or
complex partial sensory seizures in which the overriding
symptom is vertigo. Patients with vestibular seizures experi-
ence vertigo or disequilibrium, which is often associated with
body or head and eye rotation with or without nystagmus. If
nystagmus occurs, its direction and that of measurable body
motion can be the same. This finding is in contrast to
peripheral vestibular syndromes in which the direction of
nystagmus and body fall are opposite, because the latter
occurs on the basis of vestibulospinal compensation.18
A history of associated symptoms helps to distinguish a
central versus peripheral site of origin of vertigo. Patients
with vestibular epilepsy would not be expected to have posi-
tional vertigo or associated hearing loss. They would be
likely to have associated symptoms of temporal lobe dys-
function. However, these symptoms may go undetected
unless specifically sought. Phenomena suspicious of tempo-
ral lobe origin include auditory hallucinations, which may
range from simple tinnitus to hearing words or sentences.
Alterations of consciousness may occur. For example, the
patient may describe himself or herself as being in a dream-
like state during attacks. Because of the importance of the
temporal lobe in a perceptual integration, the patient may
complain of a disorder of time perception. Time may rush by
or stand still during the episode. A feeling of déjà vu or
depersonalization may also be described.19
Kogeorgos, Scott, and Swash20 reported 30 patients with
vestibular seizures. These patients had a mean age at onset
of 25 years and represented less than 1% of the author’s
population of seizure patients. They had intermittent brief
episodes of disequilibrium. Almost half experienced rota-
tional vertigo. Almost a quarter of the patients in the study
had a history of the occurrence of more generalized
seizures. Nearly half had a history of brief alterations in
consciousness (absences or other features suggestive of
temporal lobe epilepsy). EEG evaluations demonstrated a
posterior temporal lobe focus in the vast majority of
patients. Almost all responded well to AEDs.
Note that vestibular epilepsy and a peripheral vestibular
problem can both exist by chance or can be a result of a
common etiologic factor such as head trauma or vascular
disease. The suspicion of vestibular epilepsy requires eval-
uation in an EEG laboratory. If the diagnosis is confirmed,
then the search for an underlying cause of the cerebral
dysfunction must be performed. If no treatable cause is
found, then an AED can be used. If medical therapy fails,
then surgical therapy remains an option.
Vestibular Vertigo in Children
Vestibular seizure is an important diagnosis to consider in
children who have vertigo. Vertigo is not as common a
complaint nor as well studied in children as in adults. In
adults it is more commonly due to peripheral disease. In
children, central disease must be strongly considered. Eviatar
and Eviatar21 evaluated 50 children who were referred to a
neurology clinic with a chief complaint of vertigo. A high
incidence of central vertigo (42 of 50 patients) was found.
Vestibular seizure was the diagnosis in the majority of chil-
dren (25 of 42). Age of onset ranged between 3 and 18 years.
Vestibular vertigo in children can be suspected by
the presence of a positive family history of seizures. A
careful history will elicit that at least some episodes of
vertigo are associated with focal or generalized seizure
phenomena such as an alteration or loss of consciousness,
facial or extremity twitching, inability to speak, or progres-
sion of the attack to an obvious tonic-clonic generalized
seizure.
The differential diagnosis of vertigo in children includes
cerebellar and brainstem tumors, benign postural vertigo
(BPV) of childhood, perilymph fistula, labyrinthitis, post-
traumatic vertigo, otitis media, vestibular neuronitis, and
endolymphatic hydrops. BPV is an important cause of
episodic vertigo in children that does not occur in adults.
Its onset occurs when the child is between 1 and 4 years
old. The child experiences sudden episodic vertigo with-
out headache or change in consciousness. The disease is
self-limited; it resolves in months or years. BPV is thought
to be a migraine equivalent and therefore occurs secondary
to a cerebral vasomotor disorder. Approximately 50% of
affected children develop migraines as adults.18,22
Children with vertigo may require careful workup
by both a neurologist and an otolaryngologist. Even if
obvious peripheral disease is found by the otolaryngolo-
gist, this could be coincidental to the occurrence of
vertigo. In children the presence of an underlying central
disorder such as vestibular epilepsy or brain tumor must be
considered.
Vestibulogenic Seizures
Vestibular seizures need to be distinguished from a rare
phenomenon known as vestibulogenic seizures. This term
refers to seizures evoked by stimulation of the labyrinth.
The term vestibulogenic was initially applied to seizures by
Berhman and Wyke.23 Based on experimental and clinical
data, they theorized that the mechanism of initiation is
abnormal activation of the reticular system of the brainstem
secondary to caloric or rotary stimulation of the labyrinth.
Vertigo occurs and is usually followed by generalized
tonic-clonic convulsions with loss of consciousness.
Most authors believe that vestibulogenic seizures are
extremely rare.24 However, a small number of well-
documented cases of vestibulogenic seizure exist.24,25
Audiogenic Seizures
Auditory stimuli can precipitate seizure activity in rare
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
audiogenic seizures are induced by sudden loud noises.
Musicogenic seizures occur less commonly. Certain notes
or themes precipitate events in these patients.1,26,27
Patients with audiogenic seizures have not been
described as having a history of hearing impairment. In
contrast, many of the animal models that are known to be
susceptible to audiogenic seizures have been shown to
have elevated auditory thresholds. Correlation between
degree of loss and susceptibility to and severity of audio-
genic seizures has been reported in the epilepsy-
prone rat.28

SUMMARY
The neurotologist can encounter seizures in a variety of
ways. They may be the underlying cause of symptoms that
bring the patient to a physician’s office or the result of
medical and surgical management of other conditions.
Seizures are of special interest to the neurotologist in that
they need to be considered in the differential diagnosis of
complaints of vestibular and auditory dysfunction.
REFERENCES
1. Engel J Jr (ed.): Seizures and Epilepsy. Philadelphia, FA Davis,
1989.
2. Earnest MP (ed.): Neurologic Emergencies. New York, Churchill
Livingstone, 1983.
3. Grossman RG (ed.): Principles of Neurosurgery. New York, Raven
Press, 1991.
4. House WF, Luetje CM (eds.): Acoustic Tumors, vol 1. Baltimore,
University Park Press, 1979.
5. King T, Morrison A: Translabyrinthine and transtentorial removal
of acoustic nerve tumors. J Neurosurg 52:210–216, 1980.
6. Morrison A, King T: Experiences with translabyrinthine-transtentorial
approach to the cerebellopontine angle. J Neurosurg 38:382–390,
1972.
7. Cabral R, King T, Scott D: Incidence of postoperative epilepsy after
a transtentorial approach to acoustic nerve tumors. J Neurol
Neurosurg Psychiatr 39:663–665, 1976.
8. Tuxhorn I, Holthausen H, Boenigk H (eds.): Paediatric epilepsy
syndromes and their surgical treatment. London, England, John
Libbey, 1997.
9. Messing RO, Closson RG, Simon RP: Drug-induced seizures: A
10 year experience. Neurology 34:1582–1586, 1984.
10. Lüders HO (ed.): Epilepsy Surgery. New York, Raven Press, 1992.
11. Ketterer T, Gacek R: Convulsions secondary to hyponatremia
associated with labyrinthectomy. Arch Otolaryngol Head Neck
Surg 115:387–388, 1989.
Seizure Disorders 523
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.
13. Pellock JM: Efficacy and adverse effects of antiepileptic drugs.
Pediatr Clin North Am 35:435–448, 1989.
14. Barber HO, Stockwell CW: Manual of Electronystagmography.
St. Louis, CV Mosby, 1980.
15. Wiebe S, Blume WT, Girvin JP, Eliasziw M: Effectiveness and
efficiency of surgery for temporal lobe epilepsy study group: A ran-
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.
Brain 94:173–190, 1971.
17. Hughes JR, Drachman DA: Dizziness, epilepsy and the EEG. Dis
Nerv System 38:431–435, 1977.
18. Brandt T (ed.): Vertigo. Its Multisensory Syndromes. London,
Springer-Verlag, 1991.
19. Williams DJ: Central vertigo. Proc R Soc Med 60:961–964, 1967.
20. Kogeorgos J, Scott DF, Swash M: Epileptic dizziness. Br Med J
282:687–689, 1981.
21. Eviatar L, Eviatar A: Vertigo in children: Differential diagnosis and
treatment. Pediatrics 59:833–838, 1977.
22. Blayney AW, Colman BH: Dizziness in childhood. Clin
Otolaryngol 9:77–85, 1984.
23. Behrman S, Wyke BD: Vestibulogenic seizures. A consideration of
vertiginous seizures with particular reference to convulsions produced
by stimulation of labyrinthine receptors. Brain 81:529–541, 1958.
24. Barac B: Vertiginous epileptic attacks and so-called “vestibulogenic
seizures.” Epilepsia 9:137–144, 1968.
25. Tartara A, Manni R, Mira E, Mevio E: Polygraphic study of vestibular
stimulation in epileptic patients. Rev EEG Neurophysiol 14:227–234,
1984.
26. Danbe JR: Sensory precipitated seizures: A review. J Neurol Ment
Dis 141:524, 1965.
27. Mello DH: Precipitating factors in epilepsy. J Neurol Ment Dis
12:800–802, 1970.
28. Faingold CL, Walsh EJ, Maxwell JK, Randall ME: Audiogenic
seizure severity and hearing deficits in the genetically epilepsy-prone
rat. Exper Neurol 108:55–60, 1990.
 Increased Intracranial Pressure
Outline
Douglas A. Chen, MD Cerebrospinal Fluid
Dynamics
J. Diaz Day, MD
Cerebrospinal Fluid and lis
Relationship to the Inner Ear
Hydrocephalus with Elevated
Cerebrospinal Fluid Pressure
igns and symptoms of increased intracranial pressure
S may be the features that send a patient to the neurotol-
ogist. Furthermore, most neurotologic procedures subject
patients to the possible complication of increased intracra-
nial pressure. A working knowledge of this topic is essential
to the neurotologist.
Intracranial pressure is determined by the contents
within the volume-constant cranial vault, largely brain
tissue, blood, and spinal fluid. 1 This concept is known as
the Monro-Kellie doctrine. To maintain a constant pres-
sure, if one component changes, one or both of the other
two must change to compensate. Changes in blood and
spinal fluid volume, therefore, lead to changes in intracra-
nial pressure. Acute changes in intracranial pressure are
compensated for by changes in venous and cerebrospinal
fluid (CSF) volume up to a certain point beyond which
intracranial pressure is increased. The pressure-volume
relationships are nonlinear and are a function of CSF pres-
sure. In most instances, intracranial pressure is reflected
accurately through CSF pressure measurements.
Manifestations of increased intracranial pressure in
adults classically include headaches, nausea, vomiting,
abducens nerve palsies, and papilledema. Papilledema may
initially occur without visual deficits, but blurred vision,
central scotoma, and "graying out" episodes suggest the
end stages that lead to permanent visual damage.
Abducens nerve weakness and diplopia may be present
as a result of generalized increased intracranial pressure
without a localized intracranial lesion. Headaches classi-
cally occur in the morning, but can occur any time. If severe
enough, nausea and vomiting may relieve the headaches,
presumably secondary to the hyperventilation that accom-
panies vomiting. This results in hypercapnea, which causes
vasoconstriction, reducing the blood volume component
according to the Monro-Kellie doctrine.
Increased intracranial pressure may be a manifestation
of hydrocephalus. Hydrocephalus in the most literal sense
means "water head" and refers to an excessive accumula-
tion of CSF intracranially. This excessive accumulation
524
Normal-Pressure
HydrocephalUS
Pseudotumor Cerebri
Conclusion
usually takes place in the ventricular system from an
imbalance between production and reabsorption.
Numerous adjectives are used in conjunction with the
term hydrocephalus. Communicating and noncommunicating
refer to the presence or absence, respectively, of free flow
of fluid from the ventricular system to both the lumbar and
cerebral hemisphere subarachnoid space. Obstructive
hydrocephalus implies an obstruction of CSF flow any-
where along its path and is the most common type.
Acute and chronic hydrocephalus describe the time
course over which excessive CSF accumulates, acute accu-
mulation taking place over days and chronic over months
to years. Patients with acute hydrocephalus tend to be dra-
matically symptomatic, whereas those with chronic hydro-
cephalus tend to exhibit more subtle signs and symptoms
of elevated pressure. In chronic cases, neurologic signs and
symptoms may exist that are not obvious, especially if they
have occurred over a long time. Arrested hydrocephalus
refers to a cessation of whatever factors initially led to
hydrocephalus. Active hydrocephalus implies progressive
ventriculomegaly or increased intracranial pressure.
Benign intracranial hypertension, or pseudotumor cerebri, is
a syndrome of increased intracranial pressure without
apparent intracranial mass or ventriculomegaly. The term
otitic hydrocephalus refers to the condition of benign
intracranial hypertension secondary to an infectious
process of the ear. Otitic hydrocephalus is consequently a
misnomer, because by definition the ventricles are of normal
size.' Horowitz suggested otogenic intracranial hypertension as
a preferable name.' The hypertension is a phenomenon of
venous outflow obstruction, causing increased intracranial
pressure.
CEREBROSPINAL FLUID DYNAMICS
CSF is produced at a rate of approximately 500 mL/day in
adults and children. Production is an energy-dependent
process. It takes place via a sodium pump on the apical

surface of the choroidal epithelium, which transports
sodium into the ventricles. Water then flows passively.
Multiple factors, including drugs, can influence the pro-
duction rate." A classic example is the carbonic anhydrase
inhibitor, acetazolamide, which can decrease production of
CSF by as much as 50% to 60%. Acetazolamide taken orally
achieves a peak plasma level 1 hour after ingestion and is
effective for 8 to 12 hours.' Given intravenously its peak
effect occurs in 15 minutes and is effective 4 to 5 hours.?
Few hydrocephalic states result from overproduction of
CSF, with exceptions such as hypersecretion from a
choroid plexus papilloma or villous hypertrophy.o'' CSF
production may also occur in the brain parenchyma, but
control is poorly understood."
The choroid plexus is located primarily in the floor of
the lateral ventricles and roofs of the third and fourth
ventricles. Fluid leaves the lateral ventricles through the
foramen of Munro, traverses the third ventricle, and
reaches the fourth ventricle by way of the cerebral
aqueduct (aqueduct of Sylvius). Fluid passes from the
fourth ventricle through the foramina of Magendie and
Luschka into the subarachnoid space. Several pockets of
CSF exist at the base of the brain in the subarachnoid
space known as cisterns. The largest is the cisterna magna
located between the inferior surface of the cerebellum and
the medulla (Fig. 31-1).
Spinal fluid diffuses upward from the basal areas of the
brain over the cerebral hemispheres. Absorption of spinal
fluid into the venous system takes place primarily via the
arachnoid villi mostly in the walls of the superior sagittal
sinus and transverse sinuses.l'' Alternative routes of CSF
absorption may exist. Substantial drainage occurs via the
lymphatics of the nasal mucosa via the peri olfactory and
optic nerve sheath in animals."
Body of Lateral Ventricle Arachnoid
Sub Arachnoid Space
Foramen of Munro
(Interventricular Foramen)
Temporal Horn
Aqueduct of Sylvius
(Cerebral Aqueduct)
Foramen of Magendie
Foramen of Luschka
(Lateral Foramen) Cisterna Magna
t
Increased Intracranial Pressure 525
Controversy exists as to whether the brain itself can
absorb spinal fluid. The argument centers on the periven-
tricular edema seen in acute hydrocephalus and whether
this results from pressure-dependent transependymal
migration of CSF or from active absorption. I I
The pressure gradient between the ventricular system
and the subarachnoid space is referred to as the transman-
tie pressure. The precise mechanism by which fluid passes
into the sagittal sinus through the arachnoid villi is unclear
but depends on a positive transmantle pressure gradient.
Obstruction of the superior sagittal sinus results in ele-
vated transmantle pressure and subsequent hydro-
cephalus.F
CEREBROSPINAL FLUID AND ITS
RELATIONSHIP TO THE INNER EAR
The inner ear is connected to the intracranial space via two
aqueducts, the cochlear and vestibular. The cochlear aque-
duct originates on the medial wall of the scala tympani
near the round window membrane and terminates on the
upper border of the jugular fossa in the petrous portion
of the temporal bone. It is often filled with fibrous tissue.!'
In lower animal species and frequently in human adult
temporal bones, anatomically patent cochlear aqueducts
can be found.?,14,ls Physiologic patency of the cochlear
aqueduct is believed to be poor or nonexistent in most
cases.
The vestibular aqueduct originates in the scala vestibuli
near the elliptical recess and passes into the posterior cra-
nial fossa midway between the internal auditory canal and
the sigmoid sinus.l ' The vestibular aqueduct transmits an
artery, vein, and the endolymphatic duct, which dilates to
Villi
Sagittal Sinus
Third Ventricle
Figure 31-1. Formation, flow, and
absorption of CSF.
...o~l-rr Fourth Ventricle
(Medial Foramen)
526 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE

form the endolymphatic sac on the dura mater of the
posterior fossa.
Maintenance of labyrinthine fluid pressure equilibrium
in relationship to CSF has been proposed by Allen and
widely accepted by other authors.lf-" He theorized that
increased intracranial CSF pressure exerted on the endolym-
phatic sac and then to the endolymph were balanced by
increases in the perilymph transmitted from the CSF via
the cochlear aqueduct. However, recent animal experi-
ments indicate that the endolymphatic sac is incapable or
has limited capability of transmitting pressure changes
from the CSF. In contrast, the cochlear aqueduct, if phys-
iologically patent, is capable of transmitting changes in
CSF pressure without dampening effects." Furthermore,
pressure gradients as small as 2 to 5 mm H 20 between
endolymph and perilymph have been postulated to cause
inner ear membrane ruptures. I? Thus, if the cochlear
aqueduct is large and physiologically patent, the inner
ear may be susceptible to damage from sudden extreme
variations of CSF pressure. 18
Clinically, reports of both auditory and vestibular symp-
toms coexisting with hydrocephalus occur in adult and
pediatric literature. Barlas and colleagues'? reported two
cases of fluctuating hearing loss and vertigo as the pre-
senting symptoms in aqueductal stenosis and hydro-
cephalus. Symptoms in both patients were relieved by
ventricular shunts. Loppenen and coworkers/? described
audiologic findings of shunt-treated hydrocephalus in
children. Eighteen of 47 shunt-treated hydrocephalic
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.
Idiopathic causes of hydrocephalus also make up a sig-
nificant portion. Cerebellopontine angle tumors obstruct-
ing the fourth ventricle, such as an acoustic neuroma,
account for only 2 % of all cases of obstructive hydrocephalus
(Figs. 31-2 and 31-3).
Increased intracranial pressure following neurologic
surgery occurs occasionally and can be transient or pro-
longed. The cause can be cerebral edema or hydro-
cephalus. It is most common with large tumors and cases
that have been complicated by excessive brain retraction,
meningitis, and significant contamination of the CSF
pathways with blood. Blood can block the absorptive
capacities of the arachnoid villi. 25 It can also produce an
obliterative meningeal inflammatory response, as can
surgical exposure of the posterior fossa."
Clinical manifestations ofhydrocephalus include headache,
nausea, vomiting, ataxia, urinary incontinence, and visual
disturbance. The headaches tend to occur in the morning and
are usually bifrontal. As symptoms progress, they may occur
in the evening and progress into the neck. Nausea and vom-
iting usually relieve the headaches. Ataxia is usually truncal.
A wide-based, unsteady gait may also be present.
Visual disturbances include decreased visual acuity, cen-
tral scotoma, and diplopia. Momentary episodes of "gray-
ing vision" in both eyes are important signs of serious optic
nerve and retina ischemia secondary to increased intracra-
nial pressure. Papilledema and abducens nerve palsy are
nonlocalizing signs, but are indicative of increased
intracranial pressure.

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.

Figure 31-3. Coronal image of the same tumorwith moderate hydrocephalus
of the lateral and third ventricles aswell as the temporal horns.
The diagnosis of hydrocephalus is generally made with
a computed tomographic (CT) scan. Contrast agents
should be used so any underlying process can be
established. Making the diagnosis by CT scan can be prob-
lematic. The first difficulty is deciding whether the
ventricles are truly enlarged. The second difficulty is
deciding, if they are enlarged, whether the enlargement
is a result of brain atrophy or hydrocephalus. Temporal
horn dilatation, "rounding of the third ventricle," and
periventricular edema are all fairly reliable signs of true
hydrocephalus.
MRI is also useful in evaluating hydrocephalus and its
underlying cause. An advantage of MRI is its ability to
assess the flow of CSF in the cerebral aqueduct.i" In the
hydrocephalic state, CSF flow signal void in the cerebral
aqueduct is more prominent due to pulsatile CSF motion,
which is thought to be a reflection of increased ventricular
compliance."
Despite CT and MRI, spinal puncture has remained a
valued diagnostic technique in CNS diseases. Its utility in
the setting of hydrocephalus is limited to patients with
normal-pressure hydrocephalus as a provocative tool.
Drainage of CSF in this setting may result in temporary
alteration of symptoms, thus predicting a favorable out-
come from shunting the CSF. Otherwise, in patients with
elevated pressure secondary to hydrocephalus, the proce-
dure is ill-advised.
The normal CSF pressure/? in adults in the lateral
recumbent position is less than 180 mm H 20. Merrit and
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
several days. This complication is caused by continued
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.
Rarely, a blood patch is necessary to seal the dural punc-
ture site and halt further leakage of CSF.
If high-pressure hydrocephalus results from an
obstructing mass lesion, treatment is centered around
removal of the mass or shunt placement, with the former
becoming increasingly advocated. A shunt drains CSF to a
body cavity, such as the peritoneal or pleural, or a vein.
Preoperative shunting before definitive removal of an
intracranial mass has been advocated, and the results
appear to be similar to those from centers that do not
shunt preoperatively." If a shunt is not used preopera-
tively, the patient must be followed closely after surgery
and be prepared for a shunt later.
There are several common types of shunts. Ventricular
shunts are usually inserted into the frontal horn of the
lateral ventricle. Alternatively, the catheter is inserted into
the lateral ventricle via an occipital trajectory. A catheter
connecting the ventricle is buried subcutaneously and
terminates in the peritoneal or pleural cavity (Fig. 31-4).
Alternatively, the catheter may be directed into the
common facial vein and subsequently to the atrium, the
so-called ventriculoatrial shunt (Fig. 31-5). The lumbo-
peritoneal shunt drains fluid from the lumbar subarach-
noid space to the peritoneum (Fig. 31-6). This shunt is
indicated in cases of communicating hydrocephalus. A
lumboperitoneal shunt is ill advised if hydrocephalus is
noncommunicating because of the higher risk of tonsillar
herniation. All shunts have a valve system that regulates
pressure and prevents retrograde flow.
528 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
Burr Hole approximately 6cm above
and 3cm to right of Occipital
Figure 31-4. Ventriculoperitoneal shunt.
/
/ -0"
Temporary ventricular drainage into an external closed
system, a ventriculostomy, can be done under local anes-
thesia in the intensive care unit. This technique is com-
mon in cases of hydrocephalus, trauma, stroke, and
subarachnoid hemorrhage. Placement of the catheter
allows for drainage of CSF and monitoring the intracranial
pressure.
Complications of shunts include infection, shunt mal-
function, chronic subdural collections, and seizure.l?
Shunt infections are especially common in infants.
Peritoneal shunt malfunction may be the only manifesta-
tion, and CSF cultures should be obtained from the
catheter on removal or replacement. If a shunt becomes
infected antibiotics are administered. However, removal of
the entire shunt, with temporary placement of a ventricu-
lostomy, is necessary until the infection resolves.
Progressive ventricular enlargement despite shunt
placement is typically a sign of shunt malfunction.
Ventricles will usually begin to diminish in size within a
week after shunt placement, which is the best indicator
of shunt patency. In normal-pressure hydrocephalus, ven-
tricles may remain large despite good shunt function. A
shunt tap will test the patency of the catheter; however,
risk of infection exists. Inability to withdraw fluid from
the ventricular reservoir indicates ventricular catheter
Protuberance
Catheter tip in Ant. Horn
of R. Lateral Ventricle
11-12 em from Burr Hole
./---------
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
obstruction, and shunt reVISIOn is indicated. Several
radionuclide methods for determining shunt patency and
flow have been described but have met with variable
success. Radionuclide shunt evaluation determines the
clearance of radioisotope from the ventricular reservoir into
the catheter and has been found to vary greatly depending
on the various components of the system. 37,38
Chronic subdural collections occur most commonly in
normal-pressure hydrocephalus. This complication is
uncommon in high-pressure hydrocephalus.'? The mech-
anism is thought to be secondary to negative intracranial
pressure that results in tearing of bridging veins or leakage
around the ventricular catheter into the subdural space.f
Most subdural collections will not enlarge; however,
when they do, replacement with a higher pressure valve is
usually necessary."
NORMAL-PRESSURE HYDROCEPHALUS
Ventricular enlargement in the face of normal CSF pres-
sure may present a confusing clinical picture. This situation
may occur in association with neurodegenerative diseases,
such a Alzheimer's disease and cortical atrophy causing
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
is a syndrome clinically defined by the classic triad of gait
disturbance, dementia, and urinary incontinence.
It was described by Hakim and Adamsf in 1965 and then
by Adams and colleaguesf and has been referred to as the
Hakim, or Hakim-Adams, syndrome.
A number of conditions that precede the syndrome have
been identified." Most can be related to some low-grade
obstructive flow phenomenon, such as subarachnoid hem-
orrhage, tumor, meningitis, or previous intracranial surgery.
High-pressure and normal-pressure hydrocephalus probably
represent a spectrum of the same disease process with
different outcomes.
The mechanism by which hydrocephalus occurs in the
face of normal CSF pressures remains controversial.
Symon and Dorsch suggested that these patients have
episodically raised intracranial pressure, especially at
night, which may not manifest on one lumbar puncture.t"
Similarly, Di Rocco and coworkerst' postulated that CSF
pulse pressure with normal mean pressure in the ventricu-
lar system could be responsible for increasing ventricular
size. Hakim and Adarnsf suggested that according to
Laplace's law, the increased ventricular size represents
increased force on the ventricular wall despite normal CSF
pressure. Several explanations, which involve primarily
brain parenchyma, have been proposed. Extensive athero-
sclerotic changes in brains of patients with normal-
pressure hydrocephalus at postmortem have been observed;
however, they were not compared with controls.t'v"
The triad of gait disturbance, memory loss, and urinary
incontinence are the chief clinical features of normal-pressure
hydrocephalus. The gait disorder is usually characterized
by a broad-based shuffling with short steps." The patient
often reports imbalance when standing or sitting associ-
ated with a history of falling."?
The severity of recent memory loss can vary greatly.
A general degradation of mental faculties, which the family
may report as lethargy, apathy, or attention, and con-
centration difficulties may occur. CT and MRI should show
large ventricles, and a lumbar puncture may be performed
to establish CSF pressures. Pressure should be less than
180 mm H 20 and protein, sugar levels, and cell count
should also be normal.
The clinical response of normal-pressure hydrocephalus
to shunting is mild improvement in approximately two-
thirds of patients and significant improvement in one-third;
however, the range varies from 33% to 85% showing sig-
nificant improvement.t-!' The wide variation in results
probably reflects differences in patient selection criteria
and evaluation of the shunt response.
Many investigators have tried to prognosticate about
who will benefit from shunting. Certain factors have been
associated with favorable shunt results, with evidence of
altered CSF dynamics being the underlying theme.
Overnight, a CSF pressure of more than 180 mm H 20 was
associated with better shunt results.V Improvement after
lumbar puncture is akin to a therapeutic trial of temporary
shunting and has also been associated with good shunt
results.t" Lumboventricular perfusion is the measurement
of CSF absorption capacities and has had good predictive
value.P Factors that have been of little importance when
considering shunting include atrophy on CT scan,
530 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
Spinious process O;;;:;;:~\l~~6~~;
Figure 31-6. Lumboperitoneal shunt.
Catheter Tunneled
Subcutaneously
to right upper
Quadrant
radionuclide cisternography, cerebral blood flow measure-
ments, and certain electroencephalographic patterns.50
PSEUDOTUMOR CEREBRI
Pseudotumor cerebri, or benign intracranial hypertension,
is a syndrome of increased intracranial pressure without
apparent intracranial mass. The presenting signs and symp-
toms include headache and blurred vision, and it has a
predilection for young obese females.54 Diplopia and nausea
can occur but are less frequent symptoms. Pulsatile tinnitus,
hearing loss, and vertigo have been described as being
associated with it and can be the presenting symptoms.55
The tinnitus can usually be auscultated, and light digital
occlusion of the ipsilateral internal jugular vein usually
will improve the tinnitus and low-frequency sensorineural
hearing loss.56 Papilledema is invariably present on physical
exam. Sixth nerve palsies may also occur.
Causal factors associated with pseudotumor cerebri have
been identified as pregnancy, vitamin A disturbances,
drugs, anemia, arteriovenous malformations, and sinus
obstruction.57 The pathophysiology remains poorly under-
stood, but the underlying mechanism appears to be defec-
tive CSF absorption leading to interstitial brain edema.
This theory has been supported by human studies linking
pseudotumor cerebri to increased resistance to absorption
of CSF, probably at the level of the arachnoid villi of
the superior sagittal sinuses. 58,59 Why this should lead
to interstitial edema instead of hydrocephalus is unclear.
The resistance to reabsorption is probably secondary to
venous hypertension.
ANTERIOR VIEW
I
~
L4
~~~4=-::,......~'--- 1-inch incision
over L3 and L4
down to
Lumbodorsal fascia
\ J
The pathophysiology of hearing loss in patients with
increased intracranial pressure has been attributed to
transmission of increased pressure via the cochlear aqueduct
to the perilymph or stretching of the central ascending
auditory pathways.60,61 An alternative hypothesis was pro-
posed by Sismanis and colleagues.55 They postulated that
when a venous hum is present in pseudotumor cerebri, it
produces a "pseudosensorineural" hearing loss from the
masking of the low frequencies.l' The electronystagmog-
raphy findings of patients with pseudotumor cerebri were
described by Kaaber and Zilstorff.f with decreased caloric
response being the most common finding.
Neurologic imaging is important to rule out underlying
intracranial mass. Ventricular size is usually normal,
although reports of slightly large or small ventricles do
exist. Lumbar puncture is essential to confirm the diagno-
sis of elevated CSF pressures. Angiography may be indi-
cated in cases where AVM or sinus occlusion is suspected.
The treatment of pseudotumor cerebri is directed at the
underlying cause, if any can be found, such as anemia or
obesity. Direct management of the intracranial pressure
with serial lumbar punctures, acetazolamide, diuretics, and
steroids has been used.v' Lumboperitoneal shunting has
been advocated in cases refractory to medical manage-
ment. 51,64 Continued care by an ophthalmologist until
intracranial pressures are reduced is also necessary to
minimize the possibility of permanent visual loss from
papilledema.
Otitic hydrocephalus, despite its name, is actually a form
of pseudotumor cerebri.v' It is the least common of the
intracranial complications of otitis media, and only infre-
quent case reports exist in modern literature. The largest

series consists of a literature review of 44 cases by Foley.'"
Most cases were associated with lateral sinus thrombosis or
perisinus abscess, but not all. The increased intracranial
pressure is most likely related to obstructed venous flow
from the head.
The presenting signs and symptoms are the same as for
pseudotumor cerebri in association with recent or ongoing
ear disease. It is most commonly seen in children and ado-
Iescents." CT will detect the ear disease but will also rule
out intracranial lesions. Imaging of the venous system via
angiography or magnetic resonance venography is critical
to establish the status of the sinuses. Lumbar puncture
should reveal elevated pressure but is otherwise normal.v?
Treatment consists of managing increased intracranial
pressure to prevent permanent visual deficits. If steroids
and diuretics are of little benefit, serial lumbar punctures
as a temporizing measure or a shunt procedure are indi-
cated. The mainstay of treatment of the ear disease con-
sists of mastoidectomy and antibiotics.
CONCLUSION
In summary, increased intracranial pressure is primarily
a neurologic problem; however, ear signs and symptoms
can be the presenting manifestations of hydrocephalus or
benign intracranial hypertension. Neurotologic proce-
dures also can be complicated by hydrocephalus. Thus a
working knowledge of this topic should be in the arma-
mentarium of every neurotologist.
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Vertigo, Dysequilibrium, and
Imbalance with Aging
Outline
Introduction
Structural Changes
with Aging
Alterations in Vestibular
Function with Aging
Presbystasis
Evaluation
Vertebrobasilar Insufficiency
INTRODUCTION
Vestibular dysfunction is common in the elderly, with
reported prevalence of vertigo, dysequilibrium, or imbal-
ance to be as high as 47% in men and 61% in women older
than age 70.1–3 Dizziness is the most common presenting
symptom in those 75 years and older seen in an office prac-
tice.4,5 The incidence of falls in individuals older than age
65 is between 20% and 40% in those living at home.2,6–10
It is twice as frequent for the institutionalized elderly.11,12
By age 80, one in three people will have suffered a fall
associated with significant morbidity. Vestibular symptoms
precede these falls in more than half of the patients. These
falls are associated with significant morbidity and mortal-
ity and constitute one of the leading causes of death in the
elderly.13
Spatial orientation and balance is achieved through the
complex integration of visual, proprioceptive, somatosen-
sory, and vestibular information in the central nervous
system. The visual oculomotor reflexes interact with the
vestibulo-ocular reflex to produce a stable visual field
necessary to maintain orientation. Posture is maintained
through the interaction of the collicovestibular and spin-
ovestibular reflexes, segmental stretch reflexes, and several
exteroceptive sensory systems such as touch and tempera-
ture. The processing and integration of these various
sensory and motor input in the brain allows for orienta-
tion, balance, maintenance of posture, and locomotion.
The aging brain is less efficient at processing the variety of
mechanosensory inputs and effecting an appropriate
motor response to maintain perfect balance. This is likely
due to structural and physiologic alterations associated
with aging.
Chapter
32
Labyrinthine Disorders Anil K. Lalwani, MD
Other Otologic and
Neurotologic Disorders
Cervical Vertigo
Systemic Disorders
Treatment and Rehabilitation
of Vestibular Dysfunction
STRUCTURAL CHANGES WITH AGING
The vestibular system, like other organ systems, under-
goes degenerative changes with aging, resulting in variable
functional disability. The specialized neural cells of the
mammalian vestibular system are nonmitotic and thus can-
not undergo replication and renewal. During the course of
a lifetime, DNA transcription errors and insoluble pig-
ments accumulate, and protein synthesis becomes increas-
ingly inefficient. Additionally, environmental and external
factors such as noise trauma, physical trauma, ototoxic
substances, and medications also contribute to senescence.
Degenerative changes (Table 32-1) and atrophy have
been noted throughout the vestibular apparatus, including
the otoconia, vestibular epithelium, vestibular nerve,
Scarpa’s ganglion, and cerebellum.14–19 In the utricle and
saccule, statoconia progressively demineralize and frag-
ment, resulting in decreased responsiveness to gravity and
to linear acceleration.20 The migration of degenerated oto-
conial debris into the dependent ampulla of the posterior
semicircular canal may result in positional balance distur-
bances (cupulolithiasis or benign paroxysmal positional
vertigo).21 In the sensory epithelia, inclusion bodies, lipo-
fuscin, and vacuoles accumulate. In addition, cell shrink-
age and atrophy and replacement of hair cells with scar
formation occur.22,23 After age 70, the number of hair cells
in the maculae of otolith organs decreases by 20%, and the
cristae of the semicircular canals decreases by 40%.24 The
cell loss begins at about age 40.25 The type I hair cells are
affected more than type II hair cells.
The reduction in the number of cells in the Scarpa’s
ganglion as well as the number of vestibular nerve fibers
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
with Aging
Otoconia Demineralization
Fragmentation
Migration
Vestibular epithelium Inclusion bodies
Vacuoles
Lipofuscin accumulation
Hair cell loss and atrophy (type 1 > type II)
Vestibular nerve Decrease in number of fibers
Scarpa’s ganglion Decrease in number of ganglion cells
Alterations in synaptic bars
Vestibular nuclei Lipofuscin accumulation
Axonal degeneration
Membrane invaginations
Cerebellum Loss of Purkinje cell
Decreased axodendritic synapses
Reduction in size of cerebellar vermis
Lipofuscin accumulation
Rodlike inclusions
Other inclusion bodies
number of ganglion cells in the Scarpa’s ganglion is
reduced.27 Examination of the vestibular nerve synapses
has demonstrated alterations in the synaptic bars in people
40 years of age and older.25 Beginning at age 50, there is
loss of nerve fibers between the vestibule and the Scarpa’s
ganglion. Compared with those 35 years of age or younger,
the number of nerve fibers in specimens 75 years and older
is reduced by 37%.28 The greatest loss occurs among the
thick myelinated fibers of the cristae, resulting in decrease
in the neuronal condition velocity with age. Hair cell degen-
eration likely precedes vestibular neuronal degeneration.27
The effect of aging on the vestibular nuclei are less well
understood. Studies of other brainstem nuclei have failed
to demonstrate significant age-related decline in neuronal
cell populations.23 Lipofuscin accumulation in the vestibular
nuclei, similar to that seen in the hair cells, has been
observed. In the lateral vestibular nucleus of rats, membrane
invagination and axonal degeneration has been noted.29
In the cerebellum, there is loss of Purkinje’s cells begin-
ning in the fifth decade. Ellis30 reported a 38% decline in
the number of Purkinje cells in the cerebellar cortex of five
adults age 62 to 100 years compared with younger popula-
tion. Hall and colleagues31 noted a 25% reduction in
Purkinje cell population in the cerebellum with aging, with
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
normal number of cells. Glick and Bondareff32 have docu-
mented a 24% decrease with age in axodendritic synapses
in the rat cerebellar vermis paralleling cerebellar neuronal
cell loss. Raz and coworkers,33 using magnetic resonance
imaging, have demonstrated a significant reduction in the
total area of the cerebellar vermis. As in the peripheral
sensory epithelia and the vestibular nucleus, lipofuscin,
rodlike nuclear inclusions, and other inclusion bodies have
been observed to accumulate with age in the cerebellum.34,35
Other ultrastructural changes associated with aging
include a decreased amount of Nissl substance in the
perikaryon, loss of demarcation between the nucleus and
cytoplasm, and paler nucleoli.34,35 The clinical significance
of these changes is unclear.23
ALTERATIONS IN VESTIBULAR FUNCTION
WITH AGING
Vestibular testing of the elderly has demonstrated quan-
tifiable functional decline with age. A variety of testing
modalities are available, including physical examination,
electronystagmography, rotational testing, and posturog-
raphy. The physical exam may assess the eye movements,
note the presence or absence of nystagmus, perform pos-
tural testing, and evaluate gait. Potvin36 has demonstrated
decline in all postural tests with age, the most sensitive of
which was the inability of the elderly male to stand on one
leg with the eyes closed. Electronystagmography is a grad-
uated series of evaluations of the vestibular and vestibulo-
ocular system that includes caloric responses. It can be
useful in establishing the degree of vestibular function in an
ear, determining the side of pathology, and differentiating
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
time constants over a wide range of frequencies of rota-
tional stimuli.38,39
Posturography is a relatively new method for studying
the ability of the subject to maintain balance with chang-
ing visual and somatosensory input. The relative energy
required to maintain balance on the posturography test
increases linearly with age until age 70. The elderly also
have larger sway excursions on balance platforms in
posturography.40 Further, Teasdale and colleagues41 have
shown that visual deficits along with platform disruption
has a much greater effect on posture than platform alter-
ation in isolation. This and other work have highlighted
the increased reliance on visual cues on maintenance of
balance in the elderly.42,43 In addition, the posture is also
negatively affected by decreased sensation and muscle
weakness in the lower extremities and increased reaction
time.43–45 Rotational testing is available to evaluate the
vestibulo-ocular reflex. In the elderly, there is significant
decrease in gain in the vestibulo-ocular reflex to different
rotatory stimuli.46,47 Overall, aging affects the vestibular,
visual, and proprioceptive information available for central
processing, as well as the ability of the central nervous
system to process the sensory information and effect
motor response.
PRESBYSTASIS
Dysequilibrium of aging, or presbystasis, a term coined by
Belal and Glorig, is a common diagnosis in elderly patients
evaluated for dizziness.48 Its cause is multifactorial and is
related to the structural and physiologic deterioration of
the vestibular apparatus associated with normal aging as
discussed earlier.49,50 Presbystasis is the vestibular counter-
part to presbycusis, the hearing loss associated with aging
of the auditory system. It is a diagnosis of exclusion and
not a specific pathologic diagnosis. In their original study
of 740 patients older than age 65 presenting with dizziness,
79% of the patients were diagnosed with presbystasis fol-
lowing clinical evaluation.48 A specific cause for dizziness
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
with Balance Symptoms
Anticholinergics Scopolamine, promethazine, amitriptyline,
meclizine
Anticonvulsants Phenytoin, carbamazepine, phenothiazines,
chlorpromazine
Antihypertensives Furosemide, propranolol, terazosin
Antineoplastic drugs Cisplatin
Dopamine agonists L-Dopa/carbidopa
H2 blockers Cimetidine
Ototoxic drugs Gentamicin
Sedatives Barbiturates, benzodiazepines
Tricyclic antidepressants Nortriptyline
Vasodilators Isosorbide, nifedipine
noted in the examination of extraocular movements.
Otoscopic examination, to rule out middle ear disease and
cholesteatoma, should always be performed. Examination
of gait, rapid alternating movement test, finger-to-nose
testing, and heel-to-knee test are useful in assessing cere-
bellar function.
Complete audiometry should be obtained to evaluate
auditory function. Further examinations may include
electronystagmography, posturography, rotational testing,
computerized tomography, and magnetic resonance imag-
ing. When cardiac or another medical cause is suspected, a
complete evaluation by an internist should be obtained.
VERTEBROBASILAR INSUFFICIENCY
Vertebrobasilar insufficiency is an important cause of
vertigo and dysequilibrium in the elderly because it sup-
plies both the peripheral and central components of
vestibular system.58 It usually results from arteriosclerosis
with insufficient collateral circulation, but may also be due
to compression of vertebral arteries by cervical spondylo-
sis, postural hypotension, or the subclavian steal syndrome.
The classic clinical presentation of vertebrobasilar
ischemia includes vertigo with head motion (especially
looking up), dysarthria, numbness of the face, hemiparesis,
headache, and diplopia. Less frequently, visual distur-
bances, including oscillopsia, field defects, transient
blindness, cerebellar ataxia, dysphagia, and drop attacks
may occur, reflecting ischemia of the brainstem and cere-
bellum. Vertigo or dysequilibrium may occur without
other neurologic signs or symptoms. A definitive diagnosis
may be established by four-vessel cerebral angiography,
but is seldom indicated. Magnetic resonance angiography,
a noninvasive imaging modality, will likely play an increas-
ingly important role in the diagnosis of vertebrobasilar
disease. Presently, there is no effective medical or surgical
treatment for vertebrobasilar insufficiency, although reha-
bilitative measures may be beneficial in the amelioration of
the vestibular symptoms.
LABYRINTHINE DISORDERS
A host of peripheral vestibular disorders may cause ver-
tigo, including benign paroxysmal positional vertigo
(BPPV) or cupulolithiasis, labyrinthitis, vestibular neu-
ronitis, Ménière’s syndrome, labyrinthine concussion due
to trauma, and perilymph fistula among others. In younger
patients BPPV is usually secondary to trauma, whereas in
the elderly it is usually a result of degenerative
processes.21,59 The patient complains of intermittent,
irregular episodes of vertigo precipitated by rapid head
motion, particularly when turning over in bed or with neck
extension. Vertigo is of short duration usually lasting less
than a minute. The Hallpike maneuver, the brisk position-
ing of the patient’s head backward and sideways with the
test ear positioned down, performed during electronystag-
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
on subsequent testing. Vestibular suppressant medications
are of limited usefulness, except during periods of exacer-
bation. The severity of symptoms may diminish with rep-
etition due to habituation. Patients usually respond to
vestibular exercises and spontaneous resolution occurs
within a year in most cases.60 In persistent cases, singular
neurectomy may be curative.61
Ménière’s syndrome is characterized by episodic severe
vertigo, fluctuating sensorineural hearing loss, tinnitus,
and ear fullness. Pathologically, there is distension of the
endolymphatic system throughout the inner ear, presum-
ably due to dysfunction of the endolymphatic sac. Other
specific causes of endolymphatic hydrops include bacterial,
viral, immunologic, and syphilitic labyrinthitis. The clini-
cal course is highly variable, with clusters of severe
episodes interspersed with periods of remission of variable
duration. Vertigo may last from 30 minutes to several
hours and is usually associated with nausea and vomiting.
A feeling of being off-balance or of unsteadiness may
persist for several days with subsequent recovery until
the next episode. The patient may complain of worsening
hearing loss and tinnitus that may precede the acute attack
of vertigo. Management may include a low-salt diet,
diuretics, vasodilators, vestibular suppressants, and occa-
sionally surgery to decompress the endolymphatic system.
Acute labyrinthitis, which most probably results from a
viral infection of the inner ear, causes both severe vertigo
and hearing loss. Typically, it runs its course over a period
of 1 to 2 weeks, although residual hearing loss and periodic
recurrence of vertigo are frequent sequelae. In the elderly,
the recovery may be incomplete and prolonged over
several months. Vestibular neuronitis also presents with
vertigo similar to labyrinthitis, but is unaccompanied by
auditory symptoms. Electronystagmography demonstrates
unilateral reduced caloric response.
OTHER OTOLOGIC AND NEUROTOLOGIC
DISORDERS
Middle ear disease such as acute otitis media can present
with vertigo in the young and the elderly. Cholesteatoma
may cause dizziness due to serous or bacterial labyrinthitis
or direct erosion of the semicircular canals. Perilymphatic
fistula resulting from chronic otitis media, cholesteatoma,
or trauma can present with episodic vertigo. Ototoxicity

secondary to aminoglycoside therapy is more common in
the elderly and is frequently associated with simultaneous
diuretic therapy or diminished renal function.62 Acoustic
neuroma, also called vestibular schwannoma, the most
common tumor of the cerebellopontine angle, presents
with unilateral hearing loss, tinnitus, and vertigo or
dysequilibrium. Selesnick and Jackler63 found that nearly
half of the patients complained of dysequilibrium that
was directly correlated to the size of the tumor. Vertigo,
present in 19% of their patients, was more common in
smaller tumors. Other symptoms of acoustic neuroma
include facial nerve dysfunction, and other cranial neu-
ropathies, facial hypesthesia, headache, and cerebellar dys-
function. Audiogram usually reveals a unilateral,
asymmetrical, sensorineural hearing loss with poor speech
discrimination. Gadolinium-enhanced magnetic reso-
nance imaging is the study of choice and is capable of iden-
tifying tumors millimeters in size. Surgical removal is
curative. Other tumors of the cerebellopontine angle
include meningioma, epidermoid, arachnoid cyst, lipoma,
and metastatic tumor, among others.64 Clinically, they
mimic an acoustic neuroma and may present with
dizziness.
CERVICAL VERTIGO
Vertigo occurring with neck motion is defined as cervical
vertigo. The exact cause of this disorder is controversial.
Possible explanations include altered spinovestibular
input, vertebrobasilar ischemia due to compression by
osteophytes, and irritation of the vertebral sympathetic
plexus due to cervical spondylosis.65–67 The aortic arch
syndrome and subclavian steal syndrome may also cause
cervical vertigo. Cervical spine films are not helpful due to
the large prevalence of asymptomatic osteoarthritic disease
in the elderly. Neck exercises and proper posture may be
of help in relieving the symptoms.
SYSTEMIC DISORDERS
A plethora of systemic disorders may affect equilibrium
and balance in the elderly, including cardiovascular disease
(hypertension, arrhythmia, ischemic heart disease, hyper-
active carotid sinus reflex, postural hypotension), cere-
brovascular disease, peripheral vascular disease, neurologic
disorders (Parkinson’s disease, dementia, epilepsy, vitamin
B12 deficiency), visual impairment, metabolic disease
(diabetes, thyroid disorder), and musculoskeletal prob-
lems.51 Therapeutic drugs are frequently responsible for
dysequilibrium and postural instability, especially the anti-
hypertensive, antidepressant, psychotropic, and sedative-
hypnotic classes.68
TREATMENT AND REHABILITATION
OF VESTIBULAR DYSFUNCTION
Many different drugs have been tried for the symptomatic
relief of vertigo. In most common use are the antihista-
mines, sedative-hypnotics, and anticholinergics. Vestibular
Vertigo, Dysequilibrium, and Imbalance with Aging 537
suppressants should be used to lessen the unpleasant sen-
sation and to alleviate vegetative symptoms such as nausea
and vomiting. However, they should only be used for a
short duration of 1 to 2 weeks, because they adversely
affect the process of central compensation following acute
vestibular disease. In acute severe vertigo, diazepam, 2.5 to
5 mg intravenously, may abate an attack. Relief from nau-
sea and vomiting usually requires an antiemetic delivered
intramuscularly or by rectal suppository (e.g., prochlor-
perazine, 10 mg intramuscularly, or 25 mg rectally every 6
hours). Antihistamines may be used for less severe vertigo.
Examples include meclizine or dimenhydrinate, 25 to 50
mg orally every 6 hours. Transdermal scopolamine, which
is in widespread use for the suppression of motion sick-
ness, is also useful in the management of vertigo. In the
elderly, however, anticholinergic therapy is frequently
complicated by mental confusion and urinary obstruction,
the latter especially in males. The use of transdermal
scopolamine may also be limited due to side effects of dry
mouth and blurred vision and is contraindicated in glau-
coma patients. Therapeutic effect with fewer side effects
may be achieved by cutting the patch in half or even to
one-quarter size. Careful handwashing after handling the
patches is necessary to prevent inadvertent eye contact
with resultant prolonged pupillary dilatation and possible
acute narrow-angle glaucoma. Therapy with a combina-
tion of pharmacologic agents may be efficacious when
single-drug therapy has been ineffective.
Once nausea and vomiting have resolved, exercise
should be encouraged to enhance central compensation
following peripheral labyrinthine dysfunction. Physical
activity is the single most important element in functional
recovery after acute labyrinthine dysfunction.69,70 Patients
should be instructed to repeatedly perform maneuvers that
provoke vertigo—up to the point of nausea or fatigue—in
an effort to habituate them. Many patients find vestibular
exercise programs (e.g., Cawthorne’s exercises) helpful.71
A formal physical therapy program designed to identify
and correct maladaptive compensation strategies may also
prove beneficial to patients with a central or peripheral
vertigo. The benefit from vestibular rehabilitative therapy
is not significantly influenced by the age of the patient72
but may be negatively affected by the presence of multiple
causal factors. Subjective and objective benefit with
vestibular rehabilitation is seen in patients with balance
disturbance associated with migraine headache.73 Surgical
intervention may be helpful in selected patients who con-
tinue to have disabling symptoms despite a prolonged and
varied course of medical therapy. Surgical therapy may
include sectioning of the vestibular nerve in a hearing ear
or a labyrinthectomy in a deaf ear.74
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 Chapter
Cervical Proprioceptive Dysfunction
33 Outline
Mark J. Syms, MD Introduction
Definition
Cervical Proprioceptive
Function
Clinical Evidence
INTRODUCTION
A sense of balance is obtained through integration of three
sensory systems—visual, vestibular, and somatosensory.
The sensory information is redundant, which allows the
loss, or decreased input, of one sense to be compensated
for, in part, by input from the other two sensory systems.
When the information from two sensory sources conflict,
disorientation and vertigo results. The intensity of the
disorientation and vertigo is a function of the magnitude
of the sensory mismatch.
DEFINITION
Cervical vertigo, a controversial term that has been com-
monly used in the literature,1 was introduced by Ryan and
Cope2 to describe a condition affecting four patients with
vertigo and common neck complaints. Neck afferents not
only assist in coordination of the eye, head, and body, but
also influence spatial orientation and posture. On this
basis, it is argued that stimulation or lesions of the neck
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
a typical time course for the condition has not been estab-
lished. Second, reliable and well-established signs and tests
can establish a convincing alternative diagnosis in about
90% of patients presenting with vertigo.
CERVICAL PROPRIOCEPTIVE FUNCTION
The neck enables rotation of the head independently of
the trunk. In order to maintain a stabile position, the
vestibular input has to be complemented with neck pro-
prioceptive input.4 There is considerable experimental
evidence from animal studies demonstrating neck and
vestibular signals converge and interact in the brain.5–8
Anatomic studies have identified links between the cervical
540
Differential Diagnosis
Treatment
Conclusion
spine receptors and the vestibular nuclei.9,10 Large popula-
tions of receptors have been found in the neck muscle in
close proximity to the facet joints of the cervical spine.11
Various reflexes have been demonstrated between the neck
and vestibular and ocular systems. The vestibulocollic
reflex (VCR) is mediated by vestibulospinal projections.12
The function of the VCR is to stabilize the head in space
by means of neck muscle movements. The VCR operates
in conjunction with the cervicocollic reflex (CCR), which
employs proprioceptive information from the neck to sta-
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
was held stationary in space.14 Later, the cervico-ocular
reflex (COR) was demonstrated in normal human subjects
and found to contribute to visual stabilization.15 It is
thought that neck joint receptors rather than muscle spin-
dles are the primary source of neck afferents involved in
the COR.16,17 The body employs these reflexes to maintain
position of the head in space. Any perturbations of the
information or interruptions of the reflexes could poten-
tially lead to a proprioceptive disorder.
CLINICAL EVIDENCE
Despite the evidence demonstrating cervical contribution
to proprioception, skeptics argue that no reliable tests
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
complaint of vertigo.18
Since neck control is the product of input of multiple
systems, isolation of the cervical region as the source of the
“dizziness” is impossible with simple postural maneuvers.3
Animal experiments have demonstrated that surgical
deafferentation of C1–3 in squirrel monkeys19 and in the cat20
caused ataxia. Additionally, injection of local anesthesia in
the suboccipital region caused ataxia in rhesus monkeys.21
When suboccipital anesthesia is performed in humans,
 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

DIFFERENTIAL DIAGNOSIS
Skeptics of the existence of cervical vertigo argue the
symptoms of cervical vertigo have an alternative explana-
tion.24 Brandt argues that well-established signs and tests
can provide a convincing alternative diagnosis in about 90%
of patients presenting with vertigo.3 Prior to making the
diagnosis of cervical vertigo, alternative causes need to be
excluded (Table 33-2). Others argue that cervical vertigo is
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
and existence of cervical vertigo, vertigo with a cervical
component surely exists. In the context of a thorough neu-
rotologic examination, clinicians can recognize that cervi-
cal disorders are a component of the dizziness a patient is
experiencing and should attempt to address the cervical
disorder with the hope of improving the symptoms.
TREATMENT
Cervical physical therapy has been reported to be very
successful in the resolution of vertigo attributed to cervical
dysfunction. Galm and colleagues reported on a group of
50 patients who presented with symptoms of dizziness.26
TABLE 33-1. Dizziness/Vertigo after Head Injury
Author Number of Patients Incidence (%)
Linthicum and Rand27 30 90
Glaser 70 40
Procter et al28 32 50
Luxon L: Posttraumatic vertigo. In Baloh R, Halmagyi G (eds.): Disorders of the
Vestibular System. New York, Oxford University Press, 1996, pp 381–395.
Vascular
Rotational vertebral artery occlusion Ischemic depolarisation
Carotid sinus syndrome Global cerebral ischemia
Intoxication:
Positional alcohol nystagmus/vertigo Cerebellar and specific gravity
differential between cupula and
endolymph
Drugs (e.g., antiepileptics) Cerebellar and ocular motor
From Brandt T, Bronstein AM: Cervical vertigo. J Neurol Neurosurg Psychiatry
71(1):8–12, 2001.
Each patient underwent a neurologic and otolaryngologic
examination to rule out other causes of the vertigo. The
patients underwent a chiropractic evaluation, which demon-
strated dysfunction of the upper cervical spine in 31 (62%)
of the 50 patients. The remaining 19 (38%) patients did
not show signs of upper cervical dysfunction. All of the
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
patients underwent another 3 months of physical therapy
and were reevaluated 2 weeks after the completion of the
physical therapy. In the group with cervical dysfunction,
the vertigo was improved in 16 of 31 patients after the first
3 months of therapy. None of the 19 patients without
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.
The remaining seven reported no improvement. Of the
group without cervical dysfunction, only five patients
(26.3%) reported any improvement of the vertigo symp-
toms. Similarly, Karlberg and associates reported that
physiotherapy in patients with dizziness of a suspected
cervical origin significantly reduced the neck pain and
intensity and the frequency of the dizziness.25 Even skeptics
of the existence of cervical vertigo acknowledge that vertigo
542 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
can be accompanied by cervical pain and associated with
head injury or whiplash injury and that in some cases it
improves dramatically with physiotherapy.1
CONCLUSION
Cervical vertigo is a controversial entity. Despite the con-
troversy, vertigo with a cervical component surely exists.
Clinicians should perform a thorough neurotologic exam-
ination and recognize if a cervical disorder is a component
of the dizziness a patient is experiencing. If a cervical pro-
prioceptive disorder is thought to contribute to the dizzi-
ness, the patient should be referred for physiotherapy to
address the cervical disorder.
REFERENCES
1. Brandt T: Cervical vertigo—Reality or fiction? Audiol Neurootol
1(4):187–196, 1995.
2. Ryan G, Cope S: Cervical vertigo. Lancet 2:1355–1358, 1955.
3. Brandt T: Vertigo: Its Multisensory Syndromes. New York,
Springer-Verlag, 1991, pp 277–288.
4. Roberts TD: Reflex balance. Nature 244(5412):156–158, 1973.
5. Fredrickson JM, Schwarz D, Kornhuber HH: Convergence and inter-
action of vestibular and deep somatic afferents upon neurons in the
vestibular nuclei of the cat. Acta Otolaryngol 61(1):168–188, 1966.
6. Boyle R, Pompeiano O: Convergence and interaction of neck and
macular vestibular inputs on vestibulospinal neurons. J Neurophysiol
45(5):852–868, 1981.
7. Rubin AM, Liedgren SR, Odkvist LM, et al: Labyrinthine and
somatosensory convergence upon vestibulospinal neurons. Acta
Otolaryngol 86(3–4):251–259, 1978.
8. Kasper J, Schor RH, Wilson VJ: Response of vestibular neurons to
head rotations in vertical planes. II. Response to neck stimulation and
vestibular-neck interaction. J Neurophysiol 60(5):1765–1778, 1988.
9. Bankoul S, Neuhuber WL: A direct projection from the medial
vestibular nucleus to the cervical spinal dorsal horn of the rat, as
demonstrated by anterograde and retrograde tracing. Anat Embryol
(Berl) 185(1):77–85, 1992.
10. Neuhuber WL, Zenker W: Central distribution of cervical primary
afferents in the rat, with emphasis on proprioceptive projections
to vestibular, perihypoglossal, and upper thoracic spinal nuclei.
J Comp Neurol 280(2):231–253, 1989.
11. Dutia MB: The muscles and joints of the neck: their specialisa-
tion and role in head movement. Prog Neurobiol 37(2):165–178,
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
Controlling Motion: Vestibular and Sensorimotor Function. New
York, New York Academy of Sciences, 1992, pp 485–499.
13. Peterson B, Goldberg J, Bilotto G, Fuller F: Cervicocollic reflex:
Its dynamic properties and interactions with vestibular reflexes.
J Neurophysiol 54:90–109, 1985.
14. Bárány R: Augenbewegegungen durch Thoraxbewegungen ausgelöst.
Zbl Pysiol 20:298–302, 1906.
15. Barnes GR, Forbat LN: Cervical and vestibular afferent control of
oculomotor response in man. Acta Otolaryngol 88(1–2):79–87,
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
neck reflexes. J Neurophysiol 14:191–195, 1951.
18. Norre ME, Forrez G, Stevens A, Beckers A: Cervical vertigo diagnosed
by posturography? Preliminary report. Acta Otorhinolaryngol Belg
41(4):574–581, 1987.
19. Igarashi M, Alford BR, Watanabe T, Maxian PM: Role of neck
proprioceptors for the maintenance of dynamic bodily equilibrium
in the squirrel monkey. Laryngoscope 79(10):1713–1727, 1969.
20. Manzoni D, Pompeiano O, Stampacchia G: Cervical control of
posture and movements. Brain Res 169(3):615–619, 1979.
21. De Jong PT, de Jong JM, Cohen B, Jongkees LB: Ataxia and
nystagmus induced by injection of local anesthetics in the Neck.
Ann Neurol 1(3):240–246, 1977.
22. Luxon L: Posttraumatic Vertigo. In Baloh R, Halmagyi G (eds.):
Disorders of the Vestibular System. New York, Oxford University
Press, 1996, pp 381–395.
23. Baloh R, Honrubia V: Clinical Neurophysiology of the Vestibular
System. Philadelphia, FA Davis, 1990.
24. Brandt T, Bronstein AM: Cervical vertigo. J Neurol Neurosurg
Psychiatry 71(1):8–12, 2001.
25. Karlberg M, Magnusson M, Johansson R: Effects of restrained
cervical mobility on voluntary eye movements and postural control.
Acta Otolaryngol 111(4):664–670, 1991.
26. Galm R, Rittmeister M, Schmitt E: Vertigo in patients with cervical
spine dysfunction. Eur Spine J 7(1):55–58, 1998.
27. Linthicum F, Rand C: Neuro-otological observations in concussion
of the brain. Arch Otolaryngol 13:785–821, 1931.
28. Procter B, Gurdjian E, Webertser J: The ear in head trauma.
Laryngoscope 66:16–61, 1956.

Paraneoplastic Disorders
Outline
Paraneoplastic Syndromes Generated by Neurotologic Tumors
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
cancer as a paraneoplastic syndrome (PNS).1 Fundamen-
tally, a PNS describes an “association of symptoms and
signs not directly related to the site or local manifestations
of a malignant tumor or its metastases.”1 Although the term
is most appropriately used when referring to the remote
effects of cancerous lesions, for the purpose of discussion
in this chapter it is expanded to encompass the remote
effects of benign tumors as well.
PNSs are of significance to neurotologists for they may
be generated by tumors managed by neurotologists, they
may be generated by neoplasms occurring in association
with disorders managed by neurotologists, or they may
give rise to auditory and vestibular dysfunction requiring
neurotologic evaluation and management. In addition, a
PNS provides a unique vantage point from which to
observe the basic biology of the tumor cell involved.
PARANEOPLASTIC SYNDROMES
GENERATED BY NEUROTOLOGIC
TUMORS
The chief cells of paraganglions and paragangliomas (glomus
tumors) are of neural crest origin and are constituents of the
diffuse neuroendocrine system (DNES) (Table 34-1).2,3
Cells of the DNES, although seemingly disparate in
nature, are linked by shared cytochemical and ultrastruc-
tural features, particularly with regard to their capacity to
synthesize, store (in osmiophilic granules), and secrete
physiologically active products, for example, amines and
neuropeptides,4 which variably function as neurotransmit-
ters, neurohormones, hormones, and parahormones.4
The chief cells of paragangliomas have a demonstrated
capacity for catecholamine synthesis and secretion.5–9 The
metabolism of tyrosine, key in the generation of
catecholamines, is illustrated in Table 34-2.10 Only the
adrenal medulla, heart, and brain possess the enzyme
Chapter
34
A. Julianna Gulya, MD, FACS
phenylethanolamine-N-methyltransferase; thus, in para-
gangliomas dopamine and norepinephrine are produced.9,11
Tryptophan metabolism results in the production of the
indole amine serotonin (5-hydroxytryptamine) (Table 34-3),10
a capacity within the repertoire of human glomus cells, as
evidenced by their serotonin immunoreactivity.12–15
In addition, the chief cells of paragangliomas have been
documented to contain a wide variety of neuropeptides
(Table 34-4), enzymes, and other proteins typical of,
although not entirely specific for, members of the DNES.13
Neuron-specific enolase (NSE), chromogranin, and
leuenkephalin in particular serve as markers for chief cells,
and sustentacular cell markers include S-100 protein, glial
fibrillary acidic protein (GFAP),13 and nerve growth factor
receptor.
The clinical consequences of amine production by para-
gangliomas are manifested in the PNS of the “functional”
tumor. Although, as pointed out by Batasakis,16 “nearly all”
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
weight loss related to elevation of serum norepinephrine
and possibly dopamine.9 The disparity between potential
and actual catecholamine-related symptomatology is gen-
erally attributed to the requirement for a four- to fivefold
elevation of serum norepinephrine for the development of
symptoms.9 Tumor burden in and of itself does not appear
to predict whether or not a tumor will be “functional.”17
Ultrastructural and immunocytochemical analyses18 have
suggested that functional tumor cells, in contrast to those
of nonfunctional tumors, have larger secretory granules
(220 to 280 nm vs. 100 to 180 nm), contain numerous dilated
mitochondria) profiles (indicative of metabolic activity), and
express at least two of the antigens enkephalin, neuropep-
tide Y, or tyrosine hydroxylase.
The carcinoid syndrome, consisting of “episodic cuta-
neous flushing, cyanosis, abdominal cramps, diarrhea, and
valvular heart disease (and less commonly asthma and
arthropathy),”19 has been related to elevated serum levels
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-
atology resolved with resection of the tumor, providing
circumstantial evidence for the association of paragan-
gliomas with yet another type of PNS.
More convincingly, Galan and colleagues21 reported the
development of hypotension, bradycardia, and bron-
chospasm with intraoperative manipulation of a glomus
tympanicum tumor that had been associated preopera-
tively with elevated urinary 5-hydroxyindoleacetic acid
(5-HIAA), the urinary metabolite of serotonin. Within
5 minutes of the administration of intravenous octreotide,
the bronchospasm and the hemodynamic changes
resolved, and by the fifth postoperative day the patient’s
urinary 5-HIAA dropped to nearly normal.
The neuropeptides found within paraganglioma cells,
both chief and sustentacular, remain of uncertain signifi-
cance. Investigations have focused on the possibility that
neuropeptides give rise to PNS(s),22 that they prognosti-
cate tumor behavior,23 or that they can be used for tumor
localization.24
In the course of caring for patients who had undergone
infratemporal fossa removal of paragangliomas, members
of the Otology Group noted postoperative ileus, acalcu-
lous cholecystitis, and pancreatitis not seemingly related
to the surgical procedure nor the patients’ past medical
histories. In an attempt to determine whether neuropep-
tide secretion by the paragangliomas precipitated such
symptomatology, routine serum screening of paragan-
glioma and other skull base tumor patients for vasoactive
intestinal polypeptide, cholecystokinin (CCK), somato-
statin, pepsinogen I, human pancreatic polypeptide, and
thyroid-releasing hormone was undertaken. The degree of
postoperative ileus was then contrasted to the preoperative
serum levels of these neuropeptides, as well as to sacrifice
of the vagus nerve. In a review of 25 cases (19 paragan-
gliomas and 6 nonglomus tumors) it became evident that
vagus nerve sacrifice was not a determinant factor in post-
operative ileus. Interestingly enough, serum CCK levels in
patients with paragangliomas were significantly higher
( p < 0.05) than those of nonparaganglioma patients, and
the patients with more than 3 days of postoperative ileus
had preoperative CCK levels approximately twice that
of patients with postoperative ileus of briefer duration.22
A major difficulty in drawing firm conclusions from these
data is the wide variability in normal CCK serum levels;
nonetheless, further investigation appears warranted,
especially of the tracking serum neuropeptide levels post-
operatively.
A few reports of anemia, usually normochromic/normo-
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.

Two patients with nonmetastatic, cervical paragangliomas
experienced normalization of reduced hematocrits subse-
quent to tumor removal.27,29 Interference with production
of, or enhanced destruction of, erythropoietin are mecha-
nisms proposed by Schwartz and Israel26 based on their
finding of depressed erythropoietin levels in a patient with
metastatic paraganglioma. The precise mechanism of such
an “antierythropoietic effect,” if it truly exists, has yet to be
determined.
Linnoila and colleagues23 conducted immunohistochem-
ical analyses of 99 human adrenal and extra-adrenal para-
gangliomas for neuron-specific enolase and a total of 10
neuropeptides. They found that malignant paragangliomas,
that is, those with “proven regional or distant metastases,”
were positive for only an average of two neuropeptides per
tumor, in contrast to the benign tumors, which were posi-
tive for an average of five neuropeptides per tumor. They
suggested that there was a “definite relationship between
expression of neuropeptides and the biologic behavior of
these paragangliomas.”23
Lamberts and associates24 reported on the utility of 123 I-
labeled Tyr3-octreotide (a somatostatin analogue) in visu-
alizing some tumors, including paragangliomas, with
somatostatin receptors. Of the 20 paraganglioma patients
scanned, 10 jugulotympanic, 9 carotid, and 10 vagal para-
gangliomas were detected. Scanning missed small tumors
(less than 5 mm)—one carotid body and one tympanic
paraganglioma.
Scintigraphy with 111In-diethylenetriaminepentaacetic
acid octreotide (indium-111-pentretreotide) is able to reveal
tumors of at least 1 cm and perhaps as small as even 0.5 cm30
and may aid in the differentiation of paraganglioma versus
neuroma, meningioma, radionecrosis, and postoperative
scar from recurrent paraganglioma.
Octreotide may have some utility in the treatment of
unresectable or recurrent paragangliomas. In one report,31
octreotide therapy for up to 35 months was associated with
either no tumor growth or reduced tumor volume as
visualized by magnetic resonance imaging; side effects of
the therapy were mild, consisting largely of fatty stool.
PARANEOPLASTIC SYNDROMES
FROM DISORDERS ASSOCIATED
WITH NEUROTOLOGIC TUMORS
PNSs may arise from tumors occurring in conjunction
with disorders managed by the neurotologist; such situa-
tions are exemplified by the occurrence of additional non-
paraganglioma tumors with paragangliomas, as well as
with neurofibromatosis.
Paragangliomas have long been recognized for their
propensity to manifest associated lesions; approximately
10% of nonfamilial jugulotympanic paragangliomas will
exhibit another tumor of the paraganglioma type.32–34
In addition, pheochromocytomas,35,36 papillary thyroid
carcinoma,37 medullary carcinoma of the thyroid,38 and
parathyroid adenoma9 have been reported in association
with paragangliomas.
Kennedy and Nager38 pointed out a potential relation-
ship between the occurrence of paragangliomas (tympanic)
Paraneoplastic Disorders 545
with multiple endocrine neoplasia II (MEN II—Sipple’s syn-
drome), an autosomal-dominant, familial disease consisting
of pheochromocytomas, medullary carcinoma of the
thyroid, and parathyroid hyperplasia.
A familial tendency has been described for paragan-
gliomas, typified by autosomal-dominant transmission and
an exaggeration in the tendency for multiple para-gan-
gliomas,39,40 occurring in 25% to 50% of the cases39–42
and also perhaps in the occurrence of associated lesions.39
Thus, regardless of the functional status of the
paraganglioma that brings the patient to the attention of the
neurotologist, it is possible for an associated lesion to give
rise to the symptomatology of a PNS. It is important to
recognize that elevated serum epinephrine levels in a
patient with a paraganglioma mandate a thorough investi-
gation for a concurrent pheochromocytoma, because, as
discussed earlier, paragangliomas cannot metabolize
norepinephrine to epinephrine.
Patients with neurofibromatosis (von Recklinghausen’s
disease, NF1) also tend to manifest associated lesions.
For example, they have a 10-fold greater incidence
of pheochromocytoma than the general population.43
The occurrence of parathyroid adenoma in NF1 has been
speculated to represent a variant of MEN IIb, that
is, the MEN II that occurs in patients with diffuse
ganglioneuromatosis of the alimentary tract, mucosal
neuromas, and often a marfanoid habitus.44 Griffiths
and colleagues45,46 have even suggested that the triad of
NF1, pheochromocytomas, and duodenal carcinoid
constitutes a specific multiple endocrine neoplasia
syndrome, which they labeled MEN IIIa. Terminology can
cause confusion, for MEN IIb also has been referred to as
MEN III.44
Thus in managing neurofibromatosis the neurotologist
must be cognizant of the possibility of an associated lesion
with functional potential and may consider endocrinology
consultation for appropriate diagnosis and treatment.
Finally, neurofibromatosis has been associated with
pheochromocytomas, a paraganglioma (jugulare), and
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
of neural crest derivatives, or, as stated by Bolande,3 a
neurocristopathy.
As defined by Bolande,3 a neurocristopathy is a condition
with roots in aberrant neural crest development. Isolated
paragangliomas, pheochromocytomas, and carcinoid tumors
are some examples of what Bolande categorized as simple
neurocristopathies, or single, localized pathologic processes.
Complex neurocristopathies or neurocristopathic syndromes
include such entities as von Recklinghausen’s disease and the
multiple endocrine neoplasia disorders, which are typified by
a vast array of possible combinations of the simple neuro-
cristopathies. In fact, von Recklinghausen’s disease, because
it can potentially involve a wide range of neurocutaneous
and neuroendocrine disorders, is considered the prototype
of the complex neurocristopathies.3
Thus it is perhaps more useful in terms of extending our
knowledge of the basic biology of the paraganglioma not
merely to dismiss associations with other neural crest
disorders as random events, but to consider them as clues
546 NEUROTOLOGIC MANIFESTATIONS OF NEUROLOGIC DISEASE
to the existence of neurocristopathic syndromes, in which
paragangliomas represent only one manifestation.
PARANEOPLASTIC SYNDROMES
ASSOCIATED WITH CARCINOMA
Certain PNSs associated with malignancies rarely will
encompass auditory or vestibular symptomatology leading
to neurotologic consultation. Despite their rarity, such
PNSs are of significance because they provide a unique per-
spective on the biology, not only of the underlying cancer,47
but also of the auditory and vestibular systems. Substantial
progress, accelerated by advances in immunochemistry and
immunohistochemistry, has been made in elucidating the
operative mechanisms of two PNSs of potential relevance to
neurotologists, namely, paraneoplastic encephalomyelitis
(PEM) and paraneoplastic cerebellar degeneration (PCD).
PEM describes a group of neurologic PNSs sharing
inflammatory changes in neural tissue, especially perivas-
cular round cell infiltrates, microglial activation and
neuronal loss,48,49 and an autoimmune pathogenesis.50 A
small-cell lung carcinoma (SCLC) is the underlying malig-
nancy in the majority of cases.51 The various types of
PEM, namely, cerebral encephalitis, brainstem encephali-
tis, cerebellar encephalitis, subacute myelitis, and dorsal
root ganglionitis, are distinguished according to predomi-
nant anatomic site of the lesion. Clinical application of this
nosology is confronted with the reality of considerable
overlap among the various types.51
The brainstem form of PEM manifests the hallmark
inflammatory neuronal destruction, especially in the
medulla,51 that commonly involves the vestibular brain-
stem nuclei and uncommonly affects the cochlear nuclei.51
In addition, cranial nerve motor nuclei, such as XII and X
may be affected,51 and in the pons, the cranial nerve nuclei
involved include VI and VII.51
Sudden unilateral sensorineural hearing loss has been doc-
umented well in only one case of brainstem encephalitis.52
McGill52 found diffuse cochlear neuronal loss in the spiral
ganglion as well as in the dorsal and ventral cochlear nuclei
and peripheral vestibular structures ipsilateral to the side
of a sudden sensorineural hearing loss in a 54-year-old
female whose underlying SCLC was detected only on
autopsy. Such diffuse neuronal loss is not characteristic of
viral sudden sensorineural hearing loss.53,54
Márquez and coworkers55 reported the development of
a bilateral, rapidly-progressive sensorineural hearing loss
associated with gait instability in a 50-year-old man who
was subsequently found to have lung carcinoma with anti-
Hu antibodies (see following discussion). Unfortunately,
an autopsy was not performed.
PCD describes the subacute cerebellar degeneration seen in
patients with carcinoma (especially of the ovaries, breast, and
lung [SCLC]) and lymphoma.56 Histopathologically, inflam-
matory and noninflammatory variants occur,57 and although
the exact relationship of the two forms is uncertain,50 they
both share the finding of a diffuse loss of Purkinje cells.
Patients with PCD manifest progressive pancerebellar
dysfunction, particularly truncal and appendicular ataxia,
nystagmus, dysarthria, and diplopia.2,57-59 Abrupt-onset
vertigo or ataxia may be the initial symptoms of PCD,57 and
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
diagnosis of the underlying malignancy.61 Nonspecific clues
for PEM are sudden hearing loss occurring in a patient
older than 50 years in association with diffuse neurologic
symptoms. PCD is part of the differential diagnosis of
sudden-onset or progressive vertigo and ataxia, particu-
larly in a middle-aged female. Both PEM and PCD can
manifest the cerebrospinal fluid (CSF) findings of pleocy-
tosis with lymphocytic predominance, an elevated protein
count, oligoclonal bands, and an elevated IgG level.50,51
More specific tests have been developed for the diagnosis
of PEM and PCD, as discussed later.
The preponderance of evidence favors an autoimmune
pathogenesis for both PEM and PCD. The foundation of
the autoimmune hypothesis is that the cancer patient pro-
duces antibodies that react with antigens displayed by the
tumor; the antibodies may or may not have an adverse
effect on tumor growth,62,63 but they do react with anti-
gens of specific neural cells, causing their dysfunction or
death.63 Certainly, in the case of PEM, such a hypothesis
appears feasible because the cells of origin of SCLC,
Kulchitsky cells of the lung, are members of the DNES
and can express a variety of neuronal differentiation anti-
gens.64–67 Further support for the autoimmune hypothesis
has come with the identification of the antibodies anti-Hu
and anti-Yo being relatively restricted to patients with
PEM and PCD, respectively.50,68–70
Anti-Hu reacts with 35- to 36-kilodalton nucleoproteins
expressed only by brain tissue, for example, the neurons of
the nuclei of the brain (including the vestibular and
cochlear nuclei), and dorsal root and gasserian ganglion
neurons, as well as SCLC tissue. The nuclear staining
observed immunohistochemically with anti-Hu spares the
nucleolus and is not observed with satellite, Schwann, or
non-neural cells.62,71 Anti-Hu has been detected in the
blood and CSF72,73 and has also been eluted from tumor
(SCLC) and brain tissue of patients with PEM.74 The anti-
body may be taken up from the blood by central nervous
system (CNS) neurons in a process that involves endocy-
tosis and retrograde axonal transport,75 or from the CSF,
which is linked to intrathecal anti-Hu production.72 Copy
DNA (cDNA) clones have been isolated from both normal
brain tissue76 and SCLC tissue,77 which code for the Hu
antigen. A quantitative assay for anti-Hu sera has been
developed that uses the fusion protein encoded by these
cDNA clones.76 The target of the anti-Hu antibody is a
family of neuron-specific RNA-binding proteins (Hu).78
It is thought that “antibody mediated disruption of the
Hu RNA-binding activity might lead to neuronal death,”78
but the mechanism remains unclear.
Anti-Yo is the anti-Purkinje cell antibody found in the
serum and79 CSF72,80 of women with gynecologic or breast
cancer and PCD.69 Immunofluorescent study of anti-Yo
reveals a coarsely granular fluorescence of the cytoplasm,69
which by immunoelectron microscopy81 is correlated to
binding to the endoplasmic reticulum (Nissl substance) and
Golgi complexes of Purkinje cells. Two groups of proteins
(cerebellar degeneration–related [CDR] proteins)—one with

a relative molecular weight of 62 to 64 kilodaltons (CDR
62) and one with a relative molecular weight of 34 to
38 kilodaltons (CDR 34)—are recognized by anti-Yo;
CDR 62 accounts for the majority of the reactivity.82 Both
CDR 34 and CDR 62 are also expressed in the tumor tis-
sues of women with PCD, and anti-Yo, similar to anti-Hu,
is produced in the CSF,72,73 from which it is extracted by
the Purkinje cells.83,84 CDR 62 is thought to function in
the regulation of gene expression85—and if interfered with
by anti-Yo could prove lethal to the host Purkinje cell. A
sensitive and specific assay for anti-Yo sera has been devel-
oped that utilizes the fusion protein produced by a cDNA
clone, which encodes the CDR 62 antigen.85,86
Currently it is thought that the protein target of the
anti-Yo antibody is a neuronal signal transduction pro-
tein.78 The mechanism whereby anti-Yo antibodies cause
Purkinje cell death is not yet determined, although Tanaka
and colleagues87 theorize that cytotoxic T lymphocytes
may be involved.
Thus, for both PEM and PCD, the autoimmune, or
antionconeural (since the tumor is not really “self”), mech-
anism82 appears to be operational. Antibodies, anti-Hu
and anti-Yo, have been demonstrated in the serum and
CSF of patients with PEM and PCD, respectively, which
react with the neural tissue and the tumor of patients
with PNS.
SUMMARY
PNSs, or the remote effects of neoplasia, are of practical
significance to the neurotologist in terms of patient diag-
nostic evaluation and perioperative management, and
of theoretic importance in leading to a better understand-
ing of neurotologic tumors and cochleovestibular system
biology.
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 Chapter
Dizziness in Childhood

Outline
Development of the
Vestibular System
Diagnostic Evaluation
History
Physical Examination
Testing
Developmental Effects of
Vestibular Dysfunction
Congenital and Hereditary
Hearing Loss
Congenital Anomalies
Specific Disease Entities:
Peripheral
Otitis Media and Complications
of Otitis Media
Benign Paroxysmal Vertigo
of Childhood
Ménière’s Disease
Trauma
35
Perilymphatic Fistula Fred F. Telischi, MEE, MD
Vestibular Neuronitis
Grayson K. Rodgers, MD
Labyrinthitis and Meningitis
Specific Disease Entities: Thomas J. Balkany, MD
Central
Migraine
Vertiginous Seizures
Tumors
Neurosyphilis
Congenital Nystagmus
Ataxia
Familial Ataxia
Multiple Sclerosis
Other Disease Entities
Metabolic/Systemic Disease
Toxic
Functional
Summary

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
from a variety of body systems. True rotational vertigo
generally implies a disorder of the vestibular system and its
relationship to the appropriate proprioceptive and visual
systems. A team approach, involving neurotologist, neurolo-
gist, pediatrician, ophthalmologist, and audiologist/neuro-
physiologist provides the best chance for an accurate diagnosis
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-
lar system to other systems that may play a part in the
dizziness. The clinical presentation of vertigo and ataxia in
the pediatric age group may resemble that of the adult, but
the differential diagnoses in the two groups are different.
Many relatively common disorders that produce dizzi-
ness in adults are rarely seen in children. The neurologic
and vestibular systems mature during childhood, which
results in different interpretations of physical findings in
children and adults. The vestibular system is one of the
first central nervous system (CNS) projections to begin
functioning in infancy. As in adults, the history and physi-
cal examination are the basis for the majority of diagnoses,
with assorted diagnostic tests used for confirmation.
atric patient population are uncommon. Series reported
in the literature are small. Fried1 found 14 out of 2088
patients in 12 months claiming dizziness as the chief com-
plaint. Eviatar and Eviatar2 reported 24 patients with
vertigo from a pediatric neurology clinic of 5000. The
University of Nebraska experience published by Beddoe3
included 22 cases of dizziness or vertigo in children from
1960 to 1974.
DEVELOPMENT OF THE VESTIBULAR
SYSTEM
Although postural changes occur prenatally,4 the neural
interconnections among the visual, cerebellar,
labyrinthine, proprioceptive, and peripheral neuromuscu-
lar systems are incompletely developed at birth.2
Myelination of the various pathways occurs after birth.5
Vestibular pathways myelinate earlier (by 16 weeks) than
pyramidal tracts (by 24 months). Peripheral labyrinthine
functions, however, appear to be even more advanced.
When an embryo reaches the size of 8 mm, the otocyst
differentiates into a wider dorsal (vestibular) portion and
a narrow ventral (cochlear) portion. The endolymphatic
553
554 PEDIATRIC NEUROTOLOGY
duct can be recognized on the medial aspect of the otocyst
at this stage. When the embryo reaches 14 mm (6 weeks),
pouches are formed on the vestibular portion of otocyst
that will eventually give rise to the semicircular canals. At
20 mm (7 weeks), the vestibule divides into the utricle and
saccule. When the embryo has reached a 30-mm size
(8 weeks), the inner ear nearly resembles the adult form.
Although the anatomic pathways may be developed in
utero6,7 vestibulo-ocular reflexes and the Moro response
cannot be elicited until birth.4
Woollacott and colleagues8 summarized the current
understanding of the development of balance and posture
in humans. Children appear to rely more on visual sensory
information than vestibular and proprioceptive between
18 months and 3 years of age, during which time they
acquire locomotor skills. Vision becomes especially impor-
tant at transition periods when the child progresses to the
next milestone of mobility (e.g., between crawling and
standing). At school age (4 to 6 years), integration of
visual, vestibular, and somatosensory information appears
to expand and become more sophisticated, perhaps reflect-
ing functional changes in the nervous system connections.
With further maturation comes greater control reflected
by more efficient use of postural muscles.
DIAGNOSTIC EVALUATION
Disorders of the peripheral vestibular system and labyrinth
are usually reflected by tangible symptoms and signs such
as the sensation of spinning or movement, actual falling,
constitutional symptoms (nausea, vomiting, sweating), and
abnormal eye movements. Other symptomatology related
to the vestibular system also occurs, but may result from
disorders in the cerebellar, CNS, metabolic, and hemody-
namic systems, as well as being caused by exogenous
substances.
Ataxia indicates poor coordination and encompasses a
wide range of disorders. Gait ataxia refers to incoordination
of ambulation. Walking is a highly complex skill dependent
on proper functioning of a number of neuromuscular
structures and pathways.
The neurovestibular evaluation of the pediatric patient
includes a history, neurotologic exam, general neurologic
survey, and indicated testing and imaging. Emphasis should
be placed on the team approach even though referral to all
specialties may not be needed in every case.
History
Historical information provides the most important data
on the diagnosis and treatment of many dizzy patients.
Benign paroxysmal vertigo, for example, represents a diag-
nosis made almost solely by history. Unfortunately, in the
pediatric population the history may be incomplete.
Perseverance frequently is rewarded with important facts
obtained not only from parents but more frequently than
expected from the child. Obviously the age of the patient
determines the quantity and quality of information. In
younger children and infants, parental observation consti-
tutes the history. As myelinization proceeds during the first
months and years of life, the infant progresses through
various developmental milestones. Significant delays of
motor function occur in children with bilateral vestibular
dysfunction.9 When physical activity is delayed or abnor-
mal, vestibular disorders should be included in the differ-
ential diagnosis. Parents should be specifically questioned
about abnormal movements, especially of the head and
neck. Nystagmus or unusual eye movements may be noted
by the parents. Loss of consciousness or alteration of
behavior suggests seizure activity.
When the child can communicate either with the physi-
cian or with the parents, the character of the dizziness
should be elucidated. True vertigo, the sensation of move-
ment of the surroundings or self, is distinguished from
feelings of lightheadedness, faintness, floating, or “just not
being right.” Children may recognize the sensation pro-
duced by calorics or rotation testing as equal to their own
symptoms of dizziness. Vertigo arouses suspicion of a
peripheral vestibular disorder, whereas dizziness suggests
dysfunction in other systems such as cardiovascular, respi-
ratory, hematologic, or psychoneurologic. Episode vertigo
with constitutional symptoms suggests peripheral vestibu-
lar dysfunction. Hearing loss, tinnitus, and aural fullness/
pressure further localize the problems to the inner ear.
Vertigo that lasts more than 12 hours suggests a cause
central to the vestibular nerve.
Falling, difficulty ambulating with eyes closed, or diffi-
culty ambulating in the dark suggests bilaterally decreased
vestibular function. Difficulty walking under normal con-
ditions does not usually accompany isolated stable periph-
eral vestibular disease.
Finally, a thorough but directed past medical history
should be obtained, including but not limited to perinatal
problems, medications, prior otologic disease and hearing
loss, use of alcohol and illicit drugs, and neuromuscular
problems. Parents and the patient may be questioned
regarding the degree of disability caused by the vestibular
symptoms. Contrast the child who continues to play and
attend school with one fearful of leaving the house lest the
dizziness cause physical or emotional damage.
Physical Examination
The neurotologic exam of the dizzy child includes a com-
plete head and neck examination, general neurologic survey,
and specific neurovestibular testing. Many clues can be
obtained by observing the child before and during the
physician encounter.
Otoscopy identifies inflammatory processes of the ear
and mastoid. Use of the pneumatic otoscope may elicit a
positive fistula test (see the section on Perilymphatic
Fistula). A complete cranial nerve assessment should be
performed. Tuning forks identify the presence and charac-
ter of hearing loss and confirm audiometry. With a child
sufficiently mature, Romberg, tandem or augmented
Romberg, and tandem gait testing are performed.
Eye movements should be observed. Normally, a few
beats of nystagmus can be seen on extreme lateral gaze.
Pathologic spontaneous nystagmus may be observed occa-
sionally, but specific measures usually are necessary to elicit
the finding. Frenzel lenses eliminate the patient’s ability to
extinguish peripherally induced nystagmus by visual fixa-
tion. The Dix-Hallpike maneuver can elicit positionally

provoked nystagmus. Generally, positionally provoked,
fatigable nystagmus with a several-second latency accom-
panies a peripheral vestibular lesion, and nonfatiguable
nystagmus without latency accompanies a CNS cause.
Reflexes specific to neurovestibular function are present
and can be tested in infants as described by Eviatar.10
Appropriate tone and movement of the cervical muscula-
ture indicate that input from the vestibular end-organ and
cervical proprioceptive receptors exists. Abnormal postur-
ing of the neck in an infant may indicate a vestibular prob-
lem. The vertical acceleration test qualitatively measures
response in the extremities to gravitational acceleration
sensed by the otolithic organs.2 While holding the infant
in his or her arms with the head well supported, the exam-
iner abruptly lowers the patient toward the floor. A normal
response is abduction and extension of the upper extremi-
ties and an embracing posture. Semicircular canal response
can be identified by rotating the upright infant with neck
flexed 30 degrees. A doll’s eye response is elicited in the
newborn. Nystagmus with the fast component in the
direction of rotation appears at 2 to 3 weeks.
Vestibular dysfunction also may be identified by exam-
ining the righting response. This reflex involves the child
extending the arm to prevent falling in the direction of
applied force or tilt. The response presents at 6 months
and becomes voluntarily inhibited after 2 to 4 years of age.
The test should be performed with the eyes closed to elim-
inate visual input, which isolates the vestibular component
of the reflex. A patient with vestibular dysfunction will not
exhibit the reflex and may fall in the direction of tilt.
Similar righting tests can be performed in various posi-
tions until the age when the child can cooperate with the
Romberg and other tests.
A stepping test has been described in which the child
steps in place over a grid with eyes closed and arms out-
stretched.11 The angle and distance of displacement are
compared with that of normal subjects. Patients with
unilateral lesions rotate greater than 45 degrees toward
the affected side, whereas patients with bilateral lesions
display forward or backward displacement of greater than
20 inches.
Detailed cerebellar and gait examination may be indi-
cated when the history does not suggest vestibular disorder
or when the patient’s complaints focus on ambulation.12
Information from physical findings regarding the location
of dysfunction causing ataxia may help differentiate
vestibular, proprioceptive, and cerebellar causes. Problems
in the vestibular system usually become exacerbated with
the eyes closed, whereas cerebellar dysfunction may
appear or worsen during visual fixation. Proprioceptive
losses may mimic the other two in some respects but are
usually discovered during position testing of the lower
extremities. Neurologic consultation is indicated in these
circumstances.
Testing
Hearing evaluation in dizzy children becomes especially
important when considering the 49% to 95% estimates of
vestibular abnormalities in children with congenital and
acquired hearing impairments.13,14 An audiologist experi-
enced in testing children will employ a variety of tests
Dizziness in Childhood 555
based on age and disposition, including behavioral
audiometry using pure tone and speech tests, play and
startle localization, evoked auditory brainstem response
(ABR), otoacoustic emissions, and others. Children with
sensorineural hearing loss (SNHL) are at risk for vestibu-
lar hypofunction. Phillips and Backous have published a
comprehensive, detailed review of vestibular testing in chil-
dren.15 The remainder of this section outlines available tests.
Electronystagmography (ENG), rotational chair testing,
and posturography may be used in evaluating dizziness in
children. Electrical recording of nystagmus can be per-
formed even in young children. Caloric-induced nystag-
mus in children may be slower and more erratic than that
in adults due to their developing/myelinating nervous
system. Ice water may be necessary to measure vestibular
dysfunction adequately.
Rotation testing stimulates both labyrinths and may be
an appropriate alternative for children who cannot coop-
erate for calorics or when calorics cannot be measured.
Atretic or abnormal external auditory canals and perfora-
tions of the tympanic membrane are contraindications to
open system ENG testing. Patients with bilateral vestibu-
lar weakness may demonstrate some response by rotation
when calorics are negative. Rotary chair testing may be
more sensitive than calorics for identifying very early
bilateral weakness. Infants can be held in their parent’s lap
for testing. Cyr and coworkers16 developed modifications
of ENG and harmonic rotation for screening pediatric
patients for vestibular hypofunction and asymmetry.
By 6 weeks, the majority of normal infants demonstrate
nystagmus to caloric or rotary stimulation.17 It must be
remembered, however, that vestibulo-ocular response test-
ing primarily examines only horizontal semicircular canal
function and that these tests may not reflect the fluctuat-
ing nature of many pediatric vestibular disorders.
Static and dynamic posturography examine the interac-
tion of the vestibular system with the visual, propriocep-
tive, and other systems involved in maintaining balance.
Posturography can be performed in children old enough
to cooperate and, in fact, can be treated as a game.
Information similar to that in adults is obtained, although
results must be compared with size- and age-matched
normals.18 Normal children younger than 4 to 6 years
often fall in the sensory conflict situations (posturography
conditions 3 to 6), which makes this test inaccurate at
present for that age group.19
Tests of vestibular sensory organization and postural
sway strategies have been standardized to normal children
so that abnormal responses can be identified.18,20 These
examinations aid physical therapists in designing vestibular
and balance exercise programs for patients. They cannot as
yet, however, reliably localize pathology and they demon-
strate low sensitivity and specificity for the disorders of
balance in children.
ABR can be used as a screen for retrocochlear pathology
and in infants when behavioral response audiometry can-
not be performed. However, Brookhouser and colleagues21
demonstrated a lack of correlation between abnormal ABR
and abnormal vestibular testing. Prolonged vestibular
symptoms or signs of central dysfunction are evaluated
with computerized tomographic (CT) scanning or mag-
netic resonance imaging (MRI). CT is preferred when
556 PEDIATRIC NEUROTOLOGY
temporal bone structures are presumed to be involved
such as in chronic ear disease, skull base pathology, and
congenital abnormalities. MRI provides excellent detail of
soft tissues of the brain and CNS. Neurology consultation
may order electroencephalography (EEG) when seizure
activity is suspected.
DEVELOPMENTAL EFFECTS OF
VESTIBULAR DYSFUNCTION
A variety of developmental delays have been attributed to
disorders of vestibular function as reviewed by Horak and
coworkers.22 Reported disabilities usually result from bilat-
eral vestibular dysfunction and include impairments of learn-
ing, postural coordination, motor skills, and developmental
milestones. Children gradually compensate for many of the
postural problems and by the time they become teenagers
demonstrate no postural disturbances in everyday situations
compared with normals.23–25 Vestibular testing, particu-
larly posturography, will identify balance problems.
Compensation is encouraged by vigorous physical educa-
tion and, when required, by formal vestibular therapy.
Congenital and Hereditary Hearing Loss
Many congenital and hereditary hearing losses are
accompanied by vestibular deficits.26,27 Usher’s type I and
Waardenburg’s syndromes are notable for the relatively
common occurrence of vestibular abnormalities. Newborn
hearing screening is identifying hearing loss at younger
ages, and some type of vestibular assessment should be
performed in these children. This can vary from an office
neurotologic exam to more sophisticated testing. According
to the clinical circumstances, children with audiovestibular
dysfunction typically seek help because of hearing loss and
rarely list imbalance as a chief complaint. The reader is
referred to the chapter on pediatric auditory disorders
(Chapter 36) for more detail regarding hearing loss.
Congenital Anomalies
Temporal bone development anomalies often involve the
vestibular apparatus. These anomalies may affect the
membranous labyrinth only or the bony and membranous
labyrinths together. The former must be diagnosed by
histopathology, but the latter can be seen radiographically
due to the bony malformation. Jackler and colleagues28
have shown that this distinction can provide a classification
with clinical relevance and can be further broken down into
more specific subtypes. These conditions are usually con-
sidered in terms of congenital SNHL, although children
may have associated vestibular deficits that can manifest
clinically.
Children born without vestibular function will not expe-
rience vertigo because this is a static lesion. Although fine
aspects of balance may be lacking, these children will com-
pensate well with their somatosensory and visual systems.
Vestibular symptoms may occur in patients who have
vestibular function and a dynamic lesion. The enlarged
vestibular aqueduct as an isolated anomaly has received
some attention in the literature. Jackler and De La Cruz29
found many children with symptoms of incoordination
and imbalance, whereas in adults episodic vertigo was
more common. Endolymphatic sac surgery, done mainly
to stabilize hearing, was complicated by a high rate of
hearing loss in patients with an enlarged vestibular aque-
duct, and no benefit could be shown in other congenital
malformations. Sac surgery is therefore not recommended
for these patients.30
SPECIFIC DISEASE ENTITIES: PERIPHERAL
Otitis Media and Complications
of Otitis Media
Middle ear disease is, of course, extremely common in
children. Acute and chronic otitis media are commonly
seen from infancy to adulthood. Although most of these
patients present with pain, drainage, or hearing loss, dizzi-
ness may accompany the spectrum of this disease.
Serous otitis media (otitis media with effusion) can pro-
duce ill-defined balance disturbances manifesting as a
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.
The mechanism by which the dizziness is produced is
unclear, but one hypothesis is that negative middle ear
pressure causes displacement of the round window mem-
brane and subsequent movement of the perilymph in a
susceptible individual.32
When active infection is evident in the middle ear,
serous labyrinthitis can occur, which produces vertigo and
SNHL. Transmission of toxic substances across the round
window membrane presumably creates a serous labyrinthi-
tis. Treatment is aimed at resolution of the infection of the
middle ear with antibiotics and middle ear drainage. Steroid
therapy may play a role in decreasing inflammation.
Suppurative labyrinthitis as a complication of otitis
media is a very rare, but extremely serious situation. Here,
bacteria gain access to the perilymphatic space and pro-
duce a purulent inner ear infection. The route of bacterial
spread may be from the middle ear through a fistula in the
otic capsule or, more commonly, from the meninges and
cerebrospinal fluid (CSF) through the cochlear aqueduct or
internal auditory canal. Patients with bacterial labyrinthitis
are seriously ill and have severe auditory and vestibular
impairment compared with patients with serous labyrinthi-
tis. Management is directed at controlling the underlying
infection in either the middle ear/mastoid or the CSF.1,33
Cholesteatoma, acquired or (less commonly) congenital,
can erode into the otic capsule, producing a labyrinthine
fistula. The horizontal semicircular canal is the most com-
mon site for this destruction to occur, but other areas can
be involved. Cholesteatoma at this stage is generally easily
seen on otoscopy. Pneumatic fistula testing will produce
symptoms in most cases and increase suspicion of the
diagnosis. Audiometry may demonstrate SNHL in addi-
tion to the expected conductive component. CT scanning
should suggest the erosive process and allows for appro-
priate preoperative planning. Surgical management of a
fistula is quite individualized and depends on a number of
factors, such as hearing in the diseased ear, hearing in the

contralateral ear, size of the mastoid, and experience of the
surgeon.34
Benign Paroxysmal Vertigo
of Childhood
Basser35 described benign paroxysmal vertigo (BPV) of
children in 1964. Including their own cases, Finkelhor
and Harker36 in 1987 counted 113 cases reported in the
literature. Age of onset has been reported37 between 2 and
12 years of age, the majority before age 6. This disorder
should be distinguished from benign paroxysmal posi-
tional vertigo, which is rare in the pediatric population,
but common in adults.
The typical pattern involves the sudden onset of vertigo
lasting from seconds to a minute. Nausea and vomiting
may or may not be associated with the episode. The child
usually becomes frightened and clutches the nearest object
in an apparent attempt to prevent falling. Observant par-
ents will note unusual eye movements suggestive of nys-
tagmus. The child remains completely lucid with no
alteration in consciousness.
Fenichel38 first suggested an association between BPV
and migraine headache in children in 1967. Parker39
reported an overall incidence of 43% for family history
positive for migraine among series of BPV patients
reported in the English language literature. He also calcu-
lated a 13% incidence of subsequent development of
migraine along with other symptoms associated with
migraine, such as cyclic vomiting, recurrent abdominal
pain, scotomata, and photophobia. A history of motion
intolerance is a common finding. Headache provocation
tests that made use of nitroglycerin,40 histamine, and
fenfluramine37 resulted in headache or vertigo (or both) in
12 out of 12 and 10 out of 15 patients with BPV, respec-
tively. Paroxysmal torticollis of infancy (PTI) also has
been reported to precede BPV.41,42 PTI and BPV may
represent early manifestations of the full migraine com-
plex, progressing from one to the other as the nervous
system develops. The International Headache Society
now places BPV, PTI, and cyclic vomiting in the migraine
family.43
Because these patients are rarely at the doctor’s office
during attacks, audiometry and vestibular testing generally
are normal. Eighty-nine percent of 90 cases reviewed in
the literature had normal caloric responses.39 Abnormali-
ties on ENG, when present, are subtle and transitory.
Earlier reports demonstrated abnormal ENG results
(primarily with respect to calorics), whereas more recent
series have shown normal ENG findings.35,44 EEG has
demonstrated mild abnormalities in wave patterns in a
few patients with family history or other symptoms sug-
gestive of seizure activity, but generally has been normal
in BPV patients.36,37 Imaging studies have been uniformly
normal.
The natural history of BPV is one of spontaneous remis-
sion of vertiginous episodes prior to the teenage years. As
already noted, some patients resolve their vertigo only to
develop migraine. The important aspects of treatment
include ruling out other treatable conditions and reassur-
ance and counseling regarding possible later development
of migraine. Antiseizure medication has not been useful,
Dizziness in Childhood 557
although some patients have been noted to improve on
antimigraine regimens.37,40 The efficacy of pharmacologic
therapy remains unclear, given the natural spontaneous
remission.
Ménière’s Disease
Episodic vertigo, fluctuating hearing, and low-pitched
tinnitus were described in 1861 by Prosper Ménière as a
disorder localized to the labyrinth. Harrison and
Haftalin45 noted that 75% of cases occur between 30 and
60 years of age. The first case reported of Ménière’s dis-
ease in a child (6 years old) was by Crowe46 in 1938. Since
that time, only a small number of reports of this entity in
children have appeared.47 Sade and Yaniv48 outlined three
cases of Ménière’s occurring in infants having episodes of
vomiting. Specific review of pediatric Ménière’s disease
has been published by Rodgers and Telischi.49
The diagnosis of Ménière’s disease is clinical and relies
heavily on the history. In the pediatric population, it will
likely be difficult to elicit the classic history, especially in
children younger than age 10 years. Therefore, a certain
index of suspicion must be kept for this disorder. Once
hearing loss has been documented, the differential diagno-
sis of vertigo and hearing loss includes physical and acoustic
trauma, spontaneous perilymphatic fistula, allergy, inner
ear malformation (e.g., Mondini’s), cerebellopontine angle
tumor, hypothyroidism, syphilis, and adrenal pituitary
insufficiency in addition to Ménière’s disease.
The diagnostic evaluation in such patients should include
basic and impedance audiometry that is age-appropriate,
ABRs, ENG, electrocochleography, and detailed CT scan-
ning of the temporal bones. Serologic syphilis testing,
thyroid function studies, glucose tolerance testing, adreno-
corticotropic hormone-stimulated cortisol levels, and
allergy testing in selected cases should be obtained. Filipo
and Barbara50 found glycerol testing particularly helpful in
this age group for whom histories often lack important
details. They had a positive test in four of five children
with suspected Ménière’s disease.
Once a diagnosis is made, treatment is the same as for
adults. Diuretic therapy is the mainstay of the therapeutic
regimen along with dietary modification (e.g., low sodium
and decreased caffeine).
Trauma
This section is limited to closed-head trauma and
whiplash-type injuries as causes of dizziness and vertigo.
Eviatar and coworkers51 categorized post-traumatic vestibu-
lar symptoms without hearing loss into “labyrinthine con-
cussion, whiplash syndrome, vertiginous seizures, migraine
and post-traumatic neuroses.” Temporal bone fracture and
perilymphatic fistula also can be caused by blunt injuries
and result in dizziness or vertigo along with hearing loss.
Loss of consciousness at the time of trauma may or may
not be associated with all of these disorders.
Labyrinthine concussion is the name given to the symp-
tom complex similar to BPV that occurs after head trauma
with no detectable fracture or injury to the labyrinth.
Patients typically develop vertigo and imbalance immedi-
ately after the injury that persists for several days. As these
558 PEDIATRIC NEUROTOLOGY
symptoms resolve during the first week, patients are left
with residual positional vertigo, which can persist for
weeks to months. Episodes of positional vertigo last
seconds to a few minutes and may be associated with nau-
sea. Hearing loss and tinnitus are not typical complaints.
Dislodged particulate debris trapped in the semicircular
canals (posterior canal most commonly) causes these
symptoms, and treatment with partial repositioning
maneuvers is usually effective. Vestibular exercises can be
helpful as well.
Audiometry may reveal mild SNHL, although more
commonly shows no change in thresholds. ENG demon-
strates positional nystagmus and, less often, canal paresis.
Rotary chair and posturography are helpful for severe
injuries resulting in bilateral vestibular paresis.
Whiplash injuries, in addition to head trauma, can result
in positional vestibular symptoms. Hearing generally is
normal although some patients complain of tinnitus.
Physical examination and ENG may elicit positional nys-
tagmus. Audiometry is normal. A cervical collar may be
prescribed to splint the neck and minimize discomfort.
Vestibular habituation exercises may be designed to pro-
mote compensation to rapid head movements. Vestibular
suppressants and muscle relaxants are helpful initially but
not on an ongoing basis. Even severe symptoms generally
resolve during a period of weeks to months.
In some patients, no diagnosis matches the symptoms.
The physical examination is normal. Some patients may
exhibit nonspecific abnormalities on ENG or even ABR.
Eviatar and coworkers51 termed this nonspecific post-traumatic
dizziness. They postulated brainstem injury, psychosomatic
disorder, or secondary gain associated with litigation as
causes. Patients whose symptoms resolve spontaneously
during a period of weeks to months, not in association with
lawsuit settlements, are more likely to have an organic
basis for their symptoms than those whose complaints are
protracted and less specific.
Closed-head trauma can produce other conditions
manifested by dizziness or vertigo, such as perilymphatic
fistula, temporal bone fracture, and trauma-induced
migraine or seizures. These are described in detail in other
sections of this chapter or other chapters.
Perilymphatic Fistula
Perilymphatic fistulae are fluid connections between inner
and middle ear spaces. Many aspects of the diagnosis
and management, indeed even the existence, of this disor-
der are controversal.52,53 Perilymphatic leaks unrelated
to prior otologic surgery were reported initially in 1968.54
Theories of their pathogenesis have been well described.
Individual predisposition, congenitally weak areas in the
temporal bone, patent cochlear aqueduct, and other
anatomic explanations have been proposed to account
for the failure to contain the perilymph subjected to
pressure differential with respect to the CSF or ambient
pressure.
Perilymph leaks can result in vertigo, ataxia, disequilib-
rium, and nonspecific dizziness symptoms. The most com-
mon symptom is SNHL. Tinnitus occurs less commonly.
Any combination of vestibular and auditory complaints
have been reported, either stable or fluctuating over time.55
Antecedent trauma, physical exertion, or barotrauma
are reported by some patients. Supance and Bluestone56
documented such a history in 6 of 22 (27%) patients with
surgically confirmed leaks. No symptoms are pathognomic
for fistula, but some of the following historical findings
should heighten the index of suspicion:
1. No other obvious diagnosis to explain the symptoms
2. Antecedent trauma blunt or penetrating to the
temporal bone, physical straining/Valsalva’s maneu-
ver, barotrauma (atmospheric changes or internally
induced such as violent sneezing/coughing and
playing wind instruments)
3. Hearing loss associated with trauma, sudden,
fluctuating, and progressive
4. Vertigo or dizziness occurring with straining or
position changes
5. History of recurrent, unexplained meningitis
6. Vestibular symptoms brought on or magnified during
exposure to loud sounds (Tullio’s phenomenon)
7. Congenital anomalies or syndromes involving the
head and neck
Physical examination may be completely normal.
Occasionally, perilymph in the middle ear masquerades as
serous otitis media. Position changes may elicit peripheral-
type nystagmus, or the patient may exhibit spontaneous
nystagmus. Gross ataxia or abnormalities in Romberg/
tandem gait testing may be present. Congenital deformi-
ties should be noted.
The fistula test is not accurate but has been reported to
be more specific (50%) than sensitive (35%) in children.56
This test is based on acute changes in middle ear pressure
transmitted via a fistula to the inner ear, causing vertigo
and nystagmus. Properly performed, a good seal is
obtained in the external auditory canal while positive and
negative pressures of 200 to 300 mm H2O are induced
acutely, maintained for 5 to 10 seconds, and repeated several
times. Although the sensation of vertigo suggests the diag-
nosis, a positive result requires the eliciting of nystagmus or
a change in the magnitude of spontaneous nystagmus. Eye
movements may be visually documented with Frenzel
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
testing and platform posturography have been reported to
be abnormal more frequently than have oculomotor
screening, calorics, and rotation tests in children with
confirmed leaks.56 Pure tone and electrical audiometry
commonly reveal SNHL.
CT remains the best modality for imaging temporal
bone structures and should be undertaken when
labyrinthine fistula is suspected. More than half of children
with surgically confirmed fistulas exhibit abnormal tempo-
ral bone tomography. Mondini’s and other inner ear defor-
mities are the most common abnormalities identified.
Still, the only way to definitely identify a leak remains
operative exploration. Even at surgery, with Valsalva’s
maneuvers, there may be questionable fluid accumulation
and the timing of exploration may not correspond with
perilymph flow from an intermittent leak. Analysis of any
identified fluid for β2-transferrin held promise, but has not
been uniformly helpful.57

Treatment in cases of acute barotrauma in otherwise
normal patients may begin with bedrest with head elevation
and avoidance of Valsalva’s maneuvers for several days.
Significant or progressive hearing loss or persistent vertigo
mandates surgical exploration. This involves an exploratory
tympanotomy with exposure similar to that for a stapedec-
tomy. Oval and round window areas should be fully visible.
The anterior aspect of the oval window is the most com-
mon site of leak. Careful suctioning and diligent observa-
tion with Valsalva’s maneuver may identify small leaks.
Abnormalities in the ossicles, oval window niche, or round
window are commonly identified. Many surgeons will
reinforce the oval and round window areas with fibrocon-
nective tissue grafts even if a specific leak is not seen due
to the vagaries of diagnosis.
Vestibular Neuronitis
Vestibular neuronitis usually occurs in children older than
10 years and follows a clinical course similar to but milder
than that seen in adults.33,44,58,59 Vertigo occurs suddenly and
may last 1 or 2 days with nausea and vomiting. A period
of imbalance and ataxia may follow for several weeks. It com-
monly accompanies or follows a viral illness and may be diag-
nosed as gastroenteritis or a similar disorder. Intermittent
episodes of vertigo may occur, decreasing in severity during
the ensuing week. Vestibular neuronitis is not associated with
changes in hearing. As in adults, ENG frequently demon-
strates unilateral decreased caloric response. Vestibular
suppressants can be employed temporarily for symptomatic
treatment, but ultimately this is a self-limited disorder.
Labyrinthitis and Meningitis
The presence of hearing loss accompanying the acute
onset of severe vertigo, nausea, vomiting, and fever heralds
labyrinthitis. The cause may be viral or bacterial.
Labyrinthitis may be classified as serous, suppurative, or
chronic.60 Acute or chronic ear infections can result in
toxins and noxious enzymes entering the inner ear.61 Viral
infection presumably invades the membranous labyrinth
via a hematogenous route. Suppurative labyrinthitis
involves bacterial entry into and infection of the perilym-
phatic space. This may occur via a bony fistula of the otic
capsule or infected CSF through the internal auditory
canal or cochlear aqueduct.
The diagnosis is suggested by noting the acute onset of
severe vertigo with either sudden or progressive hearing
loss. Signs and symptoms of otologic disease or meningitis
support the diagnosis. A careful fistula test should be per-
formed. Audiometry and vestibular tests will demonstrate
hypofunction of one or both labyrinths. Bilateral involve-
ment suggests meningogenic spread; unilateral suggests
otologic. Management is directed at controlling the
underlying infection. Viral and serous labyrinthitis leave
mild inner ear dysfunction, and suppurative disease results
in severe auditory and vestibular hypofunction.
Vertigo following meningitis in children may be the
effect of scar traction on the meninges surrounding the
vestibular nerve or a direct postinflammatory effect on
the labyrinth or vestibular nerve.31 Vestibular exercises and
time generally result in resolution of symptoms.
Dizziness in Childhood 559
SPECIFIC DISEASE ENTITIES: CENTRAL
Migraine
Migraine is generally believed to be a vascular disorder
associated with vasospasm of vessels supplying the CNS,
which produces neurologic symptoms, followed by vasodi-
lation of extracranial vessels, hence producing headaches.
A wide spectrum of symptomatology can occur from this
process.39 An array of symptoms may be produced by the
vasospastic phase while headache, if any, symptoms occur
during the vasodilation phase. Also, the time course
between the phases can vary widely, and the phases can
occur independently. Migraine precursors, variants, or
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-
tory symptoms. As previously noted, BPV of childhood
and PTI are thought to be manifestations of migraine.
The diagnosis of migraine is one of elimination. Other
otologic or neurologic diseases should be excluded prior
to a diagnosis of migraine. A history of repeated episodes
with recovery between spells is suggestive. A detailed fam-
ily history must be obtained because a history for migraine
is often present. This history should include questioning
of family members that may have had BPV of childhood or
PTI. Migraine associated vertigo may be treated similarly
to adult disease in conjunction in consultation with pedi-
atric colleagues. Johnson has contributed a very thorough
review of migraine-related dizziness.63
Vertiginous Seizures
Changes in cognitive function and alteration or loss of
consciousness accompanying vertigo suggest seizure activ-
ity. Vertigo may be a manifestation of the ictal phenome-
non (vertiginous seizures), or the abnormal vestibular
activity may stimulate convulsion (vestibulogenic seizures).
Vertigo or dizziness not uncommonly occur as an aura pre-
ceding a generalized seizure.
Vertigo is the sole or primary symptom in vertiginous
seizures. The differentiation between this entity and other
varieties of paroxysmal vertigo is made by identifying
altered mental status and abnormal sleep-deprived EEG.
Imaging and vestibular testing will be normal but are usu-
ally indicated to rule out other disorders.
Vestibulogenic seizures are a rare form of sensory
epilepsy. Altered afferent vestibular stimuli or abnormal
central processing of robust peripheral input lead to gen-
eralized epileptic activity via the reticular activating system
in the brainstem and thalamocortical pathways. Simultane-
ous ENG and EEG recording during caloric stimulation
will reveal abnormalities.
Anticonvulsants are the primary treatment for both of
these types of seizures.
Tumors
Tumors involving the CNS at the brainstem and above
may cause vertigo. Posterior fossa tumors constitute
almost two-thirds of brain tumors in children.64 Intrinsic
cerebellar and brainstem lesions make up the majority of
560 PEDIATRIC NEUROTOLOGY
those in the cerebellopontine angle. Medulloblastomas,
astrocytomas, gliomas, hematomas, and inflammatory
masses can cause mass effect on nearby vestibular structures.
A high index of suspicion is sometimes necessary to
diagnose these lesions. The combination of vertigo with
hearing loss, other cranial nerve palsies, ataxia, or seizures
warrants a vigorous diagnostic work-up that includes
imaging. Signs of increased intracranial pressure, such as
headache, vomiting, and papilledema, also require a search
for a mass lesion. MRI with gadolinium contrast provides
detailed images of the soft tissue structures in the CNS.
CT scans are best for identifying changes in bony struc-
tures such as those caused by tumors in the skull base.
Neurosyphilis
Neurosyphilis is known to be a cause of true vertigo as well
as other forms of dizziness in childhood. The spirochete
Treponema pallidum may infect any portion of the vestibu-
lar system as well as the cochlea, eighth nerve, and central
auditory and vestibular pathways.
The onset of dizziness in childhood due to neurosyphilis
is often accompanied and overshadowed by bilateral sym-
metrical profound hearing loss. The audiogram may show
a flat configuration with disproportionately poor speech
discrimination.
Vestibular symptoms occur more commonly in congen-
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
indistinguishable from Ménière’s disease and consist of
episodic vertigo, fluctuating SNHL, and tinnitus.66,67
Congenital Nystagmus
Congenital nystagmus is characterized by horizontal,
conjugate jerky oscillations of the eyes.68 The abnormal
eye movements occur at birth or during infancy.69
Dizziness, vertigo, and oscillopsia are notably absent.
These children generally have good vision although they
may adopt compensatory head posturing to compensate
for visual changes during periods of nystagmus. This form
of nystagmus increases during fixation and decreases
during eye closure or convergence. Treatment involves
reassurance and monitoring of vision.
Ataxia
Ataxia implies impaired coordination. The causes of ataxia
are protean and affect any aspect of muscular activity.70 We
discuss those entities that manifest vertigo/dizziness as
part of the symptomatology and primarily involve gait or
balance disturbances in children.
Familial Ataxia
Familial ataxias may be inherited in a dominant, recessive,
or sex-linked fashion. Up to one-third of patients with
recessive disease do not fit current diagnostic classifications
of familial ataxia. Dominant recurrent (periodic) ataxia is
characterized by childhood onset with episodic imbalance
and vertigo.71,72 Nystagmus and ataxia are observed during
attacks, but interim examination is normal. In contrast to
many of the recessive ataxias, this dominantly inherited
disorder does not appear to involve significant progressive
neurologic or systemic impairment. A defect in pyruvate
metabolism has been postulated as the cause, leading to
cerebellar atrophy observable by MRI.73,74 Griggs and
colleagues74 and later others reported clinical response to
acetazolamide.71,75
Among a number of forms of recessive ataxia,
Friedreich’s ataxia ranks as the most common.72 This dis-
order affects many organ systems, beginning with spin-
ocerebellar degeneration of the CNS. The cause remains
unknown. Gait ataxia or scoliosis develops during child-
hood or early adolescence. Other neurologic findings
include dysarthria, loss of position and vibratory sense in
the lower extremities, muscle atrophy, and areflexia.
Eighth nerve and cochlear nucleus degeneration with
preservation of the end organ lead to hearing loss and
vestibular hypofunction.76 Visual loss from optic atrophy
and diabetes occur in less than half of patients. Most
patients die from the complications of hypertrophic car-
diomyopathy. No effective treatment exists.
A number of other inherited ataxias exist that are
beyond the scope of this chapter. Treatable varieties
include Refsum’s disease, Wilson’s disease, Hartnup
disease, Bassen-Kornzweig syndrome, urea cycle, and
multiple carboxylase enzyme deficiencies.
Multiple Sclerosis
Multiple sclerosis (MS) is uncommon in childhood, but up
to 10% of cases may present in the pediatric population.
As in adults, dizziness can occur if a focus of demyelination
(plaque) involves the vestibular system.77 Molteni78
reported 14 cases of MS in the children. Four (20%) had
vertigo as the presenting symptom. The possibility of
MS increases if other neurologic symptoms such as visual
disturbance or gait disturbance are present. The diagnosis
may only become clear as time passes and other symptoms
develop.
MRI of the brain may show the sclerotic plaques. Visual
evoked potentials and analysis of spinal fluid may be help-
ful in the diagnosis. Treatment of acute exacerbations with
steroids is often effective.
OTHER DISEASE ENTITIES
Metabolic/Systemic Disease
Imbalance and lightheadedness may be the result of cer-
tain systemic conditions. Anemia and vasovagal reactions
are common causes of dizziness. Congenital heart disease
and arrhythmias also may present with vestibular com-
plaints. Hypoglycemia is another consideration and symp-
toms should have a relationship to food intake. Adrenal
insufficiency, dysautonomia, and thyroid disease all are
other uncommon systemic causes of dizziness. A careful
history and physical examination will often lead to clues
that point to a need for further work-up. Where indicated,
a battery of blood tests can be pursued to rule out these
disorders.

Toxic
Many medications can produce dizziness as a side effect.
Therefore, a review of medications is always required, and,
where appropriate, elimination or substitution may deter-
mine if a drug is causing the symptoms. Anticonvulsants
such as phenytoin and carbamazepine as well as various
vasoactive medicines are common offenders. Patients who
experience dizziness taking these medications should have
blood drug levels checked. Another consideration is of
illicit drugs. This may be more likely in the teenage popu-
lation. Urine screening can help in this matter.
Other considerations include vestibulotoxic medications.
Aminoglycosides are by far the most common in
this category. A history of severe infection treated with
intravenous antibiotics should prompt an investigation into
which medications were used. Topical application of
aminoglycoside-containing drops to the middle ear can
result in vestibulotoxicity via round window absorption. An
audiogram, otoacoustic emissions measurement, and ENG
will reveal deficits in these cases. Other medications that
can be toxic to the vestibular system include loop diuretics,
quinine, and some cancer chemotherapeutic drugs.
Functional
Although not usually seen in very young children, the
school-age child may manifest a number of functional
symptoms that not uncommonly include dizziness.2,31
Underlying the symptom can be anxiety, behavior distur-
bance, depression, difficulty with social adaptation, and
hyperventilation. Dizziness rarely occurs as an isolated
symptom in these cases, which adds to the confusion.
Particular attention must be given to the history, which
should include the social and family dynamics. These cases
often become clearer if the physician is able to sort out this
portion of the history. All laboratory testing is normal as is
the physical examination. Treatment is directed at resolving
the underlying problem through appropriate counseling.
SUMMARY
As in adult patients, dizziness in children is a complex
problem that may be difficult to diagnose. Making matters
more difficult is the limited history possible from the
patient. Parents are helpful, but they are not the ones with
the symptoms and as such can only provide limited and
indirect information. The examination and laboratory
evaluation of the vestibular system, as well as imaging in
selected cases, can help to solidify a diagnosis. This chap-
ter has provided an outline and discussion of disorders that
can produce dizziness in children. An understanding of
these diseases helps to provide a framework of knowledge
with which each individual case can be compared. With a
systematic approach, these challenging cases can be solved.
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Central Auditory System Development
and Disorders
Outline
Development of the Central
Auditory System
Introduction
Anatomic Development
Spiral Ganglion Cells
General Aspects of Central
Auditory System
Development
Cochlear Nucleus
Superior Olivary Complex
Lateral Lemniscal Nuclei
Inferior Colliculus
Medial Geniculate Body
Auditory Cortex
Myelination
Functional Development of
the Central Auditory System
Behavioral Responses
to Sound
Hearing by the Human Fetus
Postnatal Development
of Auditory Competence
Methodology
Neonatal Period (Birth
to 28 days)
DEVELOPMENT OF THE CENTRAL
AUDITORY SYSTEM
Introduction
The human, unlike most nonprimate mammalian species,
is born with highly developed auditory sensitivity. Complete
maturation of auditory processing capabilities takes place
over the first year of life, and, to a lesser extent, perhaps for
the first several years. The recent refinement of techniques
to assess behaviorally the auditory processing skills in the
infant have added to our understanding of auditory devel-
opment. Such measures can be correlated with anatomic,
physiologic, and behavioral data from animal studies to
gain a more complete understanding of the developmental
process. Animals such as the cat and various rodents have
been extensively used for these investigations. As altricial
animals, the period of most rapid maturational change is
after birth and, hence, unlike the human, readily accessible
for study.
Chapter
36
Infancy (28 days to 2 years) Debara L. Tucci, MD
and Early Childhood
Edwin W Rubel, PhD
Central Auditory Testing
Influence of Environmental
Factors on the Developing
Central Auditory System
Abnormal Central Auditory
System Development
Conductive Hearing Loss:
Effects of Deprivation
of Sound Input
Human Studies
Animal Studies
Sensorineural Hearing Loss:
Effects of Deafferentation
Animal Studies
Human Studies
Reintroduction of Activity by
Electrical Stimulation in the
Deaf Subject: Cochlear
Implant
Pathology of the Central
Auditory System
An appreciation of the process of auditory development
is important not only for an understanding of the normal
auditory system, but also for the impact of hearing loss on
this system. In this chapter on the development of the
central auditory system, we are concerned with the well-
referenced but little understood mechanisms of neural
plasticity, which presumably allow the child to adapt to
changes in auditory input. These mechanisms for adapta-
tion have become particularly important when considering
clinical issues such as the timing and aggressiveness of
medical and surgical treatment of conditions that produce
hearing loss in children.
We will first discuss our understanding of central audi-
tory system (CAS) development as revealed in human and
animal studies of auditory system anatomy, physiology, and
behavior. We then review the literature pertaining to
changes in the system that occur in response to decreased
auditory input and attempt to draw general conclusions
that may be applied to clinical situations. Central auditory
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

Figure 36-2. Binaural auditory pathways in the brainstem illustrated for the
left CN. The connections from the other cochlear nucleus would form a mirror
image. AVCN, anteroventral cochlear nucleus; DCN, dorsal cochlear nucleus;
DLL, dorsal nucleus of the lateral lemniscus; IC, inferior colliculus; LSO,
lateral superior olive; MG, medial geniculate nucleus; MNTB, medial nucleus
of the trapezoid body; MSO, medial superior olive; PVCN, posteroventral
cochlear nucleus; VLL, ventral nucleus of the lateral lemniscus. (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 388.)
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
growth thereafter. Webster and Webster25 note that in
the mouse, the most rapid period of neuron growth takes
place between postnatal days 3 and 12, before the onset of
auditory function.
J. Moore26 has investigated neuron soma development in
prenatal human tissue as well as in the early postnatal rat.
Cellular development in human CN tissue at 20 weeks’
gestational age is similar to that of the rat at birth. In both
566 PEDIATRIC NEUROTOLOGY
Figure 36-4. The major descending auditory pathways for one side of the
brain. 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 391.)
species, cells are numerous and demonstrate a high nuclear-
to-cytoplasmic ratio. Morphology similar to adults is
achieved by 30 weeks’ gestation in the human and by
21 days postnatal in the rat, when neuropil as well as cel-
lular cytoplasm is significantly increased. Studies of human
tissue have relied primarily on classical cell body (Nissl)
and myelin stains, and little information on the intricate
complexities of dendritic, axonal, and astrocyte processes
is available.
Auditory nerve (AN) axons connect in a highly specific
fashion with large spherical (“bushy”) cells of AVCN in a
specialized synapse, the end-bulb of Held. Only one to
three AN axons contact each spherical cell in the AVCN.
End-bulbs are evident in the 2-day-old kitten; at this time
the endings appear as irregular spoon-shaped swellings.
By 45 days of age, nearly all cells exhibit characteristic
adult-like endings with highly branched terminal arboriza-
tions, which appear to envelop the postsynaptic cell body.27
The early development of this highly elaborated cellular
contact may serve to decrease the probability of multi-
cellular input to the large spherical cell. Some evidence
suggests that these developing second-order neurons may
be transiently innervated by four or more auditory nerve
fibers.28 However, the slight overproliferation of fibers
requires a small amount of “pruning” to arrive at the mature
configuration, synaptic connections formed early in devel-
opment are typically maintained.29,30 Jhaveri and Morest31,32
demonstrated that morphologic changes in the end-bulbs
are accompanied by parallel changes in their spherical
cell targets in the chick, possibly reflecting developmental
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
probably arise from the dorsal aspect of the medullary
epithelium in the region of the rhombic lip and migrate
a considerable distance to their final location in the ventral
brainstem.37 Developmental changes in the primary
olivary regions largely mirror those observed in the CN.
Lateral Lemniscal Nuclei
Information on the developmental anatomy of the lateral
lemniscal nuclei is lacking. The only information available
is that reported by Altman and Bayer,16 discussed earlier,
on the time of origin of this nuclear group.
Inferior Colliculus
Virtually all ascending (lemniscal) and descending auditory
pathways synapse in the inferior colliculus (IC). The
convergence of input from numerous sources makes this
structure critical for processing auditory information.
Several schema have been devised to subdivide the IC. All
include the central nucleus (CNIC), which is the most
highly organized and frequently studied nucleus within
this structure. Other divisions include the cortex and
paracentral nuclei, according to one classification.38 The
human IC is identifiable in the 3.7-cm (approximately
3 months’ gestation) fetus.39 The three main subdivisions
of the IC are readily identified in the kitten at birth, and
evidence suggests that the CNIC develops first.40
In CNIC laminae formed by neurons and afferent axons
correspond to isofrequency contours. This highly organ-
ized pattern is evident early in development. In fact,
neurons destined to form the IC demonstrate distinct
proliferative gradients (rostrocaudal, lateromedial, and
ventrodorsal), so that neurons generated at a certain time
will have a characteristic distribution throughout the adult
nucleus. This is in contrast to the superior colliculus,

which develops concurrently and demonstrates no obvious
spatiotemporal gradients.41
All neuronal cell types are present at birth in the cat
CNIC.42 Several changes have been documented over the
first month of life, including an increase in soma size25;
decrease in extracellular space43; increase in lipid con-
tent44; and changes in dendritic length, morphology, and
orientation.42,45,46
Adult patterns of connectivity to other CAS structures
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
(AC) are identified on postnatal day 3.48 Dendritic matu-
rational changes, not confined to the CAS, include an
increase in length, loss of hairy or filiform processes, and
a decrease in number (or complete loss) of dendritic
spines.42
Medial Geniculate Body
The medial geniculate body (MGB) comprises three main
subdivisions—ventral, dorsal, and medial—each with
component nuclei. The relatively early development of this
diencephalic structure is recognized in the human embryo.
The MGB can be defined in the 29- to 30-mm embryo
(≈8.5 weeks), before the IC is identifiable.39,49 Nuclear
organization is evident in the 6-month-old (16 to 21 cm)
fetus.49 Most investigators believe that the MGB forms
from dorsal thalamus (also see Stroer50), which is depend-
ent on the presence of the telencephalon for normal
differentiation.51
Auditory Cortex
The AC is, like other CAS structures, comprises several
divisions defined by morphologic and functional criteria.
The organization of the auditory cortex of the cat has been
described by Wong.52 AI, or primary auditory cortex, is a
laminated, tonotopically organized structure. It is sur-
rounded by subregions that either are tonotopically organ-
ized (A, anterior auditory cortex; P, posterior auditory
cortex; VP, ventral posterior auditory cortex) or demon-
strate no apparent tonotopicity (AII, secondary auditory
cortex; DP, dorsoposterior area; V, ventral auditory area;
T, temporal area). The columnar organization characteris-
tic of cerebral cortex is most highly developed in AI.
Functional properties organized according to binaural
interaction columns and tonotopicity exist concurrently
over the spatial map of this subregion.
Moore and Guan53 and Moore54 recently described the
maturation of the human auditory cortex through docu-
mentation of neurofilament proliferation in specimens
ranging in age from 16 weeks of gestation to 27 years of
age. Neurofilament proliferation reflects axon maturation
in terms of increase in diameter, myelin sheath develop-
ment, and increase in conduction velocity, and can be used
to document patterns of connectivity and general brain
maturation. During the perinatal period, between the
third trimester and fourth postnatal month, mature axons
are present only in the most superficial layer of the cortex,
with no connections to areas outside the cortex. In early
childhood, the first thalamocortical afferents are identified,
Central Auditory System Development and Disorders 567
and after age 5 years axons that connect the cerebral hemi-
spheres are evident. By age 11 to 12 years the density of
cortical axons approximates that of adults. Moore
correlates cortical maturation with advancing auditory
processing abilities, beginning in infancy when most
abilities reflect brainstem function to late childhood
and adolescence when more complex auditory skills are
perfected, such as speech perception in noise and complex
binaural processing.
Myelination
In contrast to the late development of myelination in the
auditory cortex, brainstem auditory axons develop an
adult-like content of neurofilaments between the 16th
and 28th weeks of gestation,55 and myelination of the
axons first occurs between the 26th and 28th weeks.56
There is no evidence for centripetal axonal maturation in
the human brainstem; the brainstem auditory pathway
matures as a unit, rather than sequentially from lower
centers to higher.
Latency of auditory brainstem response (ABR) wave-
forms decreases significantly with increasing age.57–60 This
change has been attributed by numerous investigators to
progressive myelination of CAS pathways.44,59,60 Walsh
and colleagues61 have quantitatively investigated myelina-
tion of the CAS of the cat. They compared rate and timing
of maturation of axons and ABR latency and amplitude.62
Interestingly, they found that the rate of myelination does
not correlate highly with either ABR latency decline or
amplitude growth during the postnatal period in the
kitten. Fibers of the AN, trapezoid, and inferior brachium
have acquired only roughly half of the adult myelin sheath
by the time the ABR latency and amplitude have achieved
adult values (Figs. 36-5 and 36-6). The authors suggest
that changes in ABR waveforms occur as a result of a
combination of developmental processes, including myeli-
nation and synaptic maturation. Moore and coworkers63
further discuss factors that interact to produce develop-
mental maturation reflected in the ABR. Based on their
structural knowledge of brainstem development, they
constructed a model that allows separate analysis of the
ABR components of axonal conduction time and synaptic
delay. These two components have different maturational
time courses—although synaptic maturation proceeds
until age 3 years, axonal conduction time is mature at
birth. Because the brainstem auditory pathways continue
to lengthen postnatally, they surmise that conduction
velocity must also continue to increase. This may be due
both to increasing thickness of the myelin sheath and
increasing axon diameter.
FUNCTIONAL DEVELOPMENT OF THE
CENTRAL AUDITORY SYSTEM
Functional capabilities of the CAS may be defined either
in physiologic or behavioral terms. Although physiologic
methods can sometimes be more objective, precise, and
less dependent on the motor system development and “state”
of the organism, behavioral measures have the advantage
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
techniques of behavioral assessment have greatly increased
the objectivity of these measures and added to our under-
standing of human infant auditory processing.
A wealth of data are available to detail the physiologic
development of animal species. Many of these studies use
precocial species, or those with immature hearing ability at
birth, so that the early events of hearing development can
be studied. In this chapter, we focus on developmental
hearing milestones that can be measured in the human.
Physiologic developmental studies are summarized by
Rubel,1 Brugge,2 Sanes and Rubel,64 and Walsh and
McGee,65 and the reader is referred to these sources for
discussions of the physiologic development of the CAS.
BEHAVIORAL RESPONSES TO SOUND
Hearing by the Human Fetus
The human auditory system is well developed structurally
by the third trimester. Furthermore, as discussed later,
behavioral studies of auditory skills of the neonate reveal
the presence of discrimination capabilities that require
perception of complex auditory cues. The existence of
these skills so early in life has led some investigators to sug-
gest that the auditory experience of the fetus may facilitate,
or even be required for normal functional auditory system
development.
Until the advent within the past decade of sophisticated
means of measuring sound transmission through the
abdominal and uterine wall, it was believed that what little
sound reached the fetus was largely masked by internal
noise.66 More recent studies have used the hydrophone,
rather than the standard microphones, to measure attenu-
ation of external sound in humans67,68 and sheep.69–72 For
low-frequency signals, at or below 250 Hz, reduction in
sound pressure levels is less than 5 dB. Above 250 Hz,
attenuation increased at a rate of about 6 dB per octave up
to approximately 4000 Hz, where the average attenuation
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-
tion, a hydrophone can be implanted surgically in the
sheep prior to delivery, whereas in the human the location
of implantation is less accurate and requires taking mea-
surements with the amnion ruptured.
Intrauterine basal noise is dominated by low frequen-
cies. Highest intensities are measured at frequencies below
32 Hz, to which the human auditory system is not respon-
sive. Measurements obtained by Querleu and colleagues73
suggest that basal noise is of sufficiently low level that
external sounds are not masked. Their A-weighted sound

Figure 36-6. Comparison between myelination of the auditory nerve
(expressed as percent of the adult average number of lamellae per axon) and
normalized ABR latency and amplitudes for wave I as illustrated. Latencies
are expressed as percent of adult values, and amplitude as percent of
maximum. (From Walsh EJ, McGee J: The development of function in the
auditory periphery. In Altschuler RA, Hoffman DW, Bobbin RP [eds]:
Neurobiology of Hearing: The Cochlea. New York, Raven Press, 1986, p 254.)
pressure level measurements of internal noise were 28 dB.
(The A-weighted scale excludes the lowest frequencies, see
Green74). Voices emerged above the basal noise level by
8 to 12 dB for exterior voices and 24 dB for the mother’s
voice. Independent observers asked to repeat what they
could hear from an interuterine recording of male and
female speakers (including the mother) were able to cor-
rectly reproduce 30% of the phonemes, regardless of the
source. Although the mother’s voice was louder, it was not
better perceived, presumably because of greater distortion
of the internally transmitted sound.
Transmission of sound into the interuterine environ-
ment is meaningful only if the fetus is capable of perceiv-
ing the stimulus. Investigators attempting to measure fetal
hearing have used a variety of unconditioned responses,
such as body movements, heart rate changes, and eye blink
responses. Such measures are primarily startle responses to
sound and are subject to rapid habituation with repetitive
stimulation.75 The earliest eye blink responses to noise
bursts can be elicited in the 25th gestational week, and
consistent eye blink, heart rate, and motor responses are
measured from the seventh month of pregnancy.76,77
Studies by Lecanuet and coworkers78 have demonstrated
response (cardiac deceleration) to stimuli of 90 to 100 dB
sound pressure level ex utero.
Postnatal Development of Auditory
Competence
Methodology
Psychoacoustic tests must be designed to optimize the
acoustic stimulus control of the subject and the adaptive-
ness of the task to the behavioral repertoire of the
subject.75 Different response strategies will be most effec-
tive at different points along the developmental timeline;
herein lies the challenge to investigators interested in
development of auditory competence. Unconditioned
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
nonsensory processes such as memory and attention may
confound interpretation of experimental results, particu-
larly for infants and young children. Thus, it is useful to
use varied experimental strategies to address each question
of human auditory system development.
Postnatal hearing development is well summarized by
Werner.79
Neonatal Period (Birth to 28 days)
The newborn is able to discriminate a number of the
elements of speech, including voiced versus unvoiced
consonants, consonants by place of articulation, and several
vowel pairs, by about 2 months of age (see Querleu et al.73
for review). DeCasper and Fifer80 determined that 3-day-old
neonates consistently respond preferentially to their
mothers’ voices. Responses rely at least partially on into-
nation patterns, as there is no preference for the mother’s
voice when text is read backwards.81
The neonate is also able to localize the origin of a
sound.82,83 Interestingly, this behavior is more difficult to
elicit in 1- to 2-month-olds, but reappears around 3 to 4
months of age.84 This developmental pattern is thought to
reflect a difficulty in organization of auditory space and
coordination with appropriate motor behavior. When the
head-orienting response reappears, it is accompanied by
visual search; this may represent the beginning of true
spatial hearing.84
A number of studies have shown a substantial improve-
ment in pure tone thresholds in quiet in the first 6 months
of life. Thresholds of 2- to 5-week-old infants have been
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
be poorest initially at high frequencies, relative to adult
thresholds, and demonstrate the most improvement during
the first 6 months of life.
Infancy (28 days to 2 years) and Early Childhood
Absolute Sensitivity and Intensity Discrimination
As reported by Werner,79 the available evidence suggests
that, in quiet, detection thresholds at 6 months are 10 to
15 dB higher than those of adults and that thresholds are not
570 PEDIATRIC NEUROTOLOGY
adult-like through the entire frequency range of hearing
until at least 10 years of age.
Although responses are initially most adult-like in the
low frequencies, high-frequency responsiveness improves
more rapidly, so that the adult values are first achieved in
the high frequencies. The trend toward earliest develop-
ment of low-frequency hearing parallels that seen in the
physiologic studies87 and behavioral studies of hearing in
animals.88 Low-frequency threshold elevation is reported
as late as 10 to 18 years of age (Fig. 36-7).89–91
Frequency Resolution
Frequency resolution capabilities are among the earliest
to mature. Werner and Bargones92 report that frequency
resolution is adult-like at all but the highest frequencies by
6 months of age. Psychophysical data obtained from chil-
dren have indicated that frequency resolution continues to
improve until at least age 4 years93,94 and may continue to
improve as late as age 12.90,95
Temporal Resolution
Animal studies of physiologic response development have
revealed that temporal response properties are the last of
the “simple” auditory system coding mechanisms to reach
maturity. Accordingly, one might expect that behavioral
measures of temporal processing would reflect this pro-
longed developmental time course. Although absolute
sensitivity and frequency resolution is nearly mature by
6 months, temporal resolution continues to mature after
6 months of age. The developmental time course of
temporal processing is difficult to assess independently
because of dependence on intensity coding. One common
Figure 36-7. Absolute thresholds as a function of age for five octave-band
noises. Individual exponential decay functions have been fit to the data
at each frequency. (From Trehub SE, Schneider BA, Morrongiello BA,
Thorpe LA: Auditory sensitivity in school-age children. J Exp Child Psychol
46:273–285, 1988, p 278.)
measure of temporal processing is gap detection. Studies
of gap detection report that this ability doesn’t reach
maturity until about age 5,96 but it is possible that stimulus
duration and adaptation effects influence this measure.
Using one technique designed to separate the effects of
intensity and temporal processing, Levi and Werner97
suggest that infants may have mature temporal resolution,
but immaturity of intensity processing contributes to the
experimental findings that reflect apparent deficits in
temporal processing.
It is possible that threshold, frequency resolution, and
temporal resolution are all nearly mature within the first
couple of years of life and that development of intensity
coding lags behind, mature by some measures by about
5 years of age.
Spatial Hearing
Clifton84 summarized the ability of infants to respond
to auditory spatial cues. Sensitivity to binaural time cues
is well developed in 4-month-olds; development of binau-
ral intensity cues has not been studied. Investigations
of minimal audible angle (MAA) have reported that
6-month-olds can discriminate a change in sound location
of 12 to 19 degrees off-midline. Gradual improvement is
noted to 18 months (6 degrees). Performance of 5-years-olds
is similar to that of adults, who can detect an MAA of
1 degree.
The “precedence effect” aids in localizing a sound by
suppression of echoes, or reflections from surrounding
surfaces. Clifton84 presents evidence that development of
this ability is delayed in infants compared with their abil-
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,
remember, or comprehend information presented to the
auditory system. Although efforts have been made to
tailor tests of central auditory function to young children,
behavioral assessments are difficult in children younger

than 6 years of age, and normative data are often lacking.
A thorough discussion of behavioral assessment of central
auditory function is provided by Keith in Chapter 17 of
this text. The reader is also referred to the discussion by
Musiek and Baran.98
Many of the shortcomings of behavioral testing in this
age group can theoretically be circumvented by the use of
carefully administered and interpreted electrophysiologic
tests for evaluation of central auditory processing skills.
Interpretation of many of these responses is poorly under-
stood. However, recent advances in the understanding of
middle latency and late responses may lead to improved
clinical utility.
A comprehensive review of the electrophysiologic tests
of central auditory system function is provided by Kraus
and McGee.99 Responses to sound are classified by latency
into early, middle, and late waveforms. The ABR, the
development of which was discussed earlier, consists of
seven peaks, all occurring within 15 msec of signal onset.
Studies of Moller and Jannetta100,101 suggest that wave-
forms are generated at sites from the peripheral AN to the
IC. The ABR provides a highly reliable indication of audi-
tory function in subjects of all ages and shows predictable
changes in neurologically impaired systems.102–104
The middle latency response (MLR) comprises a series
of waveforms (Na, Pa, Pl, and TP41) that occur between
10 and 60 msec after stimulus onset. Generator sites
include auditory pathway structures central to the IC
(“primary pathway”) as well as structures outside this
pathway, such as the so-called reticular activating system,
and nonprimary divisions of the auditory thalamocortical
pathways, which process multisensory stimuli (“nonpri-
mary pathway”). The MLR derives from multiple sources
that mature at different developmental rates and are
variously affected by anesthetics and sleep state. Whereas
the ABR is developmentally mature by 18 months of age,
the MLR exhibits a much longer developmental time
course; the primary cortical generator is likely mature by
age 10 to 12 years, but the nonprimary areas may not be
fully mature until early adulthood. McGee and Kraus105
suggest that this extended developmental process may
account for the relatively late development of selective
auditory attention.
The MLR has been used in pediatric populations pri-
marily to assess low-frequency hearing thresholds that are
not easily measured with the traditional ABR.106 One
problem with this application has been the lability of the
response in the pediatric population, particularly in sleep-
ing children. Problems of recording this response in
children may be circumvented by targeting response mea-
surements made during favorable sleep stages as described
by McGee and colleagues.107
Late auditory evoked potentials occur after 70 msec and
reflect primarily responses of structures central to the
brainstem. In general, these responses are less stimulus-
dependent and more state-dependent and, thus, variable.
Although certain of the late response waveforms are well
defined and useful as clinical entities, others are much
more variable and controversial. Some of the more well-
documented responses include the N1–P2 complex (P1, N1,
P2, N2), present at a latency range of 50–300 msec. All are
elicited by a stimulus train of repetitive identical tonal or
Central Auditory System Development and Disorders 571
click stimuli. Other late responses occur in response to
speech stimuli, with total durations out to 700 msec.
Kurtzberg and colleagues108,109 described a series of corti-
cal auditory evoked potentials (CAEPs) in response to
speech stimuli that show an orderly sequence of matura-
tion until adult-like responses are achieved at about age 2.
Patients with various brain lesions have been shown to
have abnormal late potentials, and attention of some inves-
tigators has focused on the use of these responses for iden-
tification of neurologic disease (see Kraus and colleagues110).
Another set of late responses is elicited only in reaction
to a deviant or unexpected stimulus inserted into a repeti-
tive identical stimulus train, presented in an “oddball” par-
adigm. Some of these responses include the mismatch
negativity response (MMN), P300, and the cortical dis-
criminative response (CDR).110
The MMN is a robust response that, unlike other corti-
cal potentials, appears to be mature in school-age chil-
dren.111 It is passively elicited from nonattending subjects,
in response to stimulus pairs (such as /da/ and /ga/) that
are at or above behavioral discrimination threshold.
Stimulus pairs may be within or across phonemic bound-
aries. The MMN is thought to originate from the auditory
cortex, with contributions from auditory thalamus and
hippocampus.112–115 Thus, it may be useful for evaluation
of central auditory processing skills such as auditory short-
term memory, stimulus detection in background “noise,”
temporal processing, or speech discrimination. It also may
be useful for evaluation of children with attention deficit
disorders.111 Another potentially exciting use of the MMN
is in evaluation of speech discrimination in cochlear
implant recipients, particularly children with limited audi-
tory processing skills.116
The P300, originally described by Sutton and cowork-
ers,117 is also elicited by an oddball paradigm. P3a can be
elicited in nonattending subjects, but the P3b component
requires active discrimination of the stimulus by the sub-
ject. Multiple subcortical as well as cortical sites are
thought to contribute to the response (see Kraus and
McGee99 for a review). Definitive norms have not been
established for the P300 because of great intersubject vari-
ability in latency and amplitude. For this reason, the P300
may be more useful as a measure of changes over time in
one individual subject (i.e., recovery from injury, response
to treatment, etc.). It has been suggested that the P300
correlates more with global cognitive function than with
any specific disorder.118
Speech evoked CAEPs and CDRs have been investi-
gated by Kurtzberg and colleagues108,109 in clinical popula-
tions. They studied infants identified to be at risk for
language disorders based on low birth weight or perinatal
asphyxia and discovered a high incidence of abnormal
speech-elicited responses. On follow-up, children with
abnormal responses in the neonatal period were later found
to have deficiencies of language-processing skills. The
authors concluded that the abnormal CAEPs and CDRs
were meaningful predictors of later language performance.
Finally, the N400 (latency 400 msec) is elicited only in
response to a stimulus that presents a semantic incongruity
(e.g., “I am going to walk the house”). It is elicited, as is
the P300, by auditory, visual, and sign language stimuli.119
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
studies describe the often profound effects of afferent
manipulation on the developing CAS. Conversely, effects
on the mature auditory system are usually modest or
nonexistant. Investigators have described a sensitive, or
developmental, period during which abnormal experience
can adversely influence development, and a more pro-
tracted critical period during which normal afferent input
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
ability to define for various species and experimental
conditions the time of maximal sensitivity to afferent
manipulations, the cellular mechanisms that affect the
response to environmental manipulation in the developing
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
insults (Fig. 36-8). These are usually termed deprivation and
deafferentation, based on the nature of the manipulation
intended by the experimenter. Deprivation describes a
manipulation that decreases sound transmission through
the outer or middle ear system, producing a conductive
hearing loss. Blockage of sound transmission results in a
decrease in sound-evoked activity in the CAS, but may have
little short-term effect on spontaneous activity of these
neurons.120,121 Effects of purely conductive pathology on
CAS anatomy and function are often subtle, but appear to
involve the entire CAS, in particular the CN.122–125 Depri-
vation of sound input may be unilateral or bilateral; if
unilateral, development of binaural processing strategies may
be affected. Another type of experimentally induced depriva-
tion is interference with patterned activity. For example,
introduction of a repetitive environmental sound can deprive
the CAS of the pattern of neuronal discharges evoked by a
normal acoustic environment and can disrupt the acquisition
of central auditory-processing capabilities.126,127
The second type of insult, deafferentation, occurs with
the partial or total destruction of the peripheral end-organ.
The lesion produces a sensorineural hearing loss and
invariably results in diminution or elimination of all
input—spontaneous as well as sound-evoked—to the CAS.
Deafferentation results in degenerative changes that pro-
ceed sequentially to more central structures. CAS pathol-
ogy is usually much more marked than is the case of sound
Figure 36-8. Sites of manipulations of the peripheral auditory system
represented on a section through the human ear (schematic from Pickles
1988). 1, pinna removal; 2, ear plug; 3, tympanic membrane puncture;
4, ossicular disarticulation or removal; 5, application of pharmacologic
substances to the cochlea; 6, round or oval window puncture; 7, cochlea
removal or destruction. (Reprinted with permission from Moore
DR: Developmental plasticity of the brainstem and midbrain auditory
nuclei. In Romand R (ed): Development of the Auditory and Vestibular
Systems 2. Amsterdam, Elsevier, 1992, p 299. Modified from Rubel and
Parks, 1988.)
deprivation with an intact end-organ. It should be empha-
sized, however, that a meaningful interpretation of depri-
vation and deafferentation experiments requires rigorous
quantification of the effect of the manipulation on the
pattern and amount of activity in the CAS.30,120
Conductive Hearing Loss: Effects
of Deprivation of Sound Input
Human Studies
Physicians initially assumed that because the conductive
hearing loss (CHL) typically associated with otitis media
may be mild, unilateral, and fluctuating, the functional
consequences were likely to be minimal. As early as the
1960s, however, it was noted that children with a history of
repeated episodes of otitis media with hearing loss lagged
behind their normal-hearing peers in measures of language
development and educational achievement. These early
studies lacked many of the necessary features of a well-
designed investigation of clinical outcomes, and critical
commentary took issue with the conclusions of these
investigators.128–131 Nevertheless, these early investigations
nearly universally reported a negative effect of hearing loss
on development.
By the late 1980s several research groups initiated
experimentally sound prospective studies of sufficiently
large numbers of subjects to draw statistically valid
conclusions about the consequences of CHL on hearing,
as well as on more global measures of speech, language,
cognition, behavior, and educational achievement. Some
of the most compelling evidence of long-standing deficits
in individuals with chronic CHL comes from studies
that assess performance on specific auditory processing
tasks. Hall, Pillsbury, and colleagues,132–134 and others135,136

have used the masking level difference (MLD) to assess the
ability of subjects with a history of CHL to process binau-
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-
ing the phase of the signal presented to the two ears.
MLDs are significantly smaller in children with a history
of CHL than in age-matched control children. In a study
population that was selected for placement of middle ear
ventilation tubes, the abnormality in MLDs noted prior to
tube placement, in the presence of hearing loss, persisted
in approximately half of the children after hearing thresh-
olds were normal.133 Interestingly, Pillsbury and col-
leagues132 commented that postsurgical MLDs were most
likely to be abnormal in subjects who had experienced
asymmetrical hearing losses, although this was not con-
firmed in their later studies.
ABRs have been studied in subjects who have normal
hearing and a history of CHL.137–139 All three studies
reported an increase in latency to waves III and V of the
ABR and an increase in interwave latencies. Binaural inter-
action was assessed by subtracting binaural from summed
monaural waveforms and was significantly diminished in
normal subjects and subjects with a history of otitis media
with effusion.
Prospective investigations have examined the effect of
otitis media with effusion and CHL on development of
speech and language skills and on behavior and cognition.
Vernon-Feagans140 noted risk factors that may affect lan-
guage and attention outcomes. Her model predicts that,
in the presence of an environment that facilitates commu-
nication, children develop normal speech, language, and
behavior. In less optimal situations, language skills develop
poorly, and a lack of attentive behavior complicates
language processing. Children in the latter group with a
history of hearing loss from otitis media may tend to
“tune-out” language and attend to less auditory parts of
the environment. Such children have a more difficult time
with complex listening tasks such as comprehending
extended discourse in conversation, storytelling, or
extended topic elaboration, such as they might encounter
in a school setting. Therefore, prompt and aggressive
management of childhood medical conditions associated
with hearing loss seems well advised. Such interventions
are not always implemented, secondary to lack of knowl-
edge of the implications of such impairment and to con-
troversy regarding the most cost-effective method of
medical management of disease.141,142
The above-mentioned studies provide compelling
evidence that changes in central auditory processing
abilities persist long after hearing loss resolves in children
with a history of conductive impairment. The existence of
long-term alterations in processing of auditory signals
could imply that hearing loss in early life is associated with
structural or functional modifications in the CAS. Very
little is known about the specific structural and functional
changes that occur in response to this impairment, and
the mechanisms of these neuronal changes are even less
well understood. The need to effectively manage hearing
loss in children is one ultimate goal that drives our need
to understand the factors, such as duration of impairment
and effect of developmental stage, which influence the
Central Auditory System Development and Disorders 573
consequences of CHL and the potential for reversal of any
CAS changes.
Animal Studies
Anatomic Effects of Conductive Hearing Loss
Animal models of CHL have been developed and give us
some insight into the CAS consequences of conductive
impairment. These studies must be interpreted with con-
sideration of the species studied, the developmental stage
at which the experiment is conducted, species-specific
characteristics such as the frequency range of hearing, and
the effect of the manipulation used on activity in the
auditory nerve and CAS. A valid model of CHL requires
that the manipulation used to create the hearing loss
damage only the sound-conducting mechanism of the
middle ear and not the inner ear. Results of studies in
which concomitant sensorineural hearing loss has been
inflicted are confounded by the associated degenerative
changes typically observed following cochlear damage (see
later discussion).
A number of investigations, mostly in rats and mice,
have documented that CHL or other forms of auditory
deprivation (e.g., sound isolation) introduced during a
“critical period” of auditory development result in smaller
than normal brainstem nuclei and neurons,143–152 and other
structural changes.149,153,154 Webster145 documented that
sound amplification introduced during the critical period
of auditory development in the mouse decreases the
atrophy of the CN in mice with external canal atresia
and CHL. Subcutaneous administration of a neurotrophic
agent, monosialoganglioside, significantly ameliorates
CHL-induced atrophy of spiral ganglion cells and neurons
of the VCN.155 Tucci and coworkers124,125 identified
marked changes in CAS neuronal activity using the
2-deoxyglucose method, as well as changes in capacity for
oxidative metabolism in gerbils with unilateral conductive
hearing impairment.
Investigations in chick,123 monkey,156 and ferret122 failed
to demonstrate changes in cross-sectional area of brain-
stem neurons following conductive impairment. Thus,
species differences do appear to be important in assessing
the effect of CHL. However, it is likely that other struc-
tural or functional modifications occur, particularly if the
loss is asymmetrical or unilateral. For example, in the fer-
ret, Moore and colleagues122 found, despite the lack of
change in neuron area in the CN, a significant change in
the projection from the CN opposite the affected ear to
the ipsilateral IC following unilateral conductive impair-
ment. This change may occur secondary to the newly
introduced asymmetry of peripheral input with the unilat-
eral hearing impairment (see following section).
Evidence that Unilateral Conductive Impairment
May Affect the Symmetry of Central Auditory System
Projections
As discussed earlier, unilateral conductive impairment has
been found in one experimental paradigm to change the
symmetry of projections from the CN to IC. It has also
been argued that compensatory changes occur in brain-
stem neurons of the CN opposite an ear with CHL.
574 PEDIATRIC NEUROTOLOGY
Coleman and O’Connor151 reported that the mean neuron
area in the spherical cell region of the rostral AVCN
decreased in the CN ipsilateral to a conductive hearing
impairment but increased in the contralateral CN. Tucci
and coworkers124 reported a similar effect on their measure
of oxidative metabolism in the gerbil with a unilateral
CHL. Some evidence suggests that the symmetry of input
between the two ears may be important in establishing and
maintaining neuronal projections. Killackey and Ryugo154
reported that the laminated structure of the central
nucleus of the IC in the rat is altered following unilateral
but not bilateral ear canal closure. Studies by Knudsen and
colleagues in the barn owl157 reveal evidence of reorgani-
zation of a binaurally innervated nucleus of the CAS and
altered localization cues following unilateral conductive
impairment secondary to an earplug placed during a criti-
cal period in development.
Physiologic Responses to Conductive Hearing Loss
Studies of physiologic responses from the auditory cor-
tex158 (cat) or inferior colliculus159,160 (rat) in animals with
unilateral ear canal atresias imposed at an early stage in
development show abnormal responses to binaural stimu-
lation. This apparent inability to appropriately integrate
auditory input from the two ears following unilateral ear
canal occlusion may reflect physiologic changes that could
be associated with structural abnormalities noted in the
animal studies discussed earlier. Auditory processing
abnormalities noted in children with a history of CHL,
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.
Although monaural CHL decreases the level of acoustic
stimulation that reaches the inner ear, it does not entirely
deprive the ear of patterned input. Several investigators
have examined the effect of restriction of auditory experi-
ence on CAS development. It has been hypothe-
sized29,126,127 that response properties of the CAS may
be fine-tuned through selective elimination of synapses
during development. Evidence from studies such as
Jackson and Parks28 shows that immature CAS neurons
may receive a slight overabundance of excitatory inputs.
Although which factors influence the final synaptic
configuration is unknown, it is possible that activity, both
spontaneous and evoked, influences the establishment of
mature synaptic anatomy. If this is the case and a diversity
of auditory experience is necessary for normal maturation,
it is possible that restriction of auditory experience could
result in postsynaptic cells manifesting a larger than
normal receptive field and poorer frequency resolution
secondary to failure to eliminate inappropriate inputs
during development. Sanes and Constantine-Paton126,127
tested this hypothesis by raising mice in the presence of a
repetitive click stimulus. Clicks were demonstrated to
entrain a large portion of primary afferents in both the AN
and IC during the developmental period. The investigators
demonstrated that single-unit tuning curves to tone pip
stimuli obtained from recording in the central nucleus of
the IC were less sharp (poorer frequency resolution) for
click-reared than for normal control animals. The authors
concluded that normal temporal patterns of neural activity
help to structure synapses in the developing auditory system.
From the foregoing data, it appears that experience with
a normal acoustic environment may influence cellular
response properties of the CAS. The full range of effect of
altered experience is probably not appreciated at this time.
Certainly, binaural integration is influenced by asymmetri-
cal acoustic input. Refinements in our ability to study these
properties in the nervous system are necessary to deter-
mine if other complex integrative capacities are influenced
as well. Whether a sensitive period exists during which
these abilities must develop or be lost forever is unclear.
Several of the previously cited studies seem to suggest that
certain capabilities are never achieved if hearing loss is
allowed to persist during the developmental period.
The obvious question raised to the otologic surgeon is
that of the urgency of correcting a CHL in the young
child. Agreement is widespread that aggressive interven-
tion is warranted for treatment of recalcitrant middle ear
effusion with tympanostomy tubes for prevention of
repeated infections and correction of CHL. However, less
of a consensus is achieved on the issue of correction of
other types of CHL in children, particularly when the loss
is unilateral. Bone conduction hearing aids provide rea-
sonable levels of amplification, but compliance is a prob-
lem, and identical signals are presented to both ears, thus
eliminating cues for binaural hearing.161 A treatment deci-
sion must be based in part on the needs of the child, the
wishes of the parents, and the likelihood of achieving nor-
mal hearing with surgical intervention (i.e., in the case of
congenital atresia).
Sensorineural Hearing Loss: Effects
of Deafferentation
Animal Studies
In contrast to the little-understood effects of conductive
impairment on the CAS, the repercussions of sensorineural
hearing loss (SNHL) is well documented, and investigators
are developing an increasingly sophisticated understanding
of the mechanisms of CAS changes following sensorineural
impairment. Transneuronal degenerative effects of end-
organ damage include changes in neuronal and synaptic
morphology,162–164 dendritic morphology,165,166 protein
synthesis,167 and metabolic activity.168–173 Changes are most
marked in young developing animals, and maximum sus-
ceptibility is confined to a “critical period” in develop-
ment.174–178 Neuronal changes are generally greatest in the
VCN, which receives its primary afferent input from the
ipsilateral ear. However, changes are also seen in more cen-
tral structures, including the ipsilateral LSO and contralat-
eral MNTB in young gerbils179,180 and ferrets.181,182
Morphologic changes similar to those seen following
deafferentation (destruction of the auditory end-organ)
can be produced by pharmacologic blockade of auditory
nerve activity. Tetrodotoxin (TTX), when applied at the
round window, immediately and reversibly eliminates
auditory nerve action potential.177,183–186 Presynaptic
action potentials regulate protein synthesis in second-
order auditory neurons of the chick brainstem.183 Born and
Rubel183 examined the effect of a perilymph injection of
TTX on numbers and size of neurons in nucleus magno-
cellularis (the avian equivalent of the AVCN in mammals)

and on incorporation of 3H leucine using autoradiography.
Short-term effects (1.5 hours) of TTX were very similar to
changes seen after deafferentation,167,187 but by 24 hours
after injection—as the reversible effects of TTX dissi-
pated—these changes reverted to normal. Similarly, TTX
application produces reversible cell size changes in the CN
of the gerbil.186 Synaptic activation is essential for mainte-
nance of normal cell metabolism, as antidromic activation
of neurons via electrical stimulation of axons in a brain
slice preparation did not enhance protein synthesis.184
These studies of afferent manipulation suggest that the
activity of auditory afferents regulates the metabolism and
morphology of neurons in the CAS. The early changes
observed following deafferentation (either anatomic or
pharmacologic) appear to be due to a reduction in activity-
dependent interactions between presynaptic and post-
synaptic cells.186 Studies in chicks have shown that
second-order auditory system neurons rely on eighth
nerve activity-dependent activation of a metabotropic glu-
tamate receptor to maintain physiologic intracellular cal-
cium. Loss of intracellular calcium is thought to contribute
to the early stages of neural degeneration and cell death.188
The balance of input from afferent projections to bin-
aurally innervated nuclei may influence structure and
function in the CAS. Kitzes and colleagues studied the
effects of unilateral cochlea removal in the neonatal gerbil
on patterns of connectivity and physiologic responses (see
Kitzes189 for review). Projections from the VCN, which in
the normal gerbil innervate the ipsilateral LSO, the con-
tralateral MNTB (via the ventral acoustic stria), and both
the ipsilateral and contralateral MSO, are altered after
neonatal cochlear ablation. Labeling experiments showed
aberrant projections from the unoperated side to the con-
tralateral LSO, the ipsilateral MNTB, and both MSO. It
has been suggested that these abnormal patterns of con-
nectivity may occur because of lack of inhibition or com-
petition from the projections of the lesioned side, implying
that such interactions are important for normal develop-
ment of innervation patterns.189 Further studies in the
neonatal gerbil190 demonstrated changes in the patterns of
connectivity between the CN and IC, with an increase in
the ipsilateral CN–IC projection on the side opposite
cochlear ablation, and a decrease in the CN–IC projection
on the side of the ablation. These results again suggest that
an interaction of binaural inputs may influence the final
configuration of innervation patterns for this CAS struc-
ture. Investigation of physiologic responses obtained by
stimulation of the unoperated ear in neonatally ablated
gerbils revealed larger responses from the ipsilateral IC
than was observed in normal animals or those ablated as
adults, indicating functionality of this enhanced projection
from the ipsilateral ear.191 Similar effects were noted on
recorded responses from auditory cortex ipsilateral to the
nonoperated ear of neonatally cochlear ablated cats.192
Another study of auditory cortex plasticity investigated
the tonotopic organization of auditory cortex contralateral
to a partial unilateral cochlear lesion in the guinea pig.193
Immediately after restricted peripheral lesion, neurons in
the region of cortex in which the damaged portion of the
cochlea is normally represented undergoes a change in
tonotopicity such that neuron characteristic frequencies
(CFs) are shifted outside the frequency range of the lesion.
Central Auditory System Development and Disorders 575
Thresholds for these neurons are initially grossly elevated
compared with thresholds for normal neurons in this
region, but over time neurons in this region develop near
normal thresholds at the new CFs. This progression sug-
gests that the representation of frequencies above and
below the lesion is expanded. Similar results have been
reported by Harrison and coworkers194 for the newborn
kitten and by Schwaber and colleagues195 for the adult
macaque monkey. Furthermore, studies by Recanzone and
coworkers196 in the adult owl monkey and Bakin and
Weinberger197 in the guinea pig have demonstrated that
cortical responses can be changed in response to behav-
ioral conditioning in the absence of a peripheral lesion,
thus demonstrating exceptional functional plasticity. The
functional significance of this reorganization has yet to be
understood. As pointed out by Schwaber and coworkers,195
such findings raise questions about the utility of reintro-
duction of auditory stimuli after the onset of hearing loss,
either with a hearing aid or a cochlear implant. However,
it appears likely, although not proven, that the extreme
plasticity of cortical organization would allow further
reorganization to accommodate the reintroduction of
activity.
Mutant strains of animals with congenitally determined
lesions of the organ of Corti provide another means of
assessing degenerative changes and may offer useful mod-
els for studying genetic CHL in human subjects. In this
case, deafferentation is generally gradual and bilateral.
However, unlike the case of cochlear ablation, findings
may be confounded by genetic defects in central struc-
tures, so that all observed degenerative changes may not be
secondary to peripheral destruction. In the deaf white cat,
for example, degenerative changes have been observed in
auditory brainstem nuclei prior to the time when changes
are noted in SGCs.198
One of the most widely cited studies is that of West and
Harrison199 in the deaf white cat. Pathologic alterations
observed for this species occur postnatally, from the 5th to
21st day after birth. The authors demonstrated severe
atrophy of the organ of Corti, although SGCs of the two
animals studied were largely normal in appearance.
Despite the normal ganglion cell population, the volume
of medullary nuclei and soma areas in these nuclei were
decreased compared with normal animals, much like the
results of Powell and Erulkar162 discussed earlier. Thus,
central degenerative changes may be primary rather than
secondary to SGC degeneration and loss of activity. The
authors provide an excellent summary of work on congen-
itally deaf animal models published before the date of
their study.
More recent work in the deafness mutant (dn/dn) mouse
highlights physiologic changes in central structures.200,201
Horner and Bock201 studied IC unit responses to electrical
stimulation of the periphery and discovered that, at least
by certain measures, responses measured from congeni-
tally deaf animals were more robust than those of the nor-
mal-hearing control animals. They found a preponderance
of multispike single-unit responses in contrast to the sin-
gle-spike responses more often observed in the control
animals. Similar observations have been made in animals
genetically susceptible to audiogenic seizures202 and noise-
induced hearing loss.203 The maximum number of evoked
576 PEDIATRIC NEUROTOLOGY
spikes in response to stimulation was greater in mutant
animals, and the group mean threshold of response was
lower in mutant than control animals. Peak-to-peak ampli-
tudes of responses recorded in the IC were also greater in
mutant mice.200 The absence of spontaneous activity in
this mutant was confirmed (in 6- to 7-month-old animals)
using the 2-deoxyglucose method.204
Human Studies
Investigations of the effects of deafferentation in the
human CAS are quite limited. Moore and colleagues205
reported their analysis of brainstem specimens from seven
deaf and six normal-hearing control subjects. Neuron
areas in a restricted location in the PVCN were correlated
inversely with length of period of deafness, so that the
patients with the longest period of deafness prior to death
tended to have the smallest cell size. Furthermore, consis-
tent with the foregoing discussion, the two congenitally
deaf patients in this sample were found to have the most
severe degenerative changes. They also reported a positive
correlation between cell size and spiral ganglion cell num-
ber. Therefore, even though these populations of SGCs
were receiving no or little afferent stimulation, their pres-
ence appeared to affect the population of second-order
neurons. This raises the possibility that, although short-
term studies of spontaneous activity following cochlear
lesion demonstrate dramatic loss of activity in the CN,
long-term evaluation may reveal some level of activity in
the auditory nerve that may partially sustain more central
structures. Liberman and Kiang206 studied spontaneous
discharge rates of auditory nerve fibers in cats 4 to 8 weeks
after noise trauma. Although the majority of fibers
determined to be unresponsive to sound demonstrated no
spontaneous activity, low spontaneous discharge rates were
recorded in many fibers. Those unresponsive units that
were found to have spontaneous activity had abnormal
patterns of activity, typically bursts separated by long
periods of silence.
Wu and Moore207 developed three-dimensional recon-
structions of the CN complex in normal-hearing and deaf
subjects, including two patients with acoustic neuromas.
Their findings in normal-hearing subjects were consistent
with the report of Konigsmark and Murphy208 that showed
a continuous decline in nuclear volume with increasing
age. Interestingly, in the deaf subjects, all over age 60 at
the time of death, there was a less marked decline in
nuclear volume, secondary to gliosis and replacement of
much of the neuropil by glial processes. Thus, the authors
conclude that nuclear volume is not a good correlate of
sensory loss in humans.
Reintroduction of Activity by Electrical Stimulation
in the Deaf Subject: Cochlear Implant
Human Studies
Given the apparent relationship between auditory nerve
activity and integrity of the CAS system structures, it has
been suggested that the reintroduction of electrical stimu-
lation of the auditory nerve, as via a cochlear implant,
might provide sufficient stimulation to either maintain
these central structures or, if instituted immediately after
the onset of deafness, prevent degenerative changes from
occurring. However, the limited histologic material avail-
able from human subjects who received a cochlear implant
prior to their death demonstrates no consistent effect of
chronic electrical stimulation on CAS anatomy. This state-
ment is based on the temporal bone histopathologic
studies by Linthicum and coworkers209 and the studies of
brainstem tissue conducted by Moore and colleagues205
cited earlier.
Linthicum and colleagues209 quantitatively evaluated the
number of SGCs in 22 temporal bones from 13 cochlear
implant patients. Contrary to what might be expected, SGC
population did not appear to correlate with patient per-
formance with the implant; in fact, satisfactory performance
was achieved with as few as 3212 ganglion cells, or slightly
greater than a tenth of the usual population of approximately
30,000. Interestingly, the duration of electrical stimula-
tion, which ranged from 9 months to 14 years (mean
5 years) had no effect on the number of ganglion cells.
Of the seven specimens from bilaterally deaf subjects
analyzed by Moore and colleagues,205 four subjects had
been implanted unilaterally with either a single- or multi-
channel cochlear implant. In no subject was there a signif-
icant increase in ganglion cell number or PVCN cell area
on the side of the brain ipsilateral to the implanted cochlea
(J. Moore26). Duration of stimulation for the four subjects
prior to their death was 7 months, 9 months, 2 years,
and 23 years, respectively. The last subject, however, never
responded to stimulation with the implant, and on tempo-
ral bone histology was found to have no surviving ganglion
cells. Thus, stimulation of this population was very limited.
Another way to examine plasticity is through functional
measures of implant performance. Although more global
measures are evaluated, and many potential confounding
variables are present, performance as a function of factors
such as length of deafness or duration of stimulation may
provide some insight into the ability of the CAS to use
newly available auditory information. Early studies210,211
reported that, for children and adults, age of onset of deaf-
ness, length of total auditory deprivation, and age at
implantation are all important factors in predicting
postimplant performance. Longitudinal studies of implanted
deaf children show significant gains in speech production
and language acquisition in the implanted children relative
to their matched nonimplanted peers.212–214 Best results
are obtained with early implantation, particularly before
age 3.215 Such results would seem to imply that electrical
stimulation instituted soon after the onset of profound
deafness is more effective in stimulating auditory pathways
than stimulation begun after progressive degenerative
changes have taken place.
Animal Studies
Several animal studies have addressed the questions raised
in the foregoing discussion about auditory system plastic-
ity in response to the reintroduction of electrical activity
by means of a cochlear implant. Most investigators have
concluded that electrical stimulation instituted soon after
deafening results in an increase in SGC density ipsilateral
to the stimulated ear. More central effects of stimulation
are less clearly demonstrated.

Measures of metabolic function have shown increased
activity following deafening and subsequent chronic elec-
trical stimulation. Wong-Riley and colleagues216 used the
cytochrome oxidase technique to determine if brainstem
auditory pathways in the cat would demonstrate evidence
of return of function after 5 to 6 months of deafness.
Levels of cytochrome oxidase increased to nearly control
levels after 1 month of electrical stimulation. Although
sample size was small (n = 2), they demonstrated return of
function in a previously deficient system. El-Kashlan and
coworkers217 also reported evidence of metabolic activity
in the CAS following prolonged deafferentation using the
2-deoxyglucose technique. They demonstrated response
to electrical stimulation of the CN through at least 16 weeks
after deafening.
Chouard and colleagues218 presented early evidence that
implantation and stimulation may prevent degenerative
changes following cochlear damage in the guinea pig CN.
Lousteau,219 noting Chouard’s results, first demonstrated
that the early introduction of electrical intracochlear stim-
ulation in young guinea pigs deafened with systemic
kanamycin and ethacrynic acid affected a significant
increase in spiral ganglion cell density compared with the
nonstimulated ear. Modest amounts of stimulation were
used in this study—animals were stimulated at 100 μA for
1 hour daily, 6 days a week for a 45-day period. Hartshorn
and coworkers220 also assessed SGC survival in ototoxically
deafened guinea pigs stimulated at various current levels
for a 9-week period, 2 hours per day, 5 days per week. SGC
survival was significantly enhanced for cells in the basal
turn of the cochlea only. Leake and colleagues221 reported
a similar pattern of enhanced survival of SGCs only in the
basal cochlear region following chronic intracochlear stim-
ulation in four cats (Fig. 36-9). In this investigation, new-
born kittens were ototoxically deafened, unilaterally
implanted (age 9 to 17 weeks) and chronically stimulated at
6 dB above electrically evoked ABR thresholds for 1 hour
per day for 1 to 3 months. No differences in SGC density
Figure 36-9. Pooled data for eight neonatally deafened cats that were
implanted and chronically stimulated at 2 dB above threshold for periods of
about 3 months. For each cochlear sector the mean spiral ganglion cell
density and standard errors are shown for the stimulated and control
specimens. The mean ganglion cell density averaged over all segments was
significantly higher in the stimulated cochleas than in the control specimens.
(From Leake PA, Snyder RL, Hradek FT, Rebscher SJ: Chronic intracochlear
electrical stimulation in neonatally deafened cats: Effects of intensity and
stimulating electrode location. Hear Res 64:99–117, p 107.)
Central Auditory System Development and Disorders 577
between the stimulated and nonstimulated side were
observed in two kittens that received only 4 weeks of stim-
ulation, or in implanted nonstimulated control animals.
Analysis of SGC area revealed no effect of stimulation.
In a follow-up study using the same animals, Lustig and
coworkers222 reported that, although ototoxic deafening
resulted in a 20% to 26% reduction in AVCN spherical
cell size compared with the normal cat, intracochlear stimu-
lation was associated with a 7% increase in ipsilateral AVCN
spherical cell area. No changes were seen in nuclear
volume or AVCN cell density following stimulation.
Matsushima and colleagues223 deafened four cats at age
37 to 40 days with a one-time dose of ototoxic drugs,
implanted an intracochlear electrode array at age 70 to
80 days, and delivered electrical stimulation unilaterally
beginning 10 days after surgery. Animals were stimulated
16 hours per day for a total of 3 to 4 months. An auto-
mated image analysis system was used to measure all
cells in the CN, so the chance of sampling error was
greatly reduced. Cell area in AVCN was significantly
greater ipsilateral to the stimulated ear. However, mean
cell areas for the stimulated AVCN were still less than
reported for normal-hearing cats.15,224 Thus, more robust
effects were obtained in studies with a longer duration of
stimulation and a more complete sampling of AVCN
neurons.
An alternative explanation for the failure of electrical
stimulation to completely reverse the CAS effects of deaf-
ness may involve the nature of the stimulus used in these
studies. Although the repetitive stimuli delivered chroni-
cally in the cited studies may replicate the effects of spon-
taneous activity in these structures, they allow for no
simulation of evoked activity or for any alteration in the
pattern of activity. Snyder and coworkers225 evaluated
frequency resolution of responses in the IC of cats that
underwent chronic electrical stimulation as described for
the experiments of Leake and colleagues.221 The CNIC is
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
properties of neurons in the IC of deafened nonstimulated,
deafened stimulated, and normal cats. Chronic stimulation
was found to increase the response threshold back toward
normal (compared with deaf nonstimulated animals);
decrease the average response latency of neurons in the
IC; and substantially increase the frequency of occurrence,
amplitude, and latency of long latency responses. The
578 PEDIATRIC NEUROTOLOGY
finding, similar to that reported by Horner and Bock201 of
lower response thresholds in deaf nonstimulated animals is
paradoxical, as it occurs coincident with a decrease in the
SGC population. One possible explanation is that the
disappearance of myelinated fibers from the habenula and
bony spiral lamina provides a preferential path for excita-
tion of remaining neural elements, allowing stimulation of
SGCs at lower current levels. Secondly, lower thresholds
may be secondary to denervation supersensitivity to audi-
tory nerve excitation. Interestingly, thresholds increase
toward normal following chronic electrical stimulation.
Based on these findings, the authors suggest that low
thresholds to electrical stimulation may not accurately
predict numbers of surviving neural elements in cochlear
implant patients.226
In summary, although steady progress is observed in
patients following cochlear implantation, particularly when
performed early after the onset of deafness, investigators
have not been able to document irrefutably that the rein-
troduction of chronic electrical activity substantially alters
central auditory pathways in deaf animals. It is likely that a
multitude of factors must be accounted for to document
alterations in CAS anatomy. Changes in the pattern, type,
level, duration, and intracochlear location of stimulation
are likely to be important, as is the method of data analysis.
PATHOLOGY OF THE CENTRAL
AUDITORY SYSTEM
Pathologic conditions associated with CAS abnormalities
during the developmental period include the following:
chromosomal aberrations, skeletal CNS deformities, cer-
tain forms of hereditary deafness, congenital and neonatal
infections, metabolic disorders, and storage diseases such
as leukodystrophies.227–229 In many cases, central findings
are incompletely documented, and their significance often
disputed. Primary CAS pathology is most clearly docu-
mented for two metabolic disorders: anoxia and hyper-
bilirubinemia.
Morphologic studies of the CNS have documented
structural abnormalities in patients with Down syndrome
(trisomy 21), Edwards’ syndrome (trisomy 18), and Patau’s
syndrome (trisomy 13). Gandolfi and coworkers230
reported several abnormalities in the VCN in Down syn-
drome, including reduced cell number, cell density, and
nuclear volume. Abnormalities of the VCN were also
noted in Edwards’ syndrome, and abnormalities of audi-
tory cortical neurons noted in Edwards’ and Patau’s syn-
dromes. In all cases, overall brain development is
retarded.229 Skeletal and structural abnormalities associ-
ated with Arnold-Chiari malformation and Klippel-Feil
syndrome can result in compression and kinking of the
eighth cranial nerve. In Arnold-Chiari malformation the
CN can be compressed,227 and compression of blood ves-
sels can lead to brainstem ischemic changes.231 Hearing
loss is reported in patients with this disorder, in percent-
ages ranging from 12% to 44%.232 Rydell and Pulec232
report that 20% of 29 patients studied had both vestibular
and auditory symptoms. The hearing loss can be asym-
metrical and progressive,233 and surgical decompression
has been reported to halt the progression of hearing loss.234
Although CNS abnormalities and mental retardation
have been reported for a few syndromes associated with
early-onset deafness, including Cockayne’s syndrome
(retinitis pigmentosa, dwarfism, microcephaly, premature
senility, photosensitive dermatitis), Sylvester’s disease (optic
atrophy, ataxia), and Norrie’s disease (oculoacousticocere-
bral degeneration), evidence of auditory pathway degener-
ative changes has been demonstrated only for Cockayne’s
syndrome.229 Studies have documented loss of peripheral
sensory cells, loss of over half of the spiral ganglion cell
population, and degenerative changes in auditory nuclei,
presumed secondary to transneuronal degeneration.235,236
Auditory dysfunction has been well documented for
patients with Friedrich’s ataxia, a disorder of spinocerebellar
degeneration. Abnormalities have been noted in the VCN,
medullary striae, and superior olive.237–239 Van Bogaert and
Martin238 provide a comprehensive summary of previously
published literature on auditory system involvement in
this disorder. Reports of CAS pathology are difficult to
interpret because of the paucity of data on the integrity of
the peripheral auditory system. Spoendlin240 reported that,
in two patients with Friedrich’s ataxia, the organ of Corti
was essentially intact, but severe degenerative changes
were noted in more central structures. Satya-Murti and
colleagues241 performed audiometric tests and brainstem
auditory evoked potentials on four patients with
Friedrich’s ataxia who had no subjective hearing impair-
ment. Behavioral audiometry revealed a mild to severe
bilateral SNHL in all subjects, with no consistent config-
uration. Three of the four patients demonstrated “roll-
over,” or a decrease in speech recognition scores with
increasing word intensity. ABRs for all four subjects were
markedly abnormal, with no identifiable waveforms. The
authors argue based on their findings that the primary
lesion producing auditory dysfunction in these patients is
spiral ganglion cell degeneration.
Intrauterine and early-onset infections are rarely associ-
ated with CAS abnormalities. Congenital deafness result-
ing from maternal rubella results primarily from cochlear
destruction. However, Rorke and Spiro242 documented
cerebral lesions in these patients, although not specifically
in CAS pathways. Extensive degenerative changes were
noted in association with vascular lesions, confined
primarily to the deep white matter and nuclei. Ames and
coworkers243 identified central auditory processing deficits
in children demonstrated to have congenital rubella. In a
sample of 118 affected children, 50% were found to have
central auditory impairment. Of these, none were diagnosed
as mentally retarded, and 30 patients had no concomitant
peripheral auditory system abnormalities.
Cytomegalovirus infections cause CNS abnormalities
in approximately half of affected cases. Abnormalities
include microcephaly, seizures, mental retardation, and
deafness.143,244 Again, inner ear involvement and CNS
degenerative changes have been documented, but abnor-
malities of CAS pathways have not been investigated.229
Several postnatal infections have been documented to
have CAS involvement.228 Bacterial meningitis usually
produces hearing impairment by labyrinthine destruction.245
However, the infection may spread to involve the eighth
nerve and spiral ganglion cells. Cerebral arteritis may
produce focal brain lesions, particularly in the infant.245

Meningoencephalitis due to Listeria monocytogenes or
tuberculosis may involve the CAS,229 although this pathol-
ogy has not been demonstrated in children. Syphilis
involves both the peripheral and central auditory system.
Severe demyelination and degeneration of the CN
may occur.228
Hearing impairment has been demonstrated in patients
with storage diseases, particularly those that involve white
matter degeneration, or leukodystrophies.229 Ochs and col-
leagues246 identified abnormalities in the ABRs of 10 patients
with various leukodystrophies, including poor waveform
morphology and increased interwave latencies. Abnormal-
ities were presumed to be secondary to the severe demyeli-
nation associated with these diseases. The ABR was also
studied in an infant with Gaucher’s disease. Progressive
deterioration of waveforms was noted. Postmortem patho-
logy revealed no abnormalities of the central auditory
pathways, however.247
Anoxic encephalopathy is one of the major causes of
hearing loss of central origin; this insult is typically associ-
ated with a bilateral high-frequency sensorineural deficit.248
Although the inner ear and spiral ganglion cells are
relatively immune to the effects of anoxia, the CAS, partic-
ularly the CN, is severely affected.228 Hall249 studied
brain and temporal bone specimens from 39 patients with
neonatal anoxia. Although temporal bone specimens were
essentially normal, severe degenerative changes were noted
in the CN complex. Cell loss ranged from 20% to 45% in
the VCN, and up to 66% in the DCN. Less marked changes
were observed in the IC. Degree of cell loss appeared to
correlate with length of the hypoxic period. The vulnerabil-
ity of the CN to anoxic-related injury is attributed to the
relatively high metabolic rate of this region.
Some investigators have attributed the CAS injury
produced by hyperbilirubinemia to the effects of hypoxia,
produced by hemolysis and intracapillary sludging of
erythrocytes.228 It is likely, however, that several factors
influence the development of bilirubin encephalopathy.
For example, anoxia during the perinatal period may result
in acidosis, which may increase cellular uptake of bilirubin
(discussed by Conlee and Shapiro250). Ahdab-Barmada and
Moossy251 described different patterns of CNS abnormal-
ities observed with kernicterus and anoxic/hypoxic injury.
Evidence presented by MacDonald and coworkers252,253
suggests that bilirubin neurotoxicity may act through
glutaminergic excitotoxicity in the hippocampus, and Conlee
and Shapiro250 argue that a similar mechanism may con-
tribute to CAS toxicity, particularly in AVCN and MNTB.
Crabtree and Gerrard254 presented the first evidence of
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-
tent with cochlear pathology.255 However, more recent
ABR studies have documented evidence of brainstem
pathology, a finding more consistent with reported
anatomic findings. Although inner ear pathology has been
reported in association with hyperbilirubinemia,256 most
investigators have failed to document cochlear abnormali-
ties.228,257,258 Instead, extensive degenerative changes have
been reported in the CAS, particularly in the CN.228,257
ABR abnormalities have been reported in neonates with
hyperbilirubinemia.259–261 Nwaesei and coworkers260
Central Auditory System Development and Disorders 579
recorded ABRs in nine full-term infants before and after
exchange transfusion for hyperbilirubinemia (mean
concentration 22.3 mg/dL), and noted significant improve-
ment in waveform morphology, latency, and amplitudes
following transfusion.
The homozygote jaundiced ( jj) Gunn rat, which lacks
the hepatic enzyme glucuronyl transferase necessary to
conjugate bilirubin, has been used as a model for human
bilirubin encephalopathy. Shapiro and colleagues250,262–265
have documented abnormalities of ABR waveforms and
auditory brainstem morphology in this species. In order to
accentuate neuropathologic abnormalities, brain bilirubin
concentration was artificially raised in heterozygotic (Nj)
and homozygotic Gunn rats by the administration of
sulfadimethoxine, an albumin-binding drug that increases
free bilirubin levels. Increased latencies were demon-
strated for waves II and III of the ABR, as well as the I–II
and I–III interwave latencies, following administration of
sulfadimethoxine to jj rats only.262 As with transfusion-
treated neonates,260 abnormalities were reversed after
treatment, which in this case consisted of administration of
albumin (to bind bilirubin). ABR abnormalities were found
to correlate in severity with degenerative changes in the
CN.264 Anatomic analysis of brainstems of sulfa-treated jj
rats revealed a significant decrease in CN volume, AVCN
spherical cell area, and area of principal cells in the nucleus
of the trapezoid body, as compared with treated heterozy-
gotes. The authors suggest that these two cell groups are
uniquely targeted in bilirubin toxicity, possibly through a
neurotoxic mechanism related to presumed glutaminergic
inputs.250
Auditory neuropathy, a disorder first described by Starr
and colleagues,266,267 is characterized by hearing loss for
pure tones, impaired word discrimination out of proportion
to pure tone hearing loss, absent or abnormal ABRs, and
normal outer hair cell function as measured by otoacoustic
emissions and cochlear microphonic.268 Causes of this
condition have not been determined; some patients have
an apparently isolated auditory abnormality, and others
are diagnosed with a variety of disease processes, includ-
ing Charcot-Marie-Tooth disease, hyperbilirubinemia,
Friedreich’s ataxia, multiple sclerosis,268,269 and severe
neonatal illness.270 Sites of involvement may include the
cochlea (central to the outer hair cells), the auditory nerve,
and the auditory pathways of the brainstem, or all of these
structures. In cases of delayed auditory maturation function
may improve over time; however, if the auditory neuropa-
thy is a manifestation of a generalized neurologic condi-
tion, function may deteriorate.269,271
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265. Shapiro SM, Hecox KE: Development of brainstem auditory
evoked potentials in heterozygous and homozygous jaundiced
Gunn rats. Dev Brain Res 41:147–157, 1988.
266. Starr A. McPherson D, Patterson J, et al: Absence of both auditory
evoked potentials and auditory percepts dependent on timing cues.
Brain 114:1157–1180, 1991.
267. Starr A, Picton TW, Sininger Y, et al: Auditory Neuropathy. Brain
119:741–753, 1996.
268. Doyle KJ, Sininger Y, Starr A: Auditory neuropathy in childhood:
Laryngoscope 108(9):1374–1377, 1998.
269. Berlin CI, Bordelon J, St. John P, et al: Reversing click polarity
may uncover auditory neuropathy in infants. Ear Hear
19(1):37–47, 1998.
270. Deltenre P, Mansbach AL, Bozet C, et al: Auditory neuropathy: a
report on three cases with early onsets and major neonatal illnesses.
Electroencephalogr Clin Neurophysiol 104(1):17–22, 1997.
271. Stein LK, Tremblay K, Pasternak J, et al: Auditory brainstem
neuropathy and elevated bilirubin levels. Semin Hear 17:197–213,
1996.

Cochlear Hearing Loss
Outline
Cochlear Physiology and
Sensorineural Hearing Loss
Noise-Induced Hearing Loss
Presbycusis
Ototoxicity
Aminoglycosides
Cisplatin and Carboplatin
Loop Diuretics
Salicylate and Quinine
Topical Otic Preparations
Chemical Teratogens
Monitoring during Ototoxic
Drug Administration
Idiopathic Sudden
Sensorineural Hearing Loss
Temporal Bone Trauma
Temporal Bone Fracture
Perilymphatic Fistula
Diving Barotrauma
Infectious Causes of
Cochlear Hearing Loss
Meningitis
Congenital Infections
COCHLEAR PHYSIOLOGY AND
SENSORINEURAL HEARING LOSS
Hearing allows us to be conscious of what is going on
around us. It is always working to warn us of danger. Most
important, hearing permits communication. Hearing loss
affects 28 million Americans (1 out of every 10 people).
The isolation from society that occurs with hearing loss
can lead people to depression and behavioral problems.
Understanding the pathophysiology of hearing loss neces-
sitates an understanding of the mechanism of sound trans-
duction in the cochlea. The cochlea acts as both a passive
filter and an active filter. The passive filtering properties cre-
ate a tonotopic distribution of the frequency spectrum along
the length of the cochlea, based on the inverse relationship
between the mass and the stiffness of the basilar membrane.
The basilar membrane is narrow and stiff at the base of the
cochlea, which corresponds to high-frequency tuning. At the
apex of the cochlea, the basilar membrane is wider and
less stiff, which corresponds to low-frequency tuning. Thus,
each point along the basilar membrane has a characteristic
frequency to which it is tuned.
Chapter
37
Adult-Onset Acquired Syphilis John S. Oghalai, MD
Human Immunodeficiency
Virus
Sequelae of Acute and Chronic
Otitis Media
Poststapedectomy
Sensorineural Hearing Loss
Congenital Hearing Loss
Congenital Anomalies of the
Inner Ear
Membranous Labyrinth
Malformations with a
Normal Otic Capsule
Membranous Labyrinth
Malformations with Otic
Capsule Malformations
Genetic
Metabolic Cochlear
Hearing Loss
Otic Capsule Bony Diseases
Autoimmune Hearing Loss
Active filtering properties are found only in the mam-
malian cochlea. A positive feedback loop locally amplifies
sound vibrations at each characteristic frequency along the
basilar membrane. This cochlear amplifier dramatically
increases cochlear sensitivity (the ability to hear quiet
sounds) and improves frequency selectivity (the ability to
distinguish between adjacent frequencies). Outer hair cell
electromotility (discussed below) is the source of the active
filtering of the mammalian cochlea.
The organ of Corti is a highly organized structure
(Fig. 37-1). There are a single row of inner hair cells and
three rows of outer hair cells. These cells run the length of
the cochlea and are positioned on top of the basilar mem-
brane by supporting cells. There are tight junctions between
the apex of the hair cells and the surrounding supporting
cells, which form the barrier between the endolymph and
the perilymph (the reticular lamina). Movement of the
stapes footplate at a certain frequency produces a traveling
wave that maximally vibrates the section of the organ of
Corti tuned to that frequency. This leads to sharing forces
between the hair cells and the tectorial membrane, which
deflects stereocilia and depolarizes hair cells.
589
592 PERIPHERAL AUDIOVESTIBULAR DISORDERS
Additionally, inner hair cell and supporting cell damage
begins.10 When hair cells die, a permanent hearing loss
results because mammalian cochlear hair cells do not
regenerate. With extremely loud noise trauma, such as
from a blast injury, there is widespread fracture of the tight
junctions between cells in the organ of Corti, as well as
damage to Reissner’s membrane, the basilar membrane,
and the pillar cells. This can lead to mixing of endolymph
and perilymph, resulting in a severe sensorineural hearing
loss. Other evidence of cochlear trauma secondary to noise
exposure is changes in the terminals of cranial nerve VIII.
There can be swelling of dendritic terminals at the inner
hair cell junction, as well as high densities of synaptic vesi-
cles in efferent nerve terminals on the outer hair cells.
Following a noise exposure that leads to loss of outer and
inner hair cells, there is retrograde degeneration of VIIIth
nerve fibers.
The interaction between ototoxic drugs and noise is
important. Administration of a low dose of cisplatin to
laboratory animals may cause no hearing loss and only
minimal hair cell damage. When the same dose of drug
is delivered in concert with a mild noise exposure,
however, the animal may show dramatic hair cell loss and
hearing threshold shifts.11 The pathophysiology of this
potentiation is unclear. In contrast, loop diuretics, which
cause reversible threshold shifts due to loss of the
endolymphatic potential, and salicylate, which inhibits
outer hair cell electromotility, do not potentiate noise-
induced hearing loss.12
An interesting conundrum in the investigation of patients
with acoustic trauma is a large intersubject variability to
noise-induced hearing loss. Patients can be characterized as
having “tough” ears or “tender” ears based on their suscep-
tibility.13 Although one protective mechanism against noise
damage is the middle-ear muscular reflex, efferent olivo-
cochlear projections from the brainstem to the outer hair
cells also may affect a person’s susceptibility to noise-
induced hearing loss. Animal studies have demonstrated
that cutting the efferent fibers to the ear reduces the inter-
subject variability to noise trauma.14 Efferent fibers
probably work to reduce cochlear trauma during noise
exposure by becoming activated in the presence of loud
noise. In this way, loud noise acts to hyperpolarize the outer
hair cells, reduce their electromotile response, and turn
down the gain of the cochlear amplifier.
PRESBYCUSIS
Presbycusis is defined as progressive sensorineural hearing
loss associated with aging. Several major studies have
shown the epidemiology of presbycusis. The U.K.
National Study of Hearing Disorders in 1995 involved
more than 48,000 patients.15 Twenty percent of patients
had hearing impairments greater than 25 dB, 75% of these
being older than 60 years. This large cross-sectional study
demonstrates that the majority of sensorineural hearing
loss occurs in the elderly. Longitudinal studies of hearing
loss accounting for age, sex, and noise exposure history
demonstrate that 97% of subjects experienced a decrease
in hearing over time.16 Patients younger than 55 years
lost hearing at an average rate of 3 dB per decade, and
patients 55 years and older lost hearing at a rate of 9 dB
per decade. Thus, hearing declines gradually in the
majority of the population and the rate of decline accelerates
over time.
The pathophysiology of presbycusis appears to be
predominantly a peripheral phenomenon (i.e., cochlear
and spiral ganglion degeneration). Although there is
clearly a generalized degeneration of the central nervous
system during aging, there is significant evidence against a
central lesion being the main contributor to presbycusis.
Although few, some elderly people have normal pure tone
average and word recognition scores, which suggests that
CNS atrophy does not cause hearing loss.17 Physiologic
studies concur in that otoacoustic emissions diminish with
age, lending evidence toward the hypothesis of presbycusis
being associated with peripheral degeneration.18 The best
designed studies have been performed by Schuknecht.19–21
By correlating pure tone audiometry and temporal bone
histologic findings in patients with presbycusis, four types
of presbycusis can be defined: sensory (hair cell loss), neural
(spiral ganglion cell loss), metabolic or strial (loss of the stria
vascularis), and mechanical (change in the mechanical stiff-
ness of the cochlear duct with aging). Sensory presbycusis
has histologic findings of lipofuscin deposition in hair cells
and loss of hair cell stereocilia. Neural presbycusis has a
reduction in the number of spiral ganglion neurons. About
2100 out of 35,000 spiral ganglion neurons are lost every
decade.20,21 Clinically significant sensorineural hearing loss
develops only after about 50% of the neurons are lost.20,21
Metabolic presbycusis has histologic findings that demon-
strate a thinning of the stria vascularis.19–21 This presumably
diminishes the endolymphatic potential. Mechanical pres-
bycusis (cochlear conductive) is thought to be due to a
change in the mass and stiffness of the cochlear duct and
basilar membrane. However, no clear histologic abnormality
has been identified.
Animal models for presbycusis have been developed by
maintaining animals in quiet environments as they age.
Serial histologic and electrophysiologic studies can then be
performed on the cohort. Studies in the chinchilla demon-
strate that inner hair cells degenerate at a rate of about
0.29% per year and outer hair cells degenerate at a rate of
1% per year.22 There is also mild strial and spiral ganglion
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
stria vascularis and spiral ganglion being spared.23 Others
have found the opposite.24,25 Laboratory data about the
interaction of noise and age are sparse. Because of the large
variability in age-related hearing loss, it is often difficult to
distinguish the influences of noise and age. However, aged
animals and young animals appear to be equally susceptible
to noise.24
The etiology of presbycusis is unclear. Studies with the
Framingham cohort show no association between hyper-
tension or cardiovascular disease and presbycusis.26,27
Additionally, atherosclerosis, hypercholesterolemia, and
hyperlipidemia do not appear to be associated with pres-
bycusis.18 Another potential etiology of presbycusis is
related to repeated exposure to low-intensity noise, not

loud enough to produce temporary threshold shifts.
Constant sound exposure causes an increase in calcium
in the hair cells and spiral ganglion cells. A high rate of
calcium influx could lead to cell toxicity and possibly cell
death. The association of noise and presbycusis has been
carefully studied by comparing cross-sectional studies of
noise-exposed and nonnoise-exposed populations. Non-
noise-exposed populations include the Mabaan tribe from
the Sudan, the Todas tribe in South India, and islanders in
North Scotland. The nonnoise-exposed populations had
significantly greater preservation of hearing into old age
than did subjects from noisy industrial centers.28–30
Finally, a genetic explanation for presbycusis has been
sought. Although multiple genes have been identified with
congenital hearing loss, no specific genes have been
associated with human presbycusis. It is possible that mito-
chondrial gene mutations that result in progressively lower
production of adenosine triphosphate (ATP) lead to
hearing loss. Spiral ganglion, stria vascularis, and hair cells
have large energy requirements and may be most affected
by this type of mutation. In summary, although an exact
etiology for presbycusis has not been identified, many
possibilities exist. In all likelihood, a combination of these
factors render people susceptible to progressive cochlear
degeneration and sensorineural hearing loss associated
with aging. Certainly, the genetics and history of noise
exposure for any individual play a large role.
OTOTOXICITY
Aminoglycosides
It is estimated that 6% to 16% of patients who receive
aminoglycosides suffer sensorineural hearing loss and an
equal percentage suffer some form of vestibular dysfunc-
tion. Aminoglycosides have varying degrees of vestibular
and cochlear toxicity. The more vestibulotoxic aminoglyco-
sides are streptomycin, tobramycin, and gentamycin,
whereas the more cochleotoxic aminoglycosides are
kanamycin, neomycin, and amikacin. A multistep hypothe-
sis of aminoglycoside ototoxicity has been proposed.31 The
first step is an electrostatic attraction of the positively
charged aminoglycoside molecule to the negatively charged
hair cell plasma membrane.32 The aminoglycoside is then
transported into the cell and binds to phosphatidyl-inositol
biphosphate. Toxicity is thought to occur through free rad-
ical formation. In the vestibular system, type I hair cells are
more prone to aminoglycoside toxicity than type II hair
cells.33 In the cochlea, outer hair cells are much more sensi-
tive to aminoglycosides than inner hair cells. Outer hair cell
damage first occurs at the base of the cochlea, leading to
high-frequency hearing loss. With continued intake of
aminoglycosides, the damage progresses down the length of
the cochlea, causing low-frequency hearing losses as well.33
Genetic mutations can predispose certain individuals to
aminoglycoside ototoxicity. Deafness has even been
reported after a single dose. There is a maternal form of
inheritance for this susceptibility and genetic mutations in
the 12S ribosomal RNA gene in the mitochondrial RNA
have been identified. Currently, the two known mutations
Cochlear Hearing Loss 593
(A155G and D961Cn) account for roughly 17% to 33% of
familial aminoglycoside ototoxicity.34 Further mutations
have yet to be identified.
According to one major study,35 predictors of the devel-
opment of aminoglycoside ototoxicity include the type of
aminoglycoside used, duration of therapy, presence of bac-
teremia, presence of fever, liver dysfunction, and the serum
urea nitrogen/creatinine ratio. Factors that do not predict
the development of ototoxicity include the plasma drug
level, aminoglycoside type, use of furosemide, diabetes,
age, renal function, initial hearing acuity, hematocrit value,
and the presence of shock. It should be noted that not all
studies agree with all of these findings. Neonates appear to
have an increased risk of aminoglycoside ototoxicity.36
Additionally, some data suggest that noise exposure can
potentiate aminoglycoside ototoxicity.37
The monitoring of aminoglycoside plasma concentra-
tion is an important part of most therapeutic uses of this
agent. Aminoglycosides have a low therapeutic index and
their bactericidal efficacy is related directly to their peak
concentration level (concentration-dependent killing). In
contrast, aminoglycoside toxicity is related to the total
amount of drug given.38 The pharmacokinetics f aminogly-
cosides are relatively simple. These drugs are hydrophilic,
have low-protein binding, and are excreted renally. Their
volume of distribution in the body is roughly that of the
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-
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
rate may change during therapy.39
Aminoglycoside nephrotoxicity is usually reversible, but
ototoxicity is usually irreversible. Although the best dosing
regimen for most antibiotics would be to have the
concentration of the drug at a constant level above the
minimum inhibitor concentration of the bacteria that it is
killing, the desired concentration versus time profile
for aminoglycosides is that of a high-peak concentration
(for increased efficacy) followed by low trough concentra-
tion (to prevent accumulation and toxicity). Therefore, a
large dose is used. However, the dosing interval is sub-
stantially longer than the drug’s half-life. During tradi-
tional aminoglycoside therapy (multiple daily doses), it is
routine to monitor both a peak and a trough concentra-
tion, with the peak concentration reaching roughly 6 to
10 milligrams per liter, and the trough concentration
being less than 2 milligrams per liter. Recently, there has
been a change to once daily dosing of aminoglycosides
with the same total daily dose. Measuring the peak plasma
concentration with this regimen can help to identify the
actual level of drug being delivered. However, a trough
level is not needed in patients with normal renal function
because all of the drug should have been excreted after
24 hours. Currently there are no clearly established thera-
peutic ranges for once-daily dosing39; however, the risk
of ototoxicity or vestibular toxicity with this regimen is no
higher than that with conventional dosing protocols.40,41
Providing a correct dose of drug to patients with renal
impairment and to elderly patients with impaired
594 PERIPHERAL AUDIOVESTIBULAR DISORDERS
glomerular filtration is crucial because there can be buildup
of drug over time.
Aminoglycoside ototoxicity is different from aminogly-
coside nephrotoxicity in that ototoxicity is not associated
with high plasma concentration of drug.42 This may
be because the penetration of aminoglycoside into and
elimination from the labyrinth is much slower than its
corresponding plasma or cerebrospinal fluid concentra-
tions.43,44 However, one similarity between ototoxicity and
nephrotoxicity is that similar therapies may protect both
the cochlea and the kidney from aminoglycoside toxicity.45
Coadministration of iron chelators and free radical scav-
engers with aminoglycosides has been shown to reduce
hearing loss and nephrotoxicity in animals.46,47 To date,
there is no firm evidence to suggest that free radical scav-
engers reduce aminoglycoside ototoxicity in humans.
Cisplatin and Carboplatin
Cisplatin and carboplatin are antineoplastic agents that
have permanent high-frequency hearing loss as a frequent
side effect. Cisplatin is similar to aminoglycosides in that it
is both nephrotoxic and ototoxic, presumably because of
the formation of iron-induced free radicals48 and apopto-
sis.49 Histologically, cisplatin causes outer hair cell degen-
eration.50,51 The damage starts in the basal turn of the
cochlea, producing a high-frequency hearing loss. As the
duration of treatment and total dose increase, further
hearing loss develops as outer hair cells in the lower-
frequency region of the cochlea become involved.52
Interestingly, carboplatin has similar effects in most mam-
mals; however, in the chinchilla, it appears to cause only
extensive inner hair cell damage and little, if any, outer hair
cell damage.51 The reason for this is unknown. Younger
children seem to be more affected than older patients.53,54
The ototoxicity is enhanced with the concomitant
administration of loop diuretics.36
Loop Diuretics
The loop diuretics, including furosemide and ethacrynic
acid, are direct inhibitors of the Na+-Cl−-K+ cotransport
proteins found in both the tubular cells in the loop of
Henle and in the cells of the stria vascularis.55 Because the
stria vascularis is responsible for maintaining the endolym-
phatic potential as well as the high potassium level in the
endolymph, loss of ionic transport causes reversible
hearing loss. With higher and higher doses of loop diuret-
ics, eventual permanent damage can occur; however, this is
uncommon. The exact mechanism of the permanent
ototoxicity associated with loop diuretics is unclear.
Salicylate and Quinine
Salicylate and quinine cause reversible sensorineural hear-
ing loss. This is best characterized with salicylate
(a metabolite of aspirin, which is acetylsalicylic acid).
Salicylate is known to reversibly block outer hair cell elec-
tromotility56 and disrupt membranous structures in
the outer hair cell. These effects inhibit the active process
in the cochlea responsible for the “cochlear amplifier.”
Clinically, this is seen as a reversible moderate sensorineural
hearing loss of roughly 40 dB to 50 dB. The dose of aspirin
needed to produce a measurable hearing loss is on the
order of 10 to 12 325 mg tablets per day.57 The exact
mechanism of quinine ototoxicity is unclear, but is thought
to pertain to the disruption of normal outer hair cell func-
tioning. Its effects are also reversible.
Topical Otic Preparations
Common topical otic preparations include ototoxic agents
such as aminoglycosides, antifungals, and antiseptics
(including ethanol and povidone-iodine). Although topical
ototoxicity has been demonstrated in abundant experi-
mental studies with animals, information regarding human
topical ototoxicity is minimal.58 It appears that ototoxicity
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
membrane in humans is much thicker than that in the
chinchillas and guinea pigs, common animals in studies
(40 to 70 microns compared to 10 to 14 microns).59
Additionally, in humans the round window niche is deep
and there are often mucosal folds partially covering it,
whereas this is not the case in the chinchilla and guinea
pig. Finally, humans who are receiving topical otic drops
most commonly have chronic otitis media with inflamed
middle-ear mucosa, which is thought to have a higher
absorbability than uninflamed mucosa and likely reduces
the quantity of drug reaching the inner ear. Interestingly,
a survey of 2235 otolaryngologists found that 3.4% admit-
ted to having witnessed irreversible cochlear damage as a
result of ototoxic antibiotic drops.60 However, there is no
demonstrated proof of ototoxicity in human subjects with
topical otic preparations used to treat chronic otitis media.
Of course, intratympanic gentamicin certainly can cause
hearing loss when used to treat vertigo, so clearly the
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
first choice for the treatment of chronic otitis media in
patients with a perforated tympanic membrane.
Chemical Teratogens
Although never available in the United States, even a
single dose of thalidomide taken by the mother during
a susceptible period of fetal development can produce
dramatic fetal defects. Defects in the temporal bone
include atresia of the ear canal, sensorineural hearing loss,
and paralysis of the facial nerve.62 Findings can include
malformation of the cochlea and absent acoustic and
vestibular nerves.
Ethanol is a highly abused drug throughout the world.
Sensorineural hearing loss is associated with fetal alcohol
syndrome. Most studies suggest that more than two alco-
holic drinks per day by the mother is the threshold for
teratogenicity.62 Fetal alcohol syndrome is characterized
by a series of neurologic and behavioral aberrations, in addi-
tion to craniofacial dysmorphic features. These children
have a high incidence of external- and middle-ear abnor-
malities and a 29% incidence of bilateral sensorineural
hearing loss.63

Isotretinoin is a retinoid used for the treatment of
refractory and cystic acne. Taken by pregnant mothers, it
can cause severe fetal deformities. These include shorten-
ing of the cochlea, a nearly total absence of spiral ganglion
cells, and enlargement of the sacculus and utricle.64
Monitoring during Ototoxic
Drug Administration
There are no universally recognized protocols to monitor
patients for early evidence of ototoxicity. Many experts
recommend weekly audiograms during the administration
of ototoxic medications; however, the major morbidity is
actually not hearing loss, but vestibular toxicity. Therefore,
even though conventional audiometry is the simplest mon-
itoring technique, it has the disadvantage of not being very
sensitive.65 Because most ototoxic agents cause a predomi-
nantly high-frequency hearing loss, a more sensitive test
might be high-frequency audiometry (above 8 kHz).
Additionally, otoacoustic emissions could be measured, but
detailed studies as to the sensitivity of otoacoustic emis-
sions when used to screen for ototoxicity have not been
performed. Monitoring for vestibular toxicity is limited to
serial electronystagmography and rotary chair testing.
These tests are almost never performed during the admin-
istration of ototoxic medications because of their variabil-
ity and low sensitivity. In addition, it is very difficult to
perform these tests in debilitated patients.
Overall, drug-induced ototoxicity can best be prevented
by using strategies similar to those used to prevent
nephrotoxicity. This involves keeping the patient well
hydrated and monitoring the patient’s renal function. If
the plasma drug concentration reaches toxic levels, it is
important to consider using hemodialysis or peritoneal
dialysis to remove the drug rapidly in order to limit toxic-
ity. Although a decrease in creatinine clearance definitely
increases the risk of ototoxicity, the literature is unclear as
to the importance of avoiding loop diuretics and loud
noise exposure during ototoxic medication therapy.
IDIOPATHIC SUDDEN SENSORINEURAL
HEARING LOSS
Sudden sensorineural hearing loss is defined as a threshold
increase of more than 20 dB over at least three contiguous
audiometric frequencies occurring within 3 or fewer days.
Idiopathic sudden sensorineural hearing loss is a diagnosis
of exclusion; other causes of sudden hearing loss must be
ruled out. These include cerebellopontine angle tumors,66
autoimmune disease, multiple sclerosis, infectious etiolo-
gies,67 intralabyrinthine hemorrhage, and perilymph
fistula. Additionally, ototoxicity and noise-induced hearing
loss must be considered in the differential diagnosis.
Two theories behind the etiology of idiopathic sudden
sensorineural hearing loss exist.68 The first is vascular
compromise to the inner ear through thrombosis,
hemorrhage, or vascular spasm. In support of this hypoth-
esis, the concentration of oxygen in the perilymph from
patients with idiopathic sudden sensorineural hearing loss
is 30% lower than in controls.69 Also, disturbances in
microcirculatory blood flow have been identified in
Cochlear Hearing Loss 595
patients with idiopathic sudden sensorineural hearing
loss.70 The second theory of idiopathic sudden sen-
sorineural hearing loss is viral inflammation of the cochlea
and/or auditory nerve. Many patients report having had an
upper respiratory syndrome 1 to 2 weeks before onset of
their hearing loss. Some patients have seroconverted to a
variety of viruses, including influenza B, mumps, measles,
rubella, cytomegalovirus, and varicella-zoster. All of these
viruses can cause a viral cochleitis.71 Histologic study of
temporal bones with idiopathic sudden sensorineural hear-
ing loss demonstrates features consistent with viral infec-
tion, including hair cell loss, ganglion cell loss, strial
atrophy, and inflammatory cochleitis.72
The prognosis of idiopathic sudden sensorineural hear-
ing loss is highly variable. Overall, untreated patients have
a spontaneous recovery rate of about 65% to “functional
hearing.”73,74 Recovery, however, appears to depend on the
severity and the pattern of the hearing loss. Patients with a
predominantly low-frequency loss have the best prognosis
for recovery, while those with a high-frequency hearing loss
have a worse prognosis. Patients with a flat profound hear-
ing loss across all frequencies have the worst prognosis.73
Although the spontaneous recovery rate is high, the likeli-
hood of recovery declines with time. If a patient is to
recover from an idiopathic sudden sensorineural hearing
loss, it usually occurs within the first few weeks, and typi-
cally no improvement is noted after 1 to 2 months. Luckily,
long-term follow-up studies have shown that if improve-
ment does occur, the risk of further hearing loss is low.75
The treatment of sudden sensorineural hearing loss
remains confusing and controversial. Countless studies
have been performed purporting to have identified the
ideal treatment regimen for this disease, only to have a
later study report the opposite. The difficulties in analyz-
ing this disease include its rarity, highly variable prognosis,
variable time of presentation, and variable severity of hear-
ing loss. Additionally, the spontaneous recovery rate is
quite high. Because of this confusion, many physicians
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
is important to study and characterize this disease further
with rigid statistical criteria rather than base our current
treatment protocols on anecdotal evidence and hypotheses.
The following summaries describe many of the current
treatments for idiopathic sudden sensorineural hearing. It
is important to note that although statistically significant
differences between treated and untreated groups may
have been reported, further studies have not backed this up
in the majority of cases.
Corticosteroid therapy is among the few therapies to
treat patients with idiopathic sudden sensorineural hearing
loss to have demonstrated effectiveness by randomized,
prospective study.76–82 Not all studies agree with this
conclusion, however.83,84 The specific action of steroids
is based on its anti-inflammatory properties and there-
fore should be beneficial in infectious, inflammatory, and
immune-mediated conditions. A common therapeutic reg-
imen is 80 mg of prednisone per day for 4 days, 60 mg per
day for 4 days, 40 mg per day for 4 days, 20 mg per day for
4 days, and then discontinue the prednisone. Some authors
have advocated transtympanic administration of the steroid
596 PERIPHERAL AUDIOVESTIBULAR DISORDERS
in patients who do not improve on oral steroids.85 Antiviral
therapy has not been shown to be beneficial in the man-
agement of idiopathic sudden sensorineural hearing loss.
A recent randomized double-blinded, placebo-controlled,
prospective, multicenter clinical trial comparing patients
who received prednisone and a placebo to patients who
received prednisone with valcyclovir demonstrated that
the antiviral medication did not provide any more benefit
than steroid therapy alone.86
Treatments to optimize cochlear blood flow include
vasodilatory agents (histamine, papaverine, verapamil, etc.)
or drugs that decrease blood viscosity (dextran, pentoxi-
fylline, procaine, and heparin). None of these agents
appear to offer a significant improvement in hearing
recovery over controls.68,87–91 The theory behind using
vasodilatory agents can be questioned because these drugs
predominantly cause a peripheral vasodilation. Since cere-
bral blood flow has strong autoregulatory mechanisms,
vasodilators may cause a systemic hypotension and actually
reduce blood flow from the inner ear. Carbogen inhalation
therapy (95% oxygen and 5% carbon dioxide) is one of the
few vasodilators that override intracranial autoregulation.
Although some studies have demonstrated an
improvement in the outcomes of patients with idiopathic
sudden sensorineural hearing loss with carbogen,69,92,93
others have demonstrated no improvement.84,94 The effi-
cacy of carbogen remains controversial. A stellate ganglion
block is another therapy thought to elicit vasodilation
within the inner ear since sympathetic fibers to the inner
ear vasculature originate from the stellate ganglion. No
study convincingly demonstrates that a stellate ganglion
block improves recovery over the natural rate of sponta-
neous recovery.95,96
Other therapies, including hyperbaric oxygen (to increase
cochlear oxygen levels), vitamins (free radical scavengers),
gingko biloba, and magnesium have been studied. 97 None of
these therapies have shown significant efficacy in the man-
agement of idiopathic sudden sensorineural hearing loss.68
TEMPORAL BONE TRAUMA
Temporal Bone Fracture
Temporal bone fractures represent roughly 20% of skull
fractures. Risk factors include being male and younger
than 21; more often than others, this population is
involved in risky activities that predispose them to blunt
head trauma. The most common causes are motor vehicle
accidents, falls, bicycle accidents, seizures, and aggravated
assaults. Penetrating trauma, predominantly gunshot
wounds, are much more damaging to the temporal bone
than is blunt trauma. Labyrinthine fractures are common
after a gunshot wound to the temporal bone.
Blunt trauma to the squamous portion of the temporal
bone often results in a longitudinal fracture. Longitudinal
fractures follow along the axis of the external auditory canal
to the middle-ear space, and then the course anteriorly
along the geniculate ganglion and eustachian tube, ending
near the foramen lacerum. The otic capsule is spared in a
longitudinal temporal bone fracture. In contrast, a blow to
the occipital skull often goes through foramen magnum and
results in a transverse fracture of the temporal bone.
Transverse fractures course directly across the petrous pyra-
mid, fracturing the otic capsule, and then extend anteriorly
along the eustachian tube and geniculate ganglion as well.
Longitudinal temporal bone fractures represent 80% and
transverse temporal bone fractures represent 20% of tem-
poral bone fractures.
Sensorineural hearing loss and vertigo are found in
patients who sustain a transverse temporal bone fracture
with otic capsule involvement. Audiogram usually demon-
strates a complete sensorineural hearing loss in that ear.
Clinical examination also reveals the patient to have nys-
tagmus, consistent with a unilateral vestibular deficit.
Interestingly, sensorineural hearing loss can be sustained
without otic capsule fracture if a labyrinthine concussion
occurs. This is thought to involve shearing of the mem-
branes or hair cell stereocilia caused by the rapid acceleration
and deceleration forces in the inner ear. Labyrinthine con-
cussion typically manifests as a high-frequency hearing loss.
Perilymphatic Fistula
Patients with perilymphatic fistula usually present with
disequilibrium and vertigo, although some also have
hearing loss, tinnitus, headache, and aural fullness.
Patients may state that their symptoms are least intense in
the morning but that they worsen progressively during the
day. Most important, symptoms become much worse with
any type of coughing, sneezing, or straining. Occasionally,
altitude change such as going up and down in an airplane
or in an elevator can precipitate symptoms. Patients often
complain of Tullio’s phenomenon, whereby loud noises
precipitate a vertiginous attack.
Perilymphatic fistula is difficult to diagnose. The fistula
test can be performed by insufflating air into the external
auditory canal and observing the patient for evidence of
nystagmus. This test is very insensitive, and is positive in
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-
ing loss. Vestibular testing may demonstrate a unilateral
deficit. Nystagmus brought on by straining can be docu-
mented with electronystagmographic (ENG) monitoring
and evaluation. Computed tomography (CT) is not partic-
ularly useful in the identification of a perilymphatic fistula.
Its sensitivity is estimated at 20%; however, if a fistula is
identified on CT scan, this is obviously highly specific.
The only definitive way to make the diagnosis of peri-
lymphatic fistula is surgical exploration with visualization
of the leak. Even this is not necessarily definitive because
it is quite difficult to verify that small amounts of clear
fluid in the middle-ear cavity represent a perilymphatic
leak and not serous transudate from the middle-ear mucosa.
Fluid suspicious for perilymph can be sampled on a
Gelfoam pledget and tested for β2-transferrin testing, a pro-
tein found only in cerebrospinal fluid (CSF) and perilymph.
The most common etiology of perilymphatic fistula is
head trauma. This may be either following a temporal
bone fracture involving the otic capsule or with stapes
subluxation into the oval window. Barotrauma during
scuba diving, a rapid descent in an airplane, an explosion,

or a difficult childbirth can also cause perilymphatic
fistula. Postsurgical perilymphatic fistula is also a well-
recognized entity. This can occur after stapedectomy if the
oval window fails to seal appropriately. Poor surgical
technique while performing a mastoidectomy can lead to
iatrogentic lateral canal fistula. Additionally, an expanding
cholesteatoma can erode into the lateral semicircular canal
or cochlea, causing a fistula. Finally, patients may present
with congenital perilymphatic fistula. These patients typi-
cally have stapes footplate anomalies or other temporal
bone anomalies identified on CT scan. The superior semi-
circular canal dehiscence syndrome, with a fistula from
the superior canal into the intracranial space, may be
identified by CT scan.
Fluctuating, but progressive, sensorineural or mixed
hearing loss occurs in patients with a perilymph fistula.
Also, these patients have progressive dysequilibrium. Since
there is a fistula from the middle-ear space to the inner ear,
an episode of acute otitis media is worrisome because bac-
teria in the middle ear can easily enter the inner ear and
CSF. This can lead to permanent sensorineural hearing
loss or meningitis.
Treatment is based on conservative therapy. The patient
should be on bedrest with the head elevated for 3 to 6
weeks and take stool softeners, and serial audiograms
should be obtained to follow up for evidence of disease
progression. If symptoms persist or the sensorineural
hearing loss worsens, surgical treatment is indicated. One
option is to simply draw blood from the patient’s arm and
inject it through the eardrum into the middle-ear space.
This blood seal often allows a fistula to heal. Alternatively,
a middle-ear exploration can be performed. This is done
by a transcanal approach with elevation of the tympa-
nomeatal flap and careful examination of the oval and
round windows. If a defect is noted, a graft of fascia or
muscle should be laid over the defect. Many surgeons
place fascia around both the oval window and the round
window even if a fistula is not definitively seen because
defects are quite difficult to detect.
Diving Barotrauma
Barotrauma during diving most commonly affects the
middle ear. It can involve hemorrhage and rupture of the
tympanic membrane, along with ossicular chain disloca-
tion. It is associated with a conductive hearing loss and, in
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:
(1) perilymphatic fistula and (2) inner-ear decompression
sickness.98,99 Perilymphatic fistula can occur through
either the round or oval window because of the pressure
gradient between the perilymph of the inner ear and the
middle-ear cavity. Symptoms include the acute onset of
vertigo, sensorineural hearing loss, tinnitus, nausea, and
vomiting. Treatment includes reducing intracranial and
perilymphatic pressures by bedrest, elevation of the head
of the bed, and the use of stool softeners. If conservative
treatment is ineffective, after 1 week surgical exploration
of the middle ear can be performed.
Inner-ear decompression sickness is caused by the release
of nitrogen gas bubbles into the bloodstream and tissues
Cochlear Hearing Loss 597
during ascent after a prolonged dive. Most divers breathe
compressed air, which includes both oxygen and nitrogen,
and the partial pressure of these gases increases in the
tissues as the dive deepens. Although the oxygen is
metabolized during diving, the nitrogen is not and
becomes dissolved in the body’s tissues. During rapid
ascent, the partial pressure of nitrogen decreases and the
dissolved nitrogen is released as bubbles in the blood-
stream and other tissues.100 Decompression sickness is
classified into types 1 and 2. In type 1 decompression sick-
ness, symptoms are mild and include fatigue or pain in the
joints or muscles. Type 2 decompression sickness is more
severe, with injury to the lungs, inner ear, and central
nervous system. Within the inner ear, nitrogen bubbles
can injure the delicate structures either by mechanical dis-
ruption of the membranes of the inner ear or through
labyrinthine artery occlusion.101 Studies in guinea pigs
have shown that the primary damage during hyperbaric
exposures includes inner-ear hemorrhage and damage to
the cochlear hair cells.102
When a patient is suspected of having inner-ear decom-
pression sickness, the dive profile should be evaluated,
including the depth of the dive, the time at the bottom,
and the number of earlier dives. All patients with
cochleovestibular symptoms after diving should be consid-
ered to have type 2 decompression sickness and treated
accordingly. This includes the use of 100% oxygen as
immediate first aid during transport of the patient to a
recompression facility.99 If air transport is required, the
patient should be flown at an altitude lower than 1000 feet
to reduce symptom exacerbation. The recompression pro-
tocol includes initial recompression to 60 feet of salt water
with 100% oxygen for 60 minutes, followed by decom-
pression to 30 feet of salt water for two additional periods
while breathing a mixture of pure oxygen and air.100 This
recompression therapy reduces the size of the bubbles,
allowing their resorption and dissipation. Other support-
ive therapies reported to be useful in the treatment of
inner-ear decompression sickness include steroids, diuret-
ics, low-molecular-weight dextran, heparin, and diazepam.
Long-term follow-up studies of scuba divers who
sustained inner-ear barotrauma and continue to dive
against medical advice suggest that no further deteriora-
tion of cochleovestibular function occurs after these
patients were counseled as to how to equalize middle-ear
pressure.103
INFECTIOUS CAUSES OF COCHLEAR
HEARING LOSS
Meningitis
By the age of 3 years, the percentage of children with an
acquired hearing impairment out of all those children with
bilateral profound deafness is 20%. Of those with acquired
impairments, the hearing loss of 90% is due to postmenin-
gitic sequelae.104,105 Persistent sensorineural hearing loss
has been documented in 10.3% of 185 infants and children
with acute bacterial meningitis.106 The risk of deafness
after bacterial meningitis is most frequent following
infection with Streptococcus pneumoniae (31.8%) compared
598 PERIPHERAL AUDIOVESTIBULAR DISORDERS
to Haemophilus influenzae and Neisseria meningitidis
(7.5%).104,107 The incidence of bacterial meningitis is drop-
ping because of immunization against Haemophilus influen-
zae type b.107 There have also been a few documented cases
of hearing impairment after viral meningitis, although this
appears to be quite rare. Hearing impairment after menin-
gitis can have several causes. Most commonly, a suppura-
tive labyrinthitis occurs during the episode of acute
meningitis due to direct spread of the infection from
the subarachnoid space to the inner ear via the cochlear
aqueduct. This results in destruction of the sensory struc-
tures of the inner ear, and no hearing recovery. If only a
serous labyrinthitis occurs, partial recovery of hearing is
possible. Meningitis can also lead to ischemia of the audi-
tory nerve or brainstem neuron, and result in hearing
loss. Finally, sensorineural hearing loss after meningitis can
be caused by ototoxicity from the antibiotics used to treat
the meningitis, often an aminoglycoside. The administra-
tion of steroids to patients with pneumococcal meningitis
does not affect the rate of postmeningitic sensorineural
hearing loss.108
It is important to get an audiologic assessment on every
patient with meningitis. This should start during their first
admission to the hospital if possible and should be followed
postoperatively. A common sequela of postmeningitic
sensorineural hearing loss is labyrinthine ossificans.
Presumably, the inflammation in the cochlea leads to a
fibrotic reaction, which in time ossifies. This typically hap-
pens in the first few months after the meningitis has
resolved. Studies have shown that the intense inflamma-
tory response begins around the area of the cochlear aque-
duct.109 Earlier, rather than later, cochlear implantation is
suggested in patients with postmeningitic deafness because
of the difficulty in inserting the cochlear implant in an
ossified cochlea.
Congenital Infections
Cytomegalovirus (CMV) infection has been found in 0.2%
to 2.2% of all newborn children in the United States and
is the most common intrauterine infection.107 One-third of
pregnant women are serial negative for CMV during
pregnancy and about 5% of these women become infected
during pregnancy. Of those 5%, one-fourth will transmit
the infection to their fetuses. Up to 10% of children with
congenital CMV infection demonstrate systemic symp-
toms at birth and 61% of this group of patients develop
sensorineural hearing loss.110 The hearing loss can begin
soon after birth but usually progresses over the next
5 years. It may be unilateral or bilateral, and occasionally
it fluctuates. It is recommended that children with asymp-
tomatic CMV infections receive regular hearing tests
through childhood because of the potential for late-onset
sensorineural hearing loss.
Herpes simplex infection occurs in roughly 1 in 2500
pregnancies.111 Infections are caused by exposure to the
herpes simplex type II virus during delivery. Children with
herpes simplex infection, either disseminated or localized,
usually present with symptoms within the first 3 weeks of
life. All patients with a disseminated presentation of herpes
simplex virus (HSV) II infection have sensorineural hear-
ing loss, while 40% of the children with encephalitis and
25% of the children with localized infections present with
hearing loss.107
The classic triad of congenital rubella includes congeni-
tal heart disease, ocular diseases (cataracts and retinopathy),
and sensorineural hearing loss. If the rubella infection
occurs in the second or third month of pregnancy, there is
a 50% incidence of deafness, although deafness can occur
even if the infection occurs late in pregnancy.112 Sixty per-
cent of newborns with congenital rubella have subclinical
infections in the neonatal period. However, 71% of these
children develop disease manifestations during the next
5 years. Sensorineural hearing loss is the most common
manifestation, and it affects 68% to 93% of children with
congenital rubella.112 Characteristically, the sensorineural
hearing loss is profound and bilateral, affecting all frequen-
cies equally. Since the introduction of the rubella vaccine,
congenital rubella infection has become quite rare.
The seroconversion rate of pregnant women for toxo-
plasmosis is roughly 1 in 10,000 and the overall of risk of
toxoplasma infection involving the fetus is 33%. At birth,
90% of these babies are asymptomatic; however, late-onset
sensorineural hearing loss has been reported in 10% to
15% of these children.113
Because of the increasing prevalence of syphilis in the
adult population, the prevalence of congenital syphilis has
been increasing in recent years. About 50% of newborns
with congenital syphilis are asymptomatic; however, hear-
ing loss is a late manifestation that can occur even after
2 years of age.107 The hearing loss results from active
inflammation and scarring within the inner ear. Sen-
sorineural hearing loss can even begin to develop in early
adulthood even though the infection initiated in utero. The
onset of deafness is usually sudden, bilaterally symmetric,
and profound without associated vestibular symptoms.
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
adults with late-onset congenital syphilis identified present
with Hutchinson triad: sensorineural hearing loss, intersti-
tial keratitis, and notched incisors.
Adult-Onset Acquired Syphilis
Primary syphilis occurs initially 1 week to 3 months after
inoculation as a chancre on the area of contact.
Occasionally, there is large regional lymphadenopathy.
The chancre usually heals spontaneously after 2 to 6 weeks
and 6 months after this, the patient develops secondary
syphilis. Symptoms include widespread mucocutaneous
lesions, as well as constitutional symptoms. Thereafter, the
untreated patient enters a period of latent subclinical
infection. Fifty percent of untreated patients with latent
syphilis never develop clinically evident tertiary syphilis.
Of those who do develop tertiary syphilis, sensorineural
hearing loss is most common in patients with evidence of
neurosyphilis (80%).114
Among those with sensorineural hearing loss, there is
seldom a history of primary or secondary syphilitic symp-
toms. Patients can present with either progressive or
sudden sensorineural hearing loss, as well as vestibular
symptoms. The diagnosis can be made by serologic tests of
the plasma, as well as by the visualization of spirochetes in

the CSF after lumbar puncture. Histopathologic lesions of
otosyphilis are identical for congenital and acquired
syphilis. This includes an obliterative endarteritis and
mononuclear infiltrates with varying degrees of tissue
necrosis. In tertiary syphilis, there can also be perivascular
round-cell osteitis of the temporal bone, productive
periostitis, and gummatous periostitis/osteomyelitis. A
gumma is defined histologically as an area of central necro-
sis with surrounding lymphocytic infiltration and vascular
occlusions. Gummatous changes can be found in all of the
middle-ear bones but are most frequently identified
around the labyrinthine capsule. These findings can result
in labyrinthine ossificans. Treatment of this disease is with
long-term penicillin therapy.
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) can produce
sensorineural hearing loss.115,116 The prevalence of sen-
sorineural hearing loss in this population ranges from less
than 1% to 33%.117 Patients with more severe disease have
an increased degree of hearing loss. Additionally, antiviral
drug therapy may be associated with an increased risk of
sensorineural hearing loss.118
Sequelae of Acute and Chronic
Otitis Media
Sensorineural hearing loss secondary to otitis media can
occur under several conditions. It is quite uncommon for
recurrent acute otitis media to lead to sensorineural hear-
ing loss. However, acute labyrinthitis can occur during an
episode of acute otitis media. Presumably, the causative
organism traverses into the spaces of the inner ear via fis-
sures around the oval or round windows. Initially, patients
may present with vague symptoms of vertigo and slight
symptoms of sensorineural hearing loss. This is thought to
be due to the diffusion of toxic inflammatory mediators
through the round window membrane into the inner ear.
This can progress into serious labyrinthitis if organisms
enter the inner ear. A full-blown, suppurative labyrinthitis
can result if frank inflammatory exudate forms in the inner
ear. As the degree of suppuration worsens, the patient’s
chances of permanent sensorineural hearing loss increases
dramatically. Labyrinthitis can also occur after a stapedec-
tomy or stapedotomy, presumably by the introduction of
bacteria through the fenestra in the oval window.
Suppurative labyrinthitis after stapes surgery usually
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
occur in patients with chronic otitis media. Several studies
have demonstrated a significant difference in hearing
between the two ears in patients with unilateral chronic
otitis media, both in terms of poor speech discrimination
scores and higher bone-conduction thresholds in the ipsi-
lateral ear.119–122 Although the differences are statically sig-
nificant (changes in speech discrimination scores of 4%
and changes in boned-conduction thresholds of 3 to 5 dB),
they are minimal and probably have no clinical rele-
vance.123,124 It is unclear why sensorineural hearing loss can
develop after chronic otitis media, although presumably
Cochlear Hearing Loss 599
inflammatory mediators from the middle ear diffused
through the round window into the inner ear. Alternatively,
the presence of an occult perilymphatic fistula could
produce subtle sensorineural hearing loss. Acoustic trauma
from repeated loud office suctioning of the ear could
produce noise-induced hearing loss. The use of potentially
ototoxic topical ear drops in the affected ear could also be
responsible. Ear surgery can also cause sensorineural
hearing loss because of the exposure to loud drilling noise
and ossicular manipulation. Finally, the difference in the
ipsilateral bone-conduction threshold may not represent
an actual sensorineural hearing loss. Middle-ear mass and
stiffness can affect bone-conduction thresholds (similar to
the phenomenon of Carhart’s notch in otosclerosis), and
patients with unilateral chronic otitis media certainly can
have asymmetric middle-ear mechanics.
Poststapedectomy Sensorineural
Hearing Loss
After stapes surgery, sensorineural hearing loss can
develop. This could be due to suppurative labyrinthitis as
just discussed. However, if the sensorineural hearing loss or
vertigo persist beyond 5 days postoperatively or occur after
an initial improvement in hearing, a poststapedectomy
granuloma (reparative granuloma) should be suspected.
In contrast, mild symptoms occurring within a few days
of surgery are consistent with serous labyrinthitis and are
relatively common. The incidence of reparative granu-
loma after a stapedectomy is estimated at 0.1%.125
The incidence of sensorineural hearing loss in reparative
granuloma varies from 70% to 100% of patients.126
Histologically, a reparative granuloma is not actually a
granuloma. It is a clump of granulation tissue with evi-
dence of chronic inflammation.127 When a reparative
granuloma is suspected, a CT scan should be obtained.
Evidence of soft tissue in the oval window within the cor-
rect time frame after surgery is highly suspicious of
reparative granuloma.128 Management of this entity
remains controversial and can range from either conserva-
tive management with oral steroids to early surgical inter-
vention with delicate removal of the granulation tissue. An
MRI is also occasionally useful in that it will demonstrate
labyrinthine hemorrhage (bright signal on T1 and T2
without contrast in the labyrinth), a perilymphatic fistula
(air bubble in labyrinth), a reparative granuloma, and
suppurative labyrinthitis (intense enhancement inner ear
with gadolinium contrast).129
CONGENITAL HEARING LOSS
Congenital Anomalies of the Inner Ear
Overall, about 1 in 1000 children is born with a significant
degree of sensorineural hearing loss.130 It is estimated
that about 25% of these cases of hearing loss are attributed
to identifiable prenatal or postnatal disease or trauma,
18% to undiagnosed genetic factors, 15% to autosomal-
dominant genetic mutations, 40% to autosomal-recessive
genetic mutations, and 2% to sex-linked genetic
mutations.131 The hearing loss may not be present at birth,
600 PERIPHERAL AUDIOVESTIBULAR DISORDERS
but progress during childhood (and so be missed by
newborn hearing screening).132,133 Indigent patients are at
a higher risk of neonatal hearing loss than the average U.S.
population and have a different risk factor profile.134
Malformations of the inner ear occur because of an
arrest in normal development during embryogenesis, dur-
ing the first trimester of pregnancy. This may occur
because of a genetic mutation or teratogenesis. At about
the fourth week of gestation, the otocyst develops from an
invagination of the otic placode. It then differentiates and
forms the membranous labyrinth. By the 12th week, the
cochlea has fully developed. Chondrification followed by
ossification occurs in the second trimester to form the otic
capsule. Maturation of the sensory epithelium within the
inner ear develops throughout the second trimester of
pregnancy and is essentially complete by the 26th week of
gestation.
The management of a congenital hearing loss is frus-
trating in that there is little that can be done to alter the
progression of the disease. Patients who sustain decre-
ments in hearing may be treated with steroids in an effort
to reduce further hearing loss; however, there is little evi-
dence to support the efficacy of this therapy. Patients
should be adequately rehabilitated with the use of hearing
aids initially and if this does not prove useful, then they
should be considered for cochlear implantation. The only
absolute contraindications of cochlear implantation in a
congenitally dysplastic ear are complete cochlear aplasia or
absence of the auditory nerve. Both of these conditions can
be diagnosed with the use of high-resolution CT scan of
the temporal bone. Additionally, patients with congenital
malformations of the inner ear are at a higher risk for CSF
leak and meningitis. Families need to be counseled as to
the early signs and symptoms of meningitis. Immunization
against the common organisms implicated in meningitis
should also be considered.
Abnormalities of the inner ear can be divided in those
in which the membranous labyrinth is abnormal, but the
otic capsule is normal, and those in which both are
abnormal.135,136
Membranous Labyrinth Malformations
with a Normal Otic Capsule
Malformations limited to the membranous labyrinth
account for about 90% of congenital sensorineural hearing
loss. These patients have normal otic capsules and hence
cannot be identified by current radiographic techniques.
However, it can be safely assumed that all children with
congenital sensorineural hearing loss would be found to
have abnormalities of their membranous labyrinth if they
could be examined histopathologically, unless there is a
purely central cause for their hearing loss.
Complete membranous labyrinthine dysplasia (Bing-
Siebenmann deformity) is extremely rare and may be asso-
ciated with cardiac abnormalities. It can be found in the
Jervell and Lange-Nielsen syndrome and in Usher’s
syndrome.137
Cochleosaccular dysplasia (Scheibe’s deformity) repre-
sents the most common inner-ear abnormality that results
in hearing loss. This occurs in the phylogenetically
newer portion of the inner ear, while the more ancient
semicircular canals and utriculus are normal. It is often
inherited as an autosomal-recessive gene and can be found
in diseases such as Usher’s syndrome. There is partial or
complete aplasia of the organ of Corti with collapse of the
scala media. The wall of the sacculus is collapsed onto
an atrophic sensory epithelium. Additionally, the stria vas-
cularis is degenerated.
Cochlear basal turn dysplasia (Alexander’s deformity) is
a limited malformation of the high-frequency region of
the cochlea. This condition is related to familial high-
frequency sensorineural hearing loss and there is usually
sufficient low-frequency hearing to allow good benefit
from the use of hearing aids.
Membranous Labyrinth Malformations
with Otic Capsule Malformations
Malformations of the otic capsule can be diagnosed by
radiographic imaging. Although thin-cut CT scans are
traditionally used, newer fast-spin echo T2-weighted MRI
images are also quite good at demonstrating inner-ear
anatomy. There is a wide spectrum of hearing disability
among this patient population. Although some are com-
pletely deaf, most retain some hearing into adult life and
have a slowly progressive sensorineural hearing loss.
Interestingly, there is a higher risk of sudden hearing loss
associated with even minimal head trauma. This is pre-
sumably because of latent weaknesses in the membranes of
the inner ear or the osseous spiral lamina that are easily
damaged, permitting mixture of the endolymph and
perilymph.
Complete labyrinthine aplasia (Michel’s deafness) is an
extremely rare defect in which there is a complete absence
of inner-ear structures and, therefore, total deafness. This
is likely due to a developmental arrest early in gestation,
before the formation of an otocyst. This defect has
been seen in association with thalidomide exposure and
anencephaly.138
Cochlear aplasia is absence of the cochlea with only
semicircular canals present. These are usually deformed as
well, however.
Cochlear hypoplasia results from an arrest in develop-
ment at about the sixth week of gestation. The cochlea
consists of only a small bud (1 to 3 mm in diameter) pro-
truding from the vestibule. Auditory function is quite vari-
able and may be surprisingly good, considering the small
size of the cochlea.139
Incomplete partition (Mondini’s malformation) occurs
with an arrest in development at the seventh week of ges-
tation. This is a very common cochlear malformation and
it accounts for more than 50% of cochlear deformities.
The cochlea is smaller than normal (5 to 6 mm in vertical
height instead of the normal 8 to 10 mm). It may possess
fewer turns than normal, although this is difficult to quan-
tify by CT scanning. The interscalar septum is partially
or completely absent. The severity of hearing loss is quite
variable among patients and can range from normal
hearing to profound deafness.
In the common cavity deformity the cochlea and
vestibule are confluent and form an oval space within the
otic capsule. Although there may be recognizable seg-
ments of the organ of Corti on histologic evaluation of the

specimen, overall the hair cell population is quite sparse.
Hearing is typically poor.
Dysplasia of the lateral semicircular canal is a common
malformation and is often associated with cochlear malfor-
mations as well. The lateral semicircular canal is the most
common canal to be affected by dysplasia. During its for-
mation, the lateral semicircular canal is first a confluent
broad cystic space contiguous with the vestibule. Then, a
bony septum forms in the center (like a donut hole).
Deformities range from no septum to a rudimentary sep-
tum to a nearly normal septum. There may be reduced
caloric responses noted by electronystagmography. Hearing
may be normal if the malformation is limited to the
vestibular system. This deformity may be associated with
Goldenhar’s syndrome.140–142
Semicircular canal aplasia is much less common than
semicircular canal dysplasia and is usually associated with
cochlear abnormalities. It is presumed to arise as a conse-
quence of failure in the development of the vestibular bud
before the sixth week of gestation.
Large vestibular aqueduct syndrome is the most com-
mon radiographically detectable abnormality of the inner
ear.143 The normal diameter of vestibular aqueduct is
between 0.4 mm and 1.0 mm (measured between the
common crus and the posterior face of the temporal bone).
The vestibular aqueduct is said to be enlarged when its
diameter exceeds 2.0 mm. Vestibular aqueduct abnormali-
ties often accompany cochlear and vestibular organ abnor-
malities and are quite commonly seen in conjunction with
Mondini’s deformity. Patients with large vestibular aque-
duct syndrome usually have a mild sensorineural hearing
loss that progressively deteriorates during childhood and
early adult life. Forty percent develop profound sen-
sorineural hearing loss.
Enlargement of the cochlear aqueduct has been
reported; however, most cases demonstrate a wide, funnel-
shaped opening from the cerebellopontine angle with no
evidence of widening of the remainder of the aqueduct.
Since the tube narrows to a normal diameter laterally, it is
quite possible that the wide medial end is of no conse-
quence. Hence, this entity has not been convincingly
demonstrated to be clinically important.129
A wide internal auditory canal is usually of no signifi-
cance clinically. However, patients with stapes fixation and
a wide internal auditory canal may be noted to have a
stapes “gusher” during stapes surgery (a CSF leak), partic-
ularly if the lateral end of the internal auditory canal (IAC)
is widened. In patients with congenital stapes fixation, a
CT scan of the temporal bone should be obtained before
consideration of surgery to evaluate for this entity.
A narrow internal auditory canal may indicate the
absence of the VIIIth cranial nerve. This can be crucial
during the consideration of cochlear implantation in
patients with congenital hearing loss because a diameter of
the IAC smaller than 3 mm is a strong predictor of
decreased neural population. This finding is a contraindi-
cation to cochlear implantation.144
Genetic
The identification of genes involved in deafness has made
dramatic progress over the last several years. Prior to 1996,
Cochlear Hearing Loss 601
no nonsyndromic deafness genes had been cloned. To
date, 70 loci have been identified as being involved in non-
syndromic deafness and more than 400 distinct syndromes
are associated with hearing impairment. However, clearly
many more genes remain unidentified. Although single-
gene deficits probably account for more than 50% of the
cases of congenital hearing loss, the pathophysiology of
the genetic contribution to presbycusis has not been
defined. Several animal models of genetic deafness have
been created, but relatively few of these have been shown
to be involved in human deafness. The limited overlap
between genes that cause sensorineural hearing loss in
mice and humans makes these research endeavors quite
challenging.
The genetic contribution to sensorineural hearing loss
can be associated with several areas in the cochlea. Being
unique to the inner ear, the hair cells are the most obvious
potential site of involvement. There are several essential
molecules for hair cell transduction, which if mutated, will
cause hearing loss. These include unconventional myosins
found specifically in the hair cell transduction region,
including myosins VI, VIIa, and XV. Myosin VIIa muta-
tion is associated with Usher’s syndrome type 1c. These
patients are born with congenital hearing loss and develop
progressive blindness. Mutations in these myosins lead to
abnormal stereocilia anatomy, as well as disorganization of
the stereociliary bundle.145–148 Other hair cell genes in
which mutations cause deafness include cadherin-related
genes (involved in cell-to-cell interactions), aspin (an
actin-bundling protein), and Atp2b2 (a calcium pump in
the stereocilia).145
Additionally, hair cell synaptic transmission is unique in
that very accurate timing information needs to be relayed
to the central nervous system. Mutations that disrupt this
can cause a sensorineural hearing loss. These include the
otoferlin gene (a protein located at the base of inner hair
cells involved in synaptic vesicle recycling),149 and muta-
tions in L-type calcium channels (required for calcium-
dependent exocytosis during synaptic transmission).150
The final site in a hair cell that might be a target for a
genetic mutation that produces a hearing loss would be
outer hair cell electromotility. The gene for the molecular
motor responsible for electromotility has been identified
(prestin),1 and there is evidence of patients who are deaf
because of amutation in this gene.151 Electromotility is not
found in any other cells in the body, so a mutation in this
gene causes a limited clinical phenotype (i.e., hearing loss).
Other targets in the outer hair cell that could inhibit elec-
tromotility include mutations in the exquisitely organized
cytoskeleton or in the plasma membrane.2–4
Surprisingly, mutations in other areas of the cochlea are
much more clinically relevant than hair cell mutations.
Mutations that affect the endolymphatic potential are the
most common cause of genetic hearing loss. These include
genes important for proper functioning of the stria vascu-
laris or for gap junctions in supporting cells that recycle
ions from the hair cells back to the stria vascularis. KCNQ4
encodes a potassium channel found predominantly in
outer hair cells that serves as the first step in recycling
potassium after transduction. Mutations in this gene cause
a dominant progressive hearing loss.152 Mutations in the
Kcc4 gene for a potassium-chloride cotransporter protein
602 PERIPHERAL AUDIOVESTIBULAR DISORDERS
found in supporting cells also causes deafness.73 Connexin
genes form gap junction proteins, and mutated gap junction
proteins do not permit ion recycling mutations. Mutations
in connexin genes are quite frequently involved in human
genetic deafness.153–157 The pendrin gene is expressed in
the endolymphatic duct and sac, and is mutated in
Pendred’s syndrome.158–160 The pendrin protein acts as an
iodide-chloride transporter and may be involved in
endolymph homeostasis. Finally, defects may occur in the
tectorial membrane matrix from mutations in genes
encoding alpha tectorin (Tecta), collagen 11A2 (COL
11A2), and otogelin (otog),145 producing ultrastructural
deformities of the tectorial membrane and hearing loss.
METABOLIC COCHLEAR HEARING LOSS
Renal disease is associated with sensorineural hearing loss.
Many enzymatic functions of the kidneys and the stria vas-
cularis are similar. The most important is ion transport.
Patients with renal disease can have hearing loss because of
disorders of fluid and electrolyte balance. It is possible that
altered plasma electrolyte concentrations compromise the
ability of the stria vascularis to produce the endolymphatic
potential. However, the exact pathophysiology is not
known. Additionally, it has been shown that distal renal
tubular acidosis, an autosomal-recessive inherited syn-
drome in which there is an inability of the distal renal
tubule to excrete hydrogen ions into the urine, is associ-
ated with sensorineural hearing loss at a young age.161,162
Diabetes mellitus is also probably associated with sen-
sorineural hearing loss, although evidence in the literature
is conflicting.163,164 The pathologic process is thought to
be a microvascular angiopathy with progressive decrease in
the functioning of the stria vascularis. Histologically, there
has been shown to be thickening in the stria vascluaris sim-
ilar to vascular changes seen elsewhere in these patients.165
It is also possible that there is an associated primary neu-
ropathy of the auditory nerve. Some evidence suggests that
insulin-dependent diabetes and hypertension have syner-
gistic effects that exacerbate the hearing loss.166
Hyperlipidemia and hypercholesterolemia have been shown
to be associated with sensorineural hearing loss, but again
the literature is conflicting. Presumably, this occurs due to
atherosclerotic changes in the vascular supply to the inner
ear similar to that seen in other places in the body (i.e., the
coronary arteries).
Hypothyroidism can lead to sensorineural hearing loss in
utero (cretinism). The histologic effects appear to be pre-
dominantly cochlear, with atrophy of the stria and degen-
eration of the spiral ganglion neurons and hair cells of the
organ of Corti. Pendred’s syndrome is an inherited auto-
somal-recessive trait with a deficiency of peroxidase that
prevents the organification of iodine (this has also been
associated with large vestibular aqueduct syndrome).
There is no fixed definition of hypoxia in the newborn;
however, this term is typically used when the neonate fails
to establish spontaneous regular breathing after birth.
Persistent hypoxia can lead to cerebral damage and sen-
sorineural hearing loss. Apoptosis of cells in the organ of
Corti and spiral ganglion neurons occurs.167 Retrospective
studies suggest that the frequency of sensorineural hearing
loss secondary to severe hypoxia is about 1% to 5%. This
is a difficult number to estimate because of the multiple
comorbid conditions in this complex patient population.
The auditory system is very sensitive to hyperbilirubine-
mia. Damage occurs predominantly to the auditory nerve
and brainstem nuclei, producing a sensorineural hearing
loss.168 This is usually caused by Rh incompatibility
between the mother and infant, although ABO incompat-
ibility can also be the cause. Aggressive treatment of
hyperbilirubinemia to lower the plasma levels reduces the
risk of sensorineural hearing loss.
OTIC CAPSULE BONY DISEASES
Otosclerosis is a disease of the endochondral otic capsule
bone. Although usually this disease presents as a conduc-
tive hearing loss secondary to stapes fixation, sensorineural
hearing loss can develop in the late stages of this disease.
Pathologically, there is replacement of normal compact
otic capsule bone by irregular loose or cancellous bone
with an increase in the size of the haversion canals, inter-
cellular spaces, and marrow spaces. There is an increase in
the vascularity of the involved bone. If this disease involves
the otic capsule bone adjacent to the cochlea, sensorineural
hearing loss can develop. Although the exact reason for a
sensorineural hearing loss is not known, the increased vas-
cularity of the surrounding otic capsule bone may reduce
the blood supply to the stria vascularis. Cochlear otosclero-
sis is described as a pure sensorineural hearing loss in the
presence of otosclerosis without conductive hearing loss.
This could occur if there is no fixation of the stapes, yet
the otic capsule bone around the cochlea is involved with
disease. By computed tomography, severe otosclerosis can
be seen as lucency around the cochlea (also known as a
“double ring” sign). This represents the extensive endo-
chondral demineralization of the otic capsule.
Osteogenesis imperfecta encompasses a group of connec-
tive tissue disorders with defects in bone formation. There
is a high rate of bone turnover and deposition
of immature, osteopenic bone that is quite weak and
fragile. The most common otologic condition associated
with osteogenesis imperfecta is hearing loss. The hearing
loss is mixed in 54% of cases, purely conductive in 24%,
and sensorineural in 22%. Usually, the hearing loss is
noted between the second and third decades of life.
Temporal bone CT scan findings in osteogenesis imper-
fecta are similar to those found in severe cochlear otoscle-
rosis, with lucency of the otic capsule bone surrounding
the cochlea.
Paget’s disease is another disease of bone that can cause
sensorineural hearing loss. Involvement of the otic capsule
causes hearing loss in about 50% of sufferers. The initial
finding is usually conductive hearing loss due to stapedial
ankylosis similar to otosclerosis, although most patients do
end up developing sensorineural hearing loss as the otic
capsule bone surrounding the cochlea becomes involved.
Fibrous dysplasia of the temporal bone may cause a con-
ductive hearing loss by impinging on the ossicular chain or
via external auditory canal stenosis. It does not involve the
otic capsule. However, compression of the internal audi-
tory canal could occur, with the potential for sensorineural

hearing loss due to impingement of the auditory nerve or
labyrinthine artery.
AUTOIMMUNE HEARING LOSS
This etiology of cochlear hearing loss is covered in
Chapter 40.
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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
Vestibular testing should be considered an important tool in
the evaluation and management of dizziness. A careful and
thorough bedside history and neurotologic examination is
key for making an accurate clinical diagnosis in the patient
with dizziness. The physician must couple the results of the
bedside evaluation with the results of vestibular tests to
manage the disorder. In other words, the vestibular tests of
electronystagmography (ENG) or rotary chair test (RCT)
should not be considered stand-alone diagnostic tests for
the patient with dizziness, but instead should be coupled
with clinical impressions. It is important to remember that
not every patient needs quantitative vestibular testing. Also,
other important information provided by the ENG does not
involve the vestibular system and may be of value when
treating the patient with dizziness.
Assessing the integrity of the vestibulo-ocular reflex
( VOR) is an integral part of vestibular testing. The VOR is
a reflex that acts at short latency to generate eye movements
that compensate for head rotations encountered in daily
activity. The VOR preserves clear vision during locomotion
to prevent slip of a visual image that is focused on the retina.
Measuring the VOR requires stimulation of vestibular sys-
tem and measurement of the resulting eye movements.
There are advantages but also limitations to the current
methods of this analysis, which will be discussed in the body
of this chapter (Table 38-1).
ELECTRONYSTAGMOGRAPHY
ENG is a method of monitoring eye movements. For nearly
40 years, it has been widely used in the diagnostic evaluation
of dizziness or unsteadiness. The examination consists of a
battery of tests collectively referred to as the ENG. This
battery was designed to reveal vestibular and nonvestibular
functional tests of eye movement abnormalities. The
vestibular and ocular systems are connected through the
VOR. Patients with peripheral or central balance disorders
often exhibit abnormal eye movements that can be mea-
sured and recorded. The most common method involves
monitoring eye movements using electro-oculography.
Eye Movement Recording Equipment
A variety of eye movement recording equipment is cur-
rently available. In performing the ENG, the patient’s eye
movements are measured relative to head position, which
can be achieved in a number of ways:
1. Electro-oculography (depends on the corneoretinal
potential)
2. Video-oculography (depends on video camera goggles)
3. Magnetic search coil technique
4. Infrared oculography
Electro-oculography ( EOG ) is the most common technique
of monitoring eye movements during the ENG and is
607
608 PERIPHERAL AUDIOVESTIBULAR DISORDERS
TABLE 38-1. Benefit of Electronystagmography
and Rotational Chair Testing
1. Localize a central verses a peripheral lesion.
2. Lateralize the deficit.
3. Offer documentation of clinical examination.
4. Assist in establishing a diagnosis and developing a treatment plan and
long-term management.
based on the fact that steady DC potentials—corneoretinal
potentials—exist between the corneas and retinas of the
eyeballs. These potentials create an electric field in the
front of the head that rotates as the eyes rotate in their
orbits. The cornea is relatively positively charged in com-
parison with the retina; thus, an electrical potential exists
between the two. This potential is generated by the meta-
bolic activity of the retinal pigment epithelium. The retina
is negatively charged relative to the cornea and therefore
electrical potential can be measured between the two by
means of skin surface electrodes. In neutral position the
average potential measured is about 1 mV. Movement of
the eyes causes potential changes relative to the skin elec-
trodes. Movement of this electric field produces a roughly
linear change in the voltage between electrodes attached to
the skin on either side of the eyes. Electrodes placed on the
patient’s temples monitor horizontal eye position. Vertical
eye position is monitored by electrodes placed above and
below one of the patient’s eyes. Some benefits of the EOG
surface electrodes are that they are simple and relatively
inexpensive. Disadvantages include the inability to moni-
tor ocular torsion, being subject to bioelectric noise from
facial muscles and a resolution of about 1 degree/sec while
monitoring eye movements (Fig. 38-1).
Video-oculography, a technique that has recently become
commercially available, involves digital video-recorded eye
movements. Videonystagmography (VNG) is a computer-
based system that records eye movement under test situa-
tions. The eye position is located by detecting the pupil and
tracking its center. The internal computer program plots,
measures, and analyzes the eye movements under a battery
of tests.
VNG permits visualization and recording of eye move-
ments that are conveniently stored on a database for
retrieval or transfer of data. This is helpful for later study
and for teaching of personnel and patients. This technique
is easier and quicker than using electrodes with minimal
patient preparation, and only one calibration is necessary,
speeding the over all test time. Depending on the system,
ocular torsion can be measured and video-captured, unlike
EOG. Without the bioelectric interference from facial
muscles, tracings are clean with no drift as seen with tradi-
tional EOG tracings.
Monitoring resolution can detect 0.1 degree/sec move-
ments. Blink artifact can be an issue because the eyes must
be kept open during testing, and some patients experience
claustrophobia and may not tolerate the sensation of
confinement. In addition, the test equipment is expensive
(Fig. 38-2).
The magnetic search coil technique places the patient in a
three-dimensional electromagnetic field. The patient
wears a soft contact lens in which a wire coil is embedded.
Eye movement effects a change in the magnetic field, and
this is recorded. The advantage of this method is that it
gives very high-resolution data for all types of eye move-
ments, including torsional nystagmus. Disadvantages of the
technique include slight patient discomfort (due to the
lens) and the very high cost of the procedure. This proce-
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
the photocells of the eye remain stationary while the edge
of the iris moves with the eye. As a result, the light sensed
by the photocells differs according to eye position. The
advantage of this technique is that a direct estimate of the
eye position as a function of time can be calculated. Disad-
vantages of this technique include the bulkiness of the
equipment, which limits visual stimulation somewhat, and
the interference with eyelid motion (e.g., blink), which
makes vertical recording difficult at times.
Routine Components of
Electronystagmography
The ENG test battery generally consists of seven tests.
The first four tests are primarily tests of vestibular func-
tion, although they sometimes also reveal nonvestibular
eye movement abnormalities as well: (1) the Dix-Hallpike
maneuver, designed to provoke a nystagmus response in
patients with benign positional vertigo, (2) the gaze test,
designed to detect nystagmus induced by eccentric gaze,
(3) the positional test, designed to determine if different
head positions induce or modify nystagmus, and (4) the
bithermal caloric test, designed primarily to detect unilat-
eral lesions of the labyrinth or vestibular nerve. The final
three tests are tests of nonvestibular eye movements:
(5) the saccade test, designed to detect disorders of the sac-
cade eye movement control system, and (6) the tracking
test and (7) the optokinetic test, both designed to detect
disorders of the pursuit eye movement control system.
Although saccade and pursuit eye movements are of sec-
ondary interest to those who evaluate dizziness, they are
nevertheless routinely tested because abnormalities are
occasionally detected in such patients.
For many years, eye movements were recorded on strip
charts. Recently, ENG has been computerized, permitting
efficient storage and easy retrieval of eye movement data
and eliminating the cutting and pasting of strip chart
recordings. In addition, computerized ENG allows rapid
and sophisticated analysis of saccade, tracking, and caloric
tests—analyses that could not be done on strip chart
recordings.
Dix-Hallpike Maneuver
The most frequently employed test for positioning nystag-
mus is the Dix-Hallpike maneuver. The patient is subjected
to two brisk movements, both beginning with the patient
in the sitting position. The patient’s head is first turned
45 degrees toward one side. Then the examiner, standing to
the side or behind the patient, pulls him briskly backward
so that he is lying supine with his head still turned to
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
response was elicited, the examiner repeats the same
maneuver to determine if it fatigues. Then she performs
the maneuver with the patient’s head turned 45 degrees to
the other side, and if a response is elicited, repeats the
maneuver to determine if it fatigues (Fig. 38-3).
During the backward movement, the Dix-Hallpike
maneuver normally induces a few beats of nystagmus.
After the head has reached the hanging position, normal
individuals do not have nystagmus, but some patients with
benign positional vertigo display a burst of intense
nystagmus—paroxysmal positional nystagmus—that is the
1. It has a delayed onset. Usually an interval of at least a
few (2 to 20) seconds elapses after the patient reaches
the head-hanging position before the nystagmus begins.
2. It is always transient; that is, it rapidly builds in inten-
sity (crescendos), slowly abates (decrescendos), and
finally disappears (within 45 seconds) as the head
remains in position.
3. It is always accompanied by vertigo, usually intense,
that follows the same time course of the nystagmus.
4. It is usually fatigable; that is, it progressively dimin-
ishes in intensity with repetition of the Dix-Hallpike
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

The pathophysiology of the response is believed to be
due to two types of pathology: canalithiasis and cupu-
lolithiasis, with the former being much more prevalent. In
canalithiasis, otoconia or other debris are presumed to be
floating freely in the endolymph of one of the canals. If
the head is positioned so that the involved canal is vertical
and then rotated quickly in the plane of that canal, the oto-
conia fall to the lowest position in the canal, moving
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 characteristics of the eye movement response may be
explained. The latency of the response is due to inertial drag
of the endolymph as the debris falls to the dependent posi-
tion. The nystagmus response is due to cupula deflection
and stimulation. Once the debris settles, the endolymph
flow ceases, the cupula goes to the neutral position, and the
nystagmus stops (see Fig. 38-3C).
Nearly always only one labyrinth is involved, and the
response is provoked when the Dix-Hallpike maneuver
places the involved labyrinth undermost. Paroxysmal posi-
tional nystagmus can be readily appreciated by visual
observation with the patient’s eyes open or, better yet, with
the patient wearing Frenzel’s lenses in a darkened room.
The examiner sees primarily the torsional component of
the nystagmus, with counterclockwise fast phases when the
right ear is involved and clockwise fast phases when the left
ear is involved. In other words the nystagmus seen by the
examiner appears to be torsional toward the floor of the
downward ear. ENG is useful in documenting the response
(Fig. 38-4). ENG is insensitive to the torsional component
of the nystagmus, but does record the horizontal and ver-
tical components. The horizontal component generally
has fast phases away from the undermost ear, and the ver-
tical component invariably has upward fast phases. Parox-
ysmal positional nystagmus changes somewhat with the
direction of the patient’s gaze. The torsional component is
more prominent during gaze toward the undermost ear;
the vertical component is more prominent during gaze
toward the uppermost ear.
Figure 38-4. Paroxysmal positional nystagmus in response to the
Dix-Hallpike maneuver with right ear undermost. Horizontal channel shows
left-beating nystagmus, and the vertical channel shows upbeating
nystagmus. Upward pen deflection denotes rightward eye movement on
horizontal eye position tracing and upward eye movement on vertical eye
position tracing.
Electronystagmography and Rotation Tests 611
TABLE 38-2.
Fast Phases Semicircular Canal Involvement
Upward right torsional Right posterior canal BPPV
Upward left torsional Left posterior canal BPPV
Downward right torsional Right anterior canal BPPV
Downward left torsional Left anterior canal BPPV
BPPV, benign paroxysmal positioning vertigo.
The Dix-Hallpike maneuver sometimes provokes types
of nystagmus response other than the posterior semicircu-
lar canal on the downward ear. The examiner may identify
the specific canal involved by noting the direction of the
fast phases of the abnormal nystagmus with the patient’s
eyes looking straight ahead (Table 38-2).
Horizontal semicircular canal benign paroxysmal positioning
vertigo (BPPV) can be detected with the Dix-Hallpike
maneuver. A more effective maneuver involves placing the
patient in the supine position, turning the head quickly to
the right-ear-down position, and holding it there for at least
30 seconds (or, if nystagmus is provoked, for up to several
minutes). The patient’s head is then returned slowly to the
supine position; lastly, the head is turned quickly into the
left-ear-down position and held there for at least 30 seconds
(or, if nystagmus is provoked, for up to several minutes). In
patients with horizontal canal BPPV, this maneuver
provokes horizontal nystagmus, as described by Baloh and
colleagues.3 The nystagmus of horizontal canal BPPV is
1. Geotropic (right beating in the right-ear-down posi-
tion and left-beating in the left-ear-down position) and
often followed by an ageotropic secondary nystagmus
2. Stronger when the ear presumed to be pathologic is
undermost
3. Transient (although more persistent than the
response of posterior canal BPPV )
4. Accompanied by vertigo, usually intense, that follows
the same time course as the response
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.
One limitation of the Dix-Hallpike maneuver is that it
cannot be performed on patients with cervical spine dis-
ease that limits neck extension or back disorders that
prohibit rapid positioning of the patient into the head-
hanging position. In those patients, a sideling Bojrab
612 PERIPHERAL AUDIOVESTIBULAR DISORDERS
maneuver may be employed. The senior author has been
using this technique for over 15 years as his primary
technique in elderly patients or patients with significant
cervical neck disease. This maneuver allows the same posi-
tioning of the posterior semicircular canal as with the
Dix-Hallpike maneuver, without the head hanging.
With the Bojrab maneuver, the patient is positioned sit-
ting up, facing the examiner. The head is turned to the right
45 degrees, so that the external auricle is perpendicular to
the plane of the table. The examiner then holds the head in
that position as he briskly lowers the patient onto her shoul-
der, with the head resting on the table. The position is held
for at least 20 seconds while the eye movements are
monitored. The patient is then returned to the sitting posi-
tion. If nystagmus was elicited, the examiner repeats the
same maneuver to determine whether the nystagmus is fati-
gable. The maneuver is then performed on the contralateral
side. As with the Dix-Hallpike maneuver, the ear, which is
dependent at the time the nystagmus is elicited, is usually
the one containing the diseased labyrinth (Fig. 38-5).
Gaze Test
The patient’s eye movements are monitored as she fixates
while gazing 30 degrees to the right, 30 degrees to the left,
30 degrees up, and 30 degrees down. Some examiners also
attempt to monitor eye movements in these gaze positions
with visual fixation denied, but the tracing is often difficult
to interpret.
Young normal individuals rarely have any nystagmus at
all while fixating at any of these gaze positions, but many
elderly individuals have endpoint nystagmus. This nystag-
mus is always faint with centripetal slow phases that gen-
erally are of equal intensity on right and left gaze.
Figure 38-5. Bojrab maneuver.
The gaze test detects nystagmus from vestibular origin as
well as central nervous system origin. An example of one
type—upbeat nystagmus—is shown in Figure 38-6. Upbeat
nystagmus occurs most commonly as a result of medullary
lesions involving vertical vestibular pathways.5 Leigh and
Zee describe additional types of central nystagmus seen in
the gaze test.6 Barber and Stockwell illustrate ENG
tracings of many of these.7 The gaze test may also detect
spontaneous nystagmus caused by a unilateral vestibular
lesion, although spontaneous nystagmus is better appreci-
ated during the positional test with visual fixation denied.
Positional Test
The purpose of the positional test is to determine if differ-
ent head positions induce or modify vestibular nystagmus.
The patient’s eye movements are monitored while his head
is in at least four positions: sitting, supine, right ear down,
and left ear down. If nystagmus appears or is modified in
either of the latter two positions, the patient is tested again
while lying on that side to determine if the effect was due to
neck rotation. Some examiners also test the patient in the
head-hanging position. Eye movements are monitored in
each position both with visual fixation permitted (eyes open
and fixating on a visual target at center gaze) and with visual
fixation denied. Most examiners deny fixation simply by ask-
ing the patient to close his eyes, but eye closure may inhibit
nystagmus. A better method is to monitor eye movements
with eyes open in total darkness. The examiner usually asks
the patient to perform a mental task, such as mental arith-
metic, when testing with visual fixation denied to maintain
mental alertness and thus avoid nystagmus suppression.
The most common abnormality seen in the positional
test is so-called spontaneous nystagmus (Fig. 38-7). This

Figure 38-6. Upbeat nystagmus. Upward pen deflection denotes rightward
eye movement on horizontal eye position tracings and upward eye movement
on vertical eye position tracings.
nystagmus is horizontal-torsional, although ENG is insen-
sitive to the torsional component and only records the
horizontal component. It is suppressed by visual fixation,
and often suppression is so strong that spontaneous nys-
tagmus is abolished by fixation. Poor fixation suppression
indicates a central nervous system lesion involving the
pathways responsible for VOR cancellation.
Spontaneous nystagmus is a reflection of tonic left-right
vestibular asymmetry. It is typically seen after a recent
unilateral peripheral vestibular lesion and has fast phases
away from the side of the lesion. Sometimes spontaneous
nystagmus is seen in the absence of a recent unilateral
peripheral lesion, in which case it provides evidence of a
vestibular lesion but does not localize it.
Spontaneous nystagmus has been defined as nystagmus
that is unmodulated by changes in head position and has
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-
tal-torsional vestibular nystagmus is occasionally modulated
by a change from the sitting to the supine position, and it is
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-
tion is sometimes so deep that nystagmus even changes in
direction, for example, from strongly right-beating in the
right-ear-down position, to more weakly right-beating in the
supine position, to left-beating in the left-ear-down position.
The positional test also detects another variant of posi-
tional nystagmus (Fig. 38-8). There is no nystagmus in the
sitting or supine positions. Nystagmus beats in one direc-
tion in the right-ear-down position and in the opposite
direction in the left-ear-down position. Generally strong
nystagmus appears when the patient first assumes the posi-
tion, followed by persistent nystagmus of lower intensity. If
the nystagmus is strong enough, the patient experiences
vertigo. Like spontaneous nystagmus, this type of positional
nystagmus provides evidence of vestibular dysfunction, but
is nonlocalizing.
Like the Dix-Hallpike maneuver, the positional test occa-
sionally provokes nystagmus of central origin. It also may
provoke paroxysmal positional nystagmus if the response
has not previously been provoked and fatigued by the
Dix-Hallpike maneuver.
Bithermal Caloric Test
The bithermal caloric test has proven highly sensitive to
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.

Figure 38-11. Caloric responses of a patient who has no unilateral weakness,
but who does have spontaneous nystagmus with rightward slow phases.
This nystagmus created a bias; caloric responses were sym-
metrical about a new baseline corresponding to the slow-
phase velocity of this nystagmus. It would be difficult to
distinguish between the effects of this bias and a unilateral
caloric weakness on the basis of peak slow-phase velocities if
only one temperature of irrigant were used in the caloric test.
When both warm and cool irrigants—eliciting responses in
both directions—are used and then the sum of the two peak
responses is used as the measure of response strength of a
particular ear, the effects of the bias are canceled and a valid
comparison between the two ears is possible.
Figure 38-11 shows the caloric responses of a patient
who does not have a unilateral caloric weakness, but does
have spontaneous nystagmus with rightward slow phases at
velocities of about 10 degrees/sec, which creates a new
baseline on which the caloric responses are superimposed.
The spontaneous nystagmus in this case cannot be attrib-
uted to a recent unilateral peripheral vestibular lesion, since
the caloric responses of the two ears are equal. A lesion
within the central vestibular pathways could have caused
it, but other explanations, such as recovery of a previously
compensated for peripheral lesion, are also possible.
Therefore spontaneous nystagmus that cannot be attrib-
uted to a recent unilateral peripheral vestibular lesion must
be regarded as nonlocalizing.
Although the bithermal caloric test is highly sensitive to
unilateral peripheral vestibular lesions, it is relatively
insensitive to bilateral lesions. The reason is that the
caloric stimulus is uncalibrated. Even though the stimulus
at the entrance to the external ear canal is the same for
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.
Therefore, normal limits for absolute response intensity
are extremely wide, and bilateral caloric weaknesses must
be extreme to fall below them. The usual rule of thumb is
that a bilateral weakness exists if caloric responses (warm
response plus cool response) of both ears fall below
12 degrees/sec. A bilateral weakness usually indicates bilat-
eral peripheral vestibular lesions.8,9 Central nervous system
(CNS) disorders also produce bilateral weaknesses, but
other signs of CNS dysfunction usually accompany bilat-
eral weaknesses of CNS origin. Patients with labyrinthine
hypofunction may demonstrate reduced or absent caloric
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).
Saccade Test
The purpose of the saccade test is to detect abnormalities
of saccadic eye movement. The test is performed differ-
ently in various laboratories. In one version of the test, the
patient’s horizontal eye movements are monitored as she
fixates on a computer-controlled visual target that jumps
back and forth in the horizontal plane in an unpredictable
sequence. The complete sequence consists of 80 target
jumps (40 to the right and 40 to the left) with amplitudes
ranging from 5 to 25 degrees. After testing, the computer
deletes invalid eye movement data, then calculates three
values—peak velocity, accuracy, and latency—for each sac-
cade and plots these data in graphic form.
Patients may show abnormalities on any of these three
measures. Figure 38-12 shows saccade test data of a patient
with abnormally slow saccades bilaterally, which are char-
acteristic of many degenerative and metabolic diseases of
the central nervous system. Patients may also show abnor-
malities of saccade accuracy, making saccades that are too
small or too large, indicating a lesion of the cerebellar
nodulus. They may also show abnormally long saccade
latencies, which have been associated with lesion of the
frontoparietal cortex.10
Some examiners also monitor vertical eye movements as
the patient performs vertical saccades, although the verti-
cal eye movement tracing is often difficult to interpret and
well-established normal limits are lacking. Also if the
examiner detects internuclear ophthalmoplegia during the
pretest eye movement examination, he will monitor eye
movements separately for each eye in order to document
this abnormality.
Pursuit Tests
TABLE 38-4. Limitations of Caloric Testing
1. Caloric stimulus is:
poorly controlled
poorly tolerated
an unnatural way of vestibular stimulation
considered to be a very low frequency test of vestibular function
2. Measures relative function, one ear with respect to the opposite ear
3. Measures only lateral semicircular canal function
4. Does not test the dynamic range of the vestibular system (much like
testing the auditory system with a single frequency)
616 PERIPHERAL AUDIOVESTIBULAR DISORDERS
Figure 38-12. Saccade test results of a patient with slow saccades bilaterally.
Saccade accuracies and latencies are normal.
Two tests of pursuit—the tracking test and the optokinetic
test—are commonly performed in the ENG examination.
The tracking test is performed in different ways in vari-
ous laboratories. In one version, the patient’s horizontal
eye movements are monitored as he follows a computer-
controlled visual target moving in the horizontal plane.
The target moves back and forth following a sinusoidal
waveform at frequencies from 0.2 to 0.7 Hz. After testing,
the computer deletes invalid eye movement data. Then it
deletes interpolated saccades, differentiates the eye position
signal, calculates the gain of eye velocity with respect to
target velocity separately for rightward and leftward track-
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.
Figure 38-13 shows the results of the tracking test in a
patient with a unilateral pursuit defect. The patient was
unable to follow the leftward-moving target smoothly and
instead approximated its motion using successive saccades,
producing a stairstep pattern on the eye movement trac-
ing. Tracking of rightward-moving targets was normal.
Figure 38-13. Tracking test results of a patient with an asymmetrical pursuit
defect. Upward pen deflection on horizontal eye position tracing denotes
rightward eye movement.
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
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
phases in the opposite direction.
The optokinetic test, like the tracking test, is a test of
pursuit eye-movement pathways, and the results of the
tracking and optokinetic tests agree if task difficulty is the
same. In normal individuals, the velocities of nystagmus
slow phases approximately match target velocity for both
rightward- and leftward-moving targets. Figure 38-14
shows the results of the optokinetic test for the patient
whose tracking test results were shown in Figure 38-13.
Her optokinetic nystagmus was virtually absent for left-
ward-moving targets and mildly reduced for rightward-
moving targets.
SUMMARY
Although ENG essentially replicates portions of the physi-
cal examination, it is an important part of the evaluation of
many complaints of dizziness or balance disturbance. ENG
testing has a number of advantages: (1) the results of the test
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,
the response may have been fatigued or the disease may
have gone into remission. For that patient, the test results
may be normal or indicate a unilateral vestibular weakness

on the suspect side. Nevertheless, we maintain clinical sus-
picion of BPPV, and we ask the patient to return for retest-
ing on a particularly “dizzy day.” Similarly, the patient
suspected of having MD may have a normal ENG early in
the course of the illness, and only later, on a particularly
“dizzy day,” will the caloric evaluation demonstrate a uni-
lateral peripheral weakness, gaze-evoked nystagmus, or
even spontaneous nystagmus. It is important to have
patients abstain from taking vestibular suppressant med-
ications (e.g., diazepam) for at least 48 to 72 hours prior to
ENG, as this can also be a cause of a “false-negative” test.
Abnormal Electronystagmography Does
Not Always Rule in Vestibular Disease
as the Cause of Dizziness
Some patients may present with dizziness not related to
vestibular system dysfunction, for example, syncope or
presyncope, vertebral basilar insufficiency, migraine-
associated dizziness, multiple sclerosis, ocular dizziness,
motion sickness syndrome, or cardiovascular disease. In
these patients, a unilateral weakness found on ENG does
not necessarily implicate vestibular dysfunction as the
cause of their symptoms. The ENG finding may be inci-
dental and must be considered in light of the clinical
history and physical examination.
It Is Important to Test the Patient
When Symptomatic if Possible
The ENG results may change with the course of disease;
some patients may be in remission, and others may have
their disease escalate later. We therefore try to test patients
without medication on the day of their complaint of dizzi-
ness if at all possible.
ENG testing is an important tool in the management of
dizziness. It is by no means a substitute for a thorough
neurotologic history and physical examination, and results
should be interpreted in light of the clinical evaluation.
Those who use ENG testing should have a thorough
understanding of how the test is performed, what its
components are and the significance of the results. The
clinician with a critical eye should always evaluate ENG
reports. When used properly, ENG is the single most
valuable test currently available in the vestibular laboratory.
ROTATION CHAIR TEST
History
Rotational tests have been used to evaluate vestibular func-
tion for nearly a century. Over the years, various testing
methods have been tried, but the one that has proven most
useful involves positioning the patient so that the rotational
axis is vertical and passes through the center of her head,
thus stimulating only her horizontal semicircular canals.
Horizontal eye movements are monitored.
Rotation tests have been used to evaluate vestibular func-
tion for a century. Bárány, in 1907, described an impulsive
rotation test in which the subject was brought to a sudden
stop after manual rotation of approximately 10 turns within
Electronystagmography and Rotation Tests 617
20 seconds. The status of the VOR was then evaluated by
comparing the duration of the evoked nystagmus. In 1948
Von Egmond and coworkers proposed an elaboration of
this test called cupulometry, and the duration of nystagmus
in response to a series of velocity steps was measured and
plotted as a function of stimulus velocity. The use of the
sinusoidal stimuli was introduced with the advent of the
torsion swing test. In this test, the subject was seated on a
spring-loaded chair that oscillated back and forth when the
chair was pressed against the springs and then released.
The springs were calibrated so that the chair underwent
sinusoidal oscillation at 0.05 Hz. These methods of testing
proved to be of limited clinical value due to their insensi-
tivity to common vestibular abnormalities.
Rotation testing entered the modern era in the 1960s
when methods became available for generating precise,
repeatable rotational stimuli and for making quantitative
measurements of eye movements. Today, computers
control all aspects of rotation testing including stimulus
generation, response measurement, and data analysis.
Rotary Chair Test
The most widely used rotation test is the so-called slow
harmonic acceleration test.11 The patient is seated in a chair
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
horizontal eye movements are monitored by EOG, the
same method used in ENG testing. The patient is tested in
total darkness with eyes open while performing mental
arithmetic. She undergoes sinusoidal oscillation about a
vertical axis at several different frequencies. The exact test
protocol varies somewhat among laboratories, but a com-
monly used procedure employs oscillation frequencies of
0.01, 0.02, 0.04, 0.08, 0.16, 0.32, and 0.64 Hz, with peak
angular velocities of 50 degrees/sec at each frequency.12
The patient undergoes multiple cycles of oscillation at each
frequency.
The relationship between head and eye movement dur-
ing several cycles of sinusoidal oscillation for a normal
individual is shown in Figure 38-15. The oscillation fre-
quency in this example is 0.16 Hz, which is near the mid-
dle of the test frequency range. Figure 38-15, top, shows
head angular velocity. Figure 38-15, middle, shows hori-
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
her head moves leftward. As shown in bottom graph of
Figure 38-15, the computer then differentiates the eye
position signal, removes nystagmus fast phases, and dis-
plays slow-phase eye velocity. The computer then com-
pares the head velocity and slow-phase eye velocity and
calculates three measurements—phase, gain, and symme-
try—for each of the test frequencies.
The purpose of the vestibulo-ocular reflex is to produce
eye movements that compensate for head movements. If
the reflex performs perfectly, the slow-phase eye velocity
plot in Figure 38-15, bottom, would have the mirror
image of the head velocity plot in Figure 38-15, middle.
However compensation is less than perfect. The gain of
slow-phase eye velocity signal with respect to head veloc-
618 PERIPHERAL AUDIOVESTIBULAR DISORDERS
Figure 38-15. Head and eye movement of a normal person during oscillation
at 0.16 Hz. Upward pen deflection denotes rightward movement.
ity is only about 0.6. In other words, the eyes do not move
quite fast enough during the nystagmus slow phases to
compensate entirely for head movements.
The relationship between slow-phase eye velocity and
head velocity is described by two parameters in addition
to gain. The first parameter, phase angle, is a measure
of the timing relationship between eye and head velocity.
In Figure 38-15, the direction of slow-phase eye velocity is
exactly opposite the direction of head velocity at all times;
that is, the phase angle is 180 degrees. The second param-
eter, symmetry, is the ratio of rightward and leftward
slow-phase eye velocities. In Figure 38-15, slow-phase eye
velocities are roughly equal in the two directions.
Figure 38-16 shows graphic plots of phase, gain, and sym-
metry data (from left to right in the figure) for a normal
individual over the entire range of test frequencies. Phase
and gain values show the progressive phase lead and gain
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
most severe abnormalities. Figure 38-17 shows test results
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
greater than normal phase leads, which is thought to be
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
Loss of velocity storage seems to represent habituation to
the strong tonic asymmetry produced by the unilateral
peripheral vestibular lesion.17 Loss of velocity storage is
not an exclusive feature of unilateral peripheral vestibular
lesions. It is seen in a variety of vestibular disorders, both
peripheral and central, and has also been observed in nor-
mal individuals who have undergone prolonged rotation.18
This patient also has a rightward asymmetry. That is,
nystagmus with rightward slow phases is stronger than nys-
tagmus with leftward slow phases. At low oscillation fre-
quencies, the asymmetry is about equal to the slow-phase
velocities of the patient’s spontaneous nystagmus with eyes
closed; but at higher frequencies, the asymmetry is greater
than could be accounted for by the spontaneous nystagmus.
This additional asymmetry is thought to be due either to
saturation of inhibitory responses of the intact labyrinth
during rotation toward the side of the lesion or to an asym-
Figure 38-17. Phase, gain, and asymmetry values in relation to oscillation
frequency for a patient with an acute right peripheral vestibular lesion.

Figure 38-18. Phase, gain, and asymmetry values in relation to oscillation
frequency for a patient with a chronic left peripheral vestibular lesion.
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
always toward the side of the loss.20
A second type of abnormality consists solely of abnor-
mally large phase leads at the lower oscillation frequencies.
An example is seen in Figure 38-18 from a patient with a
left acoustic neuroma. ENG showed a severe left caloric
weakness in this patient. The rotation test abnormality seen
here is presumed to reflect the same loss of velocity storage
that is seen in patients with acute vestibular disorders. The
velocity storage loss is persistent, remaining for years
following vestibular malfunction although partial recovery
nearly always occurs.21,22
The absence of tonic asymmetry in this patient illustrates
the effect of vestibular compensation. If a peripheral
vestibular lesion develops slowly, as it generally does in a
patient with acoustic neuroma, the compensation process is
able to rebalance the tonic asymmetry continuously and
therefore to prevent the vertigo and spontaneous nystagmus
that would otherwise occur. Even when the lesion develops
suddenly, as it did in the previous patient with vestibular
neuritis, compensation would quickly rebalance the tonic
asymmetry over a period of days.23 Thus the response pat-
tern in a patient with an acute lesion like that shown in
Figure 38-17 would evolve into a pattern like that shown
in Figure 38-18 if the patient were tested after a few weeks.
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
less than 50% generally did not show abnormal phase leads.
Electronystagmography and Rotation Tests 619
Figure 38-19. Phase, gain, and asymmetry values in relation to oscillation
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.
The remaining 27 patients showed various abnormalities
on ENG, mostly either evidence of CNS system dysfunc-
tion or a combination of abnormalities.
The slow harmonic acceleration test also shows abnor-
malities in patients with bilateral loss of vestibular function.
An example is shown in Figure 38-19. This is a patient with
total bilateral absence of caloric response of unknown
origin. Rotation confirmed the bilateral caloric loss. The
patient failed to show a clear nystagmus response at any
oscillation frequency.
The result shown in Figure 38-19 is actually quite
uncommon. Most patients with bilateral absence of caloric
response show absent responses or reduced response gains
at the lower oscillation frequencies, but normal gains at the
highest frequencies. An example is shown in Figure 38-20
from a patient who developed unsteadiness following a
course of gentamicin therapy and showed a bilateral
absence of caloric response. Baloh and colleagues reported
that rotation testing often demonstrates normal vestibular
function at high frequencies even when ice water irriga-
tions have failed to provoke a response from either ear.25 In
these cases, the results of caloric and rotation tests are not
contradictory, since the caloric response is a response to a
low-frequency stimulus and therefore should be similar to
responses to low-frequency rotational stimuli. However, in
Figure 38-20. Phase, gain, and asymmetry values in relation to oscillation
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
all frequencies, despite absent caloric responses, indicating
a false-positive caloric test result. Clearly the slow har-
monic acceleration test is the procedure of choice in evalu-
ating suspected bilateral loss of vestibular function. The
caloric test, even with ice water, does not define the extent
of the loss and sometimes yields false-positive results.
Clinical Indications for Rotational
Chair Testing
RCT stimulates both peripheral vestibular systems simul-
taneously; however, it may be helpful in determining the
site of lesion in certain disorders. Clinicians have made
some suggestions as to when chair testing may be helpful
in patient evaluation.
First, when the ENG is normal and oculomotor results
are either normal or observed abnormalities would not
invalidate rotational chair results. RCT is used to expand
the assessment of peripheral system dysfunction and status
of compensation. Second, when the ENG suggests a well-
compensated state, despite the presence of a clinically sig-
nificant unilateral weakness and active symptomatology.
RCT is used to expand the investigation of compensation
in a patient with a known lesion site and complaints sug-
gesting poor compensation. Third, when the caloric irriga-
tions are below 10 degrees/sec bilaterally, when caloric
irrigations cannot be performed, or when results in the two
ears may not be compared reliably because of anatomic
variability. RCT is used to verify the presence of and define
the extent of a bilateral weakness or to investigate further
the relative responsiveness of the peripheral vestibular
apparatus in each ear when caloric studies are unreliable or
unavailable. Lastly, when a baseline measure is needed to
follow the natural history of the patient’s disorder (e.g.,
possible early Ménière’s disease) or to assess the effective-
ness of a particular treatment (such as chemical ablation).
REFERENCES
1. Baloh RW, Honrubia V, Jacobson K: Benign positional vertigo:
Clinical and oculographic features in 240 cases. Neurology 37:
371–378, 1987.
2. Baloh RW, Sakata SM, Honrubia V: Benign paroxysmal positional
nystagmus. Am J Otolaryngol 1:1–6, 1979.
3. Baloh RW, Jacobson K, Honrubia V: Horizontal semicircular canal
variant of benign positional vertigo. Neurology 43(12):2542–2549,
1993.
4. Baloh RB, Spooner JW: Downbeat nystagmus: A type of central
vestibular nystagmus. Neurology 31:304–310, 1981.
5. Fisher A, Gresty M, Chambers BR, Rudge P: Primary position up
beating nystagmus: A variety of central positional nystagmus. Brain
106:949–964, 1983.
6. Leigh RJ, Zee DS: The Neurology of Eye Movements.
Philadelphia, FA Davis, 1991.
7. Barber HO, Stockwell CW: Manual of Electronystagmography,
2nd ed. St. Louis, CV Mosby, 1980.
8. Baloh RW, Jacobson K, Honrubia V: Idiopathic bilateral vestibu-
lopathy. Neurology 39:272–275, 1989.
9. Chambers BR, Mai M, Barber HO: Bilateral vestibular loss, oscil-
lopsia, and the cervico-ocular reflex. Otolaryngol Head Neck Surg
93:403–407, 1985.
10. Leigh RJ, Zee DS: The Neurology of Eye Movements.
Philadelphia, FA Davis, 1991.
11. Stockwell CW, Bojrab DI: Background and Technique of Rotational
Testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
Handbook of Balance Function Testing. St. Louis, Mosby Year Book,
1993, pp 237–248.
12. Shepard NT: Rotational chair testing. In Goebel JA (ed.): Practical
Management of the Dizzy Patient. Philadelphia, Lippincott
Williams & Wilkins, 2001, pp 129–141.
13. Stockwell CW, Bojrab DI: Interpretation and usefulness of rota-
tional testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
Handbook of Balance Function Testing. St. Louis, Mosby Year Book,
1993, pp 237–248.
14. Raphan T, Matsuo V, Cohen B: Velocity storage in the vestibulo-
ocular reflex arc (VOR). Exp Brain Res 35:229–248, 1979.
15. Honrubia V, et al: Vestibulo-ocular reflexes in peripheral
labyrinthine lesions: I. Unilateral dysfunction. Am J Otolaryngol 5:
15–26, 1984.
16. Raphan T, Matsuo V, Cohen B: Velocity storage in the vestibulo-
ocular reflex arc. Exp Brain Res 35:229–248, 1979.
17. Honrubia V, et al: Vestibulo-ocular reflexes in peripheral,
labyrinthine lesions: I. Unilateral dysfunction. Am J Otolaryngol 5:
15–26, 1984.
18. Baloh RW, Henn V, Jager J: Habituation of the human vestibulo-
ocular reflex by low frequency harmonic acceleration. Am J
Otolaryngol 3:235–41, 1982.
19. Honrubia V, et al: Evaluation of rotatory vestibular tests in periph-
eral labyrinthine lesions. In Honrubia V, Brazier MAB (eds.):
Nystagmus and Vertigo. Clinical Approaches to the Patient with
Dizziness. New York, Academic Press, 1982, pp 57–78.
20. Stockwell CW, Bojrab DI: Interpretation and usefulness of rota-
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-
tional testing. In Jacobson GP, Newman CW, Kartush JM (eds.):
Handbook of Balance Function Testing. St. Louis, Mosby-Year Book,
1993, pp 237–248.
22. Honrubia V, Jenkins HA, Baloh RW, et al: Vestibulo-ocular reflexes
in peripheral labyrinthine lesions: I. Unilateral dysfunction. Am J
Otolaryngol 5:15–26, 1984.
23. Halmagyi GM, Curthoys IS: Clinical changes in vestibular function
with time after unilateral vestibular loss. In Herdman SJ (ed.):
Vestibular Rehabilitation. Philadelphia, FA Davis, 2000, pp 172–194.
24. Stockwell CW: Vestibular function testing: 4-year update. In
Cummings CW, et al (eds.): Otolaryngology-Head and Neck
Surgery: Update II. St. Louis, Mosby-Year Book, 1989, pp 39–53.
25. Baloh RW, et al: Changes in the human vestibulo-ocular reflex after
loss of peripheral sensitivity. Ann Neurol 16:222–228, 1984.

Ménière’s Disease
Outline
Introduction
Definitions
Reporting Criteria
Incidence
Clinical Presentations and
Natural History
Etiology and Pathophysiology
Theories of Pathogenesis
Anatomic Factors
Viral/Immune Theory
Allergy
Genetics
Post-traumatic Hydrops
Delayed Hydrops
Clinical Evaluation
Differential Diagnosis
Medical Management
Acute Treatment
Prophylaxis
Diuretics
Vasodilators
Steroids
Allergy Management
Gentamicin and Surgical
Management
INTRODUCTION
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-
ology are incompletely understood. The underlying pathol-
ogy is thought to be endolymphatic hydrops, and many
processes are suspected to share this end point, including
viral infection, allergy, and autoimmunity. The treatment of
MD remains controversial partly because of the unpre-
dictable nature of the disease with periods of remission and a
substantial rate of spontaneous resolution. Empirical medical
therapy consists of low-salt diet and diuretic medication, but
this approach is unproved. Surgical intervention continues to
prompt heated debate. Randomized placebo-controlled tri-
als are very difficult to perform for several reasons: (1) MD
lends itself poorly to definition and staging, (2) defining
treatment outcomes in a disease largely characterized by sub-
jective symptoms is imprecise, and (3) placebo-controlled
trails are unfeasible as long as investigators and patients
Chapter
39
Endolymphatic Sac Surgery Stephanie Moody Antonio, MD
Endolymphatic Sac Surgery
Rick Friedman, MD, PhD
Technique
Vestibular Nerve Section
Gentamicin
Cochleosacculotomy
Cochleosacculotomy
Technique
Transcanal Labyrinthectomy
Transcanal Labyrinthectomy
Technique
Transmastoid
Labyrinthectomy
Transmastoid
Labyrinthectomy Technique
Translabyrinthine Vestibular
Nerve Section
Translabyrinthine Vestibular
Nerve Section Technique
Surgery and Hearing
Outcomes
Surgery and Quality of Life
Other Approaches
object to randomization to a nontreatment or sham treat-
ment control group.1
DEFINITIONS
The diagnosis of classical MD is suspected based on the
clinical history. People with MD experience incapacitating
vertigo, often with nausea and vomiting, typically lasting
hours. Dysequilibrium of a more constant nature may per-
sist for 24 to 72 hours after the attack, but it usually
resolves completely. Otologic complaints include tinnitis
and pressure in the head or ear during vertigo spells.
Audiologic evidence of fluctuating low-frequency or pro-
gressive sensorineural hearing loss is required to confirm
the diagnosis. Tinnitis, hearing loss and aural pressure
allow identification of the affected ear.
The term cochlear hydrops describes fluctuating
low-frequency hearing loss without associated vertigo.
Fluctuating low-frequency hearing loss with tinnitis and
621
622 PERIPHERAL AUDIOVESTIBULAR DISORDERS
aural fullness may precede MD. Eventual development of
the full syndrome occurs in 37% to 42% of patients with
cochlear symptoms.2 Of patients with definite MD, 40%
have purely hearing symptoms prior to the first vertigo
attack.3
Patients with severe and long-term MD are at risk
of developing Tumarkin otolithic crisis, or drop attacks.
These are abrupt attacks of falling after loss of lower-
extremity muscle tone without loss of consciousness.4
The incidence is reported as 6% to 7% of patients with
MD, although in one report, the incidence was as high
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
cause is unknown. This symptom may be secondary to a
cardiac, cerebrovascular, or seizure process and these must
be ruled out.7
Lermoyez’s syndrome is a variant of MD wherein hear-
ing loss and tinnitis precede an attack of vertigo by days to
months, subsiding with the onset of vertigo.8 The patho-
physiology is unknown. In one patient with the syndrome
whose temporal bones were studied, hydropic changes
were limited to the upper basal turn and saccule in contrast
to more wide involvement of the cochlea with classic MD.9
REPORTING CRITERIA
The Committee on Hearing and Equilibrium of the
American Academy of Otolaryngology–Head and Neck
Surgery publishes guidelines for defining, reporting, and
interpreting results of the treatment of MD.10 (We suggest
familiarity and attention to these criteria to anyone
reviewing the literature.) Diagnostic criteria for MD are
categorized as certain, definite, probable, or possible MD.
Certain MD includes definite MD plus histopathologic
confirmation. Definite MD is specifically defined as the
presence of recurrent, spontaneous episodes of vertigo,
documented hearing loss, aural fullness, and tinnitus.
Either tinnitus or aural fullness must be present.
The vertigo episodes last at least 20 minutes but more
commonly for hours, are disabling, and are accompanied
by nausea and vomiting. The diagnosis of MD requires at
least two definitive spells of 20 minutes or longer.
Probable MD is defined by only one episode of vertigo
with hearing loss and tinnitus or aural fullness. Possible
MD may be used to describe typical episodic vertigo with-
out hearing loss or sensorineural hearing loss with dizzi-
ness, but without definitive episodes. Underlying causes
for the syndrome (otosclerosis, syphilis, trauma, etc.) are
excluded prior to the assumptive designation of idiopathic
MD. Specific criteria were outlined by the Committee for
Requisite Hearing Loss.
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.
A numeric scale and a disability scale were suggested
(Table 39-1). These scales can be used to evaluate changes as
improved, unchanged, or worse. Hearing stage (Table 39-2)
can be applied to certain or definite MD. The criteria for
the determination that a hearing change is significant are a
change of 10 dB or more in pure tone average (PTA) of
TABLE 39-1. Reporting Recommendations
for Ménière’s Disease
Vertigo Class Numeric Score* Description
Class A 0 Complete control
Class B 1–40 Substantial control
Class C 41–80 Limited control
Class D 81–120 Insignificant control
Class E >120 Worse
*Numeric score = 100 × Spells per month in 24 months after treatment.
Spells per month in 6 months before treatment.
hearing thresholds at 500, 1000, 2000, and 3000 Hz; or a
change in a word recognition score of 15% or more. The
worst pretreatment audiogram up to 6 months before treat-
ment is compared with the worst post-treatment audiogram
at 18 to 24 months follow-up. Longer follow-up is pre-
ferred.10 These guidelines for defining the disease and
reporting treatment outcome provide a common reference
point for critical assessment of treatment efficacy as
reported in the literature. Improved methods to classify
and quantify this disease are needed.
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
provide valuable insight into the natural history and
management of MD since they allow quantification of sub-
jective symptoms. In addition, the disability resulting from
these symptoms is influenced by psychological, physical,
and social-support structures. Common scales include the
Dizziness Handicap Inventory (DHI),11 the Tinnitus
Handicap Inventory (THI),12 and the Hearing Handicap
Inventory for Adults (HHI).13
INCIDENCE
The incidence of MD is difficult to determine because of
the character of the disease, with the sometimes subtle
onset (cochlear symptoms only), fluctuating symptoms,
long periods of remission, and inconsistency in establish-
ing the diagnosis.14 Studies from Sweden and Great
Britain estimate the occurrence of MD in those popula-
tions as 46 in 100,000 people and 100 in 100,000 people,
respectively.15,16 In the population of Rochester,
Minnesota, the annual incidence between 1951 and 1980
was 15.3 per 100,000 and the prevalence on January 1,
1980, was 218 per 100,000 population.17 In Finland, the
incidence was 4.3 per 100,000 per year in 1992 to 1996
and the prevalence in 1996 was 43 per 100,000.18
The onset of symptoms peaks at 40 to 60 years of age.
The disease is uncommon in children.3,19,20 Bilaterality is oft
TABLE 39-2. Stages of Ménière’s Disease
Stage Four-Tone Average (dB)
1 ≤ 25
2 26–40
3 41–70
4 >70

debated with reported incidence ranging from 10% to
70%.3 The frequency of bilateral disease increases with
time, and at 20 years reached 47% in 161 patients followed
in Sweden.21 In Haye and Quist-Hanssen’s longitudinal
study of 111 patients and in Green, Blum, and Harner’s
study of 108 patients, 37% and 34%, respectively, developed
bilateral disease.3,20 Subclinical disease in the asymptomatic
ear was observed by Paparella who found that 78.6% of
patients with clinically unilateral MD had abnormal audio-
metric findings in the asymptomatic ear and that 32% had
the complete criteria necessary to diagnosis MD in that
ear.22 Friedrichs and Thornton used the traveling wave
velocity test (based on the stiffness of the basilar membrane)
and diagnosed subclinical hydrops in 27% of the contralat-
eral ears in 100 patients with clinically unilateral MD.23
CLINICAL PRESENTATION AND
NATURAL HISTORY
The typical presentation of MD includes sudden attacks of
vertigo with unilateral hearing loss, tinnitus, and aural full-
ness. The vertigo is incapacitating, often with nausea and
vomiting, lasting several hours. It is not uncommon for
vertigo to last only minutes or for as long as 24 hours.
Dysequilibrium accompanies the vertigo and may persist
for 24 to 72 hours after the acute vertigo subsides.
Between attacks patients are usually completely asympto-
matic, but may describe persistent disequilibrium.
Some patients describe a chronic state of dizziness with
intermittent superimposed vertigo spells. Patients may also
describe positioning vertigo. The attacks may be preceded
by an aura consisting of a vague sense of dizziness, aural
fullness, tinnitus, or a change in hearing. The attacks may
also be sudden and without warning. Associated otologic
complaints include hearing loss, tinnitus, and pressure in
the head or ear before or during the vertigo attack. All four
classical symptoms are often not recognized and may not
be present during early disease. Some patients are so
distressed by the vertigo that they have not noticed these
problems until instructed to record them. Diplacusis can
be an early signal and can sometimes be elicited by
a thorough history.
The frequency of vertigo attacks varies widely with a
mean of 6 to 11 episodes per year.21 At worst, episodes can
occur 30 times per year.3 Attacks may occur in clusters or
on a regular schedule. Periods of remission may last years,
only to be followed by recurrence. Spells tend to change in
severity over time, becoming more mild; but once again,
this is unpredictable, and a long period of time with mild
spells may be suddenly ended with a severe spell. Typically,
the disease eventually “burns out” with decline and cessa-
tion of vertigo and progressive deterioration of hearing.
With minimum follow-up of 9 years in 108 patients,
Green reported vertigo was completely absent in 54% and
decreased in 30%.20 Hearing fluctuates in the early course
of disease, but eventually becomes progressively worse,
stabilizing at about 50 dB PTA and 50% word discrimi-
nation score. Low frequency hearing loss extends to
involve high frequencies and the audiogram develops a flat
pattern.2 The majority of hearing loss occurs in the first
few years of disease.2,21 In patients who have been observed
Ménière’s Disease 623
for 20 years or longer, most have hearing loss of 50 dB or
more and all have at least 30 dB of loss.21 Tinnitus and
aural fullness are present in the majority of patients in the
long term.20
Quality of life measures suggest MD adversely affects
daily life.24,25 Symptoms of MD correlate with other
medical and psychological complaints such as dysphoria,
anxiety, insomnia, and lack of concentration.24 Using the
Medical Outcomes Survey-Short Form, Kinney found that
patients with MD functioned like patients with minor
medical conditions on physical functioning subtests, but
more like patients with major medical conditions for vitality,
social function, and role limitations, and poorer than
patients with major medical conditions for mental health.26
ETIOLOGY AND PATHOPHYSIOLOGY
The etiology and pathophysiology of MD are not known.
Some proposed etiologies of “idiopathic” MD are
anatomic abnormality, viral infection, autoimmune
disease, and allergy. The underlying cause-and-effect
relationship of these possible etiologies on the function of
the inner ear and endolymphatic system is unknown.
One of the most well accepted theories of the patho-
genesis of MD is based on the belief that endolymphatic
hydrops is the pathological correlate of MD. In this
theory, hydrops is caused by mechanical obstruction to
endolymphatic flow or by intrinsic malfunction of the
endolymphatic system resulting in an overabundance
of endolymphatic volume and/or pressure.27 There are
many proposed mechanisms that may contribute to aber-
rations in endolymphatic pressure and volume and
endolymphatic sac and duct malfunction. While reading
the following discussion on the etiology and pathophysiol-
ogy of MD, the reader should note that hydrops is not
specific to MD and several scientists have raised significant
problems with the proposed theories. No alternative
theory has been advanced.
Theories of Pathogenesis
Theories for the underlying mechanism that results in
hydrops include excessive endolymph production,
decreased endolymph resorption, fibrosis of the endolym-
phatic sac or duct, and altered glycoprotein metabolism.28
As a pathologic sign only, hydrops may or maynot be asso-
ciated with MD symptoms.27 A trigger or other mecha-
nism must therefore provoke an acute change in
physiology that results in the symptom complex of MD.
The cause of the sudden attacks of vertigo and aural symp-
toms associated with MD remains unknown. Figure 39-1
is a flowchart of these various factors. Schuknecht devel-
oped a theory to explain the acute attacks as well as the
progressing hearing loss and dysequilibrium.6
The disease probably begins with a prodromal stage of gradual
distention of the endolymphatic system, which may be associ-
ated with very few or no symptoms. As the distension progresses,
there is thinning and atrophy of the more yielding parts of the
membranous labyrinth (Reissner’s membrane and saccular wall),
which leads to ruptures and the sudden release into the reduced
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
to this potassium-rich (neurotoxic) endolymph are paralyzed,
resulting in sudden hearing loss or vertigo. As the biochemical
components of the perilymphatic compartment are restored to
normal, the symptoms subside. Aided by the collapse of the
distended membrane, the rupture heals and the stage is set for
a repetition of the process. Progressive hearing loss can be attrib-
uted to progressive disturbances in motion mechanics caused by
the distorted, dilated, and collapsed membranes (Fig. 39-3) as well
as a loss of specialized cell types and alterations in inner ear
biochemistry and bioelectric potentials.6
Another theory emphasizes a vital role of the endolym-
phatic sac. In this theory, described by Gibson and
Arenberg,29 a disturbance in longitudinal flow of
endolymph (possibly linked to a narrow vestibular aque-
duct) from the cochlear duct to the endolymphatic sac
results in hydrops. The sac is postulated to actively regu-
late the flow by maintaining an osmotic gradient and secret-
ing glycoproteins that attract movement of endolymph
toward the sac. In addition, the sac may produce saccin, a
hormone thought to increase the volume of endolymph,
which may promote faster flow. In an ear affected by MD,
metabolic debris obstructs longitudinal flow. The sac
responds by secreting saccin and glycoproteins and the sub-
sequent increase in flow overcomes the obstruction and
clears the duct. The sudden restoration of movement of
endolymph results in the sensation of vertigo. In later-stage
MD, the sac is no longer able to affect flow of endolymph
through an obstructed duct. Vertigo episodes subside but
saccin secretion may continue, resulting in worsened
hydrops and persistent hearing loss.
Anatomic Factors
Anatomic variations in the endolymphatic system may play
a role in the development of endolymphatic hydrops.
Several studies have documented that the vestibular aque-
duct and the external aperture of the vestibular aqueduct
are shorter and smaller and the endolymphatic sac and
duct are less frequently visualized radiographically, surgi-
cally, and pathologically in patients with MD.30–33
Whether this anatomic difference contributes to the
pathophysiology of MD is unclear.
Viral/Immune Theory
One of the most accepted theories of etiology for idio-
pathic MD is the viral/immune theory.34,35 In this theory, a
virus gains access to the inner ear via the middle ear or
hematogenously. The initial event might be a direct effect
of the viral infection and its inflammatory, immune, and
microvascular-mediated injury. Subsequent attacks might
not be caused by active virus but by immune-mediated cel-
lular damage to various structures of the inner ear includ-
ing the stria vascularis, dark cells, and the endolymphatic
system. The basis of this theory is that the endolymphatic
sac is primarily responsible for the immunodefense of the
inner ear.34 An alternative explanation for the recurrent
nature of attacks is reactivation of viruses commonly found
latent in the vestibular and spiral ganglion cells, resulting
in production of new viruses, which can migrate back
along axons to the peripheral branches and into the peri-
lymph, where they can cause direct injury or can provoke
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
of herpes simplex virus (HSV) DNA in the vestibular gan-
glion and intraosseous endolymphatic sac,38–40 antiviral IgE
in the sera of MD patients,41 and elevated anti-HSV IgG in
the perilymph of MD patients,36 all with levels greater than
controls. The pathologic features of axonal degeneration
are thought to be consistent with a viral etiology.35
The importance of the immunologic activity in the
pathophysiology of MD is supported by evidence of ele-
vated circulating immune complexes,42 the presence of
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
the source of the inner ear immune response.37,45 Gluco-
corticoid receptors have been identified in the stria vascu-
laris and may play a role in inner ear fluid homeostasis.46–48
In addition, Adams documented the production of
cytokines by cells of the spiral ligament.49 A positive clinical
response to corticosteroids further supports the role of an
immune phenomenon.35,36
Despite this evidence, a direct causal link of HSV or
immunological reactivity to MD cannot be definitive.28,50
Studies are needed that further demonstrate a clinical
association between MD and HSV or autoimmunity, doc-
ument virus or immune mediators in inner ear tissues of
affected patients, and establish an animal model with sim-
ilar clinical and pathologic characteristics.51
Allergy
Allergy may be another trigger for immune reac-
tions resulting in MD. A significant number of patients
with MD report airborne and food allergy.52 Patients
treated with desensitization and diet showed a significant
626 PERIPHERAL AUDIOVESTIBULAR DISORDERS
A Several observations have been made that not only sug-
B sion that occur immediately after injury, post-traumatic
Figure 39-3. A, Membrane ruptures. Cochlea with diffuse hydrops
(A). Rupture of Reissner’s membrane healed, but the thin membrane is now
distended and collapsed against the spiral ligament (B). The saccular membrane
is dilated and fused to the footplate of stapes (C). B, Rupture outpouching.
Rupture of ampullary wall (*) with collapse of healed membrane filling ampulla
(arrows). (Courtesy of Fred Linthicum, Jr., House Ear Institute, Los Angeles.)
improvement from pretreatment to post-treatment in both
allergy and Ménière’s symptoms, including significant
reduction in the number and the severity of vertigo.53
Genetics
Genetic defects in structural proteins, growth factors or
their receptors, ion channels and pumps, or proteins
responsible for regulating the developmental cascade of
the many genes involved in auditory development can lead
to auditory and vestibular dysfunction. The complex
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
in one of these “homeostatic” genes were in the germ line,
endolymphatic hydrops could be an inherited process.
There have been several reports of familial Ménière’s
disease in the literature dating back to the first reports
by Brown in 1941 and 1949 and followed two decades later
by Bernstein in 1965.54,55 Since that time, several reports
have citied an incidence between 2.5% and 12%.56,57
The vast majority of these descriptions have suggested an
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.
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-
MD occurs months to years later. The mechanism is
unknown, but fistulization of the bony labyrinth, direct
injury to the membranous labyrinth, or disruption of the
endolymphatic flow have been suggested.63
Delayed Hydrops
Delayed hydrops is the new onset of MD symptoms in the
setting of a previous severe hearing insult, usually unilat-
eral. The onset of vertigo of Ménière’s type occurs 20 years
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
of the preexisting hearing loss can be sudden deafness,
head injury, mumps, measles, mastoidectomy, meningitis,
and influenza, often occurring during childhood.64,65
Acoustic trauma has also been associated with delayed
hydrops.66,67 Pathologic findings of delayed endolymphatic
hydrops have been documented by Schuknecht.68
CLINICAL EVALUATION
The diagnosis of MD is based on the history and confirmed
by the documentation of low-frequency sensorineural hear-
ing loss. Diagnostic testing is desirable to confirm the diag-
nosis before undertaking destructive treatment procedures
and to rule out contralateral asymptomatic disease.69
Despite the introduction of several diagnostic methods,
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
Ménière’s disease, the vertigo is prolonged and is followed
by dysequilibrium that persists for months with slow
recovery.85 The histopathology includes atrophy of
peripheral vestibular nerve fibers and end organ.85 A viral
etiology is suspected.40,85–87
Vascular compression syndrome can be characterized by
recurrent disabling vertigo with or without hearing loss.
These patients typically complain of disabling motion
intolerance including dysequilibrium or vertigo when
walking, after quick head movements, and while riding in
a car.88–91 McCabe and Gantz reported an erroneous diag-
nosis of MD in 52% of patients who eventually underwent
vascular loop decompression.88 The diagnosis can be made
with constructive interference in steady state (CISS) MRI.92
Cerebellopontine angle tumors such as vestibular schwan-
noma and meningioma can cause symptoms similar to
those of MD. Endolymphatic sac tumors in the posterior
fossa have been reported to present with Ménière’s-like
symptoms.93 Dizziness or hearing loss atypical for MD or
otherwise suspicious should be evaluated with gadolinium-
enhanced MRI.
Migrainous vertigo is a diagnosis based on the presence of
episodic vertigo with migraine and/or photophobia,
phonophobia, and visual auras. In patients presenting to a
neurologic dizziness clinic, 7% were diagnosed with defi-
nite migrainous vertigo.94 Vertigo may last longer than
that of typical MD, and patients often report a personal or
family history of migraine, motion intolerance, and onset
of symptoms with visual cues. Hearing loss is uncommon
in this group and can help differentiate these patients from
those with MD.
MEDICAL MANAGEMENT
There is no cure for MD; that is, at this time intervention
does not eliminate the underlying cause of disease. The goals
of medical management of MD are control and reversal of
vestibular and cochlear injury. In light of the etiologic vari-
ability and the lack of understanding of the pathophysiology
of endolymphatic hydrops, the design and evaluation
of specific therapeutic interventions are challenging. The
prolonged but the fluctuating nature of the disease and
subjective nature of most of its important symptoms make
randomized controlled clinical trials extremely difficult to
perform. Current treatment strategies are based on anec-
dotal evidence and personal opinion. Nonetheless, clinicians
have noted that medical strategies can control disease in 80%
of patients (based on reduced frequency of acute vertigo),
although no treatment has been decidedly shown to halt the
progression of hearing loss. It is difficult to prove that any
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
loss, reduction of tinnitis and aural fullness, reduction of
progressive hearing loss, and improvement of quality of life.
Acute Treatment
Vestibular suppressant and antiemetic medications are
generally effective in controlling acute vertigo. Classes of
drugs useful for vertigo include benzodiazepines (diazepam),
antihistamines (meclizine, promethazine, diphenhydramine,
dimenhydronate), anticholinergics (meclizine, glycopyrro-
late), and antidopaminergic (prochlorperazine, droperi-
dol).95 Severe episodes may be treated with courses of oral
steroid tapering over 5 to 10 days. In the authors’ experi-
ence, steroid burst treatment may lessen the severity of
acute vertigo and promote earlier recovery of hearing.
Prophylaxis
Several good review articles address long-term medical
therapy for MD.2,95–100 Sodium restriction is the foundation
of the treatment regimen. It is commonly thought that
a low-salt diet will reduce sodium-related volume overload
with subsequent redistribution to the endolymphatic
space.95,100 The effects are likely more complicated than
a simple change of plasma or endolymph sodium level,
since a low-salt diet is known to have extremely little influ-
ence on the plasma sodium level and sodium levels in den-
dolymph are near normal in animal models with hydrops.101
Anecdotally, patients have reported acute symptoms after
excessive salt intake and a positive response to salt restric-
tion. There are no randomized controlled trials (RCT)
to support this impression. Patients should be counseled to
limit dietary salt to 2 grams per day.
Diuretics
The use of diuretics is based on circumstantial evidence
of a positive effect on hearing and vertigo with osmotic
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
anhydrase in dark cells and in the stria vascularis, thereby
reducing endolymph production. Hydrochlorothiazide
and combination hydrochlorothiazide and triamterene
are commonly employed, but the mechanism of action
is unclear. In a nonrandomized placebo-controlled study,
Klockhoff and Lindblom showed a significantly better
response of vertigo, hearing loss, and general condition
to treatment with hydrochlorothiazide than with
placebo.102 Van Deelen and Huizing published the only
RCT and used a crossover placebo-controlled design.
During 17 weeks of triamterene (Dyazide) treatment,
subjects had significantly fewer vestibular complaints,
but no reduction in hearing loss or tinnitis.103
Retrospective studies have also supported diet and diuretic
therapy.104,105 Inasmuch as the disease fluctuates over time,
patients can be weaned from treatment after 6 to
12 symptom-free months; treatment can be reinitiated
when needed.
Vasodilators
Vasodilators were historically recommended based on the
belief that ischemia of the stria vascularis caused MD.
Histamine (subcutaneous or sublingual) and betahistine
(peroral) acting on H1 and H2 receptors cause capillary
dilation.106 The authors found no RCT of histamine
therapy. Betahistine (the oral analogue of histamine) has
been studied in a few RCTs.107–109 Fraysse and colleagues

noted a significant reduction in vertigo (in frequency,
duration, and severity of attacks) at 60 days of betahistine
treatment compared to flunarizine. Cochlear symptoms
were also reduced in the group treated with betahistine.108
Schmidt and Huizing found no difference in imbalance
between the two groups.107 In a double-blind crossover
study reported by Oosterveld, patients had significant
reduction of the incidence and severity of dizziness during
6 weeks of beta-histine treatment compared with 6 weeks
of placebo treatment. This study included patients with
other types of peripheral vertigo, and interestingly, the
author’s opinion was that patients with MD responded less
than did patients with other vestibular disorders.110 Other
vasodilators such as nicotinic acid (50 to 200 mg), vitamin
C, bioflavonoid complex, probanthine (15 mg), and
diphenhydramine (50 mg) can be added, but there is little
objective evidence to support their use.95
Steroids
Mounting evidence of immune and inflammatory etiology
of MD has motivated the investigation of steroids in the
long-term management of MD. Although systemic steroid
may distribute to the endolymphatic sac, vestibular nuclei,
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
endolymph in animal models.111–113 Intratympanic steroid
treatment for MD has been suggested as an alternative to
surgical or ablative procedures when medical treatment
has failed to control vertigo. Shea reported 2-year results
after 48 patients with MD were treated with 16 mg of dex-
amethasone intravenously and 8 mg of dexamethasone
intratympanically for 3 consecutive days followed by 3 to
90 days of oral dexamethasone. Of 30 patients, 19 (63.4%)
had class A results (see Table 39-1) and 4 (13.3%) had class
B results. Hearing was improved or unchanged in 45 or 48
(93.7%) ears based on the 1995 AAOHNS guidelines.113
The study is difficult to interpret because its design was
not randomized and not controlled and treatment
consisted of three routes of steroid administration.
Silverstein and colleagues reported the only randomized
controlled trial of intratympanic steroid. Seventeen
patients underwent placement of tympanostomy tube and
adhesiolysis of the middle ear and were then treated with
either intratympanic steroid or placebo for 3 consecutive
days. After 3 weeks, a crossover treatment was initiated.
No significant difference in hearing or tinnitis was noted,
but follow-up was limited and the disease stage was late,
suggesting the patients would be unlikely to gain signifi-
cant hearing benefit from any medication.114 Vertigo was
not specifically evaluated in this study. In a nonrandomized
prospective study, the rate of substantial or complete
vertigo control after intratympanic dexamethasone
(applied by the patient through a tympanostomy tube 0.25
mg every other day for 3 months) was 72% at 18 months.
However, it was not significantly different than after
intratympanic gentamicin or endolymphatic sac decom-
pression.115 Intratympanic steroid may not produce
improvement in hearing outcome.115,116 Randomized
controlled trials are needed to further investigate the role
of intratympanic steroid.
Ménière’s Disease 629
Allergy Management
Allergy management may be indicated in selected patients.
Indications for allergy evaluation include bilateral symp-
toms, symptoms linked to food, seasons, or weather,
steroid-responsiveness, or failure to respond to traditional
treatment.53 In Derebery’s review53 of 113 patients treated
with immunotherapy and/or food elimination/rotation diet,
there was a significant reduction in vertigo, tinnitus, and
hearing loss compared to pretreatment. Although a statis-
tical comparison was not made because the allergy-treated
group had significantly worse symptoms before treatment,
the control group (patients who refused allergy treatment)
rated their symptoms worse than did the treated patients at
the end of the study. This suggests that not only did the
treated group show significant improvement, but also they
improved to levels that appeared better than the control
group. Allergy therapy may include antihistamines, nasal
steroid sprays, systemic corticosteroids, immunotherapy,
and elimination and/or rotation food diets.117 Immunosup-
pressive management is closely linked to allergy therapy for
immune-mediated MD. Preliminary studies of methotrex-
ate and etanerocept show promise, but must be evaluated
further.118–120
GENTAMICIN AND SURGICAL
MANAGEMENT
For the 10% to 20% of MD patients for whom medical
management fails, further intervention may include
vestibuloablative or nonablative and hearing preservation
or nonpreservation approaches. When considering surgi-
cal intervention, it is important to understand that the goal
is primarily to eliminate disabling vertigo and improve qual-
ity of life, since no surgical treatment has been proved to
cure the underlying disease. Ultimate control of progressive
hearing loss is ideal, but current strategies have not been
proved to significantly alter long-term hearing outcome.
Endolymphatic Sac Surgery
Endolymphatic sac surgery (ESS), a nonablative hearing pre-
serving approach, includes decompression and various
shunting techniques and was first described by Georges
Portmann in 1926.121 It has since been the focus of fervent
debate. The authors would direct the reader to examine
the extensive literature but note that the only RCTs sug-
gest limited efficacy.122,123 Quaranta and colleagues com-
pared ESS to natural history at 2, 4, and 6 years and found
a significant benefit at 2 and 4 years. The benefit did not
differ at 6 years, at which time 85% of patients who
received ESS and 74% of patients who did not had vertigo
control.124 Various nonrandomized studies have reported
50% to 75% vertigo control in.124–128 Many series report
ESS results in even higher rates of vertigo control but are
uncontrolled.129–135 On the other hand, Jackson and
colleagues reported that only 7% of their patients had com-
plete control of vertigo at 2 years.136 Silverstein and
colleagues reported no difference in a group of patients
who were offered yet declined surgery and those who
underwent ESS, both achieving a control rate of 71%
630 PERIPHERAL AUDIOVESTIBULAR DISORDERS
at 2 years.137 Studies using standardized questionnaires
found no difference in patient-scored dizziness after ESS
compared to medically treated patients.26,138 The efficacy
of the procedure is brought further into question when
considering that insertion of a ventilation tube or cortical
mastoidectomy alone may reduce vertigo.139,140 Considering
the variability of vertigo control in reports of both surgical
and nonsurgical management, the substantial spontaneous
resolution of vertigo over time, and the lack of RCTs, it is
extremely difficult to interpret the literature. Nonetheless,
ESS is associated with a low rate of complications. It is
commonly used as the first-line surgical treatment for
patients with disabling vertigo despite maximal medical
treatment because it offers an alternative to surgical
procedures with higher risks.
Endolymphatic Sac Surgery Technique
The procedure is performed under general anesthesia.
Intraoperative facial nerve monitoring and perioperative
antibiotics are not routinely used. After a routine cortical
mastoidectomy, the lateral semicircular canal and the short
process of the incus are identified through the mastoid
antrum. These two structures are critical landmarks for
the identification of the intratemporal facial nerve.
The middle fossa plate is identified superiorly and the
sigmoid sinus and presigmoid posterior fossa plate poste-
riorly. The sigmoid sinus is skeletonized, with attention to
its anterior aspect. Following the sigmoid medially, bone
over the posterior fossa dura is removed. Exposure of the
posterior fossa dura is extended toward the jugular bulb
and into the retrofacial air cells, allowing a wide decom-
pression over the sac. Air cells over the posterior semicir-
cular canal can be removed to improve visualization, but
the canal should not be excessively thinned to avoid a fis-
tula. Staying behind and medial to the posterior semicir-
cular canal and using diamond burrs will protect the
vertical facial nerve. The sac is identified by a whitish
thickening of the dura extending toward the distal aspect
of the sigmoid sinus. An elevator can be used to lift the sac
away from the overlying bone to define the operculum and
the endolymphatic duct. In contrast to the sac, the dura
appears thin and bluish. If a shunt is planned, the sac is
carefully entered with a sharp hook or a sharp microblade
and the lumen identified by its glistening character. It is
important to visualize the shiny, smooth surface of the
lumen to avoid creating a false lumen. The lumen is
opened wide with a long blunt right-angle hook with spe-
cific attention toward the duct. AT-shaped Silastic may be
placed to stent the lumen. Potential complications include
cerebrospinal fluid (CSF) leak, fenestration of the posterior
semicircular canal, labyrinthitis, and facial nerve injury.
The rate of complications is less than 1%.
Vestibular Nerve Section
Vestibular nerve section (VNS) can be performed via the mid-
dle fossa, retrosigmoid, or is a vestibuloablative but hearing
preservation approach and retrolabyrinthine approaches.
VNS can also be performed after labyrinthectomy as a non-
hearing preservation procedure. These surgeries are
discussed in Chapter 56.
Gentamicin
Chemical labyrinthectomy exploits vestibulotoxic properties
of gentamicin. The drug is administered intratympanically
via a myringotomy, tympanostomy tube, microwick,
or microcatheter. Authors have outlined numerous proto-
cols for drug delivery, each reporting excellent control
of vertigo (approximately 90%), but with variability in
rates of hearing loss (0% to 50%). Profound hearing loss
is less common.141–145 There is no consensus on the ideal
dose or protocol for delivery. When comparing protocols
for chemical ablation, the method, frequency, and duration
of installation and the treatment end point (total nonre-
sponse on ENG, nystagmus, dizziness, or hearing loss)
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-
lar function may not be necessary to abolish vertigo
attacks, and it may be associated with a higher risk of hear-
ing loss.145 The mechanism of action and the kinetics of
transtympanic gentamicin are incompletely understood.
There are various theories as to how intratympanic treat-
ment results in ototoxic effects. Gentamicin can enter the
inner ear through the round window membrane, the annu-
lar ligament, or vascular channels.146 The mechanism of
injury is through damage to the dark cells of the crista
ampullaris of the semicircular canals, the posterior wall
of the utricle, the lateral wall of the crus communes, and
the stria vascularis, resulting in a reduced production of
endolymph.146,147 Cochlear and vestibular hair cell death
has been consistently documented.148
Generally, patients report dizziness and dysequilibrium
as vestibular injury takes place. This may persist for a few
weeks and can be improved with vestibular rehabilitation
exercises. The elderly seem to have greater difficulty with
compensation.146 Although titration of dose to effect may
reduce the incidence of hearing loss, sudden and profound
hearing loss can occur. The cause of this unexpected event
is unclear and unpredictable.146
Minor has described a protocol with low risk of hearing
loss.145 Gentamicin (40 mg/mL) is buffered with sodium
bicarbonate to a pH of 6.4 and a final concentration
of 26.7 mg/mL. Phenol is used to anesthetize a small area
of the tympanic membrane. The solution is injection using
a 27-gauge needle to fill the middle ear (0.3 mL to 0.6
mL). The patient (in a supine position) is instructed to
maintain the head turned away from the affected ear and
remain in that position for 30 minutes. (Generally, the
patient is instructed to avoid swallowing during that time,
to reduce loss of medication through the eustachian tube).
The patient returns weekly for audiogram and vestibular
testing. Treatment is stopped if pure tone thresholds
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
termination of therapy. If these criteria are absent, the
patient is treated with a second dose of intratympanic gen-
tamicin and reevaluated weekly for further doses until the
end point criteria are identified. Using this protocol,
Minor reported 91% complete or substantial vertigo con-
trol in 34 patients; 21% developed recurrent vertigo 10 to
24 months later, but all responded to additional doses of

gentamicin. Only one patient (3%) developed profound
hearing loss. Long-term hearing outcome based on
AAOHNS criteria was better in 36%, unchanged in 32%,
and worse in 32%.145 Other authors have found similar
results with this protocol.143
Nedzelski and colleagues149 proposed a protocol using
the same buffered solution of 26.7 mg/mL gentamicin
(0.7 to 0.8 mL) administered through a ventilation tube
and attached catheter three times daily for 4 consecutive
days. The patient was evaluated for spontaneous and gaze-
evoked nystagmus, abnormal tandem gait, and hearing
loss prior to doses 4, 7, and 10. Treatment was discon-
tinued for abnormal findings. Of 114 patients treated
with this protocol and followed at least 24 months, 93.3%
had complete or substantial control of vertigo. Hearing
was worse in 32.5% at 1 month after treatment and at
2 years improved in 25.9%, unchanged in 50.6%, and
worsened in 25.8%; 16.4% of patients suffered profound
hearing loss.150
Other authors report good results with a single planned
injection followed by repeated injections for recurrent
symptoms.142,151
There is no consistent relation between the total dose or
the number of injections and the likelihood of profound
hearing loss. In animal studies, a wide variation in peri-
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
loss after intratympanic gentamicin therapy.152 In an
attempt to standardize dosage and better define and
manipulate the pharmacokinetics of transtympanic
gentamicin, microwicks and microcatheters have been
studied and may hold promise.153,154 Controlled clinical
trials are needed.
Cochleosacculotomy
Cochleosacculotomy is a reasonable option for relief of
vertigo when general anesthesia is contraindicated. The
operation creates an internal shunt by fracturing the
osseous spiral lamina and disrupting the cochlear duct.
The theoretic permanent fistula between the perilym-
phatic and endolymphatic spaces may end episodic vertigo
by disallowing periodic hydropic episodes. The procedure
was developed by Schuknecht based on histologic observa-
tions that the membranous labyrinth of patients with MD
can spontaneously fistulize, possibly accounting for remis-
sions and arrest of symptoms. In animal studies, fracture-
disruption of the osseous spiral lamina and cochlear duct
can result in a permanent fistula with minimal impairment
of hearing.155 Although some patients may have mild dyse-
quilibrium, cochleosacculotomy does not appear to require
prolonged vestibular compensation. Hearing loss is
common and may be profound.
Cochleosacculotomy Technique
The patient is prepared for a transcanal procedure includ-
ing anesthesia of the external auditory canal. A tympa-
nomeatal flap is elevated. The round window is exposed. A
3-mm right-angle hook is inserted through the round win-
dow membrane and guided in the direction of the oval
Ménière’s Disease 631
window while the pick is held against the lateral wall of the
inner ear. Slight resistance will be felt as the pick violates the
osseous lamina. The point of the pick will reach the saccule
and the footplate of the stapes. Occasionally, a bony over-
hang at the round window niche interferes with introduction
of the pick and can be reduced with a 2-mm diamond burr.
Momentary vertigo may result, but usually not, presumably
because the vestibular sense organs are not mechanically dis-
turbed, and the endolymph from the fistula drains into the
scala tympani rather than into the perilymphatic space of the
vestibule. The perforation in the round window is sealed
with muscle or perichondrium. The tympanomeatal flap is
replaced and secured with Gelfoam, antibiotic ointment, or
a small strip of silk cloth. Complications include hearing loss,
perforation of the tympanic membrane, facial nerve injury,
and perilymphatic fistula.
Transcanal Labyrinthectomy
Transcanal labyrinthectomy offers a few advantages over
transmastoid labyrinthectomy including shorter operating
time and perhaps less risk of CSF leak and facial nerve
injury. However, identification and removal of all vestibu-
lar end organs may be more difficult and the incidence of
incomplete labyrinthectomy may be greater.
Transcanal Labyrinthectomy Technique
A transcanal approach is performed through a tympa-
nomeatal flap after routine preparation including canal
anesthesia. After raising the flap, a curette is used to
remove the bony tympanic annulus. The horizontal seg-
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
incus are removed. The vestibular end organs are
approached by exposing the entire vestibule, either by
extending the oval window anteriorly and inferiorly or by
removing bone between the oval and round windows.
Before aspiration of the vestibule, the utricle should be
removed with a 4-mm hook. The utricle may be displaced
superiorly if the vestibule is inadvertently aspirated too
early. The saccule is destroyed by aspiration of the anterior
aspect of the vestibule. The ampulla of the lateral and
superior semicircular canals may be approached with blunt
dissection with a 4-mm hook that will drop into the
ampullary ends of the canals. The posterior canal can be
denervated by exposing the posterior ampullary nerve near
the posterior aspect of the round window niche. After
destruction of the end organs, the vestibule is packed with
Gelfoam or a small fat or muscle plug. Some surgeons use
gentamicin or streptomycin as irrigation or to soak the
Gelfoam in order to ensure complete destruction of the
neuroepithelium. The tympanomeatal flap is returned and
secured with packing. Postoperatively, patients have acute
vestibular dysfunction comparable to the level of preoper-
ative function. Hospitalization for treatment with vestibu-
lar suppressants and rehabilitation is necessary. Profound
hearing loss results. Complications include CSF leak,
incomplete labyrinthectomy (usually because of failure to
remove the utricle), and facial nerve injury.
632 PERIPHERAL AUDIOVESTIBULAR DISORDERS
Transmastoid Labyrinthectomy
Transmastoid labyrinthectomy allows a standard access to all
neuroepithelium. Generally, it is 95% to 99% successful in
obliterating vestibular function.
Transmastoid Labyrinthectomy Technique
The procedure is performed under general anesthesia with
facial nerve monitoring. Perioperative antibiotics are not
routinely required. A routine mastoidectomy is performed
with identification of the mastoid antrum, lateral semicircu-
lar canal, and incus. The descending segment of the facial
nerve is identified using the short process of the incus and
the lateral semicircular canal as landmarks. The facial recess
indicates the lateral position of the facial nerve and the hor-
izontal canal indicates its posterior extent. There is no need
to remove bone from the facial nerve. The bony labyrinth is
skeletonized by removal of perilabyrinthine air cells and
retrofacial air cells. It is helpful to clearly visualize each semi-
circular canal and the course of the facial nerve before
proceeding. A systematic approach to this dissection aids in
ensuring all the neuroepithelium is removed while protect-
ing the facial nerve. It is perhaps best to “blue-line” all the
canals before entering in order to preserve all the landmarks
until the vestibule is entered. Using a medium cutting burr
(4 mm or 5 mm), the superior-posterior surface of the lateral
canal is blue-lined, then opened. Following the horizontal
semicircular canal posteriorly, the posterior canal will be
identified. It is best at this point not to open that canal com-
pletely, but again skeletonize it so that the common crus and
superior semicircular canal are identified first. The superior
canal is followed using a circular motion and the ampullated
ends of the superior and lateral canal are then opened.
Next, the posterior canal is followed inferiorly, medial to the
facial nerve, and finally opened along the posterior aspect of
the ampullated end. All three canals are carefully dissected
with preservation of the medial walls of the superior and lat-
eral semicircular canal ampulla and the inferior wall of the
posterior canal ampulla. Just deep to the medial walls of the
superior and lateral canal ampulla lies the labyrinthine seg-
ment of the facial nerve. Just inferior to the inferior wall of
the posterior canal ampulla lies the region of the jugular
bulb. The common crus is finally followed medially into the
vestibule. The labyrinthine bone (Trautmann’s triangle) is be
saucerized, permitting complete opening of the vestibule
with a view of the utricle in the elliptical recess and the sac-
cule in the spherical recess. The medial wall of the vestibule
is the landmark for the fundus of the internal auditory canal
(IAC). At this point all five portions of the neuroepithelium
are clearly visualized (the ampulla of three canals, the utricle,
and the saccule). Each is removed under high-power
microscopy with a fine round knife and suction. The area is
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.
Translabyrinthine Vestibular
Nerve Section
Translabyrinthine VNS is a helpful adjunct when
labyrinthectomy or VNS fail to relieve vertigo and residual
nerve activity is suspected. This additional step results in
preganglionic denervation.
Translabyrinthine Vestibular Nerve
Section Technique
The procedure is performed under general anesthesia with
perioperative antibiotics. The labyrinthectomy is com-
pleted as described. Further bone removal over the
sigmoid sinus and decompression of the sinus may be
required for adequate access to the medial aspect of the
dissection. Compression of the sigmoid sinus is necessary
to obtain the angulated view of the contents of the lateral
internal auditory canal. It is helpful to leave an island
of bone (Bill’s island) over the sigmoid sinus during this
dissection to protect it from injury by the rotating burr and
retraction of the suction-irrigator. The bone overlying the
posterior cranial fossa dura is progressively removed ante-
rior to the sigmoid sinus. This bone removal extends from
the jugular bulb inferiorly to the superior petrosal sinus
superiorly. The natural starting point for this dissection
is at the vestibule, where the thin bone that separates the
fundus of the IAC from the vestibule creates a natural
blue-line. It may be sufficient to skeletonize only the lat-
eral half of the IAC, but complete dissection to the porus
may be performed. Useful landmarks include a line drawn
between the superior semicircular canal ampulla and the
sinodural angle and a line drawn posteriorly parallel to the
superior line starting at the level of the posterior canal
ampulla. Once the IAC is skeletonized, thin bone can
be lifted with a right-angle pick. The transverse crest
is exposed in the fundus using small diamond burrs.
Bill’s bar serves as a bony landmark for the facial nerve,
which lies anterior to it. A diamond burr and copious
irrigation allow identification of Bill’s bar and the fallopian
canal. The dura is opened with a sharp right-angled hook
or sickle knife. A 1-mm hook is inserted and Bill’s bar
is palpated. Then after sliding posterior to Bill’s bar, the
hook is used to avulse the superior vestibular nerve inferi-
orly. After identification of the plane between the superior
vestibular nerve and the facial nerve, small fibers are lysed
with sharp or blunt dissection. The inferior vestibular
nerve is also avulsed with specific attention to identifica-
tion and division of the singular nerve (posterior ampullary
nerve). Scarpa’s ganglion lies centrally within the IAC.
Resection of a 5-mm length of vestibular nerve, medial
to the fused portion will include Scarpa’s ganglion and
complete the denervation. The surgical site is closed
by reapproximating the dura, sealing defects with fat
strips, and packing the mastoid with fat. The incision
is closed in two layers and a bulky pressure dressing
is applied. Complications include CSF leak, facial
paralysis, and meningitis.
SURGERY AND HEARING OUTCOMES
The current literature on the ESS procedure and other
surgical procedures for MD provides conflicting evidence
as to the benefits of surgery on attenuating progressive
hearing loss. The variability in results is, in no small mea-
sure, due to the lack of randomized controlled studies with

Figure 39-5. Management protocol for suspected Ménière’s disease.
objective outcome data comparing the hearing outcome of
surgical procedures to that of MD natural history.
The VNS procedure, although highly successful in
eliminating vertigo in MD patients, does not appear to
have an effect on hearing or other MD symptoms. Hearing
loss after VNS follows the expected course of progressive
loss associated with MD: About 50% of patients have sta-
bilized or improved hearing and about 50% have worse
hearing.156–159
Hearing improvement or stabilization after ESS is sup-
ported by several published studies but disputed by others.
A frequently quoted paper by Thomsen and colleagues
Ménière’s Disease 633
compared ESS to an active placebo group (simple
mastoidectomy).122 The authors reported subjective hear-
ing loss to be “slightly” significantly better in the ESS
group than in the placebo group. Objective testing showed
no significant difference between the two groups but sup-
ported a “tendency” toward better hearing postopera-
tively in the ESS group, mainly manifested at 250 Hz.
When the data were reexamined by Welling and Nagaraja,
no significant difference in hearing outcome was found,
but the authors suggest “the data seem to favor the active
treatment even though statistical significance was not
attained.”160 Quaranta compared a control group (patients
634 PERIPHERAL AUDIOVESTIBULAR DISORDERS
who were offered but declined surgery) to patients after
ESS. At 7 to 19 years of follow-up, 65% of patients who
declined surgery and 45% of patients who had ESS had
stable or improved hearing.124 Goin and colleagues also
found no difference in hearing after ESS compared to
patients who were offered but declined surgery.161 In vari-
ous uncontrolled series, objective hearing outcome has
been reported to be better or unchanged in 43% to 78%
after undergoing ESS.124,125,127,132,161–163
SURGERY AND QUALITY OF LIFE
A review of studies using direct subjective evaluation of
tinnitus and aural fullness suggests ESS may ameliorate
these symptoms. Improvement in tinnitus has been
reported in up to 75% of patients after ESS.127,134
However, the range of improvement has been broad (21%
to 75%).123,125,127,133,134,136,162 Quaranta and colleagues
reported substantial improvement in tinnitus and aural
fullness after ESS compared to patients who declined
surgery.124 In studies of tinnitus outcome, between ESS
and VNS125,162 and ESS and placebo,123 results were not
significantly different. After VNS, tinnitis was improved
in 9% to 40%.20,156,159,164–166 Aural fullness is improved
in 28% to 79% after ESS and 43% to 64% after
VNS.20,125,126,135,136,165,166
Evaluation of self-perceived tinnitus, dizziness, hearing
handicap, and quality of life with validated questionnaires
provides an additional, possibly quantifiable mechanism
to evaluate outcomes. Kinney and colleagues used the
DHI, THI, HHI, and the SF-36 to compare treatment
outcomes for medically and surgically (20 ESS and 1 VNS)
treated patients.26 No significant difference in hearing out-
come or disease-specific measures were found among the
surgical group compared to the medical treatment groups,
but the standard deviations were high, suggesting signifi-
cant variability within the groups. Smith and Pyle reported
pre- and postoperative SF-36 scores for patients who
underwent ESS and found that although patients preoper-
atively scored significantly lower than norms, postopera-
tively the scores improved to the level of the standardized
normative scores.167 Eisenman and colleagues reviewed
HHI scores for patients after VNS and labyrinthectomy
and reported that both groups had scores suggesting mod-
erate disability with no significant difference between the
treatment groups.168
OTHER APPROACHES
Low-pulse pressure,169–171 ultrasound,172 cryosurgery173,174
and alternobaric and hyperbaric oxygen therapy175 have
been introduced, but evidence to support their use is
insufficient. Figure 39-5 shows a management algorithm.
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638 PERIPHERAL AUDIOVESTIBULAR DISORDERS
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Autoimmune Inner Ear Disease
Outline
Introduction
Autoimmune Inner Ear
Disease
Clinical Presentation
INTRODUCTION
There has long been a notion that the immune system
might be capable of damaging the inner ear or eighth
cranial nerve, leading to symptoms of hearing loss or dizzi-
ness (or both). Some well-documented examples in which
systemic autoimmune disease does this include lupus
erythematosus, ulcerative colitis, Cogan’s syndrome, and
multiple sclerosis. In some inner ear diseases, for example,
Ménière’s syndrome and idiopathic sudden sensorineural
hearing loss (SNHL), an immune-mediated mechanism
has been hypothesized but not demonstrated. One
condition, characterized by the clinical presentation of
idiopathic, rapidly progressive, bilateral SNHL, has come
to be known as autoimmune inner ear disease (AIED).
Whether all patients with this presentation have the same
underlying pathophysiology and whether that pathophysi-
ology is autoimmune are unknown. However, the disorder
is extremely important because it represents one of the
medically reversible causes of SNHL.
AUTOIMMUNE INNER EAR DISEASE
In 1979, McCabe described 18 patients with idiopathic,
rapidly progressive, bilateral SNHL who regained hearing
after administration of corticosteroids.1 He theorized an
autoimmune cause based on the response to immunosup-
pressive drugs. The next decade saw proliferation of a host
of clinical reports, diagnostic tests, and treatment proto-
cols for this entity, few of which have subsequently been
validated. The next significant step toward understanding
this disorder came in 1990 when Harris and Sharp
reported circulating antibodies against inner ear antigens
detected by use of a Western blot technique.2 Four years
later Moscicki and coworkers presented the clinical corre-
lation of idiopathic, progressive, bilateral sensorineural
Chapter
40
Diagnosis Steven D. Rauch, MD
Immunosuppressive Therapy
Conclusions and Future
Directions
hearing loss (IPBSNHL) with circulating antibodies
against a 68-kD protein antigen present in bovine inner
ear and renal extracts.3 They demonstrated that the
presence of these antibodies correlated both with activity
of disease and steroid responsiveness. Using different
experimental approaches, Billings and colleagues and
Bloch and coworkers both identified the 68-kD protein
antigen as heat shock protein 70 (Hsp70) in 1995.4,5 Hsp70
is a ubiquitous protein found in all living cells. It primarily
functions as a molecular chaperone, binding to nascent
peptide chains during protein synthesis and aiding in
intracellular and transmembrane transport of proteins. It
has a peptide binding site that makes it very “sticky”; that
is, it tends to bind to other proteins or protein fragments.
Since it is unclear why anti-Hsp70 antibodies would
specifically damage the ear and since the propensity for
Hsp70 to bind other peptides is well documented, it may
be that it colocalizes with some other inner ear antigen
that is the actual target in IPBSNHL.
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
created monoclonal antibodies against inner ear cells. One
particular antibody, dubbed “KHRI-3,” binds to support-
ing cells of the organ of Corti, creating a characteristic
“wine glass” staining pattern using immunofluorescence.6–12
Infusion of KHRI-3 into live guinea pigs produces hearing
loss.7–9 The KHRI-3 antibody also binds to a 68- to 72-kD
antigen on Western blot of inner ear extract.6 Sera from
some humans with IPBSNHL strongly stained a 68- to
72-kD inner ear antigen immunopreciptated from guinea
pig inner ear extract with KHRI-3, and these same patient
sera stained organ of Corti supporting cells in a wine glass
pattern.13 This is strong evidence that KHRI-3 and human
antibodies recognize the same inner ear supporting cell
antigen. The target antigen of KHRI-3 has not yet been
identified, but it is not Hsp70.
639
640 PERIPHERAL AUDIOVESTIBULAR DISORDERS
The Western blot assay for circulating antibodies reac-
tive with 68- to 72-kD antigen, whether it is Hsp70 or
the inner ear supporting cell antigen target of KHRI-3, is
of unproven clinical value. The assay is not standardized,
and it has not been widely applied to other inner ear
disorders nor to other autoimmune disorders in order
to characterize its sensitivity and specificity. Therefore,
IPBSNHL remains a clinical diagnosis based on historic
and audiometric criteria. Likewise, IPBSNHL is not
actually confirmed as an autoimmune disorder. Such con-
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
“lesion,” and (3) reproduction of this lesion by introduc-
tion of the specific antibodies or activated T cells into
a naive host. Until these criteria are met, it is more accu-
rate to refer to this entity by its clinical description (i.e.,
IPBSNHL) or acknowledge the undefined role of the
immune system and call it immune-mediated inner ear dis-
ease. However, the popular notion that this is an autoim-
mune disorder has taken hold, and the condition is now
widely referred to as AIED.
CLINICAL PRESENTATION
The hallmark of the condition originally described by
McCabe was the presence of rapidly progressive SNHL;
too fast to be age-related degeneration and too slow to be
sudden SNHL. This remains the most salient distinguish-
ing feature of the disorder. Moscicki and colleagues artic-
ulated a precise clinical description of AIED (which they
called IPBSNHL), which enabled them to minimize
heterogeneity in their study population and, ultimately, to
correlate this clinical presentation with results of Western
blot assays.3 Specifically, they defined the condition as a
bilateral SNHL of ≥30 dB at any frequency and evidence
of progression in at least one ear on two serial audiograms
performed ≤3 months apart; progression being defined as
a threshold shift of ≥15 dB at one frequency, 10 dB at two
or more consecutive frequencies, or a significant change in
discrimination score. A single episode of threshold shift
occurring in less than 72 hours and then stabilizing was
classified as sudden SNHL and was excluded. Fluctuating
hearing loss, however, qualified if progression also
occurred according to the previous criteria. This is still
the most explicit description of AIED in the literature.
Analogous to Ménière’s disease, in the absence of a “gold
standard” diagnostic test, adherence to these diagnostic
criteria permits comparison of observations and results
between different studies.
In the paper by Moscicki and colleagues, demographic
features, test results, and treatment outcome were
reported for 72 patients with IPBSNHL.3 Subsequently,
66 additional cases of possible immune-mediated inner ear
disease were studied using Moscicki’s same diagnostic
criteria. Five patients were excluded from analysis because
they had Cogan’s syndrome, an autoimmune vasculitis
characterized by SNHL, vertigo, and interstitial keratitis
of the eyes, leaving 61 cases. Results are tabulated in
Tables 40-1 and 40-2. Demographic features and trends in
the correlation of Western blot assay with steroid response
TABLE 40-1. Clinical Features of 61 Consecutive Patients
Evaluated for Possible Autoimmune Inner Ear Disease
Clinical Features n
Male-to-Female 32:29
Vestibular Symptoms 30 (49.2%)
Ménière’s disease 13 (21.3%)
Unilateral:Bilateral 5:8
Other Autoimmune Diagnosis 9 (14.8%)
Mean age was 47 years (range: 4–72).
in this group of patients are essentially the same as
Moscicki’s original cohort. However, the proportion of
patients with positive Western blot assay and the proportion
of Western blot-positive patients who responded to steroids
are both lower than in Moscicki’s retrospective study.
AIED and idiopathic sudden SNHL are two distinct
disorders. AIED is far rarer than sudden loss. AIED is by
definition bilateral, and sudden hearing loss is virtually
always unilateral. Sudden hearing loss develops in ≤72 hours.
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
a treatment of “window” of perhaps 2 to 4 weeks during
which a short “burst and taper” of corticosteroids must be
administered in order to achieve optimum recovery. AIED
is not urgent. Patients with progression over 6 to 12 months
can still achieve significant recovery with administration
of a long course of high-dose corticosteroids or other
immunosuppressive drugs. Throughout the otolaryngol-
ogy community some cases of SNHL are widely accepted
as potentially reversible with corticosteroids. Unfortu-
nately, however, few are aware that these two entities are
quite different in cause, presentation, work-up, and man-
agement. Hasty administration of a short tapering course
of steroids can delay diagnosis of AIED and can confuse
interpretation of serologic testing.
Approximately half of AIED patients also experience
vestibular symptoms (see Table 40-1), including dysequi-
librium, motion intolerance, positional vertigo, and
episodic whirling vertigo of the Ménière’s type. Approxi-
mately 20% of AIED patients have a combination of
fluctuating and progressing SNHL and episodic vertigo that
meets strict American Academy of Otolaryngology—Head
and Neck Surgery diagnostic criteria for Ménière’s disease.
Rauch and coworkers14 and Gottschlich and colleagues15
have reported that approximately one-third of classic
Ménière’s disease patients have a positive Western blot
assay for anti-Hsp70 antibodies. This overlap between
TABLE 40-2. Relationship of Western Blot Assay for
Anti-Hsp70 Antibodies and Response to Corticosteroid
Therapy in 61 Patients with Autoimmune Inner Ear Disease
Steroid Response
Western Blot + − No Rx
+ 14 11 7
− 5 12 8
? 2 2 −

AIED and Ménière’s disease suggests that a subset of
patients falling into both diagnostic categories may share a
common pathophysiologic mechanism.
AIED can occur in combination with other systemic
autoimmune diseases. Nearly 15% of AIED cases have
another autoimmune diagnosis (see Table 40-1), such as
multiple sclerosis, inflammatory bowel disease (ulcerative
colitis and Crohn’s disease), systemic lupus erythematosus,
rheumatoid arthritis, and ankylosing spondylitis. Though
not definitely autoimmune, several other AIED patients
listed in Table 40-1 had diabetes or thyroid dysfunction.
Some reports of certain human leukocyte antigen (HLA)
subtypes showed a correlation with immune-mediated
inner ear disease.16 This suggests the possibility of a
genetic predisposition to autoimmune disease that may
include AIED as well as other systemic disorders.
DIAGNOSIS
As noted earlier, the salient feature of AIED is audiomet-
ric evidence of progression over days to months. Serial
audiometry performed at an interval of ≤3 months is
necessary to confirm the diagnosis. When in doubt, monthly
audiograms for several months can be helpful. The pattern
of hearing loss is highly variable. As yet, no one has
described a characteristic pattern of hearing loss. The loss
may be high tone, low tone, up- or downsloping, or
predominantly affecting discrimination rather than
threshold. Exclusion of retrocochlear disease such as mul-
tiple sclerosis or acoustic neuroma is mandatory and can
be accomplished by evoked response audiometry or
gadolinium-enhanced magnetic resonance imaging (MRI).
Routine serologic tests in possible AIED patients
include complete blood count with differential white
count, erythrocyte sedimentation rate (ESR), rheumatoid
factor, antinuclear antibody (ANA), C3 and C4 complement
levels, and Raji cell assay for circulating immune complexes.
Serologic work-up is aimed at detecting evidence of
systemic immunologic dysfunction; none of these tests has
been shown to correlate with the diagnosis of AIED.
IMMUNOSUPPRESSIVE THERAPY
Corticosteroid therapy for AIED has evolved over the last
15 years based on clinical experience. No prospective, ran-
domized clinical trials have yet been conducted to validate
this empirical approach. Initial therapy for adults consists
of a therapeutic trial of prednisone 60 mg daily for
4 weeks. Pediatric patients receive prednisone 1
mg/kg/day for 4 weeks. Although occasional patients may
show a response early in the 4-week period, many do not
begin to improve until late in the month, and shorter
courses of treatment usually result in relapse. The patient’s
hearing is tested at the initiation of therapy and again at 4
weeks. If the threshold has improved by ≥15 dB at one fre-
quency or 10 dB at two or more consecutive frequencies,
or if the discrimination is significantly improved, patients
are considered steroid responders. The medication is
tapered off in 12 days for nonresponders. Responders con-
tinue full-dose therapy until monthly audiograms confirm
Autoimmune Inner Ear Disease 641
that they have reached a plateau of recovery. The medica-
tion is then slowly tapered over 8 weeks to a maintenance
dose of 10 to 20 mg every other day. This maintenance
dose is continued for a variable length of time. Clinical
observation suggests that patients with a total treatment
duration of less than 6 months are at increased risk of
relapse compared with those treated for 6 months or
longer.
Patterns of response to corticosteroid therapy vary.
Some patients have improvement in threshold, some in
discrimination only, and some show benefit to both. Some
patients with fluctuation and progression before therapy
show stabilization of their hearing without actual improve-
ment. Historically, these cases have been considered non-
responders, but this issue is currently under reassessment.
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
medication. In some instances retreatment is effective.
However, occasionally the hearing loss becomes refractory
to corticosteroids. In such cases alternative immunosup-
pressive drugs are considered. An occasional patient,
especially in the pediatric age group, may show steroid-
dependent hearing loss. In other words, they cannot be
weaned below a certain level of steroid dosage without
decline in hearing. Such patients often develop unaccept-
able side effects of chronic steroid administration.
Recently, benefit has been observed from combining
prednisone with low-dose (15-20 mg/week) methotrexate
in these steroid-dependent cases. After several weeks of
combined therapy, the prednisone can be tapered and
discontinued and the patient maintained on methotrexate
alone for an additional 2 to 3 months, at which time the
last drug is also successfully discontinued.
Corticosteroid therapy has obvious limitations. Long-
term administration has risks, including gastritis and ulcers,
fluid retention and weight gain, blood pressure lability,
altered blood sugar metabolism and diabetes, mood changes
or psychiatric problems, sleep disturbance, accelerated
cataract formation, and cushingoid habitus. Ischemic necro-
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
AIED patients. Some initial responders become refractory
at the time of subsequent relapse. Despite these limita-
tions, corticosteroid therapy remains the mainstay of
AIED treatment based on the extensive clinical experience
with its use.
Alternatives to systemic corticosteroids include
methotrexate, etanercept, and cyclophosphamide. Low-dose
methotrexate appears to be especially useful as an adjunct
in management of steroid-dependent hearing loss. It is
the first-line drug of choice for patients unable to take
corticosteroids. A low-dose protocol as for rheumatoid
arthritis or psoriasis is used. Methotrexate is administered
by mouth in three doses given at 12-hour intervals once
weekly. The initial dose is 7.5 mg/week (three doses of
2.5 mg). If this is tolerated without toxicity for 2 weeks, the
dose is doubled to 15 mg/week. This dose is continued for
6 to 8 weeks as a therapeutic trial. Medication is discon-
tinued in nonresponders; responders are carried on the
15 mg/week dose for 6 months. Potential toxicity includes
642 PERIPHERAL AUDIOVESTIBULAR DISORDERS
myelosuppression, gastrointestinal upset, oral ulceration,
acute pneumonitis, and hepatic fibrosis. This last compli-
cation is insidious and generally seen only when metho-
trexate is given for more than a year. It may be associated
with normal liver function tests, and early diagnosis is
achieved by liver biopsy. Weekly testing including a com-
plete blood count with differential white count, liver func-
tion tests, blood urea nitrogen, creatinine, and urinalysis is
recommended to monitor for signs of toxicity.
Etanercept, an inhibitor of tumor necrosis factor alpha,
has recently been used to treat AIED. Anecdotally, it
appears to work well in combination with methotrexate
because of its steroid-sparing effect. As seen in rheumatoid
arthritis, etanercept alone does not appear nearly as
effective. However, neither treatment protocol has been
studied systematically.
Cyclophosphamide is a potent cytotoxic agent generally
used for cancer chemotherapy. It is somewhat selective
for B-cell and monocyte-macrophage function.18 Although
some advocate its use as a first-line drug,19 the high risk of
toxicity makes it a better choice as a salvage drug or treat-
ment of last resort. We have used it in a small number of
patients at an initial dose of 1 mg/kg/day orally for 4 to 6
weeks. When no response is apparent, the dose is doubled to
2 mg/kg/day. Responders are treated for 6 to 12 months.
Toxicity includes severe myelosuppression, opportunistic
infection, hair loss, cystitis, infertility, and increased risk
of malignancies. Weekly monitoring of hematologic status
is mandatory. Many patients when confronted with the
risk of this medication would rather consider cochlear
implantation.
Intratympanic steroid therapy, systemic IgG injections,
and plasmapheresis are possible treatments with sound
theoretical justification. Intratympanic steroid therapy is
particularly appealing because it is minimally invasive and
enables direct application of drug to the affected site with
low risk of systemic effects; however, these treatments have
not yet been systematically applied in any published series.
Determination of the best role for any of these treatment
modalities remains to be determined.
CONCLUSIONS AND FUTURE DIRECTIONS
The story of AIED from initial description by McCabe to
present therapy routines has been presented here as a
simple and direct path. That has not been the actual case.
It has been a broad and meandering path with significant
contributions by many investigators and numerous inter-
esting and important digressions. It is a story that still
has far to go. The clinical description of this disorder is
confined to its auditory manifestations. However, as noted
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
auditory symptoms, an equal number may well have with
exclusively vestibular symptoms. Such a presentation has
not yet been reported.
Little is understood about the underlying pathophysiol-
ogy of AIED. The very fact of reversible SNHL flies in the
face of accepted dogma that SNHL is not medically recov-
erable. It is interesting to consider what pathophysiologic
mechanism could disable neural signal transduction or
transmission in the auditory system yet be reversed
months later by anti-inflammatory or immunosuppressive
drugs. Solution to this puzzle will come from systematic
research into the nature of the humoral and cell-mediated
immune response of affected patients. Though the Carey
model using KHRI-3 is promising, as yet there is no
widely accepted animal model of the AIED phenomenon
in which to carry out such research, and human studies
progress slowly due to the rarity of the clinical material.
This rarity does not diminish the significance of the topic,
however. Understanding the mechanism of AIED will
provide a new level of insight into the role of systemic and
organ-specific immune reactions in disease of the inner
ear. The fact that 20% of AIED patients have a clinical
presentation overlapping with Ménière’s disease and 33%
of Ménière’s disease patients have evidence of antibodies
to the 68- to 72-kD antigen by Western blot assay is strong
evidence of a shared pathophysiologic mechanism. Though
AIED is rare, Ménière’s disease is not. In the United States
alone an estimated 125,000 cases are reported yearly. New
ways of understanding Ménière’s disease could have great
public health benefit.
Diagnosis of AIED currently relies on clinical factors
alone. As stated earlier, the observation that many AIED
patients carry serum antibodies reactive with Hsp70 does
not prove that Hsp70 is the actual inner ear target antigen.
Hsp70 may carry an epitope shared with the true target
antigen or may otherwise colocalize with it biochemically.
Despite our poor understanding of AIED pathophysiol-
ogy, detection of this or other marker antibodies may
become clinically useful. The utility of an assay will be
greatly enhanced by development of a quantitative measure
enabling clinicians to follow antibody titers by serial test-
ing. In addition, estimation of sensitivity and specificity of
the assay must be made by its broad application to a wide
variety of ear diseases and immunologic disorders.
Current therapy of AIED is based on empirical experi-
ence over the last 15 years rather than on a clear under-
standing of the underlying pathophysiology. In the future,
therapeutic protocols must be informed by expanding
knowledge of the pathophysiology of the disorder. Large
multicenter studies are necessary to carefully evaluate the
best use of corticosteroids and other immunosuppressive
drugs. Consensus must be achieved on the clinical diag-
nostic criteria and treatment regimens to enable compari-
son between studies. Even with strict adherence to
rigorous methodology, it may take many years to address
these questions. For the foreseeable future, AIED will
remain one of the most interesting, important, and chal-
lenging problems confronting otologists and otologic
researchers.
REFERENCES
1. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol
Rhinol Laryngol 88:585, 1979.
2. Harris JP, Sharp PA: Inner ear autoantibodies in patients with rapidly
progressive sensorineural hearing loss. Laryngoscope 100:516, 1990.
3. Moscicki RA, San Martin JE, Quintero CH, et al: Specificity of
serum antibodies to a 68 kD inner ear antigen in disease associated

with hearing loss and responsivity to corticosteroid therapy. JAMA
272:611, 1994.
4. Billings PB, Keithley EM, Harris JP: Evidence linking the 68 kilo-
dalton antigen identified in progressive sensorineural hearing loss
patient sera with heat shock protein 70. Ann Otol Rhinol Laryngol
104:181, 1995.
5. Bloch DB, San Martin JE, Rauch SD, et al: Serum antibodies to heat
shock protein 70 in sensorineural hearing loss. Arch Otolaryngol
121:1167, 1995.
6. Zajic G, Nair TS, Ptok M, et al: Monoclonal antibodies to inner ear
antigens: I. Antigens expressed by supporting cells of the guinea pig
cochlea. Hear Res 52:59, 1991.
7. Nair TS, Raphael Y, Dolan DF, et al: Monoclonal antibody induced
hearing loss. Hear Res 83:101, 1995.
8. Nair TS, Prieskorn DM, Miller JM, et al: In vivo binding and hear-
ing loss after intracochlear infusion of KHRI-3 antibody. Hear Res
107:93, 1997.
9. Nair TS, Prieskorn DM, Miller JM, et al: KHRI-3 monoclonal
antibody-induced damage to the inner ear: Antibody staining of
nascent scars. Hear Res 129:50, 1999.
10. Ptok M, Nair TS, Altschuler RA, et al: Monoclonal antibodies to
inner ear antigens: II. Antigens expressed in sensory cell stereocilia.
Hear Res 57:79, 1991.
Autoimmune Inner Ear Disease 643
11. Ptok M, Carey TE, Altschuler RA: Relationship of monoclonal
antibody (KHRI 3 epitope) to cochlear supporting cell microvilli in
the guinea pig. Eur Arch Otorhinolaryngol 250:345, 1993.
12. Ptok M, Klein R, Ptok A, et al: Drug therapy of acute inner ear
hearing loss in childhood and adolescence. HNO 42:636, 1994.
13. Disher MJ, Ramakrishnan A, Nair TS et al: Human autoantibodies and
monoclonal antibody KHRI-3 bind to a phylogenetically conserved
inner-ear-supporting cell antigen. Ann N Y Acad Sci 830:253, 1997.
14. Rauch SD, Zurakowski D, Bloch DB, et al: Anti-Hsp70 antibodies
in Ménière’s disease. Laryngoscope 110:1516, 2000.
15. Gottschlich S, Billings PB, Keithley EM, et al: Assessment of serum
antibodies in patients with rapidly progressive sensorineural hearing
loss and Ménière’s disease. Laryngoscope 105:1347, 1995.
16. Cao M-Y, Thonnard J, Deggouj M, et al: HLA Class II-associated
genetic susceptibility in idiopathic progressive sensorineural hearing
loss. Ann Otol Rhinol Laryngol 105:628, 1996.
17. Zizic TM, Marcoux C, Hungerford DS, et al: Corticosteroid ther-
apy associated with ischemic necrosis of bone in systemic lupus ery-
thematosus. Am J Otol 79:596, 1985.
18. Hadden JW, Smith DL: Immunopharmacology: immunomodula-
tion and immunotherapy. JAMA 268:2964, 1992.
19. McCabe BF: Autoimmune inner ear disease: Therapy. Am J Otol
10:196, 1989.
 Chapter
Benign Paroxysmal Positional Vertigo
41 Outline

Lorne S. Parnes, MD, FRCSC Introduction and Background
Pathophysiology
Sumit K. Agrawal, BSc, MD
Posterior Canal Benign
Paroxysmal Positional
Vertigo
Lateral Canal Benign
Paroxysmal Positional
Vertigo
Epidemiology
Etiology
Diagnosis
History
Diagnostic Maneuvers
Subjective vs. Objective
Benign Paroxysmal
Positional Vertigo
Differential Diagnosis
Management
Nonsurgical Management
Vestibular Habituation
Therapy
Liberatory Maneuver
Particle Repositioning
Maneuver
Lateral Canal Benign
Paroxysmal Positional
Vertigo
Controversy
Factors Affecting
Repositioning Maneuvers
Surgical Treatment
Singular Neurectomy
Posterior Semicircular
Canal Occlusion
Summary

INTRODUCTION AND BACKGROUND
There is nothing more gratifying for a physician than man-
aging a disorder that is for the most part easily diagnosed,
and more important, simply and effectively treated using
noninvasive means. Benign paroxysmal positional vertigo
(BPPV), the most common affliction of the vestibular
labyrinth, is one such disorder.
BPPV was first described by Barany1 in 1921. He describes
several key manifestations in his clinical description:
The attacks only appeared when she lay on her right side. When
she did this, there appeared a strong rotatory nystagmus to the
right. The attack lasted about thirty seconds and was accompanied
by violent vertigo and nausea. If, immediately after the cessation
of these symptoms, the head was again turned to the right, no
attack occurred, and in order to evoke a new attack in this way, the
patient had to lie for some time on her back or on her left side.
Barany mistook the condition as an error in head position
encoding by the otoliths because the symptoms seemed to be
independent of the positioning maneuver. Dix and
Hallpike,2,3 finding histologic evidence of unilateral utricular
macular degeneration in a case of BPPV, also mistakenly con-
cluded that the disorder was caused by a lesion in the otolith
organ. In 1952, they coined the term benign paroxysmal posi-
tional vertigo in their report of 100 patients. The description
of the diagnostic nystagmus included (1) brief latency (1 to
5 seconds), (2) rotational nystagmus with the fast component
of the superior pole beating toward the affected (undermost)
ear, (3) limited duration (5 to 30 seconds), (4) reversal of the
induced nystagmus upon returning to the seated position,
and (5) fatigability of the response with repetition.
In 1969, Schuknecht4 described basophilic cupular
deposits in postmortem temporal bones of two patients
644
who had manifested benign paroxysmal positional nystag-
mus. Interestingly, the deposits were found only on the
posterior canal cupulae of the presumed affected ears while
the cupulae from the other sides were normal. Schuknecht
and Ruby5 reported another case and then studied 391
temporal bones from 245 patients without BPPV. They
discovered cupular deposits in 149 bones (37%), with small
deposits in 125 (32%), medium deposits in 20 (5%), and
large deposits in 4 (1%). However, none of these deposits
was as large as those found in the three patients with BPPV.
Schuknecht4 had initially proposed that loose otoconia
from degenerating utricular macula floated in the region of
the posterior semicircular canal cupula and caused displace-
ment. He then modified his theory and coined the term
cupulolithiasis to represent the findings of attached otoconia
to the posterior semicircular canal cupula. He proposed
that deposits would render the cupula sensitive to gravity.
Ampullifugal deflection of the posterior canal cupula in the
provocative head-hanging position was thought to account
for the nystagmus seen in posterior canal BPPV.
In 1979, Hall and colleagues6 combined these two theo-
ries on the basis of the fatigability of the nystagmus. They
proposed that BPPV could be caused by deflection of the
posterior canal cupula by fixed deposits on the cupula (non-
fatigable nystagmus) or by the motion of free-floating par-
ticles in the posterior semicircular canal (fatigable
nystagmus). Free-floating particles in the semicircular
canal has been coined canalithiasis and represents the most
common form of BPPV that is diagnosed with the Dix-
Hallpike maneuver.
Parnes and McClure7 were the first to demonstrate in vivo
free-floating endolymph particles in the posterior canal.
This intraoperative finding, from two patients with intrac-
table BPPV undergoing posterior semicircular canal

occlusion surgery, further supported the theory of canalithia-
sis. A further study by Welling and colleagues8 examined the
extracted particles from another patient undergoing canal
occlusion surgery under electron microscopy and revealed
that the particles were degenerating otoconia.
PATHOPHYSIOLOGY
Posterior Canal Benign Paroxysmal
Positional Vertigo
The vast majority of BPPV cases are of the posterior canal
variant. The pathophysiology that causes most posterior canal
BPPV cases is thought to be canalithiasis (see Fig. 41-1). This
is probably because most free-floating endolymph debris
tends to gravitate to the posterior canal, being the most
gravity-dependent part of the vestibular labyrinth in both
the upright and supine positions. It is important to note that
the cupula forms an impermeable barrier across the lumen
of the ampulla9 and is located at the shorter, more depend-
ent end of the canal. Therefore, the particles become
“trapped” and can exit the posterior canal only through the
nonampullated end (the common crus). Agrawal and
Parnes10 found obvious free-floating endolymph particles in
30% of ears undergoing surgery for posterior canal BPPV.
The mechanism by which canalithiasis causes nystagmus
in the posterior semicircular canal was described by
Epley.11,12 Particles must accumulate to a “critical mass” in
the dependent portion of the posterior semicircular canal.
The canalith mass moves to a more dependent position
when the orientation of the semicircular canal is modified
in the gravitational plane. The resulting drag must overcome
the resistance of the endolymph in the semicircular canal
and the elasticity of the cupular barrier in order to deflect
the cupula. The time taken for this to occur plus the original
cupula
ampulla
cupulolithiasis
canalithiasis
Figure 41-1. Left inner ear. Depiction of canalithiasis of the posterior
canal and cupulolithiasis of the lateral canal. (Reprinted with permission
from Parnes LS, Agrawal SK, Atlas J: Diagnosis and management of benign
paroxysmal positional vertigo [BPPV]. CMAJ 169:681–693, 2003.).
Benign Paroxysmal Positional Vertigo 645
inertia of the particles explains the latency seen during the
Dix-Hallpike maneuver.
In the head-hanging position, the canalith mass would
move away from the cupula to induce ampullifugal cupular
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
the posterior canal. In the left head-hanging position (left
posterior canal stimulation), the fast component of the
nystagmus beats clockwise as viewed by the examiner.
Conversely, the right head-hanging position (right posterior
canal stimulation) results in a counterclockwise nystagmus.
These nystagmus profiles correlate with the known neuro-
muscular pathways that arise from stimulation of the
posterior canal ampullary nerves in an animal model.13
This nystagmus is of limited duration because the
endolymph drag ceases when the canalith mass reaches the
limit of descent and the cupula returns to its neutral position.
Reversal nystagmus occurs when the patient returns to the
upright position; the mass moves in the opposite direction,
thus creating a nystagmus in the same plane but opposite
direction. The response is fatigable as the particles become
dispersed along the canal and become less effective in
creating endolymph drag and cupular deflection.
Canalithiasis in the posterior canal likely accounts for the
majority of BPPV cases. Based on studies at the Portland
Otologic Clinic, Epley12 has described two additional mech-
anisms for which diagnosis and treatment are not yet well
defined in the literature. Cupulolithiasis, or “heavy cupula,”
refers to particles adherent to or impinging on the cupula.
Unlike in canalithiasis, the observed nystagmus in cupu-
lolithiasis is gradual in onset, seldom severe, and persists
while the head is in the provocative position. A gradual
decline in the nystagmus may occur after 1 to 2 minutes. A
third proposed mechanism, known as canalith jam, is thought
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
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
that lateral canal BPPV resolves much quicker than posterior
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
the canal essentially becomes trapped within it. In contrast,
the lateral canal slopes upward and has its cupular barrier
at the upper end. Therefore, free-floating debris in the
lateral canal tends to float back out into the utricle as a
result of natural head movements.
646 PERIPHERAL AUDIOVESTIBULAR DISORDERS
TABLE 41-1. Lateral Canal BPPV Side of Origin
and Mechanism
Direction of Nystagmus
Intensity of Nystagmus Ageotropic Geotropic
Stronger on left side Right cupulolithiasis Left canalithiasis
Stronger on right side Left cupulolithiasis Right canalithiasis
In lateral canal canalithiasis, particles are most often in
the long arm of the canal relatively far from the ampulla.15
If the patient performs a lateral head turn toward the affected
ear, the particles will create an ampullipetal endolymph
flow, which is stimulatory in the lateral canal. A geotropic
nystagmus (fast phase toward the ground) will be present.
If the patient turns away from the affected side, the parti-
cles will create an inhibitory flow. Although the nystagmus
will be in the opposite direction, it will still be geotropic
since the patient is now facing the opposite direction.
Stimulation of a canal creates a greater response than inhi-
bition of a canal; therefore, the direction of head turn that
creates the strongest geotropic nystagmus (i.e., stimulatory
response) represents the affected side in lateral canal
canalithiasis (Table 41-1).
Cupulolithiasis is thought to play a greater role in lateral
canal BPPV than in the posterior canal variant. Since
particles adhere directly to the cupula, the vertigo is often
intense and persists while the head is in the provocative
position. When the patient’s head is turned toward the
affected ear, the cupula undergoes an (inhibitory) deflection,
which causes an apogeotropic nystagmus (fast phase away
from the ground). A head turn in the opposite direction
creates an ampullipetal (stimulatory) deflection, resulting
in a stronger apogeotropic nystagmus. Therefore, turning
away from the affected side will create the strongest
apogeotropic nystagmus in lateral canal cupulolithiasis
(see Table 41-1). Apogeotropic nystagmus is present in
about 27% of patients who have lateral canal BPPV.14
EPIDEMIOLOGY
BPPV is the most common disorder of the peripheral
vestibular system16 and represented 17% of patients in one
large dizziness clinic.17 The incidence is likely severely
underestimated since most untreated cases of BPPV
resolve spontaneously within a few months. Also, most
studies do not use a population-based model but determine
incidence in patients who either report vertigo as their
chief complaint or undergo vestibular testing. Mizukoshi
and colleagues18 estimated the incidence to be 10.7 to 17.3
per 100,000 in Japan. Several studies have suggested a
higher incidence in women,18–20 but in younger patients
and those with post-traumatic BPPV, the incidence in men
and women may be equal.17 The age of onset is usually
during the fifth through seventh decades of life.18,19,21 The
elderly are at an increased risk, and a study of an elderly
population undergoing geriatric assessment for non-balance-
related complaints found that 9% had unrecognized
BPPV.22 BPPV most often involves a single semicircular
canal, usually posterior, but may involve both posterior
and lateral canals in the same inner ear. Posterior canal
BPPV may convert to lateral canal BPPV following reposi-
tioning maneuvers.23 Head trauma is the most common
cause of bilateral posterior canal BPPV.17
ETIOLOGY
In most cases, BPPV is found in isolation and termed primary
or idiopathic BPPV. Rates of primary BPPV have been
reported as approximately 50% to 70% of BBPV cases.
The most common cause of secondary BPPV is head
trauma, which represents 7% to 17% of all BPPV
cases.17,19 The blow to the head may cause the release of
numerous otoconia into the endolymph, which likely
explains why many of these patients suffer from bilateral
BPPV.17 Viral neurolabyrinthitis has been implicated in up
to 15% of BPPV cases.19 The function of the posterior
canal must be preserved to a certain degree in order to be
symptomatic from BPPV.24
Ménière’s disease has also been strongly associated with
BPPV. There is a large variation in the literature regarding
what proportion of patients with BPPV also have
Ménière’s disease. One study by Karlberg and colleagues25
reviewed 2847 patients with BPPV and found 16 patients
(0.5%) with Ménière’s disease. Another retrospective
study examined only 151 patients with BPPV and found
that more than 45 patients (31%) had Ménière’s disease.26
However, upon examination of 162 patients with “defi-
nite” Ménière’s disease, Gross and colleagues27 found
9 patients (5.5%) to have “certain” posterior canal BPPV.
The causative mechanism is not well understood but may
be due to hydropically induced damage to the macula of
the utricle or by partial obstruction of the membranous
labyrinth.27
Recently, migraine headaches have been associated to
BPPV. Ishiyama and colleagues28 found that (1) the inci-
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
rate (77%) after successful repositioning. Lempert and
colleagues29 found a higher lifetime prevalence of migraine
in patients with BPPV (35% vs. 16%). They also found
that 83% of patients with BPPV and migraine were
women. This may help explain the female preponderance
of BPPV in the general population. Since vasospasm is well
documented in migraines and BPPV has been associated
with ischemic damage to the inner ear,28 vasospasm of the
labyrinthine arteries has been suggested as an etiologic
mechanism. Recurrent vasospastic ischemia of the utricular
otolith could explain the significant recurrence rate of
BPPV in patients with migraine.30
Secondary BPPV has also been described after inner ear
surgery.26,31,32 Atacan and colleagues31 reviewed 63 stapedec-
tomy cases for BPPV and found 4 patients (6%) who
developed BPPV postoperatively. All patients responded
to the Epley maneuver. The etiology is thought to be
linked to utricular damage during the procedure, leading
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
The Dix-Hallpike maneuver to diagnose posterior canal
BPPV was first described in 19522 (Fig. 41-2). The patient
is seated and positioned such that his or her head will
extend over the edge of the table when supine. The head
is turned 45º toward the ear being tested and the patient is
quickly lowered into the supine position with the head
extending below the level of the table. The patient’s head
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-
mus, rotational nystagmus is not suppressed by visual
fixation. The typical nystagmus has a brief latency (1 to 5
seconds) and limited duration (typically less than 30 sec-
onds). It consists of a slight vertical component that is up-
beating and a torsional component that has the superior
pole of the eye beating toward the affected dependent ear.
The direction of the nystagmus reverses when the patient
is brought into the upright position and the nystagmus will
fatigue with repeated testing. Along with the nystagmus,
B
Figure 41-2. Dix-Hallpike maneuver. A, The patient is seated and positioned
such that her head will extend over the edge of the table when supine. The
head is turned 45 degrees toward the ear being tested. B, The patient is
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
observes the eyes for nystagmus. (Reprinted with permission from Parnes
LS, Agrawal SK, Atlas J: Diagnosis and management of benign paroxysmal
positional vertigo [BPPV]. CMAJ 169:681–693, 2003.)
the patient will describe feeling vertiginous, the intensity
of which parallels the nystagmus response. The two poste-
rior canals are tested independently.
Superior semicircular canal BPPV is exceedingly rare and
is not well described in the literature. The frequency has
been reported as only 1% to 3% of BPPV cases.36,37 Since
the posterior semicircular canal and contralateral superior
semicircular canal lie in the same plane, the Dix-Hallpike
maneuver can be used to test for both entities. Therefore,
the left Dix-Hallpike will test for the left posterior
648 PERIPHERAL AUDIOVESTIBULAR DISORDERS
semicircular canal and right superior semicircular canal.
The observed nystagmus, however, will be opposite in both
its vertical (downbeating nystagmus) and torsional compo-
nents (superior pole beating toward the uppermost ear).15
Testing for lateral canal BPPV is done by laying the
patient supine and then quickly turning the patient’s head
(and body if necessary) laterally toward the side being
tested. A purely horizontal nystagmus occurs that is
geotropic (fast component toward the lowermost ear) in
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
horizontal nystagmus has a shorter latency and stronger
intensity while maintaining the test position, and it is less
prone to fatigue.15 Both sides are tested, and the direction
of nystagmus coupled with the direction of roll causing the
greatest nystagmus intensity often identifies the affected
side and the mechanism (see Table 41-1).
Overall, history and eye-findings during positional testing
are the gold standards for diagnosing BPPV. Additional
testing is not normally necessary and since electronystag-
mography (ENG) does not record torsional eye movements,
it adds little in the diagnosis of BPPV. More recently,
infrared videography has allowed direct eye observation
during the testing maneuvers, but three-dimensional eye
movement analysis38 is not common in clinical practice.
Rotational-chair testing and posturography have no role in
the diagnosis of BPPV. Imaging with CT or MRI scans is
unnecessary unless there are atypical or unusual features to
the assessment.
Subjective vs. Objective Benign
Paroxysmal Positional Vertigo
A certain subset of patients may not demonstrate the typical
nystagmus during the Dix-Hallpike maneuver but may still
experience the classic vertigo during positioning. This has
been termed subjective BPPV and several groups have
found repositioning maneuvers to be highly effective in
this group of patients. Haynes and colleagues,39 Tirelli and
colleagues,40 and Weider and colleagues41 found that
patients with subjective BPPV treated with various reposi-
tioning maneuvers had response rates of 76% to 93%
overall. Proposed theories to explain the lack of nystagmus
in patients with BPPV during the Dix-Hallpike maneu-
ver include (1) subtle nystagmus missed by the observer,
(2) fatigued nystagmus from repeated testing before the
maneuver, and (3) a less noxious form of BPPV that elicits
vertigo but has an inadequate neural signal to stimulate the
vestibulo-ocular pathway.39
Differential Diagnosis
Very few conditions can even remotely resemble BPPV.
In Ménière’s disease, the vertigo spells are not provoked by
position change, and they last much longer (30 minutes to
several hours). Furthermore, there is accompanying tinnitus
and hearing loss. The vertigo in labyrinthitis or vestibular
neuronitis usually persists for days. The vertigo may be
aggravated by head movements in any direction, and this
needs to be carefully extracted from the history so as not
to confuse it with specific position change–evoked vertigo.
As well, the Dix-Hallpike test should not induce the burst
of nystagmus seen in BPPV. Very rarely, posterior fossa
tumors mimic BPPV, but there are no reports in the literature
in which a tumor has perfectly replicated all of the features
of a positive Dix-Hallpike maneuver. As mentioned previ-
ously, BPPV can be secondary, so as to occur concurrently
with, or subsequent to, other inner ear or CNS disorders.
Also, being so common, it can often be a coincidental
finding with other disorders.
MANAGEMENT
Nonsurgical Management
The management of BPPV has changed dramatically in the
past 20 years as our understanding of the condition has pro-
gressed. Traditionally, patients were instructed to avoid posi-
tions that induced the vertigo. Medications were prescribed
for symptomatic relief, but one double-blind study showed
that they were largely ineffective.42 BPPV is self-limited,
and most cases resolve within 6 months. As the theories of
cupulithiasis and canalithiasis emerged, several noninvasive
techniques were developed to correct the condition directly.
Vestibular Habituation Therapy
In 1980, Brandt and Daroff43 introduced a specific series of
positional movements that they believed caused the
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
vertigo had resolved. Many believed that these exercises
worked through habituated central compensation, but the
authors concluded that the time course to the relief of
symptoms was too short for this to occur.
Brandt and Daroff found that one-third of their patients
had an abrupt resolution in symptoms and 66 of their 67
patients had resolution within 3 to 14 days. Although several
other studies found excellent initial responses (96% to 100%)
to vestibular habituation,44–46 there is a high rate of recur-
rence (76%).44 The exercises are time-consuming and poorly
tolerated by some patients, especially the obese and elderly.
Liberatory Maneuver
In 1988, Semont and colleagues47 described the liberatory
maneuver based on the cupulithiasis theory (Fig. 41-3).
It was theorized that this series of rapid changes of head
position freed deposits that were attached to the cupula.
The maneuver begins with the patient in the sitting position
and head turned away from the affected side. The patient
is then quickly put into the side-lying position, toward the
affected side, with the patient’s head turned up. After
approximately 5 minutes, the patient is quickly moved
back through the sitting position to the opposite side-lying
position with the head now facing down. The patient
remains in this second position for 5 to 10 minutes before
slowly being brought back to the sitting position.
In their large series of 711 patients, Semont and
colleagues47 found an 84% response rate after one proce-
dure and a 93% response rate after a second procedure

1
particles utricle
2 in posterior
canal
cupula
1 top panel shows the effect of the maneuver on
2 3
1 week later. Several other studies have had response rates
of 52% to 90%39,45,48,49 with recurrence rates of up to
29%.39 There has been no difference in efficacy shown
between the liberatory maneuver and particle repositioning
maneuver in studies by Herdman and colleagues48 and
Cohen and Jerabek.50 The liberatory maneuver is effective
but is cumbersome with elderly and obese patients, and it
shows no increased efficacy compared with the simple
particle repositioning maneuver.
Particle Repositioning Maneuver
Although he had been teaching his technique for many
years, it wasn’t until 1992 that Epley51 first published his
report on the canalith repositioning procedure (CRP). It is
based on the theory of canalithiasis, which currently is
thought to be the mechanism underlying most cases of
posterior canal BPPV. This highly successful procedure
is done while the patient is sedated and with mechanical
vibration to the mastoid bone and it involves moving
the patient’s head sequentially through five distinct posi-
tions. Epley postulated that the procedure caused otolithic
debris to move under the influence of gravity from
the posterior semicircular canal into the utricle. Most
clinicians today are believed to use a modified version of
the CRP.
One modified CRP is the particle repositioning maneuver
(PRM), which is a three-position maneuver that obviates
Benign Paroxysmal Positional Vertigo 649
3
Figure 41-3. Liberatory maneuver of Semont. The
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.)
the need for sedation and mastoid vibration52,53 (Fig. 41-4).
To perform the PRM:
1. Place the patient in a sitting position.
2. Move the patient to the head-hanging Dix-Hallpike
position of the affected ear.
3. Observe the eyes for “primary stage” nystagmus.
4. Maintain this position for 1 to 2 minutes (position B).
5. The patent’s head is turned 90 degrees to the opposite
Dix-Hallpike position while keeping the neck in full
extension (position C).
6. Continue to roll the patient another 90 degrees until
the head is diagonally opposite to the first Dix-Hallpike
position (position D). The change from position B,
through C, into D should take no longer than 3 to 5
seconds
7. The eyes should be immediately observed for
“secondary-stage” nystagmus. If the particles continue
moving in the same ampullifugal direction, that is,
through the common crus into the utricle, this
secondary-stage nystagmus should beat in the same
direction as the primary-stage nystagmus.
8. This position is maintained for 30 to 60 seconds and
then the patient is asked to sit up. With a successful
maneuver, there should be no nystagmus or vertigo
when the patient returns to the sitting position
because the particles will have already been reposi-
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
to compare because they vary considerably in the length
of follow-up, number of treatment sessions, number of
maneuvers per session, use of sedation, and use of mastoid
vibration. Table 41-2, adapted from Haynes and colleagues,39
summarizes the efficacy and treatment protocols of many
trials. The overall response rates range from 30% to 100%
and recurrence rates range from 5% to 30%. Most of
the studies presented are case series, however, Lynn and
colleagues54 and Steenerson and Cronin46 provide evidence
from randomized studies.
Lateral Canal BPPV
Several positioning techniques to treat lateral canal BPPV
have been developed. Perhaps the most simple is the
prolonged position maneuver developed by Vannucchi and
colleagues.55 In cases involving geotropic nystagmus, the
patient lies on his or her side with the affected ear up for
12 hours. They had resolution in greater than 90% of their
35 patients. Six of their patients converted to posterior
canal BPPV, but they were successfully treated with repo-
sitioning maneuvers.
The barrel roll was described by Epley12,56 and involves
rolling the patient 360 degrees, supine to supine, keeping
the lateral semicircular canal in the earth-vertical plane.
The patient is rolled away from the affected ear in 90-degree
increments until a full roll is completed. This is believed to
move the particles out of the involved canal into the utricle.
For less agile patients, Lempert and Tiel-Wilck57 proposed
the log roll where the patient is kept supine and only the
head is positioned. Here, the patient begins with the head
turned completely toward the affected ear. The patient is
then rapidly turned away from the affected ear in 90-degree
increments for a total of 270 degrees, with the head being
held in each position for about 1 minute. Only two
patients were in the study, but both were completely
relieved of their vertigo.
Controversy
Despite the excellent results from repositioning maneuvers,
there has been some controversy as to whether they have
an effect other than for central habituation over time.
In 1994, Blakley58 published a trial of 38 patients randomly
assigned to the particle repositioning group and the no
treatment group. No significant difference was found
between the treated and nontreated groups at 1 month,
and together, 89% showed some improvement. He con-
cluded that the maneuver was safe but did not provide
treatment benefit for BPPV. Buckingham59 examined
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
of gravity in different positions of the head. He found
that although loose macular otoliths tend to fall into the
lumen of the utricle, they are not returned to their original
position in the macula of the utricle, which lies superior in
the vestibule. He concluded that a mechanism other than
the repositioning of otoliths is responsible for the relief
of BPPV seen in repositioning maneuvers. Gacek and
Gacek60 have even questioned the entire pathophysiology
of BPPV and claim that it is simply a clinical expression
of vestibular ganglionitis. This conclusion is, however,
based on very weak evidence that involved reviewing 51
temporal bones that contained evidence of ganglion cell
degeneration and only 3 of these patients had a history
of BPPV.
Although most cases of BPPV are self-limited and spon-
taneously resolve within 6 months, a number of randomized
studies have shown that repositioning maneuvers are highly
effective. One group in Bangkok performed a 6-month
efficacy trial comparing the CRP with no treatment in
patients with BPPV.61 At 1 month, vertigo resolution was
significantly higher in the CRP group (94%) than in the
no treatment group, although this difference was not
seen at 3 and 6 months. Lynn and colleagues54 randomized
36 patients to a PRM and placebo treatment group with
blind assessment by an audiologist at 1 month. Resolution
of vertigo was significantly higher in the PRM group
(89%) than in the placebo group (27%). Steenerson and
Cronin46 randomly assigned 20 patients into either a PRM
or a vestibular habituation group and 20 patients into a no
treatment group. At 3 months, all patients in the treatment
group were resolved of their symptoms while only 25% of
the no treatment group were symptom free.
Factors Affecting Repositioning Maneuvers
Number of Maneuvers per Session
The literature contains variations regarding how many
repositioning maneuvers are performed in each treatment
session (see Table 41-2). Some perform a set number of
repositioning maneuvers regardless of response.62 However,
the majority of groups are divided between performing only
one maneuver per clinic visit and performing maneuvers
until there is a resolution of nystagmus or excessive patient
discomfort. Our objection to repeating the maneuver until
there is a negative Dix-Hallpike response is that one cannot
know whether the response is abolished because of a
successful maneuver or because of fatigued that occurs nat-
urally with repeated testing. From the literature review,
there does not appear to be significant differences among
these approaches in terms of short-term effectiveness and
long-term recurrence. Therefore, in our clinic, repeated
maneuvers are reserved for patients who do not demonstrate
an ipsidirectional secondary-stage nystagmus or those
who have a reverse direction nystagmus at position D30
(see Fig. 41-4).
Mastoid Vibration
In Epley’s original description of the CRP,51 he used
mechanical vibration of the mastoid bone thinking that it
would loosen otolithic debris adherent to the membrane
of the semicircular canal. In 1995, Li63 randomly assigned
27 patients to receive the PRM with mastoid vibration and
10 patients to receive the PRM without mastoid vibration.
He found that the vibration group had a significantly
higher rate of improvement in symptoms (92%) than did
the nonvibration group (60%).
652 PERIPHERAL AUDIOVESTIBULAR DISORDERS
These results do not, however, compare well with other
published studies (see Table 41-2), in which the majority of
authors who did not use mastoid vibration achieved much
higher success rates. In 2000, a larger study by Hain and
colleagues62 reviewed 44 patients who had the PRM with
mastoid vibration and 50 patients who had the PRM without
mastoid vibration. There was an overall success rate of 78%
with no difference in short-term or long-term outcomes
between the two groups.
Postmaneuver Instructions
Another area of divergence among experts involves the use
of activity limitations after repositioning maneuvers.
Epley51 asked his patients to remain upright for 48 hours
after the CRP. Certain investigators also request that, in
addition to remaining upright, their patients avoid lying
on their affected side for 7 days. A study by Nuti and
colleagues49 examined two sets of patients following the
liberatory maneuver. One group of patients was asked to
remain upright for 48 hours, while a second group of
patients was not given any postmaneuver instructions.
These two groups were retrospectively compared and no
difference was found in short-term vertigo control. This
finding is consistent with an earlier study by Massoud and
Ireland,64 who also demonstrated that postliberatory
maneuver instructions were not efficacious.
Objective vs. Subjective Benign Paroxysmal
Positional Vertigo
Subjective BPPV refers to the condition of patients with
positional vertigo who do not display the classic nystagmus
during the Dix-Hallpike maneuver, but who experience
the classic vertigo on history and positioning. As previously
discussed, several theories have been proposed regarding
the pathophysiology of subjective BPPV. Although most
studies in the literature include only patients with objective
BPPV, it has become clear that repositioning maneuvers in
the subjective group is nearly as effective as they are for
patients with objective BPPV.
Tirelli and colleagues40 prospectively examined two
groups of patients: 43 patients with subjective BPPV and
90 patients with objective BPPV, all treated with the PRM.
Although the objective BPPV group had a higher
complete resolution rate than the subjective BPPV group
(90% vs. 60.5%), the subjective BPPV group had 32.5% of
patients who partially improved. Therefore, the overall
success rate in subjective BPPV patients was 93%, which
compares well with the literature on objective BPPV.
Haynes and colleagues39 reviewed 127 patients with objec-
tive BPPV and 35 patients with subjective BPPV who were
all treated with the liberatory maneuver. Similar results
were found with no significant difference between the two
groups in overall success rate: objective BPPV (91%)
versus subjective BPPV (86%).
Predicting Success and Recurrence Risk
Several studies have attempted to identify variables that
would help predict initial short-term success and recurrence
risk with repositioning maneuvers. Beynon and colleagues65
followed 51 patients and reported no associations of age,
sex, etiology (primary or secondary), or the duration
of symptoms before treatment and success of the PRM.
They also found that the presence of recurrent or perma-
nent BPPV before repositioning was not related to recur-
rence risk after treatment. Macias and colleagues66
followed 259 patients with BPPV and found no significant
relationship between either short-term success or recur-
rence risk and age, sex, etiology (idiopathic or secondary),
or the number of repositioning maneuvers performed per
treatment visit. It was found, however, that patients with
bilateral disease or BPPV in a canal other than the poste-
rior canal required a greater number of treatment sessions
until resolution of symptoms. The prospective study of
168 patients using the CRP by Nunez and colleagues67
suggests a recurrence rate of 15% per year, with a 50%
recurrence rate of BPPV at 40 months after treatment.
There was no significant association between cure or
recurrence rate and sex, age, duration of symptoms, pre-
sumed cause, or treating physician.
SURGICAL TREATMENT
It should be stressed that BPPV, although incapacitating,
is a benign disease, and surgery should be reserved for the
most intractable or multiply recurrent cases. BPPV often
undergoes spontaneous remission within 6 months and is
highly amenable to physical therapy and repositioning
maneuvers. The practitioner should exclude BPPV of
the lateral and superior semicircular canals and accurately
assess for secondary causes for BPPV. Furthermore, before
the physician considers surgery, the posterior fossa
should be imaged to rule out central lesions that might
mimic BPPV.68
Singular Neurectomy
The singular neurectomy for BPPV was popularized by
Gacek69 in the 1970s. It involves a transection of the pos-
terior ampullary nerve in the singular canal. After raising
the tympanomeatal flap, the singular canal is approached
by drilling inferior to the round window. This puts at risk
both the ampulla and vestibule; if either is injured, it may
lead to severe vertigo or sensorineural hearing loss. Initial
reports by Gacek70 demonstrated high efficacy with
complete vertigo resolution in 91.7% of patients.
However, there was a 7.3% risk of sensorineural hearing
loss with the procedure. Gacek published an update of his
personal series in 199571 and decreased the rate of sen-
sorineural hearing loss to 3%. Although safe and reliable
in experienced hands, this procedure is technically
demanding and has largely been replaced by the simple
posterior semicircular canal occlusion.15
Posterior Semicircular Canal Occlusion
History
It had long been a maxim in otologic surgery that the
violation of the labyrinth would result in a “dead ear.” This
principle arose in the early days of otologic surgery when
surgeons were forced to operate under less than optimal
conditions. These included the presence of chronic infection
and the difficulty of discerning surgical landmarks because
of poor magnification.

In the early 1960s, Money and Scott72 successfully
ablated individual semicircular canals without affecting
the response of the other ipsilateral semicircular canals.
At least in the cat model, this proved that invasive inner ear
surgery did not necessarily result in a “dead ear” under
optimal operating conditions. However, although the
vestibular labyrinth was spared by individual canal occlusion,
the possibility of sensorineural deafness secondary to
cochlear damage was not addressed.
Several experiments performed in the 1950s had
attempted to address this issue. Kristensen73,74 claimed to
preserve hearing when performing partial labyrinthec-
tomies in guinea pigs. Unfortunately, hearing was crudely
measured using Preyer’s reflexes and the study failed to
control for hearing in the nonoperated ear. Wever and col-
leagues75 used cochlear potentials to determine that partial
hearing was preserved after destruction of the lateral semi-
circular canal in monkeys. The degree of hearing preserva-
tion, however, varied a great deal among the subjects.
More recently, animal studies by Kobayashi and col-
leagues76 and Smouha and colleagues77,78 have demonstrated
the preservation of cochlear function following the ablation
of a semicircular canal. In humans, individual cases of inci-
dental hearing preservation following injury to the lateral
semicircular canal have been reported following fenestra-
tion surgery for otosclerosis79,80 and chronic otitis media.81–83
It was Parnes and McClure,84 however, who first mea-
sured the effect on hearing of posterior semicircular canal
occlusion in guinea pigs. Hearing, measured by auditory
a Cutting 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.
Benign Paroxysmal Positional Vertigo 653
brainstem evoked responses, remained stable for as long as
6 months following canal occlusion.85 This study provided
the groundwork for posterior semicircular canal occlusion,
the surgical technique now used to treat intractable BPPV
in humans.
Technique
The procedure is performed under general anesthetic and
should take no longer than 2 to 3 hours (Fig. 41-5). Using
a 5- to 6-cm postauricular incision, the posterior canal is
accessed through a mastoidectomy. With the use of an
operating microscope and drill, a 1 × 3 mm fenestration is
made in the bony posterior canal. Particles can occasionally
be seen in the posterior semicircular canal after fenestration.
A plug, fashioned from bone dust and fibrinogen glue, is
used to occlude the canal. Most patients are hospitalized
for 2 to 3 days. Since the occlusion also impairs the normal
inner ear physiology, all patients are expected to have post-
operative imbalance and dysequilibrium. For most people,
the brain adapts to this after a few days to a few weeks,
with vestibular physiotherapy hastening this process.
A few variations of this technique have been published
since the original description. A carbon-dioxide laser has
been used to ablate the posterior semicircular canal with
promising results in six patients.86,87 The use of an argon
laser has been described with a guinea pig model.88
Brantberg and Bergenius89 described successful occlusion
of the anterior semicircular canal in a patient with
intractable anterior canal BPPV.
Diamond drill
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
In 2001, Agrawal and Parnes10 published the largest series in
the literature of 44 occluded posterior canals in 42 patients.
All 44 ears were relieved of BPPV, with only one having a
late atypical recurrence. Of the 40 ears with normal pre-
operative hearing, one had a delayed (3-month) sudden
and permanent profound loss, and one other had a mild
loss (20 db). Obvious free-floating endolymph particles
were found in 30% of operated ears (Fig. 41-6).
Essentially, all cases were followed by an initial 1- to
4-week period of imbalance and motion sensitivity. The
average duration of postoperative hospitalization is 2 to
656 PERIPHERAL AUDIOVESTIBULAR DISORDERS
A Benign paroxysmal positional vertigo presents with a history
B 2. Dix MR, Hallpike CS: Pathology, symptomatology and diagnosis of cer-
Figure 41-6. Sequential computer-regenerated photographs taken from an
intraoperative video of a fenestrated posterior semicircular canal. A, Note the
single white conglomerate mass in the membranous duct (arrow). B, Note
that the mass has fragmented into tiny particles 2 to 3 minutes later, after the
membranous duct has been probed (arrow). (Reprinted with permission
from Parnes LS, Agrawal SK, Atlas J: Diagnosis and management of benign
paroxysmal positional vertigo [BPPV]. CMAJ 169:681–693, 2003.)
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
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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64. Massoud EA, Ireland DJ: Post-treatment instructions in the non-
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87. Kartush JM, Sargent EW: Posterior semicircular canal occlusion
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Laryngoscope 104:1206, 1994.

Pharmacotherapy for Vestibular
Dysfunction
Outline
Introduction
Autonomic Dysfunction,
Anxiety, and Panic Attacks:
Vestibular Circuitry
Specific Pharmacotherapy
Ménière’s Disease
Chemical Labyrinthectomy
Preparation of Gentamicin
Solution
Intratympanic
Dexamethasone
Otosyphilis
INTRODUCTION
Over the past three decades, the evolution in the diagnosis
and management of peripheral and central vestibular
disorders has been dramatic. Consequently, it is rare that a
patient requires surgical intervention1; however, a clear
understanding of the pathophysiology and the scientific
basis of medical treatment will help ensure appropriate
treatment of these patients. Three peripheral vestibular
disorders are commonly encountered by the neurotologist:
benign paroxysmal positional vertigo, Ménière’s disease,
and vestibular neuronitis (neuritis), and one central disor-
der that is frequently encountered by the neurotologist
(vestibular migraine), therefore the medical management
of these disorders will be emphasized. Additional disorders
are amenable to medical management, and many of these
will also be addressed.
Pharmacotherapy of vertigo can be divided into two
general categories: specific and symptomatic. Examples of
specific therapies include antibiotics for bacterial or syphilitic
labyrinthitis, anticoagulants for vertebrobasilar insufficiency,
and diuretics for Ménière’s disease. Whenever possible,
treatment should be directed at the underlying disorder. In
the majority of cases, however, symptomatic treatment is
combined with the specific therapy or is the only therapy
available (e.g., viral vestibular neuronitis).
Common causes and mechanisms of dizziness are out-
lined in Table 42-1. Tables 42-2 and 42-3 distinguish the
common peripheral origins of vertigo from the common
central causes.2–4 The diagnosis, pathophysiology, and
treatment of most of these disorders are presented
throughout several other chapters in this section of the
Chapter
42
Vestibular Migraine P. Ashley Wackym, MD, FACS
Vertebrobasilar Insufficiency
Tammy S. Schumacher-Monfre,
Familial Ataxia Syndrome
MSN, APNP
Psychophysiologic Dizziness
Future Perspectives
Symptomatic
Pharmacotherapy
Mechanism of Action
Strategy in the Treatment
of Vertigo
Prophylaxis of Motion
Sickness
book, therefore, the focus of this chapter will be on medical
management and the scientific rationale for each strategy.
The peripheral causes of vestibular dysfunction (see
Table 42-2) are presumed to be restricted anatomically to
structures associated with the membranous labyrinth,
peripheral branches of the vestibular nerve, Scarpa’s
ganglion, and the vestibular nerve root. The central causes
of vestibular dysfunction, though, compromise central
vestibular circuits that mediate vestibular influences on
posture (via vestibulospinal and vestibulocollic pathways),
control of gaze (via vestibulo-ocular and vestibulocollic
pathways), and autonomic functions. However, unlike the
peripheral vestibular system, which may be viewed strictly
as sensors of linear and angular acceleration of the head,
central vestibular pathways are multimodal neural circuits
that integrate a variety of sensory and motor signals
related to balance, posture, and eye movements. The
vestibular nuclei are the primary central target of the
vestibular nerve. Other sites that receive primary afferents
from the vestibular nerve include several other brainstem
nuclei (abducens nucleus, nucleus prepositus hypoglossi,
cochlear nuclei [probably from the sacculus], external
cuneate nucleus, and reticular formation). Since the
vestibular nerve terminates only in the ipsilateral brain-
stem, integration of information from coplanar pairs of
peripheral vestibular end-organs (e.g., left and right lateral
canal cristae, left superior and right posterior canal cristae,
and left posterior and right superior canal cristae) is medi-
ated by commissural connections. In addition to these
vestibular inputs, the vestibular nuclei receive propriocep-
tive, visual (optic flow), and premotor/motor signals from
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
consequence of the polymodal inputs to these circuits may
be the ability to use other sensory information to compen-
sate for peripheral vestibular injury.
Specific cell groups (or circuits) within the vestibular
nuclei then contribute directly to vestibulospinal,
vestibulo-ocular, vestibulocollic, and vestibuloautonomic
pathways. The activity of each of these functional circuits
within the vestibular nuclei is modulated by specific cere-
bellar circuits in the flocculonodular lobe, the vermis of
the posterior lobe, and the anterior lobe. Classical clinical
and anatomic evidence indicate that each of these cerebel-
lar regions contribute to different vestibular motor func-
tions. For example, flocculonodular lobe dysfunction has a
primary effect on eye movements, whereas anterior lobe
degeneration (e.g., alcoholic cerebellar degeneration) pre-
dominantly influences postural control. Cerebellar regions
related to autonomic control have also been identified (for
review see Balaban5). Each of these larger cerebellar
regions, though, are subdivided into smaller circuitry units
(zones) that appear to directly influence specific vestibular
nucleus output pathways. For example, a small region
(zone) in the cerebellar flocculus contributes to the control
of eye movements in the plane of the horizontal semicir-
cular canal by connections with the vestibular nuclei.
The direct cerebellar connections to the vestibular
nuclei appear to be important for coordination and con-
tinual recalibration of motor responses to vestibular stim-
ulation. Climbing fiber input from the inferior olive
appears to play a critical role in these functions. The
climbing fibers are believed to provide a sensorimotor error
signal to cerebellar Purkinje cells, which may alter the
responsiveness of the Purkinje cells to parallel fiber inputs
via a mechanism termed long-term depression, to achieve a
rapid correction of function.
One important feature of central vestibular circuitry is
its ability to compensate for peripheral injury. Although
the phenomenon is well known, the mechanisms of
compensation are poorly understood. The present evidence
suggests that behavioral compensation involves synaptic
plasticity in both the brainstem and the cerebellum. Two
factors in compensation appear to be of particular relevance
clinically. First, the stability of the vestibular dysfunction
has an obvious influence on the efficacy of compensation.
Stable, predictable dysfunction (e.g., vestibular nerve

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

section) provides a baseline of dysfunction as a target for
compensation. Conversely, compensation for fluctuating
hypoactivity or hyperactivity (e.g., Ménière’s disease) is
expected to be ineffective because baseline function is
unpredictable or unstable. Second, the functional status of
the central nervous system (CNS), due to either age-
related or organic changes, is an important consideration.
For example, individuals with preexisting cerebellar
damage may show decreased compensatory capability.6
Autonomic Dysfunction, Anxiety, and
Panic Attacks: Vestibular Circuitry
Every clinician treating patients with vestibular disorders,
as well as astronauts experiencing the rapid changes of
vestibular input encountered during the various stages
of space flight, are well aware of the marked autonomic
dysfunction associated with these alterations of vestibular
input.7 These signs and symptoms of nausea, vomiting,
pallor, as well as changes in respiration and circulation are
clinically apparent; however, the basis for these responses
has only recently been elucidated via anatomic studies
identifying a network of vestibuloautonomic projections in
the brainstem of rabbits, rats, and cats.8,9
The finding that vestibular nuclear and secondary
visceral projections converge in the parabrachial nucleus
(and other brainstem regions) provides important insights
into potential neural substrates for phenomena such as
respiratory, cardiovascular, and gastrointestinal (emetic)
responses to vestibular stimulation, motion sickness, and
autonomic responses in altered gravitational environments.
In particular, these findings provide a potential neurologic
basis for the close relationship between vestibular dysfunc-
tion and anxiety disorders with agoraphobia.8
Anxiety, panic attacks, and agoraphobia are also com-
monly associated with vestibular dysfunction.8 In 1945 Sir
Terrence Cawthorne described the terror that patients with
acute vestibular injury may experience. Other clinicians
have identified specific situations involving changes in
spatial orientation that elicit symptoms of anxiety and
panic. Levy and O’Leary10 coined the term street neurosis to
describe the anxiety that some patients develop after an
acute vestibular attack. McCabe11 observed the supermarket
syndrome in patients with Ménière’s disease and character-
ized these patients as experiencing an intolerance to look-
ing back and forth along aisles and up and down shelves.
Patients with vestibular deficits who are visually or propri-
oceptively dependent may have symptoms of imbalance,
discomfort, anxiety, or phobic avoidance when in situations
with inadequate visual or proprioceptive balance cues. Jacob
and colleagues have termed this situational specificity space
and motion discomfort. These unpleasant manifestations of
discomfort may also be considered as referred signs and
symptoms from vestibular pathways to visceral sites and may
serve as eliciting or reinforcing stimuli for conditioned
avoidance of potentially dangerous situations.12 The diag-
nostic category space and motion phobia develops when situ-
ational distress significantly impairs a patient’s normal
activities, particularly by producing avoidance behaviors
that reduce vestibular discomfort.4 The neurologic linkage
model has been proposed to explain the association of
vestibular disorders and autonomic dysfunction, anxiety,
Pharmacotherapy for Vestibular Dysfunction 661
panic attacks, and agoraphobia.8 The linkage appears to be
mediated by (1) ascending vestibular pathways involving
the parabrachial nucleus, amygdala, and infralimbic cortex;
(2) noradrenergic pathways; and (3) serotonergic pathways.
The consequences of this intimate neurologic linkage
among vestibular function, autonomic regulation, and
affective status are of great practical importance to the cli-
nician. In particular, it is important to consider a multifac-
torial treatment plan to address the pathogenic mechanisms,
obtain symptomatic relief from vertigo and nausea, facilitate
vestibular compensation, and address the emergent anxiety
and depression of individual patients. The symptomatic
pharmacotherapy of vestibular dysfunction is discussed
later in this chapter; however, low doses of diazepam (2 mg
orally tid PRN), or lorazepam (0.5 mg orally tid PRN) are
useful in managing the associated symptoms of autonomic
dysfunction, anxiety, panic attacks, and agoraphobia. For
symptoms that occur more consistently, clonazepam
(0.25 mg bid to tid) should be considered.13,14 Adjunctive
techniques such as stress reduction methods, biofeedback,
hypnosis, and yoga can likewise prove helpful in reducing
these symptoms.
SPECIFIC PHARMACOTHERAPY
Specific forms of pharmacotherapy are directed at revers-
ing the proven or presumed pathophysiologic mechanisms
responsible for disorders associated with vestibular dys-
function. Examples of such interventional schemes are
outlined in Table 42-4.
Ménière’s Disease
Medical therapy for Ménière’s disease includes dietary
modification, physiotherapy, psychological support, and
pharmacologic intervention. Diuretic therapy and salt
restriction have long been considered the mainstay of
medical intervention for endolymphatic hydrops, based
on the assumption that these drugs can affect fluid bal-
ance within the inner ear and lead to a depletion of
endolymph.15–17 Thiazide diuretics have been a popular form
of such specific pharmacotherapy for Ménière’s disease.
These agents enhance excretion of sodium, chloride, and
water by interfering with absorption of sodium ions across
the epithelium of the cortical diluting segment of the
nephron. Other electrolyte effects include enhanced potas-
sium, magnesium, phosphate, bromide, and iodide excretion.
Long-term therapy produces decreased calcium excretion
and hypocalciuria.
Prolonged thiazide diuretic therapy can be associated
with metabolic alkalosis with hypokalemia and
hypochloremia. A potassium-sparing diuretic such as tri-
amterene or spironolactone is often used in conjunction
with thiazides to offset potassium loss (e.g., triamterene
and hydrochlorothiazide). Thiazides can induce hyper-
glycemia and exacerbate diabetes mellitus. Other potential
adverse reactions include hyperuricemia and orthostatic
hypotension. These agents may exacerbate preexisting
renal or hepatic insufficiency.
Carbonic anhydrase inhibitors (e.g., acetazolamide)
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,

approximately 10% of patients reach a point when the
symptoms are so severe that an operation or aminoglyco-
side treatment should be considered.1 Henceforward in
this chapter we will consider the aminoglycoside vestibu-
lotoxic treatments to be included under the term chemical
labyrinthectomy. When considering vestibular surgery or
chemical labyrinthectomy, it is often useful to have the
patient with Ménière’s disease consult a dietitian in order
to optimize the medical management prior to undertaking
this course. From the standpoint of the severity of symp-
toms the most appropriate group for surgical or chemical
labyrinthectomy treatment include patients who cannot
work, drive, make secure travel plans, or take care of a fam-
ily. Candidates may also include those who are managing
to carry out these activities only with great effort because
they are highly motivated to do so (American Academy of
Otolaryngology–Head and Neck Surgery [AAO-HNS]
functional levels 4, 5, and 6).21 An endolymphatic sac pro-
cedure may be considered in some cases at AAO-HNS func-
tional level 3, whereby no disability or immediate threat of
disability is evident, but daily activities are disrupted due to
the attacks of vertigo.
The overall goal of any treatment of vestibular disorders
is to help patients be as functional and comfortable as pos-
sible. The operational goals are to control episodic vertigo
and to avoid or minimize treatment-associated disequilib-
rium and hearing loss. The primary technical goal of
chemical labyrinthectomy is complete unilateral vestibular
ablation.1 The most common difficult problem to manage
after any vestibular destructive surgery (vestibular neurec-
tomy, labyrinthectomy, or aminoglycoside treatment) is
persistent, troublesome disequilibrium and this com-
plication occurs in 20% of cases.1 Nearly all patients will
experience vertigo and disequilibrium immediately after
surgical labyrinthectomy or vestibular neurectomy. With
aminoglycoside treatments, the disequilibrium begins
when the chemical labyrinthectomy effect occurs. This
effect typically occurs at least 4 days after the commence-
ment of treatment.
Patients report symptoms of acute unilateral peripheral
vestibular loss, including an acute sensation of rotational
vertigo, imbalance, a tendency to fall toward the affected
side, and intolerance to rapid head movement. They usu-
ally experience autonomic dysfunction (e.g., nausea and
diaphoresis), as well as anxiety and general malaise. These
symptoms improve spontaneously such that most patients
are able to return to full activities by 6 to 8 weeks after
labrinthectomy.1
Patients treated with intramuscular (IM) aminoglyco-
sides or those with a pretreatment contralateral vestibular
deficit may also experience oscillopsia. This symptom is a
bobbing of the visual field on ambulation. Patients will
report that they have trouble reading street signs while
driving or riding in a car or difficulty reading labels as they
move down the aisle of a store. Oscillopsia is a manifesta-
tion of reduction of vestibulo-ocular reflex due to a loss of
vestibular sensation. Oscillopsia usually improves in time,
possibly due to CNS compensation or tolerance by the
patient.
In nearly all instances, early postoperative disequilibrium
will gradually resolve following ambulation of the patient,
and additional treatment is not needed. If disequilibrium
Pharmacotherapy for Vestibular Dysfunction 663
persists or occurs later following chemical labyrinthec-
tomy, vestibular exercises or formal vestibular rehabilita-
tion are usually helpful in improving balance function and
comfort of movement.
Interest in intratympanic aminoglycoside (ITAG) has
increased in recent years as an alternative to endolym-
phatic sac surgery and vestibular neurectomy. A key advan-
tage is that ITAG can be a nonsurgical office procedure.
Nevertheless, ITAG is, at present, an imprecise treatment,
difficult to control, and in at least one current form of drug
delivery, appears to be associated with a 10% rate of deafness
in the treated ear.22 Nonetheless, vertigo can be relieved in
90% of cases.22,23 Other protocols may be associated with
a lower rate of deafness. ITAG has a place in the treatment
of Ménière’s disease, but the optimal treatment protocol
and the boundaries of its exact role remain to be defined.
Since 1994, when the first edition of this textbook was
published, most otologists have greatly decreased the
frequency with which they perform ITAG because of the
risk of hearing loss. However, a recent longitudinal study
of ITAG administration in 31 Ménière’s disease patients
reported a markedly reduced rate of profound hearing
loss.24 In this study, Wu and Minor reported profound
hearing loss in only one patient (3%). In addition, hearing
improvement was seen in 5 (16%), unchanged in 21 (65%),
and worse in 5 (16%). Vertigo was controlled in 90% of
the patients. Their protocol involves a single ITAG
administration (26.7 mg/mL gentamicin, 0.4 mL typically
injected), 30 minutes of solution contact with the round
window, and subsequent removal of the residual genta-
micin via aspiration. Minor’s protocol now involves a sin-
gle ITAG injection, and additional treatments are only
administered if episodes of vertigo have persisted at the
time of follow-up examination 3 weeks after injection.
Aminoglycosides do not seem to be concentrated in
cochlear fluids, but the elimination half-life increases with
chronic administration, suggesting sequestration of the
drug by hair cells.25 Amikacin, dihydrostreptomycin, and
kanamycin are primarily cochleotoxic, whereas gentamicin
and streptomycin are primarily vestibulotoxic.16 At high
doses, streptomycin is also cochleotoxic. For example,
streptomycin, 25 mg/kg/day, administered systematically
to cats resulted in loss of vestibular hair cells only, but at
100 mg/kg/day, both vestibular and cochlear hair cells
were lost.26
The hair cells of the cristae, the maculae, and the
cochlea degenerate to different degrees following the
administration of aminoglycosides. The primary vestibular
neurons, the cochlear nuclei, and the vestibular nuclei are
not directly affected, even at high doses.26 The basal turn
of the cochlea is the region most susceptible to permanent
loss of hair cells, resulting in an initial loss of high-
frequency hearing. Although the mechanisms of this dif-
ferential toxicity are incompletely understood, several
contributing factors have been identified, including the
route of administration, dose variables, and the specific
aminoglycoside used.
Damage to vestibular dark cells, which are thought to
play a role in the production of endolymph, has been
reported following administration of doses of aminoglyco-
side below the threshold for damage to hair cells. An
attractive hypothesis is that the impaired function of dark
664 PERIPHERAL AUDIOVESTIBULAR DISORDERS
cells would be beneficial in Ménière’s disease since
decreased production of endolymph would affect the fluid
homeostasis of the inner ear.27,28
Preparation of Gentamicin Solution
Gentamicin solution may either be used as a stock solution
of 40 mg/mL with a pH of about 5.4, or be buffered to
a pH of 6.4 to reduce the discomfort associated with
intratympanic injection. One method of preparing the
buffered solution is as follows1: 1.5 mL of gentamicin
solution (40 mg/mL) is injected into a sterile 5-mL vial. A
0.6 M sodium bicarbonate solution is prepared by com-
bining 2 mL of 8.4% sodium bicarbonate and 1.36 mL of
sterile water in a 5-mL sterile vial. Add 0.5 mL of the 0.6
M sodium bicarbonate solution to the sterile vial contain-
ing 1.5 mL of gentamicin to form 2 mL of a solution of
gentamicin (30 mg/mL, pH 6.4) ready for injection.
Injection Technique
The patient should be comfortably positioned in the
standard otologic position for examination under the oper-
ating microscope, supine with the head turned away from
the ear to be treated. In this position, the eustachian tube
will be uppermost to avoid dependent drainage of the gen-
tamicin solution out of the middle ear. This position is
maintained for 30 minutes following the injection, and the
patient is instructed not to swallow or clear the middle ear
during this period; providing a cup for gentle expectora-
tion during this period helps accomplish this goal. Topical
application of phenol to a small injection site on the surface
of the tympanic membrane provides anesthesia, and the
gentamicin is injected in the middle ear using a tuberculin
syringe and a 27- or 25-gauge spinal needle. Typically, about
0.5 mL of solution fills the middle ear. The residual gen-
tamicin is aspirated from the middle ear after 30 minutes
of contact with the round window.
Administration Protocols
Numerous administration protocols have been described.
Nedzelski and colleagues22 had patients administer gen-
tamicin intratympanically three times a day via a tympa-
nostomy tube and a small flexible tubing for 4 days. The
protocol introduced by Beck and Schmidt29 advocates a
once daily regimen until the earliest sign of ototoxicity is
observed. With this schedule, 1 to 12 doses are given, with
a mean of 4 to 6 doses. A number of other investigators use
a dosing regimen that titrates the administration of ITAG
using patient response measured by caloric response,
audiometric function, and patient symptoms. The ration-
ale is to reduce the risk of hearing loss while maintaining
control of vertigo by giving less medication per dose and
extending the time of treatment with repeated applications
as necessary. A second intratympanic injection of approxi-
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.
However, based on the far lower rate of profound hearing
loss seen with the protocol developed by Minor (3% com-
pared with 10%), it is anticipated that scheduled repeated
injections will become less common.
Selective chemical vestibulectomy had also been used as
an alternative to vestibular nerve section for refractory
cases of unilateral Ménière’s disease.22 A tuberculin syringe
is used to introduce 2.5 to 25 μg of streptomycin in solu-
tion (25 μg/mL) through a fenestration in the horizontal
semicircular canal. Shea and Norris30 have reported com-
plete elimination of caloric response and complete relief
of vertigo in 166 Ménière’s disease patients undergoing
streptomycin perfusion of the inner ear, with preservation
or improvement of hearing in 75% of patients. However,
a multi-institution trial of this technique reported hearing
loss in 68% of 47 patients undergoing labyrinthotomy
with streptomycin infusion.31
Parenteral streptomycin has been used successfully to
manage cases of refractory bilateral Ménière’s disease.
Therapy is titrated to preserve some vestibular function.
This method has helped to avoid post-treatment disequi-
librium and oscillopsia associated with complete bilateral
vestibular ablation. Total streptomycin dose varies from 5
to 70 g in patients undergoing titration therapy, with a
mean dose of approximately 25 g administered to achieve
the desired endpoint. Langman and associates32 improved
or completely relieved episodic vertigo in 16 of 19 patients
(84%) undergoing titration therapy for bilateral Ménière’s
disease. Persistent severe post-treatment disequilibrium
occurred in three patients (16%), and changes in hearing
were independent of the effect of streptomycin.
Intratympanic Dexamethasone
An emerging management technique for recalcitrant
Ménière’s disease is the intratympanic injection of dexa-
methasone. The technical aspects are identical to those
described in the ITAG section. The senior author injects
dexamethasone (24 mg/mL) and allows the patient to
remain supine with the affected ear uppermost for 20 to 30
minutes. The procedure is performed three times, 1 week
apart. Other authors have used single-dose applications
via an exploratory tympanotomy followed by application,
in the round window niche, of dexamethasone 8 mg, in
hyaluronic on an absorbable gelatin sponge. A retrospec-
tive study of the latter approach in 21 ears of 19 patients
was reported by Arriaga and Goldman.33 They found that
a single application of dexamethasone/hyaluronan solution
did not produce dramatic short-term hearing improve-
ment in patients with endolymphatic hydrops; however,
improvements of as much as a 38-dB gain in pure tone
acuity (PTA) and 38% gain in the speech discrimination
score were reported. This single patient’s gain was tempered
by three ears that experienced deterioration after treat-
ment. Conservative performance of intratympanic dexa-
methasone is appropriate; however, some patients failing
medical therapy may benefit from this technique prior to a
more aggressive surgical option. Long-term controlled
clinical trials remain to be completed that will determine
the efficacy of this treatment modality.
Otosyphilis
A presumptive diagnosis of otosyphilis is made in the
patient with unexplained cochleovestibular dysfunction
and positive fluorescent treponemal antibody absorption
(FTA-ABS). Penicillin and steroids have been the primary
treatment modalities. Although previous studies have

shown benefit of IM penicillin therapy,34 other studies
have demonstrated that the IM route of parenteral therapy
fails to achieve treponemicidal levels in cerebrospinal
(CSF) fluid. For IM therapy, treatment with 2.4 million
units of benzathine penicillin weekly for 3 successive weeks
constitutes minimal therapy. Other authors advocate
extending therapy for as long as 1 year. New outpatient
treatment regimens that include probenicid promise to
achieve antitreponemal drug levels in the CSF. Probenecid
increases the half-life and facilitates CSF penetration of
penicillin derivative antibiotics. These regimens include
1.8 million units of IM procaine penicillin G daily or 1 g
oral amoxicillin six times daily, in combination with
probenecid 500 mg four times daily.
For patients receiving IV therapy, 10 million units of peni-
cillin G per day is administered in divided doses for 10 days,
followed by 2.4 million units of IM benzathine penicillin
per week for 2 additional weeks. Patients with neurosyphilis,
documented by a positive CSF VDRL, 24 million units of
penicillin G per day is administered IV for 14 days, fol-
lowed by a 2-week course of benzathine penicillin and an
8-week course of high-dose oral amoxicillin. Patients with
documented penicillin allergy receive 500 mg of tetracy-
cline or erythromycin qid for 30 days. Alternatively, doxy-
cycline (200 mg/day for 15 to 20 days) may improve
patient compliance as it is dosed twice a day and may be
taken with food.
Many studies demonstrate enhanced efficacy when
penicillin is combined with steroid therapy. Although dose
recommendations vary, prednisone 40 to 60 mg/day for
2 weeks is accepted as minimal therapy. Therapy is contin-
ued for 4 weeks in patients who respond and is subse-
quently tapered according to patient symptomatology.
Patients receiving prolonged therapy should be placed on
an alternate-day regimen to minimize adrenal suppression.
Absolute and relative contraindications to steroid therapy
include hypersensitivity to corticosteroids, severe osteo-
porosis, brittle diabetes mellitus, peptic ulcer disease,
diverticulitis, hypothyroidism, cirrhosis, thromboembolic
disorders, and psychiatric illness. Since glucocorticoid
therapy can reactivate tuberculosis, chemoprophylaxis
should be used for patients with a history of active
tuberculosis.
Seventy-five percent of patients undergoing antibiotic
therapy for secondary syphilis will experience an acute,
febrile reaction known as the Jarisch-Herxheimer reaction.
The reaction typically begins within 4 hours after treat-
ment begins and is manifest by fever and flulike symptoms.
This reaction is probably related to release of endotoxin
from killed spirochetes or an allergic reaction to trepone-
mal breakdown products. Symptoms typically subside
within 24 hours after instituting therapy and seldom
require interruption of therapy. However, patients should
be informed of this syndrome, as some will experience a
transient exacerbation of cochleovestibular symptoms.
Administration of prednisone for 24 hours prior to the ini-
tiation of antibiotic therapy reduces the febrile component
of this reaction.35
Penicillin and steroid therapy has been reported to
improve vertigo in 58% to 86% of patients with symptoms
secondary to otosyphilis. This compares favorably with
patients with hearing loss, of which only 31% improve
Pharmacotherapy for Vestibular Dysfunction 665
with treatment.36 Patients with disabling tinnitus or
vertigo should undergo such therapy regardless of the
duration of symptoms because the likelihood of improve-
ment is reasonably high. However, patients with isolated,
long-standing hearing loss without fluctuation are less
likely to respond to therapy.37
Vestibular Migraine
Since the appearance of the first edition, much has been
learned about vestibular migraine. Likewise, the frequency
of occurrence of this disorder in both adults and children
has been recognized to a much greater degree. It is a
remarkably common disorder and no doubt represents
many of the atypical Ménière’s disease patients described in
the past. Migraine has long been considered a vascular dis-
order, with vasodilation responsible for the headache and
vasoconstriction responsible for the neurologic symptoms.
Basilar artery migraine produces symptoms related to
those areas of the CNS supplied by the posterior circula-
tion.38 However, serotonergic and central vestibular path-
ways may also be involved in migraine-associated vertigo
and vertiginous auras.8 Approximately 30% to 40% of
patients with classic migraine experience true vertigo. Other
patients can present with vertigo without concomitant
headache, referred to as a migraine equivalent.39,40 This dis-
ease also occurs in children; unfortunately, the misnomer
benign positional vertigo of childhood has been assigned by the
neurology community.41
Prophylactic therapy is indicated for those patients
whose lives are being negatively affected by the recurrent
vertigo associated with vestibular migraine, as all success-
ful regimens have potentially troublesome side effects.
The most common indication for prophylaxis is frequent
migraine, with symptoms occurring more frequently than
two episodes per month for 3 successive months.
Interestingly, adults with vestibular migraine more often
respond to tricyclic antidepressants or calcium channel
blockers than to beta blockers. Conversely, children with
vestibular migraine respond to beta blockers extremely
well. Empiric therapy with the most commonly used agent
may need to be followed with a change in class of medica-
tion until symptoms are controlled. Once symptoms are
controlled with prophylactic therapy for 6 months, patients
are weaned from their medication. If this is tolerated, then
retreatment is necessary only if symptoms recur. Sometimes
it is necessary to resume treatment with the prophylactic
agent for another 3 to 6 months before attempting to wean
the medication. Rarely, ongoing therapy is necessary, and
this decision is guided by the patients’ clinical features.
Very often, children with vestibular migraine stop having
this disorder as they approach puberty. Dietary counseling
is important, as tyramine- and caffeine-containing foods
such as blue cheese, red wine, grape juice, chocolate, and
tomatoes may serve as triggers for the migraine attacks.
Likewise, excessive caffeinated-beverage consumption,
fatigue, stress, and skipping meals may induce vestibular
migraine attacks in some patients.
Tricyclic antidepressants may be useful adjunct for pro-
phylaxis of migraine associated with panic attacks. For years,
the tertiary amine antidepressants such as amitriptyline
and imipramine have been used. Though effective, such
666 PERIPHERAL AUDIOVESTIBULAR DISORDERS
medications have adverse anticholinergic side effects such
as constipation, tachycardia, blurred vision, cognitive
impairment, and orthostatic hypotension.19 These side
effects can be detrimental, especially in the elderly popula-
tion. As individuals age, physiologic changes influence
pharmacotherapeutics. The specific changes involve water
volume, cardiac output, circulatory blood flow, bareorecep-
tor activity, gastric pH, intestinal absorption, hepatic blood
flow and function, hepatic enzymatic functions, kidney effi-
ciency, renal blood flow and general function, and visual
acuity.42 New forms of tricyclics called secondary amines
(e.g., desipramine or nortriptyline) have decreased side
effects and are effective in the treatment of migraines. For
this reason, the secondary amines are the tricyclics of
choice.
Beta blockers, calcium antagonists, anticonvulsants, and
tricyclic antidepressants are currently the most widely used
agents for prophylaxis of migraine.43 Propranolol is nor-
mally used in a high-dose range (80 to 240 mg/day) and
can produce significant side effects, including fatigue,
bronchospasm, congestive heart failure, and male impo-
tence.44 Calcium antagonists such as flunarizine (10-mg
dose at night) or verapamil (240 to 320 mg/day) have been
beneficial. However, side effects include sedation, weight
gain, depression, and extrapyramidal disorders.45,46 When
choosing a calcium channel blocker to treat vestibular
migraine in adults, the authors usually begin treatment
with verapamil (Verelan PM) 100 mg each night. This
medication is a sustained release formulation, and the dose
is increased after 3 to 4 weeks if the symptoms have not
been controlled. Recent studies also identify valproic acid
(Depakene) and divalproex sodium (Depakote) as medica-
tions for the prophylactic treatment of migraines. The
recommended starting dose is 250 mg bid, though some
patients may need to titrate to 1000 mg/day. Please note—
anticonvulsants are contraindicated in individuals with
liver function impairments.
Although infrequently used in vestibular migraine,
ergotamine tartrate has been the drug of choice for abort-
ing migraine symptoms for many years. It is a vasocon-
strictive agent that stimulates α-adrenoceptors and acts
as a serotonin antagonist. It also inhibits free uptake of
monoamines and sensitizes vascular smooth muscle to
sympathetic stimulation. This agent is contraindicated in
patients with sepsis or local infection, liver disease, and
vascular disease. It should be used with caution in patients
with hypertension or peptic ulcer disease. Usual dosage is
2 mg PO or as a rectal suppository, followed by additional
1-mg doses every half hour for two or three additional
doses if necessary. Frequent use of ergotamine can lead to
rebound headaches.47
Although sumatriptan (Imitrex) should not be used to
treat vestibular migraine, it is a common parenterally
administered vasoconstrictor that is an effective form of
abortive treatment for nonbasilar artery migraine. It is a
selective agonist for 5-hydroxytryptamine, a receptor
found on the basilar artery and in the vasculature of the
dura mater. It is administered as a 6-mg SQ injection
and relieves the headache associated with migraine within
an hour in 70% of subjects. This agent should be used
with caution in patients with hypertension, and it is
contraindicated in patients with ischemic heart disease, as
it may induce coronary vasospasm. Currently, sumatriptan
is not recommended for patients with basilar migraine.
Vertebrobasilar Insufficiency
Approximately one-third of transient ischemic attacks
(TIAs) involve the territories of the vertebrobasilar system.
These patients often manifest short-lived symptoms such
as vertigo, diplopia, dysarthria, bilateral limb weakness, gait
ataxia, variable and often bilateral sensory disturbance, and
memory loss.48 Antiplatelet therapy has been demonstrated
to effectively reduce the incidence of stroke after TIA. This
effect has been most clearly established for aspirin, which
can reduce by half the risk for stroke after TIA. Although
most previous studies have used doses of 1200 mg daily, it
is likely that 325 mg/day is equally effective.49,50
Ticlopidine (Ticlid) is another platelet aggregate
inhibitor shown to lower the risk for stroke after TIA,
particularly for cases of vertebrobasilar insufficiency. This
agent may be more effective than aspirin, reducing the risk
for stroke by 48% compared with aspirin during the first
year after TIA. However, this agent is associated with a
risk of neutropenia, which may be life-threatening, and
therefore it should be reserved for patients who are intol-
erant to aspirin therapy. All patients on ticlopidine therapy
should have complete blood count (CBC) and white cell
differential determination made at least once every 2 weeks
through the first 3 months of therapy. Neutropenia
reverses within 1 to 3 weeks after discontinuing treatment.
The efficacy of other compounds remains unproven.
Dipyridamole (Persantine) and sulfinpyrazone (Anturane)
confer no added benefit to aspirin therapy and are no
longer recommended.50 Pentoxyifylline (Trental) is a xan-
thine derivative that decreases blood viscosity and enhances
microcirculation. This agent has been shown to enhance
tissue oxygen levels in patients with peripheral vascular
disease, and it may be useful for cases of vertebrobasilar
insufficiency.
Full anticoagulation is typically reserved for patients
with impending or evolving stroke. Occasionally, anticoag-
ulants are used for tight stenosis of intracranial arteries,
particularly if TIAs persist despite antiplatelet therapy.50
Therapy is commenced with continuous IV infusion of
heparin to maintain a partial thromboplastin time that is
1.5 to 2.5 times normal. Subsequently, warfarin is added,
and heparin is discontinued when the prothrombin time is
elevated to 1.5 to 2.5 times normal.
Over 150 drugs have been reported to speed recovery
after a stroke, but none has been proven to be effective by
a careful clinical study. Glucocorticoids have been used
extensively to limit cerebral edema, which may render
viable brain that is sensitive to further ischemic damage.
However, clinical studies indicate that steroids are ineffec-
tive after ischemic infarction. Other commonly employed
interventions, including osmotic and loop diuretics and
hyperventilation, have not been subject to adequate clini-
cal trial to confirm efficacy.51
Several compounds are currently being investigated and
may prove beneficial for recovery after acute stroke. Such
agents include gangliosides, free-radical scavengers, 21-
aminosteroids, and amphetamine.51 Preliminary studies
show that dihydroergocristine, an ergot alkaloid with

potent dopaminergic activity, may reduce hypoxia-induced
cerebral metabolic changes.52 The calcium channel antag-
onist flunarizine has been shown to protect brain tissue
against neuronal damage in several models of cerebral
ischemia.53 The ultimate utility of these agents in stroke
patients awaits further clinical investigation.
Familial Ataxia Syndrome
Familial ataxia syndrome is a rare, autosomal-dominant
disorder that manifests by recurrent episodes of vertigo and
ataxia in several members of a family. Other prominent
symptoms can include diplopia, dysarthria, tinnitus, and
paraesthesia, but symptoms can vary considerably between
families. Familial ataxia syndrome is one of the most treat-
able causes of chronic episodic vertigo. Acetazolamide, a
carbonic anhydrase inhibitor diuretic, effectively prevents
the episodic vertigo and ataxia. The mechanism of this
action remains unclear. Systemic acetazolamide produces
CNS acidosis by reducing serum lactate and pyruvate, but
serum levels of lactate and pyruvate are normal in patients
with this syndrome. The antihistamine dimenhydrinate,
the benzodiazepine alprazolam, and the calcium antagonist
flunarizine have been shown to be effective for treating
symptomatic vertigo associated with the familial ataxia
syndrome.54,55 Recently, mutations in the calcium channel
gene CACNA1A have been demonstrated in patients suffer-
ing from episodic ataxia type 2.39 This subtype of familial
ataxia syndrome is characterized by episodic vertigo and
ataxia. In contrast, mutations in CACNA1A have not been
observed in families with migraine headaches and episodic
vertigo.56
Psychophysiologic Dizziness
Dizziness is associated with a wide range of psychiatric
illnesses. Patients with anxiety disorders manifested by
panic attacks are particularly susceptible to experience dis-
equilibrium, often described as a feeling of imbalance or
even a sensation of spinning inside the head. At present,
the term psychiatric dizziness should be restricted to dizzi-
ness (1) that is a component of a recognized psychiatric
syndrome and (2) that cannot be explained by clinical
evidence of vestibular dysfunction.4 Psychiatric disorders
associated with frequent complaints of dizziness include
psychosis, abasia, depression, hysteria, panic disorder with
agoraphobia, acrophobia, phobic postural vertigo, light-
headedness secondary to hyperventilation during panic,
and the obsessive personality disorder. Patients with
schizophrenia are more susceptible to motion sickness
and show an increased incidence of abnormalities on
vestibular testing. Certain compounds, including lactate,
caffeine, isoproterenol, yohimbine, and benzodiazepine
antagonists, have been shown to elicit panic attacks in sus-
ceptible individuals. This evidence suggest a possible
organic basis for the disequilibrium associated with psy-
chophysiologic dizziness that would be amenable to specific
pharmacotherapy.55
Treatment of psychophysiologic dizziness relies on
patient reassurance, psychotherapy, and pharmacotherapy.
Three classes of compounds have been shown to be
effective in reducing the frequency of panic attacks.
Pharmacotherapy for Vestibular Dysfunction 667
These agents include the benzodiazepines, tricyclic anti-
depressants, and monoamine oxidase inhibitors. Though
clinically all are effective, the side effects must be taken
into consideration.3,16
Benzodiazepines can have rebound symptoms following
medication cessation. In addition, anxiety disorders are
highly comorbid with depressive disorders and in fact can
be exacerbated by benzodiazepines. Addictive tendencies
also must be taken into consideration. Tricyclic antide-
pressants have high anticholinergic side effects. Safety
becomes an issue in patient populations with coronary
artery disease or cardiac dysrhythmias. Monoamine oxi-
dase inhibitors have multiple food and drug interactions.
In fact, they are contraindicated in populations with heart
failure, pheochromocytoma, hypertension, liver disease,
cardiovascular disease, seizure disorders, diabetes, and
suicidal tendencies.13,19 Nevertheless, when used appropri-
ately, these drugs can be highly effective.
Because of the numerous side effects of the previously
stated compounds, a fourth class of drugs is presently
under investigation. These include the selective serotonin
reuptake inhibitors (SSRIs) such as Prozac, Zoloft, Paxil,
Luvox, and Celexa. Side effects such as agitation, headache,
gastrointestinal upset, insomnia, and sexual dysfunction
may occur. Formal analysis is pending at this time although
the preliminary data look promising.13
Future Perspectives
The pharmacotherapy of vertigo caused by other common
causes of vestibular dysfunction currently relies on non-
specific suppression of symptoms. This is often the case
because the underlying pathophysiology of many vestibu-
lar syndromes remains poorly understood. Current tech-
niques of molecular biology promise to expand our
understanding of both the physiology and pathophysiol-
ogy of the human vestibular system. This knowledge may
lead to the development of future forms of specific phar-
macotherapy. For instance, cell and molecular biologic
techniques such as immunohistochemistry, in situ hybridiza-
tion histochemistry, and immunoelectron microscopy have
been used to identify neurotransmitters and receptors
involved in modulation of primary afferent pathways in the
vestibular neuroepithelium.7 These types of studies could
lead to the development of pharmacotherapy aimed specif-
ically at the vestibular end-organ.
Vestibular neuronitis (neuritis) is an idiopathic form of
acute unilateral vestibular paresis that is the third most
common cause of vertigo. Current management relies on
nonspecific treatment employing vestibular sedatives,
physical therapy, and vestibular exercises.55 The epidemic
occurrence of this condition, frequently following upper
respiratory tract infections, suggests that viral infection
of the vestibular nerve may explain the underlying patho-
physiology of vestibular neuronitis. Polymerase chain
reaction amplification of nucleic acids from archival human
celloidin-embedded temporal bone sections57 would pro-
vide an extremely sensitive tool to search for specific viral
agents in patients with a history of vestibular neuronitis.
This technique has recently been employed successfully to
localize varicella-zoster genomic DNA in temporal bone
sections from patients with Ramsay Hunt syndrome, a
668 PERIPHERAL AUDIOVESTIBULAR DISORDERS
polycranial viral neuropathy with clinical involvement of
the vestibular nerve in some of the cases.58,59 Histopatho-
logically, degenerative changes in the vestibular nerve,
Scarpa’s ganglion, vestibular neuroepithelium, and decreased
synaptic density within the ipsilateral vestibular nuclei are
consistent findings.60,61 Epidemiologic and serologic data
suggest a viral cause.62,63 The latent virus (e.g., herpes sim-
plex virus) is thought to remain dormant within the
vestibular primary afferent neurons (Scarpa’s ganglion).
Identification of viral genomic DNA in the temporal bone
of patients with vestibular neuronitis may lead to the
development of new forms of such specific antiviral ther-
apy. A few small studies appear to demonstrate benefit of
high-dose, IV acyclovir (Zovirax), which acts as a substrate
for virus-specific thymidine kinase during DNA synthesis,
in patients with Ramsay Hunt syndrome.64,65 In addition,
the new so-called pro-drugs such as valacyclovir (Valtrex)
and famciclovir (Famvir) are available and have the advan-
tage of achieving adequate therapeutic tissue levels via an
oral route. Some of the herpes viruses (e.g., varicella-zoster
virus) require an IV route for acyclovir to reach tissue levels
necessary to treat these infections. Likewise, the use of oral
steroids would be appropriate in combination with an
antiviral medication.
Gene transfer therapy is presently being developed for
the treatment of peripheral hearing and balance disorders.
One strategy, termed in vivo gene therapy, employs defective
viral vectors to introduce a functional gene to replace a
damaged gene within the inner ear. Several groups have
successfully developed and introduced nonreplicating viral
vectors and other vehicles into ganglion cells in vitro or
directly into the cochlea in vivo.66 These methods will add
an important weapon to our surgical armamentarium after
more mechanisms of vestibular and auditory dysfunction
are characterized at the molecular level.
SYMPTOMATIC PHARMACOTHERAPY
The commonly used antivertiginous medications and their
doses are listed in Table 42-5. The effectiveness of each
drug has been determined empirically; however, it is diffi-
cult to predict which drug or combination of drugs will be
most effective, since a patient may respond to one drug but
not to others in the same class. Antivertigo drugs are typi-
cally classified by their chemical structure (e.g., diazepam
is a benzodiazepine), behavioral properties (e.g., diazepam
has sedative and anxiolytic properties), or mechanisms of
action (e.g., benzodiazepines enhance inhibition via
GABAA receptor-gated chloride channels; see Table 42-5).
As a group, current antivertigo medications have multiple
mechanisms of action, which include potentially effica-
cious actions that range from antagonism of muscarinic
cholinergic, histiminergic, and monoaminergic transmis-
sion to calmodulin inhibition and blockade of voltage-gated
calcium channels (see Table 42-5). It is also important to
note that the direct effects of these drugs may also affect
central neurotransmitter levels, which have the potential
to affect vestibular pathways. For example, promethazine
reduces dopamine turnover and increases noradrenaline
turnover, dimenhydrinate reduces dopamine turnover, and
meclizine has little effect on monoamine metabolism.67
Furthermore, although flunarizine was characterized ini-
tially as nonspecific Ca2+ channel and Na+ channel blocker,68
more recent studies indicate that acute doses increase69,70
and chronic treatment decreases extracellular striatal
dopamine and metabolites70 and that flunarizine administra-
tion inhibits dopamine uptake.71 Although ample evidence
supports the contention that monoaminergic, histaminer-
gic, muscarinic cholinergic, and GABAergic mechanisms
are present within the vestibular nuclei (for review see
Smith and Darlington72), there is inadequate evidence to
associate the efficacy of these medications with any specific
central or peripheral sites. Four general classes of drugs are
useful for treating vertigo and the associated autonomic
symptoms of nausea and vomiting.16 The classes include
anticholinergic agents, monoaminergic agents, antihista-
minic agents, and antidopaminergic agents. Miscellaneous
agents that are also effective include the benzodiazepine
diazepam (Valium), the calcium antagonist flunarizine, and
the histaminic agent betahistine. Recent evidence has also
favored the use of SSRIs and clonazepam,13 which are also
particularly useful in minimizing the associated symptoms
of anxiety and panic. Carvedilol, a beta blocker that has
found clinical applications for treatment of hypertension,
is currently being investigated as an agent for the sympto-
matic relief of vertigo.73
Mechanism of Action
Numerous animal studies have documented that drugs
with anticholinergic and monoaminergic activity diminish
the excitability of neurons in the vestibular nucleus.74,75
Anticholinergic drugs suppress both the spontaneous
firing rate and the response to vestibular nerve stimula-
tion.76–78 Iontophoretically applied acetylcholine, metha-
choline, and carbamylcholine excite neurons in the medial
and lateral vestibular nuclei; this excitation is blocked with
atropine.79 These observations suggest a cholinergic
innervation on secondary vestibular neurons. In addition,
cholinergic neurons in the nearby reticular formation
project to the vestibular nuclei. However, since muscarinic
cholinergic mechanisms are distributed widely in the
brain, actions at other levels of central vestibular pathways
are also likely.
Drugs with significant antihistaminergic activity have
long been used in treating vertigo and preventing motion
sickness, yet little is known about their mechanism of
action. More recent evidence (see Table 42-5) further
indicates that standard antihistaminergic antivertigo
medications have significant antimuscarinic cholinergic
activity in addition to antagonism of histamine H1 recep-
tors. Since histamine excites neurons in the vestibular
nuclei,80 it is expected that the combination of antihista-
minergic and antimuscarinic actions of these drugs will
depress activity in the vestibular nuclei. Since appreciable
histaminergic innervation is also present in brainstem
autonomic regions and the parabrachial nucleus, the anti-
motion sickness efficacy of these drugs may reflect actions
at multiple levels in vestibuloautonomic pathways.
Antagonism of dopamine D2 receptors, serotonin 5-HT2
receptors, and α1-adrenoreceptors are common features of
antivertigo drugs with significant antiemetic actions. These
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
butyrophenones haloperidol (Haldol) and droperidol
(Inapsine). The antiemetic actions are presumed to be due
to effects at sites other than the vestibular nuclei.
However, several potential direct actions are possible on
vestibular pathways. Since these drugs have antihistamin-
ergic (H1) activity, they are expected to share actions with
the antihistaminergic antivertigo drugs. Chlorpromazine
also has antimuscarinic activity and has been shown to
depress the responsiveness of vestibular nucleus neurons.
The possible actions of these drugs on noradrenergic and
serotonergic transmission in the vestibular nuclei are more
complex. For example, norepinephrine has been reported
to increase and decrease the background activity of
vestibular nucleus neurons, presumably via both α1- and
α2-adrenoceptors.81 Since serotonin also has excitatory,
inhibitory, and biphasic effects on different vestibular
nucleus neurons, the precise mechanisms of action are
unknown. However, the emergence of symptoms of a bal-
ance disorder after abrupt discontinuation of an SSRI
(SSRI discontinuation syndrome)8 indicates that serotonin-
ergic mechanisms are perhaps a critical component of cen-
tral vestibular neurochemistry. Clinically, it is important to
note that extrapyramidal side effects of these medications
result from their affinity for dopamine receptors.
Several tranquilizers are effective in suppressing vertigo.
Diazepam (Valium) decreases the resting activity of
vestibular nuclei neurons, possibly by decreasing another
reticular facilitative system. It also affects crossed vestibu-
lar and cerebellovestibular inhibitory transmission and it
decreases the production of CSF centrally.77,78,82,83
Strategy in the Treatment of Vertigo
The choice of drug or drug combination is based on the
known effects of each drug (see Table 42-5) and on the
severity and time course of symptoms. Prolonged severe
vertigo is an extremely distressing symptom. The patient
prefers to lie still with eyes closed in a quiet, dark room. In
this setting sedation is desirable, and the tranquilizing
medications listed in Table 42-4 are most effective. Each of
these drugs has significant side effects, however, and there-
fore must be used with caution. Parenteral diazepam, for
example, can cause respiratory depression and hypotension
and should be used only in a hospital, where emergency
resuscitation equipment is available. If nausea and vomit-
ing are severe, the antiemetic prochlorperazine can be
combined with the antivertiginous medication.
The patient with chronic recurrent vertigo usually
attempts to carry on normal activity, and therefore sedation
670 PERIPHERAL AUDIOVESTIBULAR DISORDERS
is undesirable. Antihistaminic, monoaminergic, and anti-
cholinergic medications are useful. Of the antihistamines,
promethazine (Phenergan) has the most sedating effect
and is therefore useful only when moderate sedation is
desired. A combination of promethazine and the sympath-
omimetic ephedrine (25 mg of each) produces less sedation
than promethazine alone and is more effective in relieving
associated autonomic symptoms.16,19 Meclizine (Antivert),
cyclizine (Marezine), dimenhydrinate (Dramamine), and
scopolamine can be effective in treating mild episodes of
vertigo.
Central compensation for peripheral vestibular dysfunc-
tion appears to involve changes in contributions of the
intact labyrinth, use of alternative gravitoinertial sensory
cues (vision, proprioceptive, somatosensory, and cardio-
vascular), and adoption of different strategies for perform-
ing movements. Since this process is a form of motor
learning, it is essential that the patient return to normal
activity to recalibrate central vestibular pathways. Viewed
from this perspective, the combined sedative and antiver-
tigo properties of medications for symptomatic relief
require a therapeutic trade-off of acute relief at the
expense of attenuating compensation. On the other hand,
sympathomimetics and vestibular rehabilitation therapy
can be added to facilitate the compensatory process.
Symptomatic management of positional vertigo is diffi-
cult because, although the vertigo is severe, it is short-lived.
To completely suppress these brief episodes, heavy sedation
throughout the day would be required, which is usually
unacceptable to the patient. The most common variety,
benign paroxysmal positional vertigo, has a short duration
(usually 30 seconds or less); however, some patients will
complain of vestibular dysfunction lasting for much longer
intervals. This initial patient response can be extremely mis-
leading, unless the otolaryngologist aggressively attempts to
separate the episode of true vertigo from the autonomic dys-
function that follows. The severity of the autonomic dys-
function varies on any individual and may be severe with
disabling imbalance and unsteadiness combined with nausea
and diaphoresis. Other patients will experience mild true
vertigo with movement in the plane of the involved semicir-
cular canal. Very often the patient will identify the plane of
rotation that elicits the vertigo and assiduously avoid this
movement. Spontaneous remission occurs in more that
90% of patients within 6 months, although a small percent-
age do have recurrence.84 A simple explanation of the nature
of the disorder and its favorable prognosis helps to relieve
the patient’s anxiety. Medications with mild sedative effects
(e.g., diazepam, meclizine, or cyclizine) are useful when the
episodes recur frequently and to decrease the autonomic
dysfunction that commonly impairs the patient’s quality of
life. Particle repositioning maneuvers and vestibular reha-
bilitation therapy are extremely effective in the treatment of
benign positional vertigo. In rare cases of intractable benign
positional vertigo, transection of the posterior ampullary
nerve or plugging of the posterior semicircular canal has
resulted in prompt remission of symptoms.1
Prophylaxis of Motion Sickness
Generally the antivertiginous medications listed in Table
42-5 are also effective in treating and preventing motion
sickness. The principal symptoms of motion sickness are
malaise and nausea rather than vertigo, which may be con-
sidered as visceral referred symptoms of somatic origin.2
Tolerance develops after 2 or 3 days of constant stimulation,
and prophylactic use of drugs several hours before travel is
more effective than treatment of symptoms.16,85
Oral or parenteral scopolamine was one of the first
drugs used to treat motion sickness and was the first drug
proved effective in its prevention. In the 1940s controlled
drug trials were carried out on military recruits during
amphibious training, aviation training, and swing tests. A
dose of 0.6 to 0.8 mg of scopolamine protected 50% of
susceptible subjects for at least 8 hours. However, unto-
ward effects (primarily drowsiness, dryness of the mouth,
and blurred vision) limited the use of oral or parenteral
scopolamine for motion sickness.19,42
With the introduction and subsequent general use of
antihistamines, particularly dimenhydrinate, scopolamine
was neglected for many years. Interest in scopolamine was
rekindled, in the form of transdermal scopolamine
(Transderm-Scop). With this delivery system, scopolamine
is gradually released through a microporous polypropylene
membrane contained in a patch that is placed on the skin
behind the ear. A small dose (0.05 mg) is slowly released
and absorbed over a 3-day period. Initial clinical trials
indicate that transdermal scopolamine is effective in pre-
venting motion sickness with minimal side effects, the
main side effect being dryness of the mouth.86,87 The use
of transdermal scopolamine for more than 3 consecutive
days can, on discontinuation of therapy, result in with-
drawal symptoms that mimic motion sickness, including
dizziness, nausea, vomiting, and headache.88,89 To be effec-
tive the patch must be in place several hours before expo-
sure to motion; however, production of this product has
been suspended. Future studies will determine whether
other antivertiginous drugs can be effectively administered
in this manner.
Clinical trials of antimotion sickness drugs under
controlled laboratory conditions have shown that combi-
nations of drugs are often more effective than any single
drug.16,19,42 Particularly effective combinations have
included scopolamine (0.6 mg), promethazine (25 mg) and
dextroamphetamine (10 mg), and promethazine (25 mg)
and ephedrine (25 mg). As in the treatment of vertigo, it is
difficult to predict which drug or drugs will be most effec-
tive in preventing motion sickness in an individual. In
controlled laboratory experiments the responses of normal
volunteers to the same drug or combination of drugs often
vary greatly, even when identical motion stimuli are used.
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 Chapter
Surgical Neurotology: An Overview

Outline
The Contemporary Concept
of Neurotologic Skull Base
Surgery
Fundamental Considerations
Special Operating Room
Requirements
Patient Positioning
Instrumentation
Hemostasis
Vascular Considerations
Approaches to Lesions
Primarily in the Cranial Base
Temporal Bone
Petrous Apex, Petroclival
Junction, and Foramen
Lacerum
Clivus
Jugular Foramen
Infratemporal Fossa
43
Transbasal Approaches The Ventral Surface Robert K. Jackler, MD
to Intracranial Tumors of the Brainstem
Internal Auditory Canal and Combined Craniotomy of
Cerebellopontine Angle the Middle and Posterior
Retrosigmoid Approach Cranial Fossae
Transpetrosal Approaches Transcochlear Approach
Middle Fossa Craniotomies Meckel’s Cave
Middle Fossa Approach The Craniovertebral Junction
to the Internal Auditory Surgical Anatomy
Canal Indications
Extended Middle Fossa Technical Considerations
Approach to the Advantages
Cerebellopontine Angle Disadvantages
Middle Fossa-Transpetrous Vertebrobasilar Lesions
Apex Approach to the Reconstruction of the
Ventral Pons and Anterior Cranial Base
Cerebellopontine Angle Closure of Defects
Intracranial Aspect of Prevention of Cerebrospinal
Jugular Foramen Fluid Leakage

THE CONTEMPORARY CONCEPT OF simple platelike calvaria in preference to navigating the

NEUROTOLOGIC SKULL BASE SURGERY
The earliest surgical efforts to approach the skull base took
place not long after the introduction of anesthesia in the
latter portion of the nineteenth century. Pioneering efforts
include those of Krause, Frazier, and others to approach
the trigeminal ganglion in Meckel’s cave for the relief of tic
douloureux.1 It was obvious even to early surgeons that the
most direct approach to certain inaccessible intracranial
lesions was through the cranial base rather than the con-
vexity. Transtemporal approaches to the cerebellopontine
angle were first proposed by Panse in 1904 (although he
never performed the procedure) and were tentatively
explored by Borchardt in 1905, Quix in 1911, and a few
others during the early decades of the twentieth century.2–4
The openings provided in these fledgling efforts proved too
deep and narrow for effective action against the giant
tumors typical of the era. In addition, the problem of closure
against cerebrospinal fluid (CSF) leakage had not yet been
surmounted, nor had methods been invented to permit
atraumatic removal of bone from the carotid artery, the
facial nerve, or other important neurovascular structures
that traverse the base of the skull. Thus, for the first two-
thirds of the twentieth century, surgeons preferred to expose
tumors in and around the base of the brain by opening the
dauntingly complex osteology of the cranial base. This sim-
pler solution was seen as expeditious despite the fact that it
frequently required injurious degrees of brain retraction. In
the early 1960s, House and others, armed with modern
operating microscopes possessing potent sources of illumi-
nation and controllable high-speed drill systems, resur-
rected and ultimately made practical a number of skull base
approaches that had been tried much earlier and discarded
as impractical. (See William F. House’s personal commen-
tary on this early microsurgical era in this text’s foreword.)
As a specialized endeavor, skull base surgery is a rela-
tively new field. It defined itself during the 1980s as a direct
result of the introduction of three fundamental technolog-
ical innovations: (1) high-resolution multiplanar imaging
(computed tomography [CT], magnetic resonance imaging
[MRI]) to provide detailed tumor maps, (2) improvements
in microsurgical optical systems and instrumentation, and
(3) the invention of neurophysiologic monitoring. Two
nontechnological factors were also essential in the devel-
opment of contemporary skull base surgery. The first was
the increasing willingness of patients to travel from their
home region to distant centers with specialized expertise
and technical resources. This fostered the accumulation of
sufficient experience to both hone skills and undertake
meaningful outcomes analysis. The second nontechnical
675
676 SURGICAL NEUROTOLOGY
advance has been the willingness of surgeons to collaborate
in a multidisciplinary fashion to share expertise and to
mitigate the limitations imposed by operator fatigue in
prolonged microsurgical procedures.
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
resection when morbidity can be kept low. The current
trend, in selected situations, is toward less than total resec-
tion when the risk of debilitating neuropathy (e.g., diplopia,
facial palsy) is high. In many cases such remnants will not
grow or can be controlled with stereotactic radiosurgery.
Although their place in the surgical armamentarium contin-
ues to evolve, it has become abundantly clear that skull base
surgical approaches have greatly improved the prognosis for
patients afflicted by lesions in and around the skull base in
terms of both the likelihood of cure and the preservation
of brain and cranial nerve function.
The term skull base surgery is somewhat of a misnomer in
that only a minority of these procedures in neurotology are
actually carried out for disease intrinsic to the skull base.
Rather, a majority are undertaken to provide exposure for
inaccessible intracranial disease located either beneath the
cerebral cortex or adjacent to the brainstem. A high percent-
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
essence, the fundamental concept of transbasal craniotomy is
the removal of skull base bone to minimize (or even prevent)
the need for retraction of the brain (cerebrum, cerebellum).
In line with this concept, the organization of this chapter has
two major sections: (1) approaches to lesions that are largely
intrinsic to the cranial base (e.g., glomus jugulare, petrous
apex cholesterol granuloma) and (2) procedures undertaken
to expose primarily intracranial disease (e.g., meningioma,
schwannoma, epidermoid).
It has been traditional to present the subject of skull base
surgery by rostering each operative approach and explaining
its utility. However, rational treatment decisions are based
on an analysis of the advantages and disadvantages of the
various technical options for a given anatomic location. It
hope that the topical organization of this chapter according
to the anatomic site of interest will prove more useful
during treatment planning. For additional illustrations of the
procedures introduced in this chapter, please refer to this
volume’s accompanying surgical atlas5 (Fig. 43-1).
FUNDAMENTAL CONSIDERATIONS
Special Operating Room Requirements
To be suitable for neurotologic surgery an operating room
must be fairly large to accommodate the variety of instru-
mentation required for these procedures. Arrangement of
the room requires complex planning to efficiently position
the operating microscope, surgical drill, mono- and bipo-
lar cautery, neural monitoring equipment, as well as a large
table of surgical instruments and the considerable comple-
ment of devices needed to monitor the patient undergoing
neuroanesthesia. In addition, many situations call for the
7,8
IAC
CO
GG
ME 5
EAC
P
M
Cb
SCC
CPA
SS
4V
Figure 43-1. An axial view of the skull through the level of the internal
auditory canal and cerebellopontine angle. Cb, cerebellum; Co, cochlea;
CPA, cerebellopontine angle; EAC, external auditory canal; GG, geniculate
ganglion of the facial nerve; IAC, the internal auditory canal; M, mastoid air cell
system; ME, middle ear; P, pons; SCC, semicircular canals; SS, sigmoid sinus;
4V, fourth ventricle; 5, trigeminal nerve; 7, facial nerve; 8, audiovestibular nerve.
use of specialized surgical tools such as the Cavitron ultra-
sonic aspirator (e.g., CUSA) or laser. An electrically quiet
environment is essential during neurotologic surgery
because 60-cycle noise readily obscures the faint potentials
detected by neural monitoring equipment. The need for a
television monitor to display the microsurgical view is
obvious in educational settings, but it is also important to
provide context to the neurophysiologic monitoring team
and to involve the scrub nurse and circulator better in the
progress of the procedure.
Patient Positioning
The great majority of neurotologic procedures are done
with the patient in the supine position with the head rotated
away from the surgeon (Figs. 43-2 and 43-3). Exposure of
the suboccipital region may be accentuated by use of a bol-
ster under the ipsilateral shoulder. A headholder (e.g.,
Mayfield design) that permits removal of the rostral portion
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.
Overrotation of the head should be avoided because it might
impair venous return via the vertebral system, thereby cre-
ating a tendency toward cerebellar swelling. The true lateral
or park bench (3/4 rotated) positions may also be used, but
with greater pressure on the contralateral arm and hip.
Insufficient padding during a prolonged procedure may lead
to pressure necrosis or neurologic injury, particularly to the
brachial plexus or ulnar nerve. The prone position is impor-
tant for midline cerebellar tumors, but it has little role in the
extra-axial tumors typically addressed by the neurotologist.
The sitting position, which is still employed for poste-
rior fossa surgery by a few centers, is steadily decreasing

Figure 43-2. Operating room setup used in neurotology for a lateral
transtemporal procedure.
in popularity. The primary advantage of the upright posi-
tion is that blood drains away from the operative field.
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
in which to perform a prolonged microsurgical procedure.
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
flap is planned, the patient’s back must be prepped and
draped. During mobilization of the flap, the patient is tem-
porarily rotated into the lateral position.
During neurotologic surgery the operating table should
be reversed so that the patient’s head is located at the foot
of the bed. This permits the surgeon to sit during micro-
surgery without obstruction under the table that might
interfere with a comfortable leg position. Since a reversed
table might tend to tip over with obese patients, use of an
extra heavy table is desirable. Alternatively, additional
weight (e.g., sandbags) can be tied to the end of the bed to
counterbalance this tendency. The operating table is fre-
quently turned from side to side during neurotologic proce-
dures. An electrically controlled bed-positioning system,
which can be operated by either the anesthesiologist or
nurse, is a substantial convenience. A typical operating table
has a limited range of side-to-side tilt, usually approximately
15 degrees. Certain models permit rotation in the range of
30 degrees, which can be of significant advantage during
neurotologic procedures. To help maintain position when
using extreme tilts, it is important to support the patient
Surgical Neurotology: An Overview 677
Figure 43-3. Operating room setup used in neurotology for a middle fossa
procedure.
with a well-padded kidney brace or a similar apparatus
attached to the bed frame.
Instrumentation
In neurotologic surgery, a diverse set of microsurgical instru-
ments are required. Heavy, blunt elevators are needed for
elevation of the periosteum and mobilization of dura from
the cranial base. More delicate dissection tools are needed
for mobilization of brain and cranial nerves as well as dissec-
tion of arachnoid planes. To accommodate for the deep field
of action typical of neurotologic procedures, instruments
must have considerably longer shafts than those used in con-
ventional otologic surgery. An excellent collection of instru-
ments for neurotologic surgery is the Rhoton microsurgical
instrument set, which includes a selection of arachnoid
knives of various sizes, hooks, needles, fine curettes, as well
as blunt dissectors in several sizes and angulations.
A variety of suction instruments between 5 and 12 French
are needed. Large-bore suction catheters are required
when rapidly removing bone or during episodes of brisk
hemorrhage. Smaller, fenestrated suctions facilitate main-
taining a dry field while minimizing the potential of acciden-
tally injuring a cranial nerve or small vessel. Tip fenestrations
reduce the unwanted tendency of the suction to ingest and
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).
It is often helpful to have two suction lines available during
neurotologic procedures, one of which can be attached to
the posterior arm of a retractor to facilitate removal of
irrigant solution.
Although it should be minimized whenever possible, a
degree of brain retraction is required in many neurotologic
procedures. Brain retractors may be anchored to the surgical
table (e.g., Greenberg), to a headholder (e.g., Mayfield), or
on a Weitlander style retractor (e.g., Apfelbaum, Wiet,
Silverstein). As a general rule, the cerebellum is more tol-
erant to brain retraction than the temporal lobe. Moderate
cerebellar retraction seldom leads to dysmetria; elevation
of the temporal lobe to a similar degree occasionally
results in a transient dysphasia and memory disturbance,
particularly when the dominant side is involved.
The removal of most tumors managed by neurotologists
can be considered as two stages: (1) debulking of the tumor’s
core and (2) microdissection of the brain, cranial nerves, and
vessels from the tumor’s capsule. Several special tools have
been developed to facilitate the former task. The ideal tumor
debulking implement works rapidly, incites minimal hemor-
rhage, and respects the tumor capsule in order to avoid acci-
dental injury to a vessel or cranial nerve coursing on the
tumor surface. The ultrasonic aspirator (e.g., Cavitron ultra-
sonic surgical aspirator) rapidly debulks lesions while mini-
mizing the risk of inadvertently violating the capsular plane.7
The House-Urban rotatory dissector is also in widespread
use but is less respectful of the capsular surface and is there-
fore more dangerous, especially in inexperienced hands.
Finally, the surgical laser performs the debulking task
admirably, but high-power densities are needed to provide
reasonable speed.8 Unfortunately, none of these special tools
is particularly useful in liberating delicate structures from the
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
and tenacious. Development of the capsular planes requires
painstaking microdissection using fine scissors along with a
combination of both sharp and blunt dissectors.
A surgical drill used in neurotologic surgery must be suf-
ficiently powerful to rapidly excavate bone as well as delicate
enough to permit removal of thin osseous edge adjacent to a
naked cranial nerve. Suitable designs with variable torque are
available powered by either electricity or compressed air.
Although most work may be accomplished with a straight
handpiece, an angled handpiece affords improved visibility in
deep and narrow operative fields. Special handpieces with
long, narrow shafts have been developed for particularly con-
stricted exposures. Burrs in a variety of sizes and both cutting
and diamond varieties are needed. Large diamond burrs
(e.g., 6 mm, 8 mm, and 10 mm) are especially important
because they permit atraumatic removal of bone from dural
surfaces. Copious irrigation while the surgeon is drilling
should both increase burr life as well as avoid untoward heat
buildup, which may injure underlying neural structures. The
use of topical antibiotics (e.g., bacitracin) in irrigant solutions
during neurotologic procedures has been suggested as a
means of lessening the bacterial inoculum, thereby reducing
infectious complications.9 It should be noted that bacitracin
solution induces a froth that may occlude the values in the
surgical suction line.
Hemostasis
Hemostasis is important in neurotologic surgery both for
the obvious reason of reducing blood loss and to maintain
a blood-free field to permit an orderly microsurgical
dissection. Bipolar cautery is most important intracranially
to limit current spread to the adjacent neural structures.
Recently developed bipolar cautery units with automated
irrigation systems are most convenient and reduce the ten-
dency of the forceps to adhere to the cauterized tissue. At
times, use of cautery is unwise either because of the prox-
imity of the bleeder to a cranial nerve or because the hem-
orrhage is diffuse and not amenable to pinpoint control. In
such cases, an application of thrombin-soaked Gelfoam
pledgets or a pad of lyophilized collagen (Avitene) may
control minor oozing.
Control of bone bleeding can usually be accomplished
with diamond burrs, especially if irrigation is momentarily
halted. Diamond burrs create a fine bone paste, which
impacts and occludes small vascular channels in bone.
Reversing the direction of a cutting burr may accomplish the
same task. More stubborn bone bleeders can be controlled
through the application of bone wax.
Not infrequently, while the surgeon is working around
dural sinuses, hemorrhage develops due to either a mural
tear or avulsion of an emissary vein. This may be controlled
by placing a wad of oxidized cellulose (Surgicel) over the
defect and holding it in position with a retractor. When
controlling bleeding from a major sinus or the jugular bulb,
it is important to prevent embolization of the packing mate-
rial. This risk is minimized by extraluminal application of a
piece of Surgicel substantially larger than the defect. If fur-
ther drilling is required near the Surgicel packing, it must be
covered by a smooth material such as Telfa because Surgicel
fibers readily become entangled in the shaft of the drill.
Vascular Considerations
The three major arterial braches of the vertebrobasilar sys-
tem traverse the cerebellopontine angle: posterior inferior
cerebellar artery (PICA), anterior inferior cerebellar artery
(AICA), and the superior cerebellar artery (SCA) (Fig. 43-4).
The skill required to preserve these arterial structures is
essential for a surgeon performing intracranial tumor
microdissection.
PICA is located inferiorly, passing close to the roots of
the lower cranial nerves. It may become enmeshed in the
intracranial aspect of jugular foramen tumors and is occa-
sionally involved in meningiomas of the lower clivus and
craniovertebral junction. Disruption of PICA gives a
lesion of the lateral medullary (Wallenberg’s) infarc-
tion characterized by a variable combination of dysphagia,
dysarthria, vocal cord paralysis, vertigo, facial paralysis,
and ataxia, as well as ipsilateral Horner’s syndrome and
contralateral hemisensory disturbance.10
AICA is often mentioned to possess a “loop” in the CPA,
which gives off a distal branch into the IAC, which sup-
plies the inner ear (internal auditory artery).11 However,
AICA has in reality two loops, the first of which is applied
to the brainstem surface and provides nutrient perforators
to the brainstem (Fig. 43-5). The second, more distal loop
lies laterally in the CPA, where it gives rise to the IAC
artery. Interruption of the first loop gives a devastating

IAA
SCA
PICA
AICA
Figure 43-4. The major arteries of the cerebellopontine angle. AICA, anterior
inferior cerebellar artery; IAA, internal auditory artery; PICA, posterior
inferior cerebellar artery; SCA, superior cerebellar artery.
neurologic injury with hemiplegia and multiple central
cranial nerve dysfunctions, whereas loss of the distal loop
causes a more focal cerebellar peduncular infarction with
persistent ataxia11,12 (Fig. 43-6).
The superior cerebellar artery is sometimes placed at
risk in exposing transtentorial tumors. Injury to the SCA
causes dysmetria, dysdiadochokinesia, dysarthria, ataxia,
vertigo, and sometimes diplopia.13
Preservation of the veins of the posterior fossa is much
less critical than preservation of the arteries. The petrosal
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
auditory artery.
Surgical Neurotology: An Overview 679
Figure 43-6. Occlusion of the proximal trunk of the anteroinferior cerebellar
artery results in an extensive pontomedullary infarction (gray region).
Blockage of the distal segment give a focal infarction of the middle cerebellar
peduncle (dark circle).
vein (also know as Dandy’s vein) parallels the trigeminal
nerve just beneath the tentorium. It can often be preserved,
but in large tumors is frequently taken without conse-
quence. Rarely does its division lead to cerebellar venous
congestion.14 Numerous veins travel roughly rostrocaudally
on the brainstem surface. At least some of these need to be
taken during removal of a large CPA tumor and, fortunately,
their interruption seldom leads to adverse consequences.
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 43-7. The vein of Labbé, which bridges from the cortex to enter the
transverse sinus, drains the temporoparietal region.
680 SURGICAL NEUROTOLOGY
B upon presentation.
Figure 43-8. A, Two common courses of the vein of Labbé in its route
toward the transverse sinus. The vein may lie on the upper surface of the
tentorium or even run between its leaves. B, To avoid the vein of Labbé
during tentorial division in the combined middle and posterior fossa
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
placed more medially to prevent injury to this important venous structure.
craniotomy, great care is taken to preserve this functional
end vein whenever possible.
APPROACHES TO LESIONS PRIMARILY
IN THE CRANIAL BASE
Temporal Bone
Several tumor types may necessitate extensive resection of
the temporal bone.16 The most common such tumor is
invasive squamous cell carcinoma arising from the external
auditory canal. Relatively early, it extends beyond the con-
fines of the ear canal and grows along the skull base into
the infratemporal fossa. The inner ear, dura, and vascular
compartment of the temporal bone can be involved in
advanced cases. Adenomatous tumors, especially the
aggressive papillary adenocarcinoma of endolymphatic sac
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
The degree of temporal bone resection is determined by the
anatomic extent of the tumor and its biologic tendencies.17
The minimal temporal bone resection for squamous carci-
nomas entails en bloc removal of the external auditory
canal (Figs. 43-10 and 43-11). The so-called sleeve excision
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
mandibular joint may be included in the specimen. Medial
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
endolymphatic sac tumors, the posterior fossa dura must be
included in the specimen, and the ear canal can sometimes
be preserved. Resection in adenocystic carcinoma should
be thorough but not unnecessarily radical. These lesions
are seldom cured even when the primary lesion is small and
initial surgery extensive. Fortunately, they tend to progress
slowly. Surgery in temporal bone sarcomas is only adjunc-
tive to chemotherapy. Since perimeningeal or intracranial
spread are risk factors for recurrence, cytoreduction by
removing the peridural component is often desirable.
One general theme in temporal bone resection is that,
unless it is grossly infiltrated by tumor, a functioning facial
nerve should be preserved whenever possible. When post-
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
carotid artery has been skeletonized.
the cartilage that fills foramen lacerum19 (Fig. 43-14). These
originate at the petroclival junction and may erode laterally
into the inner ear and medially into the clivus.20 Posteriorly,
they may prolapse into the cerebellopontine angle.
Secondary involvement of the petrous apex may occur due to
lateral spread of clival chordoma or deep penetration of
intratemporal tumors such as squamous cell carcinoma.
The surgical approach to petrous apex chondrosarcoma
is via a subtemporal craniotomy (Fig. 43-15). Extradural
Figure 43-14. Chondrosarcoma of the petroclival junction arising in the
cartilage of foramen lacerum.
Figure 43-15. Exposure of a petroclival junction chondrosarcoma
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.
elevation of the temporal lobe brings into view the anterior
surface of the petrous ridge. The tumor is approached by
resecting the petrous ridge between the internal auditory
canal and Meckel’s cave. This necessitates division of the
greater superficial petrosal nerve with resultant dry eye.
Dissection can be carried medially into Meckel’s cave but
caution must be exercised to avoid injury to the sixth nerve
in Dorello’s canal. The floor of the apical resection is
the horizontal course of the intrapetrous carotid artery.
Figure 43-16. Clival chordoma.

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
remnants oriented along the midline of the cranial base
(Fig. 43-16). Chordomas that have remained extradural and
are confined to the midline skull base are approached ante-
riorly, most commonly via either a transsphenoethmoidal or a
transoral approach.21–23 The anterior strategy is to create a
modest opening into the tumor cavity and then blindly exca-
vate the gelatinous tumor by scraping the cavity walls with
curettes. The neurotologist becomes involved in chordoma
surgery when the tumors spread intradurally or spread
laterally behind the intrapetrous carotid arteries.
Chordomas that breech the posterior fossa dura compress
the midbrain, pons, and/or medulla and abut the basilar
artery. Anterior approaches are not advisable for intradural
tumors because they
1. Provide a deep field of action ill suited for microdis-
section
2. Approach the brainstem-tumor interface from a dis-
advantageous direction
3. Traverse contaminated spaces
4. Present great difficulty in resealing the dura to avoid
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
single opening consisting of a limited petrosectomy (retro-
labyrinthine approach) and a middle fossa opening joined
by division of the tentorium. As is discussed throughout this
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)
and the complex of cranial nerves VII–VIII, and also
between cranial nerves VII–VIII and the root entry of the
fifth nerve. Although this presigmoid combined approach
affords excellent access to the posterior intradural compo-
nent, it is limited anteriorly in the cranial base. A second
stage anterior approach to address a ventrally situated tumor
(e.g., in the perisphenoid region) may be required.
Jugular Foramen
The jugular foramen is traversed by the jugular vein along
with the glossopharyngeal (IX), vagus (X), and accessory
nerves (XI)25 (Fig. 43-17). Anteromedially is the internal
carotid artery. Superiorly is the hypotympanum and
Surgical Neurotology: An Overview 683
Figure 43-17. Overview of jugular foramen relationships.
otic capsule. Laterally is the mastoid and, very important,
the vertical segment of the facial nerve canal. Posteriorly
are the lower reaches of the posterior fossa adjacent to the
lateral aspect of the pontomedullary junction and medulla.
The most common tumors of the jugular foramen are
paraganglioma (glomus jugulare), schwannoma of the
lower cranial nerves, and meningioma. Glomus tumors and
meningiomas often present with a visible component in the
middle ear, whereas schwannomas do not. Each may occur
in one of four anatomical varieties: (1) limited to the jugular
foramen in the cranial base, (2) pear-shaped with a compo-
nent in the infratemporal fossa, (3) pear-shaped with a lobe
in the posterior cranial fossa, and (4) dumbbell-shaped with
sizable components both intra- and extracranially.
Common to all jugular foramen operations is a transmas-
toid opening of the jugular foramen and exposure of the
great vessels in the upper neck. Safe surgery in the jugular
foramen requires proximal (sigmoid sinus) and distal (jugu-
lar vein) vascular control. Since the descending facial nerve
CA
P
9
TM 12
10
JV
SCC
11
JB
FN
SS
Figure 43-18. Jugular foramen approach. It is possible to expose the jugular
foramen without rerouting the facial nerve or destroying the conductive hearing
apparatus. Jugular foramen surgery requires that the sigmoid-jugular complex
be controlled both proximally (either by suture ligature or extraluminal packing,
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;
JB, jugular bulb; JV, jugular vein; P, parotid gland; SCC, semicircular canals;
SS, sigmoid sinus; TM, tympanic membrane; 9, glossopharyngeal nerve;
10, vagus nerve; 11, accessory nerve; 12, hypoglossal nerve.
684 SURGICAL NEUROTOLOGY
Figure 43-19. The fallopian bridge approach in which the vertical segment of
the facial nerve is skeletonized to afford exposure of the jugular foramen.
overlies the jugular bulb, many advocate an anterior rerout-
ing to provide unhindered access.26 Others, including the
author, prefer a fallopian bridge technique, leaving the facial
nerve in situ and working around it27 (Figs. 43-18) through
43-22). Unless there is extensive destruction of the middle
ear and ear canal (assuming integrity of the inner ear and
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
obliteration with adipose tissue. Of course, this creates a
maximum conductive hearing loss. When necessary, tumor
can usually be microdissected from the genu of the carotid
artery with minimal risk of injury. When the tumor is
markedly adherent to the carotid wall, a thin remnant
should be left and thoroughly coagulated with bipolar
cautery. Planned carotid resection is not indicated in
benign tumors of the jugular foramen. Intracranial exten-
sion of a jugular foramen tumor necessitates a transjugular
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.
This otoscopically visible “tip of the iceberg” is often the clinical feature that
leads to the detection of these lesions.
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
exposure requires anterior rerouting of the facial nerve and a canal wall down
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
blood supply to the jugular foramen. In the presence of a vascular tumor, it is
often much larger than it is depicted here. AP, ascending pharyngeal artery; C1,
transverse process of C1; DM, digastric muscle; EAM, external auditory meatus;
EC, external carotid artery; IC, internal carotid artery; JV, jugular vein; MC,
mandibular condyle; SCM, sternocleidomastoid muscle; SM, styloid muscles;
7, facial nerve; 9, glossopharyngeal nerve; 10, vagus nerve; 11, accessory
nerve; 12, hypoglossal nerve.
Infratemporal Fossa
The term infratemporal fossa is generally used to describe the
complex of structures located beneath the temporal bone.28
This region includes a number of different anatomic com-
partments (e.g., parapharyngeal space, pterygomaxillary
fossa) and contains within it the deep portion of the parotid
gland, pterygoid muscles and their associated vascular plexus,
cranial nerves IX–XII, the jugular vein, and the carotid
artery. The more common primary lesions in this area
include tumors of the deep lobe of the parotid gland, glomus
Figure 43-22. A large glomus tumor, which erodes the genu of the internal
carotid artery. It has significant intraluminal components in both the sigmoid
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
not deeply invade the internal auditory canal. In such cases, it may be
possible to open the internal auditory canal without violating the inner ear.
The endolymphatic sac and aqueduct are often helpful landmarks in
preventing injury to the otic structures. C, cochlear division of the eighth
nerve; 7, facial nerve; 8, audiovestibular nerve.
Figure 43-29. Retrosigmoid approach to selective vestibular neurectomy.
A small craniotomy is performed with minimal cerebellar retraction, just
sufficient to expose the entry zone of the seventh and eighth nerve
complexes. To denervate the vestibular system, the rostral portion of the eighth
nerve is divided. C, cochlear division of the eighth nerve; Ch, choroid plexus;
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
wound. However, it is now understood that the normal
mastoid air cell system is sterile and thus wound inocula-
tion seldom occurs. The second consideration is CSF leak-
age, which remains problematic especially when extensive
pneumatization is present. Transected air cells are sealed
with either bone wax or hydrophobic bone cement. To be
most effective, not only should sealant be impacted into
opened air cells, but a continuous thin sheet should be
created as well.
Due to the thickness of the musculature overlying this
region, the bone may be simply removed (craniectomy)
without leaving a particularly vulnerable skull defect.
Some argue that the persistence of a bone defect permits
adherence between the posterior fossa dura and the sub-
occipital musculature, a condition that may contribute to
the development of headaches. In addition, meningoceles
may occur, particularly in patients with hydrocephalus. To
avoid this, an osteoplastic bone flap may be created, but
this is technically difficult to produce without injuring the
sigmoid sinus. We favor replacing the morselized bone
fragments harvested during opening into the defect at the
end of the procedure. In our experience, this is more readily
achievable technically than a bone flap and heals satisfac-
torily as a firm bony plate.
The relative position of the sigmoid sinus effects exposure
via the RS approach. An anterior lying sigmoid sinus is
favorable, affording a more directly lateral point of view.
Conversely, a posterior lying sigmoid sinus may be a hin-
drance, forcing the exposure to a disadvantageously posterior
perspective. In such circumstances, some have recom-
mended that a mastoidectomy be performed with decom-
pression of the sinus, thus allowing its retraction anteriorly
with dural stay sutures. An inferiorly located transverse
sinus may similarly impose limitations as it forces the
surgeon to work from a more inferior perspective. When
the patient’s neck is short and the shoulder is large, there
may be both limited access to the retrosigmoid region and
the need to carry out dissection at a relatively awkward
angle. This circumstance may also prevail in patients with
limited neck mobility due to advanced age or disease of the
cervical spine. The surgeon should avoid the tendency to
compensate for unfavorable anatomy by overrotating the
head because this may crimp the vertebral veins and con-
tribute to a tendency for cerebellar swelling. In extreme cases
of a short and fat neck or cervical immobility, the sitting
position may be chosen.
After dural opening, it is essential to liberate CSF from
the cisterna magna before retracting the cerebellum. This
is accomplished by gently elevating the cerebellum and
fenestrating the cistern’s arachnoid covering. Failure to
release CSF at an early stage risks untoward swelling of
the cerebellum during premature efforts at retraction.
Such cases of cerebellar swelling, which may rarely occur
despite meticulous technique, require abandonment of the
procedure. In cases of massive swelling, the protuberant
cerebellum may need to be resected followed by a loose clo-
sure, leaving the dura open. Under such dire circumstances,
opening of the foramen magnum ring may discourage
postoperative tonsillar herniation.
To expose the midportion of the CPA, the cerebellum
must be gently retracted medially. In the RS approach,
surprisingly little retraction is often needed. In exposing
the mid-CPA, our measurements indicate the need for only
1 to 2 cm of medial displacement in the average case. After
draining the cisterna magna and administering intravenous
mannitol to shrink the cerebellum, the more lateral por-
tion of the CPA can often be visualized without retraction.
A substantially greater degree of retraction is required,
however, when the tumor deeply invaginates the pons and
cerebellar peduncle. Resection of the lateral one-third of
the cerebellum to improve exposure, a maneuver formerly
in widespread use, is virtually never required today. To
prevent injury to its surface, it is best not to place a retrac-
tor directly on the cerebellum. We prefer to use a Telfa
strip (approximately 2 × 6 cm) under the retractor.
Alternatively, a Silastic-coated malleable retractor blade
may be used. Narrow retractors tend to indent or even lac-
erate the cerebellar surface. Wider retractor blades tend to
distribute the retraction force over a wider surface and
minimize potential for injury.
When tumors penetrate the IAC, the canal’s osseous
posterior lip must be removed. Intradural drilling produces
copious amounts of bone dust, which is a meningeal
irritant that may contribute to postoperative aseptic
meningitis and persistent headache. An effort should be
made to confine the debris created while drilling so that it
can be evacuated with suction. This may be achieved, with
incomplete success, by placing Gelfoam into the CPA and
covering it with a rubber dam. Despite these precautions,
it is not uncommon to find bone dust adhering to relatively
inaccessible arachnoid surfaces in the prepontine cistern
along the basilar artery as well as in the jugular foramen
region.
Adequate exposure of the IAC contents requires not
only visibility, but sufficient room for the unrestricted use
of microsurgical instruments. Generally, this necessitates
creation of troughs that are several millimeter wide above
and below the IAC, which are deepened beyond the plane
of the anterior face of the canal. This deep excavation is nec-
essary to permit insinuation of a hook or other angled
instrument into the plane between the tumor and the ante-
riorly located facial nerve. On occasion, an unusually high
jugular bulb may lie against the inferior aspect of the IAC
or even overlap it to some degree. Care must be taken to
avoid injury to this structure because it is difficult to com-
press it sufficiently without obscuring the intracanalicular
portion of the tumor. A high jugular bulb inhibits forma-
tion of a trough beneath the IAC, particularly in the
medial portion of the canal adjacent to the porus acusticus.
This limitation can generally be overcome by elevating the
tentorium and addressing the IAC component primarily
from above.
When hearing conservation is a goal, it is important to
be aware that only approximately the medial two-thirds
of the IAC may be opened via the RS approach without
violating the vestibule of the inner ear (see Figs. 43-27 and
43-28).38,39 Some have advocated using the endolymphatic
sac and aqueduct as a guide to avoid entry into the
labyrinthine structures. In most cases, we prefer opening the
canal to the level of the tumor’s deepest penetration, regard-
less of its relationship to the inner ear. This allows tumor
dissection to commence with direct visualization of the
tumor-nerve interface and greatly reduces the likelihood of

tumor recurrence due to incomplete resection from the
fundus. Unlike tumor remnants in the CPA, which are
often devoid of vascular supply, tumor residual in the fundus
of the IAC is likely to possess a vascular stalk capable of
supporting tumor regrowth.40 In a few patients with normal
or near normal hearing, undertaking the risk of an indirect
dissection may be warranted. In such cases, an attempt
should be made to confirm complete excision from the lat-
eral recess of the canal by visualization with an endoscope
or mirror.
Opening of the IAC may transect mucosally lined air
cells that are present in proximity to the canal in 30% to
40% of adults. To avoid CSF leakage, these must be closed
with bone wax or hydrophobic bone cement. In addition,
many surgeons place a tissue graft into the petrosal defect
created by opening the IAC. A free graft of either muscle
or fat may be employed, which may be maintained in posi-
tion by a dural suture, autologous fibrin glue, or a combi-
nation of the two. Since muscle may simulate recurrent
tumor on subsequent enhanced MRI, fat is preferred in
most centers because its signal can be suppressed. When
pneumatization is extensive, we use a prophylactic lumbar
subarachnoid drain to discourage CSF leakage.
Advantages
The primary advantage of the RS approach is its versatil-
ity. Because it provides a relatively panoramic exposure of
the posterior fossa from the tentorium to the jugular fora-
men, the RS approach is suitable for use in a wide variety
of tumors as well as vascular abnormalities affecting this
region. In selected lesions, it affords the possibility of
hearing preservation.41–43
Disadvantages
The RS approach, due to its relatively posterior angle of
view, provides only limited visualization of the region
ventral to the brainstem. Exposure of the ventral surface of
the pons and medulla and the posterior aspect of the clivus is
obstructed both by cranial nerves V through XI, which
bridge the CPA, as well as by the interposed lateral surface of
the brainstem. The presigmoid transtemporal approaches,
which offer a more anterior angle of view, are more suitable
for the majority of tumors in front of the brainstem.
Some argue that the need for cerebellar retraction is a
disadvantage of the RS approach. However, when per-
formed gently, retraction seldom leads to postoperative
cerebellar dysfunction. A more important disadvantage is
the frequent occurrence of persistent postoperative
headaches. In a study of CPA tumors at the University of
California at San Francisco, headache persisted beyond the
sixth postoperative month in 64% of patients following RS
craniotomy but in only 34% after the TL approach.44
More important, 12% of RS patients reported long-lasting
severe and disabling headache, whereas no TL patients
were so afflicted. Of interest, most severe headache suffer-
ers had small tumors and had undergone a hearing conser-
vation attempt. The reason for the higher incidence of
headache following the RS approach is uncertain, but it
may well be related to the widespread soilage of posterior
fossa arachnoid with bone dust generated during
intradural drilling of the posterior lip of the IAC. During
a transtemporal craniotomy, by contrast, all drilling is
Surgical Neurotology: An Overview 689
completed before opening the dura. Presumably, the irri-
tation of bone dust may lead to a form of chronic aseptic
meningitis. Arguing in favor of this etiology is the relative
responsiveness of such headaches to corticosteroids and
nonsteroidal anti-inflammatory drugs. An additional
observation that supports this mechanism is the frequent
occurrence, during a severe headache, of a bulging opera-
tive site suggestive of transient increased posterior fossa
pressure. Other possible etiologies of post RS craniotomy
headache include occipital neuralgia and a coupling of the
posterior fossa dura with the suboccipital musculature. In
support of the latter hypothesis is the fact that post RS
headache is triggered by cough or straining in some
patients. In this regard, such headaches are similar to those
associated with the Arnold-Chiari deformity and other
malformations of the craniovertebral junction. Recently, it
has been reported that reconstruction of the suboccipital
skull somewhat reduces the risk of persistent headache.45,46
Some have maintained CSF leak has been more common
following RS craniotomy than following transtemporal tech-
niques, as well as more stubborn and difficult to manage.47,48
Via the RS approach, it is technically difficult to hermeti-
cally seal all transected cells when the petrous apex is
extensively pneumatized. In addition, closure is attempted
at only one location—along the cut edge of petrous bone.
In the transtemporal approaches, a second line of defense
is created either at the entrance of the aditus-ad-antrum or
through obliteration of the eustachian tube. As opposed to
CSF otorhinorrhea, CSF wound leak may be less common
following the RS approach due to the multilayer closure
afforded by the thick occipital musculature. In a recent
study at the University if California at San Francisco, the
incidence of CSF leakage was equal (approximately 10%)
following the translabyrinthine (TL), RS, and middle fossa
(MF) approaches.49
Transpetrosal Approaches
The transpetrosal approaches (also known as transtemporal)
are a family of three craniotomy techniques (retro-
labyrinthine, translabyrinthine, and transcochlear) (see
Fig. 43-24), which progress from a limited petrosectomy
that provides only a small view of the CPA to radical
resection of the contents of the petrous pyramid with wide
posterior fossa exposure.
Retrolabyrinthine
Surgical Exposure: The retrolabyrinthine (RL) approach
consists of a small posterior fossa craniotomy, which is
performed between the sigmoid sinus and the otic capsule
(Figs. 43-30 and 43-31).50,51 It provides limited exposure of
the posterior fossa, confined to the region of the entry
zone of the fifth, seventh, and eighth nerves. More lateral
structures, such as the porus acusticus and IAC, cannot be
visualized because they are blocked by the otic capsule.
Indications: The RL approach was first described in the
early 1970s as an approach to the root entry zone of the
trigeminal nerve in tic douloureux, but was not used
widely until the early 1980s when it gained popularity as a
means of exposing the brainstem entry of the eighth nerve
for vestibular neurectomy.34,52,53 In recent years, the ret-
rosigmoid approach has regained favor for this procedure
690 SURGICAL NEUROTOLOGY
Figure 43-30. Retrolabyrinthine craniotomy in axial view. Note that the bone
overlying the sigmoid sinus is removed together with 1 to 2 cm of
retrosigmoid occipital plate.
due to its wider exposure. Much less common, the RL has
been used to perform vascular decompression of the
eighth nerve for tinnitus or chronic vertigo or even as an
approach to midbasilar artery aneurysms.54,55 Recently, a
combined retrolabyrinthine and subtemporal exposure has
L material. The possibility of air embolism should also be
ES P sion of the sigmoid sinus, it is retracted posteriorly and the
7 medially both along the superior petrosal sinus and toward
8 quently must be mobilized through release of its arachnoid
Figure 43-31. Retrolabyrinthine craniotomy (left side) illustrating the surgical
anatomy of the posterior fossa exposure. The dura has been incised anterior
to the sigmoid sinus, allowing the endolymphatic sac (ES) to be retracted
forward. A limited posterior fossa exposure in the region of the brainstem
entry of cranial nerves 7 and 8 is provided. L, lateral semicircular canal;
P, posterior semicircular canal; 7, facial nerve; 8, audiovestibular nerve.
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
retractor to guard the sinus from inadvertent injury. The sig-
moid sinus must be exposed superiorly from the transverse-
sigmoid junction to the jugular bulb region inferiorly in
order to obtain the maximum posterior fossa exposure
afforded by this technique. Although a 6- to 8-mm diamond
burr is satisfactory for this task, we prefer a 10- to 12-mm
burr, which is quicker and less traumatic. Frequently,
mastoid emissary veins are encountered, which must be
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
kept in mind by the surgeon, although this risk is very low
when the patient is in the supine position. After decompres-
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
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-
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.
Advantages: The purported advantage of this approach
compared with retrosigmoid craniotomy is a lower incidence
of persistent postoperative headaches. However, little data
is available that compares the two openings. Although
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
associated peduncles, and the proximal portion of cranial
nerves V, VI, VII, and VIII (Figs. 43-32 and 43-33).8,58–63
The root entry zone and CPA course of nerves IX, X, and
XI is seen to a variable degree depending on the course of
the sigmoid sinus.
Indications: The primary indication for the TL approach
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,
and other tumors of the CPA when hearing is poor.71,72
Figure 43-33. Translabyrinthine craniotomy (left side) illustrating the surgical
anatomy of the posterior fossa exposure. Ca, cochlear aqueduct orifice;
Cb, cerebellum; Ch, choroid plexus; D, dura; Fl, flocculus; GG, geniculate
ganglion; IV, inferior vestibular nerve; JB, jugular bulb; JV, jugular vein;
SPS, superior petrosal sinus; SS, sigmoid sinus; SV, superior vestibular
nerve; TS, transverse sinus. Cranial nerves: 5, trigeminal; 7, facial;
8, audiovestibular; 9, glossopharyngeal; 10, vagus; 11, accessory
(cranial portion).
Cochleovestibular neurectomy can also be accomplished
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
compartment of the jugular foramen or foramen magnum.
The TL approach has also been advocated for aneurysms
of the midportion of the basilar artery. For transtentorial
lesions, the TL approach may be combined with a
subtemporal opening (see later section on combined
craniotomies).60,74 A combined TL and RS opening with
sacrifice has been advocated for certain large CPA tumors
in the past, but it is seldom used today.75
Technical Considerations
In the TL craniotomy the bony opening extends from the
posterior aspect of the external auditory canal to behind the
sigmoid sinus.76 The amount of retrosigmoid bone removal
depends on the size of the tumor being removed and the
position of the sigmoid sinus. Although the distance between
the sigmoid sinus and the ear canal is initially narrow, pro-
gressive removal of the petrous bone enlarges it substantially.
Thorough removal of the bone overlying the sinus and the
posterior fossa dura behind it is essential to permit its mobi-
lization. This is accomplished by use of cutting burrs until
the blue tint of the sinus is evident through a thin sheet of
bone. The remaining plate is removed using large diamond
burrs (see section on RL approach for further discussion).
Use of large burrs is important because they are rapid and
also present a relatively large working surface and are there-
fore less likely to tear the sinus or dura. The sigmoid should
be decompressed from the transverse-sigmoid junction supe-
riorly to the jugular bulb inferiorly. There is much variabil-
ity to the anatomic location of the sigmoid sinus. When the
sigmoid sinus lies far forward, it may even contact the ear
canal. Even with such an adverse configuration, ample CPA
exposure can be obtained.
Following sigmoid mobilization, the remainder of the
mastoid is rapidly removed to the level of the semicircular
canals. In the process, bone is removed from the sinodural
angle to expose the superior petrosal sinus. Labyrinthectomy
is performed using a cutting burr, commencing in the
sinodural angle. By creating troughs parallel to the middle
and posterior cranial fossa dura, the remaining labyrinth can
be removed with the side of the cutting burr. This is prefer-
able because the tip of a rotating burr tends to skate and is
therefore more difficult to control. The facial nerve is
closely related to the inferior aspect of the lateral semicircu-
lar canal and to the inferoanterior end of the posterior semi-
circular canal. The final remnant of the semicircular canals
is removed with a diamond burr to permit atraumatic expo-
sure of the horizontal and second geniculate portions of the
facial nerve. Deepening the opening beneath the facial
nerve exposes the vestibule of the inner ear with all three
semicircular canal ampullae and the otolithic organs.
Obtaining this exposure is important in gaining access to the
terminal portions of the superior and inferior vestibular
nerves. Partial labyrinthectomy with sealing of the tran-
sected portion of the inner ear with bone wax has been pro-
posed as a means of possibly sparing hearing.77 However,
complete exposure of the fundus requires a wide opening of
the vestibule, a maneuver very likely to severely traumatize
the membranous labyrinth. Following labyrinthectomy, the
bone deep to the labyrinth is then rapidly removed to the
level of the IAC. As the exposure progressively deepens,
the plate of bone over the posterior fossa dura is gradually
removed to the level of the porus acusticus. Removal of the
middle fossa plate from the subtemporal dura is optional.
Softening of the temporal floor permits extradural elevation
of the temporal lobe and is indicated during exposure of
large tumors. It is also helpful in small tumors when the
tegmen lies at an unusually low level.
Wide exposure of the IAC is an essential part of the
procedure. Deep bony troughs are drilled above and below
the canal to bring it into high relief. Superiorly, a furrow is
created between the IAC and the middle fossa dura. Care
must be exercised while removing the last eggshell of bone
from the superior aspect of the canal because the facial nerve
lies immediately beneath the dura in this location. The infe-
rior furrow is created between the IAC and the jugular bulb.
The cochlear aqueduct is often encountered while removing
this bone and is a useful landmark in the identification and
preservation of the dural envelope of the neural compart-
ment of the jugular foramen.78 When the jugular bulb is
atypically high, it may impede the creation of the inferior
bony trough. In extreme cases, it may cover part or all of
the IAC just proximal to the porus. Some have advocated
decompression and inferior displacement of the high jugular
bulb in such cases. This remains an option but adequate
exposure can usually be obtained, in spite of this anomaly, by
elevating the temporal dura and extending the superior
trough to the level of the tentorium to provide enhanced
exposure of the canal from its superior aspect. It is important
to realize that a high jugular bulb, even though it may
obstruct visualization of the midportion of the canal and the
porus, does not obscure the lateral end of the IAC. Thus,
even when the bulb is very high, the proximal facial nerve
plane may be readily established. It should be stressed that
the removal of bone around the IAC, particularly at the
porus acusticus, should be aggressive. Inadequate beveling of
the porus may leave an overhang that impedes visualization
of the facial nerve at its vulnerable abrupt turn immediately
medial to the porus. When the tumor is large, it is important
to extend the bony opening well beyond the level of the IAC
into the petrous apex to provide enhanced exposure of the
anterior aspect of the CPA.79
The dura of the IAC is incised slightly inferior to its
meridian to avoid potential injury to the facial nerve (FN),
which usually lies superior and deep to the superior
vestibular nerve. Separate flaps are then peeled superiorly
and inferiorly to fully expose the canal contents. There are
several methods of opening the dura of the posterior cra-
nial fossa in the TL approach. In most widespread use is
a flap that parallels the superior petrosal sinus above and
inferiorly spans the gap between the sigmoid sinus and the
apex of the jugular bulb. These are connected across the
mouth of the porus acoustic, thereby creating a rectangu-
lar dural flap, which is then dissected off of the cerebellar
surface.
When opening the dural overlying the CPA does not
result in the free flow of CSF, the inferior aspect of the
cerebellum should be gently elevated to permit incision of
the arachnoid of the cisterna magna before commencing
tumor dissection. With this decompression accomplished,
the cerebellar attachments to the tumor can be liberated,
permitting its gentle retraction laterally. After mobilization
of the cerebellum’s arachnoidal and vascular tethers, partic-
ularly to the petrosal veins superiorly, little retraction is

required in smaller tumors. Significant cerebellar retrodis-
placement may still be needed in large tumors that deeply
invaginate the cerebellar peduncle.
In a properly performed TL craniotomy, excellent
exposure of the CPA is provided from the tentorium to the
jugular foramen. Much as a high jugular bulb may obscure
the IAC, a high lying sigmoid course may inhibit visualization
of the inferior aspect of the CPA. While there is some asso-
ciation between high sigmoid course and high jugular bulb,
either may occur in the absence of the other. Restricted
access to the inferior portion of the CPA is seldom prob-
lematic in acoustic neuromas which, once debulked, readily
mobilize into the operative field. In addition, acoustic
tumors rarely adhere to the lower cranial nerves.
Meningiomas, by contrast, adhere to dural surfaces and
typically do not easily mobilize. They also are more likely
to enmesh the lower cranial nerves. For this reason, we do
not use the TL approach in nonacoustic tumors that extend
inferiorly toward the jugular foramen and/or foramen
magnum unless a concurrent transjugular craniotomy is
planned.
A partial dural repair is often possible following a TL
craniotomy, but a substantial dural defect typically persists.
Obliteration of both the osseous and dural defects is
customarily accomplished with fat harvested from the
abdomen or iliac crest region. Fat is laid in strips into
the cavity until it tightly fills the defect from the dura to the
skull surface. Frequently, some fat prolapses into the cavity
left behind by tumor dissection and comes to abut the
brainstem. Fortunately, adipose tissue is pliable and seldom
induces a mass effect. Following a TL approach, the primary
route for CSF leaks is via the aditus-ad-antrum, a narrow
cleft located quite superficial within the craniotomy opening.
A strip of fascia (temporalis or rectus) may be lain over this
area in an attempt to seal it. Some surgeons prefer to
obstruct the eustachian tube orifice through a facial recess
approach. However, this opening increases the communi-
cation between the craniotomy cavity and the middle ear
and provides only limited access to the tube orifice, making
closure via this method somewhat insecure.
Advantages: When compared with RS craniotomy, TL
approaches have a somewhat lesser morbidity.47 This is
most notable in the reduced incidence of persistent post-
craniotomy headaches, which are quite frequent following
the RS approach.44 Several factors may contribute to this
including the minimization of brain retraction, the reduced
level of trauma to the suboccipital musculature, and the
ability to complete all drilling before the dura is opened. In
the RL approach to acoustic tumors, the IAC must be
drilled open intradurally, a maneuver that inevitably leads
to some soilage of the posterior fossa arachnoid with bone
dust and may contribute to postoperative aseptic meningitis.
Although the literature is quite variable on its relative inci-
dence, in our experience CSF leak is equally common
among the various approaches to the CPA.49,80–83 Persistent
CSF leak that follows an RS craniotomy is often repaired
through a transtemporal approach.84
A second advantage of the TL approach becomes apparent
when the facial nerve has become disrupted. To avoid a
nerve graft, it is possible to mobilize the nerve out of its
redundant course through the temporal bone, thereby gain-
ing between 10 to 15 mm of length. This “mastoid-meatal”
Surgical Neurotology: An Overview 693
rerouting permits repair of short FN deficiencies with a
single anastomosis, which is preferable to the two anasto-
moses required with interposition graft. In the RS
approach, the only option for repair of an FN dehiscence
when the ends are not approximated is nerve grafting.
The TL approach also has a relative advantage over the
RS approach under certain circumstances in the angle of
view toward the brainstem. The more anterior perspective
permits a more direct view of the brainstem surface, partic-
ularly when the tumor has posteriorly rotated and deeply
indented the pons and middle cerebellar peduncle. By
comparison, the exposure of the tumor interface via the RS
approach is more tangential in such cases.
A widely touted advantage of the TL approach is the
ability to identify the FN at the lateral end of the IAC prior
to its involvement with tumor. Although it is certainly
reassuring to the surgeon to locate the FN at the earliest
possible time, we have never had particular difficulty in
identifying or preserving the FN during removal of the
intracanalicular portion of an acoustic tumor. This advantage
may be more important when anatomic arrangements are
less predictable than in acoustic neuroma, such as in
meningioma or in revision cases.
Disadvantages: The primary disadvantage of the TL
approach is the necessity of sacrificing hearing in the
operated ear. This is less of a concern in acoustic tumors,
where useful hearing can seldom be preserved, that it is for
other lesions of the CPA and IAC such as meningioma and
epidermoids. In many cases, the decision algorithm used to
choose among the various surgical approaches is quite
complicated and depends on numerous factors including
tumor size, location, and type. While sacrificing hearing in
an ear should never be taken lightly, in many cases it is
warranted when the probability of preserving hearing is
remote or when the anatomic features of the tumor indicate
the need for more anterior exposure.
A minor disadvantage of the TL approach is the require-
ment for a fat graft to obliterate the defect. To some indi-
viduals, this may create an undesirable abdominal scar. This
can be easily avoided in women, who usually have a fat pad
in the hip region, which is accessible through an incision
placed just below the iliac crest. This hides the scar under
the waistband of most bathing suits.
As previously mentioned, the TL approach provides only
limited exposure of the lower portion of the CPA, particu-
larly when the lower sigmoid sinus course is relatively high.
As a general rule, we prefer not to use this opening for nona-
coustic tumors that extend inferiorly medial to the jugular
foramen or toward the foramen magnum unless a concurrent
transjugular exposure is planned.
When the facial nerve takes an acute anterior angulation
at the porus acusticus, the course of the displaced nerve is
less well seen with the TL approach than with the RS
approach due to its more posterior angle of view. It is
possible to overcome this obliquity by mobilizing the
nerve into the operative field, but we feel that dissection
of the nerve-tumor interface is less traumatic when the
nerve is left in situ throughout its cisternal course.
Fortunately, the geometry involved is seldom troublesome
and, in our experience, FN functional outcome in acoustic
neuroma surgery is the same following either the TL or
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
The extended MF approach is a modification of the MF
approach to the IAC designed to increase the degree of
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
of a small extracanalicular tumor component can then be
achieved by elevation of the superior petrosal sinus and ten-
torium. Increased exposure of the CPA may be realized by
either of two maneuvers: exenteration of the otic capsule or
division of the superior petrosal sinus and tentorial edge.
Indications
The extended MF approach to the CPA has been used
increasingly in recent years. Its proponents recommend
its use in small and medium-sized acoustic neuromas that
possess both an IAC and CPA component.99–101 The prac-
tical upper limit on the use of this technique is with a
tumor that has significant brainstem contact (approximately
15 to 18 mm) in the CPA component. Substantial hearing
conservation has been achieved in these larger tumors but
at the cost of some increased facial nerve morbidity.102
Technical Considerations
Following a standard MF opening with unroofing of the
IAC, bone anterior and posterior to the porus is exenter-
ated to the level of the dura of the posterior petrous face
(Fig. 43-39). The posterior limit of the opening is the
superior semicircular canal. The theoretical anterior limit
is the lateral wall of Meckel’s cave, although it is not usually
necessary to remove bone that far forward. A particularly
wide mobilization of the subtemporal dura is required to
permit elevation of a broad segment of the superior petrosal
sinus and tentorium. If division of the sinus is elected, its
cut ends are controlled with hemoclips.
Advantages
When the otic capsule is preserved, the extended MF
approach offers the possibility of removing small and
Figure 43-39. Extended middle fossa approach to an acoustic neuroma with
a 2-cm component in the cerebellopontine angle. To achieve greater posterior
fossa exposure, the superior petrosal sinus and the tentorium are divided.
medium-sized acoustic neuromas with the preservation of
hearing.
Disadvantages
The main disadvantage of the extended MF approach is
that the facial nerve may lie over the superior surface of
the tumor in a position that requires it to be manipulated
to a greater extent during tumor removal than with lateral
(TL) or posterior (RS) techniques. At least in theory, the
requirement for more prolonged and relatively vigorous
retraction of the temporal lobe may increase the risk of
postoperative speech and/or memory disturbance and may
contribute to the delayed development of a seizure disorder.
Fortunately, these complications are seldom encountered.
Another concern is the limited exposure of the inferior
aspect of the CPA. This may render it difficult to control
vessels, such as the AICA and PICA, which may be situated
below the tumor.
Middle Fossa-Transpetrous Apex Approach
to the Ventral Pons and Anterior
Cerebellopontine Angle
Surgical Anatomy
The middle fossa-transpetrous apex (Kawase) approach
employs a middle fossa opening to create a small poste-
rior fossa craniotomy via removal of the medial portion of
the petrous pyramid and the lateral aspect of the clivus
(Fig. 43-40). 103,104 Conceptually, it is similar to the extended
middle fossa approach but instead of exposing the mid-CPA,
the target is the anterior CPA and the ventral surface of the
pons (Fig. 43-41). The bony window in the petrous pyra-
mid is rhomboidal. It is bounded posteriorly by the otic
capsule and IAC, anteriorly by Meckel’s cave, inferiorly by

Figure 43-40. Middle fossa-transpetrous apex (Kawase) approach to the
ventral pons and the anterior cerebellopontine angle as viewed from above.
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
pons is provided.
the petrous carotid artery, and superiorly by the tentorium.
Posterior fossa exposure includes the pons, basilar artery,
and cranial nerves V through VII. The posterior fossa
exposure is limited inferiorly by the carotid artery in the
base of the petrous pyramid. Enhanced inferior exposure
can be obtained by displacement of the intrapetrous
Figure 43-41. Middle fossa-transpetrous apex approach to the ventral pons
and the anterior cerebellopontine angle in surgical view. Following downward
retraction of the zygomatic arch and temporalis muscle, the temporal lobe is
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),
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
division of the trigenical nerve at foramen ovale.
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
cave and the cavernous sinus, intradural exposure is typically
required. During removal of the dura of the anterior petrous
face, the greater superficial petrosal nerve must be sacri-
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
maximize the bony opening, the dura of the medial IAC
and Meckel’s cave is exposed. Caution must be observed
toward the lateral end of the IAC due to the proximity of
the cochlea. The depth of petrous apex removal is dictated
by the most inferior extent of the tumor in the posterior
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-
tion than the classically described middle fossa-transtentorial
approach.
Disadvantages
The primary disadvantage of the middle fossa-transpetrous
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.

HC
Figure 43-42. A saggital section through the midline illustrating the jugular
foramen and its osseous relations from the medial perspective. Tumors of
the jugular foramen are often dumbbell shaped, possessing both an
intra- and an extracranial component connected by a segment within the
cranial base. HC, hypoglossal canal; IAC, internal auditory canal.
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
first because this serves to devascularize the intracranial
aspect.
Technical features of a transjugular craniotomy include
wide pre- and postsigmoid dural exposure. The sigmoid
sinus is ligated just below the transverse-sigmoid junction,
the jugular view is tied off in the upper neck, and the petrosal

VA
XI
X
V IX
Ch
Cb
VII, VIII
Figure 43-44. Transjugular craniotomy illustrating the degree of intracranial
exposure obtained following resection of the sigmoid-jugular system and
wide opening of the posterior fossa dura. Note the multiple small rootlets of
the lower cranial nerves emanating from the lateral surface of the medulla.
In contrast to extracranial procedures, the sigmoid sinus is ligated proximally
rather than packed extraluminal. Cb, cerebellum; Ch, choroid; F, flocculus;
VA, vertebral artery; 5, trigeminal nerve; 7, facial nerve; 8, audiovestibular
nerve; 9, glossopharyngeal nerve; 10, vagus nerve; 11, accessory nerve.
sinuses are controlled with Surgicel in the medial aspect of
the jugular bulb. In most cases the ear canal and inner ear
can be left in situ. Hearing can often be conserved in JF
tumors even with large intracranial components. The ear
canal is removed and the meatus sewn shut in only two
circumstances: when extensive erosion of the middle ear
and canal wall precludes their preservation and when
Figure 43-45. Transjugular craniotomy without rerouting of the facial nerve.
Leaving the facial nerve in situ is not an impediment to exposure to the
intracranial region adjacent to the jugular foramen.
Surgical Neurotology: An Overview 699
Figure 43-46. Exposure of a jugular foramen schwannoma after transection
and removal of the sigmoid sinus and jugular bulb. Note that the fan of fibers
comprising the ninth, tenth, and eleventh nerves takes an oblique course
between their horizontally oriented intracranial roots and their vertically
aligned peripheral trunks. In this case, the residual nerve fibers are
positioned on the medial surface of the tumor.
augmented anterior exposure of the apical petrous bone
and carotid artery is needed. In our experience, rerouting
of the facial nerve is seldom required even with extensive
intracranial disease.
The relationship of the lower cranial nerves to the tumor
penetrating the jugular foramen is the key determinant in
whether the nerves can be preserved.110,112 When the
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
retrosigmoid and middle fossa craniotomies has been
employed by some surgeons, but this approach has several
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
and posterior fossae will be reviewed. Tumors that traverse
the tentorial plane usually pass through the tentorial
notch, Meckel’s cave, or the space between the clivus and
Figure 43-49. Combining a retrolabyrinthine posterior fossa craniotomy with
a middle fossa craniotomy and splitting the tentorium provides exposure of
transtentorial tumors that involve the lateral aspect of the pons and
midbrain. Retraction of the posterior portion of the temporal lobe should be
gentle to prevent injury to the vein of Labbé (VL).

4 and is bounded superiorly by the petroclival ligament. Its
Figure 43-50. Combined approach craniotomy to a meningioma involving
the posterior petrous pyramid, the clivus, Meckel’s cave, and the cavernous
sinus. 4, trochlear nerve.
as the tentorial notch, or incisura. The trochlear nerve closely
parallels the free edge of the tentorium and is frequently at
risk in transtentorial procedures. Immediately beneath this
edge is the petrosal vein (Dandy’s vein) and the superior
cerebellar artery usually lies just above it.
TL
T
9 T
7
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
Figure 43-51. The exposure obtained from a left retrolabyrinthine-middle
fossa approach to a clival tumor. This technique is indicated when the lesion
has an intimate relationship with the anterior surface of the brainstem 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
anterior approaches. The tentorium has been incised to provide exposure of
both posterior and middle cranial fossae through gentle retraction of the
cerebellum and temporal lobe. The tumor can be seen prolapsing posteriorly
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;
9, glossopharyngeal nerve; 4, trochlear nerve; 5 trigeminal nerve; 7, facial
nerve; 8, audiovestibular nerve.
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
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
be divided into two broad classes: those that require a wide
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
fossae, meningioma is by far most common. In the spectrum
of technical difficulty, meningiomas that arise from the
tentorium are usually more readily approached due to
their lateral location. At the other end of the difficulty
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
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
can be approached via a middle fossa-transpetrous apex
approach. Conversely, when the posterior fossa component
predominates, a limited opening through Meckel’s cave
may be created during posterior fossa craniotomy. In
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
The details of the various middle fossa and transtemporal
approaches (retrolabyrinthine, translabyrinthine, and
transcochlear) will not be repeated here and the reader is
directed to the relevant section of this chapter. A special
consideration of the combined approaches is the need to
divide the tentorium. The superior petrosal sinus can usually
be easily controlled by application of hemoclips. Care must
be exercised when dividing the free edge of the tentorium
to prevent injury to the trochlear nerve.
702 SURGICAL NEUROTOLOGY
The cortical veins on the inferior aspect of the temporal
lobe merit special mention because they are a potential
cause of significant morbidity during extensive subtemporal
procedures.130 The vein of Labbé constitutes the major
superficial venous drainage of the posterior temporal and
inferior parietal lobes (Fig. 43-7). Interruption of Labbé’s
vein on the dominant side frequently induces aphasia. The
left side is dominant in approximately 95% of individuals—
100% of right-handed and 80% of left-handed persons.
Less common, massive swelling may occur followed by
uncal herniation and ultimately death due to brainstem
herniation. Labbé’s vein is at greatest risk posteriorly, near
its entry to the transverse sinus. Retraction of the posterior
portion of the temporal lobe must be performed gently,
lest traction be placed on this vein, which tears quite easily.
Since prolonged retraction of the temporal lobe may
induce thrombosis of Labbé’s vein, it is wise to release
retraction periodically for short periods during lengthy
procedures and to use the minimal degree of retraction
needed to provide adequate surgical exposure. To reduce
traction placed on the vein of Labbé during combined
procedures, Spetzler and Daspit advocate division of the
sigmoid sinus (when the contralateral sinus is patent) distal
to the takeoff of the superior petrosal sinus.121,131 This
permits the lateral sinus, along with the entry of the vein
of Labbé, to be retracted superiorly along with the
tentorium.
Advantages
Combining a posterior and middle fossa exposure into a
single craniotomy around and/or through the temporal
bone has a number of advantages. First and foremost, it
reduces the amount of brain retraction needed to expose
complex lesions adjacent to the brainstem. Second, it
typically requires only a single-stage procedure where two
stages might otherwise have been needed. Finally, combined
transbasal craniotomy often permits a greater degree of
tumor resection than could be achieved by separate retrosig-
moid and subtemporal procedures.
Disadvantages
There are few disadvantages of combined posterior and
middle fossa craniotomy when compared with separate
procedures. Of course, aggressive removal of the temporal
bone sacrifices hearing, but a hearing-sparing retro-
labyrinthine-middle fossa technique often provides sufficient
exposure. Although unilateral hearing loss may be required
for tumors extending ventral to the brainstem, this is not an
unreasonable sacrifice in the context of these serious lesions.
Posterior facial nerve rerouting (transcochlear-middle fossa
approach), which induces at least a temporary facial palsy,
should be reserved for particularly complex tumors located
largely in front of the pons.
Transcochlear Approach
Surgical Exposure
The transcochlear (TC) approaches are a group of three
anterosigmoid posterior fossa craniotomies which, when
compared with the translabyrinthine approach, provide
an enhanced view of the anterior aspect of the CPA.
There are actually three varieties of “transcochlear”
approaches: (1) the original TC approach described by
House in 1976 to approach the anterior CPA, (2) the
extended TC approach to the prepontine region and clivus,
and (3) the transotic approach described by Fisch to remove
small acoustic neuromas.132–135 The term transcochlear
has been adopted to describe an extension of the
translabyrinthine approach that entails an exenteration of the
entire inner ear, not just the semicircular canals. It should be
noted that many TC operations involve a great deal more
than mere removal of the cochlea and may be more aptly
termed transpetrosal or even petroclival craniotomies.
Intracranial structures that can be exposed by the classical
TC approach include the entire lateral aspect of the pons
and upper medulla, cranial nerves V through XI, as well as
the midbasilar artery. Its posterior fossa exposure is exten-
sive except inferiorly where it is limited in the area of the
jugular foramen and foramen magnum. The degree to
which the neural compartment of the jugular foramen is
visible depends on the height of the jugular bulb.
Modifications to the TC approach have been described
which, in addition to the exposure provided by the standard
TC approach, permit visualization of the anterior aspect of
the pons, both sixth nerves, and improves visualization of
the basilar artery and vertebrobasilar junction.133,136 The
transotic approach of Fisch is the most limited of the
three, designed to expose only the IAC and mid-CPA.132
Indications
The primary indication for the TC approach are CPA
tumors such as meningiomas, which penetrate the petrous
apex medial to the IAC. Lesions that arise in the apex
(e.g., chondrosarcoma, chordoma) can also be approached
in this manner particularly when they possess substantial
intradural components. For tumors limited to the upper
aspect of the prepontine space that do not encase the basilar
artery, the subtemporal transpetrosal approach is occasion-
ally a viable alternative. An additional indication for the
TC approach is a large recurrent or residual acoustic
neuroma when the facial nerve has been disrupted during
the earlier surgery. When the audiovestibular and facial
nerves are intact, every effort should be made to employ an
alternative approach that does not sacrifice these functions.
In our institution, the TC approach has been seldom used
in recent years because of its morbidity (deafness, facial
nerve dysfunction), having been supplanted in most cases
by the combined-approach craniotomy. The TC approach
is still used in cases of preexisting facial palsy and for certain
vascular lesions such as midbasilar artery aneurysms.
The extended TC approach is indicated for tumors that
lie ventral to the brainstem, typically between the clivus
and pons. The most common reason for performing an
extended transcochlear approach is meningioma of the
clivus of petroclival region. The conventional retrosig-
moid approach to lesions that lie directly anterior to
the pons is limited by (1) the narrow opening between
the pons and petrous pyramid when viewed from behind,
(2) cranial nerves V, VII, and VIII, which bridge across the
exposure and constrain working space to narrow intervals
between these nerves, and (3) the need for vigorous retrac-
tion of the cerebellum and pons (Figs. 43-52 and 43-53).
In contrast to purely prepontine tumors, many petroclival

CA
ET
Figure 43-52. Transcochlear approach to a prepontine tumor seen
schematically in axial view. The facial nerve has been fully rerouted from the
brainstem to the stylomastoid foramen and the external auditory canal, as
well as both middle and inner ear have been removed. The eustachian tube
(ET) is occluded. The intrapetrous carotid (CA) is the anterior limit of the
exposure.
lesions can be removed successfully via the retrosigmoid
approach. Such lesions displace the brainstem toward the
opposite side, thereby opening the choke point between
the pons and petrous bone. This geometric arrangement
can be appreciated on preoperative MRI scans. The addi-
tional morbidity of the extended TC approach (unilateral
hearing loss, transient facial palsy) is justified by the direct
and unencumbered view provided of the anterior and lateral
pontine surface. In these life-threatening lesions, direct
visualization of the tumor-brainstem and tumor-basilar
artery interface is critical to achieve adequate tumor
resection and limit the risk of pontine infarction. The
extended TC approach also provides a more favorable
angle for the identification and preservation of the
abducens nerve.
Technical Considerations
The initial stages of the TC approaches are identical to
those of the TL approach. In addition, both of the TC and
extended TC approaches involve complete exenteration of
the inner ear (cochlear and semicircular canals) as well as a
posterior rerouting of the facial nerve. The facial nerve is
elevated from its canal over its entire course from the sty-
lomastoid foramen to the porus acusticus. It is then rotated
posteriorly and inferiorly on the cerebellar hemisphere and
posterior fossa dura. This removes the major impediment
to anterior exposure in a transtemporal craniotomy. These
maneuvers permit opening of the posterior fossa dura to
extend substantially more anteriorly and medially than
with the TL approach.
In the classical TC opening the external auditory canal
and middle ear are left intact, but in the extended TC
Surgical Neurotology: An Overview 703
Figure 43-53. Transcochlear approach to a prepontine tumor seen
schematically in axial view (a) and in surgical perspective (b) (left side). By
rerouting the facial nerve and exenterating the entire otic capsule, petrous
apex, and lateral aspect of the clivus, an unobstructed view is obtained of the
ventral aspect of the pons. Cb, cerebellum; Ch, choroid; ET, eustachian tube;
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.
approach both of these structures are removed and the
external auditory meatus is closed in a fashion that is
watertight to resist CSF pressure. Extended TC proce-
dures remove the entire apical petrous bone and often the
lateral aspect of the clivus as well. The inferior limits
of exposure inferiorly are the jugular bulb and intrapetrous
portion of the carotid artery. In both the classical and
extended TC approaches the operative defect is obliter-
ated with abdominal fat. In the extended TC approach
the eustachian tube is obliterated to prevent CSF leakage,
typically with bone wax followed by a muscle plug.
The transotic approach differs substantially for the TL
and other TC approaches in that the sigmoid sinus is not
decompressed and only a limited posterior fossa opening is
created. As in the extended TC approach, the ear canal and
middle ear are completely removed, the meatus sewn shut,
and the eustachian tube obliterated. The transotic technique
is the only version of the TC approach that leaves the
facial nerve in situ.
Advantages
The TC approaches, especially the extended TC approach,
provides access to tumors anterior to the pons that would, in
many cases, otherwise be considered inoperable. Often, the
ventral surface of the pons can be visualized without the
need for brain retraction.
The transotic approach has been recommended by its
inventor as a means of approaching small acoustic neuromas
without brain retraction while minimizing the risk of CSF
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
The operative approach to Meckel’s cave depends on
whether the tumor is largely in the middle fossa, posterior
fossa, or bilobed with substantial components in both
fossae5,137 (Figs. 43-54 through 43-56). Analogous to
opening of the IAC during the RS approach, Meckel’s cave
may also be exposed to a degree working from behind and
below. By removing the bone of the petrous apex between
the IAC and tentorium, the posterior and inferior aspect of
Meckel’s cave and the trigeminal ganglion within it can be
exposed. This maneuver is particularly helpful in the
removal of petroclival meningiomas that penetrate Meckel’s
cave as well as in trigeminal schwannomas that possess only
a small subtemporal component. The rhomboidal bony
opening created in opening Meckel’s cave from behind is
identical to that exenterated from above during the
subtemporal-transpetrosal (Kawase) approach. Meckel’s
cave tumor with substantial components in both fossae are
approached via a combined retrolabyrinthine-subtemporal
craniotomy138–140 (Fig. 43-57).
The Craniovertebral Junction
Surgical Anatomy
Although most posteriorly placed tumors that involve the
foramen magnum (FM) region are purely neurosurgical
Figure 43-55. Trigeminal schwannoma with a predominant posterior fossa
component is approached via a retrosigmoid posterior fossa craniotomy in
which Meckel’s cave is opened from behind.
problems, approaches to anteriorly placed intradural
lesions may benefit from the skills of a neurotologist who
is familiar with the posterolateral skull base. Conventional
FM approaches involve removal of the posterior aspect of
the osseous ring combined with suboccipital craniotomy
and laminectomy of one or more cervical vertebra.
However, this opening affords negligible exposure of the
ventral aspect of the medulla and upper cervical spinal cord.
A transoral route has long been used successfully for anteri-
orly placed extradural lesions (e.g., odontoid fractures,
intraosseous tumors). The problem with such exposures
for intradural lesions is the need to create a large and dif-
ficult-to-reconstruct opening between the pharynx and the
subarachnoid space with resultant high risk of CSF leakage
and infection.42 An additional problem with the midline
transoral approaches is its limited ability to deal with lat-
eral tumor extensions.141,142 Anterior transcervical
approaches that traverse the clivus have also been
proposed.143 These limitations with anterior and posterior

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.
The lateral approach to the FM provides exposure of the
lateral aspect of the pons, medulla, and upper cervical spinal
cord.144–150 The space ventral to the brainstem and spine is
also brought into view to a variable degree depending on
both the aggressiveness of bony removal (particularly the
extent of condylectomy) and the degree to which the tumor
has posteriorly displaced these structures. Cranial nerves IX
through XII and the upper cervical nerve roots are in the
surgical field. The approach is readily combined with a wide
posterior fossa craniotomy with exposure of cranial nerves V
through VIII in the cerebellopontine angle.
remaining suboccipital convexity is removed to the level of
the foramen magnum ring. The attachments of the suboc-
cipital musculature can be liberated rapidly with electro-
cautery. As the FM is approached, caution must be
exercised while dividing muscles and ligaments not to stray
from the plane of the cranial base to prevent injury to the
vertebral artery coursing over the arch of the atlas.
Extradural elevation of the cerebellum opens the narrow
cleft at the lateral aspect of the craniovertebral junction
and permits orderly removal of bone using a rotating burr.
As the last portion off the FM ring is removed, a diamond
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
Figure 43-60. Far lateral approach to the foramen magnum. The osseous
opening involves retrosigmoid craniotomy, upper cervical laminectomy, and
mastoidectomy to permit tracing of the inferior aspect of the sigmoid sinus
to the jugular bulb without risking injury to the descending facial nerve.
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 upper cervical roots. The view of the brainstem is obscured, in this
illustration, by the presence of a lower clival meningioma.
As removal of the ring proceeds anteriorly, it broadens to
form the occipital condyle. A variable portion of the occip-
ital condyle is removed depending on the location of the
tumor. In the process of removing the condyle, the posterior
condylar vein is encountered. This often impressively
large branch, which communicates with the jugular bulb,
is occluded with bone wax or Surgicel. After dural incision
the tumor can be seen ventral to the medulla and spinal
cord through the overlying lower cranial nerves IX
through XII and the upper cervical roots. Tumor removal
is impeded somewhat by the interposition of these nerves
so the surgeon must either work through the narrow inter-
vals between nerve fibers or sacrifice some of them. The
spinal portion of the accessory nerve is at particular jeopardy.
We have found that electrophysiologic monitoring of the
lower cranial nerves provides the surgeon useful information
while dissecting around these nerves.154
Anterior lesions at the FM are typically intimately
related to the vertebral artery and vertebrobasilar junction.
Exposure of the vertebral artery from its emergence out of
foramen transversarium across the atlas to its dural pene-
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.
Advantages
The primary advantage of the far lateral approach is its abil-
ity to expose inaccessible lesions ventral to the brainstem
while minimizing brain retraction. When compared with
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
beneficial.
Excessive removal of occipital condyle may theoretically
lead to craniovertebral instability or torticollis, although
this has not been our experience to date. Reconstruction of
the condyle with a bone graft may reduce this risk.
Vertebrobasilar Lesions
Cranial base approaches are sometimes used in vascular
lesions of the vertebrobasilar system. The subtemporal-
transapical approach was first described by Kawase for the
exposure of basilar tip aneurysms.155,156 Rare aneurysms of
the horizontal segment of the intrapetrous carotid artery
may all be exposed subtemporally. Aneurysms of the mid-
basilar artery are among the most challenging of intracranial
vascular lesions (Figs. 43-61 and 43-62). In contrast to
most prepontine tumors, the brainstem has neither been
posteriorly displaced nor rotated to facilitate exposure of
its ventral aspect. Exposure of midbasilar artery aneurysm
is one of the few instances in which we still recommend
the classical transcochlear approach with complete rerout-
ing of the facial nerve and sacrifice of hearing.157 A lateral,
transcondylar approach to foramen magnum is often helpful
in the exposure of aneurysms of the vertebrobasilar
junction and intracranial segment of the vertebral artery.
Intraparenchymal vascular malformations of the brain-
stem are sometimes best approached via the lateral
perspective afforded by the transtemporal approach.
Exophytic brainstem tumors that involve the CPA can also
be approached transpetrosally.158
RECONSTRUCTION
OF THE CRANIAL BASE
Closure of Defects
The workhorse for closing skull base defects (see also
Chapter 59) is free adipose tissue harvesting from the

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
extensive defects, particularly to repair the temporal floor
in encephalocoele, a temporalis muscle rotational flap is
versatile (Fig. 43-64). Most often only the posterior half is
needed, thus avoiding a cosmetically significant hollowing
of the temple. This flap is also commonly used in temporal
bone resection for cancer to provide a vascularized closure
in preparation for radiation therapy.
In extensive defects of the cranial base, particularly
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 43-62. Aneurysm of the midbasilar artery viewed through a
transcochlear approach. The facial nerve had been posteriorly rerouted. The
anterior limit is the carotid genu.
Surgical Neurotology: An Overview 707
Figure 43-63. Obliteration of a translabyrinthine defect with overlapping
strips of abdominal adipose tissue.
Prevention of Cerebrospinal
Fluid Leakage
Prevention of CSF leakage is a central theme in neuroto-
logic surgery. Free adipose tissue grafts, which shrink by
about 50% of their initial volume over time, obliterate
defects and foster formation of a neodura on their medial
aspects. Others advocate use of hydroxylapatite or other
synthetic obliterative material.159 In transtemporal cra-
niotomies, it is sometimes possible to reconstruct the dural
Figure 43-64. Temporalis muscle rotation flap. Often only the posterior half
of the muscle provides sufficient coverage. Using only this portion of the
muscle eliminates the need for fenestration of the zygomatic arch and
prevents a cosmetic defect in the temporal region.
708 SURGICAL NEUROTOLOGY
Skin incision
Muscle incision
Pivot point
of flap
Figure 43-65. Use of a trapezius myocutaneous flap to close a temporal
bone defect.
defect with a fascia graft. Options for harvesting include
the adjacent temporalis fascia, splitting the rectus sheath
when harvesting fat graft, or fascia lata.
Closure can be supplemented by covering the fossa
incudis with an onlay of fascia. Some surgeons advocate
extraction of the incus with insertion of fat or muscle plug.
However, if this maneuver inadvertently distracts the
stapes from the oval window, this creates a direct pathway
from the craniotomy defect into the middle ear. When the
ear canal has been resected, closure of the eustachian tube
under direct vision can be achieved with bone wax or other
substance.
Many methods have been put forward for the operative
management of postoperative CSF leak that persists
despite conservative measures such as fluid restriction and
lumbar subarachnoid drainage. A highly reliable method is
to close the meatus, remove the ear canal, hermetically
close the eustachian tube under direct visualization, and fill
the resulting cavity with a free adipose graft. When CSF
otorrhea traverses a hearing ear, less aggressive measures
such as rewaxing transected cell tracts may suffice but has
a substantial failure rate.
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 Complications in Neurotologic Surgery
Outline
G. Robert Kletzker, MD, FACS Introduction
Perioperative Considerations
Robert J. Backer, MD
Vascular Management
John P. Leonetti, MD in Neurotologic Surgery
Peter G. Smith, MD, PhD Control of Venous Bleeding
Control of Arterial Bleeding
Hemorrhage
Blood Transfusions
Intracranial Complications
INTRODUCTION
Surgeons involved in neurotologic surgery need to be
acquainted with the potential complications. Hemorrhage,
cerebral edema, arterial or venous infarction, pneumo-
cephalus, cerebrospinal fluid (CSF) leak, infection, and
acquired cranial nerve deficits may occur in any surgical
procedure in which transcranial approaches are used.
Specific compartments of the cranial cavity have varying
degrees of tolerance to operative alterations. For example,
relatively small changes in the blood flow in the posterior
fossa may severely alter the delicate functions of the brain-
stem. 1 Removal of lesions of the skull base may leave large
intracranial or extracranial communications, requiring
complex reconstructive techniques for closure.
Manipulation of cranial nerves may affect the patient's
appearance and daily function.
Minimization of complications begins with a compre-
hensive preoperative neuroradiographic assessment,
including high-resolution computed tomography (HRCT),
magnetic resonance imaging (MRI), and conventional or
magnetic resonance angiography (MRA) (Fig. 44-1).
Anticipation of the limits of resection and the neurovascu-
lar structures that may be encountered during the dissec-
tion are the foundation of the collaborative planning by a
cranial base team to achieve a safe, oncologically sound
resection.v" Advances in technologies have made intraop-
erative imaging available with MRI scanners based in the
operating theater. Few institutions currently use this
expensive equipment. More widespread use of stereotactic
navigational systems is improving the safety of neuroto-
logic surgery in a cost-effective manner. Commercially
available systems allow for 1 to 3 mm of accuracy in local-
izing anatomic structures during surgery. Preoperative
images (CT and MRI) are computer loaded, and surgical
712
Postoperative Stroke:
Evaluation and Managemeilt
Cerebral Edema: Evaluation
and Management
Pneumocephalus
Seizures
Cerebral Spinal Fluid Leak
Infections
Cranial Nerve Injuries
instruments are registered to anatomic and fiducial
reference points, after the patient is secured on the opera-
tive table (Fig. 44-2). The systems provide confirmation of
anatomic landmarks with visualization of the correlate
position on the scans, in three-plane views. Fixed boney
structures of the skull base are ideally suited to stereotac-
tic navigational systems for confirmation of anatomy and
the precise localization of instruments. This is advanta-
geous for estimating distances to anticipated vital struc-
tures particularly in narrow dissection fields, such as
approaches to the petrous apex and middle cranial fossa
(Fig. 44-3). Because the images do not show resected
structures or shifts in brain, which occur with tumor
removal, there is a lack of "real time" quality to the systems
which must be considered when utilizing stereotactic
imaging. The technology is adjunctive but not a substitute
for anatomic knowledge. The time required to register the
patient's anatomic reference points to confirm the accu-
racy of positions on the computerized images and the
expense of the systems, have been proven cost effective at
institutions which are proficient in the use of stereotactic
navigational systems.v"
Intraoperative monitoring of the cranial nerve provides
information to the operative team on the nerves' physio-
logic status and thus aids in neural protection. Electro-
physiologic information of the functional integrity of
cranial nerves has become both sophisticated and stan-
dardized in neurotologic surgery. Advances in interven-
tional radiology have added to the safety and efficiency of
cranial base surgery. Balloon occlusion testing of the inter-
nal carotid artery estimates the patient's tolerance to
carotid artery ligation and competency of the circle of
Willis. Selective arterial occlusion with embolization tech-
niques has proven beneficial in the management of
selected highly vascular lesions.
 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
if the head is elevated above the level of the heart; a problem
more often encountered in the sitting than in the supine
position. In the event of the inadvertent opening of the sinus
heralded by the brisk outflow of deoxygenated blood, the
anesthesiologist should be alerted so as to monitor for air
Figure 44-4. Sagittal MRI of large recurrent trigeminal schwannoma.
emboli. Intravascular crepitation, hypotension, tachycar-
dia, or a decline in end-expiratory Pco, are the signals of
air emboli, which require immediate treatment. Rotation
of the table to a left Trendelenburg position should isolate
any intravascular air into the right cardiac ventricle where
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.
1990.)

Discontinuance of nitrous oxide, administration of 100%
oxygen, positive pressure ventilation, and vasopressors are
infused while digital pressure is applied over the venous
opening. Aggressive attendance to the earliest warning
signs of intravascular air can prevent the major complica-
tion of a stroke from air emboli.P-'?
The planned resection of dural sinuses may be indicated
for such lesions as glomus jugulare tumors. The sigmoid
sinus may be ligated with vascular clips or 2-0 silk sutures
passed circumferentially around the vessel through small
stab incisions in the dura, several millimeters from the
margin of the sinus. IS Maintaining the patency of the trans-
verse sinus is of paramount importance whenever the
sigmoid or superior petrosal sinuses are ligated. Retrograde
thrombosis through the inferior cerebral vein of Labbe is a
potential complication of transverse sinus ligation, leading
to catastrophic venous cerebral infarction.'? The petrosal
vein may lie in close proximity to the superior petrosal
sinus; preserving this vein with transpetrosal approaches
minimizes the risk of brainstem venous infarction.i?
Proximal control of the internal carotid artery and jugular
vein with placement of vessel loops in the high cervical
region preempts resection of tumors within the jugular
bulb via infratemporal fossa approaches. This precaution-
ary measure should be taken as well when any approach
requires extensive dissection around the petrous portion of
the internal carotid artery.n,n
Venous bleeding from the cavernous sinus is often
encountered with resection of lesions, such as menin-
giomas, chondrosarcomas, or chordomas, from the trigem-
inal ganglion and petroclival regions. Venous tributaries
from the ophthalmic, cerebral, and retinal veins of the
superior orbital fissure, as well as the sphenoparietal and
petrosal (inferior and superior) sinuses, carry highly
oxygenated, bright red blood that may appear arterial.
Venous bleeding in this area may also have a pulsatile
quality, further replicating an arterial hemorrhage.
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
angiogram, the ligation of selected arteries is planned and
Complications In Neurotologlc Surgery 715
carried out early in the procedure. Contrary to the occlu-
sion of draining veins, the selected intentional ligation of
arteries has a more beneficial effect when there is a time
lapse between arterial ligation and tumor removal. The
longer the time between venous occlusion and tumor
excision, however, the greater the potential for vascular
congestion within the tumor and intraoperative bleeding.
Tumors arising in the infratemporal fossa and upper
aerodigestive tract often have contributing vascularity
from the external carotid system. Preoperative angiogram-
directed embolization of arterial feeders, 1 to 2 days before
resection, is often helpful in hernostasis.i" This technique
has been used most successfully with paragangliomas,
meningiomas, and angiofibromas (Fig. 44-6). Ligation of
the arteries as close to the tumor as possible offers signifi-
cant vascular control, particularly when embolization has
not been feasible.
Specific vessels that require control to gain adequate
tissue mobilization for tumor exposure vary with the
approach. Care in electrocoagulation is warranted, keeping
in mind adjacent structures that may be injured, as hemo-
stasis is obtained. The facial nerve, which is skeletonized
or mobilized in posterior approaches, is vascularized by
the stylomastoid artery in the vertical mastoid segment.
Medial to the digastric ridge, this artery causes bleeding
that requires coagulation. The facial nerve, because of its
close proximity, may suffer irreversible electrothermal
injury if it is included in the field of cautery. Bipolar coag-
ulation at a low setting, with concomitant irrigation will
minimize this risk. Mobilizing the facial nerve with its
fibrous covering and attendant artery at the stylomastoid
foramen allows transposition without compromising its
vascular supply." Similarly, isolation and ligation of the
superior occipital artery from the underlying 11th cranial
nerve is preferred over unipolar coagulation to obtain
hemostasis with neural preservation. Isolation of the cranial
nerves exciting the jugular foramen, prior to ligation of the
Figure 44-6. Angiogram of glomus jugulare tumor showing preoperative
vascularity (left), much decreased after embolization (right).
716 SURGICAL NEUROTOLOGY
internal jugular vein, is a standard principal of neck dissec-
tions proven successful in protecting adjacent nerves while
obtaining vascular control.
Control of the internal carotid artery (lCA) is of para-
mount importance in resection of the temporal bone. The
pterional and infratemporal fossa approaches are used
when the carotid must be mobilized from its petrous
encasement (Fig. 44-7). Ideally, adequate proximal and
distal exposure is obtained prior to any carotid mobiliza-
tion. 26 ,27 Intraluminal balloon occlusion affords distal
control in managing pathologic lesions of the petroclival
region, where complete exposure is impaired.i'v"
Preoperative balloon occlusion testing provides invaluable
information concerning the collateral cerebral circulation
and the patient's ability to tolerate carotid resection with-
out suffering irreversible neurologic sequelae.'? Failure of
the carotid occlusion trial warrants bypass grafting of the
internal carotid artery with a vein graft if the malignant
histopathology dictates ICA resection.l'<" The petrous
portion of the carotid is more often not included in the
resection, but may need to be mobilized for adequate
exposure (Fig. 44-8).34 The caroticotympanic artery arises
from the posterior aspect of the ICA proximal to the genu
at the bony-cartilaginous junction of the eustachian tube.
This small-caliber vessel can bleed profusely if avulsed
during carotid mobilization. Exposure of the petrous
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
arrow) and the facial nerve (small arrow) after removal of boney encasement.
gentle tissue handling and frequent irrigation of the carotid's
surface with isothermal saline. Despite these precautions,
vasospasm may develop. The sequelae of carotid artery
vasospasm vary with the severity and duration of the
constriction. In our experience the most profound conse-
quences occurred in the younger patients whose vascular
tonicity and reactivity were relatively hypersensitive.tv'"
Hemodilution and hypertensive therapy, as for vasospasm
following subarachnoid hemorrhage, may be effective in
preventing catastrophic infarction. At the earliest detec-
tion of segmental reduction of the vessel caliber, topical
application of 10% lidocaine, 1.5% or 3% papaverine,
and 25 mg/mL chlorpromazine have been shown to
inhibit vascular smooth muscle contraction. These agents
are effective spasmolytics, which may be applied to the
constricting vessel to counteract the myogenic response.
The efficacy of calcium channel blockers (e.g., nimodipine)
has not been proven in large-vessel spasm, although it is
systemically administered in the management of medium-
caliber cerebral artery spasm.
The sequelae of prolonged vasospasm are endothelial,
intimal, and vessel media injuries. Spasm unabated for as
little as 2 hours can lead to irreversible injury and throm-
bosis. The darkened coloration of the vessel surface in
the region of constriction is an ominous sign of significant
vascular injury and impending thrombosis. Decreased vessel
Figure 44-8. Three-dimensional CT of a meningioma that encased the ICA
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

session. Intense clinical monitoring of the patient's status
and expedient imaging studies are mandated to detect and
manage any intracranial complications, and thus minimize
resultant deficits.
Cerebral Edema: Evaluation
and Management
Tumors such as meningiomas may incite edema in the
adjacent brain tissue (Fig. 44-11).52 Retraction or manipu-
lation of the brain during tumor extirpation leads to vary-
ing degrees of cerebral swelling, which most commonly
manifests in the first 3 postoperative days. Preoperative
CT and MRI provide the initial assessment of tumor
volume, cerebral edema, mass effect, and midline shift.
Ventricular size and shape allow the volume of CSF and
the likelihood of hydrocephalus to be estimated. Cerebral
compromise evident prior to surgery increases the likeli-
hood of significantly worsened cerebral edema with tumor
removal. Clinically significant edema is most commonly
heralded by evidence of increased intracranial pressure as
measured by an intraventricular drainage catheter, a decline
in the patient's mentation or level of alertness, or progres-
sive focal neurologic deficits such as aphasia or limb weak-
ness. Generalized edema that occurs as a result of brain
manipulation or retraction, or venous outflow obstruction
becomes most pronounced several days after surgery. 53-55
Depending on the degree of lethargy, rapidity of the
neurologic decline, or severity of the process, the first step
in management is to obtain a CT scan. Expansile lesions,
such as a subdural hematoma or hydrocephalus, must be
Figure 44-11. Cerebral edema adjacent to a large petroclival meningioma.
Complications In Neurotologlc Surgery 719
eliminated as a cause of the clinical decline prior to institu-
tion of pressure-reduction maneuvers. Surgical exploration
to evacuate intracerebral blood clots or subdural hematomas
is performed on first detection of these causes of compro-
mised cerebral function. Controlling bleeding and removal
of pressure-producing lesions often arrests progressive
neurologic injury if therapy is instituted quickly. The prin-
ciples of treatment rely on the ability to alter the volume
of brain, CSF, or blood to control intracranial pressure.P-"
Reduction of elevated intracranial pressure begins with
pharmaceutical, mechanical, and ventilatory measures.
Ischemia will result from diffuse cerebral edema and should
be addressed in an aggressive manner to prevent neuro-
logic injury. 58,59
Regulation of the intracranial fluid volume during sur-
gery affords greater exposure and reduces the need for brain
retraction. Closed-system lumbar or intraventricular
catheters placed in a sterile fashion preoperatively provide
access for CSF drainage and the regulation of intracranial
pressure. Lumbar CSF drainage may be contraindicated in
large posterior fossa or transtentorallesions when there is a
risk of brain herniation with decompression (Fig. 44-12).
Epidural manometry to monitor intracranial pressure is an
alternative when drainage of CSF is prohibited. An intra-
ventricular catheter is the preferred device for both removal
of CSF and direct measurement of intracranial pressure."
In selected cases, preoperative intravenous steroids
(dexamethasone in 4- to lO-mg doses) are begun preoper-
atively and continued every 6 hours for 3 days. The dose is
tapered and discontinued over the ensuing 3 to 10 days, as
the patient's recovery allows.P'' This regimen is routinely
Figure 44-12. Bilateral acoustic neurofibromas responsible for aqueduct
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'<"

The method of reconstruction significantly influences the
incidence of CSF leakage. When the continuity of the dura
has been disrupted, reestablishing a water-tight seal is
more difficult. Fascia grafts may be used to reconstitute
the dura. Autologous fat grafts to fill a limited posterior
fossa dural defect in the mastoid cavity will provide a
water-tight seal. This reconstruction has proven reliable in
translabyrinthine approaches for decades. Skull base sur-
gery, which exposes large areas of the basicranium, requires
more sophisticated methods of reconstruction.w-? Free-
tissue transfer, with myogenous and myocutaneous grafts,
has markedly decreased the incidence of postoperative CSF
leaks and subsequent wound infections (Fig. 44_14).7 3,74
Intraoperative lumbar drainage catheters are used to
assist in the control of intracranial pressure and in the
relaxation of the brain to minimize retraction. Postop-
eratively the catheter may be left in place to drain CSF at
a maximum rate of 300 mLl24 hours, to help prevent the
development of a CSF leak. The spinal fluid drainage may
be used for 5 days with the patient on strict bedrest, with
the head of bed elevated 15 to 30 degrees. A sterile mas-
toid or Barton's dressing is maintained over the wound to
promote water-tight healing. Antibiotics are continued for
the duration of the catheter's placement.Z'v" Excess pro-
duction of spinal fluid may need to be reduced if a persist-
ent CSF leak or hydrocephalus develops following
discontinuation of the lumbar drain. Acetazolamide
sodium (Diamox 500-mg) is administered orally or intra-
venously twice a day.
Advances in imaging modalities, stereotactic navigational
systems, electrophysiologic monitoring, and standardiza-
tion of skull base approaches have improved the safety of
Figure 44-14. Sagittal MRI demonstrating a rectus abdominis myogenous,
free-tissue graft filling the surgical defect of the infratemporal fossa.
Complications In Neurotologlc Surgery 721
neurotologic operations. Anticipation of potential prob-
lems associated with the manipulation of delicate neurovas-
cular structures helps to prevent complications. Meticulous
patient preparation and refined surgical techniques in
resection and reconstruction help to optimize treatment
results. Early recognition of complications and expedient
intervention can minimize the sequelae of complications
associated with neurotologic and cranial base surgeries.
CSF leaks contribute to wound infections, fistulae forma-
tion, and meningitis. Prevention of these complications is
best accomplished by wound closure with well-vascularized
tissues. Pedicled myocutaneous or vascularized free flaps is
required to reconstruct large defects of the basicranium. In
the event of a CSF leak despite taking these precautionary
measures, wound exploration and secondary reconstruc-
tion may be required. Detection of clear rhinorrhea or
otorrhea, with a "halo sign" on a cotton sheet, alerts
the clinician to the likelihood of a leak. If a sample of fluid
can be collected, chemical analysis showing a glucose con-
centration greater than 30 mg/mL or identification of
transferrin (~-1 or -2) by immunoelectrophoresis is confir-
matory for CSF.77,78 Fluid in the nasopharynx, which is
suspected to be CSF, can be collected in cotton pledgets
and scanned for radioactive isotopes 12 hours following
intrathecal nucleotide instillation. This study is beneficial
when chemical and protein analysis of fluid is inconclusive.
Contrast cisternography with CT imaging is often helpful
in confirming and localizing the site of a spinal fluid leak.
INFECTIONS
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
by combining clindamycin phosphate (Cleocin 600 to 900
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-
able for a baseline examination to rule out any corneal abra-
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
is necessary in those individuals who develop significant
ectropion or have extreme lower lid laxity that prevents
complete corneal protection. Marked disfigurement of the
face with asymmetry and oral incompetence may need to be
corrected by muscle sling procedures using the temporalis
or masseter muscles. Primary or crossed facial nerve graft-
ing or hypoglossal-to-facial nerve anastamosis is useful in
restoring tonus to the facial musculature, as are primary
nerve grafts in suitable candidates.P-" Electrical stimulation
of the face, massages, and biofeedback exercises are directed
by the physical therapists and are often helpful in maximiz-
ing the effects of the facial reanimation procedures.
The cochlear vestibular system is often sacrificed, a
complication that is without remediation. Recent attempts
to implant electrodes on the cochlear nucleus in the brain-
stem offer some hope of restoring audition in patients
whose tumor removal sacrifices all remaining hearing.
This is a major benefit to patients with neurofibromatosis
who have bilateral acoustic neuromas."
Problems with deglutition and phonation are not infre-
quent following glomus tumor surgery due to the paresis or
paralysis of the glossopharyngeal and vagus nerves.
Perioperative pulmonary toilet through the tracheostomy
helps prevent pneumonia. Decannulation of the tra-
cheostomy is accomplished along with assessment of the
vocal cord function by direct fiber-optic laryngoscopy and
swallowing evaluation by modified barium cineradiography
(Fig. 44-20). Persistent aspiration may require medialization
of the vocal cord by endoscopic injection of Teflon or colla-
gen or an external thyroplasty procedure. Pooling of secre-
tions in the pyriform sinus, which causes aspiration, may be
corrected by cricopharyngeal myotomy.'" This problem
may be particularly bothersome and seems to be caused by
the lack of pharyngeal sensation following glossopharyngeal
nerve section. Swallowing training by a speech pathologist
is often most beneficial to these patients.
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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.
HISTORY
Acoustic neuroma was first described in the latter part of
the 1700s and by the mid-1800s, neurologists understood
that patients who manifest unilateral deafness, facial
numbness, and progressive blindness caused by “optic
neuritis” (papilledema) were afflicted by a tumor of the
cerebellopontine angle (CPA)1–4 (Fig. 45-1). At this time
the only intracranial tumors that could be reliably local-
ized involved either the motor strip or cranial nerves at the
base of the brain. ANs figured prominently in the early
development of neurologic surgery because they were
readily diagnosable with signs and symptoms alone. The
earliest attempt to remove an AN was performed in 1891
by Charles McBurney of New York, who has been immor-
talized by the appendectomy incision that bears his name.5
They reported that after opening the suboccipital plate
with a mallet and gouge, the cerebellum swelled massively,
so much so that it became necessary “to shave off the
excess.” No tumor was removed and the patient expired
12 days later. The first successful results were achieved in
1894 by Ballance in London and Annandale in Scotland.6–9
In these early attempts a unilateral suboccipital cran-
iotomy was employed, complete removal was performed
by finger dissection, hemostasis was obtained by packing
the CPA with gauze, and there was great emphasis on oper-
ative speed (Fig. 45-2). The outcome was dismal. At the
International Congress of Medicine in London in 1913 the
results of Victor Horsley (London), von Eiselsberg
(Vienna), and Fedor Krause (Berlin) were presented.10 In
63 patients, surgical mortality was 78% and most of the
survivors were severely crippled. It should be realized that
all of these early cases were moribund at the time surgery
was undertaken. Indeed, hydrocephalus was virtually uni-
versal in AN surgical candidates well into the 1930s and
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.)
was frequent until the computed tomography (CT) and
magnetic resonance imaging (MRI) era. In the past 5 years
at our institution hydrocephalus was present in only 4% of
patients with ANs.11
The next era in AN surgery was ushered in by Harvey
Cushing of Johns Hopkins and later Harvard (Fig. 45-3). In
1905, he advocated decompression of the posterior fossa by
extensive removal of suboccipital bone.12 He reasoned that
few tumors could be safely removed and that bony decom-
pression alone might be beneficial. After this proved fruit-
less, he developed a technique of subtotal tumor debulking
via a bilateral suboccipital craniectomy. Cushing’s greatest
contributions were that he was gentle with tissues, meticu-
lous with hemostasis, and operated deliberately without
undue emphasis on speed.13,14 For hemostasis he employed
Horsley’s bone wax (described in 1892) and two of his
own innovations: silver clips (1911) and electrocautery
(1928).15–17 By gutting only the core of the tumor, he
avoided interrupting the vasculature of the brainstem and
often preserved cranial nerve function. The mortality rate
of his surgical patients, which was 20% in 1917, decreased
following adaptation of further technical refinements, such
as partial cerebellar resection, to only 4% by 1931.18
Although Cushing’s operative mortality was low, many
patients succumbed to their residual tumor in later years.
The next era in AN surgery was pioneered by Walter
Dandy of Johns Hopkins, a pupil of Cushing. In 1916,
while still a resident in training, Dandy reported a case in
which he removed an AN completely.19 Cushing, who had
vehemently maintained that attempts at total removal were
“foolhardy in the extreme” was infuriated. Subsequent
reports by Dandy in 1922, 1925, 1934, and 1941 described
a unilateral suboccipital approach during which, following

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.)
gutting of the tumor, he gently drew the capsule away
from the brainstem.20–23 His eventual surgical mortality
rate of about 10% was higher than Cushing’s, but this
reflected his more radical philosophy of total tumor
removal. There remained much animosity between
Cushing and Dandy throughout their careers and the two
rarely spoke with each other.24
The translabyrinthine approach, which was eventually
perfected by William House in the early 1960s, has a rich
early history. It was proposed by two authors in 1904, one
in America and one in Europe. Rudolph Panse, an
otopathologist from Dresden, proposed a translabyrinthine
approach but did not actually perform one.25 George
Woolsey and Charles Elsberg of New York also suggested
it, citing the poor results with the suboccipital approach of
the day.26 They performed cadaver dissections in which
they determined that the shortest route to the CPA
commenced 1 cm to 2 cm behind the ear. In 1905,
M. Borchardt performed the first combined suboccipital-
transtemporal approach during which he chiseled away the
temporal bone to the level of the internal auditory canal to
improve exposure of the tumor.27,28 The first purely
translabyrinthine craniotomy was performed by F. H. Quix
of Utrecht in 1911.29 The initial operation was aborted
because of bleeding from the superior petrosal sinus. It was
completed at a second stage 4 days later. The operation
consisted of radical mastoidectomy followed by chiseling
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.)
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
examination revealed that only a tiny amount of tumor had
been removed. Several reports followed by H. Marx of
Heidelberg (1913),30 Von Schmiegelow of Copenhagen
(1915),31 and Zange of Berlin (1915),32 but the technique
passed into obscurity because of problems with inadequate
exposure, hemorrhage from the surrounding venous
sinuses, cerebrospinal fluid leak, and meningitis. The
translabyrinthine approach was dismissed by Cushing in
his classic monograph Tumors of the Nervus Acusticus (1917)
in which he maintained that it was a deep wound with a
narrow field of action, which would be suitable only for
tiny tumors.13 In 1921, writing in Laryngoscope, Cushing
stated: “If the otologist has ambitions to treat these lesions
there is no possible route more dangerous or difficult than
this one which has been proposed by Panse, Quix, and
Schmiegelow.”14 He went on to say that “A proposal of this
sort I am sure would never occur to an otologist who has
general surgical training before he engaged in the particular
surgery of his specialty.” These sentiments were echoed by
Dandy who in 1925 called the translabyrinthine approach
“a wholly impractical suggestion.”21 Such vehement opinions
from the masters of their day relegated the translabyrinthine
technique to utter obscurity until William House, armed
with a surgical drill and operating microscope, successfully
resurrected it in the early 1960s.33–35 The degree to which
these early failed attempts passed from the common
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

childhood and a rather substantial fraction during
advanced age.52–54 Tumors in childhood may attain large
size and, presumably due to a rapid growth rate, may pos-
sess an unusual degree of vascularity.
Neurofibromatosis type 2 is a rare disease, with a
prevalence in the population of about 1 in 30,000 to
50,000 people. This means that there are no more than
several thousand afflicted individuals in the United States.
NF1, by contrast, is much more common than NF2 with a
prevalence of some 30 to 40 per 100,000 people. There are
approximately 80,000 individuals with NF1 in the United
States. Virtually all patients with NF2 eventually manifest
bilateral ANs, but they are rare in NF1. The literature on
NF1 and NF2 was often ambiguous and overlapping until
relatively recently.55 Although the exact incidence is
unknown, probably fewer than 2% of NF1 patients develop
a unilateral AN and virtually none develop bilateral
tumors.56
TUMOR BIOLOGY
Pathogenesis
Acoustic neuromas are schwannomas that arise from
the vestibular division of the eighth cranial nerve57,58
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.)
Acoustic Neuroma (Vestibular Schwannoma) 731
(Fig. 45-4). Technically, they are neither neuromas nor
acoustic, at least in the sense that their origin is not from
auditory fibers. Because the term acoustic neuroma is a mis-
nomer, a Consensus Development Conference of the
National Institute of Health on the subject recommended
that this widely used term be replaced by the more accurate
vestibular schwannoma.59 The vestibular nerve, which has an
approximately 2-cm course between the brainstem and the
inner ear, possesses two divisions. Although formerly some
have maintained that superior vestibular schwannomas pre-
dominate, current opinion favors an equal origin in the
superior and inferior divisions of the nerve.60 A recent study
from Japan suggests that about 85% of VSs originate in the
inferior vestibular nerve.58
The eighth nerve is unusual among cranial nerves in
that it possesses a long segment of central myelin. It has
been proposed that ANs may arise in the region of the
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
schwannomas originate lateral to the glial-schwannian
junction of the nerve and not from the transition zone.62 In
the proximal segment of the eighth nerve, myelin is laid
down by oligodendroglial cells, while distally it is produced
by Schwann cells. The neuroglial-neurilemmal junction
732 SURGICAL NEUROTOLOGY
most often occurs in the vicinity of the vestibular (Scarpa’s)
ganglion, but its location varies considerably. This variability
has been argued to account for the variable site of origin of
ANs along the vestibular nerve. Arguing against the transi-
tion zone as the site of AN formation is the appearance of
schwannomas apparently originating distal to it as well as
multicentric origins of AN along the eighth nerve in the
same patients, particularly those who have NF2s.61,63 A rea-
sonable alternative explanation based on available evidence
is that ANs originate from the Schwann cell population
associated with the vestibular ganglion. It has been
observed that the greatest density of Schwann cells along
the eighth nerve exists at this location.64 Also supportive of
this hypothesis is the finding that the junction zone and
other segments of the nerve possess a consistently lower
density of Schwann cells than the ganglion region does.
In larger tumors, it is seldom possible to ascertain the
precise site of origin along the nerve. Observations from
smaller tumors indicate that most ANs arise in the internal
auditory canal (IAC). A small minority of tumors originate
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
arose in the medial half of the cisternal course or in the
brainstem root entry zone. A few schwannomas have even
been reported to have arisen in the inner ear, presumably
from myelinated dendrites of the vestibular nerve proximal
to Scarpa’s ganglion.65,66
Molecular Genetics
Great strides have been made in recent years concerning
the genetic basis of AN formation. Through a variety of
molecular genetic techniques, the gene responsible for AN
associated with NF2 has been localized to the long arm of
the chromosome 22.67–70 The disease gene was identified in
1993, and codes for a 587 amino acid protein.71,72 The
product of this gene resembles certain proteins (moesin,
ezrin, and radixin), which are thought to link the cell
membrane with cytoskeletal components. The NF2 gene
has been shown to be inactivated both in familial as well as
sporadic cases. Oncogenes are regions of the genome that,
when damaged, lead to tumor formation. In many instances,
the defective gene elaborates a product that induces a neo-
plasm. In AN, by contrast, evidence points to the existence
of a “tumor suppressor” gene, which, if inactivated, results
in tumor growth.57 It has been speculated that the gene
product is a substance that regulates Schwann cell division
which, when deficient, results in excessive cellular prolif-
eration. Because the absence of this gene product results in
tumor formation, it is necessary for both copies of the
involved chromosome to be dysfunctional. Thus, two muta-
tions are required to induce an AN—one that damages
each chromosomal copy. This “double hit” hypothesis fits
well with theories on the genetic origin of sporadic ANs as
well as those associated with NF2. In sporadic AN, two
silencing mechanisms must occur in one cell to incite
tumor growth. For this to occur, it must be assumed that
the gene has a high spontaneous mutation rate; otherwise,
such a dual event would be extraordinarily rare. It has been
demonstrated that patients with NF2 carry a defective
copy of the gene. When a spontaneous event inactivates
the sole remaining functional copy of the AN suppresser
gene, a tumor results. Because spontaneous events happen
fairly frequently, these individuals eventually develop
multiple schwannomas.
The nature of the genetic injury of chromosome 22 in AN
has been studied in some detail.73 A major rearrangement of
the chromosome was detected in 57% (23/39). The most
common finding was a large interstitial deletion. Deletion
of one entire copy of chromosome 22 (monosomy) was
also noted in some cases as was terminal deletion, mitotic
recombination, and deletion with reduplication. In the 43%
(16/39) of tumors in which no chromosomal rearrangement
was detected, more subtle mutations through the AN
suppresser gene were suspected that were beyond the
resolution of the methods employed in the study. Newer
studies reveal that nearly all sporadic VSs show evidence of
NF2 gene inactivation.74
Chapter 5 (Molecular Genetics in Neurotology) offers a
more detailed discussion of the molecular genetics of this
condition.
Molecular Mechanisms
Although the biochemical aberrations that lead to AN
growth have yet to be elucidated, some investigations have
been performed concerning the possible role of substances
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
connective tissue types, has been found in AN.75 Of interest,
FGF mRNA was not elevated in meningiomas, a type of
tumor that often coexists with AN in NF2 patients. One
growth-promoting substance that may be implicated
circumstantially in AN pathogenesis is platelet-derived
growth factor (PDGF). The gene for this polypeptide is
located on chromosome 22 near the NF2 gene. Evidence
of a role for any of the above-mentioned growth factors in
AN formation is decidedly preliminary. In recent studies,
the NF2 gene product, Merlin/Schwannomin, has been
found to interact with the two PDZ domains (postsynaptic
density domains) that contain protein EBP50/NHE-RF,
which is itself known to interact with the PDGF receptor
(PDGFR) in several cell types. An up-regulation of both
PDGFR and EBP50/NHE-RF and an interaction of both
proteins were found in primary human schwannoma tissue.
Upon PDGF stimulation in culture, Merlin/Schwannomin
appeared to inhibit the activation of the MAPK and PI3K
signaling pathways, impinging on the phosphorylation of
Erk 1/2 and Akt, respectively. The data suggest that
PDGFR is more rapidly internalized by the schwannoma
cells overexpressing NF2. Therefore, this process is sug-
gested as a model for a mechanism of Merlin/Schwannomin
tumor suppressor function, which intermediates accelera-
tion of the cell surface growth factor degradation.76
Another recent study suggests that a major cellular
consequence of NF2 deficiency in primary cells is an
inability to undergo contact-dependent growth arrest and
to form stable cadherin-containing cell-to-cell junctions.
These studies indicate that merlin functions as a tumor
and metastasis suppressor by controlling cadherin-
mediated cell-to-cell contact.77

Endocrine Relationships
A possible influence of sex hormones over AN growth has
been postulated based on several clinical and experimental
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
morbidity among NF patients born to an affected mother
than among those born to an affected father.78 Clinical
series have consistently observed a slightly higher incidence
of AN in women than in men, particularly postmenopausal
women.44 In addition, the onset of NF2 may be earlier in
women than men. It has also been proposed that the AN
growth rate may accelerate during pregnancy.79 A number
of investigations have been carried out in an attempt to
clarify the possible influence of estrogen, progesterone,
and testosterone in AN growth.80–82 High-affinity estrogen
and progesterone receptors have been identified in a variable
percentage of ANs. 82,83 In one investigation, cytosolic estro-
gen receptors were identified in 30% of ANs, cytosolic prog-
esterone receptors were detected in 40%, and cytosolic
androgen receptors in 80%.82 In a recent series, 33% of
schwannomas showed expression for progesterone receptor;
estrogen receptor mRNA levels were undetectable in all
tumors.80 While the possible molecular mechanism of
estrogen and progesterone effect on AN has yet to be
elucidated, it is possible that they promote growth through
inducing proliferation of the vascular endothelium.84
In breast carcinoma, the presence of estrogen receptors is
an important factor in predicting responsiveness to anti-
hormonal chemotherapy. An evaluation of antiestrogen
chemotherapy may be undertaken in the future in both
sporadic AN as well as in NF2. However, the relatively low
rate of receptor positivity predicts that only a small subset of
tumors, if any, will be influenced by this form of treatment.
The level of gastrointestinal hormones has also been
evaluated in AN.85 In an evaluation of 19 ANs, some
tumors demonstrated elevation of the precursors of gastrin
and cholecystokinin, but enhancement of the active peptides
was not present. The significance of these observations
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
and 86 control subjects.88 In patients who used cellular
telephones, the tumor occurred more often on the con-
tralateral than ipsilateral side of the head. The relative risk
Acoustic Neuroma (Vestibular Schwannoma) 733
was 0.9 (P = 0.07) and did not vary significantly by the
frequency, duration, and lifetime hours of use. The short
duration of widespread cellular telephone use, however,
precludes definite exclusion as a risk for AN development.
GROSS AND MICROSCOPIC PATHOLOGY
Gross Pathology
The great majority of ANs are benign, relatively slowly
growing neoplasms. Upon gross inspection, they are usually
yellowish-white or gray and frequently possess cystic com-
ponents. Many ANs appear internally heterogeneous and
contain interspersed regions of soft and firm consistency.
Their surface is typically smooth and regular. The most
pronounced vascularity appears on the tumor surface, taking
its origin from numerous small vessels of the IAC, CPA,
and brainstem surface. Although ANs are frequently
described as well encapsulated, little true capsule appears
evident. Nevertheless, as a general rule, the tumor surface
does tend to be firmer and more vascular than its central
regions.
Histopathology
Classically, histopathologic examination of AN reveals two
morphologic patterns: Antoni A and B89–92 (Fig. 45-5).
Antoni type A describes a densely packed cells with small,
spindle-shaped, densely staining nuclei. Antoni type B
refers to a looser cellular aggregation of vacuolated, pleo-
morphic cells. The Antoni B morphology seems to occur
predominantly in larger tumors. In a particular AN,
one type may predominate or they may be thoroughly
admixed. The predominance of one variety does not
appear to be of clinical significance. A whirled appearance
of Antoni A type cells is a Verocay body. Nuclear atypia is
occasionally seen and does not necessarily imply greater
clinical aggressiveness. In Antoni B configurations, the
presence of large, atypical, hyperchromatic nuclei has been
Figure 45-5. Photomicrograph of an acoustic neuroma with regions of both
Antoni type A (more dense) and B (looser) morphology. Verocay bodies,
palisading nuclei around regular central regions, are also typical of
schwannomas. (From Armed Forces Institute of Pathology: Tumors of the
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.

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
of the thymidine analog 5-bromodeoxyuridine. In this
study, the fraction of tumor cells in replication (S-phase)
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-
fixed tissue subjected to flow cytometric analysis.105 The
S-phase fraction varied from 1.1% to 20.7% (mean 6.3%).
Of interest, evaluation of the clinical records of the
49 patients in this study failed to reveal a correlation
between proliferative rate and patient gender, symptom
manifestation, or tumor size. A possible correlation with
tumor growth rate could not be excluded from this study.
It has also been observed that small tumors have a lower
mitotic index on average than larger tumors.106 No corre-
lation has been detected between the age of the patient and
the proportion of mitotically active cells in AN.106
Several studies have been performed using Ki-nuclear
antigen as well as PCNA (proliferative nuclear antigen) as
an indicator of tumor growth.107,108 The results suggest
that the growth rate of vestibular schwannomas varies and
Acoustic Neuroma (Vestibular Schwannoma) 735
B
Figure 45-8. Illustration (A) and MRI scan (B) in the axial plane of
an acoustic neuroma in the cisternal stage.
may explain the difficulties in estimating the growth of
neuromas on the basis of clinical aspects only.
Although ANs grow at a variable rate, they are, by and
large, slowly growing tumors (Table 45-3). Only in recent
years, since the advent of CT and MRI scanning, has accu-
rate serial measurement of untreated tumors become pos-
sible. There are numerous studies of ANs serially studied
by high-resolution imaging studies in the literature. When
the available data are analyzed, ANs increase in diameter
an average of 0.1 cm to 0.2 cm per year. In one large study,
50 patients were followed an average of 41.7 months with
a range of 7 to 152 months.109 The mean diameter growth
was 0.11 cm per year with a range from −0.51 cm (reduc-
tion in size) to 0.98 cm growth per year. Although only a
few patients had a reduction in tumor diameter, 34%
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).
One must be cautious in interpreting these data to indicate
that a large fraction of ANs remain stable over the long
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
dramatic or rapid-paced symptomatology would not have
been managed conservatively and thus the patient popula-
tion is somewhat biased. Second, insufficient observations
are available for 5-, 10-, or even 20-year intervals and
patients often relate a gradual symptomatic progression
over such periods. It is probable that most tumors that are
B
Figure 45-10. Illustration (A) and MRI scan (B) in the axial plane of an
acoustic neuroma in the early brainstem compressive stage.
apparently stable for 1 or 2 years will eventually demonstrate
clinically relevant progression if observed for a decade or
longer. Third, the criteria to measure the tumor size are
still variable and not even consistent in the same institution.
For this reason, the clinician is wise to avoid overly rea-
ssuring younger patients. Fortunately, the fraction of rapidly
dividing tumors (exceeding 1 cm per year) is small, perhaps

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
tumor, this tends to remain consistent over time.111 This
observation may be helpful in counseling the older patient
regarding likely growth of the tumor over his or her
predicted lifespan. Nevertheless, the correlation between
the rate of tumor growth and the pace of symptomatic
progression is imperfect. Some patients suffer symptomatic
Acoustic Neuroma (Vestibular Schwannoma) 737
B
Figure 45-12. A, Coronal representation of the brainstem deflection
associated with a large acoustic neuroma. (From Cushing H: Tumors of the
Nervus Acusticus and the Syndrome of the Cerebello-Pontile Angle.
Philadelphia, Saunders, 1917). B, Coronal MRI scan illustrating dramatic
pontine compression caused by a large acoustic neuroma. Note the
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.

Measurement of Acoustic Neuromas
There is still no universally accepted method of measuring
ANs. However, a common language for expressing tumor
size is essential for valid comparisons among diagnostic
and therapeutic modalities. Two features of ANs complicate
measurement: their irregular geometry and the nonlinear
relationship between tumor diameter and volume. Were
ANs spherical, then a simple assessment of tumor diameter
in a single plane would be sufficient. However, inclusion of
the narrow tongue of tumor in the IAC in diameter mea-
surements tends to substantially overestimate tumor size.
Most authors advocate description of an AN’s size in terms
of the diameter of the CPA component of the tumor as
measured in three axes: (1) parallel to the petrous ridge,
(2) perpendicular to the petrous ridge, and (3) vertically.115
The first two measurements are determined from axially
oriented scans, the third from coronal images (MRI or CT).
Thus, a tumor may be expressed as being 3.2 × 4.1 × 3.9 cm,
for example. For ease of comparison, many would simplify
this to the single largest axial dimension (e.g., 4.1 cm).
As little data is published in the literature using other than
a single diameter measurement, this method is used in the
present chapter. Of course, wholly intracanalicular tumors
must be considered separately because they possess no CPA
component. Definition of AN size ranges into small, medium,
large, and giant sizes is useful in permitting comparison
among treatment groups. While there is no unanimity in
defining these ranges, it is reasonable to divide ANs into
the following categories: intracanalicular, smaller than
1.0 cm, 1.0 cm to 2.5 cm, 2.5 cm to 4 cm, and larger than
4 cm. Attempts are under way to establish an internationally
accepted measurement standard.115,116
It has been pointed out that relatively small increases in
tumor diameter produce a much greater increase in tumor
volume.117 If it is assumed that the CPA component of
most ANs are roughly spherical, then the interrelationship of
tumor diameter and volume can be estimated as 4/3 πr3
where diameter = 2r. As computed imaging programs
become more sophisticated, comparison of tumor size based
on volumetric calculations is likely to replace diameter-based
measurement systems.
TABLE 45-4. Clinical Symptoms of Vestibular Schwannoma
Clinical Manifestations Cushing13 Mathew350
Hearing Loss 100% 97%
Tinnitus 66%
Dysequilibrium 46%
Vertigo 5%
Trigeminal Nerve 63% 33%
Facial Nerve 77% 22%
Headache 100% 29%
Visual Symptoms 87% 15%
Lower Cranial Nerves
Dysphagia 53%
Papilledema
Asymptomatic
Modified after Driscoll CLW: Acoustic Neuroma. In Jackler RK, Driscoll CLW: Tumors of the Ear and Temporal Bone. Philadelphia, Lippincott Williams & Wilkins, 2000.
Acoustic Neuroma (Vestibular Schwannoma) 739
CLINICAL MANIFESTATIONS
Typical Clinical Presentation
Although it is possible to describe a typical clinical presen-
tation of AN, it is important for the clinician to be aware
of remarkable degree of variability in the manifestations of
these tumors (Table 45-4). With this caveat in mind, it is
helpful for the diagnostician to develop a mental framework
based on the most representative symptom complex for
each stage of AN growth. The symptoms associated with
intracanalicular ANs are typically limited to the eighth
nerve: hearing loss, tinnitus, and vestibular dysfunction.
During the cisternal stage, hearing loss may worsen and
vertigo gradually becomes replaced by dysequilibrium.
At about the time when brainstem compression begins,
trigeminal symptoms commence, initially in the midfacial
region. As brainstem compression becomes severe, the
fourth ventricle collapses and hydrocephalus results.
Chronic hydrocephalus frequently results in visual loss and
persistent headache. The terminal stages involve contralat-
eral long tract signs (e.g., hemiparesis) and eventual respira-
tory death due to herniation of the cerebellar tonsils.
Signs and Symptoms
Hearing Loss
Occurring in well over 95% of patients, hearing loss is the
most frequent symptom of AN. The mechanism, in most
cases, is from compression and/or infiltration of auditory
nerve fibers. Impairment of the blood supply to the nerve
or inner ear also plays a role in some cases. In the majority
of patients, hearing loss progresses gradually over many
years, eventually leading to total deafness in the tumor ear.
The loss is typically unilateral or asymmetric which, in its
early stages, preferentially involves the high frequencies.
Characteristically, speech discrimination is affected out of
proportion to pure tone hearing loss.
Atypical forms of hearing loss are relatively frequent. In
a study of a large group of patients with ANs, only 66% had
a high-frequency biased hearing loss and approximately
20% had an upsloping or trough-shaped loss, configurations
Selesnick11 Matthies119
85% 95%
56% 63%
48% 61%
19% 61%
20% 16.5%
10% 17%
19% 12%
3% 1.8%
0% 2.7%–3.5%
0%
1.6%
740 SURGICAL NEUROTOLOGY
frequently ascribed to other causes.118 A sudden decrease
in hearing, often equated by clinicians with viral infection
or vascular occlusion, occurs in some 26% of ANs.48,119
Presumably, sudden hearing loss results from a spasm or
occlusion of the internal auditory artery as a result of
tumor compression. In some patients it may be triggered
by head trauma or vigorous physical exercise. The loss may
be partial or total, and spontaneous recovery is possible.120
Sudden loss may be the sentinel event that leads to a diag-
nosis or it may occur months or years before the tumor’s
discovery. The diagnostician’s dilemma stems from the
fact that only some 1% to 2% of patients who have sudden
hearing loss will ultimately prove to have an AN. As a
general rule, we advocate a diligent search for ANs in
patients with sudden hearing loss.
A small fraction of patients with ANs have either normal
hearing or symmetric hearing loss.48,121 Before the era of
high-resolution imaging, most series showed 1% to 3% of
patients with AN had normal hearing. In a recent series
from the MRI era, 15% of patients with ANs had subjec-
tively normal hearing, of whom 4% were audiometrically
normal (SRT < 25 dB, SDS >85%). In addition, 7% of
patients had audiometrically symmetric hearing. It is clear
that the clinician must be alert to nonauditory symptoms if
such tumors are to be detected early.
Tinnitus
Tinnitus is very frequent in AN since it is many inner ear
diseases. In several studies, up to 70% of the patients suffered
preoperative tinnitus.48,119,122 In most cases, the tinnitus is
high pitched and localized to the tumor ear.123 However,
the symptom may be nonlocalizing and may be of unusual
pitches. The tinnitus is seldom very disturbing to the
patient. A few patients with AN have unilateral tinnitus in
the absence of subjective hearing loss. Thus, unilateral tin-
nitus without explanation is an indication for an evaluation
for AN.
Vertigo, Dysequilibrium, and Dysmetria
Disturbance of the vestibular and cerebellar functions may
generate a variety of symptoms in patients with ANs.
Vertigo, the cardinal symptom of peripheral vestibular
dysfunction, is an illusion of motion that is usually evoked
or worsened by a change of head position. Subjectively, the
typical complaint is of a whirling sensation, but other sen-
sations such as that of ground rolling or falling backward
may occur. Vertigo is episodic, and dysequilibrium is a
continuous sense of instability. The patient with dysequi-
librium may complain of a minor incoordination or clum-
siness, particularly of gait, as well as a generally unsteady
feeling. Although there is some overlap, the symptoms of
vertigo and dysequilibrium are usually quite distinct in
patients with ANs.
True vertigo is not commonly associated with ANs. In a
recent series, only 19% of individuals reported this symp-
tom, most of whom had small tumors.48 Vertigo is decidedly
infrequent with larger tumors at the time of diagnosis,
although some patients relate having been through an
episode some years before the discovery of their tumor.
Thus, it appears that vertigo is generated early in AN growth,
perhaps by destruction of the vestibular nerve or through
interruption of the blood supply to the labyrinth.
Dysequilibrium is much more prevalent than vertigo,
occurring in nearly half of patients with ANs.48 In contrast
to vertigo, which decreases in incidence with increasing
tumor size, dysequilibrium becomes more frequent with
larger tumors. Larger tumors (>3 cm) have a higher than
70% incidence of this disturbing symptom. The most
likely mechanisms involved in causing dysequilibrium are
uncompensated unilateral vestibular deafferentation and
persistent perverse input from the diseased vestibular
nerve.
The characteristic symptoms of cerebellar dysfunction
are intention tremor and gait ataxia. Large ANs indent the
lateral cerebellar lobe and peduncles and may impair the
output of a sizable fraction of the ipsilateral cerebellar hemi-
sphere. Somewhat surprisingly, overt cerebellar dysfunction
is uncommon in ANs and is limited to large tumors.124
Although little information is available on its exact incidence,
truncal ataxia appears to be more common than limb
ataxia. Patients tend to fall toward the side of the tumor,
although not invariably so.
Facial Anesthesia and Pain
Facial sensory dysfunction occurs in approximately 50% of
tumors larger than 2 cm and is rarely present with smaller
lesions.48,125 Hypesthesia of the midfacial region is the most
common symptom. This decreased sensation is often
associated with tingling. Many patients and physicians alike
erroneously attribute these symptoms to sinus or dental
disease. Gradually, the upper and lower divisions of the
trigeminal nerve become involved with the evolution of
more widespread hypesthesia, which eventually progresses
to anesthesia. In patients with symptomatic trigeminal nerve
dysfunction, the corneal reflex is almost always decreased or
absent. Of note, the corneal reflex is also impaired in a con-
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-
ralgia is an uncommon but certainly not rare manifestation
in large tumors.126 Tumor-associated pain responds quite
well to therapy with carbamazepine in much the same
manner as the idiopathic form of the disease (tic douloureux).
A possible pathogenic mechanism is displacement of a vessel
(e.g., the superior cerebellar artery or the petrosal vein) by
the tumor into the root entry zone of the trigeminal nerve.
Contralateral trigeminal neuralgia has also been reported
but is very rare.127
Dysfunction of the motor division of the trigeminal
nerve is a symptom limited to a few advanced ANs.
Unilateral temporal wasting and masseter atrophy may be
noted on exam, and cross bite is a possible functional seque-
lae. We have encountered one NF2 patient with bilateral
masticatory paralysis, a situation that made gavage feeding
of puréed foods necessary.
Facial Weakness and Spasm
It is indeed surprising, given the location of the facial nerve
(FN) in the epicenter of tumor growth, that disturbances of
facial mimetic function are uncommon during the natural

history of AN growth. The FN appears to be robust in that
it can sustain substantial compression, stretch, and torsion
from an AN and maintain its functional integrity.
Although overt weakness is uncommon except in very
large tumors, a degree of facial twitching occurs in approxi-
mately 10% of patents.48 Facial hyperfunction appears to
be independent of tumor size. The most common manifes-
tation is a minor quivering of the orbicularis oculi muscle.
Hyperfunction can coexist with weakness. Full hemifacial
spasm is uncommon. In one such case encountered in our
group, an artery displaced by the tumor appeared to
impinge on the root entry zone of the FN. The great major-
ity of patients with ANs possess clinically normal facial func-
tion; however, subclinical motor impairment is occasionally
detected electromyographically. Abnormalities in evoked
electromyography and the blink reflex may be demon-
strated in a minority of patients with apparently normal
facial function.128
The FN is a mixed nerve that possesses a sensory
component. It is distributed over the posterior aspect of
the ear canal and conchal bowl of the pinna. Diminished
sensation over this region has been described as a sign of
AN, although it is of little practical significance. This obser-
vation is generally known as Hitzelberger’s sign.129
Headache
The incidence of headache with ANs depends greatly on
size. Very few patients with small tumors have headaches
that can reasonably be attributed to the tumor. In
medium-sized tumors (1 cm to 3 cm) the incidence is
approximately 20%, and in large tumors it exceeds 40%.48
Headache associated with AN is variable.2,124,130 Most
commonly it is either focused in the suboccipital region or
generalized. It is attributable to hydrocephalus in only a
minority of cases. Interestingly, not all patients with
obstructive hydrocephalus due to AN suffer from
headache.
Ophthalmologic Manifestations
The most common ophthalmic manifestations of AN are
nystagmus and decreased corneal reflex.131 A degree of
spontaneous nystagmus in the horizontal plane is frequent
with even small tumors, presumably as a result of vestibular
nerve involvement. There is a tendency for the nystagmus
to beat toward the intact side, although much variation
exists.132 With large tumors, however, pronounced vertical
plane nystagmus may be seen as a consequence of brainstem
compression.
Another important ophthalmic manifestation is
papilledema from hydrocephalus. Historically, increased
intracranial pressure was ubiquitous at the time of AN
diagnosis. Today, it has become a rare finding. In our
series, only 4% of patients with ANs had hydrocephalus.48
While hydrocephalus is usually obstructive, due to collapse
of the fourth ventricle, it may also be communicating.
Communicating hydrocephalus presumably results from
substances secreted by the tumor into cerebrospinal fluid
(CSF), which impairs the resorptive function of arachnoid
granulations. Chronic increased intracranial pressure may
lead to optic atrophy manifested by progressive loss of
Acoustic Neuroma (Vestibular Schwannoma) 741
peripheral vision, the development of tunnel vision, and
eventual blindness. It should be noted that not all patients
with increased intracranial pressure develop papilledema,
and not all patients with papilledema develop visual loss. In
one study of eight patients with papilledema due to AN,
none demonstrated impaired vision.131 Papilledema is
usually bilateral and symmetric, although visual loss is
frequently asymmetric.
Diplopia is an unusual finding in AN. Either the fourth
or sixth nerves can be paralyzed by a large AN, although
this is extremely rare. The function of the sixth nerve can
also be impaired secondarily, as a result of increased intracra-
nial pressure.
Lower Cranial Nerves
Dysfunction of the lower cranial nerves (IX–XII) can result
in hoarseness, aspiration, dysphagia, and/or weakness of the
ipsilateral shoulder. Even very large ANs seldom penetrate
the jugular foramen, although the intracranial course of
these nerve fibers may lie draped on the lower pole of the
tumor. Dysfunction of these nerves is sufficiently rare
(up to 3.5 %119) that, when present, suspicion of a coexisting
schwannoma of the jugular foramen region is warranted.
Late Symptoms
As a result of much improved diagnostic modalities, the
advanced symptoms of AN are seldom seen today. In many
ways it is illuminating to read the classical descriptions of
the agonal stages of the natural history of AN’s symptomatic
evolution.3,13 Long tract signs are seldom reported in
contemporary studies. Indeed, patients may have advanced
brainstem compression and hydrocephalus with severe loss
of balance but still have motor and sensory function to the
extremities. The progression from hyperreflexia to paresis
to paralysis can be quite rapid as increased intracranial
pressure becomes critical. The level of injury may be
pontine, from direct tumor pressure, or indirect at the
lower medulla due to herniation of the cerebellar tonsils.
Ipsilateral findings characterize the first mechanism, and the
latter may cause bilateral or even contralateral dysfunction.
In the final stages of the AN natural history, depressed
consciousness and stupor results. Intractable vomiting may
occur. In the terminal event, the patient lapses into coma
and expires with respiratory arrest.
Sudden Neurologic Deterioration
Intratumoral hemorrhage is a rare occurrence in patients
with ANs but may result in sudden neurologic deterioration
due to the onset of an acute CPA syndrome (see Fig.
45-14).113,133 The patient may experience hearing loss,
acute facial spasm or weakness, facial sensory disturbance,
hoarseness, and even somnolence and long tract signs.
Episodes of hemorrhage might be triggered by vigorous
physical exercise or head trauma. Emergent surgical inter-
vention may be required.
Extratumoral hemorrhage also occurs in association
with AN but is very rare. The patient suddenly develops
signs and symptoms of subarachnoid hemorrhage with
severe headache, nuchal pain, nausea and vomiting, and
742 SURGICAL NEUROTOLOGY
mental status changes. One possible cause of subarachnoid
hemorrhage is rupture of a contact aneurysm arising from
a vessel laying against the tumor capsule. In one reported
case, the posterior inferior cerebellar artery was aneurys-
mal.134 Other possible mechanisms include bleeding from
a tumor surface vessel or rupture of a hemorrhagic cyst.135
AUDIOLOGIC DIAGNOSIS
Pure Tone and Speech Audiometry
Because Chapter 7 (Hearing Loss in Neurotologic
Disease) comprehensively covers the audiologic diagnosis
of AN, only a brief summary is provided here. The primary
role of audiologic tests is to help identify the population at
risk of an AN.48,121,125,136,137 Conventional pure tone and
speech audiometry remain the most useful and cost-effec-
tive screening tools in helping to define who should
undergo auditory brainstem responses or an imaging study.
Based on these two tests a classification has been proposed
by the Committee on Hearing and Equilibrium of the
American Academy of Otolaryngology-Head and Neck
Surgery to establish guidelines for reporting results in
hearing preservation surgery. Therefore, this classification is
used in this chapter (Fig. 45-15).
The so-called special testing battery, a mainstay in the
detection of ANs during the 1960s and 1970s, has essentially
no role today. This includes short increment sensitivity
index, alternating bilateral loudness balance, tone decay,
and other tests. This protocol has been largely abandoned
due to its lack of specificity and sensitivity in AN detection
when compared with auditory brainstem response
(ABR). Two components of this test regimen remain in
Figure 45-15. The American Academy of Otolaryngology-Head and Neck
Surgery classification system for hearing following acoustic neuroma
surgery. The vertical axis represents the four tone average (500, 1000, 2000,
3000 dB) and the horizontal axis is word recognition score (%).
widespread use: rollover and acoustic reflex decay. In
rollover, the speech discrimination worsens with increas-
ingly loud presentation of the phonetically balanced word
list. In reflex decay, the acoustic reflex fades during a pro-
longed presentation of the signal presumably due to fatigue
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
and speech results show little cause for suspicion.
Auditory Brainstem Responses
The ABR is the most sensitive and specific of all audiologic
tests for AN. In documented ANs, a review of the litera-
ture reveals that approximately 20% to 30% have no
waves, 10% to 20% have only wave I and nothing there-
after, 40% to 60% have all waves but a wave V latency
delay, and 10% to 15% have normal findings.138 Among
abnormal ABRs, the ABR pattern most specific for AN is
the presence of a wave I and nothing thereafter. As a gen-
eral rule, the larger the tumor, the more severe the ABR
abnormalities. However, notable exceptions exist and we
have encountered large tumors with normal ABRs.
The diagnostic efficiency of ABR has been extensively
studied for both its sensitivity and specificity in AN diag-
nosis.139 Many reports give the sensitivity of ABR in the
diagnosis of AN in the range of 96% to 99%.138 However,
these studies typically rely on CT scanning or even poly-
tomography as the gold standard of diagnosis. Recent
experience, from the era of enhanced MRI scanning,
demonstrates a substantially higher rate of false-negative
results. Numerous reports of false-negative ABRs have
appeared in the literature.138,140 In 1992, Wilson and
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
assessing the economic efficiency of diagnostic protocols
used in the evaluation of patients with suspected ANs.
Of note, it has been reported that the specificity of a

positive ABR is considerably greater in younger individ-
uals.145 In large tumors that cause much brainstem defor-
mation, the contralateral ABR may be abnormal.147
Currently a new ABR technique called stacked ABR
seems to show a higher detection rate of VN with fewer
false-positive results. Time and studies, however, must
show whether this technique has additional value.148–150
Otoacoustic emissions
In theory, otoacoustic emissions (OAEs) should make an
excellent screening tool for ANs because they reflect outer
hair cell function. With OAEs, significant sensory hearing
loss suggests a retrocochlear cause. Unfortunately, ANs
cause both sensory and neural hearing loss. The sensory
hearing loss is presumably caused by either decreased
blood supply to the inner ear or other unknown factors.
In recent years, several studies have proposed the use of
otoacoustic emissions in ANs as risk stratification for
hearing conservation.151–154 These studies focused on the
identification of patients with impaired retrocochlear con-
duction but intact cochlear function. Particularly patients
with preoperative class C and D hearing and largely
immeasurable ABR could benefit from hearing conserva-
tion surgery in case of intact cochlear function. However,
the number of patients with these criteria seems to be very
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
Further studies will have to evaluate the role of OAEs in
AN surgery.
VESTIBULAR TESTING
Electronystagmography
Vestibular evaluation with electronystagmography (ENG),
rotatory testing, and dynamic posturography is frequently
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
most readily quantifiable test in the battery and the one
most able to localize the side of pathology. In the setting of
AN, a depressed or absent caloric response indicates injury
to the superior vestibular nerve or impaired vascularity to
the labyrinth from compression of the internal auditory
artery. When tumors of all sizes are considered, approxi-
mately 50% of tumor ears have absent caloric responses,
and most of the remaining patients have a partial reduced
response.157,160 While very few larger tumors have normal
caloric responses, as many as 50% of small tumors demon-
strate caloric symmetry. Since the caloric response is gen-
erated by the superior vestibular nerve (innervation to the
lateral semicircular canal), tumors originating from this
nerve demonstrate a higher frequency of abnormalities.
It has been reported that 98% of ANs originating from the
superior vestibular nerve show a reduced caloric response;
this is true for only 60% of those arising from the inferior
division.159 Of course, once an inferior vestibular nerve
tumor has attained considerable size, it can be expected to
destroy the adjacent superior division. It has been suggested
Acoustic Neuroma (Vestibular Schwannoma) 743
that improved sensitivity for small tumors of inferior
vestibular nerve origin may be achieved using an infrared
video system that records rotatory nystagmus, which can
be missed by conventional systems.161
Pathologic nystagmus takes a variety of forms in patients
with ANs and may result from either eighth nerve or brain-
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-
ter of the nystagmus also differs between small and larger
tumors. In small tumors, it tends to be characteristic of
peripheral labyrinthine dysfunction; in tumors with brain-
stem compression, central patterns predominate (vertical
plane, ageotrophic, nonfatiguing). The nystagmus can be
spontaneous, positional, gaze paretic, or dissociated and
may be unilateral or bilateral. As a general rule, nystagmus
tends to beat preferentially away from the tumor ear.132
Several ENG abnormalities in patients with ANs are
attributable only to brainstem compression, and thus are not
encountered in smaller tumors. Fixation suppression of
caloric induced nystagmus is impaired in roughly 20% to
50% of large tumors.157,160 Disturbances in vestibulo-ocular
control may also occur. Asymmetries in optokinetic nystag-
mus and poor tracking on smooth pursuit are present in a
minority of large tumors. Deficient optokinetic responses
tend to occur in the direction opposite from the tumor ear.132
Rotatory Testing
The integrity of the vestibulo-ocular reflex can be assessed
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
phase lag (72%), gain (62%), and symmetry (100%).162 In
another investigation involving 84 tumors, far fewer
abnormalities were noted. Overall 74% of patients were
normal, including 100% of patients with small tumors.157
In yet another series of 24 patients, 33% of patients with
ANs demonstrated no abnormalities on rotatory testing.163
Dynamic Posturography
In a study of 40 patients with ANs, a wide variation of
responses on sensory organization tests was noted from
normal to falling.156 Average performance was somewhat
below normal levels. No correlation between posturography
performance and caloric test results was found. The
authors recommend the test as a means of quantifying the
complaint of unsteadiness as well as to monitor the effects
of surgery and to guide postoperative rehabilitative efforts.
In a retrospective study of six patients with small tumors,
patients with inferior vestibular nerve tumors had greater
instability at higher sway-referenced gains than did those
with superior vestibular lesions.164 Because each patient
with inferior vestibular nerve tumors had normal calorics
and abnormal posturography, it was proposed that postur-
ography might help to make the preoperative distinction
between superior and inferior nerve origin. An awareness
of the probable nerve of origin may be relevant to the
decision of whether to pursue a hearing conservation
approach (as discussed later).
744 SURGICAL NEUROTOLOGY
Utility of the Vestibular Test Batteries
Unfortunately, no vestibular test taken alone or in conjunc-
tion with others has demonstrated sufficient sensitivity or
specificity to be of much use in the diagnosis of AN. The
high false-negative rates (i.e., normal test results in patients
who have a tumor) preclude using normal vestibular data to
exclude a patient from consideration of AN. The high
false-positive rate (i.e., abnormal tests results due to causes
other than AN) means that vestibular test data, if taken
alone, would tend to excessively recommend referral for a
definitive imaging study. For these reasons, we do not
routinely perform vestibular investigations in patients
suspected of having an AN, preferring to rely instead on
ABR and imaging studies to decide the issue. Of course,
when features of history or physical examination suggest
chronic vestibulopathy and AN has been excluded by other
investigations, then a vestibular test battery is obtained to
guide therapy and rehabilitation.
The vestibular test battery can be helpful in prognosticat-
ing the speed and completeness of vestibular compensation
following AN resection. With progressive growth of an
AN, the involved vestibular nerve is gradually rendered
nonfunctional. Because this is a slow process, compensation
is often imperceptible to the patient who remains function-
ally intact. However, during tumor removal all residual
functioning vestibular fibers are interrupted. This helps to
explain the paradoxic finding that patients with small
tumors (and thus a greater fraction of intact vestibular
nerve fibers) suffer more immediate postoperative vertigo
than those with large lesions. On preoperative ENG, the
more depressed the caloric response in the tumor ear, the
less acute vestibular withdrawal is noted postoperatively.
We do not routinely obtain ENG for prognostic purposes
because knowledge of this status does not materially alter
management of the patient.
RADIOLOGY
Chapter 21 (Imaging the Cerebellopontine Angle)
comprehensively covers the radiographic diagnosis of AN,
so only a brief summary is provided here. There have been
four major eras in the evolution of imaging technology in
the diagnosis of AN: plain films of the IAC (1910s), poly-
tomography (1950s), CT (1970s), MRI (early 1980s). Both
plain films and polytomography do not image the tumor
directly, but rather rely on detection of osseous changes
involving the IAC. Because a high percentage of ANs do
not expand the IAC or do so only minimally, these were
not sensitive methods. The addition of contrast (e.g.,
Pantopaque) into the CPA cistern improved diagnostic
efficiency with polytomography, but it was invasive and
often difficult to interpret. Contrast-enhanced CT scanning
was a substantial advance over prior studies. Tumors larger
than 2 cm could be reliably detected, but small lesions were
often overlooked. Diagnostic yield could be improved
through instillation of several mL of gas into the CPA cis-
tern and IAC, however, this was frequently followed by
spinal headache. In addition, gas-contrast CT had a rela-
tively high false-positive rate due to poor penetration of the
gas into the IAC. This had the tendency to create a convex-
bordered filling defect suggestive of an intracanalicular AN,
particular when the IAC was narrow.
The introduction of MRI in the early 1980s was a major
improvement in AN diagnosis. Early MRIs demonstrated
an excellent ability to detect ANs but were somewhat
unreliable when it came to intracanalicular lesions. This
has been greatly improved since the introduction of
gadolinium-enhanced MRI (Gd-MRI).165,166 ANs enhance
with contrast more brightly on T1-weighted scans than
any other intracranial tumor. The sensitivity of a thin-section
Gd- MRI scan targeted to the IAC is excellent, with lesions
as small as 1 millimeter within its resolution.
MRI also provides information relevant to surgical
approach, which was not made available by earlier studies.
Of particular importance in selecting the optimal surgical
approach is the depth to which tumor penetrates the IAC.
By examination of the lateral extremity of the tumor in
relation to the surrounding inner ear structures, which are
evident on T1- and especially T2-weighted scans, it is pos-
sible to predict whether the tumor can be removed without
violating the inner ear.
False-negative Gd-MRI scans seem to be very rare,
although the exact incidence is hard to establish because
no more sensitive study is currently in existence. One
potential pitfall occurs when a only a screening MRI study
of the entire brain is obtained. With such a study, which is
typically performed in thick sections (e.g., 10 mm), it is
possible to overlook a small lesion that falls between
slices. False-positive Gd-MRI studies have also been
reported.167–169 The most common cause appears to be viral
mononeuritis of the seventh or eighth nerve.170 In such
cases, the neural complex enhances brightly, but it can usu-
ally be differentiated from tumor by its normal diameter.
Another possible source of mistaken AN diagnosis stems
from a reliance solely on contrast-enhanced scans. Because
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
for comparison. For example, a globular region of bone
marrow (which is rich in fat and therefore bright on
T1-weighted images) adjacent to the IAC may erroneously
suggest the presence of a tumor. Such mistaken impressions
can be prevented by obtaining both pre- and postcontrast
T1-weighted scans. Noncontrast MRI sequences have
been recently suggested as an alternative for screening
examinations to decrease the cost of imaging (Fig. 45-16).
However, these new protocols have a decreased sensitivity
particularly for small intracanalicular ANs. Therefore, the
gold standard is still a gadolinium-enhanced sequence in
order to optimize the detection of small AN.171,172
In addition, enhanced MRI has proved very useful in the
evaluation of the postoperative patient.173 It readily identi-
fies residual and recurrent tumor and can usually differen-
tiate it from any associated scar tissue. Scar tissue may
enhance to a degree, but it typically appears less intense
than tumor, and its distribution usually suggests its true
nature. It is common for the meninges of the IAC and
CPA to enhance to a degree following AN surgery, and
this should not be confused with recurrence. A free muscle
graft placed in the drilled IAC during a retrosigmoid or
middle fossa procedure may enhance postoperatively. This
enhancement is usually not as intense as tumor, but serial

Figure 45-16. Fast spin-echo T2-weighted high-resolution MRI of a small
intracanalicular acoustic neuroma. The seventh and eighth nerves can be
seen emanating from the medial aspect of the tumor, which shows up as a
filling defect in the IAC through the exclusion of CSF, as they course toward
their brainstem entry.
imaging studies may be required to confirm that it does
not represent residual or recurrent disease. Following a
translabyrinthine procedure, during which an adipose
graft is placed in the craniotomy defect, it is important to
employ fat-saturation techniques to permit recognition of
any subtle enhancing components.
Although the radiographic differential diagnosis of AN
is large, as a practical matter only meningioma is likely to
lead to any confusion.174 In a substantial majority of cases
it is possible to distinguish between AN and meningioma
of the CPA based on their typical imaging characteristics
(Table 45-5).175 The reliable feature that differentiates the
two is that meningiomas are sessile, typically possessing a
broad base along the petrous pyramid, and ANs are glob-
ular. It is important to be aware that one of the most char-
acteristic features of meningioma, an enhancing dural tail
extending for several millimeters from the periphery of the
lesion, can also occur with AN.176,177
DIAGNOSTIC PROTOCOLS FOR
SUSPECTED ACOUSTIC NEUROMA
Much discussion has appeared in the literature concerning
the optimal evaluation of the patient suspected of having
an AN or other mass lesion of the CPA, and it should be
TABLE 45-5. Characteristics of Common CPA Tumors
on MRI and CT Scans
Acoustic Neuroma
Globular
Centered on IAC
Typically penetrate the IAC
Often erode the porus acusticus
May be cystic
Meningioma
Sessile
Usually extrinsic to IAC
Eccentrically placed to long axis of IAC
Hyperostosis
Calcification
Enhancement of adjacent dura (meningeal sign)
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
and are therefore not economically efficient. While 10-dB
or 15-dB asymmetry isolated to 4000 Hz and 8000 Hz very
seldom indicates an AN, this same degree of asymmetry
across the auditory spectrum is more suspicious. Of
course, greater amounts of asymmetry usually should be
evaluated. Also of substantial importance are the results of
speech discrimination testing. A decrease in speech dis-
crimination score out of proportion to the pure tone loss is
well accepted as a cause for heightened suspicion. The
timing and audiologic pattern of the asymmetric SNHL
also affect risk assessment. Fluctuant, low-frequency
SNHL accompanied by the sensation of aural pressure is
only rarely a sign of AN. In this circumstance, the clinician
may reasonably choose to follow the patient only if no other
suspicious indicators are present. By contrast, many clini-
cians have been falsely reassured by sudden hearing losses,
under the mistaken assumption that they are seldom associ-
ated with AN. The coexistence of vestibular symptoms also
increases suspicion of AN to some degree unless the clinical
pattern is characteristic of a peripheral disorder such as
endolymphatic hydrops. For example, very few patients
with AN exhibit severe episodes of vertigo typical of
Ménière’s syndrome. The same cannot be said for individu-
als with intermittent positioning vertigo or chronic dysequi-
librium. The presence of trigeminal nerve dysfunction
(hypesthesia, anesthesia, dysesthesia, or pain) coexisting
with an asymmetric SNHL is highly suspicious for a mass
lesion of the CPA. Until more comprehensive data becomes
available on the relative risk of the various historical and
audiologic points suggestive of retrocochlear pathology, the
decision as to when to proceed with a retrocochlear evalua-
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
that a hierarchic combination of auditory, vestibular, and
imaging studies are included in the algorithm, but the
number and sequence of tests varies considerably.146,178
Elaborate schema have been proposed based on complex
numeric treatments of test results intended to guide efficient
use of expensive imaging studies.179 In our opinion, such
synthetic constructions have little validity and are cumber-
some and impractical in their implementation. In recent
years, the our diagnostic protocol has become quite simple.
Following a routine diagnostic audiologic evaluation,
patients considered at low risk of having an AN undergo
ABR, providing that sufficient hearing remains to generate
an evaluable response. If the ABR is entirely normal,
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
low risk include those with minimal pure tone asymmetry,
a decades long history of stable asymmetric loss, and uni-
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-
enhanced MRI scan. A technically well-performed
enhanced MRI with a negative result effectively excludes
AN for diagnostic consideration. For patients who cannot
undergo MRI because they have metallic implants or
claustrophobia, contrast-enhanced CT scan is obtained.
Because CT often misses ANs smaller than 1.5 cm in diam-
eter, a gas-contrast cisternogram should be obtained in
high-risk individuals if the enhanced CT is negative. CT is
also a reasonable, and less costly, alternative in elderly
individuals in whom a small tumor would be considered
clinically inconsequential.
the United Kingdom, and Canada) than it is in the United
States. We can only hope that the incidence of late diagno-
sis will not rise as a consequence of these economic realities.
MANAGEMENT
Three treatment options are currently available: (1) obser-
vation with serial imaging, (2) microsurgery, and
(3) stereotactic radiation.
The choice of option is based on the preservation of life
considering the natural course of these benign tumors,
possible neurologic sequelae (e.g., cranial nerve dysfunc-
tion, ataxia), tumor removal, preservation of facial nerve
function, and preservation of hearing. Individual morbidities
associated with surgery and radiation have to be considered
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.

factor for the patient who knows about the lesion should
not be underestimated.
Microsurgical Management
The priorities in AN surgery are first the preservation of
life, second the maintenance of facial nerve function, and
third the preservation of socially useful hearing in the
tumor ear. Among these goals, the first is nearly always
achieved, the second is obtained with regularity, and the
latter is realized only under favorable circumstances.
Contemporary AN surgery requires an operating micro-
scope, cranial nerve monitoring, and good neuroanesthesia
(see Chapter 57, Intraoperative Monitoring of Cranial
Nerves). A substantial institutional commitment is necessary
to provide appropriate instruments, skilled operating
room personnel, cranial nerve monitoring equipment,
postoperative intensive care, and the ready availability of
neurodiagnostic imaging.
AN surgery can be performed by either a neurotologist
or neurosurgeon alone, but many centers have found that
collaboration between the specialties is desirable because it
takes best advantage of the special skills of each.186
Another factor that favors the use of a surgical team is that
removal of an AN often requires prolonged delicate
microsurgical dissection. The availability of two surgeons
minimizes fatigue, which can lead the operator to become
impatient and less facile, neither of which is conducive to
optimal functional outcome.
Surgical procedures employed in the management of
AN take place in two broad stages: (1) craniotomy and
exposure of the tumor and (2) microdissection of the
tumor away from brain, cranial nerves, and adjacent vascular
elements (Fig. 45-17). A variety of surgical approaches are
used to expose an AN. The most used procedures are the
retrosigmoid (RS), translabyrinthine (TL), and middle
fossa (MF) approaches. In a few centers, the transotic (TO)
and extended MF techniques are in use as well.187,188 Each
of these options has advantages and disadvantages, which
must be considered by the surgeon in selecting the optimal
operative approach to a particular tumor. For a more
detailed description of each procedure, see Chapter 43
(Overview of Surgical Neurotology). Centers with a special
interest in ANs tend to fall into three broad categories in
terms of surgical preference: retrosigmoid preferred,
translabyrinthine preferred, and eclectic. Surgeons who
adhere to the first two philosophies usually do so as a result
of their greater familiarity and comfort with a particular
method based on their training and experience. The eclectic
philosophy, in which the choice of opening is made
according to the attributes of the tumor being exposed, is
being adopted by an increasing number of surgical teams,
especially those in which neurotologists and neurosurgeons
collaborate in the patient’s care.189–192 While it would be
desirable from a technical and experiential standpoint to
always perform the same approach, in our opinion the
differential morbidity among the various options justifies
the complexity of a selective protocol. In any event, the
choice of opening technique is not the most important
determinant of success in AN surgery; rather, the micro-
surgical skills the surgeons employ while removing the
tumor are. The protocol discussed next is the one our team
Acoustic Neuroma (Vestibular Schwannoma) 747
at Stanford University uses (Fig. 45-18); however, no con-
sensus exists among experts on the relative role of the various
approaches.
Selection from the various approaches depends on a
number of factors including the level of serviceable
hearing, the depth of tumor extension into the IAC, the
size of the tumor, and the experience and familiarity of the
surgeon.192 The TL, RS, TO, and extended MF techniques
all provide exposure of both the IAC and CPA, and the
standard MF approach is suitable only for tumor confined
to the IAC. Of all the factors taken into account, the amount
of residual hearing is most influential. Conservation of
useful hearing is a highly desirable goal which, as will be
discussed later, is achieved relatively infrequently. Only
two procedures afford the possibility of maintaining residual
hearing; the RS and MF approaches. Undoubtedly, surgeons
would always attempt to save hearing were there not
potential adverse consequences from having undertaken
the effort. For tumors that involve the CPA, the choice
usually boils down to the TL versus the RS approach. The
TL approach inherently sacrifices hearing as it traverses
the inner ear in the process of creating the craniotomy.
However, compared with the RS approach, which provides
some chance of hearing conservation, the TL method has
a somewhat lower morbidity. This is particularly notable
in the incidence of persistent headache. Tumor size, in and
of itself, has little effect on the choice between the TL and
RS approaches. Either allows removal of even the largest
AN. Criticism of the TL approach for insufficient expo-
sure of larger tumors stems from inexperienced temporal
bone surgeons who achieved insufficient CPA exposure. In
experienced hands, the TL approach is capable of expos-
ing even the largest AN.193,194 The primary anatomic
limitation of transtemporal craniotomy for posterior fossa
tumor is exposure of the inferior aspect of the CPA, par-
ticularly when both the jugular bulb and sigmoid sinus
course are high (see Figs. 43-8 and 43-9 in Chapter 43,
Overview of Surgical Neurotology). Since ANs seldom
extend into the lower reaches of the CPA, this limitation is
seldom relevant. Even when an AN has an atypically infe-
rior extension, its capsule can usually be mobilized, follow-
ing tumor debulking, away from the nerves of the jugular
foramen into the central portion of the operative exposure
where resection can take place under direct binocular
vision.
The depth to which the tumor penetrates the IAC, as
visualized on gadolinium-enhanced MRI scans, is also a
major determinant in the selection of surgical approach.
Although the TL approach is capable of exposing the
entire IAC from fundus to porus acusticus, the RS and MF
approaches often require, particularly at the lateral end, a
blind dissection to permit removal of the intracanalicular
component of the tumor without need for exenteration of
a portion of the inner ear.195 Our current practice is to
inform patients that the MF approach is clearly superior
for hearing but it carries a higher incidence of persistent
facial paresis and synkinesis in tumors with 10- to 18-mm
CPA components. The patient then judges the relative
importance of hearing and facial function for himself or
herself.196
In the RS approach only approximately the medial two-
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
maintaining residual hearing.197–199 In one study where
postoperative CT scan was used to assess labyrinthine
integrity, entry into the inner ear was highly correlated
with loss of hearing.200 However, minor labyrinthine
entries do not inevitably result in deafness. Our preference
is to expose the most lateral extension of the tumor in the
IAC to permit direct visualization of the tumor interface
with its nerve of origin. Indirect dissection of the fundus is
sometimes selected, however, particularly in case of good
hearing, even though it carries a small possibility of recur-
rence. Some individuals have tried using right-angled
endoscopes to inspect the end of the canal to identify
tumor remnants. In our experience, this has not proved
helpful because it has been difficult to distinguish, from
indirect inspection, between blood-stained neural tissue
and residual tumor. In patients with an inner ear extension
of the vestibular schwannoma, a transcochlear approach
has been reported as the most suitable approach.201–203
Hearing status also has a major influence in the choice
of surgical approach. When the hearing is poor (<50 dB
SRT, <50% speech discrimination), we advocate the TL
approach regardless of tumor size and location. When the
hearing is serviceable, an RS approach is selected providing
that the CPA component of the tumor is smaller than
2.5 cm in maximal diameter and the lateral third of the
IAC is free of tumor. The tumor size limitation in hearing
conservation approaches is based on the observation that
useful hearing is almost never preserved following removal
of tumors larger than 2.5 cm in diameter.204 This rule need
not be adhered to rigidly. It is reasonable to attempt hear-
ing conservation in tumors with even relatively large CPA
components when the hearing is particularly good and the
IAC is minimally involved. Although the probability of

success in such cases is very limited, the well-informed
patient might accept the somewhat higher morbidity of an
RS craniotomy in hopes of the remote possibility of
maintaining some hearing. The importance of the patient’s
participation in the treatment planning cannot be
overemphasized.
Either the RS or MF can be used during a hearing con-
servation attempt to an intracanalicular tumor. The MF
approach probably has the best chance of saving hearing,
but this comes at the expense of a greater need to manipulate
the FN. From the perspective of the MF approach, the FN
may lie between the surgeon’s point of view and the tumor;
Figure 45-18. Acoustic neuroma microsurgical management algorithm used
at Stanford University. This scheme represents a general guideline only.
Individualized treatment selection depends on numerous factors. Size is
expressed in diameter of the CPA component. MF, middle fossa;
RS, retrosigmoid; TL, translabyrinthine.
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.
this is seldom the case with the posterior approaches
(RS and TL) (see Fig. 43-32 in Chapter 43, Overview of
Surgical Neurotology).
The choice of approach to intracanalicular tumors that
fill the IAC from fundus to porus involves a number of
factors. If the amount of residual hearing is marginal and
preoperative indicators (e.g., ABR) are not favorable, then
a TL approach is recommended under the assumption that
minimizing the risk of facial neuropraxia is more important
than undertaking an MF approach, which is unlikely to
maintain even imperfect hearing. The liability of FN
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
is the extent to which the bony walls of the IAC are
eroded.196 Our impression is that extensive erosion of the
IAC, particularly of its anterior wall, is an adverse prognos-
tic sign. Similarly, if the tumor prolapses into the cochlear
750 SURGICAL NEUROTOLOGY
modiolus on gadolinium-enhanced MRI scan, the proba-
bility of hearing preservation is diminished.
Once the craniotomy has been completed, tumor
removal proceeds in two stages: (1) debulking the central
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
facilitated by use of an ultrasonic aspirator, laser, or suction
dissector. The biggest challenge in AN surgery is preser-
vation of the cranial nerves, which lie draped on the
tumor’s surface. Since it shares the IAC and CPA with the
audiovestibular nerve, the FN is invariably affected by
acoustic tumors. Within the IAC, the FN becomes
compressed between the tumor and the osseous walls of
the canal (Fig. 45-19). Fortunately, the nerve is seldom
very adherent to the tumor in this location. In the CPA,
progressive tumor growth stretches the FN over the tumor
surface, most commonly in the anterior direction.
Anterosuperior and anteroinferior courses are also frequent,
and posterior courses are decidedly rare (Fig. 45-20).
Familiarity with the variations of the FN course is essen-
tial if optimal functional results are to be obtained. Unlike
in the IAC, the FN is often adherent to the tumor in the
CPA, particularly in the segment just medial to the porus
acusticus. The process of removing the tumor from the FN
usually commences with the identification of the nerve in
the distal IAC. After removal of the intracanalicular com-
ponent of the tumor, the CPA component is debulked and
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.
the FN brainstem entry is identified visually and electrically.
The tumor capsule is then sequentially liberated and excised
until only a small portion of capsular peel persists on the
most adherent segment of the tumor-nerve interface.
THE ROLE FOR INCOMPLETE RESECTION
It is generally held that completely excised ANs do not recur.
Under certain circumstances, it is reasonable to consider less
than complete removal despite the attendant increased risk
of regrowth.205–210 This may be planned preoperatively,
elected during surgery as a concession to cranial nerve
preservation, or mandatory in the case of adverse patient
response to efforts at tumor removal. A planned incomplete
resection may be undertaken when a more prolonged
operation is judged unwise because of the patient’s
advanced age or medical condition. Incomplete removal
may be elected intraoperatively when dissection planes are
poor and the surgeon judges that total tumor removal carries
a high risk of anatomically disrupting the FN. The hearing
status of the contralateral ear is also relevant. If it is impaired
from a second AN or other otologic disease, incomplete
removal increases the odds of hearing conservation.211
Whether the surgeon proceeds with radical resection or
performs an incomplete removal depends on several factors.
Most advocate a more aggressive approach in younger
patients. When deciding on the extent of dissection, it is
 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
neural preservation versus the risk of suffering recurrent
disease. On rare occasions, incomplete resection becomes
mandatory when a patient deteriorates intraoperatively,
either medically or neurologically, necessitating premature
termination of the procedure. An example of this situa-
tion is the development of bradycardia associated with
hypertension (Cushing’s reflex) during dissection of the
tumor from the brainstem. This same phenomenon can
also occur during tumor dissection from the trigeminal
nerve and can be controlled by either deepening the anes-
thesia or applying local anesthetic topically to the nerve
without need for curtailing the procedure.
In any discussion of incomplete resection, it is impor-
tant to distinguish whether removal has been “subtotal”
or “near total” because it has substantial impact on the
risk of recurrence (Fig. 45-21). In subtotal excision, a sub-
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
a small, thin capsular peel (<25 mm2, <2 mm thick).
Because ANs receive their blood supply from both the IAC
and brainstem, residual tumor left in contact with these
sites carries a higher risk of generating recurrence.
Fragments of tumor left in the fundus of the IAC are well
known to be capable of generating a recurrence.209,212 By
contrast, the thin capsular remnant that hangs free in the
CPA after near-total excision is likely to be devitalized and
carries a substantially lower likelihood of regrowth. CT
and unenhanced MRI are relatively insensitive to small
amounts of residual tumor. Gadolinium-enhanced MRI,
however, is quite sensitive to tumor fragments.166
(Fig. 45-22). However, enhanced MRI is not always able to
differentiate postoperative scar or dural enhancement from
tumor. When the presumed residual or recurrent disease is
small, only progressive growth on serial enhanced MRI
scans provides convincing evidence of the neoplastic
nature of the lesion. Enhanced MRI should be able to
detect the residual tumor in all cases of subtotal excision;
following near-total excision, MRI is able to visualize the
known tumor remnant in only some 50% of cases.206,208
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
In our group we routinely use fat-saturation MRI in all cases
to differentiate tumors from scars and dural enhancement.
Little has been published on the long-term follow-up of
near-total excision cases. In our experience, the recurrence
rate after a near-total resection (1/33 = 3%) is low, but it is
10 times higher after a subtotal resection (6/19).210 In one
other series of patients followed an average of 5.3 years
postoperatively, 38% (3/8) subtotally resected tumors
demonstrated signs of growth but none (0/15) of the
nearly totally removed did.206 In another study, 29% (4/14)
of tumor residuals less than 5 mm in diameter enlarged
over a mean follow-up of 5.8 years.208 This study also
suggested that cauterization of the tumor remnant reduced
the incidence of regrowth. Recurrent tumors enlarged at a
rate similar to that of unoperated tumors, an average of
approximately 2 mm per year.213 Very-long-term follow-
up is required in order to assess the impact of recurrent
disease on the patient’s longevity. In one study, a group of
139 patients with presumed incomplete removal (the IAC
was never drilled open during the operation) was evaluated
between 20 and 30 years following surgery. Compared
with the population at large, there was no excessive mortality
C

Figure 45-22. Axial postgadolinium T1-weighted MRI scan illustrating a less
than complete resection of an acoustic neuroma. The thin remnant of the
tumor surface can be visualized where it was left in situ along the adherent
course of the facial nerve. The temporal bone defect is filled with adipose tissue.
beyond the first postoperative year. Two symptomatic
recurrences were encountered 13 and 17 years following
treatment. This emphasizes the need for late scans to detect
slowly evolving recurrence. Following complete excision
of an AN, we recommend enhanced MRI scanning including
fat-saturation technique at 3 years to screen for unantici-
pated recurrence. After incomplete removal, scans are
obtained yearly for 5 years and then biannually until a
decade of stability has passed and more frequently if growth
is noted as clinical circumstances warrant.
Cystic tumors are particularly likely to recur when merely
debulked. We have encountered two cases, both in elderly
individuals, where brainstem compression recurred within
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
growth in the residual neoplastic component of the tumor.
As a general rule, we strive to achieve total removal of
AN whenever possible. Near-total excision is most often
elected when continued dissection threatens disruption of
the FN. In a recent series from the University of Michigan,
near-total excision was elected in 17% of AN surgeries,
typically as a concession to neurologic preservation.206
This incidence is in line with our experience of less than
10% incomplete resection.210 Our policy is to avoid subtotal
removal whenever possible, particularly when the tumor
possesses a cystic component.
OUTCOME OF ACOUSTIC
NEUROMA SURGERY
Decentralized versus
Centralized Hospitals
Results in AN surgery, perhaps to a greater degree than
with other intracranial tumors, depends on the experience
and microsurgical skill of the surgical team. The vast major-
ity of the published results are derived from experienced
groups who have a special interest in the management of
these tumors. Results from surgeons who operate on these
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
facial function was maintained in only 6%.215 A recent
study in the United States revealed significantly better
outcomes after surgery at high-volume hospitals or by
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
surgeons, which lead to a significant difference in length-
of-stay as well as costs.216 In the anecdotal experience of
the author, as well as that of many others interested in the
management of these tumors, the findings of the Danish as
well as the U.S. study are not aberrations, but rather
represent an accurate picture of results by well-intentioned
but less experienced surgeons undertaking AN removal.
While such arguments put forward by one with a special
interest in AN management may seem self-serving, the
differential outcome implies that patients with ANs bene-
fit substantially when managed at a center with experi-
enced personnel and the institutional commitment to
achieve optimal results.
Mortality
The mortality of AN surgery has fallen steadily over
recent years to a level under 2% in most major centers.
However, there is a significant difference in outcome of
patients who had surgery at lowest-caseload-quartile hospi-
tals (1.1% died), compared with 0.6% at highest-volume-
quartile hospitals.216 Causes of mortality fall into two
broad categories: tumor related and medical. Most common
among tumor-related causes are ischemic brain injury due
to arterial or venous interruption, acute postoperative
CPA hemorrhage, meningitis, and air embolism.217,218
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
and underlying medical condition than it is to tumor sta-
tus. The possible lethal medical complications of AN sur-
gery are the same as those associated with any major
operative procedure: pneumonia (atelectasis or aspiration),
pulmonary embolus, peptic ulceration, and myocardial
infarction, among others.
Complications
Postoperative complications are relatively frequent follow-
ing AN surgery, occurring in approximately 20% of
patients.219 See Chapter 44 (Complications in Neurotologic
754 SURGICAL NEUROTOLOGY
Surgery). However, in recent years a significant reduction
in large series has been reported.220 As with mortality, the
incidence of morbidity is higher in elderly and infirm indi-
viduals, in those with large tumors, and in hospitals with
fewer skull base procedures. Fortunately, the vast majority
of complications are successfully managed and the patient
recovers without sequelae. Nevertheless, these contribute
to patient discomfort, can prolong recovery, and add to the
cost of care. A small minority of complications lead to lasting
functional deficits.
Intracranial Vascular Complications
One of the most devastating complications of AN surgery
stems from interruption of the anterior inferior cerebellar
artery (AICA) or one of its branches. This artery is
intimately related to the capsular surface of ANs. Since the
vessel often loops into the vicinity of the porus acusticus,
it is at risk during removal of even relatively small tumors.
The full-blown AICA syndrome results in extensive infarc-
tion of the pons and is usually fatal. Fortunately, with mod-
ern microsurgical techniques, complete AICA syndrome
has become very rare. Partial AICA syndrome, caused by
disruption of the terminal branches of the AICA, results in
ischemic injury to the middle cerebellar peduncle and
a variable amount of the lateral aspect of the pons221,222
(Fig. 45-23). Although we have never encountered a com-
plete AICA syndrome, several of our patients have developed
the partial variety. The dominant symptoms in such cases
have been ataxia and dysmetria resulting from blockage of
cerebellar connections with the brainstem. Long tract signs,
manifested as hemiparesis or hemisensory disturbance,
Figure 45-23. Axial T2-weighted MRI scan demonstrating hyperintensity in
the cerebellar peduncle and lateral pons due to an interruption of the distal
branches of the anterior inferior cerebellar artery (arrows). This patient
suffered from transient ataxia and dysmetria for several months
postoperatively.
occur to a variable degree. The prognosis for the partial
AICA syndrome is generally favorable, with gait rehabilita-
tion gradually progressing over a matter of months. Limb
ataxia also improves, but writing skills and the ability to
perform precise manual tasks may remain impaired on the
operated side. Postoperative ischemia may also occur as the
result of vasospasm involving the vertebrobasilar system.223
Venous infarction can also occur following AN surgery,
but is less common than arterial injury. The sigmoid sinus
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,
the required surface tamponade with a hemostatic such as
Surgicel may lead to formation of a thrombus, which even-
tually clots off the entire vessel. Sudden loss of a one sig-
moid/transverse system seldom results in significant
venous ischemia. In rare cases where the surgical side carries
most of the cerebral venous outflow, congestion and even
hemorrhage can occur. Because it may be particularly
intense in the temporoparietal region, speech disturbance
may result. Rarely, venous congestion due to sigmoid sinus
thrombosis is fatal due to progressive cerebral edema.
Another possible sequela of sinus occlusion is papilledema
with progressive visual loss. In one of our patients, this
required fenestration of the optic nerve sheath to relieve
neural compression. We have also encountered one case
of isolated cerebellar venous infarction associated with
hemorrhage, the cause of which was uncertain. It may be
speculated that it resulted from interruption of the
petrosal vein (Dandy’s vein), which is routinely divided in
larger tumors to permit mobilization of the cerebellar
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
venous line placed. At the first sign of air embolization, the
field should be flooded with irrigant solution and the
patient’s head lowered. Air within the right side of the heart
may be aspirated through the central venous catheter.

Traumatic Parenchymal Injury
The cerebellum, pons, and temporal lobe are vulnerable to
injury during resection of ANs. This can result from either
retractor injury or a breach of the pial lining during tumor
microdissection. Cerebellar and temporal lobe injury are
more likely to result from excessive retraction, and pontine
injury is more likely due to traumatic dissection. Among
these cerebellar injury is fairly common. Postoperative
MRI scans frequently reveal a degree of malacia involving
the lateral 1 to 2 cm of the cerebellar parenchyma
(Fig. 45-24). This is particularly common following the
RS approach where retraction is relatively more vigorous.
The functional significance of this radiographic finding is
not well delineated, and most of these patients recover
uneventfully from their surgery. T2-weighted scans are par-
ticularly sensitive to detecting subtle degrees of parenchy-
mal injury and often remain permanently abnormal. Rarely,
cerebellar injury extends more deeply toward the midline.
In such cases prolonged ataxia, which may take many
months to resolve, may result. In the past, resection of the
lateral third of the ipsilateral cerebellar hemisphere was a
fairly common maneuver intended to improve exposure and
provide space to accommodate postoperative swelling.
Although this was usually well tolerated, modern surgical
and neuroanesthetic methods have made it unnecessary.
In rare instances, the cerebellum massively swells during
surgery. The most likely factors contributing to this are
insufficient use of brain-shrinking measures (e.g., mannitol,
hyperventilation) and premature application of the cerebel-
lar retractor before liberating CSF from the cisterna magna.
Very recently, electroencephalogram (EEG) changes (low-
frequency activity and IEA) have been reported as part of
the middle cranial fossa procedure; in translabyrinthine-
operated patients EEG changes are fewer.227
Injury of the brain surface during microdissection of the
tumor capsule from it can nearly always be prevented. In
the vast majority of ANs, an arachnoid plane can be main-
tained throughout tumor dissection. Occasionally, particu-
larly with very large tumors, the cerebellar and/or pontine
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.
Acoustic Neuroma (Vestibular Schwannoma) 755
planes are sufficiently obscure that the dissection becomes
subpial in places. The underlying brain tissue may be
markedly softened or even gelatinous when compression
has been extreme and long standing. Although this phe-
nomenon is of little concern on the cerebellar surface, it
could be very dangerous on the pons. By employing sharp
dissection and using the pontine surface veins as a guide, it
is usually possible to prevent direct injury to the brainstem.
However, in the rare instances where the capsule is inex-
tricable without risking pontine injury, we favor leaving a
thin capsular peel on the most adherent regions. It is
important to realize that most pontine injuries associated
with AN removal arise indirectly, through vascular com-
promise, rather than as a result of direct injury.
Cerebrospinal Fluid Leak
CSF leakage is the most common complication of AN sur-
gery, occurring in some 5% to 15% of patients in most
series with a trend toward a higher rate in older
patients.219,220,228,229 CSF can escape through either the
skin at the wound site or mucosa via the nose (Fig. 45-25).
CSF otorhinorrhea is much more common than seepage
through the wound. In our experience, CSF otorhinorrhea
complicates approximately 13% of translabyrinthine, 10%
of middle fossa, and 10% of retrosigmoid procedures.
Neither surgical approach nor tumor size affects the rate
of postoperative cerebrospinal fluid leakage.230 Wound
leaks are substantially less common and occur with
approximately equal incidence from the two procedures.
Leakage via the wound most often results from too loose a
closure of the muscle layers and subcutaneous tissue.
However, even the most stoutly closed wound can fail
under the onslaught of increased intracranial pressure or
when healing is retarded through high-dose corticosteroid
therapy.
Precautionary measures to decrease the incidence of
postoperative complications related to CSF leak in patients
with preoperative hereditary coproporphyria (HCP) are
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 45-25. Cerebrospinal fluid rhinorrhea.
756 SURGICAL NEUROTOLOGY
pressure with a ventricular or lumbar drain. Patients with
persistent symptomatic HCP after tumor excision should
be treated with a ventriculoperitoneal shunt. Delaying this
decision until the postoperative period is safe and avoids
unnecessary shunting in the majority of patients, accord-
ing to a recent study.231
In mucosal leaks associated with the RS or MF
approaches, the most common route of egress is via the
transected pneumatic cells of the apical petrous bone,
which surround the IAC. Extensive peri-IAC pneumatiza-
tion is present in approximately 30% of adults. A second
possible pathway into the temporal bone exists more
superficially at the anterior edge of the RS craniotomy.
The retrosigmoid air cells are extradural in this location,
but dural closure is often not watertight and CSF may thus
gain access to transected cells at this location. Both peri-IAC
and retrosigmoid leaks may occur despite diligent efforts
by the surgeon to seal opened pneumatic tracts with bone
wax, autogenous tissue, fibrin glue, and/or bone cement.
Most surgeons occlude transected air cells with bone wax
overlain with an autologous tissue graft. Some advocate
the use of fibrin glue to augment this closure, although we
did not find it helpful in a several-year trial.232 Ionomeric
bone cement shows promise as a superior material for filling
bony defects and may replace bone wax in the future.233
Transmucosal CSF leaks following a TL craniotomy occur
via the fossa incudis directly into the middle ear. These
may be discouraged by sealing the communication to the
middle ear with a fascial graft or by obliteration of the
eustachian tube. Once CSF has entered the temporal
bone’s air cell system, the fluid traverses the middle ear and
eustachian tube en route to the nasopharynx. Cutaneous
CSF leaks are obvious, but the more common transmucosal
leaks can be subtle and hard to diagnose. The characteristic
finding of episodic gushing of clear fluid from the nose
triggered by positional change or exertion is not always
present. Some patients report only a sensation of postnasal
dripping or a salty taste in the mouth, both symptoms that
are hard to confirm objectively.
While prevention of CSF leakage begins with meticulous
closure of the wound and sealing of any transected air cells,
postoperative measures are also important. A tight bandage
helps to redirect the CSF gradient medially and discourages
wound leaks, as well as those through the exposed retrosig-
moid air cells. Compressive bandages probably have little
effect on peri-IAC leaks because surface compression is
unlikely to transmit significantly to this depth. Additional
measures to discourage CSF leakage include elevation of
the head of the bed by 30 degrees and fluid restriction for
several days following surgery. Prophylactic placement of
a lumbar subarachnoid lumbar drain to divert CSF flow is
undertaken when extensive entry into well-developed air
cells around the IAC has occurred during a RS approach.
We do not routinely employ postoperative corticosteroids,
except in very large tumors or when surrounding parenchy-
mal edema is evident on preoperative T2-weighted MRI
scans. However, when a patient shows signs of postoperative
aseptic meningitis (headache, fever, bulging wound), they
are instituted. The detrimental tendency for steroids to
inhibit wound healing must be weighed against their
beneficial ability to reduce the acute hydrocephalus, which
may accompany aseptic meningitis.
The initial management of postoperative CSF leak
involves simple medical measures such as limited activity,
fluid restriction, and administration of the carbonic anhy-
drase inhibitor acetazolamide (Diamox) to reduce CSF
production and stool softeners to obviate the need for
straining. Only wound leaks are handled surgically from
the outset. These are oversewn at the bedside with one or
more vertical mattress sutures. If the leak continues
despite these measures, then a lumbar subarachnoid drain
is placed and left in for 3 days. The same algorithm is used
for CSF otorhinorrhea except that reoperation is undertaken
only if the leak persists despite lumbar drainage or recurs
once the drain is removed.234–236 In transnasal leaks that
traverse a deaf ear, we favor subtotal petrosectomy with
closure of the external auditory meatus and blockade of the
eustachian tube under direct vision with bone wax followed
by a muscle plug.237 When useful residual hearing persists,
an intact canal wall mastoidectomy is performed and the
fossa incudis is obstructed with an autogenous tissue graft.
Transnasal obliteration of the eustachian tube is another
method that has been advocated in cases of CSF otorhin-
orrhea.228 Following surgery for CSF leak, a fresh lumbar
drain is placed and left in place for 3 days. A few leaks persist
despite all medical and surgical efforts to stem the flow. In
such cases, hydrocephalus is often the underlying cause.
These persistent leaks are often best managed by permanent
CSF shunting. In communicating hydrocephalus, which pre-
dominates in this situation, a lumboperitoneal shunt is used.
A rare complication of CSF fistula through the ear is ten-
sion pneumocephalus.238,239 Some amount of intracranial air
is inevitable following posterior fossa craniotomy, but the
accumulation of large amounts under pressure is unusual.
Contributing to the development of this complication are
large-diameter CSF fistulae, the presence of a unidirec-
tional flap valve over the leakage tract, and frequent nose
blowing or performance of Valsalva maneuver. Another
factor that can trigger tension pneumocephalus is excessive
drainage of CSF via a shunt or lumbar drain.
Meningitis
Meningitis is among the more common complications of
AN surgery. In reported series, the incidence varies
between 2% and 10%.219,228,240 The majority of infectious
cases occur in association with CSF leak, which permits
bacterial contamination from the nose or across the skin.
Meningitis also arises as a complication of lumbar subarach-
noid drainage or as a result of aseptic necrosis of free
fat graft placed during neurotologic surgery (Lipoid menin-
gitis).241 The peak incidence of meningitis is the third
through the fifth postoperative day. Rarely does it present
earlier than this, especially following intraoperative contam-
ination with a particularly virulent microorganism. Delayed
meningitis, occurring weeks or months following surgery,
is usually due to cryptic CSF otorhinorrhea. The use of peri-
operative antibiotics to discourage the development of
meningitis is controversial. At Stanford University, we
administer 2 grams of ceftizoxime just prior to incision and
irrigate the wound with a bacitracin solution at the end of
the procedure. Favorable outcome in postoperative meningi-
tis hinges on early recognition of this complication. A high
or persistent fever, unusually severe headache, and/or any

sign of altered mental status can indicate the need for
cytologic and chemical evaluation of the CSF. Since post-
operative fever is common and headache is ubiquitous
immediately following surgery, much clinical judgment is
required. Nuchal rigidity, a hallmark of meningitis diagnosis
in most settings, can be difficult to evaluate following AN
surgery as a result of surgical trauma to the cervical mus-
culature. As a general rule, the clinician is wise to have a
low threshold for performing a lumbar puncture when a
suspicion of meningitis arises.
Interpretation of CSF findings following AN surgery is
complicated by the pleocytosis that normally follows
posterior fossa craniotomy. Aseptic meningitis is even more
common than bacterial in the postoperative AN patient.
While a high white blood cell (WBC) count (>1000) with a
left shift is suggestive of bacterial meningitis, these bench-
marks are often breached in aseptic cases as well.242
Conversely, when the clinical index of suspicion is high,
intravenous antibiotics should be commenced despite rela-
tively benign CSF findings and continued until the culture
results become known. Adequate treatment of postsurgical
bacterial meningitis requires a minimum of 7 days of intra-
venous antibiotics.
Aseptic meningitis usually commences somewhat later
than infectious cases. The cause appears to be meningeal
inflammation induced by blood products, aseptic necrosis
of free-fat graft and other irritants (e.g., bone dust) liberated
into the posterior fossa during surgery. 240–242 The clinical
picture consists of headache, malaise, and occasionally
low-grade fever. Symptoms may be rapidly ameliorated by
administration of a course corticosteroids. In some cases,
symptoms recur with withdrawal of corticosteroids. When
this occurs, a prolonged taper or every other day dosing
may be given. May patients can be weaned from cortico-
steroid by gradual substitution of a nonsteroidal anti-
inflammatory drug such as ibuprofen.
IMPACT OF AN REMOVAL
ON THE QUALITY OF LIFE
Facial Mimetic Function
Vulnerability of the Facial Nerve
Most well-informed patients with ANs expect that they
will survive AN surgery and avoid major brain injury. Of
greatest concern to most individuals is preservation of
facial function.243 The FN is dysfunctional preoperatively
in only a small minority of patients; however, paresis and
paralysis are frequent consequences of surgery. Numerous
factors contribute to the probability of maintaining FN
integrity.244 Tumor size has a major influence because as
the tumor’s diameter increases, the nerve becomes pro-
gressively more thin and splayed over its capsule.245 Of
even greater importance is the nature of the interface
between the tumor and the nerve. The degree of adherence
is typically greatest just outside the porus acusticus.
Dissection is generally more difficult in larger tumors, but
there are exceptions. Occasional intracanalicular tumors
are markedly adherent while some very large tumors dissect
with remarkable ease. It has also been suggested that the
FN is more intimately applied to the tumor capsule in
Acoustic Neuroma (Vestibular Schwannoma) 757
NF2 than it is in sporadic AN.63 However, little comparative
data has been published to support this contention, and
the author has observed a number of NF2 tumors that
have dissected readily.
There are a variety of potential mechanisms for FN
injury during AN surgery.246 Stretch or torsion on the
nerve can cause significant damage. In this regard, it is
important to avoid pushing the tumor anteriorly because it
further deforms the nerve in its typical direction of greatest
stretch. Similarly, it is important to avoid traction along
the course of the nerve because it risks disrupting the
nerve’s most fragile segment. It is important in preserving
both anatomic and functional integrity to maintain the nerve
in its deflected position, contained within its surrounding
arachnoid, rather than pull it up into the cavity created by
tumor debulking. This helps both to preserve its blood
supply and to provide mechanical support for otherwise
fragile fiber bundles. Thermal injury may also occur, partic-
ularly during bipolar coagulation or through heat generated
while drilling. Dissipating heat buildup through copious
irrigation is important in preventing this type of neural
damage. Probably the most frequent cause of FN injury is
mechanical disruption of attenuated nerve fibers during
microdissection of the nerve from the tumor capsule.
When it appears that radical removal will result in
anatomic discontinuity of the nerve, some surgeons elect
to leave a thin veil of tumor capsule attached to the most
adherent portion of the nerve.205 The willingness to consider
a near-total removal is predicated on the assumption that a
tiny devascularized capsular peel is unlikely to generate a
recurrence. The decision whether to undertake a near-total
removal is complex and depends on a number of factors.
Prominent among them are the age and the patient’s own
priority regarding maintenance of facial function versus
assurance of tumor control.
Role of Facial Nerve Monitoring
A substantial improvement in FN outcome has been realized
in recent years. Intraoperative FN monitoring has
contributed, in no small measure, to this favorable trend.
(See Chapter 57, Intraoperative Monitoring of Cranial
Nerves.) Several studies have verified the impact of FN
monitoring on functional outcome following AN surgery.
In a study that compared 91 monitored patients with 91
unmonitored controls, only slightly improved outcomes
were noted in small and medium-sized tumors. In large
tumors, however, anatomic continuity improved from
41% to 71% when monitoring was used.247 In another
study, 111 monitored patients were compared with 207
unmonitored historical controls.248 A reduction in the rate
of total paralysis from 15% to 4% was noted when FN
monitoring was used. Good predictors of initial facial
nerve function are due to a combination of electrophysio-
logic intensities and tumor size.249 It is now widely
accepted among experts in the field that FN monitoring,
when skillfully employed, improves FN outcome in AN
surgery. Other factors contribute as well to this trend
toward better FN prognosis. Of considerable importance
is the fact that, in many countries, AN surgery has become
concentrated in regional centers. This permits the surgical
team to accumulate the experience necessary to obtain
758 SURGICAL NEUROTOLOGY

TABLE 45-7. Anatomic Preservation of the Facial Nerve
in Acoustic Neuroma Surgery
Anatomic
Author Year No. of Patients Preservation
House353 1979 500
Glasscock190 1986 616
Sterkers354 1988 800
Tos355 1988 400
optimal results. The existence of a distinct “learning
curve” in AN surgery, where functional results gradually
improve over time, is widely acknowledged.250 Another
important factor in improved FN outcome is the progres-
sive refinement of microsurgical instrumentation and
tumor debulking implements such as the ultrasonic aspira-
tor and laser. Finally, increasingly sophisticated diagnostic
technology has permitted detection of an increasing frac-
tion of small tumors, thus favoring FN preservation.
Results in Contemporary Series
In this chapter no attempt has been made to review
exhaustively all the published series on FN outcome fol-
lowing AN surgery. Rather, results from selected series are
presented as representative of the state of the art in FN
preservation. For a more detailed analysis, consult a recent
comprehensive review article on the subject.251 The major-
ity of the published series dwell on anatomic preservation
of the nerve as the primary measure for success or failure.
Results from large series are impressive, with continuity
maintained in between 82% and 97% of cases (Tables 45-7
and 45-8). Of course, the patient cares less about anatomy
than physiology and is little consoled when the surgeon
says the nerve was intact if it never recovers functionally.
In addition, operative estimations of neural integrity
are affected by subjective factors and may not always
accurately represent the actual status of the nerve. For
these reasons, the most apt measure of success in FN
preservation is the level of function after the recovery
period.
To facilitate interstudy comparison of results, assessment
of FN function following AN surgery should be performed
using standardized measures, preferably the widely accepted
grading scale proposed by House and Brackmann.252
Reported functional results vary widely, at least in part as
97% a result of differences in patient population and grading
82% criteria (see Table 45-8). It is clear that, in many centers,
94% the occurrence of permanent severe or total paralyses has
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-
comes is similar for the RS and TL approaches. One cost
of the hearing preservation attempt in our 10- to 18-mm
MF group was a significantly worse long-term
(>1 year) facial nerve outcome when compared with a
size-matched TL cohort (81% grade 1 or 2 compared
with 100%).
The Course of Postoperative Facial Palsy
The great majority of postoperative facial palsies occur in
cases where the FN has been left anatomically intact after
completion of tumor resection. The time course of neural
recovery depends on the extent of neural injury, as well as
its location. The pace of recovery falls roughly into two
time courses. In less severe injuries, recovery often occurs
within 2 months. More severe injuries, presumably those
that require remyelination, typically take 8 to 15 months
to recover. The more delayed the onset of recovery, the
less likely that the patient will regain near normal levels of
function and the more likely that some degree of synkinesis
will develop. The time course of recovery is typically gradual
and is initially evident as improvement in symmetry and
tone at rest. Return of voluntary movements usually
proceeds from the lower face to the midface and finally the
forehead. The process of recovery is often accompanied by
an element of hyperfunction, manifested as subtle twitching,
less commonly as frank spasm. Following severe injuries
with long recovery times, misdirected reinnervation is
common. This is manifested as mass motion where the eye
tends to close during smiling and the corner of the mouth
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.

It is possible, to some extent, to predict the degree and
time course of recovery of facial function from the appear-
ance of the nerve at the end of the procedure and its
electrical stimulability. When surgical planes have been
favorable, the nerve does not appear unduly splayed, and a
low threshold for electrical stimulation persists at the
nerve exit from the brainstem, then complete recovery is
likely. Conversely, a wide and attenuated nerve that is
discolored where it adhered to the tumor and does not
stimulate proximally is at substantial risk of poor recovery.
Recently, we examined the reliability of FN stimulability
proximal to the lesion at the end of surgery as a prognostic
indicator of eventual FN functional recovery. None of the
102 patients with a threshold less than 0.4 volts had a
recovery at 1 year worse than a grade 3/6. When stimulation
was present under 0.1 volts, all achieved grade 1 (89%) or
grade 2 (11%) results. A word of caution is in order
regarding the prognostic value of electrical stimulability.
When the nerve is very splayed, excellent stimulability
may remain for a small subpopulation of the FN fibers
even when the majority have been disrupted. Thus, when
the nerve is very ribboned, it is important to establish
whether the lowest threshold is representative of the entire
wide band or only one limited region.
Postoperative electrodiagnostic testing may also be of
value in assessing the patient with postoperative facial
paralysis. Electrical stimulability of the nerve may be
assessed using either the maximal stimulation test or elec-
troneuronography.253 If the nerve conducts any electrical
response to the facial muscles, a more favorable prognosis
is established. When no stimulability is found, electromyo-
graphy may provide some prognostic information. In the
late postoperative period, polyphasic reinnervation poten-
tials are an early sign of pending recovery, whereas electrical
silence is ominous in that it suggests muscular atrophy.
Fibrillation potentials identify surviving muscle elements
but imply that reinnervation has yet to commence.
Transcutaneous electrical stimulation of the facial muscles
has been proposed as a means of maintaining facial muscular
tone while awaiting reinnervation. This modality has the-
oretical appeal; however, there is little scientific data to
support its use. Indeed, it has been suggested that it may
adversely affect recovery through encouraging the devel-
opment of synkinesis (K. Doyle, MD: personal communi-
cation, 1993).
It is not uncommon for a patient to awake from surgery
with facial function only to have it gradually deteriorate in
the early postoperative period. Although this usually
occurs within 72 hours of surgery, we have observed it as
much as several weeks later. The probable etiology of
delayed weakness is neural edema, perhaps vasogenic,
which may be associated with the sterile arachnoiditis that
frequently follows AN surgery. As a general rule, the prog-
nosis of delayed onset facial palsy is favorable. Many
recover within a matter of weeks as edema subsides. Others
require many months to recover, a course suggestive of
demyelination. Occasionally patients with delayed facial
palsy have incomplete functional return, but only rarely is
recovery completely absent. Perioperative administration
of corticosteroids has been suggested as a means of reducing
the incidence of delayed facial palsy through reduction in
neural edema. This treatment has theoretical appeal, but no
Acoustic Neuroma (Vestibular Schwannoma) 759
data is available to support its efficacy and our anecdotal
experience is that corticosteroids are ineffective in this
regard. Because neural edema may be expected to be
especially problematic within the bony confines of the
Fallopian canal, performing a bony decompression of the
labyrinthine segment at the time of tumor removal has
been suggested as a means of preventing the evolution of
delayed palsy.254
The nonmotor components of the FN may also be dis-
turbed following AN surgery. Transient taste disturbance
is not uncommon following AN surgery due to dysfunction
of the taste fibers that supply the anterior two-thirds of the
tongue. Typically, this resolves within several months. Dry
eye due to decreased lacrimation (parasympathetics travel
with the greater superficial petrosal nerve) is also a common
sequelae of AN surgery, even when facial motor function
has been preserved. In the absence of facial paralysis, this
problem is a mild nuisance to most, although it may make
wearing of contact lenses difficult. Aberrant reinnervation
of the lacrimal fibers may result in gustatory tearing. So-
called crocodile tears usually constitute only a nuisance.
When they are particularly severe, relief may be obtained
through partial excision of the lacrimal gland.
Management Options when
the Facial Nerve is Disrupted
Clinicians must be aware of the distress felt by some
patients experiencing facial palsy after AN surgery and
that the level of distress may not be related to the clinical
grade of the facial nerve paralysis. According to a recent
study, people with low self-esteem, young people, and
women suffer from more distress from the facial palsy.
Clinicians should thoroughly counsel patients before and
after surgery and should implement measures that increase
patients’ self-esteem and decrease their distress, especially
in these high-risk groups.255
Primary Reconstruction of the Facial Nerve
Conceptually, immediate repair of a disrupted FN following
tumor removal is appealing. It avoids the need for a second
surgery and, unlike nerve crossover procedures, it creates
no new neurologic deficits. There are three methods of
immediate FN repair: direct suture, mastoid-meatal
rerouting and suture, and interposition grafting. The sim-
plest way to repair cranial nerves VII–VII is by mobilization
of the transected ends followed by direct suture (Fig. 45-26).
In our experience, this is seldom possible because the
length of the deficient segment prohibits tension-free
anastomosis. In the TL approach, the redundant FN in the
mastoid can be mobilized, yielding 5 mm to 10 mm of addi-
tional length and permitting repair by direct anastomosis256
(Fig. 45-27). Defects that cannot be bridged in this manner
require an interposition graft. During most neurotologic
procedures, the greater auricular nerve is used because it is
readily available and a good size match. Repair with an
interposition graft differs from that with a mastoid-meatal
rerouting in that it require two anastomoses. When
performing an intracranial anastomosis, it is important to
realize that the intracranial segment of CN VII possess no
epineurium. For a suture to hold, it must be placed
through the substance of the nerve. For this reason, typically
760 SURGICAL NEUROTOLOGY
Figure 45-26. Direct facial nerve repair during the translabyrinthine approach
through mastoid-meatal rerouting. Mobilization of the redundant
intratemporal course provides an additional 10 mm to 15 mm of length to
bridge a gap.
only one suture is used passing through the center of the
nerve. A reasonable alternative is the use of a nonsuture
anastomosis such as a collagen tube or fibrin glue.257,258 The
theoretical benefits of sutureless grafting include technical
simplicity, reduced foreign body reaction, and prevention of
neural trauma caused by the suture needle. Results
with direct nerve repair, with or without use of a graft,
are modest. The usual result achieves at best a grade 3 or
4 function. Success rates (grade 4 or better) in representative
Figure 45-27. Facial nerve repair in the cerebellopontine angle with a greater
auricular nerve interposition graft.
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.
The nerve crossover procedure in most widespread use
is the hypoglossal to facial anastomosis (Fig. 45-28). One
advantage of using the innervation of the tongue is that it,
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
following tumor removal. It is usually unwise to undertake
this procedure at the time of tumor resection because
the neck and parotid flaps may fill with CSF flowing from
the craniotomy defect. In most individuals, sacrifice
of the hypoglossal nerve leads to little difficulty with
speech or swallowing, in part due to the partially bilateral
innervation of the tongue. However, when vagal and
Figure 45-28. Schematic of the relationship between the hypoglossal and
facial nerves in preparation of XII–VII anastomosis for reanimation of the
paralyzed face.

glossopharyngeal deficits exist, sacrifice of the hypoglossal
nerve is contraindicated because this may decompensate
the deglutition mechanism. Satisfactory results, defined as
rest tone with some motion, are obtained in more than
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,
the procedure may be delayed 1 year or even longer and
still have an excellent chance of success. The facial reani-
mation afforded by a hypoglossal to facial anastomosis is
imperfect. At best, patients have excellent symmetry at rest
and can train themselves to make a fairly natural smile.
Despite excellent reinnervation, many patients obtain an
imperfect result due to excessive tone (occasionally with
spasm) and marked synkinesis.
An anastomosis between the spinal accessory and facial
nerves is another reconstructive option. Success rates are
similar to the hypoglossal to facial anastomosis if done
early after resection of the lesion. However, results are less
favorable when the reconstruction has been delayed. To
avoid the donor deficit of a weak and possibly painful shoul-
der, using only a portion of the nerve has been suggested to
minimize loss of function.
Patient satisfaction with the various facial reanimation
techniques has been assessed through a survey of the mem-
bership of the AN Association.264 This report included
opinions from 61 patients who underwent CN XII–VII
anastomosis and 6 who had CN XI–VII crossover. Slightly
less than half of the XII–VII group reported a functional
return of greater than 50% when compared to the opposite
normal face. In the majority of patients, poor eye closure
and unsatisfactory facial appearance while smiling persisted.
The few patients who had undergone XI–VII procedures
were even less satisfied than the XII–VII group.
A number of additional options for reanimation of the
paralyzed face following excision of AN are available
including masseter and temporalis muscle transfers, cross
face anastomosis, and innervated microvascular muscle
transplants.265 Little data is available on the results of these
procedures in patients with ANS.
Care of the Eye in Facial Palsy
Poor eye closure caused by facial weakness creates a risk of
corneal desiccation. A dry cornea may become ulcerated
which, if not meticulously managed by physician and
patient alike, may lead to the formation of permanent
opacities. The facial paralysis that follows AN surgery is
usually accompanied by decreased lacrimation resulting
from disruption of the parasympathetic innervation to the
lacrimal gland. In addition, dysfunction of the fifth nerve,
which is frequent with larger tumors, leads to impaired
corneal sensation. A dry, anesthetic eye that lacks a blink
reflex is virtually certain to develop corneal decompensa-
tion without aggressive intervention. Medical management
includes the liberal application of artificial tears and lubri-
cating ointments. At night, the eye may be taped shut or
protected with an occlusive plastic shield.
The classical surgical treatment for the paralyzed eye is
tarsorrhaphy, the suturing together of the eyelids to narrow
the palpebral fissure and thus improve eye closure.
However, tarsorrhaphy is both esthetically and functionally
Acoustic Neuroma (Vestibular Schwannoma) 761
suboptimal for most patients. In recent years, restoration
of eye closure through use of upper eyelid gold weights or
springs has largely supplanted tarsorrhaphy in most major
centers.266,267
Hearing Conservation
Pathology and Pathophysiology
of Cochlear Nerve Involvement
Preservation of hearing in the tumor ear is one of the more
challenging goals in AN management. There are approxi-
mately 30,000 fibers in the human cochlear nerve.
Quantitative histologic studies in experimental animals
have shown that up to 75% of the nerve population to a
given region of the cochlea can be destroyed without
raising the hearing threshold.268 Because greater numbers
of functioning fibers are needed to convey complex
information, speech discrimination may be affected out of
proportion to pure tone loss. Cochlear nerve fiber dys-
function can result either directly from tumor infiltration
or indirectly from pressure-induced demyelination or
ischemia.
Several studies have assessed the frequency of cochlear
nerve infiltration by ANs. Although these tumors originate
from the vestibular division of the eighth nerve, micro-
scopic involvement of the cochlear division is frequent even
when the surgeon sees no gross involvement.96–98,269,270
When the cochlear nerve adheres to the tumor surface, it
is probably infiltrated to some degree. The converse, that
infiltration is absent when the tumor separates from the
nerve easily, is not always true. In a study by Neely, in 3 of
15 cases where the cochlear nerve appeared normal during
microdissection from the tumor capsule, residual tumor
was noted infiltrating between fibers.97 More important,
the proximal eighth nerve trunk medial to the tumor was
infiltrated despite a normal appearance in all 6 of 6 cases
investigated. Of note, the cochlear nerve lateral to the
tumor in the fundus of the IAC was often free of tumor.
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
with nerve fibers. A clinical-pathologic correlative study of
22 tumors showed significant fiber destruction and tumor
infiltration even when the hearing was relatively good and
the tumor small.98 In none of these cases was a well-defined
connective tissue plane between the tumor and cochlear
nerve identified. In another study, immunochemical investi-
gation of the tumor-cochlear nerve interface in 10 medium-
sized tumors demonstrated neural invasion in 6.95 Results
somewhat at variance with the above-cited studies come
from a study of 10 tumors scrutinized by both light
and electron microscopy, which detected a relatively low
incidence of cochlear nerve invasion.270 Actual cochlear
nerve invasion was confirmed ultrastructurally in only
three patients, each of whom had NF2. This greater
tendency for cochlear nerve invasion in NF2 has been
reported by others as well.271 An attempt to distinguish
subtle cochlear nerve involvement through the use of
staining for the neural tissue–specific protein S-100 was
unrevealing as both AN and cochlear nerve stained for this
marker.93
762 SURGICAL NEUROTOLOGY
Another factor that influences the probability of
cochlear nerve invasion by AN is whether the tumor arose
from the superior or inferior vestibular nerve. Because the
cochlear nerve lies in the inferior compartment of the
IAC, inferior vestibular schwannomas are typically more
intimately related to it. Tumors that involve the fundus of
the IAC may also be more prone to invade the cochlear
nerve due in part to the confined space of this lateral
recess. Such tumors also have the potential of invading the
cochlea via the modiolus.65 The most important implica-
tion of microscopic invasion of the cochlear nerve by AN is
not the fear of leaving residual disease, but rather the jeop-
ardy it places the nerve in during tumor microdissection.
Undoubtedly, this tendency for the tumor to interdigitate
with cochlear nerve fibers contributes to the difficulty of
preserving hearing in these tumors. The risk of leaving
microscopic tumor residuals, in terms of generating recur-
rent disease, is unknown, but it is probably small (see the
section on “Incomplete Tumor Removal”).
There are three requirements for success in a hearing
preservation effort: (1) The tumor capsule must be separated
from the cochlear nerve without disrupting or unduly
traumatizing it, (2) the blood supply of the cochlea and
nerve must be maintained, and (3) the inner ear must not
be destroyed in the process of exposing the tumor. In only
a small minority of ANs is it possible to fulfill all of these
requirements and totally excise the tumor. The most fre-
quent reasons for failure of hearing conservation efforts
are gross infiltration of the cochlear nerve, which requires
its resection, and the necessity of drilling away a portion of
the inner ear to expose the lateral terminus of the tumor in
the IAC (see the section “Microsurgical Management”).
However, it is disconcerting how often the cochlear nerve
can be anatomically preserved, at times seemingly having
sustained little or no apparent trauma, but nevertheless
hearing is lost or seriously degraded postoperatively.
There are probably multiple causes for this phenomenon.
Dissection along the compressed segment of the nerve
may interrupt microvasculature and result in fiber damage
or intraneural hemorrhage. Animal studies point to retrac-
tion of the cerebellum as a frequent precipitator of auditory
dysfunction.272 Clinical observations from intraoperative
electrophysiologic changes confirm the occurrence of this
phenomenon in humans. Not uncommonly we have
observed a sudden loss or substantial latency prolongation
of wave V accompanied by preservation of wave I occurring
at the time of cerebellar retraction. It is possible that this
maneuver places the eighth nerve and its arachnoid tethers
under tension, thereby stretching the nerve and/or vasa
nervorum. Traction on the nerve can also lead to nerve
fiber disruption at one of two particularly weak points.
One site of mechanical weakness occurs at the junction of
central and peripheral myelin (the Obersteiner-Redlich
zone).272 At this transition the central myelin is surrounded
by delicate astrocytic processes, and the peripheral fibers
are reinforced by a collagenous endoneurial tube. Neural
separation at this point may occur preferentially in the
central portion of the nerve and thus not be visible externally.
A second potential point of weakness exists laterally where
the cochlear nerve splays into many small fibers as it pene-
trates the modiolus. Medially directed traction originating
anywhere along the course of the nerve from IAC to
brainstem entry may avulse these fragile fiber bundles
from the base of the cochlea.
Interruption of vascular supply to the cochlea undoubtedly
accounts for some hearing losses associated with AN removal.
Either physical interruption or thrombotic occlusion of
the internal auditory artery results in cochlear infarction.
In contrast to cochlear nerve injury, cochlear dysfunction
affects all waves of the ABR. Vasospasm may play a role in
intraoperative hearing loss. Topical application of a vasodilator
(e.g., papaverine hydrochloride 30 mg/mL) occasionally
reverses a sudden deterioration in electrophysiologic
measures.273 Based on experiences in an animal model, intra-
operative monitoring of cochlear blood flow using a laser-
Doppler technique has been proposed as a means of providing
the surgeon an early warning of cochlear ischemia.274
Some insights into the pathophysiology of intraoperative
hearing loss may be gleaned from observations of postoper-
ative patients. Delayed hearing loss occurring in the first
postoperative week is fairly frequent following AN surgery.
This has been associated with intraoperative deterioration
of wave V with preservation of wave I.275 Presumably, late
hearing loss results from progressive neural edema or
ischemia. Occasionally an ear with poor hearing in the
early postoperative period spontaneously improves
weeks or months later. This type of delayed recovery is
consistent with resolution of a transient neural conduction
defect.276 Electrophysiological observations have been
made in patients with an anatomically preserved cochlear
nerve but no postoperative hearing.277 In two of three
patients studied, promontory stimulation revealed pre-
served electrical stimulability of the cochlear nerve despite
deafness. This implies that cochlear infarction with
death of hair cells was causative of the hearing loss in these
cases.
A recent study278 showed that the presence of either
the ABRs or near-field cochlear nerve action potentials
(CNAPs) was not related to AAO-HNS class outcome.
Both techniques had a useful rate of prediction of hearing
preservation surgery outcome but in nearly one-quarter of
the cases, there was no association between ABR or CNAP
responses and hearing preservation.
These results have to be considered when determining
the clinical usefulness of these techniques.
Assessing Candidacy for a Hearing
Conservation Attempt
A cardinal issue in hearing conservation is who should be
considered a candidate. Because the probability of success
greatly influences the decision process, preoperative prog-
nostic factors are important.279–281 As a general rule, the
better the hearing, the more likely is success in a hearing
conservation effort. No rigid auditory criteria can be
developed because the decision must always take into con-
sideration the level of hearing in the opposite ear. When
the contralateral hearing is normal or nearly so, most sur-
geons would not recommend a hearing conservation
approach when the SRT is greater than 50 dB and/or the
SDS is less than 50%. If the concept of useful hearing is
taken into account, these exclusionary criteria could rea-
sonably be placed at greater than 30 dB SRT and/or less
than 70% SDS. A normal or near-normal ABR is also a

favorable indicator. Conversely, an absent or severely dis-
torted ABR, even when the hearing level is quite good, is
an unfavorable prognostic factor. An intact stapedial reflex
may also be an auspicious sign. In terms of vestibular testing,
a reduced caloric response has been said to be favorable
because it suggests superior vestibular origin to the tumor.280
Tumor location and size also play a key role in determining
candidacy. The depth to which the tumor extends into the
IAC is often the determining feature in the ability to conserve
hearing.192 The degree of IAC erosion can also affect results.
It seems probable that substantial canal erosion predicts a
greater compression of the eighth nerve, although this fea-
ture has yet to be studied as an independent variable. Success
is only rarely achieved in tumors exceeding 2 cm in cisternal
diameter. Nevertheless, this size limit should not be rigidly
enforced. A few patients with larger tumors have excellent
hearing, nearly normal ABR responses, and a minimal IAC
component. While the success rate in such patients is not
high, it is also not negligible. It should be emphasized that
these criteria apply to AN alone and are not necessarily
applicable to other tumors of the CPA. In angle tumors
not originating from the eighth nerve (e.g., meningioma,
epidermoid), hearing conservation is much more probable
than with an AN of similar size and location.
Definition of a Successful Result
When one considers hearing conservation in AN, the
criteria for success must be appropriately defined. Many
studies report favorable outcome as mere persistence of
any residual hearing in the operated ear. As has been aptly
pointed out, when the contralateral ear is normal, most
patients derive little benefit from a postoperative tumor
ear that hears substantially below normal levels.282,283 The
Stenger effect predicts that the patient will little appreciate
hearing in the worse ear when it has a threshold in the
speech frequencies more than 30 dB higher than the better
side. Such rules of thumb have long been employed by
otologic surgeons when considering surgery for patients
with conductive hearing loss, but this type of analysis has
seldom been applied in AN surgery. Speech discrimination
is another very important measure of “useful” hearing in a
postoperative ear. A speech discrimination score 30%
below the better side is unlikely to enhance the patient’s
overall communicative ability. Using this 30/30 parameter
in assessing potential benefit allows the clinician to counsel
the patient more realistically about treatment options.
Overly optimistic counseling about hearing conservation
may lead to disappointment on the part of the patient
whose surgeon proudly points to a postoperative audiogram
demonstrating “successful” hearing preservation when he
or she can discern little actual benefit. Rather than use a
single criterion to assess hearing outcome, a classification
system analogous to the House-Brackmann scale used in
reporting postoperative facial function has been proposed
for reporting hearing results.284
Results in Clinical Series
In recent years, a number of major centers have reported
their results with attempts at hearing conservation.
Most reports emphasize use of either the middle fossa or
Acoustic Neuroma (Vestibular Schwannoma) 763
retrosigmoid approaches (Table 45-9A and B). Others advo-
cate using either approach depending on the characteris-
tics of the tumor undergoing treatment.190–192,285 Reports
on the rate of success in maintaining hearing following AN
excision vary widely. Much of the published data is impossi-
ble to analyze because the amount of residual hearing is not
specified. Still other studies reporting a degree of success
include no audiologic data at all.
It is important to realize that hearing results discussed
next refer only to that subset of patients with ANs who are
deemed to be candidates for hearing conservation surgery.
While this fraction of the entire AN population varies
according to the availability of sensitive diagnostic tools
such as ABR and MRI, to the surgical team’s referral pattern,
and other factors, it probably constitutes between 10%
and 30% of all patients with ANs. With the MF approach
to intracanalicular tumors, “measurable” hearing is main-
tained in approximately 50% of cases.196,281,286 However,
“useful” hearing is probably achieved in no more than 25%
of these most favorable cases. In our own series of 150 patients
with the MF approach and tumors smaller than 18 mm in
the CPA, the following results were recorded. In the MF
group, class A or B hearing was preserved in 62% of patients
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
for hearing preservation in the MF approach seemed to be
the preoperative hearing status, ABR, and intraoperative
tumor origin data.153 A major drawback of the MFA tech-
nique is the fact that complete resection of IAC tumors
involving the fundus requires some degree of blind dissec-
tion. Therefore, specialized tools and techniques are
required to minimize the risk of neural injury during this
indirect dissection. In addition, inspection of the fundus
with either mirror or endoscope is often necessary to
exclude the possibility of retained tumor fragments.195
In the RS approach to tumors with a cisternal compo-
nent larger than 2 cm, preservation of useful hearing is
diminished.286–289 In our own series, up to 25% of patients
retained good hearing.290 The results are, however,
dependent on the age of the patients.291
Overall estimates of hearing success rates are less impor-
tant in deciding the optimal course for a given patient than
the interpretation of that individual’s prognostic factors. In
the very best group with a small tumor, little IAC involve-
ment, excellent hearing, and a normal ABR, the chance of
preserving useful hearing may well reach 50%, whether
operated via the RS or MF approach. Indeed, a few fortunate
patients will actually achieve an improvement in hearing
following tumor removal.292 By contrast, patients whose
hearing and tumor characteristics place them at the fringes
of candidacy for hearing conservation may have very little
chance of success. Taking into account the relatively small
fraction of patients with ANs who are candidates and the
limited probability for success, it can be estimated that only
about 5% of patients with ANs maintain useful hearing in
the tumor ear following surgical excision.
Long-Term Hearing Results
Only recently has long-term follow-up become available for
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
notable tendency for gradual deterioration in both pure
tone threshold and speech discrimination. In 14 of 25
patients operated via the MF route (mean follow-up = 8.1
years), SRT diminished an average of 12 dB while SDS fell
by 25%.293 A similar hearing deterioration was noted in
only one of the nonoperated ears. In a study of 11 patients
operated via the RS approach, 4 showed significant hearing
deterioration over the 3- to 5-year follow-up period.279
The authors suggested fibrosis and impaired vascularity as
causes of the progressive loss. In yet another study, 4 of 18
patients demonstrated significant hearing deterioration in
the tumor ear over a mean of 5.4 years follow-up.294
Over the long term, an unknown fraction of patients
who have had a hearing conservation approach will develop
recurrent tumor. We have managed several patients who
suffered symptomatic recurrence some years following RS
approach with incomplete exposure of the fundus. This
has been noted by others, particularly following a failed hear-
ing conservation attempt.209,279 In these cases it is suspected
that a macroscopic portion of tumor was left in the lateral
terminus of the IAC, where it retained a blood supply. It is
unclear at this time whether microscopic amounts of
tumor left in the cochlear nerve are capable of generating
a recurrence.
Special Considerations in Bilateral
AN and Only Hearing Ears
Management of bilateral AN (NF2) differs in a number of
ways from sporadic, unilateral AN (see Chapter 46)51,295
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%.

bilateral deafness over time, they should be advised to
learn lip reading soon after the initial diagnosis. Because
these patients are never “cured” of their disease in that the
tendency to form intracranial tumors is lifelong, the ther-
apeutic priority should be to maintain function, even at the
expense of incomplete tumor removal, should this be
required.296 One general rule we follow is that once the ear
has become deaf, the tumor should be removed. When
both ears hear well, we often recommend a hearing con-
servation attempt be performed on the side with the larger
tumor. Incomplete removal is elected if the eighth nerve
appears invaded or if the IAC is penetrated deeply. When
removal is successful, the tumor in the second ear may be
similarly approached. Unfortunately, even incomplete
removal can impair or eliminate residual hearing. We pre-
fer to avoid surgery on the better hearing ear, unless the
tumor substantially compresses the brainstem or is enlarg-
ing rapidly. Even when both tumors have been successfully
removed, this does not preclude the development of new
eighth nerve tumors. It is important to realize that in NF2,
ANs are not just bilateral, they are also frequently multiple
on each side. As long as residual eighth nerve fiber is left in,
it may continue to generate new tumors. Some have advo-
cated preserving those eighth nerve fibers that are not obvi-
ously involved by tumor, even in a deaf ear, to maintain the
possibility of later electrical stimulation via a cochlear
implant. In our opinion, once an eighth nerve has become
nonfunctional in a patient with NF2, it should be com-
pletely excised. If both eighth nerves become nonfunc-
tional, consideration should be given to hearing
rehabilitation through electrical stimulation of the brain-
stem (see Chapter 82, Auditory Brainstem Implant).
Osseous decompression of the IAC has been suggested
as a means of slowing the hearing loss associated with AN
in NF2.297 The theory is that reducing the pressure cone in
the IAC permits continued tumor growth for a time with
less constriction of the cochlear nerve and IAC artery.
Unfortunately, results reported to date have not been
impressive. Even chemotherapy has been tried in patients
with NF2, although experience is too meager to draw any
conclusions.298
Rarely, a patient has deafness in an ear contralateral to
an AN due to causes other than a second tumor (e.g.,
labyrinthitis, trauma, Ménière’s disease). A conservative
approach to such tumors is also warranted, unless the his-
tory of the disease is a rapid hearing loss of the remaining
hearing, brainstem compression has become substantial,
rapid tumor growth is evident, or operative intervention
carries relatively low risk of hearing loss.299,300
Hearing Loss in the Ear Contralateral
to an Acoustic Neuroma
It is not widely appreciated that AN surgery may have an
effect on the contralateral ear. Sporadic cases in which an
apparently normal contralateral ear has become deaf
following surgery have been reported.301 The possible
roles of meningitis or CSF pressure changes have not been
well established. We have observed several patients who
suffered a transient (days to weeks) contralateral sen-
sorineural hearing loss in the postoperative period that
resembles endolymphatic hydrops in some cases.302
Acoustic Neuroma (Vestibular Schwannoma) 765
Although permanent deafness can result, in most of our cases
the contralateral hearing loss was temporary and returned to
preoperative levels within 1 to 3 months. It could be hypoth-
esized that low cisternal CSF pressure, transmitted to the
inner ear via the cochlear aqueduct, could result in com-
pensatory endolymphatic hydrops.303 Contralateral hear-
ing loss has also been reported in cases of bilateral ANs.304
Noise-induced hearing loss caused by cranial drilling is
unlikely to explain severe losses.193 Delayed contralateral
sensorineural loss over the long term may also occur,
although this phenomenon has not been well studied. It
has been proposed that patients with ANs may suffer long-
term contralateral hearing loss due to activation of autoim-
mune mechanisms at the time of surgery.305 In rare cases,
decompression of the brainstem may improve auditory
function on the opposite side.306
Rehabilitation of Unilateral Hearing Loss
Profound hearing loss in one ear constitutes only a minor
inconvenience for most individuals, and most choose not
to use amplification devices. Because sound directed toward
the deaf ear readily passes around the head, ordinary con-
versations are usually unimpaired. However, difficulty may
occur when the good ear is masked by competing sounds
in a noisy environment. Two rehabilitative strategies to
partially overcome this limitation reroute sounds from the
deaf side toward the better hearing ear. When the con-
tralateral ear hears normally, a transcranial strategy can be
employed in which a powerful hearing aid is placed on the
deaf side to transmit sounds through the cranial base to
stimulate the intact cochlea.307 Alternatively, two devices can
be placed—one on the deaf ear with a receiving microphone
and a second on the good ear with a speaker (CROS).
These may be connected by a wire across the back of the
neck or wirelessly through an RF transmitter. When the
contralateral ear hears imperfectly, the signal in the better
hearing ear can also be amplified (BICROS). While the
effects of the head shadow can be partially corrected
through the above strategies, deficiencies in stereo hearing
and the inability to localize sounds associated with monaural
hearing are not correctable. Bone-anchored hearing aids
(BAHAs) in transcranial routing of signal by implanting
the deaf ear are currently under investigation. According to
two current studies, patients seem to have a significant
improvement in speech intelligibility in noise and greater
benefit from BAHA compared with CROS hearing aids as
well as a reduced aversion to loud sounds.308,309 In compar-
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
Although unilateral hearing loss is seldom a severe func-
tional deficit, loss of hearing in the tumor ear may result in
substantial psychological distress to the patient. Once an
AN has been discovered, both patient and physician want
to cure the tumor without creating new neurologic deficits
or worsening existing ones. Intellectually, the physician is
aware that unilateral deafness is a relatively small price to
pay for ridding oneself of a life-threatening intracranial
tumor, and most well-informed patients adjust to this reality
quite well. Emotionally, however, it is discouraging to both
patient and surgeon that it is seldom possible to maintain
766 SURGICAL NEUROTOLOGY
or restore useful hearing. Despite thorough and realistic
preoperative counseling, an occasional patient becomes
clinically depressed postoperatively over the loss of hearing
and may benefit from short-term psychiatric care. We
have seen this phenomenon even in patients who had large
tumors who have made an otherwise excellent recovery. It
can only be hoped that the high level of interest in hearing
preservation on the part of clinical investigators in recent
years will ultimately lead to improved techniques that yield
a greater degree of success in this endeavor.
Tinnitus
Tinnitus is a common complaint in patients with ANs.
The effect of tumor removal on tinnitus has been assessed
in several studies.122,311–313 One study of 134 patients found
that those with preoperative tinnitus showed a small but
statistically significant improvement postoperatively
although it seldom resolved entirely.311 Of note, those
patients with no tinnitus preoperatively had a 50% chance
of developing it following resection of their lesion. In
another large study (273 patients), 62% complained of
tinnitus before surgery, half of whom improved postoper-
atively.313 Most studies report that very few patients with
ANs find the tinnitus very bothersome or intolerable. It
remains unpredictable which patients will improve, which
will show no change, and which will deteriorate; age and
tumor size do not seem to be associated with the impact of
surgery on tinnitus.122 The data also suggest that tinnitus
may be of relatively minor importance in the overall quality
of life of patients following AN surgery. However, candidates
for surgery should be thoroughly informed about the
possible effect of the operation on their tinnitus.
There is reason to suspect that hearing conservation
approaches, which leave the cochlear nerve anatomically
intact, might have a higher incidence of postoperative tin-
nitus. However, almost all of the published data on post-
operative tinnitus comes from patients who underwent a
TL procedure, so it is not possible to ascertain the relative
incidence following the various surgical approaches. In a
report of an exceptional patient with very distressing post-
operative tinnitus following a hearing conservation
approach, reexploration and section of the cochlear nerve
was performed.312 The neurectomy did not alter the tinnitus,
which suggests an autonomous source in the central auditory
system may be causative, at least in some patients.
Vestibular Rehabilitation
Preoperatively, many patients with AN have a degree of
vertigo and/or dysequilibrium, often accompanied by a
unilaterally reduced or absent vestibular response on
caloric testing. After tumor removal, the unilateral deficit
becomes complete if it was not so already. The vast majority
of patients compensate well using the contralateral intact
labyrinth together with their proprioceptive and visual
systems. Compensation is a gradual process, however, and
typically takes several weeks or months to achieve the ulti-
mate level of recovery.314 The decompensated state that
follows tumor removal is often quite severe, especially for
patients with smaller tumors and relatively intact vestibular
nerves. Severe vertigo accompanied by nausea, vomiting,
and vigorous nystagmus typically abates over 1 to 3 days.
In the short term, administration of vestibular suppressants
and antiemetics may comfort the patient. However, when
used beyond the early postoperative period, such medica-
tions may retard vestibular compensation and are best
avoided. The most important factor influencing the com-
pensation process is physical activity. Patients are encour-
aged to ambulate as soon as possible and given vestibular
adaptation exercises to practice. Over the long term, even
fully compensated patients are not always entirely normal.
Having only one functioning labyrinth makes an individ-
ual somewhat more dependent on visual and proprio-
ceptive cues for maintaining balance and coordinating
movements. Because of this subtle deficit, patients with
ANs, whether before or after tumor removal, often notice a
mild imbalance in dark or visually confusing environments.
From an occupational standpoint, this mild disability is
seldom important, unless the individual is required to per-
form tasks that take place at heights or otherwise require
fine balance skills.
An objective measure of the pace and completeness of
vestibular compensation following AN removal has been
obtained through a comparison of preoperative and sequential
postoperative rotatory chair testing results in 26 patients.315
As expected, tumor removal was associated with a acute drop
in vestibulo-ocular reflex (VOR) gain, which gradually
returned toward normal over time. Abnormalities were most
marked at 1 week following surgery and were largely
resolved by 3 months. Changes were most notable at lower
frequencies (e.g., 0.0125 Hz) with few abnormalities noted
above 0.05 Hz. The rate of compensation was not signifi-
cantly affected by clinical variables such as tumor size,
patient age, and gender. The lack of effect of advanced age
on the rate of compensation was an important observation,
which contradicts conventional wisdom. Many clinicians
assume, perhaps incorrectly, that older individuals adapt
poorly following an acute loss of vestibular input. Of course,
the elderly are more apt to have coexistent sensory deficien-
cies such as poor vision or a loss of proprioception which can
adversely affect recovery. While the size of the tumor had lit-
tle effect on the pace of the compensation process, it did
influence the ultimate level of compensation achieved. It has
been hypothesized that larger tumors, through compression
of the brainstem, may adversely affect the ability of the
vestibular nuclei to reach full compensation.
Only a few clinical studies that address recovery of equi-
librium following AN removal appear in the literature. In a
survey of 57 patients queried between 1 month and 13 years
following surgery, balance was generally impaired tem-
porarily following surgery but returned to the preoperative
level over time.316 In the early postoperative period, 60%
complained of difficulties with walking, running, and stair
climbing and 82% had difficulty when rapidly turning the
head. In another study of 156 patients, following surgery
dysequilibrium was better in 47%, worse in 17%, and
unchanged in 29%.313 In a study of postural control ability
in 57 patients with ANs both before and 6 months following
surgery, a significant improvement was demonstrated
following removal of the lesion.317 Based on observations of
body sway with eyes both closed and open, it was postulated
that decompression of the pons improved the use of visual
clues in the feedback control of posture.

Headache
As with all craniotomies, some degree of headache is
inevitable during the early postoperative period following
AN surgery. Significant headache persisting beyond the
first month, however, occurs only in a minority of individu-
als. Persistent headache after AN removal is occasionally
focused toward the operative site but is more commonly
generalized. The headaches are typically episodic and may
be quite severe, even debilitating in rare cases. Many
patients report that headache is triggered by coughing or
straining. In a few cases, exacerbation may follow ingestion
of alcoholic beverages. The time course is variable, but
most often headaches wax and wane over several months
and eventually disappear. Headache seldom persists
beyond 1 year; in rare cases the headache diathesis appears
to be long lasting.318
The incidence of persistent headache following AN
surgery varies according to the surgical approach and the
tumor size. In one study, 100 patients (50 TL, 50 RS) were
evaluated for headache during the first postoperative year.
At some time during the interval between 1 and 6 months
following surgery, 32% of RS patients and 16% of TL
patients reported severe headache. By 6 months following
surgery, 12% of RS patients continued to suffer severe
headache (based on both intensity and frequency) while
the incidence in TL patients was zero. Of interest, an
inverse relationship between tumor size and the incidence
of headaches was noted. The patients at highest risk of suf-
fering persistent postoperative headaches were those with
small tumors (<1 cm diameter) whose surgeries took an RS
approach for hearing conservation purposes. In addition,
craniectomies tend to do worse in respect to postoperative
pain.319,320 In a survey of 541 patients enrolled in the AN
Association, 34% identified headache as a significant
residual problem following their operation.321 In a series of
273 patients from Denmark, headache was identified as a
persistent problem in 29%.313
According to a recent study from Finland, the major risk
factors for postoperative problems with headache are a
retrosigmoidal approach, postoperative gait problems,
preoperative headache, and small tumors.322 These series
also suggests that if headache is present before surgery, it
tends to continue after surgery, and if headache continues
for 1 year, it usually persists without being reduced.
Management of persistent post-AN headache is largely
empirical. In the early postoperative period, narcotics can
usually be replaced by nonsteroidal anti-inflammatory
drugs such as indomethacin and ibuprofen. These are
generally best taken regularly as a preventive measure.
This strategy is usually more effective than medicating in
response to each episode. As the headaches become mild
or infrequent, the medication should be tapered rather
than abruptly discontinued. Headaches refractory to this
regimen require additional therapy. During the first few
postoperative months, a short course of oral corticosteroids
many bring dramatic relief. This improvement may be
long lasting, but most often is transient with headache
recurring following withdrawal of the drug. Occasionally,
steroid-responsive headaches can be gradually resolved
with low-dose corticosteroids. When possible, they should
be administered every other day and gradually tapered
Acoustic Neuroma (Vestibular Schwannoma) 767
over weeks or months. As a general rule, it is best to avoid
long-term use of oral narcotics, although occasional use
for particularly severe episodes may be warranted. Simple
measures such as neck muscle massage, application of heat
or cold, and biofeedback therapy bring relief to some
patients. Surgical measures to abort persistent postoperative
headaches have generally not proved successful. This
includes avulsion of the occipital nerve as well reoperation
for the purpose of disrupting possible adhesions between
the nuchal muscle and the dura.
It is important to analyze the mechanism of postopera-
tive headache following AN removal because insight into
the underlying cause may suggest preventive strategies.
Numerous pathogenic mechanisms have been proposed,
including extracranial factors such as nuchal muscle spasm
and entrapment of the occipital nerve in the surgical scar
with resultant neuropathy. Although these mechanisms
may be responsible in a fraction of cases, most clinicians
believe that either low-grade aseptic meningitis or an
abnormal coupling of the posterior fossa dura with the
nuchal musculature are causative in the majority of cases.
In the classically performed RS craniectomy, the suboccipital
bone is discarded. Dense adhesion between the neck muscles
and the dura has been frequently observed clinically and
demonstrated histologically in at least one reported case.318
This phenomenon may be avoided by creation of a bone
flap, which is replaced at the end of the procedure.320
However, the suboccipital bone plate is relatively thick and
turning a flap may be technically difficult, particularly on
the edge adjacent to the sigmoid sinus. In recent years, we
have removed the suboccipital plate piecemeal and
replaced the bone chips at the end of the procedure. In our
experience, this reliably heals into a rigid plate, which
effectively partitions dura from nuchal musculature.
Arguing against dura to muscle adhesion as a common
cause of persistent postoperative headache is the observation
that headache less frequently follows RS craniotomies per-
formed for other purposes (e.g., hemifacial spasm, tic
douloureux, cerebellar tumors) than it does for AN. An
alternative explanation for long-lasting postoperative
headaches is chronic, aseptic meningitis. RS craniotomy
for AN differs from other posterior fossa procedures in
that bone is drilled intracranially in the process of exposing
the intracanalicular portion of the tumor. Despite efforts
to contain it, this tends to disperse bone dust widely
throughout the arachnoidal surfaces of the infratentorial
compartment. With the TL procedure, by contrast, all
drilling is completed before the dural is opened. Evidence
in favor of the aseptic meningitis theory includes the
greater incidence of headache following the RS as opposed
to the TL approach, the frequency of corticosteroid
responsiveness, and the occasional wound swelling noted
in association with headache episodes. The anecdotal
observation that headache is more frequent following RS
vestibular neurectomy when the IAC is drilled open than
when it is left intact also tends to confirm the culpability of
bone dust. Although one or more pathogenic mechanisms
may predominate in postoperative headache, undoubtedly
a multiplicity of causes exist. Vascular headaches, including
migraine variants, are seen occasionally following AN sur-
gery. In one of our RS patients, classical cluster headaches
onset following tumor resection. The clinician must be
768 SURGICAL NEUROTOLOGY
alert to the possibility of infectious meningitis, particularly
in the early postoperative period. Clues to this complication
include the severity and duration of the headache as well as
its association with fever, malaise, nuchal rigidity, and
other neurologic symptoms. Cryptic CSF leak can also
cause chronic headache due to low CSF pressure.
Historical clues to this entity include positional and exer-
tional triggers, watery rhinorrhea or postnasal drip, and a
history of meningitis.
Social and Occupational Rehabilitation
In recent years, several aspects on the social and occupational
recovery of patients from AN surgery has been published. In
a survey of 541 members of the AN Association (a patient
information and support organization), only 5% were
unable to return to work following tumor removal.321
Eight percent reported an inability to resume normal
social life, and 15% noted easy fatiguability. Even these
relatively low percentages of global lifestyle changes are
probably overestimates because many members join this
group for help coping with long-term disability. This self-
selection skews the patient population toward those with
less favorable outcomes.
In a Danish study of 273 patients, adverse vocational
impact was noted in 14%, 9% of whom ceased to work and
5% required a change of employment. In a study of
57 patients from Japan, only 63% returned to their same
occupation following surgery and 70% resumed driving a
car.316 It is intriguing to note that 80% of patients continued
to play golf after their surgery. Several factors may con-
tribute to the wide discrepancies in success of occupational
rehabilitation among the different countries, including the
amount of social support provided to disabled workers. In
addition, the availability of sophisticated diagnostic tools
such as MRI varies around the world, a factor that may
affect the size mixture of tumors at the time of diagnosis
and thus create a variable incidence of less favorable long-
term outcome.
Depression at some time in the postoperative course was
noted in 38% of patients in a study from the United States,
and it was noted in 17% in the Danish study.313,321 These
data are derived from patient response questionnaires and
do not reflect actual psychiatric diagnoses. In addition,
neither the severity nor the duration of depression was
indicated in either study.
In our experience, global recovery of a patient following
AN surgery depends most on the tumor’s size323 and the
patient’s age. It would be highly unusual for an individual
younger than 60 years with a tumor smaller than 2 cm not
to make an excellent functional recovery. If fact, most
younger patients with even very large tumors resume
active and productive lives within several months of
surgery. By contrast, some elderly individuals remain dis-
abled despite having only small tumors whether they
were operated, radiated, or simply observed. The most
common cause of disability in the aged is chronic imbal-
ance. In summary, the economic, social, and psychological
impact of AN and its surgical management appears to be
relatively minor, with few individuals having life-altering
consequences.324
RADIATION THERAPY
Conventional Radiotherapy
There are two forms of radiation therapy in use in the
treatment of AN: conventional and stereotactic.
Conventional radiotherapy is seldom used in the developed
world today although it is still occasionally employed in
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
of 4 to 6 weeks to reach a total dose of approximately
50 Gy.325,326 Since radiation injury preferentially affects
dividing cells, one benefit of fractionation is the opportu-
nity for a greater number of cells to enter mitosis during
the treatment course. However, because ANs have a very
low index of mitoses, only a relatively small number of
tumor cells would enter this vulnerable stage during the
treatment course.
Few reports are available on the effectiveness of con-
ventional irradiation. In one study of 20 patients followed
7 to 46 months (mean 30 months) after radiation, 2 died of
their tumors, 2 died of unknown causes, 2 patients developed
hydrocephalus, and 2 required salvage surgery.326 Such
results are clearly poorer than those of surgical excision
and modern stereotactic radiation. The effects of conven-
tional radiotherapy on partially excised AN has also been
studied. In a study of 31 patients with ANs, it was concluded
that fractionated radiotherapy was of no benefit to those
who had undergone total or near-total tumor removal.325
Following subtotal excision, however, 46% (6/13) of unra-
diated tumors recurred and only 6% (1/17) of irradiated
tumors showed signs of symptomatic progression. This
seemingly convincing data is open to several criticisms.
The two groups may not have been equivalent because
patients accrued over nearly 40 years and the term subtotal
may have had different meanings to various surgeons over
the decades of the study. In addition, recurrence was defined
as symptomatic progression, and many seemingly controlled
patients could well have had tumor growth if they had
been evaluated radiographically. Finally, this study showed
a poor prognosis for patients irradiated at the time a post-
surgical recurrence was detected. Based on the published
data, there is little to commend conventional radiotherapy
in the management of ANs.
Stereotactic Irradiation
The fundamental concept of stereotactic radiation (SR) is to
deliver a precise, conformal dose of radiation with isodose
lines tailored to the margins of the tumors. In contrast to
conventional radiotherapy, in which a large number of
fractions are delivered over many weeks, stereotactic radi-
ation is designed to induce necrosis in the irradiated tissue
through a single large dose delivered during a single session
or a few fractions delivered within a short period of time.
The dose delivered to the center of the tumor is more
intense than that at the margin. Stereotactic radiation with
photons is most commonly delivered either by a multisource
Cobalt-60 gamma unit (the Gamma Knife) (Fig. 45-29).
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
Stereotactic Radiation
Although stereotactic radiotherapy has been used in AN
for more than 40 years after being introduced by Lars
Leskell and his team in Stockholm, only recently has a
substantial body of outcome data been accumulated.
Following stereotactic radiotherapy, the tumor remains in
situ; the goal is stabilization against future growth rather
than the lesion’s disappearance. A modest degree of
shrinkage has been reported in roughly one-third to two-
thirds of patients (Tables 45-10, 45-11, and 45-12). Not
uncommonly, the tumor swells somewhat during the first
6 to 18 months after treatment. This phenomenon, which
likely stems from radiation-induced edema, should not be
mistaken for neoplastic growth. Often a diminution of
gadolinium enhancement in the center of the tumor is
observed (Fig. 45-31).
Numerous earlier studies have examined short-term
outcome within the first few years, an inadequate period to
assess long-term therapeutic efficacy. Only a few studies,
totaling no more than a few hundred patients, report
follow-up longer than 5 years (see Tables 45-10, 45-11,
and 45-12). In these studies, regrowth was observed in
approximately 5% of cases over time. This contrasts with
an approximately 50% chance an AN will demonstrate sig-
nificant growth over a 3-year period based on the natural
history of the disease. Caution must be observed in combin-
ing earlier studies in which an @ 16 Gy marginal dose was
used rather than the @ 12 Gy of protocols popular at pres-
ent. Nevertheless, a substantial body of data has been accu-
mulated indicating that stereotactic radiation controls ANs
in a substantial majority of cases. One special circumstance is
cystic tumors, which have a higher rate of recurrence due to
expansion of the cystic component following radiation.334
A recent trend has been toward experimentation with
fractionated stereotactic radiation.335,336 Doses are divided,
often into a few fractions delivered over 1 to 2 weeks. The
concept of fractionation is to reduce complications, espe-
cially neuropathy, by allowing biologic recovery time from
radiation injury. Unfortunately, fractionation without
increasing total dose also reduces the biologic effort on the
tumor itself. No significant long-term data has been pub-
lished to elucidate whether or not fractionation increases
risk of recurrence.
Audiovestibular Function
after Stereotactic Radiation
Little data exists concerning the fate of hearing over the
long term. In three recent studies that followed fewer than
100 patients for 4 years, good hearing (Gardner-Robinson
grade 1 or 2) was preserved in 47% to 62% (Table 45-13).
Higher dose has been correlated with poorer hearing out-
come.337 It is not yet clear whether fractionation improves
hearing outcome, although preliminary data suggest that it
does.338 Hearing preservation in bilateral ANs associated
with NF2 appears to be somewhat less favorable than with
sporadic unilateral AN.338–340 Hearing results do not
appear to be as favorable with proton beam therapy as with
photon-based modalities 328,335
Little data exists concerning the outcome of vestibular
function after stereotactic radiation. Because the diseased
vestibular nerve remains, persistent aberrant vestibular
input is likely to remain in a sizable fraction of patients.
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)

TABLE 45-12. Fate of Tumors after Proton Beam Radiation
Report Year No. of Patients Follow-up
Harsh328 2002 64 0.5–8 yr
(2.8 mean)
radiation does not help older individuals with small tumors
and deteriorating balance.
Cranial Nerve Function following
Stereotactic Radiation
Facial neuropathy has been observed following stereotactic
radiation, typically commencing 6 to 12 months following
therapy. In the great majority of cases, it is transient and
the patient recovers facial function. The incidence of facial
neuropathy has been reduced by lowering the marginal
tumor dose. In the 1970s, rates of facial neuropathy were
nearly 40%.341 The rate at 16 Gy marginal dose, common
through the early 1990s was on the order of 10% to 20%.
At current dose regimens of 12 Gy, the incidence appears to
be on the order of 5% with some series reporting even less.
Trigeminal neuropathy, which was formerly quite preva-
lent at higher doses, occurs infrequently with current dose
regimens. Hypesthesia is the most common symptom.
The occurrence of trigeminal neuropathy is correlated
with larger tumors. Preliminary data suggests that frac-
tionation does reduce the risk of trigeminal or facial
neuropathy.338 Proton beam appears to have a higher risk
of new neuropathy than photon therapy.328
Complications following
Stereotactic Radiation
Hydrocephalus may occur following stereotactic radiation,
presumably caused by leakage of proteins from the tumor
surface leading to impaired CSF resorption. This complica-
tion appears to occur in a small percentage of patients.
Most neurologic injuries following radiation have onset
latencies measured in months; however, a few reports of
early deterioration have appeared. In one case, facial palsy
Acoustic Neuroma (Vestibular Schwannoma) 771
Marginal Dose Stable Smaller Larger
12 Gy 55% 39% 6%
(11–18)
and permanent deafness evolved 2 days following radiation
of a small NF2 tumor.342 Vertigo, seizures, and persistent
new headaches have been reported in the immediate post-
treatment period.343 The author has seen several cases of
devastating brainstem injury following stereotactic radiation
(Fig. 45-32).
Precipitous enlargement of the tumor necessitating
urgent microsurgical decompression has been reported in
a few cases.344 This appears to be a phenomenon primarily
for tumors larger than those typically radiated at most
centers.
Secondary Oncogenesis following
Stereotactic Radiation
When contemplating radiation therapy for a benign neo-
plasm, the risk of inducing a secondary malignant tumor
must be carefully weighed. Five cases of malignancy that
evolved following stereotactic radiation for AN have been
reported in the literature to date (Table 45-14).
Unfortunately, each case was lethal. Three were malignant
schwannomas and one each glioblastoma and meningeal
sarcoma. In three of the five cases, biopsy confirmed an
initially benign AN. The other two, who were treated
without biopsy, had clinical scenarios highly suggestive of
benign AN from the outset. Interestingly, the latency
period was 5 to 7.5 years in reported cases, much shorter
than the more usual decades-long interval following con-
ventional radiotherapy.
The key issue, yet to be determined, is the rate of occur-
rence of radiation-induced neoplasia following stereotactic
radiation for AN. In the best studied intracranial model of
conventional radiation, pituitary adenoma, the risk is about
1% at 10 years, 2% at 20 years, and 3% at 30 years.345
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
analogy is approximate at best.
Indications for Stereotactic Radiation
in Unilateral Acoustic Neuroma
Because roughly 50% of ANs show little growth over a
3-year period, it is reasonable to withhold treatment for
smaller tumors that are minimally symptomatic, especially
in older individuals, until the tumor has proved that it
needs intervention by demonstrating growth on serial
imaging studies. Much controversy exists concerning
the relative roles of microsurgery and stereotactic
radiation. At the extremes of the range, some centers favor
microsurgery almost exclusively and others advocate a
similar policy for radiation. The majority of centers use the
different modalities in a variable mixture based on criteria
that are not always consistent among groups. In general,
centers are more likely to recommend radiation for smaller
tumors in older individuals and microsurgery for younger
patients with a tumor of any size. Most large tumors are still
managed with microsurgery. The rationale is that younger
patients are more vulnerable to the potential long-term
adverse consequences of radiation (e.g., secondary neopla-
sia, vaso-occlusive disease). Also, microsurgery is usually
definitive, whereas MRI monitoring is needed indefinitely
following radiation. Because after radiation therapy a
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

These tumors can now be detected in their earliest stages
at a time when treatment offers excellent prospects for
functional preservation. Microsurgical techniques have
been refined to the point where mortality has been
reduced to less than 1% of patients, even for those with
large tumors. Increasingly favorable facial and auditory
nerve preservation rates are also being realized. Stereotactic
radiosurgery (Cyberknife and Gamma Knife) shows
increasing promise as a therapeutic option for selected
patients. Recent genetic investigations have provided fasci-
nating insights into the molecular genetic aberrations that
trigger these tumors. Ultimately, the ideal solution lies in
either reversing the pathophysiologic changes of the tumor
cells or in preventing their occurrence through genetic
engineering. Such modalities, which may seem quite
far-fetched today, will undoubtedly be realized once the
complex mysteries underlying the tumor’s biology have
been unraveled.
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a vestibular schwannoma after gamma knife radiosurgery. Lancet
27;360(9329):309–310, 2002.
373. Comey CH, McLaughlin MR, Jho HD, et al: Death from a malig-
nant cerebellopontine angle triton tumor despite stereotactic
radiosurgery. Case report. J Neurosurg 89:653–658, 1998.
374. Arriaga MA, Chen DA: Facial function in hearing preservation
acoustic neuroma surgery. Arch Otolaryngol Head Neck Surg
127:543–546, 2001.

Neurofibromatosis 2
Outline
Introduction
Neurofibromatosis 2
Differentiated from
Neurofibromatosis 1
Clinical Characteristics
of Neurofibromatosis 2
Definition of
Neurofibromatosis 2
Prevalence and Incidence
Molecular Genetics
Family History
Tumor Types
Auditory Changes in Patients
with Vestibular
Schwannomas
Other Tumor Types in
Neurofibromatosis 2
Treatment Options for
Vestibular Schwannomas
in Neurofibromatosis 2
INTRODUCTION
Neurofibromatosis 2 (NF2) presents unique challenges to
the neurotologist. The disease is quite invasive, requiring a
multispecialist team approach. At the same time, the
primary impairment is hearing loss due to bilateral vestibu-
lar schwannomas. Usually, the presenting complaint will be
hearing loss or balance problems, and the neurotologist
will be the first specialist to diagnose the disorder. Here we
review the differential diagnosis of NF2 from neurofibro-
matosis 1 (NF1), characteristics of the disease, current
treatment, and management options.
NEUROFIBROMATOSIS 2 DIFFERENTIATED
FROM NEUROFIBROMATOSIS 1
NF1 has a distinctly different clinical presentation from
that of NF2. Positive differentiation of NF2 from NF1 has
occurred with genetic analysis. NF1 has been localized to
chromosome 17, NF2 to chromosome 22. NF1 is defined
as having two or more of the following:
• Six or more café au lait macules
• Two or more neurofibromas
Chapter
46
Hearing Preservation William H. Slattery III, MD
Observation without
Laurel M. Fisher, PhD
Surgical Intervention
Middle Fossa Craniotomy
and Internal Auditory
Canal Decompression
without Tumor Removal
Retrosigmoid Craniotomy
with Partial Removal
Nonhearing Preservation,
Translabyrinthine/
Suboccipital Approach,
Total Tumor Removal
Auditory Brainstem Implant
Stereotactic Irradiation
Management of
Neurofibromatosis 2
Genetic Testing
Summary
• Freckling
• Optic glioma
• Lisch nodules (iris hamartomas)
• Osseous lesion (sphenoid dysplasia, thinning of the long
bone cortex)
• A first-degree relative with NF1
Some patients manifest learning disabilities or language
disorders as well. A careful examination and a detailed
history of the patient’s symptoms will help to distinguish
the two diseases.
Clinical Characteristics
of Neurofibromatosis 2
Definition of Neurofibromatosis 2
In 1987, the National Institutes of Health Consensus
Development Conference on NF developed the guidelines
for diagnosis of NF2 as distinct from NF1. NF2 is distin-
guished by bilateral acoustic neuromas (or vestibular
schwannomas [VS]) with multiple meningiomas, cranial
tumors, optic gliomas, and spinal tumors.1 A definitive diag-
nosis is made on the basis of the presence of bilateral vestibu-
lar schwannomas, or developing a unilateral vestibular
783
784 SURGICAL NEUROTOLOGY
schwannoma by the age of 30 and a first-degree blood
relative with NF2, or developing at least two of the follow-
ing conditions known to be associated with NF2: menin-
gioma, glioma, schwannoma, or juvenile poster subcapsular
lenticular opacity/juvenile cortical cataract1 (Table 46-1).
As the definition implies, the presentation of the disease
and the genetic mutation linked to the manifestations of
the disease exhibit considerable heterogeneity. Yet, within
a family, the expression of NF2 tends to be very much the
same.2 These two facts, taken together, indicate a large
genetic component to the disease, yet with much variabil-
ity within those parameters in the observed phenotype.
Studies have indicated that a truncating mutation (non-
sense and frameshift) may be linked with the more severe
form of NF2.3–5 The more severe form, termed the Wishart
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
40. Despite the strong genotype-phenotype correlation,
individual differences in tumor growth occur within
subjects, making it difficult to predict how an individual
tumor will change over time even when the genotype is
known.
The mild, or Gardner form, of NF2 is less debilitating.
The schwannomas may remain the same size for years, few
meningiomas will develop, the patient may not develop
symptoms until late in life, and will have fewer disabili-
ties.2–4,6–12 However, the genetic basis of the mild form has
not been well described.
Prevalence and Incidence
Patients tend to be diagnosed with NF2 around age 25
after experiencing symptoms of the disease for an average
of 7 years (Fig. 46-1). There are no differences in the pro-
portion of men versus women who develop NF2 and no
1.0
Kaplan-Meier Cumulative Proportion
0.8
0.6
Figure 46-1. Time from first symptom to first
surgery.
0.4
0.2
0.0
0 10
TABLE 46-1. Neurofibromatosis 2 Diagnostic Criteria
Individuals with the following clinical features have confirmed (definite) NF2:
Bilateral vestibular schwannomas (VS) or family history of NF2 (first-
degree family relative) plus
1. Unilateral VS < 30 years or
2. Any two of the following: meningioma, glioma, schwannoma, juvenile
posterior subcapsular lenticular opacities/juvenile cortical cataract.
Individuals with the following clinical features should be evaluated for NF2
(presumptive or probable NF2):
Unilateral VS < 30 years plus at least one of the following: meningioma,
glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/
juvenile cortical cataract.
Multiple meningiomas (two or more) plus unilateral VS < 30 years or one
of the following: glioma, schwannoma, juvenile posterior subcapsular
lenticular opacities/juvenile cortical cataract.
NF2, neurofibromatosis 2.
prevalence differences by ethnicity. Epidemiologic studies
place the incidence of NF2 between 1 in 40,000 live
births13 and 1 in 87,410 live births.14
Molecular Genetics
In 1987, the NF2 gene was mapped to chromosome 2215
and was localized to 22q12.2 in 1993.16,17 Various types of
mutations have been identified, among them single-base
substitutions, insertions, and deletions.4,18–20 The mild, or
Gardner, type NF2 may be associated with missense muta-
tions, whereas associations between the other mutations
and phenotypes are not as clear.21 The occurrence of NF2
is not restricted to families known to carry the mutation.
Frequently, genetic mosaicism occurs,22 which may not
be picked up by common mutation analytic techniques.
It appears that unilateral vestibular schwannoma may
exhibit the same type of genetic markers as NF2.23
However, the mutation is confined to the affected tissue.
Family History
Yes
No
20 30
Years

In persons with NF2, the mutation is present in other types
of cells as well.22
Family History
Individuals at risk for developing NF2 must be screened to
provide an early diagnosis. Individuals at risk include chil-
dren of NF2-affected patients and their siblings. Because
NF2 has a 50% penetrance, all children of NF2 patients
have a 50% risk of developing the disease. Siblings of a
diagnosed NF2 patient are at risk, especially if the parent
has also been identified with NF2. The clinical presenta-
tion of NF2 is usually similar within families. The likeli-
hood of NF2 occurring in related individuals who do not
exhibit similar clinical symptoms to an affected family
member is small. Consideration may still be given for
screening.
The type of screening and the timing of screening
depends on each NF2 center’s preferences. However, we
advocate early screening, so that tumors may be diagnosed
presymptomatically.
We screen potentially affected individuals with a post-
contrast T1-weighted MRI of the full head, with fine cuts
(at most 3 mm slices, no skip) through the internal audi-
tory canals (IACs). This test will identify most affected
NF2 patients by showing any vestibular schwannomas.
Screening of the spine or ophthalmology exams should be
A B
C
Neurofibromatosis 2 785
considered if the cranial MRI scan is positive. An audio-
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
diagnose presymptomatically.
MRI scanning is recommended for an at-risk minor
when this test can be performed without sedation. This
usually occurs when the child is 7 through 9 years of age.
A recommended first step for children younger than age 7
is an audiogram. Any child with an NF2-associated symp-
tom (e.g., hearing loss or facial weakness) should be
screened without regard to the need of sedation or age
and should be performed as soon as possible after the
symptoms are apparent.
TUMOR TYPES
Bilateral vestibular schwannomas (also acoustic neuroma)
are benign neoplasms of the acoustic or eighth cranial
nerve24 (Fig. 46-2). The tumors typically are located on
the superior vestibular nerve at the glial-Schwann cell
junction within the internal acoustic meatus. The conse-
quences of a vestibular schwannoma are numerous, includ-
ing dizziness, imbalance, tinnitus, hearing loss progressing
to deafness, facial nerve paralysis, brainstem compression,
and, if left untreated, death.
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.
786 SURGICAL NEUROTOLOGY
Despite the strong genotypic effect in NF2, there is enor-
mous variability in the number of tumor types (Table 46-2),
the rate of progression, and the disabilities experienced.
This enormous variability is also found in patient presen-
tation; surprisingly, some patients may be asymptomatic.
Patients who have no symptoms when diagnosed have
generally been identified on the basis of genetic analysis,
conducted because a blood relative has NF2. Although the
National Institutes of Health (NIH) criteria for NF2
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
meningiomas (cranial and spinal) and no vestibular
schwannoma.9,25 Although the NIH criteria for NF2 imply
that all NF2 patients will develop bilateral vestibular
schwannoma, some researchers are not convinced of this.26
Evans26 based his conclusion on the observation of a pos-
sible variant form of NF2 presenting with skin and spinal
tumors in the absence of vestibular schwannomas.
Nevertheless, in general, the phenotype is reflective of the
underlying genotype.
Preliminary data from the Natural History of Vestibular
Schwannomas in NF2 study conducted at House Ear
Institute shows that 10 of 80 (12.5%) enrolled subjects had
no symptoms at diagnosis, and 23 (28.8%) had cranial
meningiomas and spinal meningiomas in addition to bilat-
eral vestibular schwannoma. Nearly half (47.5%) had one
vestibular schwannoma removed prior to enrollment.
Generally, the tumor resected prior to enrollment was
removed 1.5 years after discovery and was an average of 2.1
cm at removal. Few Natural History patients had spinal
tumors or meningiomas removed prior to enrollment. The
preliminary data would indicate that, for this sample of NF2
subjects, the most salient medical issue is the growth of their
vestibular schwannoma.
NF2 subjects tend also to develop cortical and posterior
subcapsular cataracts, which can lead to blindness27
(Table 46-3). Retinal hamartomas have been observed in a
few cases,2,28–30 but are not as frequent. Some subjects (2%
to 3% of subjects)31,32 present with numbness or tingling in
their arms or legs. Upwards of 30% of NF2 subjects may
have surgery to remove spinal tumors, but the progression
of spinal tumors associated with NF2 is not well described.
At this time, the presence of vestibular schwannoma in
NF2 and the consequences of not treating them are rela-
tively well known, and these tumors may be the most
debilitating.
Rarely does a vestibular schwannoma turn malignant,
and sometimes the unilateral vestibular schwannoma may
regress in size altogether. Growth of the tumors does not
seem to be related either to loss of heterozygosity (genetic
TABLE 46-2. Tumor Type
Tumor Type Percentage of Patients
Bilateral vestibular schwannoma 99
Skin 50
Meningioma 46
Spinal 60
TABLE 46-3. First Symptoms of Neurofibromatosis 2
Symptoms Percentage of Patients
Neurologic 17.5
Skin tumor 11.7
Vision loss 10.7
Asymptomatic 10.7
Tinnitus 7.8
Weakness 2.9
Vertigo 1.0
Other/Unspecified 4.9
level of analysis) or to auditory functioning (phenotype level
of analysis). For this reason physicians recommend at least
yearly MRI scans to track changes in size.33–40 Others have
suggested that, after a baseline scan, the next scan be at
6 months in order to determine if the tumor is fast- or
slow-growing.41
Auditory Changes in Patients
with Vestibular Schwannomas
Hearing loss is well documented as the most common
presenting symptom in patients who have vestibular
schwannoma.42–51 Auditory changes over time in vestibular
schwannoma patients are less well known. Rosenberg52
studied the natural history of 80 patients with non-NF2
unilateral vestibular schwannoma for an average of 4.4 years.
Rosenberg found a positive correlation between tumor
growth and worsening pure tone average. However, there
was no statistically significant correlation between positive
tumor growth and speech discrimination, change in brain-
stem auditory evoked response, and bithermal caloric
electronystagmography test responses over time. Lalwani
and colleagues53 reported that pure tone patterns, speech
reception threshold, and word recognition scores were
significantly worse in NF2 patients who had a mild form
of NF2 and large tumors compared with patients with
mild NF2 with small tumors. Loss of acoustic reflexes and
prolonged wave III and V were also associated with larger
tumors. In contrast, patients with severe NF2 showed
no relationship among tumor size and pure tone levels,
speech reception threshold, or word recognition scores.
The lack of association may have been due to the complete
loss of hearing in the severe NF2 patients at the time of
the assessment. The larger tumors were associated with
prolonged ABR wave III and V latencies. No data across
time were reported. In general, hearing is progressively
impaired with increasing growth of vestibular schwanno-
mas, necessitating the need for surgical intervention or
medical treatment in NF2 patients.
Other Tumor Types
in Neurofibromatosis 2
NF2 has been associated with multiple central nervous
system tumors, the most common of which are intracranial
meningiomas (Fig. 46-3), spinal tumors, and optic gliomas
(in addition to cataracts).54 Nearly all NF2 patients
will develop these tumors in time: 50% of NF2 patients
present with schwannomas and meningiomas, 90% present
with spinal tumors in addition to schwannomas.25

Figure 46-3. Multiple meningiomas can be seen in severe forms of NF2.
Meningiomas may occur throughout the cranium and skull base area.
The presence of more than one type of tumor within an
individual usually indicates a more aggressive disease
course. The co-occurrence of vestibular schwannomas and
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
sporadic schwannoma or meningioma.55,56 Despite the
high numbers of patients with multiple tumors, initially,
most meningiomas and spinal tumors are asymptomatic
and are first seen on an MRI. In addition, multiple skin
tumors are found in persons with NF2.
A variety of spinal tumors (Fig. 46-4) occur in NF2
patients and can be found in the cervical, thoracic, and
lumbar regions. These tumors are further categorized as
either extramedullary or intramedullary tumors, depending
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
large, causing compression of the spinal cord and nerve roots. Excision is
necessary when neural function is compromised.
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,
relieving the pressure inside the skull or at the spinal cord.
Growing meningiomas result in increased intracranial
pressure, intractable headache, hydrocephalus, and seizure
disorders.59–61 Continued growth of spinal tumors causes
loss of motion, numbness, tingling, and, eventually, para-
lysis. Treatment of optic gliomas frequently results in
removal of the eye (thus, blindness).27
Treatment Options for Vestibular
Schwannomas in Neurofibromatosis 2
The treatment options for a patient with bilateral vestibular
schwannomas vary considerably as a result of the wide
variety of tumor sizes and clinical presentations. Associated
symptoms (brainstem compression or hydrocephalus), loss of
useful hearing, and the status of other intracranial tumors all
must be considered when discussing treatment intervention.
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-
cephalus does not result. Initially, an MRI is performed
6 months following diagnosis, and then annual MRI scans
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
is either too large for hearing preservation or the hearing
loss is already at a significant level and hearing preserva-
tion is not considered. This approach is used for individu-
als with large tumors who have brainstem compression
even if serviceable hearing exists. The translabyrinthine or
suboccipital craniotomy approaches may be used for this
procedure. However, the risk of a recurrent tumor is
slightly higher with the suboccipital approach and with
inexperienced surgeons because residual tumor is often left
in the lateral aspect of the IAC.
B
Figure 46-5. Histology of a vestibular schwannoma. A, Unilateral non-NF2
vestibular schwannoma. Typical schwannoma stain with Bodian silver stain.
It stains only the nerve fiber, so the schwannoma cells are not evident.
However, the fibers on the surface of the tumor are visible. Nerve fibers of
non-NF2 vestibular schwannomas are displaced by the schwannomas cells.
B, This slide shows another Bodian silver stain with black strands embedded
within the tumor, representing the nerve fibers invaded by the tumor. This
invasion is different than seen with non-NF2 solitary vestibular schwanno-
mas. Non-NF2 solitary tumors invade the aggregates of cells and push the
fibers aside rather than invading between the fibers. Thus, NF2 vestibular
schwannomas are histologically different from non-NF2 sporadic, unilateral
tumors.

Auditory Brainstem Implant

The auditory brainstem implant was developed at the
House Ear Institute to allow electrical stimulation of the
cochlear nucleus following bilateral vestibular schwan-
noma removal. The device is placed on the brainstem
(Fig. 46-6) during translabyrinthine vestibular schwan-
noma removal. This device is indicated in individuals who
have no serviceable hearing and are undergoing vestibular
schwannoma removal. The majority of patients obtain
enhanced communication skills with the device.
Stereotactic Irradiation
Stereotactic irradiation has been recommended for some
NF2 patients, but its use must be carefully considered
since radiation exposure may induce or accelerate tumors
in a patient with an inactivated tumor suppressor gene. It
was recently reported that two of four patients who had
previously received radiation therapy developed a malig-
nancy in the irradiated ear.64
Many algorithms have been proposed as treatment
plans, but none are widely accepted among NF2 special-
ists. The range of treatment options is large, larger than
for any other nervous system tumor. The potential bene-
fits of treatment are great (hearing preservation), but the
potential risks are also significant, and the riskiest proce-
dures have the greatest potential benefit. Often patients
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-
ilies, and care providers need to know the natural history of
these tumors to better make rational recommendations
and decisions regarding these treatment options. In addi-
tion, noninvasive and tumor-related markers of behavior
need to be identified that can further tailor our anticipatory
guidance for any one patient.

Figure 46-6. CT scan demonstrating placement of auditory brainstem
implant within the lateral recess of the fourth ventricle.
Management of Neurofibromatosis 2
Initial evaluation of an NF2 patient can be very complex
because this is a multisystem disease. However, an inade-
quate diagnosis may render a patient impaired because
early diagnosis and treatment may have prevented further
impairments. NF2 patients may typically see many differ-
ent physicians, each with experience in a different field of
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
neurotologist may all function as the lead physician,
depending on the NF2 center.
A comprehensive battery of tests is necessary for tumor
detection and adequate staging. The initial MRI scan
demonstrating the presence of bilateral vestibular schwan-
nomas may be inadequate for tumor follow-up. As an
example, a cranial scan may not have included the IACs, or
a spine series may have focused on only one segment of the
spine. An MRI with gadolinium and thin cuts through the
IAC is necessary for the head. Particular attention is
focused in the IACs, caverness sinus, and jugular foramen
areas. Any cranial nerve may have tumor formation and
thus should have complete imaging.
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
thresholds, and speech testing. Some centers prefer addi-
tional testing with ABR to assess cochlear nerve function.
This is particularly helpful when considering a hearing
preservation procedure. Electronystagometry testing has
benefit in determining tumor location; however, its utility
for clinical assessment is still under investigation.
A complete neurologic exam is required for individuals
with suspected NF2. The standard neurologic assessment
of dermatomes and muscle strength is required for assess-
ment of potential spinal cord impairment. Cranial nerve
testing may find subtle abnormalities for which the patient
has slowly compensated. In addition, the patient may not
even be aware of his or her own impairment. This is par-
ticularly true of the lower cranial nerves.
A complete MRI spinal cord survey is required to iden-
tify tumors within the spine. The use of spine screening is
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
among NF2 specialty centers. We recommend repeat test-
ing at 6 months and then yearly testing consisting of an
MRI of the head and spine, neurology examination, and
audiometric testing. Once the growth rate from the
tumors has been determined, some of these tests may be
spread out over time. Spinal tumors tend to be very slow-
growing and, once diagnosed, may be imaged every 1 to 5
years. The potential for new tumor formation exists espe-
cially in patients with severe disease, and it is important
that this information be conveyed to the NF2 patient so
that comprehensive follow-up may occur.
Genetic Testing
Identification of the NF2 gene on chromosome 22 has made
genetic testing possible. It is recommended that patients with
NF2 see a genetic counselor to discuss the hereditary conse-
quences of this disease. Genetic blood screening is able to
identify the defect on the NF2 gene in approximately 70%
to 75% of patients with a known diagnosis of NF2. If the
defect is identified, then potential family members may be
screened. If the gene is not identified, then blood screening
of family members can be performed. The use of blood
screening for patients without a diagnosis or with a suspected
diagnosis of NF2 is not recommended. New mutations in
patients with mild presentation are most likely missense
mutations, which are difficult to identify by genetic testing.
SUMMARY
Care of the NF2 patient requires knowledge of all tumors
and symptoms involved with the disorder. The role of the
neurotologist in this care is determined by the specialty
center. It is recommended that patients receive care in a
center with expertise in NF2.
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 Chapter
Meningiomas of the Posterior Fossa
and Skull Base
47 Outline
Ameet Singh, MD History
Epidemiology
Samuel H. Selesnick, MD
Etiology
Radiation
Trauma
Gender
Viruses
Molecular Pathogenesis
Pathology
Gross Pathology
Microscopic Pathology
Grade I Meningioma
Histopathology
Grade II Meningioma
Histopathology
Grade III Meningioma
Histopathology
Immunohistochemistry
Diagnosis
Audiovestibular Testing
Radiology
Plain Radiography
Angiography
Computed Tomography
and Magnetic Resonance
Imaging
General Surgical Principles
Preoperative Considerations
HISTORY
The term meningioma was proposed by Harvey Cushing
in 1922 to describe a benign intracranial tumor of the
meninges.1 Prior to this historic naming, the nomenclature
surrounding this tumor had been shrouded in controversy.
The uncertainty involving the meningioma’s cell of
origin had produced a plethora of descriptive names—
meningoexothelioma, endothelioma, mesothelioma, and
arachnoidal fibroblastoma to name just a few.2 To elimi-
nate confusion, avoid a commitment to a histologic origin,
and coalesce several pathologic tumor types arising from
different locations, Cushing coined the term meningioma.
This was followed by a defining manuscript on meningiomas
by Cushing and Eisenhardt in 1938, setting the tone for
future investigations of this tumor.3
Acknowledgment: The authors wish to thank Marc Edgar, MD, for
supplying the histopathologic material and for his comments on that
section.
792
Posterior Fossa Meningiomas Origin and Classification
Cerebellopontine Angle Clinical Presentation
Meningiomas Imaging
Introduction Surgical Approach
History Surgical Management
Epidemiology Jugular Foramen
Origin Meningiomas
Classification Introduction
Clinical Presentation Classification
Diagnosis Clinical Presentation
Surgical Management Diagnosis
Complications Surgical Approach
Internal Auditory Canal Surgical Management
Meningiomas Foramen Magnum
Clival and Petroclival Meningiomas
Meningiomas Introduction
Introduction Epidemiology
Origin and Classification History and Classification
Extension Clinical Presentation
Clinical Presentation Diagnosis
Diagnosis Surgical Approach
Preoperative Considerations Surgical Results
Approach Selection Hearing Preservation
Surgical History Facial Nerve Preservation
Resection Recurrence
Mortality and Quality of Life Radiation Therapy
Meckel’s Cave Meningiomas
Epidemiology
Meningiomas are thought to have been present as far
back as the prehistoric era, as demonstrated by hyperosto-
sis found in the skulls of the pre-Colombian Incas from the
Peruvian Andes.4 The first description of a meningioma,
however, was noted by a Swiss physician, Felix Plater, in
1614. He described a tumor as “a round fleshy tumor, like
an acorn … hard and full of holes and … as large as a medium
sized apple … covered with its own membrane … free of all
connections with the matter of the brain.”5 Although the
first illustrations of a meningioma were published in 1730,
the earliest work that dealt exclusively with these tumors
was written in 1774 by Antoine Louis in Mémoires de l’
Academie Royale de Chirugie. In his manuscript, Louis named
them tumeurs fongueuses de la dure-mere, or fungoid tumors
of the dura mater.6 Virchow, who noted the presence of
granules in meningiomas named them psammomas (sandlike
tumors) in 1859, and considered them akin to sarcomas.7
Golgi, on the other hand, named them endotheliomas in
1869, indicating a more benign histology.8 Several names

were used to describe these tumors even after Cushing’s
Cavendish lecture in 1922.
The first known radiologic account of a meningioma was
written by Mills and Pfahler in 1902.9 This was followed by
several similar reports, including one by Heuer and Dandy in
1916. They described the radiographic findings in 100 brain
tumors, 9 of which were meningiomas.10 Ventriculography,
a technique described by Dandy in 1918, although slowly
adopted, marked a significant improvement in intracranial
tumor localization and diagnosis. Skull radiographs and cere-
bral angiography also aided in the diagnosis of brain tumors
in the first half of the century. In addition, the development
of sensitive film improved radiographic imaging by replac-
ing glass plates and decreasing the time of exposure. The
advent of computed tomographic (CT) scanning in the
mid-1970s followed by magnetic resonance imaging (MRI)
with contrast agents, diffusion weighted imaging, and fluid
attenuated inversion recovery sequences have greatly
improved the preoperative diagnosis, therapeutic planning,
and surgical outcomes of meningiomas.
The surgical removal of a meningioma was first attempted
in 1743 by Heister, a German surgeon from Helmstead,
Germany. He applied a caustic of lime juice to a menin-
gioma in a 34-year-old Prussian soldier who subsequently
developed an infection and died. One of the first successful
meningioma operations was performed by Zanobi Pecchioli,
an Italian surgeon who extracted a right sinciput menin-
gioma in 1835. The patient was well at 30 months follow-
ing the operation. In 1887, William Keen, a pioneer of
American neurosurgery, was the first to successfully
remove a meningioma in the United States. Using metic-
ulous aseptic technique in a 2-hour operation, he extracted
an 88-g, left frontotemporal tumor from a 26-year-old car-
riage maker. The patient, who had a history of head trauma
at the age of 3 and presented with headaches, seizures, and
partial blindness, recovered and lived over 30 years after
the operation. The turn of the century marked an
improvement in the outcome of neurosurgical procedures
primarily due to aseptic principles, localization of cerebral
function, and better surgical techniques.4
EPIDEMIOLOGY
A review of six large neurosurgical series accounting for
18,171 tumors found meningiomas to constitute approxi-
mately 20% of all intracranial neoplasms.11 In 1938,
Cushing and Eisenhardt reported that 13.4% of 2203
brain tumors were meningiomas.3 Multiple series since
then have estimated meningiomas to comprise 13% to
26% of all primary brain tumors, with a total annual inci-
dence of approximately 6 per 100,000 people.12 These fig-
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-
giomas are benign lesions that remain asymptomatic dur-
ing life, they represent over 30% of incidental tumors
found at autopsy. In symptomatic patients, however, the
incidence for benign meningiomas is 2.3 per 100,000 and
0.17 per 100,000 for malignant meningiomas.13 In study of
the incidence of primary intracranial neoplasms in
Rochester, Minnesota, from 1935 through 1977, autopsies
Meningiomas of the Posterior Fossa and Skull Base 793
on subjects 55 years and older found meningiomas in
slightly more than 1%.14
Meningiomas are most commonly found in middle-aged
and elderly individuals, with a peak incidence in the sixth
and seventh decades of life. These tumors rarely occur in
children and show a marked female predominance, with a
female to male ratio of 3:2 or 2:1 in a majority of studies.12
This gender bias is reflected in the overall incidence for
meningiomas, which ranges from 2 to 7 per 100,000 in
women and from 1 to 5 per 100,000 in men.15 In males, the
overall age-adjusted incidence rate of cases diagnosed before
death was 8.3 per 100,000 population per year, which
included a rate of 1.2 for meningiomas. Among females,
the overall rate was 10.1, which included a rate of 2.6 for
meningiomas.14 The female preponderance seen only in
middle-aged patients has been attributed to the effects of
estrogen on meningioma growth and development.12
The incidence of meningiomas increases with age. In
one series of patients treated from 1950 to 1977 in
Rochester, Minnesota, where the postmortem examination
rate approaches 70%, approximately 69% of meningiomas
were diagnosed at autopsy. Long-term reports also suggest
that the incidence of meningiomas is increasing over
time.15 In addition, both an improved life expectancy and
better neuroimaging to detect asymptomatic meningiomas
may result in an increasing prevalence of meningiomas in
future epidemiologic studies.
Although the incidence of meningiomas is similar in most
countries, several series from Africa found that menin-
giomas accounted for anywhere from 24% to 38% of all
intracranial lesions.16 These studies also reported a male
rather than female predominance and found that 20% of
meningiomas occurred in the second decade of life.2 This
high incidence of meningiomas in Africa may be relative and
can be explained by a lower incidence of gliomas rather than
an absolute increase in meningiomas. However, a popula-
tion-based survey in Los Angeles, California, also reported
a higher incidence of meningiomas (3.1 per 100,000) in
African Americans than whites (2.3 per 100,000), thereby
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-
inance (71%) and present at a mean age of 10.9 years—
higher than that observed for other childhood brain
tumors. The incidence of intraventricular (17%), posterior
fossa (19%) locations is higher for childhood meningiomas
than their adult counterparts.18 Childhood meningiomas
are more likely to be malignant. In one study of 51 menin-
giomas in patients younger than 21 years of age, a higher
incidence of the papillary variant, a histologically aggressive
subtype, was observed. Approximately 24% of these tumors
were associated with neurofibromatosis type 2 (NF2).2
ETIOLOGY
Radiation
Although head trauma, viruses, and gender are all hypoth-
esized as causal factors in meningioma development,
radiation exposure is the only unequivocal risk factor
identified in the genesis of these tumors. In fact,
794 SURGICAL NEUROTOLOGY
meningiomas are the most common radiation-induced
neoplasms of the central nervous system (CNS). Radiation
is thought to introduce single- and double-stranded breaks
in deoxyribonucleic acid (DNA) strands. These errors,
when permanently incorporated into genes regulating the
cell cycle, may lead to tumor formation.19 Although, most
animal models have shown the induction of sarcomas and
gliomas with radiation, few have shown the development
of spinal meningiomas. An example can be found in the
rabbit model. When rodents are exposed to cobalt-60
implanted under the dura, meningiomas develop.20
Radiogenic meningiomas can be divided into two major
categories based on the dose of radiation administered: low-
dose are defined as less than 10 Gy radiation-induced menin-
giomas. They are discovered years after treatment of
nonneoplastic diseases of the head and neck such as tinea
capitis. High-dose is defined as less than 20 Gy radiation-
induced meningiomas that appear after treatment for head
and neck tumors, most frequently medulloblastoma in child-
hood. A third category, recently proposed, includes a small
group of meningiomas that were induced in patients sub-
jected to intermediate doses of radiation between 10 and
20 Gy to the head and neck, application of radium to the skin
for vascular nevi, or Thorotrast myelography (visualization of
the CNS using thorium dioxide, a radiopaque substance).20
The first case of a high-dose radiation-induced menin-
gioma was reported by Mann and colleagues in 1953. It
involved a 4-year-old boy who received 65 Gy to the orbit
for an optic nerve glioma. Four years after treatment, he
developed a histologically malignant, supraorbital menin-
gioma.21 Meningiomas developing in high-dose irradiated
fields have been described in the subsequent literature, but
only represent approximately 10% of radiation-induced
meningiomas.22 The overwhelming majority of these
meningiomas arise in patients treated with low-dose radi-
ation for tinea capitis (ringworm of the scalp). In a study of
10,834 children in Israel treated with radiation doses of 1 to
2 Gy for tinea capitis between 1948 and 1960, 19 patients
developed meningiomas. The average latency period from
radiation exposure to diagnosis was 20.7 years.15 Results
also showed that 89% of the meningiomas could be attrib-
uted to radiation exposure that these patients received dur-
ing childhood. A retrospective review of these children
revealed that the incidence of meningiomas in the irradi-
ated children was 4 per 10,000 compared with the inci-
dence of 1 per 10,000 observed in nonexposed subjects.18
Radiation-induced meningiomas are often multiple and
more likely to occur over the convexities. Eighty percent
of radiogenic meningiomas were found over the convexi-
ties compared with 46% of spontaneously occurring
meningiomas. The average patient age at presentation for
low-, moderate-, and high-dose radiation-induced menin-
giomas was 45, 32.3, and 34.2 years, respectively. The
average time interval from radiation exposure to tumor
discovery was 35.2, 26.1, and 19.5 years, respectively. In
general, increasing doses of radiation are associated with
shorter latency periods and a younger patient age at tumor
presentation.23 A female predominance, with a male to
female ratio of 1:1.2 and 1:1.6, was also found in moder-
ate- and high-dose radiation-induced meningiomas. Low-
dose radiation-induced tumors, however, were found to
have a male to female ratio of 1.2:1. This was attributed to
an overwhelmingly male predominance in individuals
treated with low-dose radiation for tinea capitis.20
Radiation-induced meningiomas present with an aggres-
sive histologic growth pattern: high cellularity, cellular
pleomorphism, and an increased number of giant cells.18 In
a study of seven radiogenic meningiomas identified at the
Mount Sinai Hospital, three were characterized as atypical.20
In another series of 10 high-dose radiation-induced menin-
giomas, 4 of 8 tumors examined histologically were con-
sidered atypical and had a high bromodeoxyuridine (BrdU)
labeling index. In general, radiogenic meningiomas follow-
ing low-dose radiation to the head have a high recurrence
rate of 18.7%, even after complete surgical removal.23
Trauma
Berlinghieri, an Italian surgeon from Pisa, Italy, was the
first to consider trauma as a cause of meningiomas in
1813.4 Although head trauma has been suggested as
another cause of meningiomas, the evidence for such an
association remains unconvincing. In a review of 295
patients by Cushing and Eisenhardt, 94, or 30%, had a
history of head trauma that appeared to be related to the
development of meningiomas. A scar, previous swelling, or
depressed fracture was noted in 24 of these patients, thus
supporting trauma as for a cause of meningiomas.3 Reports
of tumors associated with skull fracture lines, a retained
intracranial foreign body, and dural scarring have been
found in the literature.24 A recent case-controlled study of
189 women with meningiomas also found a higher
incidence of patient-reported trauma than either of the
control groups.18 In a 2002 population-based case-control
study of 200 case and 400 control subjects, Phillips and
coworkers found an increased risk of meningioma forma-
tion with head trauma. This statistically significant corre-
lation was found to be especially significant for head
trauma occurring 10 to 19 years prior to the diagnosis of
a meningioma.25 One theory suggests that release of
bradykinin, histamine, and arachidonic acid during trauma
may increase the permeability of the blood-brain barrier
(BBB), thereby allowing the passage of harmful substances
that may lead to the development of meningiomas.18
In 1971, Boldrey commented that, “It is certainly no
compliment to our civilization that a tumor more com-
monly encountered in women than in men should be
regarded to have trauma as a major etiologic factor.”16
Several studies have not supported an association between
head trauma and meningioma formation. In one such study
of 2953 patients at the Mayo clinic with a 29,859 person-
year follow-up, an increased risk of meningioma formation
was not found in individuals who sustained head trauma, a
skull fracture, or post-traumatic amnesia.26
Gender
The female predominance in patients with meningiomas
suggests a role for sex hormones in the growth and devel-
opment of these tumors. An association between breast
cancer and meningiomas, the presence of estrogen and
progesterone receptors on meningiomas, and evidence that
meningiomas increase in size during pregnancy further
support this hypothesis. A population-based case-control

study of adult brain tumors demonstrated a reduced
relative risk (RR) for meningiomas in postmenopausal
women (RR = 0.59; 95% confidence limits = 0.18 − 1.94).
Oophorectomy-induced menopausal patients also exhib-
ited a reduced relative risk for meningioma development
(RR = 0.12; 95% confidence limits = 0.01 − 1.30).18 Other
case-control studies have shown an increase in menin-
gioma size during pregnancy. The presence of estrogen
receptors in 30% of patients and progesterone receptors
in 70% of patients in a study of 330 meningiomas support
the theory that varying levels of estrogen may contribute
to meningioma growth.15
Viruses
Several types of adenoviruses, a few polyoma viruses, and
a subgroup of papovaviruses have produced CNS tumors
in laboratory animals. A papovavirus antigen, as well as BK
viral DNA, SV-40, and adenovirus DNA have been found
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
MOLECULAR PATHOGENESIS
The overwhelming majority of meningiomas are sporadic
tumors, but approximately 2% are hereditary and associ-
ated with a number of familial cancer syndromes.27 Most
of these hereditary tumors occur in association with NF2,
an autosomal-dominant disorder in which patients have a
propensity to develop multiple meningiomas, vestibular
schwannomas, and, infrequently, ependymomas. Approxi-
mately 35% of NF2 patients have meningiomas.28 Heredi-
tary tumors are also found with an increased frequency in
Werner’s syndrome, Gorlin’s syndrome, and Cowden’s syn-
drome. However, the association of meningiomas with these
syndromes is less well defined.12
Meningiomas were among the first solid tumors in
which a distinctive cytogenetic alteration was identified.
Abnormalities of chromosome 22 in human meningiomas
were discovered in 1972 and later verified in 61% to 80%
of all meningiomas.29 Early molecular studies reported
the loss of heterozygosity (LOH) for all sequences on
chromosome 22 in meningiomas. Soon thereafter, the
NF2 gene was located by linkage analysis on chromosome
22 and subsequently cloned. Recent studies have identified
mutations in the NF2 gene on the long arm of chromo-
some 22 as an important aberration in the development of
meningiomas. NF2 mutations are detected in approxi-
mately 30% to 35% of all meningiomas and 40% to 60%
of sporadic meningiomas.30,31 The majority of these muta-
tions are small insertions and deletions or nonsense
mutations, which alter splice sites and cause frameshifts
or create stop codons. These modifications alter the
production of a protein called merlin, which serves as a
structural link between the cytoskeleton and several
proteins in the cytoplasmic membrane.12 Merlin is thought
to be a tumor suppressor, so that when inactivated in
the mouse by targeted mutagenesis, a variety of malignant
tumors with a high rate of metastasis arise.32
Meningiomas of the Posterior Fossa and Skull Base 795
Although a majority of benign meningiomas exhibit a
diploid karyotype or monosomy 22, a significant number
have been found to harbor additional mutations. The loss of
additional chromosomes or hypodiploidity is associated
with progression of benign (grade I) meningiomas to atypi-
cal (grade II) or even to anaplastic (grade III) meningiomas.
This is in contrast to the hyperdiploidity encountered in the
progression toward increasing malignancy of most other
solid tumors.27 Atypical meningiomas often contain allelic
losses of chromosomes 1p, 6q, 10q, 14q, 17p, and 18q. The
above-mentioned aberrations as well as frequent losses of
chromosomes 6q, 9p, 10, and 14q are typically found in
anaplastic meningiomas. High-grade meningiomas are also
found to have chromosomal gains specifically for chromo-
somes 20q, 12q, 15q, 1q, 9q, and 17q.12 Demonstration of
these genetic and chromosomal alterations, specifically the
frequently observed deletion of chromosomes 1p and 14,
may lead to the establishment of a molecular diagnostic tool
for meningioma grading and prognostication.31
PATHOLOGY
Gross Pathology
Meningiomas are derived from arachnoidal cap cells, the
external layer of the arachnoid membrane. These tumors
are firm, rubbery, and well-circumscribed, with an uneven
nodular or smooth surface. Meningiomas can be differen-
tiated into three overall macroscopic appearances: the exo-
phytic tumor, the “en plaque” tumor causing expansion of
the meninges over a wide area, and a third variant associ-
ated with bony hyperplasia.22
Classically, meningiomas have a broad and firm attach-
ment to the dura. En plaque meningiomas are sheetlike
tumors that expand within the meninges. These tumors
are commonly associated with hyperostosis and frequently
seen at the sphenoid ridges. Irregular, dumbbell-shaped
meningiomas are observed to originate from the meninges
separating compartments of the cranial cavity. Examples
include falcine meningiomas that penetrate the falx and
occupy the frontal lobes and tentorial meningiomas that
may expand into both the posterior and middle fossae.2,22
The consistency of meningiomas is associated with their
intratumoral contents. Calcific psammoma bodies (often
found in smaller growths and spinal meningiomas) give
these tumors a characteristic “gritty” texture (Fig. 47-1).
Advanced mucoid or fatty degeneration, edema, and
necrosis can soften the consistency of a tumor. Occasion-
ally, tumors are fluctuant to palpation secondary to the
presence of cysts lying near the periphery. In addition,
osseous changes in meningiomas can also result from
metaplasia within the tumor.2,16,33
Meningiomas have a pinkish gray color, which changes
to grayish white after fixation in formalin. Recent or old
hemorrhages, which occur in highly vascularized tumors,
can cause a reddish brown discoloration. Also, lipid accu-
mulation in the cells may change the appearance of the
tumor to yellow.2,22
Significant changes to the surrounding parenchyma,
bone, and neurovascular structures can accompany menin-
gioma growth. Pressure atrophy of adjacent parenchyma,
796 SURGICAL NEUROTOLOGY
Figure 47-1. Large psamomma bodies are prevalent in this transitional
meningioma (H&E, ×200).
invasion of the venous sinuses, and encasement of intracra-
nial vasculature are not common findings. In contrast,
frank invasion of neural tissue; infiltration of arterial walls;
and extension into extracranial compartments such as the
pericranium, petrous bone, and orbit are rarely observed
(Fig. 47-2). Hyperostosis, an osteoblastic process at the
base of the tumor, is observed in approximately 25% of
meningiomas.34 Direct bony involvement and increased
subperiosteal bone formation secondary to reduced blood
supply are both thought to contribute to this phenomenon.
A recent study showed that meningiomas associated with
hyperostosis were found to have a threefold increase in
alkaline phosphatase.2
Microscopic Pathology
The enormous diversity of meningioma histology has
defied simple, well-integrated classification. In 1938,
Cushing and Eisenhardt were the first to propose an
Figure 47-2. Atypical meningioma with brain invasion. Note the many
well-defined nests of meningioma invading the bland neural tissue
(H&E, ×100).
Figure 47-3. Microcystic meningioma with prominent pale vacuoles
(H&E, ×200).
extensive histologic classification, which included nine
types and 22 variants.3 Since then, several additional
classification systems have been proposed. Controversy
persists because the histology of these tumors has gener-
ally shown poor correlation with tumor topography and
clinical behavior. However, overall histologic categoriza-
tion of these tumors has aided in determining their prog-
nosis. In addition, altered histologic changes in a recurrent
meningioma have been useful in identifying anaplastic
transformation.
In 1992, a landmark study of 1799 meningiomas from
1582 patients defined three histologic subtypes: classic,
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)
defines groups of meningiomas on the likelihood of recur-
rence and grade. Grade I tumors are benign and include
meningothelial, fibrous (fibroblastic), transitional (mixed)
(see Fig. 47-1), psammomatous, angiomatous, microcystic
(Fig. 47-3), secretory (Fig. 47-4), lymphoplasmacyte-rich,
Figure 47-4. Secretory meningioma features pseudopsamomma bodies that
exhibit epithelial differentiation (H&E, ×100).

Figure 47-5. Clear-cell meningioma is found most often in the posterior
fossa. The clear cells are filled with glycogen. Also note the long collagen
bundles in this section (H&E, ×100).
and metaplastic subtypes. These tumors constitute 90% of
meningiomas and have a low risk of recurrence and aggres-
sive growth. Grade II tumors are atypical and include the
atypical (see Fig. 47-2), clear cell (intracranial) (Fig. 47-5),
and chordoid (Fig. 47-6) variants. These tumors comprise
7% of meningiomas and are associated with a higher like-
lihood of recurrence and aggressive behavior. Grade III
tumors are anaplastic and include the rhabdoid, papillary,
and anaplastic (malignant) subtypes, as well as tumors
of any grade with a high proliferation index with or with-
out brain invasion. These aggressive tumors comprise
3% of meningiomas and have the greatest likelihood of
recurrence (Table 47-1).33
Grade I Meningioma Histopathology
Common Benign Subtypes
Meningothelial, fibrous, and transitional tumors are the
most common histologic subtypes of meningiomas.
Meningothelial tumors are characterized by uniform,
polygonal (arachnoid-like) tumor cells forming lobules
defined by thin collagenous septae. These cells have oval
nuclei with an even chromatin pattern that often show
central clearing secondary to glycogenation. Whorls and
TABLE 47-1. WHO Histopathologic Classification for Meningiomas
WHO Grade Incidence
Grade I—Typical Common
Rare
Grade II—Atypical
Grade III—Anaplastic
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.
Meningiomas of the Posterior Fossa and Skull Base 797
Figure 47-6. Chordoid meningioma may be confused with a chordoma
(H&E, ×400).
psammoma bodies are uncommon in these tumors but are
poorly formed when present. These tumors also have a
propensity to bleed.
Fibrous (fibroblastic) tumors are formed by predomi-
nantly spindle-shaped, fibroblast-like cells that form parallel
and interlacing bundles, rich in collagen and reticulin.
Whorls and psammoma bodies are infrequent, and
meningothelial features are often present.
Transitional (mixed) tumors contain features of both the
meningothelial and fibrous variants (see Fig. 47-1). Lobules
and fascicles are found in close arrangements. Tight con-
centric whorls and psammoma bodies are frequently seen
in this subtype.
Psammomatous tumors possess a plethora of psammoma
bodies, which may become confluent and form irregular
calcified and sometimes ossified masses. Occasionally, these
tumors are completely replaced with psammoma bodies.
They typically occur in the thoracic spine and are typically
seen in middle-aged women.
Angiomatous tumors contain blood vessels that are
dominant in the background of a typical meningioma. The
majority of blood vessels are small, thin-walled structures
and may obscure the histopathology of the tumor. Unlike
hemangiopericytomas, these meningiomas are not aggres-
sive tumors. The size of the meningiomatous vessels may
Recurrence/
Histologic Subtype Aggressiveness
Meningothelial, fibrous, transitional, Low
psammomatous, angiomatous
Secretory, microcystic, lymphoplasmacyte- Low
rich, metaplastic
Atypical, clear-cell, chordoid Low
Anaplastic, papillary, rhabdoid High
Tumors with high proliferation
index or brain invasion
798 SURGICAL NEUROTOLOGY
be helpful in distinguishing these tumors from vascular
malformations and capillary hemangioblastomas.
Rare Benign Subtypes
Secretory tumors are characterized by focal epithelial
differentiation with glandular lumina containing keratin
and staining potential for periodic acid-Schiff (PAS) and
carcinoembryonic antigen (CEA) (see Fig. 47-4). The
surrounding meningothelial cells are positive for cytoker-
atin. These tumors may be associated with marked peritu-
moral edema.
Microcystic tumors consist of cells with elongated
processes on a loose mucinous background (see Fig. 47-3).
This histology gives the tumor an appearance of small
cysts. Pleomorphic cells are abundant in this subtype.
Lymphoplasmacyte-rich tumors are a rare subtype
composed of extensive chronic inflammatory cells on a
background of meningothelial cells. This variant is associ-
ated with polyclonal gammopathies or anemias. Diagnosis
of these meningeal-based hematologic conditions must be
considered with this tumor.
Metaplastic tumors exhibit prominent focal mesenchymal
differentiation. Meningothelial, fibrous, and transitional
tumors may show osseous, cartilaginous, lipomatous,
myxoid, and xanthomatous changes.
Grade II Meningioma Histopathology
Atypical meningiomas have greater than or equal to
4 mitoses per high-power field (hpf) and satisfy three
or more of the following: increased cellularity, small cell
population with an increased nuclear-to-cytoplasmic
ratio, prominent nucleoli, uninterrupted patternless or
sheetlike growth, foci of spontaneous or geographic necrosis,
and brain invasion (Fig. 47-7). These tumors have moder-
ately high proliferation-associated antigen-labeling (MIB-1)
indices and correlate with a higher rate of recurrence.
Clear-cell tumors are characterized by patternless
polygonal cells with few classic meningioma features (see
Fig. 47-5). The tumor cells are PAS-positive and have a
clear and vacuolated cytoplasm, rich in glycogen. The
cerebellopontine angle (CPA) and cauda equina are
Figure 47-7. Darkly staining atypical mitotic nucleii (H&E, ×400).
preferred locations for these tumors which are associated
with aggressive behavior, particularly when discovered at
these sites.
Chordoid tumors consist of lobules of eosinophilic,
vacuolated chordoid cells in a myxoid matrix (see Fig. 47-6).
These lesions can mimic the histologic appearance of
chordomas, with the exception of the following features:
absence of typical physaliphorous cells, whorl formation,
positive staining for vimentin and epithelial membrane
antigen (EMA), and absence of cytokeratin staining.
Chronic inflammatory cells are often present, and peritu-
moral and intratumoral lymphoplasmacellular infiltrates
are prominent in younger patients. Few of the patients
with these tumors have hematologic conditions, such as
Castleman’s disease. These tumors are also associated with
a high rate of recurrence after a subtotal resection.
Grade III Meningioma Histopathology
Anaplastic meningiomas have more than 20 mitoses per
hpf and features of frank malignancy which include
whorls, banding, onion skin features, an increased nuclear-
to-cytoplasmic ratio, increased cellularity, increased rate of
mitoses, micronecroses, increasing proliferation fraction
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
cytology can be similar to that of sarcomas, carcinomas, or
malignant melanoma.
Papillary tumors are a rare meningioma variant that
tends to occur in children. They are aggressive lesions
defined by perivascular psuedopapillary pattern formation
in at least part of the tumor. Local and parenchymal inva-
sion, tendency to recurrence, and metastases occur in 75%,
55%, and 20% of these lesions, respectively.36
Rhabdoid tumors are a recently described entity
composed of rhabdoid cells with the following features:
rounded cells, eccentric nuclei, prominent nucleoli, and
inclusion-like eosinophilic cytoplasm composed of whorled
intermediate filaments. These cells may be present only
at the time of recurrence. These tumors display anaplas-
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
between these tumors.37

Staining for S-100, a nuclear antigen, can be used to
distinguish between schwannomas and meningiomas.
Strong positive staining for S-100 is seen in 100% of
schwannomas, whereas a patchy and weak reaction is
found in only 41% of meningiomas.22 Secretory menin-
giomas strongly stain for CEA, an immunostain primarily
seen in the pseudopsammoma bodies of these lesions.
These tumors are also known to be associated with an
elevated circulating level of CEA. Cytokeratin positivity is
also often seen in secretory meningiomas, with far less
staining seen in the meningothelial and transitional
subtypes. Overall, approximately 20% of meningiomas
stain for cytokeratins, and 4% stain for CEA.12,22
DIAGNOSIS
Audiovestibular Testing
Audiovestibular findings have been studied in only a few
series of CPA meningiomas. Basic audiometric data,
primarily in the form of pure tone average (PTA) and
speech discrimination scores (SDS), have not been
reported in a majority of patients. Audiometric brainstem
response (ABR) and electronystagmography (ENG) have
been studied in even fewer patients. Although abnormal
audiologic findings were found in patients harboring CPA
meningiomas, none of these series made any definitive
conclusions on the topic. Furthermore, only a small
percentage of patients in each series underwent compre-
hensive audiovestibular testing and therefore were perhaps
not representative of the entire series. Since CPA and IAC
meningiomas have no clear and distinctive audiometric
features, most authors agree that audiovestibular testing is
a useful but not necessary adjunct to the radiologic inves-
tigation of these tumors.38,39
In a 1997 series of 25 patients, Baguley and colleagues
reported normal hearing in 5 of 25 (20%) patients, a low-
frequency hearing loss in 3 of 25 (12%), a flat loss in 9 of
25 (36%), a midfrequency hearing loss in 3 of 25 (12%),
and a profound hearing loss in 5 of 25 (20%). In contrast,
the authors found normal audiometry in only 1.9% of 361
patients with vestibular schwannomas.38 Furthermore,
none of the patients with CPA meningiomas exhibited the
characteristic high-frequency hearing loss seen in vestibu-
lar schwannomas.34,38 Granick and coworkers in a study
of 32 patients, of which audiometric data was available
for only 23, reported normal hearing in 6 of 32 (26%), a
mild hearing loss (20 to 45 dB) in 2 of 32 (9%), a moder-
ate hearing loss (50 to 80 dB) in 7 of 32 (30%), and a pro-
found hearing loss (>85 dB) in 8 of 32 (35%) patients.40 An
abnormal SDS was noted in approximately 50% of
patients.38,39 In 1985, Laird and colleagues noted an abnor-
mal SDS in 57% of patients, a slightly higher percentage
than in other series. The authors of this series reported a
median SDS of 76%, compared with 8% for vestibular
schwannomas.41
ENG abnormalities have been found in over 90% of
patients with CPA meningiomas. Laird and colleagues
reported decreased vestibular responses in 9 out of 10
patients, and Granick and coworkers noted the same in 19
of 20 (95%) patients.40,41 Baguley and colleagues found a
Meningiomas of the Posterior Fossa and Skull Base 799
reduction in the caloric response in 12 of 18 (67%) patients,
and Aiba and coworkers noted the same in 9 of 12 (75%)
cases.38,42 Baguley and colleagues also found no significant
relationship between tumor size and abnormal results for
audiometry, speech audiometry, and caloric testing.38
The ABR is a useful noninvasive screening technique for
diagnosing lesions of the CPA and IAC. Not surprisingly,
ABR better reveals evidence of retrocochlear pathology in
CPA meningiomas than does basic audiometry.43 Baguley
and colleagues noted an abnormal ABR in all 18 patients
tested. This abnormal result was also found in patients
who had exhibited a normal PTA and SDS. This led the
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
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-
ing on the auditory pathway.38 In a study comparing the
clinical characteristics of rare CPA lesions, Aiba and
coworkers noted an abnormal ABR in 8 of 10 (80%) CPA
meningiomas. The authors found a relatively low frequency
of ABR and ENG abnormalities in CPA meningiomas
compared with vestibular schwannomas.42 In 1995, Hart
and Lillehei reported an abnormal ABR in five of seven
(71%) cases.39 Granick and colleagues and Laird and
coworkers found the same in 100% of their patients.40,41
Although ENG and ABR testing is useful, they are neither
specific nor sensitive in discriminating meningiomas from
vestibular schwannomas or any other CPA tumors.
Radiology
The first radiologic diagnosis of a meningioma was made
with plain radiography by Mills and Pfahler in 1902. The
tumor was localized with a radiograph that showed a
shadow between the frontoparietal suture and posterior
meningeal artery.9,44 A more consistent and methodical
approach to the radiologic diagnosis of meningiomas,
using plain radiography, was introduced by Sosman and
Putnam in 1925. Their analysis of 95 intracranial menin-
giomas showed that 49% of these tumors had characteris-
tic changes on radiographs. These alterations included
sclerosis, bone destruction, spicule formation, enlarged
vascular channels, calcification, and pneumosinus dilatans, a
dilation of the paranasal sinus.45 Ventriculography and
pneumoencephalography, two diagnostic techniques intro-
duced by Dandy in 1918 and 1919, respectively, enhanced
the localization of meningiomas. However, tumor diagno-
sis of meningiomas with these techniques remained elusive.
For example, differentiating extra-axial from intra-axial
lesions was difficult in the absence of additional findings,
such as hyperostosis or increased vascularity.44,46
Cerebral angiography was initially described by Moniz
in 1927. Two years later, he reported the first angiographic
features of meningiomas with Pinto and Lima. An extensive
characterization of the angiographic features of 125 tumors,
20 of which were meningiomas, was conducted by List
and Hodges in patients undergoing cerebral angiogra-
phy. The development of computed tomography (CT)
by Hounsfield in 1973 and subsequent introduction of
intravenous (IV) contrast agents improved the extra-axial
800 SURGICAL NEUROTOLOGY
localization, detection, and characterization of menin-
giomas. Soon thereafter, MRI was pioneered by Lauterbur
and offered extraordinary anatomic detail using magnetic
field gradients and multiplanar imaging. The development
of IV contrast agents further enhanced the diagnosis of
brain tumors, making MRI a superior technique for
meningiomas.45,46
Plain Radiography
The advent of newer imaging modalities such as CT
and MRI have made plain radiography obsolete for the
diagnosis of meningiomas. However, characteristic find-
ings of meningiomas found incidentally on a radiograph
taken for different reasons can lead to a tumor diagnosis.47
X-ray films are also helpful in defining the extent of a pre-
vious surgical procedure or in planning a surgical approach
in a patient who previously underwent a craniotomy or
metallic cranioplasty.11 Hyperostosis, the most common
finding of meningiomas on plain radiograph, has an inci-
dence of 38% to 61%. It is most easily visualized when it
involves the cranium or sphenoid bone. Blistering, a
pathognomonic finding in meningiomas of the paranasal
sinuses, is defined by hyperostosis of the planum sphe-
noidale, as seen on plain radiography.47
Increased vascularity is the second most common finding
for meningiomas on radiographic imaging. A widening of
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-
ciated with meningiomas. However, this feature may also
be seen with arteriovenous malformations and prolonged
carotid occlusive disease.48 Prior to the introduction of CT,
calcification was seen in 3% to 18% of meningiomas on
plain radiography at initial presentation. It is a rare finding
and usually presents in a diffuse, fine, or nodular pattern.47
Angiography
Cerebral angiography is often used for the surgical plan-
ning and preoperative embolization of a meningioma.
Although imaging techniques such as CT and MRI have
better sensitivity and specificity, angiography is still used in
circumstances of diagnostic uncertainty. Meningiomas
classically have a “sunburst” or “spokeswheel” appearance
on angiography. This pattern represents a radial arrange-
ment of meningeal vessels that enter at the hilum or dural
attachment of the tumor. Dural branches supplying blood
to the tumor are large, tortuous vessels that usually arise
from meningeal branches of the external carotid system.
Typically, the blood supply arises from the vasculature that
perfuses the anatomic location where the tumor develops.
Large meningiomas may also parasitize pial vessels to
supply the periphery of the tumor. A delayed capillary
blush is also a classic angiographic feature of a menin-
gioma that is caused by the contrast that persists into the
late venous phase. Meningiomas of the CPA and skull base
often stain poorly on angiography.48,49
Preoperative planning for the resection of a meningioma
may be enhanced by information gleaned from angio-
graphic features of the tumor. Angiography can provide
information about the size and location of arterial feeders,
nature of the arterial blood supply (dural, pial, or mixed),
overall tumor vascularity, patency of vessels, venous drainage
pattern, and the degree of displacement or encasement of
arteries and veins. Definitive knowledge of the vasculature
involved with the meningioma can greatly aid its resection.
Furthermore, preoperative embolization can decrease the
overall vascularity of the tumor to diminish operative
blood loss and facilitate resection of the tumor.49
Cerebral angiography was extensively employed in the
past to make the diagnosis of a meningioma. In a study
addressing the utility of angiography, this technique made
a specific diagnosis of a meningioma in 83% of cases; it was
uncertain or negative in a mere 8% of patients.48 Yet, some
of the literature argues that the pattern of tumor vascular-
ity is nonspecific for meningiomas and does not help to
differentiate between other hypervascular tumors.50 Imaging
techniques such as MRI, and more recently magnetic reso-
nance angiography (MRA), offer a safe, noninvasive, and
highly sensitive and specific modality for the diagnosis of a
meningioma. Although, a recent meta-analysis of cerebral
angiography found a 0.07% risk of a permanent neurologic
deficit and a 0.6% risk of an adverse non-neurologic
outcome, the complication rate remains higher than for
the noninvasive imaging technologies available today.49
Angiography is also seldom requested by surgeons for the
preoperative planning of small- or moderate-sized tumors,
which can be removed without significant blood loss.
Computed Tomography and Magnetic
Resonance Imaging
Detection
CT and MRI have not only improved the detection and
diagnosis of meningiomas, but also enhanced the surgical
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
imaging technique for several reasons, including its capac-
ity to identify intracranial processes (hemorrhage, hydro-
cephalus, and mass effect) requiring urgent therapeutic
intervention and its ability to exclude nonneoplastic
pathology. CT also remains an excellent initial screening
tool, given its wide availability in hospitals, good tolerance
to patient motion, easier access to acutely ill patients
during imaging, and lower cost.48,50
Initial studies comparing CT with MRI showed that
small tumors with minimal mass effect or edema were
more easily detected with CT. Approximately 10% of
lesions were found to be undetectable by MRI and were
easily visualized by CT. However, the introduction of IV
contrast agents such as gadolinium diethylenetriamine
pentaacetic acid (Gd-DTPA) enhanced the ability of MRI
to detect even the smallest tumors.47 Recent improvements
in the magnetic field strength, acquisition time, slice thick-
ness, and software associated with MRI systems have
reduced the diameter of detectable intracranial lesions to
less than 3 mm with or without contrast enhancement.49
Excellent delineation between anatomic structures, multi-
planar imaging, and three-dimensional computer-generated
reconstructions have made MRI the premier diagnostic
imaging tool.

Morphology
The morphology of intracranial lesions, particularly menin-
giomas, plays an important role in their radiologic diagnosis.
Meningiomas usually present as well-circumscribed, extra-
axial, sessile lesions with a broad dural attachment. These
tumors are usually smooth, but are often lobulated when sit-
uated adjacent to a rigid anatomic structure. Pedunculated
lesions commonly originate from the edge of the falx and
have a narrow dural base. En plaque meningiomas are
uncommon lesions that usually present at the base of
the brain as a narrow band of tissue. Even rarer are intra-
ventricular meningiomas, which present in the lateral
ventricles, and fissural meningiomas, which are completely
surrounded by brain parenchyma and often mistaken for
intra-axial tumors.47
Since most meningiomas are primarily extra-axial,
differentiating between intra-axial and extra-axial lesions is
an important clue in their diagnosis. Multiplanar imaging
and the elimination of beam-hardening artifact on MRI
have improved the visualization of the dural base of any
lesion, regardless of its location. Coronal and parasagittal
imaging can differentiate superficial intra-axial lesions
from meningiomas of the high convexity, tentorium, and
parasellar region. Metastatic lesions, low-grade astrocy-
tomas, and exophytic masses may also grow intra-axially, and
spread along the dural surface, thereby mimicking extra-
axial lesions.47
An interface seen between the lesion and cortex is
another morphologic feature helpful in establishing an
extra-axial location. Displaced arteries and veins, including
pial vessels found on the periphery of meningiomas, are
hypointense on all pulse sequences. T1-weighted images
(T1WI) best identify the interface between a hypointense
tumor and hyperintense edema surrounding the lesion.
Arachnoid cysts, which often overshadow meningiomas,
have a low density on CT, a low intensity on T1WI, and a
high intensity on T2-weighted images (T2WI). White
matter buckling and “arcuate bowing of adjacent cortical
gyri in an accordian-like manner” also suggest an extra-
axial tumor.48 Although an extra-axial location may be
appreciated on CT, MRI is better at perceiving subtle mor-
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
15% of meningiomas display atypical densities and inten-
sities. Most of these meningiomas are hyperdense on CT
and hypointense on MRI. Less than 5% of meningiomas
Meningiomas of the Posterior Fossa and Skull Base 801
demonstrate mild to moderate hypodensity on CT,
hypointensity on T1WI, and hyperintensity on T2WI.47
Flocculent and peripheral curvilinear hyperdensities
can be seen in 20% to 30% of meningiomas on CT.47
Approximately 84% of meningiomas exhibit a mottled or
speckled heterogeneity on T2WI. This heterogeneity is
suspected to be secondary to tumor vascularity, cysts, and
calcification. In addition, hypointense punctate or curvi-
linear shapes representing tumor vessels can be visualized
on T1WI and T2WI.48 A majority of meningiomas
enhance brightly with Gd-DTPA. Dense calcification and
cystic lesions present in some meningiomas prevent their
homogeneous enhancement.47 The enhancement with
Gd-DTPA is more sensitive than that seen with iodinated
contrast on CT. Thus, MRI is the preferred imaging tech-
nique for visualizing small or multiple meningiomas, the
latter most often seen in patients with NF2.46,50
Contrast enhancement of meningiomas with Gd-DTPA
on MRI often reveals a “dural tail,” a flat layer of enhanc-
ing dura that extends a few millimeters away the base of
the lesion (Fig. 47-8). Although, once thought to be
pathognomonic for meningiomas, recent studies have
shown its presence in a number of lesions, including super-
ficial intra-axial masses, dural metastases, and vestibular
schwannomas. Dural tails have also been found in inflam-
matory processes, as well as aneurysms. Pathologic
examination and electron microscopy have concluded that
although a dural tail may indicate tumor infiltration, it
could also represent a nonneoplastic reactive change.
These could include hyperemia, tissue proliferation,
hypervascularity, increased permeability to contrast, or
dilation of dural vessels.46,48,49 In one histopathologic study
of 54 patients with meningiomas, 31 (57%) were observed
to have a meningeal tail on MRI. Tumor invasion was
detected in 20 (65%) patients, thereby arguing for wide
resection of the tumor to reduce the risk of recurrence.52
Bone Changes
Changes in adjacent bone are seen in 15% to 25% of
meningiomas. These changes can present as a mild “reactive
process” or direct tumor infiltration of the bone. Minor
Figure 47-8. Axial T1WI postgadolinium MRI scan revealing a small
meningioma on the posterior surface of the porus acousticus, demonstrating
a dural tail found at the transition of the tumor mass with the normal
meninges posterior to it.
802 SURGICAL NEUROTOLOGY
bony changes on CT include minimal hyperostosis, blister-
ing, and mild erosion secondary to direct pressure of the
tumor or dilated vasculature. Gross invasion of bone is
marked with striking hyperostosis or bone destruction.48
Extensive hyperostosis is associated with larger menin-
giomas, especially those located near the sphenoid bone.
Hyperostosis may also be the principal manifestation of a
en plaque meningioma.49 Osseous changes associated with
meningiomas are better appreciated on CT with the use of
bone windows, specific settings used to enhance the visu-
alization of these findings.48
Subtle bony changes are better delineated by CT than
MRI. CT is therefore the favored imaging modality for this
purpose. However, severe hyperostosis, bone destruction,
tumor invasion, and obliteration of the diploic spaces can be
distinguished on MRI. Tumor infiltration is best appreci-
ated on T1WI as hypointense signals taking the place of the
normally hyperintense fat in the bone marrow. Hyperostosis
is also seen as a hypointense signal on T1WI.46
Calcification
Calcification is present in 15% to 20% of meningiomas
(Fig. 47-9). It is easily visualized on noncontrast CT and is
found in a variety of forms: punctate (psammomatous), dif-
fuse, rimlike, chunky, or nodular.48 Punctate calcifications
are most common and give the meningioma a fine speck-
led appearance on CT. Central areas of hyperdensity often
represent dense calcifications, which can prevent contrast
enhancement of a meningioma.51 Calcification, often con-
fused with hemorrhage, can be differentiated with density
measurements or by studying bone windows.48 Although
small punctate or rimlike calcifications are undetectable on
MRI, large nodular calcifications can be easily visualized.
Calcium is usually hypointense on T1WI and T2WI, with
the latter being more sensitive in the detection of
calcium.46
Figure 47-9. Axial CT scan of the head revealing a calcified left petroclival
meningioma.
Edema
Peritumoral edema is found in 46% to 92% of menin-
giomas.48 Approximately 66% of patients with symptomatic
meningiomas are estimated to have a varying degree of
surrounding edema.49 The amount of peritumoral edema
is variable and can range from unremarkable to massive.
On CT, edema appears as a low-density area surrounding
the lesion. On MRI, edema is hypointense on T1WI and
hyperintense on T2WI. T2WI is the preferred diagnostic
modality for detecting and measuring the amount of peri-
tumoral edema.48 The cause of edema formation remains
uncertain, although, blood vessels within meningiomas are
known to have endothelial fenestrations. Gap junctions are
also known to exist between vessels.11 Venous obstruction,
although never proven, has also been suggested as a possi-
ble cause of edema formation.51
Tumor size, location, histology, blood supply from pial
arteries, degree of parenchymal infiltration, and duration
of symptoms have been shown to correlate with the pres-
ence of peritumoral edema.11,49 Convexity, falx, parasaggi-
tal, sphenoid wing, and frontobasal meningiomas are often
associated with edema. In contrast, suprasellar, posterior
fossa, and intraventricular meningiomas have little to no
edema. Meningothelial and transitional meningiomas are
also known to be associated with peritumoral edema.48
Secretory meningiomas have also recently been shown to
have a significant amount of surrounding edema. Although
numerous studies have established factors correlating with
the presence and amount of edema, other studies have
found few, if any, associations.12
Vascular
Displacement, encasement, narrowing, or occlusion of
vascular structures can be caused by meningiomas.
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
high attenuation on T2WI.48 Necrotic areas do not enhance
on contrast administration. Occasionally, meningiomas

undergo complete necrosis and present as ring-enhancing
lesions, thereby widening the differential to include
abscesses, thrombosed aneurysms, and intra-axial tumors,
in particular glioblastomas. Morphologic features can help
to distinguish meningiomas from many intra-axial lesions.
Hemosiderin deposited in the walls of aneurysms seen
with MRI can also help to differentiate between these vas-
cular malformations and meningiomas.51
Hemorrhage is seen in 5% of meningiomas. The imag-
ing characteristics vary depending on the age of the
blood.48 On CT, an acute hemorrhage is isodense or
hyperdense to surrounding tissue and may be confused
with calcification. Two to 3 weeks later, after liquefaction
of the clotted blood, hemorrhage appears isodense to brain
parenchyma and after 4 weeks is hypodense to surround-
ing tissue.51 On MRI, hemorrhage appears hyperintense
on T1WI and hypointense or hyperintense on T2WI.
Multiple bleeds over days may produce variable densities
and intensities. In addition, massive hemorrhage into the
subdural or subarachnoid spaces can complicate or obscure
the diagnosis.47
Cystic meningiomas represent only 2% to 4% of all
meningiomas. Cysts present as nonenhancing, hypodense
areas on CT. On MRI, they are hypointense on T1WI
and hyperintense on T2WI. Cysts on the periphery of
the tumor may represent secondary arachnoid cysts.
The differential diagnosis of cystic meningiomas also
includes hemangioblastomas, gangliogangliomas, and cys-
tic gliomas.48 Diffusion weighted imaging (DWI) is a tech-
nique that may help to differentiate between solid and cystic
tissue. Cystic areas have a low signal intensity as opposed
to tissue, which has a high signal intensity on DWI.
Lipomatous degeneration, which involves replacement of
tissue with fat, is a rarely found in meningiomas. These
areas are hypodense on CT, hyperintense on T1WI, and
hypointense on T2WI.50
GENERAL SURGICAL PRINCIPLES
Skull base meningiomas pose significant surgical chal-
lenges due to their ability to invade dura and bone, compress,
and encase critical neurovascular structures. The decision
to operate is at least partially based on the balance between
the morbidity of tumor removal versus the natural history
of the untreated tumor. The anticipated risk of short-term
impairment must be weighed against the probability of a
similar or worse ultimate outcome if the surgery is not
performed. The patient’s lifestyle and occupation should
also be taken into account.53 The surgeon should discuss
the surgical goal, expected results, and anticipated
morbidity with the patient. If the patient is asymptomatic
with a small tumor and a surgical intervention is deferred,
the patient should be available for regular clinical and radi-
ologic follow-up and understand the risks of deferring
treatment.54
Patient factors as well as tumor characteristics play a
significant role in predicting the morbidity of a surgical
procedure. A patient’s age, estimated life expectancy, pre-
operative Karnofsky performance score, neurologic status,
and associated medical conditions such as uncontrolled
hypertension, diabetes, bleeding disorder, or infection
Meningiomas of the Posterior Fossa and Skull Base 803
influence the decision for surgery.11,34 Minimal morbidity
from a surgical procedure is expected in a young patient
with a good functional status and minimal or no comor-
bidities. The size, location, vascularity, sinus involvement,
and extent of a tumor are important factors in determining
its resectability. Large vascular meningiomas infiltrating into
the dura, bone, and sinuses, as well as those compressing the
neurovasculature, are difficult lesions to resect and are
expected to cause considerable impairment. In general,
young symptomatic patients with a good functional status
afflicted with a growing tumor causing progressive neuro-
logic symptoms are the most suitable candidates for surgery.
Patients with a strong preference for removal of a tumor
that is likely to become symptomatic in the future are also
good surgical candidates.55
The basic goals of any surgery are to prolong life and
preserve function. To meet these objectives, a surgical pro-
cedure must maximize tumor resection without causing
damage to the neurovasculature or intra-axial structures.56
The decision to perform a total or subtotal resection rests
once again on the functional status of the patient and
tumor characteristics. A complete resection of the tumor
including a dural margin and removal of any infiltrated
bone remains the objective. Petroclival meningiomas,
especially those with cavernous sinus involvement, are the
most difficult to completely resect. In the event that only a
subtotal resection is feasible, the goals must be modified to
entail the procurement of an accurate tissue diagnosis and
reduction of the mass effect caused by the lesion.53 Prior to
surgery, the surgeon must select the approach, review the
relevant intracranial anatomy, and study the images dis-
playing the relationship of the neurovascular structures
with the tumor. The approach must be selected not only
based on the anatomic location of the tumor but also the
individual patient. Elderly patients with multiple comor-
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
Unexpected and unforeseen intraoperative emergencies
such as brain swelling, damage to venous sinuses, and
significant arterial bleeding must be anticipated for every
surgical procedure.11
The relationship of a meningioma to the adjacent cranial
nerves is much less predictable than for a vestibular
schwannoma. To optimize the functional outcome, it is
important for the surgeon to understand the anatomic
relationship between the cranial nerves and the tumor. A
premeatal (anterior to the IAC) meningioma displaces the
facial nerve over its posterior aspect. In contrast, the most
common course for the facial nerve in the case of a vestibu-
lar schwannoma is anterior. In the case of CPA menin-
giomas, CN VII often lies between the surgeon and the
meningioma, making it more vulnerable to surgical
trauma. Retromeatal (posterior to the IAC) meningiomas
displace the facial nerve anteriorly, thereby placing the
tumor directly between a surgeon’s instruments and the
cranial nerve.57,58
Hearing preservation should be attempted with the sub-
occipital/retrosigmoid or petrosal approach for all patients
with retromeatal meningiomas with good preoperative
hearing. The suboccipital/retrosigmoid approach, in par-
ticular, provides good access for tumors located posterior
804 SURGICAL NEUROTOLOGY
to the porus acousticus with a minimal risk of significant
morbidity. Multiple authors have suggested using this
approach to maximize hearing preservation even for patients
with large tumors and poor preoperative hearing.59,60 Cases
in which hearing is to be safeguarded, tumors involving
the IAC may be approached with a middle fossa or
extended middle fossa approach. Patients with large
meningiomas of the IAC with evidence of bony invasion
and poor hearing may be treated with a translabyrinthine
approach.34 Tumors of the lateral IAC with invasion of the
inner ear have been reported. Resection of the inner ear
has been proposed in these cases to prevent recurrence.61
Meningiomas may also involve other basal foramina, such
as Meckel’s cave, the jugular foramen, and the foramen
magnum, which may necessitate the use of alternative
approaches.
PREOPERATIVE CONSIDERATIONS
Given the differential diagnosis of the CPA and IAC, a
preoperative evaluation should include an effort to deter-
mine the specific type of tumor present. As stated previ-
ously, CT and MRI remain the premier noninvasive tools
for detecting and diagnosing specific lesions in the CPA and
IAC. These imaging techniques provide specific anatomic
information such as length and width of the IAC, precise
location of the semicircular canals and jugular bulb, and
the extent of pneumatization of the petrous and mastoid
bones. This information is especially helpful for the sur-
geon planning the details of the procedure. The amount
and direction of tumor extension may also be gleaned from
these data. In cases of hearing loss, hearing tests may also
be performed; the loss of discrimination is a more sensitive
index than hearing threshold for detecting a neural origin
of a hearing disorder. High-resolution cochleomeatal
scanning (CMS) of the IAC may be performed to detect
the presence of tumor in the canal as well as ascertain the
position of basilar vessels rostrally and the jugular vein
caudally.62
Angiography was extensively used in the past for diag-
nosing meningiomas. Today, however, it is rarely used,
given the availability of noninvasive imaging techniques
such as CT and MRI. It may be indicated in meningiomas
of the cavernous sinus and in evaluation of the
intrapetrous carotid to determine the patency and feasi-
bility for resection by balloon occlusion testing.
Angiography can also be used to determine the patency of
any dural sinuses involved with tumor. These tests may
rarely cause complications, so they must be selected after
weighing their benefits and risks. Preoperative emboliza-
tion of the external carotid contributions to the tumor’s
blood supply may be selected by the operating surgeon.
Embolization reduces blood loss intraoperatively and
may soften the tumor due to tissue necrosis so that the
tumor may be removed by the cavitron ultrasonic suction
aspirator (CUSA).34
Blood should be available and cross-matched before sur-
gery. This is especially important for large, hypervascular
meningiomas located in close proximity to significant vas-
cular structures. Meningiomas causing significant cerebral
edema should be treated with perioperative steroids (4 mg
of dexamethasone every 6 hours).34 These agents improve
intracranial compliance and protect the brain from the
trauma of surgery. Treatment with anticonvulsants for the
prevention of seizures is controversial. Most surgeons
administer anticonvulsant therapy prior to the surgery so
that therapeutic concentrations may be achieved before
the patient is taken to the operating room. Although these
medications protect against seizures, they are sometimes
associated with lethargy, confusion, and, rarely, an allergic
response. In addition, surgeons often question the need for
anticonvulsant therapy in the absence of preoperative
seizures.11,53 Antibiotic coverage is also recommended for
a period of 24 hours to protect against infections. Several
medications and techniques may be used to reduce brain
edema and shrink the intra-axial structures. These include
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-
pation of a prolonged brain retraction for skull base
lesions.11,56
Neuromonitoring plays an important role in preserving
function in meningioma surgery. Cranial nerve monitor-
ing, especially facial nerve monitoring, is routinely
conducted for meningiomas in the CPA and IAC. The
trigeminal nerve and recordings from the extraocular mus-
cles are also monitored during surgery for meningiomas
involving Meckel’s cave and the cavernous sinus. The
cochlear nerve is often monitored in cases selected for
hearing preservation. Electrodes may also be placed in the
tongue, neck, pharynx, trapezius, or sternocleidomastoid
muscles for monitoring the lower cranial nerves (IX
through XII) when the meningioma extends to the jugular
foramen.34,63 Repetitive, irregular, high-frequency discharges
on spontaneous electromyography (EMG) recordings
alert a surgeon that a cranial nerve is being acutely
stretched or compressed. Specific stimulation of a cranial
nerve using electrical stimuli can not only confirm the
identity of a particular nerve but also reassure the surgeon
that the pathway is intact from the point of stimulation to
the muscles generating the recordings.63
POSTERIOR FOSSA MENINGIOMAS
Posterior fossa meningiomas account for 9% to 10% of all
intracranial meningiomas and represent 7% of all posterior
cranial fossa tumors.64–68 In Olivecrona’s series of 4185 brain
tumors, posterior fossa meningiomas made up 8.45% of all
intracranial meningiomas and 1.7% of all brain tumors.69
Meningiomas are the second most common tumor of the
posterior cranial fossa after vestibular schwannomas.39
Prior to the advent of modern neuroradiologic (CT, MRI,
angiography) techniques, diagnosis of these tumors was dif-
ficult due to conflicting signs and symptoms.64 Early man-
agement of these rare lesions was also challenging due to
the inability of surgeons to identify their precise location
preoperatively.64,65,70 Early series reported high morbidity
and mortality rates for the surgical resection of these
lesions. The operative mortality rates ranged between
approximately 20% and 30%, and the perioperative mor-
tality rate ranged from 0 to 15.7%.64,65 The slow growth
rates of these lesions posed a dilemma for the surgeons

who had to weigh the significant morbidity of surgical
removal against progressive functional deterioration of
the patient due to an increasing tumor size.65 The intro-
duction of modern neuroradiologic techniques, skull base
approaches, and microsurgical techniques have lessened
the morbidity and mortality associated with the surgical
resection of these tumors.64–66,71
Cushing and Eisenhardt proposed one of the first classi-
fication systems for posterior fossa meningiomas in 1938.3
They divided posterior fossa meningiomas into tumors of
the basilar groove, posterior cerebellar convexity, the
acoustic foramen, and the lateral recess. Since then, several
different classification schemes have been proposed to
organize posterior fossa meningiomas. In 1953, based on
their radiologic and postmortem examinations of 71 pos-
terior cranial fossa meningiomas, Castellano and Ruggerio
divided these tumors into five groups. These groups con-
sisted of tumors arising from the cerebellar convexity, tento-
rium, posterior petrous region, clivus, and foramen magnum
and were classified on the basis of the tumor’s site of dural
attachment (Fig. 47-10). The posterior petrous ridge was
the most common site of dural attachment (42%) followed
by the tentorium (30%), clivus (11%), cerebellar convexity
(10%), and foramen magnum (4%).72 Russell and Bucy, on
the other hand, classified posterior fossa meningiomas
according to their location within the posterior cranial
fossa, not their site of origin. The CPA was the most com-
mon location for these tumors according to these authors.73
Yasargil and Mortara proposed yet another classification
system, which divided meningiomas of the posterior cra-
nial fossa into CPA, foramen magnum, clival, petroclival,
and sphenopetroclival regions based on his intraoperative
findings.74
In a 1983 study of 38 posterior fossa meningiomas,
Martinez and coworkers divided these tumors based on
their site of dural attachment and also detailed the vascular
Figure 47-10. A view of potential sites of origin of posterior fossa
meningiomas including the cerebellopontine angle, petroclival region,
cerebellar convexity, and the jugular foramen. (Used with permission from
Jackler RK: Atlas of Neurotology and Skull Base Surgery. Philadelphia,
Mosby, 1996.)
Meningiomas of the Posterior Fossa and Skull Base 805
supply to these tumors. The lesions were divided into five
groups: CPA meningiomas, meningiomas of the cerebellar
convexity, tentorium cerebelli meningiomas, peritorcular
meningiomas, and clival meningiomas. CPA meningiomas
included lesions attached to the posterior ridge of the
petrous bone that derived their blood supply from the
meningeal branches of the vertebral artery. Meningiomas
of the cerebellar convexity originated from the dura cover-
ing the cerebellum and obtained their vascular supply from
the vertebral and occipital arteries. Tentorium cerebelli
meningiomas extended both supratentorially and infraten-
torially and were supplied by the IAC, the middle meningeal
artery, the occipital artery, and terminal branches of the
basilar artery. The meningeal branches of the vertebral
artery, the middle meningeal artery, and occipital arteries
provided blood supply to peritorcular meningiomas. Clival
meningiomas obtained their blood supply primarily from
the meningeal branches of the IAC and vertebral artery.66
The aforementioned classification schemes illustrate the
two primary methods, namely, site of dural attachment and
location, that have been used to subdivide posterior fossa
meningiomas. Creation of these groupings is necessary to
compare surgical morbidity and mortality. Both methods,
however, have limitations that complicate the objective com-
parison of surgical data. Despite the availability of sophisti-
cated, multiplanar imaging techniques, the primary site of
dural attachment is difficult to determine preoperatively. In
addition, the size and location of the tumor make this deter-
mination challenging even intraoperatively.69 Yasargil and
Mortara cautioned, “at time … even with close observation
through the operating microscope, a precise origin cannot be
ascertained.”74 Classifying meningiomas based on their loca-
tion is also problematic, given the frequent extension of
tumors into different areas of the posterior cranial fossa.
This lack of a consistent and unified classification scheme has
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,
type VI meningiomas are unclassified tumors.65 Although
plagued with the same imperfections mentioned for
other classification schemes, this is a comprehensive and
detailed scheme that may further the accurate collection,
806 SURGICAL NEUROTOLOGY
interpretation, and comparison of surgical morbidity
and mortality.
CEREBELLOPONTINE ANGLE
MENINGIOMAS
Introduction
The term cerebellopontine angle (CPA) was introduced in
1902 by Henneberg and Koch when they found two
patients with bilateral vestibular schwannomas (acoustic
neuromas) in a location they called kleinhirnbruchenwinkel
(kleinhirn = cerebellum, bruchen = pons or bridge, winkel =
angle).75 The CPA is most simply defined as the space
bound by the cerebellum, pons, and petrous temporal
bone. It is traversed by multiple neurovascular structures
entering or exiting the cranial vault.76,77 It is a large
intracranial basal cistern filled with cerebrospinal fluid
(CSF) that has a meningeal lining. The CPA is bounded
posteriorly by the flocculus and petrosal surface of the
cerebellum. Anteriorly, it is enclosed by the posterior sur-
face of the petrous pyramid and lateral aspect of the clivus.
The lateral aspect of the tentorium marks the superior
limit of the CPA. Inferiorly, this cistern extends along the
lateral surface of the medulla. The lateral limit of the CPA
is approximated by the posterior aspect of the petrous
pyramid and internal acoustic meatus (IAM). The medial
limit of this space is defined by the pons.77 Important neu-
rovascular structures that reside in the CPA cistern are the
CN VII through VIII nerve complex; the anterior inferior
cerebellar artery (AICA) and its branches; the posterior infe-
rior cerebellar artery (PICA); and numerous veins draining
the petrosal surface of the cerebellum, the pons, and
medulla, which empty into the superior petrosal vein.76,77
History
The first CPA meningioma was reported by Rokitansky
in 1855.77 Soon thereafter in 1863, Virchow described a
“psammoma” originating from the posterior lip of the
IAC.7 Although multiple surgical excisions were attempted,
the first successful removal of a meningioma was described
in 1894 by Charles Ballance. Although the author reported
the tumor to be a vestibular schwannoma (acoustic neu-
roma), evidence reviewed by Cushing suggested that he
was one of the first of many who have confused the identity
of the two tumors.34 Cushing considered the broad dural
attachment of the tumor and the absence of auditory
symptoms to strongly suggest that the tumor removed by
Ballance was more likely a meningioma.3 Henshen went
on to give an account of three CPA meningiomas in 1910
and also reviewed the literature on these specific tumors.77
The history of CPA meningioma surgery continued
when Olivecrona detailed the removal of two posterior
petrous pyramid meningiomas in 1927 and 1929, with only
the latter being associated with a good outcome.77 In a
1938 report on 23 meningiomas, which accounted for
2.4% of his surgical series, Cushing detailed the manage-
ment of 7 CPA meningiomas. Only one of those patients,
however, was reported to have a favorable outcome and
was reported to be alive and well 9 years after the operation.
This particular patient had a meningioma that arose from
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
Guillaume described the removal of a CPA tumor.
Postoperatively, the patient experienced an improvement
in hearing, a significant accomplishment given the absence
of modern magnification and surgical techniques.77 In
1953, Castellano and Ruggerio reviewed Olivecrona’s
series of 71 meningiomas, 29 of which were classified as
CPA tumors. Approximately 79% of the lesions underwent
complete excision but this was accompanied by an
appalling mortality rate of 43%. The mortality rate for the
total resection of CPA meningiomas remained dismal until
1980 when Yasargil and Mortara reported complete
removal for 30 of these tumors with a nearly 0% mortal-
ity.74 Since then, multiple series have reported excellent
surgical excision for CPA meningiomas with minimal or
no mortality.
Epidemiology
Although, the CPA is the eighth most common site of
involvement for all intracranial meningiomas, it is the
most common location for meningiomas in the posterior
fossa.78,79 Approximately 8% to 18% of all intracranial
meningiomas and 30% to 58% of all posterior fossa
meningiomas are found in the CPA. Meningiomas account
for only 3% to 12% of CPA tumors, making them the
second most common tumor in the angle.34,40,41,76,80–83
These tumors tend to occur most frequently in middle-
aged females. In one of the larger series of CPA menin-
giomas, Matthies and coworkers reported that meningiomas
comprised 18% of tumors in the CPA, a much higher fig-
ure than other series.84 Although meningiomas represent a
noteworthy pathology in the CPA, the most common
lesion remains the vestibular schwannoma, which makes
up almost 90% of all lesions in the angle.41,75,78,83
Origin
Meningiomas originate from the arachnoid lining cells
found in clusters at the tips of arachnoid villi, which serve
as the sites of CSF absorption. Arachnoid villi are finger-
like projections of the arachnoid mesothelium that pro-
trude into the sinus wall.85 Intracranially, meningiomas are
found along the dural sinuses, their large tributary veins, as
well as the exit foramina for vessels and cranial nerves.78,85
In the CPA, meningiomas are thought to arise from arach-
noid villi that are associated with large and small venous
channels surrounding the petrous portion of the temporal
bone.83 These tumors are typically situated near the sigmoid
sinus, jugular foramen, torcula, and superior and inferior
petrosal sinuses. Concentrations of arachnoid cells found
within the IAC, the jugular fossa, the geniculate ganglion,
and along the greater and lesser superficial petrosal nerves
may also give rise to meningiomas.34,78,85
Classification
Akin to the classification schemes for posterior fossa menin-
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
was described in 25%, and trigeminal neuralgia was
reported in 16%.40,87 Lower cranial nerve abnormalities
were noted in 13% of patients. Less common symptoms
were headache (22%), visual changes (19%), limb weak-
ness (9%), otalgia (6%), and facial weakness (3%). On
physical examination, common otologic and neurologic
findings were nystagmus (50%), decreased facial sensation
(44%), ataxia (41%), reduced hearing (28%), and facial
weakness (28%).40,87 Overall, cranial nerve dysfunction
and cerebellar deficits were the most prominent signs and
symptoms among patients with CPA meningiomas.
Impairments of multiple cranial nerves are some of the
earliest clinical signs and symptoms seen in CPA menin-
giomas. Vestibulocochlear nerve dysfunction is the most
frequently reported symptom in multiple series of CPA
meningiomas. In one of the earliest series, Grand and
Bakay reported on 30 posterior fossa meningiomas,
noting eighth nerve dysfunction in 94% of patients with
CPA meningiomas.64 The frequency of hearing loss
ranged from approximately 60% to 75% in a majority of
studies.40,41,64,69,74,79,84 In a retrospective review of
Olivecrona’s 71 CPA meningioma cases, Castellano and
Ruggerio reported hearing loss as an initial symptom in
57% of their patients.72 In a series of 30 CPA menin-
giomas, Yasargil and Mortara described hearing loss as a
clinical sign on admission in 67% of their patients.74
Sekhar and Jannetta, however, found a significantly lower
incidence of hearing loss (14%) in their series of 22 CPA
meningiomas. In contrast, these authors reported a far
higher incidence of trigeminal nerve dysfunction (73%).80
Martuza suggested that a difference in referral patterns,
specifically Jannetta’s interest in trigeminal neuralgia, was
more than likely the reason for this discrepancy.80,87
Dysequilibrium, which included imbalance and vertigo,
had a more variable presentation, with a large number
of series reporting frequencies ranging from 50% to
66%.40,41,69,79,84 Yasargil and Mortara and Minor and
colleagues noted low incidences of dysequilibrium at 36%
and 37%, respectively.74,88 Castellano and Ruggerio as
well as Sekhar and Jannetta reported even lower incidences
of dysequilibrium at 27% and 32%, respectively.72,80
Tinnitus was also reported in an unpredictable pattern in
a majority of series, with frequencies ranging from 43%
to 66%.41,64,79,80,84,88
Trigeminal nerve dysfunction is another commonly
reported symptom for patients with CPA meningiomas.
Sekhar and Jannetta described trigeminal neuralgia in 64%
and facial numbness in 9% of patients in their series.80
This reported incidence of facial pain is significantly
higher than that in other series, which found frequencies
ranging from 7% to 31%.40,41,64,72,74,79,84 Facial hypesthesia
was reported to be present in 25% of patients by Laird and
colleagues.41 Facial numbness was found in 19% to 64% of
patients in a majority of series.40,41,72,74,79,88 This range
excluded the low incidence of 9% reported by Sekhar and
Jannetta. On physical exam, a decreased corneal reflex was
noted in 50% to 60% of patients.41,72,74
Facial nerve abnormalities, which included weakness,
and facial spasm were noted by Grand and Bakay in 44%
of their patients.64 Martinez and coworkers, in a study of
19 CPA meningiomas, found a similar incidence of seventh
nerve irregularities in 47% of their patients.66 Facial weak-
ness was reported as a symptom in multiple series ranging
from 3% to 53%. On further examination, this large range
of frequencies can be separated into three distinct group-
ings: 3% to 7.5%,40,41,79,84 18% to 25%,64,80,82 and 50% to
53%.72,74 The difference in the involvement of the facial
nerve based on the location of the majority of tumors
in each series was most likely the cause of the variance.
The authors of three separate studies found a difference in
the frequency of facial weakness reported by the patient
versus that noted on neurologic examination. Granick and
colleagues found only 3% of patients complaining of facial
weakness. On exam, however, he noted that 28% of
patients had mild to moderate facial weakness.40 Laird and
colleagues noted a similar difference, in which only 5% of
patients mentioned facial weakness, but 15% were found
to have the sign on physical exam.41 Matthies and cowork-
ers found the two frequencies to be 3% and 11%.84 Facial
spasm was noted in three different studies to be 6.7%,
12.5%, and 36%.72,79,80
Lower cranial nerve (IX, X, XI, XII) abnormalities were
reported in 13% to 25% of patients in multiple
series.40,41,64,66,72,74,79,80,84 Dysarthria was reported in 10% of
patients by Laird and colleagues. Grand and Bakay noted
25% of patients complaining of dysarthria, but 19% men-
tioned it on physical examination. The frequency of dys-
phagia was found to be between 5% and 19% in multiple
studies on CPA meningiomas.40,41,64,72,79,84 Cerebellar signs
were also frequently noted on physical exam for patients
with CPA meningiomas. Ataxia was noted on neurologic
exam with a frequency of 6% to 81%.40,64,69,72,74,79,88 Non-
specific symptoms such as headache, nausea, emesis, and
dizziness were also reported with varying frequencies in
multiple series. Akin to many brain tumors, headache is
one of the earliest clinical symptoms reported by patients
with CPA meningiomas.66 Papilledema was noted in 5% to
26% of patients, signifying an increase in intracerebral
pressure.41,64,66,69,79,80,82 Sekhar and Jannetta noted postpa-
pilledemic optic atrophy in 5% of their patients.80
Several uncommon signs and symptoms noted for
patients with CPA meningiomas in a small subset of
series were visual disturbances (2.7% to 19%), diplopia (8%
to 25%), sixth nerve irregularities (3% to 18%), dementia
(13% to 14%), hemiparesis (5% to 16%), and otalgia (5%
to 6%). Yasargil and Mortara reported subarachnoid hem-
orrhage as an interesting and unusual presenting symptom
in 6.6% of their patients with CPA meningiomas.74
The mean time from the onset of symptoms to diagno-
sis of a CPA meningioma has been reported in multiple
series to range from 4 to 6 years. Martinez and coworkers
found a lower mean time of 3.5 years in their series.
Granick noted the mean time between the onset of symp-
toms to the first time the patient consulted a physician to
be 6 years, with a range of 1 month to 34 years. The largest
time lapse between the first consultation with a physician
to the actual diagnosis of a CPA meningioma was 18 years,
with a mean time of approximately 4 years. The authors of
this study found this delay to be the direct result of a mis-
diagnosis in 55% of cases.40,87 Yasargil and Mortara also
noted a mean interval of 4 years from the first medical
evaluation to the diagnosis of a CPA meningioma. The
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-
cular or neural involvement and extension into the IAC,
petrous apex, Meckel’s cave, IAC, petroclival region, and
jugular foramen. MRI is also more reliable in differentiat-
ing meningiomas from vestibular schwannomas. Although
both lesions appear isointense to hypointense on T1WI,
with a variable presentation on T2WI, vestibular schwan-
nomas enhance significantly with gadolinium administra-
tion compared with meningiomas.89,90
Surgical Management
CPA meningiomas have posed a challenge for surgeons,
given their close proximity to neurovascular structures and
their predisposition to attain massive sizes prior to clinical
diagnosis. The likelihood operative morbidity and mortal-
ity has been high ever since Cushing reported the first
successful removal of a CPA meningioma (Table 47-3).80
These tumors are particularly difficult to excise because of
their hypervascularity and attachment to large sinuses
in the subtentorial space.91 The difficulties with resecting
these tumors also include their variable origin and unpre-
dictable growth extension.84 The introduction of the new
skull base approaches, the operating microscope, and
microsurgical techniques have dramatically improved the
rate of resection, minimized postoperative complications,
and preserved functionality. The outcome for patients with
CPA meningiomas depends on the patient’s preoperative
condition, the location of the tumors, degree of tumor
resection, tumor histology, and the use of adjunctive modal-
ities.92 In addition, postoperative imaging has also improved
the detection of small asymptomatic recurrences.80
In a study of 56 patients with temporal bone menin-
giomas in 1992, Arriaga and colleagues reported the use of
six surgical approaches: the (1) retrosigmoid, (2) translaby-
rinthine, (3) transcochlear, (4) retrolabyrinthine, (5) infra-
temporal, and (6) middle fossa approaches. The authors
studied the use of these surgical approaches with respect to
the tumor location, morbidity associated with the proce-
dure, and long-term functional outcome. The translaby-
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
approach in 9% of cases, the infratemporal fossa approach
in 4%, and the retrolabyrinthine approach in 2%. Total
excision of the tumor was accomplished in 86% of cases.93
In a series of 22 CPA meningiomas in 1984, Sekhar and
Jannetta used the retrosigmoid craniectomy in 19 cases,
achieving a complete removal of tumor in 12 patients. The
authors employed a subtemporal approach in the remaining
three patients and were successful in total excision of the
lesion in two patients.80 In a series of 41 CPA meningiomas
in 1996, Thomas and King divided these tumors based on
their anatomic location. They used the retrosigmoid
approach in 10 patients with tumors in close proximity to
the IAC and the translabyrinthine approach for midpet-
rosal and IAC lesions. Complete resection was realized in
all groups except for petroclival meningiomas, which are
discussed in the next section.69 In a more recent study of
40 CPA meningiomas in 2000, Voss and coworkers used a
petrosal approach in 18 of 40 (45%) patients, a suboccipital/
retrosigmoid approach in 11 of 40 (27%), and a translaby-
rinthine approach in 7 of 40 (17%). The transcochlear and
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
82% of cases, with a subtotal excision in 18% of patients.79
The primary reasons for an incomplete resection were
brainstem invasion, cavernous sinus extension, and stub-
born adherence of the tumor to the neurovasculature.79,80
Complications
Cranial nerve palsies and CSF leaks are the two most
common complications following surgery for CPA menin-
giomas. Bacterial meningitis, aseptic meningitis, wound
infection, hydrocephalus, and hemorrhage are less com-
monly seen complications. Dysfunction of CN V, VII, and
VIII, and, less commonly, CN IX, X, and XI are often
noted after surgery for CPA tumors.94 CSF leaks usually
result from the incomplete obliteration and sealing of the
mastoid or petrous apex air cells after a craniectomy for
the surgical approach to a CPA meningioma. Increased
intracranial pressure, hydrocephalus, or infection can
often initiate or exacerbate a CSF leak. Drainage of clear
fluid into the middle ear, through the eustachian tube, into
the pharynx or nose that worsens with a Valsalva’s maneu-
ver is suggestive of a true CSF leak. Management initially
includes placement of a lumbar drain. CSF leaks may also
be observed at the wound site secondary to poor wound
healing, hydrocephalus, and infection.94
In 2000, Voss and coworkers reported multiple postop-
erative cranial nerve deficits in their series of CPA menin-
giomas. These included facial nerve dysfunction in 12 of
40 (30%) of patients, trigeminal neuropathy in 6 of 40
(15%), and vestibulocochlear nerve dysfunction in 5 of 40
(13%). Neuropathies of CN IV, VI, as well as IX and X
were noted in 8%, 5%, and 8% of patients, respectively.
Not surprisingly, the authors noted a significant difference
in the frequency of postoperative cranial nerve dysfunction
based on the location of the CPA meningioma with respect
to the porus acousticus. Seven of 10 (70%) patients with
meningiomas with an origin anterior to the IAC and 6 of
8 (75%) patients with an origin inferior to the IAC dis-
played new cranial nerve deficits after surgery. Postopera-
tive facial nerve paresis in these patients was 60% and
50%, respectively. In contrast, only two of eight (25%)
patients with meningiomas arising posterior to the IAC
and two of seven (28%) patients with meningiomas origi-
nating superior to the IAC developed new cranial nerve
problems. Only 15% of these patients developed postop-
erative facial nerve paresis. CSF leaks were reported in 9 of
40 (23%) patients, necessitating four wound revisions and
two lumbar-peritoneal shunt placements.79
In the study of 56 temporal bone meningiomas, Arriaga
and colleagues reported facial nerve preservation in 92%
of patients postoperatively. Patients with meningiomas
originating from the petrous ridge, petroclival region, or
tentorium had a worse long-term facial nerve function
than those with tumors located in the region of the sig-
moid sinus, IAC, or jugular foramen. Similarly, patients
approached with a transcochlear or infratemporal
approach that involved direct manipulation of the facial
nerve had the worst long-term facial nerve function. The
retrolabyrinthine and retrosigmoid approaches, although
used in only a handful of patients, were successful at
preserving a HB (House-Brackmann) grade of I or II in
100% of patients after more than a year of follow-up. The
translabyrinthine approach used in 11 patients was
successful in doing the same in 64% of patients. Other
complications reported included postoperative ataxia in
35%, long-term ataxia in 27%, CSF leaks in 12%, and
meningitis in 7%. More than 90% of patients returned to
their preoperative functional status after surgery.93
INTERNAL AUDITORY CANAL
MENINGIOMAS
The majority of meningiomas found in the IAC originate
from outside the canal, typically arising from the posterior
face of the petrous bone and prolapsing slightly into the
canal. Completely intracanalicular meningiomas are
extremely rare. Less than 15 well-documented cases have
been reported in the literature (Table 47-4).38,61,81,83,95–103
These tumors arise from the meningeal lining of the IAC
and are completely centered on the canal wall. Meningiomas
with a significant component in the IAC usually have a broad
base along the posterior petrous bone, thus making the
determination of the origin particularly difficult.61
The first meningioma of the IAC was reported by
Virchow, who noted a histologically proven meningioma
arising from the porus internus.3 The next intracanalicular
meningioma was reported more than a hundred years later
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
lateral end of the IAC that also involved the ampullated
end of the lateral semicircular canal.99 Another case involv-
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
IAC in the literature.61,96,98,101–103 Nager and Masica noted
the tendency of intracanalicular meningiomas to invade
deeper portions of the temporal bone via the lateral end of
the IAC.85 These tumors were seen to grow along the
nerve fibers into the cochlea, vestibule, and semicircular
canals. Infiltration of the perilabyrinthine tracts has also
led to the involvement of the middle ear and mastoid por-
tions of the temporal bone.61 Given the deeper involve-
ment of intracanalicular meningiomas, if the lateral end of
the IAC is involved, exenteration of the cochlea and the
semicircular canal should be considered.34,61
IAC meningiomas are most common during the fourth to
sixth decades of life. They occur more frequently in women
than men, with a ratio of 5:2.3.102 Their clinical presenta-
tions are related to compression of the vestibulocochlear
nerve complex rather than parenchymal involvement. Akin
to CPA tumors, these lesions become symptomatic as they
increase in size within the bony IAC.61,98,101 The advent of
high-resolution CT and MRI has permitted the diagnosis of
small intracanalicular lesions before irreversible cranial
nerve damage has occurred.96 In 12 well-documented cases
of IAC meningiomas, 9 (75%) had unilateral hearing loss,
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,
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
RK: Atlas of Neurotology and Skull Base
Surgery. Philadelphia, Mosby, 1996.)
tinnitus, fullness, vertigo, and facial palsy. PTA demon-
strated a unilateral hearing loss in 9 of 12 (75%) patients and
was normal in 3 of 12 (25%).61,96,99,101–103
CLIVAL AND PETROCLIVAL
MENINGIOMAS
Introduction
Clival and petroclival meningiomas are some of the most
difficult skull base lesions to manage, given their close prox-
imity to critical neurovascular structures.104,105 Due to their
location and insidious growth pattern, these tumors may
present with significant brainstem compression, involve-
ment of multiple cranial nerves, and encasement of arteries
arising from the vertebrobasilar system. Clival and petrocli-
val meningiomas are usually detected after they have
attained an enormous size, as their insidious early growth
often occurs in the absence of significant signs and symp-
toms.105 The surgical resection of these lesions is made even
more difficult with their propensity to extend to the petrosal
and cavernous sinuses, middle cranial fossa, parasellar area,
Meckel’s cave, IAC, and foramen magnum.86,104,106–110 Given
their depth of location within the skull and anterior rela-
tionship to the posterior cranial fossa nerves, the skull base
surgeon is relegated to dissecting these tumors between the
often attenuated and displaced cranial nerves (Fig. 47-12).57
TUMOR
JB
5
7 8
Ch F1

Prior to the availability of the operating microscope, micro-
surgical techniques, skull base approaches, advanced imag-
ing, and intraoperative monitoring, the surgical resection of
these tumors was associated with significant morbidity and
mortality.106 Although recent series report a dramatic
increase in complete resection of these meningiomas
accompanied by a decline in postoperative neurologic
impairment, considerable morbidity is still associated with
the surgical management of these tumors. In a study of 33
petroclival meningiomas, Bricolo and colleagues in 1992
stated that “In nearly all cases, the patient is in a worse clin-
ical and neurological condition after surgery than before,
and therefore requires constant and meticulous assis-
tance.”86 In a review of petroclival meningiomas, Sekhar and
coworkers believe that although improvements have been
made in the management of these tumors, the temporary
and permanent postoperative morbidity after surgical resec-
tion remains underreported.104
Origin and Classification
Akin to other posterior fossa meningiomas, clival and
petroclival meningiomas have undergone changes in defi-
nition over time. Comparisons between series of patients
with clival and petroclival meningiomas have been limited
due to the inconsistencies in the classification of these
tumors.111 In 1953, using postmortem examinations to
localize the site of the tumor, Castellano and Ruggerio
defined clival meningiomas as tumors arising from the
superior part of the clivus displacing the pons posteriorly.72
Hakuba and colleagues, in 1977, also adopted this defini-
tion in a report of six meningiomas of the clivus.112 In
1963, Dany and Mortara described clival meningiomas as
tumors originating from any part of the anatomic clivus
growing anterior to the basilar artery.106 This definition,
however, excluded rare cases in which the meningioma
rests between the basilar artery and the pons. Based on
their intraoperative observations in 1980, Yasargil and
Mortara defined clival meningiomas as tumors “attached
at any of the lateral sites along the petroclival borderline,
where the sphenoid, petrous, and occipital bones meet.”74
Despite the attempts of these authors to describe and clas-
sify these tumors, a precise definition for clival and petro-
clival meningiomas remains undecided. However, most
authors agree that clival tumors arise from the upper two-
thirds of the clivus, whereas petroclival tumors originate
from the petrous ridge anterior to the IAC or the upper
two-thirds of the clivus. As previously mentioned, other
authors, particularly Bricolo and coworkers, consider
petroclival tumors to have an origin strictly medial to the
trigeminal nerve.86 Sekhar and colleagues argue that
although these definitions aid the surgeon, they fall short
of helping to plan the operative approach or gauge the
technical difficulties associated with a particular tumor.
For example, a soft petrous middle clival tumor poses a
very different intraoperative challenge from a hard, vascu-
lar, middle clival tumor encasing the basilar artery and
multiple cranial nerves.104
Extension
Clival and petroclival meningiomas often extend and grow
into various regions of the posterior fossa. In a study of
Meningiomas of the Posterior Fossa and Skull Base 813
41 clival meningiomas, Sekhar and colleagues, in 1990,
divided the clivus into three parts: the upper clivus (region
above the trigeminal nerves), the middle clivus (region
between the trigeminal nerves and the glossopharyngeal
nerves), and the lower clivus (region between the glos-
sopharyngeal nerves and foramen magnum). Only 7 of 41
(17%) patients had single involvement of the upper, middle,
or lower clivus, whereas the majority of cases, specifically
24 of 41 (59%) patients, had involvement of two regions of
the clivus. Only 10 of 41 (24%) patients were found to
have tumors in all three regions of the clivus. In the same
study these clival meningiomas had various intracranial
extensions: the tentorial notch in 32 of 41 (78%) patients,
the cavernous sinus in 21 of 41 (51%), the petrous ridge in
19 of 41 (46%), Meckel’s cave in 18 of 41 (44%), the sella
turcica in 12 of 41 (29%), the IAC in 9 of 41 (22%), and
the middle cranial fossa in 7 of 41 (17%). Cranial and
extracranial extensions to the petroclival bone were found
in 16 of 41 (39%) patients, to the sphenoid sinus in 5 of 41
(12%), to the infratemporal fossa in 4 of 41 (10%), and the
C1–2 area in 3 of 41 (9%).113
Clinical Presentation
The average age at presentation for a patient with a clival
or petroclival meningioma is in the middle of the fifth
decade of life, with an age range of 5 months to 69
years.105,106 Females are affected twice as often as males in
a majority of studies. Mayberg and Symon reported that
females constituted 64% of their series versus males who
made up 36%. The authors also found females to be
afflicted at an earlier age of 47 years, versus 54 years for
the males.111 In contrast, Castellano and Ruggerio in 1953
and Hakuba and coworkers in 1977 reported an equal inci-
dence of males and females. The duration between the
onset of symptoms to diagnosis was reported to average
from 3 to 5 years, with a range from 1 month to 17 years
in a majority of series.72,112
The incidence as well as the order of symptoms and
signs are variable and inconsistent among series. In a
review of 44 cases in 1977, Hakuba and coworkers
reported a constellation of clinical signs and symptoms,
which included increased intracranial pressure (70%),
cerebellar involvement (70%), CN V palsy (68%), hearing
loss (64%), facial nerve palsy (57%), involvement of the
corticospinal tract (57%), CN VI palsy (40%), involve-
ment of CN IX and X (34%), CN III palsy (27%), nuchal
rigidity (25%), nystagmus (25%), sensory impairment in
the limbs (16%), and psychological disturbance (1%).112
In a later study of 35 meningiomas of the clivus and
petrous bone in 1986, Mayberg and Symon reported dis-
turbance of gait and imbalance to be the most common
complaints on admission. These were followed by headache,
diminished auditory acuity, and facial pain. Vomiting,
dysarthria, dysphagia, and somatic motor and sensory dis-
turbances occurred later in the course of the disease.
Cranial nerve deficits were noted in more than 90% of
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-
ment with the tumor. The authors did not find any signif-
icant correlation between the clinical signs and symptoms,
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
Figure 47-14. A left translabyrinthine
approach to the cerebellopontine angle.
Note that this is a anterosigmoid exposure
allowing excellent visualization of the jugular
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
ganglion; IV, inferior vestibular nerve; JB,
jugular bulb; JV, jugular vein; SPS, superior
petrosal sinus; SS, sigmoid sinus;
SV, superior vestibular nerve; TS, transverse
sinus; T, tentorium. (Used with permission
from Jackler RK: Atlas of Neurotology and
Skull Base Surgery. Philadelphia, Mosby,
1996.)
Resection
Gross resection of clival and petroclival tumors has
markedly improved within the span of little more than a
decade. The rate of complete resection of clival and petro-
clival tumors has ranged from 26% to 85% in a majority of
series (Table 47-6).74,86,105–108,111,113,115,117,119,123 With the
exclusion of two of the early series by Yasargil and col-
leagues and Mayberg and Symon as well as a recent one by
Jung and coworkers, the percentage of total resection varied
between 68% to 88%. In a recent meta-analysis of six sepa-
rate studies on clival and petroclival meningiomas totaling
298 patients, complete resection was possible in 68% of
cases.57 Yasargil and Mortara pointed to the extradural inva-
sion of bone as the primary factor in preventing complete
removal of tumor, a feat accomplished in only 35% of
patients.74 Fierce adherence of the meningioma to the
neurovasculature, invasion of the cavernous sinus, and
extradural spread to bone were some of the reasons reported
by Mayberg and Symon for subtotal resection of tumors in
1986.111 In a more recent study of 38 petroclival menin-
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%),
cavernous sinus invasion in 6 of 38 (6%), hypervascularity of
the tumor in 4 of 38 (11%), encasement of major vessels in
3 of 38 (8%), and inadequate exposure in 3 of 38 (8%).105
GG
JV
7
7
Ca
JB
I S
V V
11 10 9 SPS
7 8 6
Ch 5
F1
Cb
SS T
D
TS
Although gross total resection is preferred, subtotal
resection has been associated with a good functional out-
come followed by long periods of survival. In 1986, Mayberg
and Symon reported that only 4 of 26 (15%) patients
demonstrated tumor progression and subsequently died.111
In a series of 22 petroclival meningiomas in 1986, Sekhar
and Samii104 found only 1 of 5 (20%) patients had clinical
symptomatology suggestive of tumor growth after a subto-
tal resection. Samii and coworkers113 also reported no
reoperations on patients known to have residual tumor.
Residual tumor was most likely to be found in the
cavernous sinus or in the clivus.104,113 In 2000, Jung and
coworkers noted that during a mean follow-up of 47.5
months, tumor progression occurred in 16 of 38 (42%)
patients who had a subtotal resection of tumor. The
authors also reported that during a follow-up period ranging
from 6 months to 141 months (mean 47.5 months), 33 of 38
(87%) patients with subtotal resections had a Karnofsky
performance score of more than 80. Although postopera-
tive cranial nerve deficits were observed in 12 of 38 (32%)
patients, the degree of impairment was mild.105
Mortality and Quality of Life
Prior to 1970, the cumulative mortality rate in a majority
of series was greater than 50%.57,111 With the introduction
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
mortality rates of 17% and 15%, respectively.74,112
Mayberg and Symon in 1986 reported a postoperative
mortality rate in 3 of 35 (9%) patients within 6 months of
surgery and in 4 of 35 (11%) patients after 6 months of
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
demonstrate a significant number of patients sustaining
new neurologic deficits after surgical resection of petrocli-
val meningiomas. The majority of these deficits involved
injury to cranial nerves and affected approximately 35% of
patients.57
In 1977, Hakuba and coworkers reported six cases of
total removal of petroclival meningiomas. Two patients
were in excellent condition postoperatively, three patients
had mild to minimal impairment, and one died.112 In 1980,
Yasargil and colleagues reported 20 cases of clival and
petroclival meningiomas. Eleven (55%) patients experi-
enced a good recovery, five had a fair recovery, and two
had a poor functional status postoperatively.74 Mayberg
and Symon assigned patients preoperatively and postoper-
atively to one of five clinical grades based on physical
examination and functional status. These grades were
defined as follows: grade I (no deficit), grade II (neurologic
deficit but able to work or manage household), grade III
(unable to work but able to care for self ), grade IV
(requires nursing care), grade V died of disease. Approxi-
mately 57% of patients were assigned a worse clinical
grade in the immediate postoperative period. The majority
of these patients, however, showed improvement within a
month.111 In their series of 24 patients with petroclival
meningiomas, Samii and colleagues reported that 12 (50%)
patients were able to return to their preoperative level of
activity, 8 (33%) were independent but were unable to
function as they previously had, and 4 (17%) required
nursing assistance.108
MECKEL’S CAVE MENINGIOMAS
Epidemiology
Lesions of Meckel’s cave comprise less than 0.5% of
all brain tumors.125–128 A wide range of lesions are found
in this region, including meningiomas, chordomas, lipo-
mas, arachnoid cysts, schwannomas, cholesteatomas,
malignant melanotic schwannomas, metastatic carcinomas,
sarcomas, melanocytomas, amyloidomas, cylindromas, neu-
roepitheliomas, fibrous xanthomas, and cysticercosis.125,129
Although several pathologic entities may occupy Meckel’s
cave, schwannomas and meningiomas are the most com-
mon tumors in this region.126,129 Primary meningiomas of
Meckel’s cave are rare tumors that comprise approximately
1% of all intracranial meningiomas.127 In their series of
295 intracranial meningiomas in 1938, Cushing and
Eisenhardt noted only 5 meningiomas arising from
Meckel’s cave.3 Among 1454 intracranial meningiomas
studied at the Mayo Clinic from 1914 to 1960, only 14
were found to be in Meckel’s cave, yielding an incidence
of 1%.128 Of the 1511 intracranial meningiomas undergo-
ing surgery at the Neurosurgical Department of Rome
University, 16 were noted to be Meckel’s cave menin-
giomas, also giving an incidence of 1%.129 In 1992, only
70 cases of Meckel’s cave meningiomas had been reported
in the literature, with few other reports noted in the
English literature since then.129
Origin and Classification
Meckel’s cave meningiomas originate from the dura
mater of Meckel’s cave and compress the trigeminal gan-
glion, which lies in the posteromedial portion of the mid-
dle cranial fossa.126 These tumors may invade the middle
or posterior cranial fossa, and may infiltrate into the
cavernous sinus, or surround the internal carotid artery
and the cranial nerves.127 In a retrospective review of 12
meningiomas of Meckel’s cave in 1975, Nijensohn and
coworkers divided these tumors into three groups on the
basis of their clinical presentation and prognosis. The first
and largest group of patients (group I) experienced typical
trigeminal neuralgia only; the second group of patients
(group II) had a history of atypical trigeminal neuralgia
without any neurologic deficits, and the third group (group
III) experienced trigeminal symptoms as well as other
cranial nerve deficits. The authors noted an excellent
prognosis (no tumor recurrence, and resolution of pain)
after complete removal of tumor for patients in group I. In
contrast, the authors observed a high incidence of tumor
recurrence due to subtotal removal, and a return of
intractable pain for patients in the group III. Patients in
the group II had an intermediate rate of tumor recurrence
and trigeminal pain.128
In their series in 1992, Delfini and colleagues did not
note a significant difference between patients with typical
and atypical neuralgia, with or without other trigeminal
nerve impairment. These authors divided Meckel’s cave
meningiomas into two instead of three groups. Patients in
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
confined to Meckel’s cave. Group II patients experienced
symptoms of trigeminal dysfunction combined with
impairment of other cranial nerves.129 These were larger
tumors originating from Meckel’s cave and extending
beyond. Delfini and colleagues defined group I patients
not only on their distinct clinical characteristics but also
noted that these individuals had small globular menin-
giomas measuring less than 3 cm that only involved
Meckel’s cave. Patients in group II were afflicted with
larger tumors no longer confined to Meckel’s cave.129 In
two separate comments following the report by Delfini
and colleagues, Sekhar and Sen considered the larger
meningiomas in group II to be cavernous sinus menin-
giomas. Sekhar suggested that these tumors may have
originated in the cavernous sinus or petroclival region and
subsequently extended to Meckel’s cave. Both authors
agreed that determining the origin is difficult despite
information garnered from MRI. No clinical or radiologic
evidence of recurrence was found in any patients in group
I, with an average follow-up of 6.1 years. Four of 8 (50%)
patients in group II showed evidence of recurrence with an
average follow-up of 4.5 years. Three of 8 (38%) patients
in group II were reported to have tumor progression.129

A B
Samii and coworkers reclassified his series of 21 Meckel’s
cave meningiomas into four groups based on tumor loca-
tion and extension. Type I meningiomas were confined to
Meckel’s cave. Types II and III meningiomas originated in
Meckel’s cave and extended into the middle fossa and pos-
terior fossa, respectively, without any infiltration into the
cavernous sinus. Type IV meningiomas were dumbbell-
shaped tumors that arose in Meckel’s cave and extended
into the middle and posterior fossae with or without infil-
tration into the cavernous sinus. The authors excluded
meningiomas that had a dural attachment close to Meckel’s
cave or those that involved it secondarily (Fig. 47-16).127
Clinical Presentation
Meningiomas are more common in women than in men.
Multiple authors have found this is also true for patients
with Meckel’s cave meningiomas. Of the 12 patients in
their series reported in 1975, Nijensohn and coworkers
noted that 9 were women and 3 were men, with a mean age
of 56 years and an age range of 35 to 71 years.128 In an
analysis of 30 cases in 1983, Butti and coworkers also
found that meningiomas were more common in women
(22 cases) than men (8 cases). The author noted an average
age of 52 years, with a range of 22 to 71 years.126 In a series
of 16 Meckel’s cave meningiomas, Delfini and colleagues
noted a female-to-male ratio of 1.6 to 1. The mean age at
diagnosis was 41.6 years, with the age range between 22 to
60 years. The mean duration of symptoms was 2.7 years,
with a range of 1 month to 20 years. The authors also
noted a difference in the mean age between group I and II
to be 34.5 years and 57.7 years, respectively. The mean
duration of clinical symptoms for group I was 11 months
and 4.1 years for group II.129 In the series of 21 Meckel’s
cave meningiomas, Samii and coworkers noted a mean
patient age of 46.5 years, with an age range of 17 to 72 years.
The average time of onset of symptoms to diagnosis was
3.3 years.127 Tumors of Meckel’s cave are most often asso-
ciated with dysfunction of the fifth cranial nerve.125 In a
study of 12 patients with lesions of Meckel’s cave, of which
4 were meningiomas, Beck and Menezes noted that 9 of 12
(75%) patients presented with CN V deficits. Trigeminal
neuralgia was noted in only three patients. Two of these
patients were found to have histologically proven menin-
giomas. Seven of 12 (58%) patients experienced other
cranial nerve involvement.125 Not surprisingly, the most
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.)
C
common symptom of meningiomas located in Meckel’s
cave is a deficit of the fifth cranial nerve.129 Typical and
atypical trigeminal neuralgia has been noted in approxi-
mately 65% of all published cases.126,129 In one large study
on meningiomas of Meckel’s cave in 1992, typical or atyp-
ical trigeminal neuralgia was noted in 10 of 16 (63%)
patients. Cranial nerve impairment was found in 7 of 16
(44%) patients in this series.129 In 1997, Samii and colleagues
noted trigeminal nerve impairment as the earliest sign in
15 of 21 (75%) patients, with hearing loss mentioned as the
next most common symptom. The authors also reported
trigeminal pain and hypesthesia as the main symptoms of
types I and III meningiomas.127
In their series in 1975, Nijensohn and coworkers noted
that patients in group I described their facial pain as super-
ficial, intense, brief, and paroxysmal—typical symptoms of
trigeminal neuralgia. This pain was observed to be limited
to some part of the trigeminal nerve distribution. In addi-
tion, most of these patients reported trigger points at some
time during the course of their disease. Patients in group II
reported atypical facial pain that was described as constant,
burning, and deeper than that experienced by patients in
group I. Patients in group III experienced atypical facial
numbness and pain. These patients also had other cranial
nerve involvement. One patient had ipsilateral optic atro-
phy and a decreased sense of smell as well as partial CN III
and IV palsies. Another patient experienced hearing loss
with intact labyrinthine function.128
In 1967, Kerr proposed that the progressive breakdown
of the myelin sheaths due to degenerative changes second-
ary to tumor growth was the probable cause of trigeminal
neuralgia.128 In their series, Beck and coworkers noted that
the three patients with facial pain had lesions that extended
into the posterior fossa, compressing the root entry zone
of the fifth nerve.125 In contrast, patients with tumors that
remained confined to the Meckel’s cave had no CN V dys-
function. These findings are in agreement with current
theories on the causes of trigeminal neuralgia.
Imaging
CT and MRI are the diagnostic modalities of choice for
lesions involving Meckel’s cave. Precise information on the
size, location, and nature of the lesion may be obtained
with the use of CT multiplanar high-resolution imaging.
CT is particularly useful for detecting bony changes and
820 SURGICAL NEUROTOLOGY
Figure 47-17. T1-weighted gadolinium-enhanced axial MRI scan revealing a
meningioma of Meckel’s cave extending toward the posterior aspect of the
cavernous sinus.
intratumoral calcification. MRI is useful for identifying
tumor invasion into cavernous sinus and for accurately
identifying trigeminal nerve compression (Fig. 47-17).
Postoperative gadolinium-enhanced MRI images are able
to delineate the extent of tumor resection. Delfini and col-
leagues also believe that cerebral angiography is necessary
for detailing the precise anatomic relationship between the
tumor and surrounding vascular structures, especially the
carotid artery.129
Surgical Approach
Small tumors localized to Meckel’s cave may be
approached with the subtemporal intradural approach.
Delfini and colleagues used this approach in 12 of 16 (75%)
patients, the majority of whom had small, globular menin-
giomas measuring less than 3 cm confined to the postero-
medial portion of the middle cranial fossa.129 Compared
with the intradural approach, the extradural approach pro-
vides the surgeon with a better exposure and reduces the
risk of damage to the superficial petrosal nerve damage.
However this approach is inadequate for patients with
tumor extension into the cavernous sinus (see Fig. 47-17).
Delfini and colleagues used a frontotemporal craniotomy
followed by a superior or lateral approach to cavernous
sinus for tumors involving the cavernous sinus. Tumors
with extension into the posterior cranial fossa can be
approached with a combined subtemporal-suboccipital
approach. Two skull base approaches with excellent expo-
sure include the petrosal approach and the subtemporal
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
Meckel’s cave lesions in 1987, Beck and Menezes noted
that although the CN V palsies persisted after surgery,
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,
Nijensohn and coworkers reported that patients in group I
had small, friable tumors, which were easily removed and
did not recur. These patients also reported complete alle-
viation of their trigeminal neuralgia after surgical resec-
tion of the tumor and a trigeminal sensory rhizotomy.128
In one of the largest series of Meckel’s cave menin-
giomas, Delfini and colleagues reported a Simpson grade I
(macroscopically complete resection of tumor and its dural
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
in all eight patients. In addition, no new neurologic deficits
were present postoperatively. In contrast, grade I removal
was accomplished in only 1 of 8 (13%) patients in group II.
A Simpson grade II (macroscopically complete resection of
tumor with endothermy coagulation of its dural attach-
ment) removal was reported in five patients (63%), and a
Simpson grade III (macroscopically complete resection of
tumor without coagulation of its extensions) removal was
noted in two patients (25%). One patient died intraopera-
tively and another succumbed after recurrence of the
meningioma. This difference in outcome was reflective of
the large and extensive tumors present in group II
patients.129 In the most recent series in 1997, Samii and
coworkers reported radical surgical removal in 76% of
their patients with complete excision of all type I and III
meningiomas. Subtotal resection (Simpson type III or IV )
was noted in the single type II meningioma and 4 of 5 (80%)
type IV meningiomas due to cavernous sinus invasion. Facial
pain was alleviated in all patients after surgical removal,

but trigeminal hypesthesia was resolved in only 35% of
patients. Immediate postoperative complications included
cranial nerve impairment, hemiparesis, and diplopia.127
Radiotherapy has been used as adjuvant treatment of
subtotally resected or unresectable meningiomas of
Meckel’s cave. It may also be used in elderly patients with a
poor preoperative functional status and short life expectancy
who have large tumors with a high risk of operative and
postoperative mortality.
JUGULAR FORAMEN MENINGIOMAS
Introduction
The jugular foramen is a depression on the medial and
inferior surface of the petrous bone formed at the interface
of the temporal and occipital bones. It measures approxi-
mately 15 mm × 10 mm. In two-thirds of cases, the right
jugular foramen is larger than the left.130–132 The antero-
medial aspect of the foramen is occupied by the inferior
petrosal sinus and CN IX, X, and XI. The jugular bulb and
internal jugular vein are found in the posterior aspect of
the foramen.130,133 Three major tributaries, the inferior
petrosal sinus, the condylar vein, and the sigmoid sinus,
empty into the jugular bulb.130,133 The sigmoid sinus has
a constant drainage pattern into the jugular bulb, whereas
the inferior petrosal vein and condylar vein are more vari-
able. The jugular bulb is separated from the carotid artery
by a dense fibrous band and a thin plate of bone called
the carotid crest. The three most common tumors in the
jugular foramen include glomus jugulare tumors (paragan-
gliomas), schwannomas, and meningiomas. Paragan-
gliomas are the most common lesions of the jugular
foramen followed by schwannomas of CN IX, X, and XI.
Chondrosarcoma, invasive squamous cell carcinoma, chor-
doma, and metastatic disease from renal or thyroid carci-
noma are rarer lesions of the jugular foramen.130,132–134
IAC
HC
Meningiomas of the Posterior Fossa and Skull Base 821
Classification
Tumors of the jugular foramen may be divided into
primary and secondary lesions.133 In a review of 55 lesions
of the jugular foramen, Samii and Bini noted that 25
tumors were located in the jugular foramen and were
defined as primary tumors, whereas 30 tumors involved
the foramen but did not arise from it and were defined as
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
associated with the jugular bulb and in close association
with the lower cranial nerves (Fig. 47-18).85 These tumors
are centered on the jugular foramen and may erode into
the hypotympanum, infralabyrinthine temporal bone,
and middle ear. Larger primary jugular foramen menin-
giomas often have simultaneous intracranial or extracra-
nial extensions.133,134
Secondary extrinsic jugular foramen meningiomas
are intracranial lesions that can extend to the jugular fora-
men from above or arise inferiorly in the upper neck
(Fig. 47-19).133,135 These lesions are typically large CPA or
petroclival meningiomas. Small tumors, however, posi-
tioned in the lower clivus or along the medial and inferior
portions of the posterior petrous bone may also extend to
the jugular foramen directly or by invading and destroying
the temporal bone. The degree of jugular foramen involve-
ment may vary from minor tumor invasion to extensive
extracranial extension into the neck. Jugular foramen
meningiomas may directly invade the internal jugular vein
and upper neck and extend through the adjacent occipital
bone to the foramen magnum. Meningiomas of the jugu-
lar foramen can encase individual cranial nerve filaments
and spread into the sheaths surrounding the nerves at the
skull base. In contrast, the lower cranial nerves are usually
compressed against the surface of glomus jugulare
tumors.133,135
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.)
822 SURGICAL NEUROTOLOGY
Figure 47-19. Coronal view of a T1-weighted gadolinium-enhanced MRI scan
revealing extension of a posterior fossa meningioma into the jugular
foramen.
Clinical Presentation
The clinical signs and symptoms of patients with menin-
giomas of the jugular foramen vary due to their proximity
to the lower cranial nerves. Hearing loss, pulsatile tinnitus,
hoarseness, and dysphagia have been reported as the most
common symptoms for these tumors.131,134,136 In a com-
prehensive chapter on meningiomas of the jugular foramen,
Thompson and Cass reviewed the clinical manifestations
for 19 primary jugular foramen meningiomas reported in
the literature. Mixed conductive and neurosensory-type
hearing loss was reported in 15 of 19 (79%) patients. A vis-
ible middle ear mass was noted in 11 of 19 (58%) patients.
Tinnitus was noted in 9 of 19 (47%) patients with pulsatile
tinnitus present in 5 of 9 (55%). Cranial nerve deficits
(V through XII) were noted in 10 of 19 (53%) patients,
with CN IX and X neuropathies reported in 5 of 10 (50%)
patients each. Six of 19 (32%) patients were reported to
suffer from multiple cranial neuropathies.133 Patients with
meningiomas of the jugular foramen commonly present
with multiple cranial nerve deficits; a combination of CN
IX, X, and XI neuropathies is known as Vernet’s syndrome
and a combination of neuropathies of CN IX, X, XI, and
XII is known as Collet-Sicard syndrome.130,131 Headache,
facial pain, visual loss/diplopia, vertigo, and ataxia are
additional symptoms noted in patients with jugular fora-
men meningiomas.
In contrast, Thompson and Cass noted that secondary
jugular foramen meningiomas were more likely to present
with a neurosensory hearing loss, a weak voice, and dys-
phagia, due to their involvement of multiple cranial nerves.
In one of the larger series on jugular foramen menin-
giomas, Molony and coworkers noted that hearing loss
accompanied with a middle ear mass was present in 7 of 8
(88%) patients. Six of eight (75%) patients complained of
tinnitus, which was pulsatile in four. Lower cranial nerve
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
Diagnosis
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-
nosis, determine the extent of the disease, and formulate a
therapeutic strategy. CT, MRI, and angiography are the
primary diagnostic modalities for assessing meningiomas
of the jugular foramen. The characteristic findings of
meningiomas on CT, MRI, and angiography have been
previously described. High-resolution CT images with
bone detail in multiple planes are required to adequately
visualize meningiomas of the temporal bone. Mild hyper-
ostosis and destruction of bone may be seen well beyond
the cortex of the jugular foramen, given the propensity of
these meningiomas to spread locally. In contrast, glomus
jugulare tumors exhibit far greater bony changes, typically
in the form of irregular bony destruction of the jugular
fossa. When these changes are present on CT, the
surrounding bone is commonly described as looking
“moth-eaten.” The difference in the degree of bone
destruction may help to differentiate between these two
tumors. The intense signal enhancement of the jugular bulb
on postinfusion images sometimes prevents identification of
the jugular foramen meningiomas. However, menin-
giomas with significant intratympanic or extracranial
extension can be easily discovered with enhancement.133
MRI remains the preferred imaging modality for detect-
ing intracranial and extracranial extension of jugular fora-
men meningiomas. Identifying tumor extension into the
nose, nasopharynx, paranasal sinuses, middle ear, mastoid,
parapharyngeal space, infratemporal fossa, and cervical
region is important in the preoperative evaluation of the
tumor. Angiography with preoperative embolization may
be considered for a highly vascular jugular foramen
meningioma. When a meningioma is limited only to the
jugular foramen, it may not be easily visible with angiog-
raphy. Angiography, however, may be useful for differenti-
ating meningiomas from glomus jugulare tumors, which
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
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.)
encasement, infiltration of the lesion, and extent of resec-
tion influence the morbidity associated with surgical exci-
sion. In a review of 25 patients with jugular foramen
meningiomas, Thompson and Cass in 1996 reported the
following postoperative cranial nerve neuropathies: CN X
in 14 of 25 (56%) patients, CN IX in 13 of 25 (52%), CN
XI in 7 of 25 (28%), CN XII in 7 of 25 (28%), and CN VII
in 6 of 25 (24%). CSF leaks were reported in 3 of 25 (12%)
patients, and hemiparesis was noted in 1 patient (4%).133
The complex relationship between the tumor and the
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
originate laterally with the jugular vein and bulb, medial to
the inferior petrosal sinus, or centrally along the fibro-
osseous partition on which the cranial nerves lie. Lustig
and Jackler noted a unique and consistent relationship
between the neurovasculature and each of the three most
common tumors of the jugular foramen, namely, glomus
jugulare (paragangliomas), schwannomas, and menin-
giomas. Knowledge of the jugular foramen anatomy com-
bined with characteristic tumor growth patterns help the
surgeon assess the risk of cranial nerve injury and accord-
ingly plan the degree of tumor resection leading to the
best possible functional outcome.135
Meningiomas are much more variable in their relation-
ship to the lower cranial nerves and vasculature in the
jugular foramen than glomus tumors. Meningiomas origi-
nating in the lateral aspect of the jugular foramen lend
themselves to excellent neural preservation since the
tumor lies between the surgeon and cranial nerves. In
addition these tumors also occlude the jugulosigmoid
JV
VA
venous complex early in their growth. Complete excision
of meningiomas arising in the medial aspect of the jugular
foramen are associated with a high risk of CN IX, X, and
XI injury.135 Meningiomas deeply penetrating the dural
envelope of the jugular foramen, however, are always asso-
ciated with a high risk of injury to the cranial nerves,
regardless of their origin. Sudden injury to CN X may
leave the patient with an incompetent larynx and require
that the patient undergo a tracheostomy and gastrostomy
for airway protection and nutrition.
FORAMEN MAGNUM MENINGIOMAS
Introduction
The foramen magnum lies within the occipital bone.
Multiple structures lie in close proximity to this foramen,
including the caudal medulla, rostral spinal cord, cerebel-
lar tonsils, inferior vermis, fourth ventricle, and the lower
cranial and upper cervical nerves. The spinal cord is
attached to the lateral dura by the dentate ligaments, the
most rostral of which serves as an important landmark in
the surgery of tumors of the foramen magnum. The lateral
aspect of this ligament is in close association with the ver-
tebral artery where it enters the dura with the posterior
spinal artery and dorsal root of C1. After entering the
dura, the vertebral artery gives rise to the posterior infe-
rior cerebellar artery (PICA) superior to the foramen mag-
num. The vertebral artery continues superiorly to merge
with the contralateral vertebral artery to form the basilar
artery.139,140

The lower cranial nerves arise from the anterolateral
medulla and spinal cord. These nerves are usually affected
by tumors of the foramen magnum since they lie in close
proximity to this region. Cranial nerves IX through XI
arise as rootlets from the anterior medulla and spinal cord
and exit the skull base though the jugular foramen. A con-
tribution to CN XI passes through the foramen magnum
from C2.139,140
Epidemiology
Meningiomas represent the majority of tumors originating
at the foramen magnum, yet they are exceedingly rare
lesions. In 1953, in a review of Olivecorona’s series of
posterior fossa meningiomas, Castellano and Ruggerio
noted only three foramen magnum meningiomas.72 In
1971, Lecuire and Dechaume studied a series of 240 pos-
terior fossa meningiomas, only 20 of which were foramen
magnum meningiomas.82 In 1980, Yasargil and Mortara
reported only three foramen magnum meningiomas in a
large series of posterior fossa meningiomas.74 In a chapter
review of multiple series of foramen magnum menin-
giomas in 1991, Scott and Rhoton found these tumors to
account for approximately 1.8% of all intracranial menin-
giomas, 6% to 7% of all posterior fossa meningiomas, and
8% to 9% of all spinal meningiomas.139 A more recent
paper by Pirotte and coworkers in 1998 reported that fora-
men magnum meningiomas account for 0.2% of all
intracranial tumors, 1% of all intracranial meningiomas,
and 5% of posterior fossa meningiomas.141 Meningiomas
represent approximately 70% of all benign tumors arising
from the foramen magnum and are the most common
tumor entity at this location.140,142
Akin to all other intracranial meningiomas, foramen
magnum meningiomas are more common in females than
in males. Multiple series have noted a female-to-male ratio
of approximately 2:1 to 3.6:1.140 Although the age at pres-
entation varies from the fourth to the sixth decade, the age
range ranges from 4 to 88 years.140 Meyer and colleagues
reported patients’ ages to range from 12 to 81 years, with
an average of 49 years. The average interval from the first
symptoms to diagnosis was between 2.5 to 4 years in most
series.143
History and Classification
In 1929, Elsberg and Strauss reported the first successful
removal of a foramen magnum meningioma in a 36-year-old
patient with Brown-Sequard syndrome.140 In 1938,
Cushing and Eisenhardt defined foramen magnum menin-
giomas as those tumors located on the margin of the fora-
men magnum.3 Castellano and Ruggerio defined them as
tumors involving the lower third of the clivus.72 Cushing
and Eisenhardt divided foramen magnum tumors into two
anatomic groups: craniospinal and spinocranial. Cran-
iospinal meningiomas arise in the basilar groove anterior
or anterolateral to the spinal cord projecting inferiorly
to the foramen magnum. Spinocranial meningiomas
originate posterior or posterolateral to the medulla and
projecting superiorly to the cerebellar cistern. The authors
made this distinction primarily based on the clinical pres-
entation and on the difficulty of surgical excision.3,140 In
Meningiomas of the Posterior Fossa and Skull Base 825
1941, Dandy agreed with the classification and felt that it
was important for planning an operative approach.139 In
1953, Castellano and Ruggerio proposed their classification
of posterior fossa meningiomas based on their site of dural
attachment. Given this criterion, only meningiomas aris-
ing from the foramen magnum were considered foramen
magnum meningiomas, not meningiomas arising else-
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
magnum meningiomas.139 Comparing outcomes between
series of foramen magnum meningiomas has been diffi-
cult, given their scarcity as well as wide variations in their
classification.
Clinical Presentation
A wide range of clinical signs and symptoms have been
observed for patients with foramen magnum menin-
giomas. In 1953, Castellano and Ruggerio stated that “the
possibility of a meningioma of the foramen magnum
should always be considered in the presence of a capricious
clinical history with long remissions and illogicalness.”72
In a series of 102 benign extramedullary tumors of the
foramen magnum, Meyer and colleagues found that 40%
of patients had a normal neurologic exam at initial evalua-
tion.143 The clinical presentation of these tumors has fre-
quently simulated and been diagnosed as cervical
spondylosis, multiple sclerosis, demyelinating disease, sev-
eral degenerative diseases, and even occasionally hyste-
ria.140 A high degree of suspicion is required to make the
diagnosis of a meningioma before the tumor has grown to
cause significant impingement of the neural axis. In a study
of 16 benign extramedullary tumors of the foramen mag-
num, half of which were meningiomas, Akalan and cowork-
ers reported that only five cases were diagnosed within 6
months of their initial symptoms. Patients with symptoms
that began at least a year before admission had multiple
incorrect diagnoses prior to their final diagnosis and
appropriate treatment.144
Initially, patients often complain of a deep, aching pain
in the suboccipital and cervical regions. This pain is often
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
dura covering the anterior aspect of the posterior
fossa.139,140 Several sensory and motor deficits develop with
an increasing growth of the tumor. The deficits often sim-
ulate the relapsing-remitting pattern of multiple sclerosis
and therefore are very difficult to diagnose. Cold or burn-
ing dysthesias have been described as some of the most
common sensory changes in patients with foramen mag-
num meningiomas. These dysthesias often progress to
hypesthesias, diminished temperature sensation, and loss
of tactile or position sense. Trigeminal sensory loss in an
“onionskin” pattern, hyperesthesia, and trigeminal neural-
gia have also been reported as signs of foramen magnum
meningiomas.139
Progressive spastic quadriparesis or asymmetrical
pyramidal quadriparesis has been described as a common
clinical presentation in patients with foramen magnum
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

Preliminary results for the transcervical and transoral
approaches were dismal due to injury of the lower cranial
nerves and brainstem during tumor removal, resulting in a
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
tumor through posterior routes, the outcomes with these
approaches have also been disappointing. The far and
extreme lateral approaches were designed through modifi-
cations of the posterior approaches to obtain a better expo-
sure for anteriorly placed lesions. These approaches have
had better success at visualization of the foramen magnum
and may be combined with a variety of transpetrosal
approaches (Fig. 47-23).140,149 Some authors have also pro-
posed the use of a dorsolateral transcondylar approach for
ventral or ventrolateral meningiomas of the foramen mag-
num with little or no additional neurologic impairment or
craniospinal instability.148,150 In a recent paper studying
the role of occipital condyle resection in the far lateral
approach, Nanda and coworkers found that this was not
necessary for the safe and total resection of anterior
intradural foramen magnum meningiomas.151
In a recent report on 17 foramen magnum menin-
giomas, Goel and colleagues took a conventional poste-
rior suboccipital approach with a midline incision and
extension of the craniectomy laterally toward the side of
the tumor. With a tumor size ranging from 2.1 to 3.8 cm,
and a majority of lesions displacing the brainstem posteri-
orly, complete tumor resection was achieved in 14 of
17 (82%) patients and a subtotal resection was performed
in the other 3. No significant postoperative complications
occurred in the majority of patients, with an average follow-
up of 43 months. The authors concluded that a majority
C
C1
O
Meningiomas of the Posterior Fossa and Skull Base 827
of foramen magnum meningiomas can be resected
with a lateral suboccipital approach with microsurgical
techniques.142
Surgical Results
Dismal results have been reported for the surgical resec-
tion of foramen magnum meningiomas. In several early
series multiple lower cranial nerve deficits and brainstem
injuries were reported for the surgical excision of foramen
magnum meningiomas. These patients were often left
with severe postoperative deficits, including labile hyper-
tension, aspiration, and respiratory arrest.139,140 Patients who
survived surgery were often left with brainstem and lower
cranial nerve deficits that often required a tracheostomy
and feeding gastrostomy.
In a chapter review on foramen magnum meningiomas
in 1991, George reported an overall mortality rate of 13%
for 161 foramen magnum tumors. Approximately 68% of
patients had good results, 10% had fair results, and 9%
had poor results.146 In one of the earliest series of 74 fora-
men magnum meningiomas in 1941, Love and coworkers
reported 34 perioperative deaths due to complications.152
In 1980, Yasargil and Mortara reported an overall mortality
rate of 13.2% for these meningiomas in a review of 114
surgically treated cases. The overall neurologic outcome
was described as good in 79 of 114 (69.3%) patients, fair in
9 of 114 (7.9%), and poor in 11 of 114 (9.6%).74 In 1988,
Guidetti and Spallone also noted an operative mortality
rate of 11%.139 In a series of 102 benign intradural
extramedullary foramen magnum tumors in 1984, Meyer
and colleagues reported an operative mortality rate of 5%
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.)
C2
828 SURGICAL NEUROTOLOGY
Results were excellent in 75% of patients, mildly impaired
in 12%, and poor in 13%.143
In a recent series of 40 foramen magnum meningiomas
in 1996, George and coworkers achieved complete
removal (Simpson grade I or II) in 86% of these lesions
and 94% of intradural tumors. The posterolateral approach
was used in 31 of 40 (78%) patients. Subtotal resection
(Simpson grade III) was accomplished in 11% of cases.
Significant intradural extension and bony invasion were
the primary reasons for an incomplete resection.153
Clinical improvement, defined by the authors as a better
postoperative than preoperative functional status was
reported in 90% of patients, with worsening noted in
7.5% of patients. Three patients died as a result of surgery,
and no recurrences were noted with a mean follow-up of
4.8 years.153
In another recent series of 40 craniocervical junction
meningiomas in 1996, Samii and colleagues reported com-
plete removal in 63% and subtotal removal in 30% of
patients. The authors noted that an intracranial origin,
infiltrative or en plaque growth, and encasement of the
vertebral artery were independent predictors of incom-
plete tumor removal.154 Complications from surgery were
reported in 30% of patients. Postoperative tracheostomies
were necessary in four patients, and gastrostomies were
required in three. Aspiration secondary to lower cranial
nerve dysfunction was noted in four patients, two of whom
died after developing pneumonia, resulting in an overall
mortality of 6%.154 Other complications included transient
worsening of caudal cranial nerve function, facial nerve
palsies, and temporary gait ataxia. Three recurrences were
reported in this series, two of which were noted in patients
8 years after an incomplete removal of meningiomas.
Although preoperative cranial nerve deficits remained
postoperatively, sensory changes, dysesthesias, pain, and
gait ataxia improved during the first year following
surgery. The average Karnofsky score also improved from
63 ± 17 to 73 ± 12 after surgery.154
HEARING PRESERVATION
Hearing preservation after the surgical removal of a CPA
meningioma has been reported in multiple series to vary
between 33% and 100%.41,92,137,155–159 The variation in the
rate of hearing preservation is due to the unpredictability
of the tumor site in the CPA, the different degrees of audi-
tory nerve involvement as well as the scarcity of literature
on hearing preservation, and the inadequate reporting of
preoperative and postoperative audiometric data.92,137 In
addition, the absence of a universal classification scheme
and specific inclusion criteria for hearing results has made
TABLE 47-7. Hearing Classification of the American Academy of Otolaryngology
Hearing Class Description Pure Tone Average (PTA)
Class A Good PTA ≤ 30 dB
Class B Serviceable PTA ≤ 50 dB
Class C Measurable
Class D “Dead ear”
PTA, average of 500 Hz and 1, 2, 4 kHz.
the collection and analysis of hearing preservation data
particularly difficult.
The Committee on Hearing and Equilibrium guidelines
of the American Academy of Otolaryngology has estab-
lished a classification system by which preoperative and
postoperative audiometric data can be reported (Table 47-7).
This classification scheme is similar to one proposed by
Shelton and Hitselberger in 1991. Class A hearing is
defined as socially useful hearing with a PTA (500 Hz and
1, 2, and 4 kHz) of less than 30 dB and an SDS of greater
than 70%. Class B is described as serviceable hearing with
a PTA of less than 50 dB and an SDS of greater than 50%.
Class C hearing is defined as any measurable hearing loss,
and class D hearing is equivalent to the absence of any
measurable hearing.158 In a series studying the preopera-
tive and postoperative auditory function in patients with
CPA meningiomas, Schaller and coworkers proposed a
slightly different classification system: Classes I and II
correspond exactly to classes A and B of the prior classifi-
cation scheme. Class III was more specifically defined as a
PTA between 51 dB and 90 dB and an SDS between 5%
and 49%. Class IV was described as a PTA ranging from
91 dB to 100 dB with an SDS between 1% to 4%. Class V
was defined as a PTA and SDS with no response, corre-
sponding to class D. The combination of classes III and IV
hearing corresponds to class C.92
Hearing classification schemes have been used by some
authors and not by others. Samii and colleagues in 1985,
reported measurable hearing in 11 of 15 (73%) patients
postoperatively, but they provided no information regard-
ing the quality of the postoperative hearing.62 In a series of
12 patients in 1992, Nassif and coworkers reported an
overall hearing preservation in 11 of 12 (92%) patients, with
8 of 12 (67%) patients retaining class A or B hearing.137
Approximately 75% of patients in this series preserved their
preoperative hearing after the surgical excision of a CPA
meningioma.137 In 1995, Schaller and colleagues also
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
maintaining a class A or B level of hearing postopera-
tively.92 Like Nassif and colleagues,137 Schaller and col-
leagues92 also reported a similar percentage (69%) for
preservation of preoperative hearing. In 1996, in a study of
16 patients, Grey and coworkers reported a hearing
preservation in 8 of 16 (50%) patients. However, if serv-
iceable hearing or better (class A or B) was present preop-
eratively, 8 of 11 (73%) patients achieved preservation of
their hearing. Class A hearing, or socially useful hearing,
was maintained in 6 of 9 (67%) cases.158 In the most recent
study by Batra and coworkers in 2002, hearing preserva-
tion was attained in 10 of 11 (91%) patients, and 9 of
Speech Discrimination Score (SDS)
SDS ≥ 70%
SDS ≥ 50%
Any measurable hearing loss
Absence of any measurable hearing
 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
(Table 47-8).159 None of the patients in these studies expe-
rienced an improvement in hearing after surgery except
those in Schaller and colleagues’s study, who reported an
improvement in 2 of 13 (15%) patients.92
The ability to preserve hearing is based on multiple fac-
tors: the level of preoperative hearing, quality of hearing
in the contralateral ear, location of the tumor, extent of
cochleovestibular nerve involvement, size of the tumor,
age, and general health of the patient.158,160 Hearing
preservation surgery is usually performed via the suboc-
cipital/retrosigmoid, petrosal, middle fossa, extended mid-
dle fossa approach, or the petrosal approach (Figs. 47-24,
47-25, and 47-26).155 The retrosigmoid approach provides
Figure 47-24. Surgeon’s view of the floor of the middle cranial fossa. The
temporal lobe dura has been retracted, and the superior petrosal sinus can
be seen medially. The triangle region over the internal auditory canal
designates a safe region of drilling where the superior semicircular canal
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
performed medially at the level of the porus acousticus. Drilling should be
performed directly over the internal auditory canal when progressing
medially to laterally to avoid entering the otic capsule structures. Also note a
quadrangular region anteriorly known as Kawase’s quadrangle of the petrous
apex. Drilling in this quadrangle allows for the exposure of the ventral portion
of the cerebellopontine angle and posterior fossa. (Used with permission
from Jackler RK: Atlas of Neurotology and Skull Base Surgery. Philadelphia,
Mosby, 1996.)
a wide exposure for the removal of posteriorly but not
anteriorly based meningiomas. The middle fossa approach
allows for resection of tumors in the IAC as well as the
middle cranial fossa. Anteriorly located lesions as well as
meningiomas with a significant component in the CPA can
be resected with an extended middle fossa approach. Grey
and coworkers reported that 6 of the 16 patients required
additional exposure with the retrolabyrinthine and middle
cranial fossa approaches. Although this indicated the
increased size of the tumors and the difficulty encountered
in their removal, four of the six patients (66%) retained
their preoperative hearing. The authors suggest that addi-
tional bony removal did not result in a significant loss of
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
premeatal tumors had a class IV or V hearing preopera-
tively.92 The authors considered these patients as having
nonserviceable hearing preoperatively and therefore
excluded them from being considered for hearing preserva-
tion surgery. In the series by Batra and coworkers, hearing
preservation surgery was attempted in 10 patients with
retromeatal tumors. Class A hearing was preserved in eight
of nine (90%) patients, with one patient relegated to class B
hearing. Another patient with a class B hearing achieved a
class C hearing status postoperatively. Ten of the 11 patients
with premeatal tumors did not have serviceable hearing pre-
operatively, and therefore hearing preservation surgery was
830 SURGICAL NEUROTOLOGY
Figure 47-25. The surgeon’s view of a
transtentorial combined middle and posterior
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.)
Figure 47-26. The petrosal approach may be further enlarged by resecting
the bone of the middle fossa floor primarily in Kawase’s quadrangle. This is
still a hearing conservation approach as the cochlea, labyrinthine apparatus,
and the internal auditory canal are kept intact. (Used with permission from
Jackler RK: Atlas of Neurotology and Skull Base Surgery. Philadelphia,
Mosby, 1996.)
VL
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
did the same. Although this may seem like a noteworthy dif-
ference, the authors did not find this result to be statistically
significant (p = 0.54, Mann-Whitney U test).158 Schaller and
colleagues also did not find an association between tumor
size and preservation of preoperative hearing. In their study

Figure 47-27. Axial T1-weighted gadolinium-enhanced MRI scan revealing a
large posterior petrous face meningioma, which is posterior to the cranial
nerves. Despite the size of this tumor, it is easily accessible since arachnoid
planes separate the anterior portion of the tumor from the left-sided posterior
fossa cranial nerves.
of 13 patients, all 3 patients with meningiomas less than 2
cm and the 1 patient with a tumor between 2 cm and 3 cm
retained their preoperative hearing classification. In con-
trast, only six of nine patients (66%) with meningiomas
larger than 3 cm maintained their preoperative hearing sta-
tus.92 However, this difference also did not achieve statisti-
cal significance. Multiple authors including Nassif and
coworkers have not found any relationship between hearing
preservation and the size of the a CPA meningioma.137
Several investigators have also studied the effect of
tumor extension into the IAC and hearing status. Grey and
coworkers discovered that the likelihood of having class D
hearing preoperatively was directly related to the presence
of tumor in the IAC. If tumor involvement was present in
the IAC, the chance of profound hearing loss was 45%
versus 5% if no involvement was present.158 The authors
noted that the preoperative hearing class was maintained
in 2 of 3 (66%) cases when the meningioma occupied the
IAC, 1 of 3 cases when the tumor entered the porus
acousticus, and 5 of 10 cases when the tumor did not enter
the IAC. In agreement with the data presented by Grey
and coworkers, Schaller and colleagues also demonstrated
that extensive tumor infiltration in the IAC is associated
with class D hearing.92 Furthermore, they found that the
amount of tumor in the IAC does not necessarily correlate
with the presence of hearing. The authors proposed that
tumor involvement of the IAC may be an “all or none”
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
reported similar preoperative and postoperative hearing
results for all three of their patients with CPA menin-
giomas. In particular, they described a dramatic hearing
improvement in one patient 6 months after surgery.155
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-
leagues, who recommended not pursuing a hearing preser-
vation approach for patients with less than a class A
hearing status, themselves reported an improvement in
postoperative hearing in two (15%) of their patients with a
poor preoperative hearing status.92 Goebel and Vollmer
mention that even when patients have poor preoperative
auditory function, a hearing preservation approach should
be attempted.160 Maurer and Okawara go so far as to rule
out the use of a translabyrinthine approach given the
possibility of hearing preservation.59 In a study of CPA
meningiomas in 2000, Voss and coworkers suggested that
a retromeatal meningioma, with minimal IAC involve-
ment, and absence of inner ear invasion on temporal bone
CT scans should prompt hearing preservation surgery despite
a poor preoperative hearing status.79 Although several authors
agree in part with this assessment, Batra and coworkers
correctly point out that more data are required before
hearing conservation surgery can be recommended for all
patients regardless of their preoperative hearing loss.159
Two theories have been offered for the cause of vestibu-
locochlear dysfunction even in the presence of an anatom-
ically preserved CN VIII. Vascular compromise of the
labyrinth or the nerves themselves is believed to be the
most likely cause of auditory and vestibular dysfunction.158
Intraoperatively, the vascular compromise is thought to
result from a spasm of the labyrinthine arteries induced
by mechanical irritation of the neurovascular bundle or
832 SURGICAL NEUROTOLOGY
coagulation of the labyrinthine vessels in the event of a
persistently bleeding tumor.92 Belal and coworkers pre-
sented evidence that postoperative hearing loss was due to
compromise in vascular supply. Stretching and trauma to
the nerve have also been postulated to play a lesser role in
the loss of function.158 The use of evoked otoacoustic emis-
sions may help to differentiate between the above-men-
tioned causes of CN VIII dysfunction since emission loss
is encountered only with disruption of vascular supply to
the cochlea and not retrocochlear nerve damage. Grey and
coworkers reported that only one of their patients with
class D hearing had evoked emissions preoperatively, and
so attributed the profound hearing loss to vascular com-
promise in the rest of their patients.158
Recent reports have shown the preservation of hearing
even after surgical removal of a large meningioma suspected
to have caused significant vascular compromise to the
labyrinth. A hypothesis for the remarkable postoperative
hearing in some patients was recently suggested by
Buchheit. The blood supply to the cochlea is usually
derived from the internal auditory artery, a branch of the
basilar artery. Buchheit believes that some collateral circu-
lation to the cochlea is provided by the stylomastoid artery,
a branch of the posterior auricular artery. This is not, how-
ever, a universally held belief. Thus, even in cases of severe
damage to the internal auditory artery, blood flow would
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
of hearing preservation in difficult cases even with the
most experienced surgeons.59
Although current opinion given case studies of dramatic
hearing improvement suggests that hearing preservation
surgery should be attempted even in patients with poor
preoperative hearing, some authors suggest a hearing abla-
tive approach such as the translabyrinthine or transcochlear
approach if the lateral two-thirds of the IAC or vestibule
are extensively involved or if massive IAC involvement or
encasement by the tumor of the vestibulocochlear complex
occurs.160 However, a good level of preoperative hearing
and questionable status of the contralateral ear may also
prompt the surgeon to attempt hearing preservation sur-
gery at the expense of reduced exposure and increased oper-
ative time.160 Grey and coworkers disagreed with Schaller
that hearing preservation surgery should be reserved for
patients with class A hearing only. These authors felt that
class B hearing is still serviceable, whereas Schaller and
colleagues believe that preservation of a classes B or C
hearing is of little functional importance.92,158
The preservation or recovery of clinical vestibular
function after surgical removal of CPA meningiomas was
reported by Prasad and colleagues in 1993.157 All three
patients in the study experienced an improvement in
clinical vestibular function after surgery, despite an absent
or minimal caloric function. The vestibular results reported
by Grey and coworkers158 also suggested improvement
following surgical resection. Eight of 13 patients com-
plained of imbalance preoperatively, whereas only 1 of
16 experienced unsteadiness postoperatively. However,
six patients were found to be unsteady postoperatively
when the vestibular system was stressed with tests that
required the patient to walk in the dark or turn rapidly.
A comprehensive clinical examination including the assess-
ment of cerebellar ataxia, dysdiadochokinesis, Romberg’s
test, walking along a line with eyes open (WALEO), and
walking along a line with eyes closed (WALEC) were con-
ducted to assess the cerebellar and vestibular function of
each patient. Improvement was noted for patients with all
tests except the WALEC, signifying the importance of the
visual system compensation in patients with vestibular dys-
function.158
Given the possibility of hearing preservation for menin-
giomas and the poorer relative hearing results associated
with vestibular schwannomas, it is imperative to obtain an
accurate preoperative diagnosis of any CPA lesion.92 The
availability of modern imaging techniques has not only
assisted in making the diagnosis of a CPA meningioma but
also identifying the precise location of the tumor. The
preoperative identification of a meningioma may alter the
surgical strategy since the factors influencing the risk of
damage to the CN VII–VIII nerve complex are different
from those for vestibular schwannomas.92 The position of
the meningioma also helps to plan the surgical approach as
well as set realistic expectations for hearing and vestibular
nerve preservation. Although imaging techniques are still
in their infancy, the knowledge collected in these studies
serves as encouragement for surgeons to plan and expect
to preserve the CN VII–VIII nerve complex.158
FACIAL NERVE PRESERVATION
Satisfactory preservation of the facial nerve has been noted
in most series in the literature. Facial nerve preservation
defined as an absent to moderate postoperative impair-
ment after removal of a CPA meningioma was recently
noted in two large series to be 69% and 94%.92,159 Similar
to the results available for hearing preservation, minimal
preoperative and postoperative data exist for facial nerve
function in the literature. The location, and the size of the
meningioma play a role in the postoperative function of
facial nerve. The degree of tumor involvement in the
region of the IAC may also affect facial nerve preservation.
In contrast to the data accumulated for hearing preserva-
tion, however, surgeons have, of late, consistently used the
facial nerve grading system introduced by House and
Brackmann to quantify postoperative CN VII function.165
In a recent study, the facial nerve was anatomically pre-
served in 11 of 13 (85%) patients. Schaller and colleagues
reported an HB grade I preservation in 6 of 10 (60%)
patients. The other four patients who had no preoperative
deficits were noted to have a postoperative CN VII dys-
function of HB grade II, 20%, HB grade III/IV, 10%, and
HB grade VI, 10%. All three patients with a preoperative
functional weakness (HB grade II–VI) had a total facial
nerve deficit (HB grade VI) immediately after surgery.92 A
similar percentage of normal facial nerve function was
recorded by Batra and coworkers, who reported an HB
grade I preservation in 11 of 17 (65%) patients in their
series of 21 patients, 17 of whom had facial nerve preser-
vation data available. Two of 17 (11.5%) patients each
retained an HB grade II and III, respectively, and 1 of 17
(6%) patients each maintained an HB grade IV and VI,
respectively. Overall, 13 of 17, 76%, of patients maintained

an HB grade I or II postoperatively. The facial nerve for
the patient with a postoperative HB grade VI had to be
transected due to encasement of the nerve in tumor. One
patient with a preoperative HB grade of VI improved to an
HB grade IV after tumor removal (Table 47-9).159 Given
these reasonable results, the facial nerve dissection should
be attempted in every CPA meningioma case.
Size does not appear to have a significant effect on
the postoperative CN VII function. Schaller and col-
leagues noted a preoperative and postoperative total facial
nerve paralysis (HB grade VI) in patients with large
tumors. One of three (33%) patients with meningiomas
less than 2 cm had a worsening of facial nerve function
compared with none of the patients with tumors between
2 and 3 cm and three of nine (33%) patients with tumors
greater than 3 cm. The facial nerve was transected in 2 of
11 (15%) patients with large meningiomas, leading the
author to conclude that the risk of poor facial nerve func-
tion increased in large tumors due to a difficult intraoper-
ative dissection.92 Batra and coworkers also noted that
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
sizes between 2 and 4 cm, and one of two patients (50%)
had normal CN VII function postoperatively. Based on the
data, tumor size was not found to statistically affect the
postoperative facial nerve function using the Fischer exact
test ( p = 0.52).159
Akin to hearing preservation, continuity of CN VII has
been reported to vary based on the site of a meningioma.
Facial nerve dysfunction was noted to be higher in tumors
located anterior to the IAM, thereby displacing the nerve
posteriorly, partially obstructing tumor resection primarily
due to a difficult intraoperative dissection of nerve. Schaller
and colleagues reported a grade I through IV preservation
of the facial nerve in all eight meningiomas located poste-
rior to the IAM. However, only one of five (20%) patients
with premeatal meningiomas retained grade I through IV
facial function.92 The authors reported a preservation of
HB grade I in six of eight (75%) patients with retromeatal
meningiomas. In contrast, a HB grade I was not seen in
either of the two patients (0%) with premeatal tumors.92
Batra and coworkers also reported a statistically significant
difference ( p = 0.025) in the preservation of postoperative
facial nerve function and retromeatal tumors. All 10 of 10
patients (100%) with retromeatal tumors treated with a
retrosigmoid approach retained their HB grade I facial
function. In contrast only one of seven patients (14%) with
premeatal tumors maintained HB grade I facial function
postoperatively. The CN VII function in the rest of their
patients was as follows: HB grade II in two patients, HB
TABLE 47-9. Facial Nerve Results for CPA Meningiomas—
Five Series; 35 Cases
Preoperative Postoperative
HB Grade I–II 30 23
HB Grade III–IV 1 6
HB Grade V–VI 4 6
Data taken from references 59, 61, 112, 178, and 182.
Meningiomas of the Posterior Fossa and Skull Base 833
grade III in two patients, HB grade IV in one patient, and
HB grade VI in the final patient.159
The causes for the dismal rate of facial nerve preserva-
tion in meningiomas located anteromedial to the IAM are
similar to those reported for poor hearing preservation for
these tumors after surgery. The intimate relationship
between premeatal tumors and the neurovascular bundle
as well as the presence of the CN VII–VIII complex
between the surgeon and the tumor are the primary rea-
sons for the poor facial nerve preservation during dissec-
tion of a premeatal meningioma.57,158 Preoperative facial
nerve paresis has also been noted as a risk factor for post-
operative CN VII dysfunction. Schaller and colleagues
reported that all three patients with preoperative facial
nerve weakness ended up with HB grade VI postopera-
tively.92 Batra and colleagues described one patient with
HB grade III before surgery declining to HB grade VI
after tumor removal. However, the authors also noted the
improvement of CN VII function from HB grade VI to
grade IV.159
RECURRENCE
Although surgical excision is the definitive therapy for the
treatment of meningiomas, recurrence and progression of
disease have plagued surgeons for decades, despite the
seemingly complete removal of these tumors.166 Multiple
factors influencing recurrence have been recognized ever
since Cushing began operating on patients for the surgical
resection of meningiomas.167 In his series of 295 patients,
43 required reoperation for “actual or symptomatic” recur-
rence. In addition, 76 patients died due to an incomplete
removal of the meningioma. Although Cushing did not
report a recurrence rate, an analysis of his data by Simpson
suggests that it was more than 15%. In 1957, Simpson
reemphasized the role of the extent of resection, location,
and histology of the tumor in influencing the recurrence
of meningiomas.168 Since then, several authors have
attempted to elucidate the factors hastening tumor recur-
rence in order to initiate close follow-up and early postop-
erative treatment (e.g., radiotherapy) in patients with an
increased risk of tumor growth and progression.166
Few papers in the literature have addressed the incidence
and causes of recurrence extensively. One of the reasons is
that meningiomas are benign tumors that grow slowly and
therefore lend themselves to retrospective study. In addi-
tion, several early papers oversimplified the statistical
analysis required for calculating the recurrence rate. In
many cases recurrence was calculated as a proportion of all
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
correct for the differences in the follow-up period known
as life-table analysis.166,169 However, this method cannot
correct for the quality of postoperative follow-up, which
varies tremendously among studies. In many studies,
patients are not followed until clinical recurrence has
occurred. Also, the rate of late recurrence for menin-
giomas is unknown because few patients are followed for
periods of 15 to 20 years.169 Furthermore, the methods
used for detecting recurrence have varied; in early series
834 SURGICAL NEUROTOLOGY
recurrence was defined by a return of clinical symptoms,
whereas in others recurrence was measured with modern
imaging techniques. Finally, subjective data such as the
functional status of a patient is rarely used as a criterion to
measure recurrence after surgery; consideration of only
objective data such as radiologic evidence or the need for
a second operation for assessing recurrence result in an
underestimation of the survival and recurrence rates.166
In 1957, Simpson defined recurrence as the reappearance of
symptoms due to tumor growth after a period of sympto-
matic relief.168 In 1983, Adegbite and coworkers introduced
the term progression, which implied a “continuance in
growth” subsequent to incomplete tumor removal.167 With
the advent of modern imaging techniques, the definition of
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
despite complete excision.166 These authors defined the pro-
gression as an increase in tumor size after subtotal removal,
confirmed with imaging studies. Using this definition of
recurrence, Melamed and coworkers calculated an overall
recurrence rate of 29% in a series of 126 patients in 1979.
This figure was calculated without life-table analysis.170 In
contrast, in 1986 Jaaskelanian estimated the overall recur-
rence rate to be 19% at 20 years using life-table analysis in a
series of 657 patients.169 In a study of 225 patients in 1985,
Mirimanoff and colleagues reported an absolute 5-, 10-, and
15-year survival probability of 83%, 77%, and 69%, respec-
tively.166 In 1983, Adegbite and coworkers noted similar
recurrence-free rates of 80% at 5 years, 70% at 10 years,
and less than 50% at 20 years in their report on 114
patients.167 In the most recent study of 286 patients with
intracranial meningiomas in 1999, Ayerbe and coworkers
reported recurrence rates of 14%, 37%, and 61% at 5, 10,
and 15 years, respectively. All these patients were followed
with either CT or MRI from 3 to 17 years since the initial
surgery.171
A classification scheme for measuring the degree of sur-
gical excision was proposed by Simpson in 1957. The author
introduced five distinct grades of surgical resection: Grade I
is defined as a macroscopically complete excision of tumor
including its dural attachments and abnormal bone. This
includes removal of the sinus wall if infiltrated with tumor.
A grade II resection is described as resection of the tumor
and its extensions with coagulation of its dural attach-
ments. Grade III is defined as a resection of the intradural
tumor without removal or coagulation of its dural attach-
ments. A grade IV resection is described as an incomplete
tumor removal, and a grade V excision is a simple decom-
pression with or without a biopsy (Table 47-10).168
The extent of surgical resection has been reported to
play a major role in the recurrence rate of meningiomas.
Multiple studies in the literature have noted a higher inci-
dence of recurrence/progression with an incomplete or
partial resection. In an early series of 126 patients,
Melamed and coworkers noted that two-thirds of patients
with a radical excision of the tumor remained recurrence-
free. The authors defined radical excision as either the
complete removal of the tumor with resection of the
meninges and invaded bone or total tumor removal with
or without cauterization of the meninges. In contrast,
nearly one-half (44%) of patients with an incomplete
TABLE 47-10. Simpson’s Grading Scheme for Extent
of Tumor Resection
Simpson’s Grade Degree of Removal
Grade I Macroscopically complete removal of the tumor
with excision of its dural and bony attachments
Grade II Macroscopically complete removal of the tumor
and its extensions with endothermy coagulation
of its dural attachments
Grade III Macroscopically complete resection of tumor without
removal or coagulation of its extradural extensions
Grade IV Partial removal leaving intradural tumor in situ
Grade V Simple decompression of the tumor
From Simpson D: The recurrence of intracranial meningiomas after surgical treatment.
J Neurol Neurosurg Psychiatry 20:20–39, 1957.
removal of tumor experienced recurrence in this study.170
Simpson noted recurrence rates of 9%, 19%, 29%, and
40% at 10 years for patients with a grades I, II, III, and IV
resection, respectively.168 In a more recent series using life-
table analysis, Mirimanoff and colleagues noted a 5-, 10-,
and 15-year recurrence-free survival rate of 93%, 80%,
and 68%, respectively, following complete tumor removal.
In contrast, after a subtotal excision for the same period,
the authors reported a progression-free survival rate of
63%, 45%, and 9%, respectively. This difference was
highly statistically significant ( p < 0.0001) when assessed
with the Mantel-Haenszel test. In addition, patients with
subtotally excised meningiomas had a high likelihood of a
second operation at 5, 10, and 15 years (25%, 44%, 84%)
when compared with 6%, 15%, and 20% for patients with
completely resected meningiomas.166
Adegbite and coworkers also noted the grade of the ini-
tial surgery to have a statistically significant influence on
recurrence. In their series, the percentage of patients free
of recurrence 5 years after a grade I, II, III, and IV surgi-
cal excision were 86%, 82%, 100%, and 48%, respectively.
The number of patients with a grade III removal were too
few for an accurate statistical analysis. Nevertheless, the
trend suggested that a higher degree of tumor removal was
associated with a lesser likelihood of recurrence. The dif-
ference in results between patients with a grade I and II
surgical removal versus those with a grade IV excision was
statistically significant.167 In an analysis of 53 patients,
Marks and coworkers found a recurrence rate of 9.5%
after complete resection of tumor versus a rate of 18.4%
after subtotal removal.172 In a study of 257 patients, simi-
lar results were noted by Chan and Thompson in 1984,
who reported a frequency of tumor recurrence after a
grade I, II, III, IV, and V removal to be 11%, 22%, 50%,
37%, and 100%, respectively. A difference of 3.3 years was
found in the average survival time between patients with
complete removal versus those with partial removal of the
tumor.173 Given these data, a surgeon must balance the
extent of resection with the likelihood of recurrence and
postoperative functional status of the patient.
The likelihood of recurrence or progression of a menin-
gioma has also been reported to vary based on the location
of the tumor. Parasagittal meningiomas were noted by
Simpson and Melamed and coworkers to have a high rate
of recurrence.168,170 Melamed and coworkers suggested
that this was most likely due to invasion of the superior

sagittal sinus wall.170 Waga and colleagues, on the other
hand, found meningiomas of the convexity to be associated
with the highest rates of recurrence.167 However, the
authors noted that when malignant tumors were excluded,
meningiomas of the falx were found to recur most often.167
Contradicting these findings, Mirimanoff and colleagues
reported low recurrence and progression rates at 5 and
10 years for meningiomas of the convexity (3% and 25%)
and parasagittal area (18% and 24%).166 In an analysis of
risk factors for recurrence, Ayerbe and coworkers found
tumors at the petroclival and parasaggital locations to cor-
relate with a high degree of recurrence.171
Posterior fossa meningiomas were reported to have a
high risk of recurrence by Melamed and coworkers in
1979. These tumors showed a recurrence of 54.5% in one
of the earliest series studying the recurrence of intracranial
meningiomas. The authors attributed this high rate of
recurrence to the incomplete removal of these tumors due
to their close proximity to critical neurovascular struc-
tures.170 In the series by Mirimanoff and colleagues in 1985,
complete excision was noted in only 10 of 31 (32%) poste-
rior fossa meningiomas, with a subtotal resection in the
other 68% of these tumors. The lesions displayed overall
5- and 10-year recurrence rates of approximately 20% and
40%, respectively.166 In a study of 257 patients in 1984,
Chan and Thompson reported an overall recurrence rate
of 20% for posterior fossa meningiomas. They reported
no recurrence for patients with a grade I resection 0/7
(0%) and only one recurrence for a patient with a grade II
resection. However, 8 (42%) recurrences were noted in
the 19 patients that underwent a grade IV or V removal.173
Due to the low rate of total excision in the posterior fossa,
meningiomas in this location were associated with inter-
mediate to high rates of recurrence when compared with
tumors in other locations.
In contrast to these data, Adegbite and coworkers
reported no significant influence of location on recur-
rence. Although differences in the percentage of tumor
recurrence were observed between convexity, parasagittal,
sphenoid wing, and posterior fossa meningiomas among
others, this variation was not statistically significant.167
However, given that the location of a meningioma deter-
mines the extent of resection which in turn influences
the rate tumor recurrence, the site of a meningioma may
be considered an indirect factor in tumor recurrence and
progression.
The complete removal of tumor also resulted in a longer
observed survival time as well as an improved quality of life
compared with partial tumor excision. Given the difficulty
of complete tumor resection, posterior fossa meningiomas
had the lowest observed average survival period of 5.9 years
compared with parasagittal, falcine, convexity, olfactory
groove, and sphenoidal ridge meningiomas.173 Further-
more, patients with gross total removal of recurrent tumor
had a significantly longer duration of subsequent survival
with good functional status than those with partial tumor
resection. A longer period of survival was also found in
patients with meningiomas smaller than 4.5 cm in diame-
ter.173 Patients with smaller meningiomas did not have
longer survival rates than individuals with larger menin-
giomas but led a better quality of life after tumor removal.
The most important factor for determining postoperative
Meningiomas of the Posterior Fossa and Skull Base 835
survival, however, remains the preoperative clinical condi-
tion of the patient.
In a study of 124 intracranial meningiomas in 1989,
Kajiwara and colleagues reported an association between
meningioma recurrence and the age of the patient, with
the majority of recurrences found in patients younger than
age 60 years. A particularly high recurrence rate was found
in individuals younger than age 40. In addition, the mean
age of patients with recurrent tumors was younger than
that for patients with no recurrences.174 In contrast, several
other studies do not report an association between a
patient’s age or gender with an increased rate of recurrence
and progression. In the 34 cases of recurrence, Melamed
and coworkers in 1979 reported a male-to-female ratio of
3:2, equal to that found in the entire group of 126
patients.170 In 1985, Mirimanoff and colleagues found no
association between recurrences or progression of the
tumor with such factors as the age, gender, or duration of
symptoms. The recurrence or progression-free survival
rates at 5 and 10 years for females (83% and 68%) and
males (84% and 66%) were nearly identical. There was
also no difference in the rates at 5 and 10 years between
patients younger than 50 years (83% and 61%) and indi-
viduals older than 50 years old (84% and 75%).166 In
addition, the time from the onset of symptoms to surgical
resection was less than 6 months in 59 patients, 6 months
to a year in 54 patients, 1 to 2 years in 60 patients, and
more than 2 years in 52 patients. The recurrence- or
progression-free rates of 76%, 63%, 65%, and 71% were
similar in all four groups at 10 years.166
Melamed and coworkers in 1979, reported no correla-
tion between the consistency of the meningioma defined
as hard, friable, “suckable,” necrotic, or vascular and the
rate of recurrence.170 In contrast, in a study of 657 patients
in 1986, Jaaskelanian reported soft consistency of the
tumor to strongly and independently correlate with recur-
rence (p < 0.01). The author reported that 15 of the 79
meningiomas had been soft and “suckable” during surgery,
resulting in a recurrence rate of 34% at 20 years. The
author suggested that soft meningiomas tended to recur
because they were more apt to tear and be left behind in
the tumor bed during surgical removal. In addition to soft
consistency of the tumor, the author also found simple
coagulation of the tumor base and invasion of bone to be
risk factors for recurrence. Approximately 34% to 56% of
patients with two of the three risk factors, 15% to 24% of
patients with one of the three risk factors, and 11% with
no risk factors experienced a recurrence within 20 years.169
Specific histologic types of meningiomas have been
noted to correspond to a higher rate of recurrence. In 1970,
Crompton and Gauthier-Smith suggested that syncytial
meningiomas are most likely to recur, whereas fibroblastic
meningiomas are least likely to do so.175 However, recent
studies have not found a statistically significant correlation
between a particular histology and the duration to recur-
rence. Simpson in 1957 and Melamed and coworkers in
1979 found no correlation between any particular histology
and an increased rate of tumor recurrence.168,170 Adegbite
and coworkers did not find any relationship between
recurrence and the three most common histologic groups
for meningiomas, namely, the syncytial, transitional, and
fibroblastic subtypes.167 The authors did, however, find a
836 SURGICAL NEUROTOLOGY
5-year recurrence-free survival rate of only 32% for
angioblastic and malignant meningiomas. However, the
small sample size of these tumors did not allow for a sta-
tistically significant comparison.167 Chan and Thompson
reported that the average survival of 3.6 years for patients
with malignant tumors was not significantly different from
that for benign meningiomas.173
Although no specific histology is associated with an
increased recurrence, high cellularity is often observed in
recurrent meningiomas. Two early studies by Skullerud and
Loken in 1974 and Jellinger and Slowik in 1975 found an
increased cellularity and mitotic rate in recurrent tumors.176
Waga and coworkers also noted histologic malignant
changes in 6 of 19 recurrent meningiomas.167 Crompton
and Gautier-Smith believed that an increased number of
mitoses, greater extent of necrosis within the tumor, and
infiltration of the tumor into adjacent brain predicted a
greater chance of recurrence.175 Melamed and colleagues, in
agreement with these authors, also found that cerebral infil-
tration, numerous mitoses, and cellular pleomorphisms
were associated with a higher rate of recurrence.170 The
study by Adegbite and coworkers in 1983 noted that 6 of
the 21 recurrent meningiomas displayed a greater degree of
cellularity or increased mitotic figures.167 Marks and col-
leagues in 1986 also noted mitoses and areas of focal necro-
sis to correlate with a higher recurrence rate.172 In a review
of 82 cases in 1986, De la Monte and coworkers noted
the following histopathologic factors were associated with
recurrence: hypervascularity, hemosiderin deposition,
growth of tumor in sheets, prominent nucleoli, mitotic fig-
ures, single cell or group necrosis, nuclear pleomorphism,
and an atypical or malignant tumor grade.177 All these stud-
ies suggest a more aggressive cellular histology for recurrent
tumors. In a study of 286 patients in 1999, Ayerbe and
coworkers found atypical and malignant histologic types,
nucleolar prominence, and the presence of greater than 2
mitoses/hpf to correlate with a higher rate of recurrence.171
The assessment of DNA has also been used to predict
meningioma recurrence. A high proliferation index deter-
mined by flow cytometry analysis has been associated with
recurrent meningiomas.178 In a study by May and colleagues
in 1989, a higher proliferation index was observed in recur-
rent meningiomas than in nonrecurring ones. The two
groups of patients with recurrent and nonrecurring tumors
were matched for age, gender, and length of follow-up.
A greater number of mitoses and areas of focal necrosis
were noted in the recurrent group. Foci of necrosis were
seen in four of the nonrecurring tumors compared with
seven of the recurrent ones. In addition, mitotic figures were
seen in 4 of nonrecurring tumors compared with 12 for the
recurrent group.178 Flow cytometry may play a role in pre-
dicting the clinical behavior and therefore recurrence in
these cases. This study concluded that a proliferative index
of greater than 20% in any tumor suggests that it may
recur, despite complete resection and a benign histology.
RADIATION THERAPY
The benefit of radiotherapy as an adjunctive treatment
for meningiomas has been established in a few limited stud-
ies. In a study of 58 patients in 1975, Wara and coworkers
studied the role of fractionated external beam radiotherapy
(5000 to 5500 cGy) in treatment of subtotally resected
(Simpson grade IV) meningiomas. Approximately 5 years
after treatment, the authors found a recurrence rate of 29%
in the irradiated group versus 74% in the nonirradiated
group.179 In a more recent study of 135 meningiomas not
localized to the posterior fossa, Barbaro and coworkers in
1987 noted a similar difference in the recurrence rates
between meningiomas receiving and those not receiving
radiation treatment. Of the 51 patients who underwent a
complete resection and did not receive radiation therapy,
only 2 (4%) had a recurrence. Among the 84 patients in the
study who underwent an incomplete resection, a recurrence
rate of 60% was noted in the 30 patients who did not receive
radiation treatment, whereas the 54 patients who were given
radiotherapy had a recurrence rate of 32%. The authors also
reported a longer median time to recurrence in the irradi-
ated versus the nonirradiated group, with a 125-month hia-
tus in irradiated patients versus 66 months in patients who
did not receive irradiation, (p < 0.05). This large series con-
tained 23 posterior fossa meningiomas, 21 of which under-
went subtotal resection. Of these 21 posterior fossa
meningiomas, 16 did not receive radiation treatment.180
A more recent study of benign partially resected menin-
giomas by Miralbell and colleagues in 1992 compared the
recurrence rates between 36 patients treated with surgery
and radiation therapy versus those in 79 patients treated
with surgery alone. The authors found a recurrence rate of
12% for patients treated with subtotal resection and radi-
ation therapy (5000 to 6000 cGy). This compared with a
rate of 52% for patients treated only with a subtotal resec-
tion. The paper did not reveal the anatomic distribution of
meningiomas in this study.181 All these studies suggested
that radiotherapy is beneficial as adjunctive therapy for
incompletely resected benign meningiomas. However,
additional studies need to be performed to prove an
unequivocal benefit in these patients.34 Patients with
malignant meningiomas, however, have been determined
to greatly benefit from radiation therapy. Radiation ther-
apy may also be used for the palliation of inoperable and
recurrent tumors.167
Stereotactic photon-beam radiosurgery (gamma knife),
which was initially used for a limited number of patients, is
now being used with greater frequency. Patients with subto-
tally resected meningiomas, individuals with recurrent
tumors in locations associated with unacceptable surgical
morbidity, and elderly patients with poor functional status
are some of the groups that have benefited from stereotac-
tic radiosurgery. In a study of 50 patients with intracranial
meningiomas, which included six posterior fossa menin-
giomas, Kondziolka and colleagues reported a 2-year tumor
growth rate control of 96%.182 Some of the complications
with this treatment modality were reported by Al-Mefty and
coworkers in a series of 58 patients who received an aver-
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-
gioma, were noted in 19% of patients.183 Brainstem and
cerebellar necrosis was also noted by Miralbell and col-
leagues in their series of meningiomas.181 The role of
stereotactic radiation therapy is expected to increase in the
treatment of meningiomas in the near future.

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172. Marks SM, Whitwell HL, Lye RH: Recurrence of meningiomas
after operation. Surg Neurol 1986;25:436–440.
173. Chan RC, Thompson GB: Morbidity, mortality, and quality of life
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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

Congenital cholesteatoma, or epidermoid cyst of the tem-
poral bone, may occur in the middle ear, the mastoid, the
petrous apex, or in the cerebellopontine angle (CPA).
Cruveilhier' in 1829 was among the earliest to identify
intracranial epidermoid tumors. After his descriptions of
three cases, they were called Cruveilhier's pearly tumors in
the literature for the next 100 years. Muller2 first used the
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
was not always present in the four cases he presented. In
1897, Bostroem" outlined the embryology of these tumors
and dubbed them epidermoid. By 1943, Rand and Reeves'
found about 200 cases in their review of the world litera-
ture and added 21 cases of their own.
Epidermoid cysts comprise 0.2% to 1.5% of all intracra-
nial tumors, and the posterior fossa is the most frequent
intracranial site for their appearance." In the CPA, epider-
moid cysts are the third most common lesion, constituting
4.6% to 14% of all tumors in this region.Y Other locations
by decreasing frequency include the parasellar area, clival
area, lateral recess of the fourth ventricle, and petrous
apex." Mahoney!" analyzed 142 cases of cranial and
intracranial epidermoid cysts and found 53 (37%) in the
CPA Yamakawa and colleagues II reported the location of
45 intradural epidermoid cysts: 46% CPA, 15% middle
fossa,.15% cerebral hemisphere, 9% suprasellar, 9% third
ventricle, and 6% fourth ventricle. Nager" reviewed the
literature and concluded that 30% to 40% of epidermoid
cysts are found in the CPA, where they account for 6% to
7% of all CPA tumors. The tumors extend linearly along
planes of least resistance to the middle fossa, foramen
magnum, and to the contralateral CPA; enveloping neu-
rovascular structures along the way.9,12 Multiple epidermoid
cysts almost never occur." CPA epidermoid cysts appear in
any age group, but the majority are identified in the third
and fourth decades.V They present with progression of
symptoms after a long period of slow growth. 8
extradural (cranial or diploic) epidermoid cysts and from der-
moids. Intradiploic epidermoid tumors are slow-growing
masses that present as a painless swelling of or defect of the
cranium.'! These tumors probably develop from indusion
of ectodermal elements during closure of the neural
groove.f-!' Dermoid tumors contain hair follicles and
gland tissue and tend to occur in the midline" and are four
to nine times less common than epidermoid cysts.'?
EMBRYOLOGY
In 1854, Von Remak first advanced the view that epider-
moid cysts arise from epithelial cell rests early in embry-
onic development.l" Bostroem" also leaned toward an
epithelial origin of epidermoid cysts, suggesting that they
arose from embryonic epithelial rests at a fairly late stage
of fetal development. Bostroem regarded dermoids as
developing from a younger and more primitive cell layer
that may give rise to epithelial and mesothelial tissues,
unlike epidermoid cysts, which are composed of deriva-
tives of epithelial tissue only." Scholtz'! described the
inclusion of ectodermal elements at the time of the closure
of the neural groove during the third to fifth week of
embryonic life, when the neural ectoderm separates from
the cutaneous ectoderm; he surmised that these misplaced
cells give rise to dermoid or epidermoid tumors in the
midline. Later, other authors added to the epithelial rest
theory, hypothesizing that epidermoid cysts layaway from
the midline as a result of epithelial misplacement during
development of the secondary otic and optic cerebral vesi-
cles in the forebrain and metencephalon during the fourth
or fifth week of development.S'? Fleming and Botterel'?
hypothesized that epidermoid cysts formed from the
proliferation of multipotential embryonic cell rests located
more laterally than the neural tube closure site. Migratory
properties of CPA epidermoid cells were observed in
vitro, similar to acquired cholesteatomas of the middle ear
and mastoid. Because this migratory ability is unique to
841
842 SURGICAL NEUROTOLOGY
epithelium derived from the first branchial groove (no
other epithelium in the head and neck shares this prop-
erty), the authors suggest a first branchial groove site of
origin for CPA epidermoid cysts.l"
PATHOLOGY
Bailey'? gave an almost poetic description of the macro-
scopic appearance of epidermoid tumors:
"Grossly the tumors resemble startlingly mother-of-pearl both
in tint and luster. The surface is smooth, silky, with irregular
pea-sized or larger elevations and peels away easily from the
surroundings. The surface layers are tough, with about the
malleability of heavy tin foil. From the surface, with a knife blade,
flakesmay easily be separated which show beautifully the charac-
teristic luster."
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.
The superficial layers are usually cornified, and intercellular
bridges are occasionally seen.i? Epidermoid cysts contain
keratin debris and frequently, cholesterol crystals. This
debris is the result of progressive desquamation and break-
down of keratin from the epithelial lining of the cyst, form-
ing concentric lamellae. The interior of the epidermoid is
usually soft, white, waxy material. Sometimes the contents
are thick, viscid, and dark brown or gray. They are devoid of
blood supply, but often are in surface contact with arteries."
To further differentiate epidermoid cysts and dermoids, der-
moids contain other elements of normal skin, such as sweat
glands, sebaceous glands, hairs, or hair follicles, whereas
epidermoid cysts have only squamous and sometimes basal
epithelium present.
Montgomery and Finlayson/? presented an interesting
case of a tumor involving the middle fossa as well as the
posterior fossa. The middle fossa portion had dermoid fea-
tures (sebaceous glands and hair follicles), whereas the
posterior fossa part exhibited more epidermoid character-
istics. They argued that this was evidence that epidermoid
cysts and dermoids were the same tumor, but this is the
only case of its kind in the literature.
The growth rate of epidermoid cysts is linear, like nor-
mal skin, unlike the exponential growth demonstrated by
most neoplasrns.P This linear rate of growth is expected of
tumors derived from a single layer of basal germinal cells
spread out over a surface area. The slow growth rate
enables adjacent structures to adjust gradually, and epider-
moid cysts spread with finger-like projections along pre-
formed clefts and spaces. They tend to engulf nearby blood
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
"multilobulated masses that adapt themselves to the avail-
able space between the skull and the brain." There are four
possible routes of spread from the CPA. Anteriorly tumor
may spread to the prepontine cistern, engulfing or displac-
ing the basilar artery, and toward the contralateral side.
Inferior extension toward the foramen magnum risks the
lower cranial nerves, the vertebral artery, and the posterior
inferior cerebellar artery. Superior extension across the
tentorium results in middle fossa involvement. Finally,
tumor may extend medially into the foramen of Lushka
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
the incisura into the parasellar cisterns, and 4 appeared to
be supratentorial tumors extending back to the posterior
fossa. Samii'? reported the location and extension of CPA
epidermoid cysts in 40 patients: 15 were confined to the
CPA, 3 had transtentorial extension, 5 had middle fossa
extension, 9 had extension to the foramen magnum, and
8 had both transtentorial and foramen magnum extension.
The only change to the brain produced by an epider-
moid is local atrophy attributable to the pressure exerted
by the expanding cyst. 20 Ganglion cells disappear, and fre-
quentlya mild degree of gliosis occurs. No inflammatory
reaction is typically seen.
CLINICAL SIGNS
Posterior fossa epidermoid cysts, because they are very
slow-growing, may be asymptomatic for years. Before
imaging techniques became available, patients could exhibit
symptoms for decades before diagnosis. In 1964, Ulrich!'
recorded patients with intracranial epidermoid cysts whose
durations of symptoms were as long as 29 and 53 years.
Even with the advent of modern imaging techniques, diag-
nosis may be delayed more than 20 years. 9,12,26-28
The symptoms of CPA epidermoid cysts include hear-
ing loss, tinnitus, dizziness, and gait disturbance. 12,23
Hearing loss and tinnitus are the usual initial symptoms in
80% of patients, and gait disturbance and headache are the
initial complaints in 20%.29 Other less common presenting
symptoms are intention tremor, tic douloureux, facial numb-
ness, facial spasm, facial palsy, impaired taste, impaired
lacrimation, dysarthria, dysphagia, tongue deviation, nau-
sea and vomiting, and loss of consciousness." Nager"
reported that 50% to 75% of patients with epidermoid cysts
of the CPA complained of progressive sensorineural hearing
loss, tinnitus, unsteadiness, and facial nerve symptoms. He
also found that 25% to 50% of tumors manifested as atyp-
ical trigeminal neuralgia (atypical because it was of longer
duration and might, not have trigeminal nerve impair-
ment). Samii summarized potential mechanisms for tic
douloureux: direct compressive effect, indirect pressure
by causing vascular compression, or local irritation from
cyst content seepage.V The most common cranial nerve
abnormalities are VIII (50% to 55%), VII (18% to 45%),
V (25% to 43%), and VI (10% to 30%).9,12
DIAGNOSIS
Before the advent of computed tomography (CT) and
magnetic resonance imaging (MRI), the diagnosis of
intradural epidermoid cysts was difficult. Presenting symp-
toms and signs pointed to CPA tumor, but it was impossible
to predict the pathology preoperatively because acoustic
neuroma, meningioma, arachnoid cysts, and other lesions

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"
Computed Tomography
In the 1970s, CT permitted a more reliable radiologic
diagnosis of CPA epidermoid cysts. In a study of nine
patients with CPA epidermoid cysts comparing earlier
imaging techniques to C'I, skull radiographs were normal
in four patients and nonspecific in five, radionucleotide
brain scans were normal in seven, and angiography was
nondiagnostic in every case. CT detected the lesion in
eight of nine cases."
On CT, CPA epidermoid cysts are homogeneous and
low density (low absorption values from -22 to +18
Hounsfield units: 500 scale) (Fig. 48-1). Bone erosion may
be demonstrated (Figs. 48-2 and 48-3). By C'I, a CPA epi-
dermoid may be difficult to distinguish from a subarach-
noid cyst, which is also homogeneous and of low density,
but the subarachnoid cyst usually has a sharply defined,
rounded margin compared with the irregular periphery of
the epidermoid tumor. 12,32 Enhancement of the capsule is
uncommon.12,33
The appearance of epidermoid cysts may vary on CT.
Increased density has been reported for some epidermoid
tumors. Braun and coworkers'? reported three cases of
posterior fossa epidermoid cysts with increased density
Figure 48-1. CT examination of leftCPA epidermoid (arrow); demonstrates
characteristic homogeneous lowdensity without enhancement.
Epidermoid Cysts of the Cerebellopontlne Angle 843
Figure 48-2. Normal right lAC.
(80 to 120 Hounsfield units), with two of them demon-
strating scattered peripheral densities consistent with
calcification (140 to 160 Hounsfield units). They could
find no histologic reason for the increased CT density
and termed the lesions dense epidermoid cysts. Nagashima
and colleagues-" identified four patterns of CT findings:
(1) homogeneous low density, (2) homogeneous low den-
sity with calcification or small dense nodules, (3) isodense,
and (4) homogeneous high density. They were able to find
a pathologic correlate in that the low or isodense epider-
moid cysts were pearly appearing containing a white, waxy
material rich in cholesterol, whereas the high-density
epidermoid cysts were cystic and contained brown, viscous
fluid with saponification of the debris. Dunn and cowork-
ers" described another CT dense posterior fossa epider-
moid cyst where the tumor contained a viscous brown fluid.
They also pointed out that all reported cases of dense
epidermoid cysts have occurred in the posterior fossa of
females. Another interesting finding reported by Laster and
colleagues was of freely movable fatty material within the
ventricles and subarachnoid space seen in association with
a CPA epidermoid, with negative absorption values by CT
scan within the CSF space." The authors suggested that this
Figure 48-3. Bone program axial CT of leftCPA epidermoid, with extension
to and erosion of petrous bone involving the left lAC (arrow). Compare with
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%
of epidermoid cysts are characterized by an increase and
about 15% by a decrease of T2 relaxation time; and in
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-
dermoid cysts.9, 12,43 Horowitz suggested cystic epidermoid
tumors with dense capsules had bright signal in Tl images
due to high lipid content, whereas classical pearly tumors
were hypointense on T'I images.t! Another study demon-
strated that 4 of 20 surgically verified epidermoid cysts
exhibited hvperintensitv on Tl images and hvpoinrensitv
Figure 48-4. MRI of leftCPA epidermoid. Typical T1-weighted appearance
(low intensity).
Figure 48-5. MRI of leftCPA epidermoid. Demonstrates typical T2-weighted
appearance (high intensity). This large CPA epidermoid has extended
anteriorly to surround the pons.
on T2 images.t" Steffey and coworkers'! emphasized the
variability of consistency on MRI of five epidermoid
tumors: four of the five showed heterogeneous internal
signal intensity; the fifth was homogeneous yet different
from brain and CSF. They felt that this variability did not
preclude the use of MRI to distinguish epidermoid cysts
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
complete removal of tumor was out of the question when
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'"
outlined treatment of 22 epidermoid cysts, including 4 of
the CPA. They removed these tumors subtotally, via sub-
occipital craniotomy, but emphasized that their patients did
not require further operations. The mortality rate from
their entire series was 23 %, and they did not offer separate
mortality figures for the CPA epidermoid cysts. MacCarty
and coworkers 5a reported 24 intracranial epidermoid cysts
treated before 1959, 8 of which were located in the CPA.
Four patients had surgery, and three tumors were com-
pletely removed. One patient died, one was lost to follow-
up, and two were alive with some neurologic problems and
facial paralysis.
Surgeons continue to employ the suboccipital craniotomy,
but have added other surgical approaches to the armamen-
tarium for removal of CPA epidermoid cysts, including
the translabyrinthine, middle fossa, and transcochlear
approaches. The choice of approach is based on the hear-
ing, cranial nerve symptoms, and extent of the tumor,
including presence of contralateral or middle fossa exten-
sion. The retrosigmoid or suboccipital approach provides
access to the prepontine region with adequate exposure of
cranial nerves V to XI. It may allow hearing preservation.
Any extension superiorly over the tentorium will require a
middle fossa approach. With the middle fossa approach,
division of the superior petrosal sinus and tentorium
further widens the operative field." Larger lesions involv-
ing the posterior and middle fossa may be approached
with a combined extended middle fossa (exposing petrous
ridge to clivus) and retrolabyrinthine/retrosigmoid
approach, called the petrosal approach. Wide access to the
middle fossa, lAC, and posterior fossa is obtained while
still preserving the otic capsule and, hence, hearing.
Transtemporal approaches to CPA epidermoid cysts are the
translabyrinthine and transcochlear procedures. The trans-
labyrinthine operation permits direct access to the CPA
without cerebellar retraction, via extended mastoidectomy,
labyrinthectomy, and removal of the bone surrounding
the lAC. A translabyrinthine approach is attempted when
hearing preservation is not an option and provides good
exposure to tumor in the prepontine cistern, contralateral
side, and foramen magnum." In cases with tumor involve-
ment of the area anterior to the brainstem, the opposite
CPA, and the carotid artery, the transcochlear approach is
used. The facial nerve is rerouted posteriorly after the
translabyrinthine approach is carried out, and bony
removal of the cochlea to the internal carotid artery is
completed.51 This enables access to the midline structures,
including the clivus, basilar artery, vertebral arteries, cra-
nial nerves V through XI, and the opposite lAC.
With microdissection techniques, mortality, morbidity,
and recurrence rates have improved. Generally, intracra-
nial epidermoid cysts should be treated by complete surgi-
cal excision. However, complete removal can be limited by
the encasement of neurovascular structures and the risk of
increased morbidity with sacrifice of functioning cranial
nerves. In these cases, it may be preferable to perform an
incomplete removal, since recurrence may occur slowly and
reoperation may not be required for many years. 8, 12 Despite
careful technique, postoperative cranial nerve deficits are not
uncommon. Mohanty and colleagues reported 40% of their
patients had postoperative deterioration in cranial nerve
function. 52 It must be kept in mind, however, that rates of
preoperative dysfunction may also be high,9,l2,52 and some
patients may experience an improvement in function, espe-
cially notable for cranial nerve V l2
Table 48-1 summarizes the published surgical results
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
is noteworthy that subtotal resection remains a common
occurrence. Second operations are required in 0 to 36% of
patients. The mortality rate has substantially improved.
Yamakawa and colleagues!' surgically treated 15 cases of
CPA epidermoid cysts from 1963 to 1988. Seven patients
had total tumor removal, six were subtotal, and two, sub-
capsular. There were two deaths, and three patients needed
at least one additional operation. Excellent postoperative
functioning was reported for 71 % of the patients ("excel-
lent function" was not defined in the study).
De Souza and coworkers 53 reported surgical results of
patients with 30 CPA epidermoid cysts from 1966 to 1986
in India. The suboccipital approach was used in 27 patients,
and the middle fossa was used or added in 4. Incomplete
removal was the rule. One patient died, three developed
meningitis, and four patients had postoperative facial paral-
ysis. Two patients were reoperated on for recurrence. Six
patients had bipolar coagulation of the epithelial remnants,
and none of these developed symptoms or signs of recur-
rence by 3 years after surgery.
Brackmann and Andersorr" reported results of 12
patients who had translabyrinthine removal from 1964 to
1977. Eight tumors were removed subtotally due to adher-
ence of the capsule to brainstem or vessels. Three patients
required additional surgery for recurrences. Two postop-
erative deaths occurred, one due to bleeding and one from
postoperative infection.
De la Cruz! reported the use of the transcochlear
approach for seven CPA cholesteatomas. Total tumor
removal was achieved in all patients. One patient with dia-
betes died postoperatively of pyelonephritis, and autopsy
revealed no residual tumor. Three patients had permanent
facial paralysis, one patient had persistent headaches, and
one had ongoing facial pain. None had evidence of recur-
rence from 2 to 5 years postoperatively.
In 2002, Moffat and colleagues'! reported a series of
15 patients treated with retrosigmoid, retrolabyrinthine,
transotic, or translabyrinthine approaches combined with
middle fossa as needed. They based the surgical manage-
ment on a new classification stage of disease extent.